Nootropic, anxiolytic and CNS-depressant studies on different plant sources of shankhpushpi.

PubMed

Malik, Jai; Karan, Maninder; Vasisht, Karan

2011-12-01

Shankhpushpi, a well-known drug in Ayurveda, is extensively used for different central nervous system (CNS) effects especially memory enhancement. Different plants are used under the name shankhpushpi in different regions of India, leading to an uncertainty regarding its true source. Plants commonly used under the name shankhpushpi are: Convolvulus pluricaulis Chois., Evolvulus alsinoides Linn., both from Convolvulaceae, and Clitoria ternatea Linn. (Leguminosae). To find out the true source of shankhpushpi by evaluating and comparing memory-enhancing activity of the three above mentioned plants. Anxiolytic, antidepressant and CNS-depressant activities of these three plants were also compared and evaluated. The nootropic activity of the aqueous methanol extract of each plant was tested using elevated plus-maze (EPM) and step-down models. Anxiolytic, antidepressant and CNS-depressant studies were evaluated using EPM, Porsolt?s swim despair and actophotometer models, respectively. C. pluricaulis extract (CPE) at a dose of 100 mg/kg, p.o. showed maximum nootropic and anxiolytic activity (p < 0.001). E. alsinoides extract (EAE) and C. ternatea extract (CTE) showed maximum memory-enhancing and anxiolytic activity (p < 0.001) at 200 and 100?mg/kg, respectively. Amongst the three plants, EAE and CTE showed significant (p < 0.05), while CPE did not exhibit any antidepressant activity. All the three plants showed CNS-depressant action at higher dose levels. The above results showed all the three plants possess nootropic, anxiolytic and CNS-depressant activity. The results of memory-enhancing activity suggest C. pluricaulis to be used as true source of shankhpushpi.

Anxiolytic-like effects of alverine citrate in experimental mouse models of anxiety.

PubMed

Gupta, Deepali; Radhakrishnan, Mahesh; Kurhe, Yeshwant

2014-11-05

Anxiety disorders are widely spread psychiatric illnesses that are a cause of major concern. Despite a consistent increase in anxiolytics, the prevalence of anxiety is static; this necessitates the development of new compounds with potential activity and minimum unwanted effects. A serotonergic (5HT) system plays an important role in pathogenesis of anxiety and predominantly involves 5HT1A receptor action in mediating anxiety-like behavior; the antagonism of 5HT1A receptor has demonstrated to produce anxiolytic-like effects. Alverine citrate (AVC) is reported as a 5HT1A antagonist; however, its effects on anxiety-like behavior are not investigated. Thus, the present study, by utilizing a neurobehavioral approach, examined the anxiolytic-like effects of AVC in experimental mouse models of anxiety. Mice were acutely treated with AVC (5-20mg/kg, i.p.)/diazepam (DIA, 2mg/kg, i.p.) and subjected to four validated anxiety models viz. elevated plus-maze (EPM), light/dark (L/D), hole-board (HB) and marble burying (MB) tests. AVC (15-20mg/kg) and DIA significantly increased open arm activity in EPM, exploration in light chamber in L/D test, exploratory behavior in HB and reduced MB behavior in marble burying test. AVC (5mg/kg) had no effect on all behavioral tests, while AVC (10mg/kg) produced partial effects. It revealed anxiolytic-like effects of AVC. Furthermore, anxiolytic-like effects of AVC at higher doses (15-20mg/kg) were more pronounced than lower doses (10mg/kg) and were quite similar to the standard drug DIA. The present finding demonstrates, for the first time, the anxiolytic-like effects of AVC, which may be an alternative approach for management of anxiety-related disorders. Copyright © 2014 Elsevier B.V. All rights reserved.

Anxiolytic action of pterostilbene: involvement of hippocampal ERK phosphorylation

USDA-ARS?s Scientific Manuscript database

Pterostilbene, a natural analog of resveratrol, has diverse health-beneficial properties. However, the neurological activities of this compound are largely unexplored. Here we report that pterostilbene shows anxiolytic action by downregulating phosphorylated levels of ERKs in the hippocampus of mice...

Anxiolytic-Like Actions of Fatty Acids Identified in Human Amniotic Fluid

PubMed Central

García-Ríos, Rosa Isela; Rodríguez-Landa, Juan Francisco; Contreras, Carlos M.

2013-01-01

Eight fatty acids (C12–C18) were previously identified in human amniotic fluid, colostrum, and milk in similar proportions but different amounts. Amniotic fluid is well known to be the natural environment for development in mammals. Interestingly, amniotic fluid and an artificial mixture of fatty acids contained in amniotic fluid produce similar anxiolytic-like actions in Wistar rats. We explored whether the lowest amount of fatty acids contained in amniotic fluid with respect to colostrum and milk produces such anxiolytic-like effects. Although a trend toward a dose-response effect was observed, only an amount of fatty acids that was similar to amniotic fluid fully mimicked the effect of diazepam (2 mg/kg, i.p.) in the defensive burying test, an action devoid of effects on locomotor activity and motor coordination. Our results confirm that the amount of fatty acids contained in amniotic fluid is sufficient to produce anxiolytic-like effects, suggesting similar actions during intrauterine development. PMID:23737729

Antidepressant-like effects of methanol extract of Hibiscus tiliaceus flowers in mice

PubMed Central

2012-01-01

Background Hibiscus tiliaceus L. (Malvaceae) is used in postpartum disorders. Our purpose was to examine the antidepressant, anxiolytic and sedative actions of the methanol extract of H. tiliaceus flowers using animal models. Methods Adult male Swiss albino mice were treated with saline, standard drugs or methanol extract of H. tiliaceus and then subjected to behavioral tests. The forced swimming and tail suspension tests were used as predictive animal models of antidepressant activity, where the time of immobility was considered. The animals were submitted to the elevated plus-maze and ketamine-induced sleeping time to assess anxiolytic and sedative activities, respectively. Results Methanol extract of H. tiliaceus significantly decreased the duration of immobility in both animal models of antidepressant activity, forced swimming and tail suspension tests. This extract did not potentiate the effect of ketamine-induced hypnosis, as determined by the time to onset and duration of sleeping time. Conclusion Our results indicate an antidepressant-like profile of action for the extract of Hibiscus tiliaceus without sedative side effect. PMID:22494845

The differential effect of the anxiolytic agent 8-OH-DPAT during lactation is independent of pup withdrawal and maternal behavior.

PubMed

Picazo, O; Rosenblatt, J S; Fernández-Guasti, A

2000-10-01

Injection of the serotonergic agonist, 8-hydroxy-2-(di-n-propylamino-tetralin (8-OH-DPAT) (0.5 mg/kg ip) produced a clear anxiolytic-like effect (as measured in the burying behavior test), after parturition, which remains until day 6 of lactation. Thereafter 8-OH-DPAT completely lacked action. In order to analyze whether lactation prevented the action of 8-OH-DPAT, dams were separated from their pups for five consecutive days. The blockade of the anxiolytic effect of 8-OH-DPAT does not disappear by isolation of the mothers from their offspring or from neighboring pups. Finally, to investigate the possible role of maternal behavior in the blockade of the anxiolytic effect of 8-OH-DPAT a third experiment was made in which ovariectomized females were rendered maternal by the sensitization procedure. These females respond normally to the antianxiety actions of 8-OH-DPAT. Results suggest that a long-term clue triggered by lactation, possibly related to prolactin secretion, interferes with the anxiolytic effect of 8-OH-DPAT.

Involvement of the strychnine-sensitive glycine receptor in the anxiolytic effects of GlyT1 inhibitors on maternal separation-induced ultrasonic vocalization in rat pups.

PubMed

Komatsu, Hiroko; Furuya, Yoshiaki; Sawada, Kohei; Asada, Takashi

2015-01-05

Several studies have shown that glycine transporter 1 (GlyT1) inhibitors have anxiolytic actions. There are two types of glycine receptor: the strychnine-sensitive glycine receptor (GlyA) and the strychnine-insensitive glycine receptor (GlyB); however, which receptor is the main contributor to the anxiolytic actions of GlyT1 inhibitors is yet to be determined. Here, we clarified which glycine receptor is the main contributor to the anxiolytic effects of GlyT1 inhibitors by using maternal separation-induced ultrasonic vocalization (USV) by rat pups as an index of anxiety. We confirmed that administration of the benzodiazepine diazepam or the selective serotonin reuptake inhibitor escitaloplam, which are both clinically proven anxiolytics, or the GlyT1 inhibitor SSR504734 (2-chloro-N-[(S)-phenyl[(2S)-piperidin-2-yl] methyl]-3-trifluoromethyl benzamide), decreases USV in rat pups. In addition, we showed that another GlyT1 inhibitor, ALX5407 ((R)-N-[3-(4'-fluorophenyl)-3(4'-phenylphenoxy)propyl]sarcosine) also decreases USV in rat pups. SSR504734- or ALX5407-induced decreases in USV were dose-dependently reversed by administration of the GlyA antagonist strychnine, whereas the diazepam- or escitalopram-induced decreases in USV were not. Furthermore, GlyT1-induced decreases in USV were not reversed by administration of the GlyB antagonist L-687,414. Together, these results suggest that GlyA activation is the main contributor to the anxiolytic actions of GlyT1 inhibitors and that the anxiolytic actions of diazepam and escitalopram cannot be attributed to GlyA activation. Our findings provide new insights into the importance of the activation of GlyA in the anxiolytic effects of GlyT1 inhibitors. Copyright © 2014 Elsevier B.V. All rights reserved.

A comparison of the effects of psychotomimetics and anxiolytics on punished and unpunished responding maintained by fixed interval schedules of food reinforcement in the rat.

PubMed

Evenden, John; Duncan, Bertina; Ko, Tracey

2006-02-01

Characterization of anxiolytic drugs often employs conflict paradigms in which the drug effects on punished and unpunished responding can be compared. In this study, a fixed interval schedule generating a range of baseline response rates allowed comparison of the effects of anxiolytic drugs with those of psychotomimetic drugs on equivalent and differing rates of punished and unpunished responding. The first response made by the rat after a 40-s fixed interval elapsed resulted in food pellet delivery. In punished intervals, signalled by the illumination of stimulus lamps above each lever, a 0.6-mA shock was delivered after every 20th response, resulting in a lower rate of responding than that in the unpunished intervals. Three psychotomimetic agents, D-amphetamine, MK801 and DOI were compared with the anxiolytics chlordiazepoxide, NS2710 and pregabalin. The three psychotomimetics preferentially increased rates of unpunished responding compared with those of punished responding. Chlordiazepoxide, NS2710 and, to a lesser extent, pregabalin increased rates of both unpunished and punished responding. In comparison studies, yohimbine also increased rates of both unpunished and punished responding whereas the antidepressant citalopram had no effect. In conclusion, stable baseline performance over many months allowed the direct comparison of several different drugs in the same subjects with no need to adjust shock levels or equate baseline response rates. The drugs had systematic and replicable effects in this procedure, which, in the case of amphetamine and chlordiazepoxide, were similar to those in other species, and psychotomimetic drugs could clearly be distinguished from anxiolytic drugs. The procedure, however, has limited value for characterizing novel anxiolytic agents as the examples used here increased punished and unpunished responding to the same extent, and were indistinguishable in that regard from the clinically anxiogenic agent, yohimbine.

[Trends in the consumption of anxiolytic and hypnotic drugs in a Colombian population].

PubMed

Machado-Alba, Jorge Enrique; Alzate-Carvajal, Verónica; Jimenez-Canizales, Carlos Eduardo

2015-01-01

In Latin America, psychotropic medications are the third most marketed drug group, especially antidepressants (35%) and anxiolytics (5%). The objective of this study was to determine the trends in the consumption and the costs of anxiolytic and hypnotic drugs in a population of patients enrolled in the Health System of Colombia. A descriptive, observational study was performed using the data recorded inprescriptions for any anxiolytic or hypnotic drug prescribed to outpatients in the period between January 2008 and December 2013 in a population of 3.5 million people. Sociodemographic, pharmacological variables, overall costs, and cost per thousand inhabitants per day (CHD), were also recorded. The number of patients who received the drugs studied varied from 11,097 to 19,231 between 2008 and 2013. The most used drugs were clonazepam (44.1% of formulations), alprazolam (31.2%), and lorazepam (13.2%). The invoiced value of anxiolytics increased from US$ 207,673.63 in 2008 to US$ 488,977 in 2013, an increase of 135.4%. The CHD was US$ 0.31 for benzodiazepines, and US$ 0.02 for zaleplon, zolpidem and zopiclone (Z drugs) for 2008, and US$ 0.36 and US$ 0.02 in 2013 respectively. The CHD declined after 2010 following the introduction of generic drugs. Patients receiving benzodiazepines in Colombia are mostly women, average age 55 years, with very low frequency in defined daily doses per thousand inhabitants when compared with other countries. Copyright © 2014 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.

Quetiapine and its metabolite norquetiapine: translation from in vitro pharmacology to in vivo efficacy in rodent models

PubMed Central

Widzowski, D; Maciag, C; Zacco, A; Hudzik, T; Liu, J; Nyberg, S; Wood, M W

2015-01-01

Background and Purpose Quetiapine has a range of clinical activity distinct from other atypical antipsychotic drugs, demonstrating efficacy as monotherapy in bipolar depression, major depressive disorder and generalized anxiety disorder. The neuropharmacological mechanisms underlying this clinical profile are not completely understood; however, the major active metabolite, norquetiapine, has been shown to have a distinct in vitro pharmacological profile consistent with a broad therapeutic range and may contribute to the clinical profile of quetiapine. Experimental Approach We evaluated quetiapine and norquetiapine, using in vitro binding and functional assays of targets known to be associated with antidepressant and anxiolytic drug actions and compared these activities with a representative range of established antipsychotics and antidepressants. To determine how the in vitro pharmacological properties translate into in vivo activity, we used preclinical animal models with translational relevance to established antidepressant‐like and anxiolytic‐like drug action. Key Results Norquetiapine had equivalent activity to established antidepressants at the noradrenaline transporter (NET), while quetiapine was inactive. Norquetiapine was active in the mouse forced swimming and rat learned helplessness tests. In in vivo receptor occupancy studies, norquetiapine had significant occupancy at NET at behaviourally relevant doses. Both quetiapine and norquetiapine were agonists at 5‐HT1A receptors, and the anxiolytic‐like activity of norquetiapine in rat punished responding was blocked by the 5‐HT1A antagonist, WAY100635. Conclusions and Implications Quetiapine and norquetiapine have multiple in vitro pharmacological actions, and results from preclinical studies suggest that activity at NET and 5‐HT1A receptors contributes to the antidepressant and anxiolytic effects in patients treated with quetiapine. PMID:26436896

Optogenetic stimulation of infralimbic PFC reproduces ketamine's rapid and sustained antidepressant actions.

PubMed

Fuchikami, Manabu; Thomas, Alexandra; Liu, Rongjian; Wohleb, Eric S; Land, Benjamin B; DiLeone, Ralph J; Aghajanian, George K; Duman, Ronald S

2015-06-30

Ketamine produces rapid and sustained antidepressant actions in depressed patients, but the precise cellular mechanisms underlying these effects have not been identified. Here we determined if modulation of neuronal activity in the infralimbic prefrontal cortex (IL-PFC) underlies the antidepressant and anxiolytic actions of ketamine. We found that neuronal inactivation of the IL-PFC completely blocked the antidepressant and anxiolytic effects of systemic ketamine in rodent models and that ketamine microinfusion into IL-PFC reproduced these behavioral actions of systemic ketamine. We also found that optogenetic stimulation of the IL-PFC produced rapid and long-lasting antidepressant and anxiolytic effects and that these effects are associated with increased number and function of spine synapses of layer V pyramidal neurons. The results demonstrate that ketamine infusions or optogenetic stimulation of IL-PFC are sufficient to produce long-lasting antidepressant behavioral and synaptic responses similar to the effects of systemic ketamine administration.

Nitric Oxide Synthase Inhibitors as Antidepressants

PubMed Central

Wegener, Gregers; Volke, Vallo

2010-01-01

Affective and anxiety disorders are widely distributed disorders with severe social and economic effects. Evidence is emphatic that effective treatment helps to restore function and quality of life. Due to the action of most modern antidepressant drugs, serotonergic mechanisms have traditionally been suggested to play major roles in the pathophysiology of mood and stress-related disorders. However, a few clinical and several pre-clinical studies, strongly suggest involvement of the nitric oxide (NO) signaling pathway in these disorders. Moreover, several of the conventional neurotransmitters, including serotonin, glutamate and GABA, are intimately regulated by NO, and distinct classes of antidepressants have been found to modulate the hippocampal NO level in vivo. The NO system is therefore a potential target for antidepressant and anxiolytic drug action in acute therapy as well as in prophylaxis. This paper reviews the effect of drugs modulating NO synthesis in anxiety and depression. PMID:27713253

Pharmacodynamic response profiles of anxiolytic and sedative drugs.

PubMed

Chen, Xia; Broeyer, Freerk; de Kam, Marieke; Baas, Joke; Cohen, Adam; van Gerven, Joop

2017-05-01

Centrally-acting acutely anxiolytic drugs, such as benzodiazepines, barbiturates and gabapentinoids, affect various central nervous system (CNS) functions, which reflects not only their anxiolytic effects but also neuropsychological side-effects. To validate the pharmacodynamic biomarkers for GABA-ergic anxiolytics, this study determined the pharmacodynamics of two anxiolytics and a nonanxiolytic control, and linked them to their anxiolytic and sedative effects, during an anxiety-challenge study day. Twenty healthy volunteers were randomized in this placebo-controlled, double-blind, four-way cross-over study with single-dose alprazolam (1 mg), diphenhydramine (50 mg), pregabalin (200 mg) or placebo. The Neurocart was used between repeated fear-potentiated startle assessments. Thus, the potential influence of anxiety on CNS pharmacodynamic markers could be examined. Compared to placebo, VAS calmness increased with alprazolam (2.0 mm) and pregabalin (2.5 mm) but not with diphenhydramine. Saccadic peak velocity (SPV) declined after alprazolam (-57 ° s -1 ) and pregabalin (-28 ° s -1 ), more than with diphenhydramine (-14 ° s -1 ); so did smooth pursuit. The average responses of SPV and smooth pursuit were significantly correlated with the drug-induced increases in VAS calmness . The SPV-relative responses of VAS alertness , body-sway and adaptive-tracking also differed among alprazolam, pregabalin and diphenhydramine. Compared with the antihistaminergic sedative diphenhydramine, alprazolam and pregabalin caused larger SPV reduction, which was correlated with simultaneous improvement of subjective calmness, during a study day in which anxiety was stimulated repeatedly. The different effect profiles of the three drugs are in line with their pharmacological distinctions. These findings corroborate the profiling of CNS effects to demonstrate pharmacological selectivity, and further support SPV as biomarker for anxiolysis involving GABA-ergic neurons. The study also supports the use of prolonged mild threat to demonstrate anxiolytic effects in healthy volunteers. © 2016 The British Pharmacological Society.

Involvement of CRF but not NPY in the anxiety regulation via NMDA receptors.

PubMed

Wierońska, Joanna M; Szewczyk, Bernadeta; Pałucha, Agnieszka; Brański, Piotr; Smiałowska, Maria

2003-01-01

The study attempts to evaluate whether neuropeptide Y (NPY) and corticotropin-releasing factor (CRF) are involved in anxiogenic and anxiolytic reactions induced by NMDA receptor ligands. The animals were given MK-801 (1 mg/kg, ip), a non-competitive NMDA-receptor antagonist, which acts as anxiolytic agent, or NMDA (15 mg/kg, ip), which has an anxiogenic effect. The anxiogenic or anxiolytic actions of these compounds were evaluated in the plus-maze test. The animals, which were given MK-801, were administered BIBO 3304 (130 ng/0.5 microl/site) intraamygdalarly and the animals which were given NMDA were administered alpha-helical CRF (500 ng/0.5 microl/site). BIBO 3304 did not attenuate MK-801-induced anxiolysis and alpha-helical CRF abolished NMDA-induced anxiogenesis. Our results show that anxiogenic effect of NMDA is mediated via CRF1 receptors and anxiolytic action of MK-801 is not dependent on Y1 receptors.

How various drugs affect anxiety-related behavior in male and female rats prenatally exposed to methamphetamine.

PubMed

Macúchová, E; Ševčíková, M; Hrebíčková, I; Nohejlová, K; Šlamberová, R

2016-06-01

Different forms of anxiety-related behavior have been reported after a single drug use of many abused substances, however, less is known about how males and females are affected differently from exposure to various drugs. Furthermore, chronic prenatal methamphetamine (MA) exposure was shown to predispose the animal to an increased sensitivity to drugs administrated in adulthood. Using the Elevated plus-maze test (EPM), the first aim of the present study was to examine how male and female rats are affected by acute drug treatment with subcutaneously (s.c.) administrated (a) MA (1mg/kg); (b) drugs with a similar mechanism of action to MA: amphetamine (AMP, 1mg/kg), cocaine (COC, 5mg/kg), 3,4-methylenedioxymethamphetamine (MDMA, 5mg/kg); and (c) drugs with different mechanisms of action: morphine (MOR, 5mg/kg), and Δ 9-tetrahydrocannabinol (THC, 2mg/kg). The second aim was to determine if prenatally MA-exposed (5mg/kg) animals show an increased sensitivity to adult drug treatment. The parameters analyzed were divided into two categories: anxiety-related behavior and anxiety-unrelated/exploratory behavior. Our results showed in female rats a decreased percentage of the time spent in the closed arms (CA) after MA, and an increased percentage of the time spent in the open arms (OA) after MA, AMP, and COC treatment, indicating an anxiolytic-like effect. In females, MDMA and THC treatment increased the percentage of the time spent in the CA. An increased percentage of the time spent in the CA was also seen after MOR treatment in females as well as in males, indicating an anxiogenic-like effect. As far as the interaction between prenatal MA exposure and adult drug treatment is concerned, there was no effect found. In conclusion, it seems that: (a) in some cases female rats are more vulnerable to acute drug treatment, in terms of either anxiogenic- or anxiolytic-like effects; (b) prenatal MA exposure does not sensitize animals to the anxiety-related effects of any of the drugs. Copyright © 2016 ISDN. Published by Elsevier Ltd. All rights reserved.

Association between bystander cardiopulmonary resuscitation and redeemed prescriptions for antidepressants and anxiolytics in out-of-hospital cardiac arrest survivors.

PubMed

Bundgaard, Kristian; Hansen, Steen M; Mortensen, Rikke Nørmark; Wissenberg, Mads; Hansen, Malta; Lippert, Freddy; Gislason, Gunnar; Køber, Lars; Nielsen, Jimmi; Torp-Pedersen, Christian; Rasmussen, Bodil Steen; Kragholm, Kristian

2017-06-01

This study aimed to examine rates of redeemed prescriptions of antidepressants and anxiolytics, used as markers for cerebral dysfunction in out-of-hospital cardiac arrest (OHCA) survivors, and examine the association between bystander CPR and these psychoactive drugs. We included all 30-day survivors of OHCA in Denmark between 2001 and 2011, who had not redeemed prescriptions for antidepressants or anxiolytics in the last six months prior to OHCA. Main outcome measures were redeemed prescriptions of antidepressants and anxiolytics within one year after OHCA. Among 2,001 30-day survivors, 174 (8.6% died and 12.0% redeemed a first prescription for an antidepressant and 8.2% for an anxiolytic drug within one year after arrest. The corresponding frequencies for redeemed prescribed drugs among age- and sex-matched population controls were 7.5% and 5.2%, respectively. Among survivors who received bystander CPR, prescriptions for antidepressants and anxiolytics were redeemed in 11.1% [95% CI 9.2-13.3%] and 6.3% [95% CI 4.9-8.0%] of the cases, respectively, versus 17.2% [95% CI 13.9-21.1%] and 13.4% [95% CI 10.5-17.0%], respectively, among patients who had not received bystander CPR. Adjusted for age, sex, year of arrest, comorbidity, witnessed status and socioeconomic status, bystander CPR was associated with significant reductions in redeemed prescriptions for antidepressants, Hazard Ratio (HR) 0.71 [95% CI 0.52-0.98], P=0.031; and anxiolytics, HR 0.55 [95% CI 0.38-0.81], P=0.002. Relative to no bystander CPR, redeemed prescriptions for antidepressants and anxiolytics were significantly lower among 30-day survivors of OHCA who received bystander CPR, suggesting a cerebral dysfunction-lowering potential of bystander CPR. Copyright © 2017 Elsevier B.V. All rights reserved.

Amniotic Fluid or Its Fatty Acids Produce Actions Similar to Diazepam on Lateral Septal Neurons Firing Rate

PubMed Central

Gutiérrez-García, Ana G.; Vásquez-Hernández, Diana Idania

2013-01-01

Human amniotic fluid (AF) contains eight fatty acids (FATs), and both produce anxiolytic-like effects in adult rats and appetitive responses in human newborns. The medial amygdala and lateral septal nucleus function are related to social behavior, but the action of AF or its FATs in this circuit is known. We obtained 267 single-unit extracellular recordings in Wistar rats treated with vehicle (1 mL, s.c.; n = 12), human AF (1 mL, s.c.; n = 12), a FAT mixture (1 mL, s.c.; n = 13), diazepam (1 mg/kg, i.p.; n = 11), and fluoxetine (1 mg/kg, p.o.; n = 12). Compared with the vehicle group, the spontaneous septal firing rate in the AF, FAT mixture, and diazepam groups was the lowest and in the fluoxetine group the highest. Cumulative peristimulus histograms indicated that the significant change in septal firing occurred only in the AF and FAT mixture groups and exclusively in those neurons that increased their firing rate during amygdala stimulation. We conclude that human AF and its FATs produce actions comparable to anxiolytic drugs and are able to modify the responsivity of a circuit involved in social behavior, suggesting facilitation of social recognition processes by maternal-fetal fluids. PMID:23864826

Evidence of a role for GABA in benzodiazepine effects on food preference in rats.

PubMed

Hodges, H M; Green, S E

1981-01-01

It has previously been shown that chronic treatment with the GABA-transaminase inhibitor ethanolamine-O-sulphate (EOS), which elevates brain GABA levels by around 200%, selectivity enhances novel food consumption in rats treated with chlordiazepoxide (CDP) and given a food preference test. To replicate and extend these findings, the effects of two doses of CDP with and without EOS pretreatment were compared with those of EOS or saline alone. EOS alone had no significant effects except to decrease eating rate but, in combination with 2.5 mg/kg CDP, it antagonised the increase in weight of familiar food eaten found with CDP alone and marginally increased weight eaten and duration of novel foot eating episodes. EOS magnified the effects of 5.0 mg/kg CDP to increase markedly the weight eaten and duration of episodes for novel chocolate drops. As no additive effects of EOS and CDP on rate of eating were found, the results are consistent with a facilitation of novel food consumption by an anxiolytic action of the two drugs, rather than by a rate-retarding action which might bias animals toward novel food. Finally, that EOS alone did not mimic the effects of CDP suggests that the role of GABA in the anxiolytic action of CDP may be indirect.

Pharmacological evaluation of the anxiolytic-like effects of EMD 386088, a partial 5-HT6 receptor agonist, in the rat elevated plus-maze and Vogel conflict tests.

PubMed

Jastrzębska-Więsek, Magdalena; Siwek, Agata; Partyka, Anna; Kubacka, Monika; Mogilski, Szczepan; Wasik, Anna; Kołaczkowski, Marcin; Wesołowska, Anna

2014-10-01

The 5-HT6 is one of the most recent additions to the 5-HT receptor family. Its pharmacological profile and anatomical distribution is suggestive of a putative role in mood disorders. Most of preclinical evidence suggests an anxiolytic-like action of 5-HT6 receptor antagonists. Evaluation the anxiolytic-like effects of EMD 386088, a partial 5-HT6receptor agonist, and its putative mechanism of action in rats. EMD 386088, administered intraperitoneally at a dose of 2.5 mg/kg evoked specific anxiolytic-like activity in the automated version of the conflict drinking Vogel and the elevated plus-maze tests visible by increasing all parameters indicating a potential anti-anxiety effect. Its activity was blocked by the selective 5-HT6 receptor antagonist SB 271046, but not by the selective GABAA/benzodiazepine receptor antagonist flumazenil. EMD 386088 did not intensify an anxiolytic-like effect produced by diazepam in the elevated plus-maze test. These findings suggest that EMD 386088, a 5-HT6 receptor agonist, produces anxiolytic-like activity after systemic administration which may result from direct stimulation of 5-HT6 receptors. Copyright © 2014 Elsevier Ltd. All rights reserved.

5-HT1A receptor blockade reverses GABAA receptor α3 subunit-mediated anxiolytic effects on stress-induced hyperthermia

PubMed Central

van Oorschot, Ruud; Korte, S. Mechiel; Olivier, Berend; Groenink, Lucianne

2010-01-01

Rationale Stress-related disorders are associated with dysfunction of both serotonergic and GABAergic pathways, and clinically effective anxiolytics act via both neurotransmitter systems. As there is evidence that the GABAA and the serotonin receptor system interact, a serotonergic component in the anxiolytic actions of benzodiazepines could be present. Objectives The main aim of the present study was to investigate whether the anxiolytic effects of (non-)selective α subunit GABAA receptor agonists could be reversed with 5-HT1A receptor blockade using the stress-induced hyperthermia (SIH) paradigm. Results The 5-HT1A receptor antagonist WAY-100635 (0.1–1 mg/kg) reversed the SIH-reducing effects of the non-α-subunit selective GABAA receptor agonist diazepam (1–4 mg/kg) and the GABAA receptor α3-subunit selective agonist TP003 (1 mg/kg), whereas WAY-100635 alone was without effect on the SIH response or basal body temperature. At the same time, co-administration of WAY-100635 with diazepam or TP003 reduced basal body temperature. WAY-100635 did not affect the SIH response when combined with the preferential α1-subunit GABAA receptor agonist zolpidem (10 mg/kg), although zolpidem markedly reduced basal body temperature. Conclusions The present study suggests an interaction between GABAA receptor α-subunits and 5-HT1A receptor activation in the SIH response. Specifically, our data indicate that benzodiazepines affect serotonergic signaling via GABAA receptor α3-subunits. Further understanding of the interactions between the GABAA and serotonin system in reaction to stress may be valuable in the search for novel anxiolytic drugs. PMID:20535452

4-phenylselenyl-7-chloroquinoline, a novel multitarget compound with anxiolytic activity: Contribution of the glutamatergic system.

PubMed

Reis, Angélica S; Pinz, Mikaela; Duarte, Luis Fernando B; Roehrs, Juliano A; Alves, Diego; Luchese, Cristiane; Wilhelm, Ethel A

2017-01-01

A growing body of evidence demonstrates that quinoline compounds have attracted much attention in the field of drug development. Accordingly, 4-phenylselenyl-7-chloroquinoline (4-PSQ) is a new quinoline derivative containing selenium, which showed a potential antioxidant, antinociceptive and anti-inflammatory effect. The present study was undertaken to evaluate the anxiolytic-like properties of 4-PSQ. Mice were orally pretreated with 4-PSQ (5-50 mg/kg) or vehicle, 30 min prior to the elevated plus-maze (EPM), light-dark (LDT) or open field (OFT) tests. A time-response curve was carried out by administration of 4-PSQ (50 mg/kg) at different times before the EPM test. The involvement of glutamate uptake/release and Na + , K + -ATPase activity in the anxiolytic-like effect was investigated in cerebral cortices. In addition, the effectiveness of acute treatment with 4-PSQ was evaluated in a model of kainate (KA)-induced anxiety-related behavior. Finally, acute toxicity of this compound was investigated. 4-PSQ produced an anxiolytic-like action, both in EPM and LDT. In OFT, 4-PSQ did not affect locomotor and exploratory activities. 4-PSQ anxiolytic-like effect started at 0.5 h and remained significant up to 72 h after administration. Treatment with 4-PSQ reduced [ 3 H] glutamate uptake, but the [ 3 H] glutamate release and Na + , K + -ATPase activity were not altered. KA-induced anxiety-related behavior was protected by 4-PSQ pretreatment. Additionally, 4-PSQ exposure did not alter urea levels, aspartate (AST) and alanine aminotrasferase (ALT) activities in plasma. Parameters of oxidative stress in brain and liver of mice were not modified by 4-PSQ. Taken together these data demonstrated that the anxiolytic-like effect caused by 4-PSQ seems to be mediated by involvement of the glutamatergic system. Copyright © 2016 Elsevier Ltd. All rights reserved.

AVCRI104P3, a novel multitarget compound with cognition-enhancing and anxiolytic activities: studies in cognitively poor middle-aged mice.

PubMed

Giménez-Llort, L; Ratia, M; Pérez, B; Camps, P; Muñoz-Torrero, D; Badia, A; Clos, M V

2015-06-01

The present work describes, for the first time, the in vivo effects of the multitarget compound AVCRI104P3, a new anticholinesterasic drug with potent inhibitory effects on human AChE, human BuChE and BACE-1 activities as well as on the AChE-induced and self-induced Aβ aggregation. We characterized the behavioral effects of chronic treatment with AVCRI104P3 (0.6 μmol kg(-1), i.p., 21 days) in a sample of middle aged (12-month-old) male 129/Sv×C57BL/6 mice with poor cognitive performance, as shown by the slow acquisition curves of saline-treated animals. Besides, a comparative assessment of cognitive and non-cognitive actions was done using its in vitro equipotent doses of huprine X (0.12 μmol kg(-1)), a huperzine A-tacrine hybrid. The screening assessed locomotor activity, anxiety-like behaviors, cognitive function and side effects. The results on the 'acquisition' of spatial learning and memory show that AVCRI104P3 exerted pro-cognitive effects improving both short- and long-term processes, resulting in a fast and efficient acquisition of the place task in the Morris water maze. On the other hand, a removal test and a perceptual visual learning task indicated that both AChEIs improved short-term 'memory' as compared to saline treated mice. Both drugs elicited the same response in the corner test, but only AVCRI104P3 exhibited anxiolytic-like actions in the dark/light box test. These cognitive-enhancement and anxiolytic-like effects demostrated herein using a sample of middle-aged animals and the lack of adverse effects, strongly encourage further studies on AVCRI104P3 as a promising multitarget therapeutic agent for the treatment of cholinergic dysfunction underlying natural aging and/or dementias. Copyright © 2015. Published by Elsevier B.V.

Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug.

PubMed

Zuardi, A W; Crippa, J A S; Hallak, J E C; Moreira, F A; Guimarães, F S

2006-04-01

A high dose of delta9-tetrahydrocannabinol, the main Cannabis sativa (cannabis) component, induces anxiety and psychotic-like symptoms in healthy volunteers. These effects of delta9-tetrahydrocannabinol are significantly reduced by cannabidiol (CBD), a cannabis constituent which is devoid of the typical effects of the plant. This observation led us to suspect that CBD could have anxiolytic and/or antipsychotic actions. Studies in animal models and in healthy volunteers clearly suggest an anxiolytic-like effect of CBD. The antipsychotic-like properties of CBD have been investigated in animal models using behavioral and neurochemical techniques which suggested that CBD has a pharmacological profile similar to that of atypical antipsychotic drugs. The results of two studies on healthy volunteers using perception of binocular depth inversion and ketamine-induced psychotic symptoms supported the proposal of the antipsychotic-like properties of CBD. In addition, open case reports of schizophrenic patients treated with CBD and a preliminary report of a controlled clinical trial comparing CBD with an atypical antipsychotic drug have confirmed that this cannabinoid can be a safe and well-tolerated alternative treatment for schizophrenia. Future studies of CBD in other psychotic conditions such as bipolar disorder and comparative studies of its antipsychotic effects with those produced by clozapine in schizophrenic patients are clearly indicated.

Comparison of psychotropic prescriptions between oncology and cardiology inpatients: result from a pharmacy database in a teaching hospital in Malaysia.

PubMed

Ng, Chong Guan; Mohamed, Salina; Wern, Tai Yi; Haris, Azwa; Zainal, Nor Zuraida; Sulaiman, Ahmad Hatim

2014-01-01

To examine the prescription rates in cancer patients of three common psychotropic drugs: anxiolytic/ hypnotic, antidepressant and antipsychotic. In this retrospective cohort study, data were extracted from the pharmacy database of University Malaya Medical Center (UMMC) responsible for dispensing records of patients stored in the pharmacy's Medication Management and Use System (Ascribe). We analyzed the use of psychotropics in patients from the oncology ward and cardiology from 2008 to 2012. Odds ratios (ORs) were adjusted for age, gender and ethnicity. A total of 3,345 oncology patients and 8,980 cardiology patients were included. Oncology patients were significantly more often prescribed psychotropic drugs (adjusted OR: anxiolytic/hypnotic=5.55 (CI: 4.64-6.63); antidepressants=6.08 (CI: 4.83-7.64) and antipsychotics=5.41 (CI: 4.17-7.02). Non-Malay female cancer patients were at significantly higher risk of anxiolytic/hypnotic use. Psychotropic drugs prescription is common in cancer patients. Anxiolytic/hypnotic prescription rates are significantly higher in non-Malay female patients in Malaysia.

Double-blind, placebo-controlled, multiple-ascending-dose study on the pharmacodynamics of ABIO-08/01, a new CNS drug with potential anxiolytic activity. 2. EEG-tomography findings based on LORETA (low-resolution brain electromagnetic tomography).

PubMed

Saletu, Bernd; Anderer, Peter; Wolzt, Michael; Nosiska, Dorothea; Assandri, Alessandro; Noseda, Emanuele; Nannipieri, Fabrizio; Saletu-Zyhlarz, Gerda M

2009-01-01

Effects of ABIO-08/01, a new potentially anxiolytic isoxazoline, on regional electrical brain generators were investigated by 3-dimensional EEG tomography. In a double- blind, placebo-controlled, multiple-ascending-dose study, 16 healthy males (30.2 +/- 5.7 years) received 3 oral drug doses (10, 20, 40 mg) and placebo for 7 days (8-day wash-out) in a randomized non-balanced design for phase-1 studies. A 3-min vigilance-controlled (V) EEG, a 4-min resting (R) EEG with eyes closed, a 1-min eyes-open (EO) EEG and psychometric tests were performed 0, 1 and 6 h after taking the drug on days 1 and 5. Low-resolution brain electromagnetic tomography (LORETA) was computed from the spectrally analyzed EEG data, and differences between drug and placebo were displayed as statistical parametric maps. Data were registered to the Talairach-Tournoux Human Brain Atlas available as a digitized MRI. An overall omnibus significance test followed by a voxel-by-voxel t test demonstrated significant regional EEG changes after ABIO-08/01 versus placebo, dependent on recording condition, dose and time. While in the EO-EEG specifically the lowest dose of ABIO-08/01 induced pronounced sedative effects (delta/theta and beta increase) 1 h after acute and slightly less so after superimposed administration, in the 6th hour a decrease in alpha and beta activity signaled less sedative and more relaxant action. In the V-EEG these changes were less pronounced, in the R-EEG partly opposite. Hemisphere-specific changes were observed, suggesting increases in LORETA power over the left temporal, parietal, superior frontal regions and decreases over the right prefrontal, temporal pole and occipital regions. These LORETA changes are discussed in the light of neuroimaging findings on anxiety and anxiolytics. 2009 S. Karger AG, Basel.

A Novel Integrative Mechanism in Anxiolytic Behavior Induced by Galanin 2/Neuropeptide Y Y1 Receptor Interactions on Medial Paracapsular Intercalated Amygdala in Rats.

PubMed

Narváez, Manuel; Borroto-Escuela, Dasiel O; Santín, Luis; Millón, Carmelo; Gago, Belén; Flores-Burgess, Antonio; Barbancho, Miguel A; Pérez de la Mora, Miguel; Narváez, José; Díaz-Cabiale, Zaida; Fuxe, Kjell

2018-01-01

Anxiety is evoked by a threatening situation and display adaptive or defensive behaviors, found similarly in animals and humans. Neuropeptide Y (NPY) Y1 receptor (NPYY1R) and Galanin (GAL) receptor 2 (GALR2) interact in several regions of the limbic system, including the amygdala. In a previous study, GALR2 enhanced NPYY1R mediated anxiolytic actions on spatiotemporal parameters in the open field and elevated plus maze, involving the formation of GALR2/NPYY1R heteroreceptor complexes in the amygdala. Moreover, the inclusion of complementary ethological parameters provides a more comprehensive profile on the anxiolytic effects of a treatment. The purpose of the current study is to evaluate the anxiolytic effects and circuit activity modifications caused by coactivation of GALR2 and NPYY1R. Ethological measurements were performed in the open field, the elevated plus-maze and the light-dark box, together with immediate early gene expression analysis within the amygdala-hypothalamus-periaqueductal gray (PAG) axis, as well as in situ proximity ligation assay (PLA) to demonstrate the formation of GALR2/NPYY1R heteroreceptor complexes. GALR2 and NPYY1R coactivation resulted in anxiolytic behaviors such as increased rearing and head-dipping, reduced stretch attend postures and freezing compared to single agonist or aCSF injection. Neuronal activity indicated by cFos expression was decreased in the dorsolateral paracapsular intercalated (ITCp-dl) subregion of the amygdala, ventromedial hypothalamic (VMH) nucleus and ventrolateral part of the periaqueductal gray (vlPAG), while increased in the perifornical nucleus of the hypothalamus (PFX) following coactivation of GALR2 and NPYY1R. Moreover, an increased density of GALR2/NPYY1R heteroreceptor complexes was explicitly observed in ITCp-dl, following GALR2 and NPYY1R coactivation. Besides, knockdown of GALR2 was found to reduce the density of complexes in ITCp-dl. Taken together, these results open up the possibility that the increased anxiolytic activity demonstrated upon coactivation of NPYY1R and GALR2 receptor was related to actions on the ITCp-dl. GALR2-NPYY1R heteroreceptor complexes may inhibit neuronal activity, by also modifying the neuronal networks of the hypothalamus and the PAG. These results indicate that GALR2/NPYY1R interactions in medial paracapsular intercalated amygdala can provide a novel integrative mechanism in anxiolytic behavior and the basis for the development of heterobivalent agonist drugs targeting GALR2/NPYY1R heteromers, especially in the ITCp-dl of the amygdala for the treatment of anxiety.

Valeriana officinalis root extracts have potent anxiolytic effects in laboratory rats.

PubMed

Murphy, K; Kubin, Z J; Shepherd, J N; Ettinger, R H

2010-07-01

Valerian root (Valeriana officinalis) is a popular and widely available herbal supplement, primarily used to treat insomnia and anxiety. Until recently, its mechanism of action has remained unknown. Neurobiological research has begun to show that the herb, with its active valerenic acid, interacts with the GABA(A)-ergic system, a mechanism of action similar to the benzodiazepine drugs. This series of experiments sought to corroborate these findings with behavioral measures, compare them to the benzodiazepine diazepam, and to analyze the chemical composition of Valeriana officinalis. Rats were administered either ethanol (1 ml/kg), diazepam (1mg/kg), valerian root extract (3 ml/kg), valerenic acid (3mg/kg), or a solution of valerenic acid and exogenous GABA (75 microg/kg and 3.6 microg/kg, respectively) and assessed for the number of entries and time spent on the open arms of an elevated plus maze. Results showed that there was a significant reduction in anxious behavior when valerian extract or valerenic acid exposed subjects were compared to the ethanol control group. The evidence supports Valeriana officinalis as a potential alternative to the traditional anxiolytics as measured by the elevated plus maze. (c) 2009 Elsevier GmbH. All rights reserved.

Overexpression of CB2 cannabinoid receptors decreased vulnerability to anxiety and impaired anxiolytic action of alprazolam in mice.

PubMed

García-Gutiérrez, María S; Manzanares, Jorge

2011-01-01

Mice overexpressing CB2r (CB2xP) were exposed to open field (OF), light-dark box (LDB) and elevated plus maze (EPM) tests. Corticotropin-releasing factor (CRF) and pro-opiomelanocortin (POMC) mRNA were measured in paraventricular (PVN) and arcuate (ARC) nuclei of the hypothalamus after 30 minutes of restraint stress (RS). Anxiolytic effects of alprazolam (45 or 70 µg/kg, ip) were evaluated. GABA(A)α(2) and GABA(A)γ(2) mRNA were measured in the hippocampus (HIPP) and amygdala (AMY) of CB2xP and wild type (WT) mice. No differences were observed in the total distance travelled by CB2xP and WT mice in OF. Central and peripheral distances travelled significantly increased and decreased in CB2xP mice. Overexpression of CB2r reduced anxiety-like behaviours in LDB and EPM. In WT mice, RS increased CRF (82%) and POMC (42%) mRNA in the PVN and ARC nuclei, respectively. In CB2xP mice, RS also increased POMC (22%) mRNA in the ARC nucleus, but had no effect on CRF mRNA in the PVN nucleus. Administration of alprazolam was without effect in CB2xP mice. An increase of GABA(A)α(2) and GABA(A)γ(2) mRNA in the hippocampus and amygdala of CB2xP mice was observed. Our findings revealed that increased expression of CB2r significantly reduced anxiogenic-related behaviours, modified the response to stress and impaired the action of anxiolytic drugs.

Evaluation of the antidepressant, anxiolytic and memory-improving efficacy of aripiprazole and fluoxetine in ethanol-treated rats.

PubMed

Burda-Malarz, Kinga; Kus, Krzysztof; Ratajczak, Piotr; Czubak, Anna; Hardyk, Szymon; Nowakowska, Elżbieta

2014-07-01

Some study results indicate a positive effect of aripiprazole (ARI) on impaired cognitive functions caused by brain damage resulting from chronic EtOH abuse. However, other research shows that to manifest itself, an ARI antidepressant effect requires a combined therapy with another selective serotonin reuptake inhibitor antidepressant, namely, fluoxetine (FLX). The aim of this article was to assess antidepressant and anxiolytic effects of ARI as well as its effect on spatial memory in ethanol-treated (alcoholized) rats. On the basis of alcohol consumption pattern, groups of (1) ethanol-preferring rats, with mean ethanol intake above 50%, and (2) ethanol-nonpreferring rats (EtNPRs), with mean ethanol intake below 50% of total daily fluid intake, were formed. The group of EtNPRs was used for this study, subdivided further into three groups administered ARI, FLX and a combination of both, respectively. Behavioral tests such as Porsolt's forced swimming test, the Morris water maze test and the two-compartment exploratory test were employed. Behavioral test results demonstrated (1) no antidepressant effect of ARI in EtNPRs in subchronic treatment and (2) no procognitive effect of ARI and FLX in EtNPRs in combined single administration. Combined administration of both drugs led to an anxiogenic effect and spatial memory deterioration in study animals. ARI had no antidepressant effect and failed to improve spatial memory in rats. However, potential antidepressant, anxiolytic and procognitive properties of the drug resulting from its mechanism of action encourage further research aimed at developing a dose of both ARI and FLX that will prove such effects in alcoholized EtNPRs.

Anxiolytic action of neuromedin-U and neurotransmitters involved in mice.

PubMed

Telegdy, G; Adamik, A

2013-09-10

Peptide Neuromedin-U (NmU) is widely distributed in the central nervous system and the peripheral tissues. Its physiological effects include the regulation of blood pressure, heart rate, and body temperature, and the inhibition of gastric acid secretion. The action of NmU in rats is mediated by two G-protein-coupled receptors, NmU-1R and NmU-2R. NmU-2R is present mainly in the brain, and NmU-1R mainly in the periphery. Despite the great variety of the physiological action of NmU, little is known about its possible effects in different forms of behavior, such as anxiety. In the present work, NmU-23 (the rodent form of the peptide) was tested for its effect on anxiety in elevated plus maze test in mice. For detection of the possible involvement of neurotransmitters, the mice were pretreated with receptor blockers: haloperidol (a D2, dopamine receptor antagonist), propranolol (a β-adrenergic receptor antagonist), atropine (a nonselective muscarinic acetylcholine receptor antagonist), phenoxybenzamine (a nonselective α-adrenergic receptor antagonist) or nitro-l-arginine (a nitric oxide synthase inhibitor). The peptide and nitro-l-arginine were administered into the lateral brain ventricle, while the receptor blockers were applied intraperitoneally. An NmU-23 dose 0.5μg elicited anxiolytic action, whereas this action is faded away when the dose was increased. For further testing therefore 0.5μg i.c.v. was used. Propranolol and atropine fully blocked the NmU-induced anxiolytic action, while haloperidol, phenoxybenzamine and nitro-l-arginine were ineffective. The results suggest that β-adrenergic and cholinergic mechanisms are involved in the anxiolytic action of NmU. © 2013.

Combined treatment with subchronic lithium and acute intracerebral mirtazapine microinjection into the median raphe nucleus exerted an anxiolytic-like effect synergistically.

PubMed

An, Yan; Inoue, Takeshi; Kitaichi, Yuji; Chen, Chong; Nakagawa, Shin; Wang, Ce; Kusumi, Ichiro

2016-07-15

Although preclinical and clinical studies have established the efficacy of lithium augmentation of antidepressant drugs, the mechanism of action of lithium augmentation is not fully understood. Our previous study reported that subchronic lithium treatment enhanced the anxiolytic-like effect of systemic mirtazapine. In the present study, we examined the effect of subchronic lithium in combination with acute local intracerebral injection of mirtazapine on fear-related behaviors in a contextual fear conditioning test in rats to clarify the target brain region of lithium augmentation of mirtazapine. After conditioning by footshock, diet (food pellets) containing Li2CO3 at a concentration of 0.2% was administered for 7 days. Ten min before testing and 7 days after conditioning, mirtazapine (3μg/site) in a volume of 0.5µl was acutely injected into the median raphe nucleus (MRN), hippocampus or amygdala. The combination of subchronic lithium and acute mirtazapine microinjection into the MRN but not the hippocampus or the amygdala reduced fear expression synergistically. These results suggest that intra-MRN mirtazapine treatment with subchronic lithium exerts the anxiolytic-like effect through the facilitation of the MRN-5HT pathway. Copyright © 2016 Elsevier B.V. All rights reserved.

Dietary and botanical anxiolytics

PubMed Central

Alramadhan, Elham; Hanna, Mirna S.; Hanna, Mena S.; Goldstein, Todd A.; Avila, Samantha M.; Weeks, Benjamin S.

2012-01-01

Summary Drugs used to treat anxiety have many negative side effects including addiction, depression, suicide, seizures, sexual dysfunction, headaches and more. Anxiolytic medications do not restore normal levels of neurotransmitters but instead manipulate the brain chemistry. For example, selective serotonin reuptake inhibitors (SSRIs) prevent the reuptake of serotonin from the synapse allowing serotonin to remain in the area of activity for a longer period of time but does not correct the lack of serotonin production. Benzodiazepines, such as Valium and Xanax®, stimulate GABA receptors, thus mimicking the calming effects of GABA but again do not fix the lack of GABA production. Often, the brain becomes accustomed to these medications and they often lose their effectiveness, requiring higher doses or different drugs. In contrast to anxiolytic drugs, there are herbs and nutrients which can stimulates neurotransmitter synthesis and more naturally effect and even adjust brain chemistry in the absence of many of the side effects experienced with drugs. Therefore this paper explores several herbal and nutritional approaches to the treatment of anxiety. PMID:22460105

Anxiolytic-like effects of noribogaine in zebrafish.

PubMed

Kalueff, Allan V; Kaluyeva, Aleksandra; Maillet, Emeline L

2017-07-14

Noribogaine is the main psychoactive metabolite of the hallucinogenic drug ibogaine, and is a particularly interesting compound potentially useful to treat dependence and various psychiatric disorders. Here, we report the effects of noribogaine on anxiety and locomotion in zebrafish (Danio rerio), a new promising model organism in neurobehavioral and psychopharmacological research. Adult zebrafish were subjected to the 5min novel tank test (NTT) following an acute, 20-min drug immersion in 1, 5 and 10mg/L noribogaine. Overall, noribogaine produced robust anxiolytic-like behavior in zebrafish (increasing the time spent and transitions to the top half compartment and reducing freezing bouts) without overt effects on fish locomotion. Taken together, these results indicate that noribogaine modulates the components of the acute stress response related to emotionality and anxiety behaviors, implicating this drug as a potentially useful non-sedative anxiolytic agent. Copyright © 2017 Elsevier B.V. All rights reserved.

[Effect of the economic crisis on consumption of psychotropic drugs in Asturias (Spain)].

PubMed

Nicieza-García, María Luisa; Alonso-Lorenzo, Julio C; Suárez-Gil, Patricio; Rilla-Villar, Natalia

To assess whether the economic crisis of 2008 has changed the consumption of anxiolytics, hypnotics-sedatives and antidepressants in Asturias (Spain). We conducted a descriptive study of drug use from 2003 -2013. The defined daily doses of 1000 inhabitants per day (DHD) were calculated for anxiolytics, hypnotics-sedatives and antidepressants. Linear regression coefficients (b) of the DHD were obtained for the pre-crisis period (2003-2008) and the crisis period (2009-2013). The consumption of anxiolytics increased by 40.25%, that of hypnotics by 88.11% and that of antidepressants by 80.93%. For anxiolytics: b-(2003-2008)=4.38 DDI/year and b-(2009-2013)=1.08 DDI/year. For hypnotics-sedatives: b-(2003-2008)=2.30 DDI/year and b-(2009-2013)=0.40 DDI/year. For antidepressants: b-(2003-2008)=5.79 DDI/year and b-(2009-2013)=2.83 DDI/year. The rise in consumption of the three subgroups during the crisis period was lower than that of the pre-crisis period. This study does not confirm the influence of the economic crisis on the rise in consumption of these drugs. Copyright © 2016 SESPAS. Publicado por Elsevier España, S.L.U. All rights reserved.

50 years of hurdles and hope in anxiolytic drug discovery

PubMed Central

Griebel, Guy; Holmes, Andrew

2014-01-01

Anxiety disorders are the most prevalent group of psychiatric diseases, and have high personal and societal costs. The search for novel pharmacological treatments for these conditions is driven by the growing medical need to improve on the effectiveness and the side effect profile of existing drugs. A huge volume of data has been generated by anxiolytic drug discovery studies, which has led to the progression of numerous new molecules into clinical trials. However, the clinical outcome of these efforts has been disappointing, as promising results with novel agents in rodent studies have very rarely translated into effectiveness in humans. Here, we analyse the major trends from preclinical studies over the past 50 years conducted in the search for new drugs beyond those that target the prototypical anxiety-associated GABA (γ-aminobutyric acid)–benzodiazepine system, which have focused most intensively on the serotonin, neuropeptide, glutamate and endocannabinoid systems. We highlight various key issues that may have hampered progress in the field, and offer recommendations for how anxiolytic drug discovery can be more effective in the future. PMID:23989795

Direct effects of diazepam on emotional processing in healthy volunteers

PubMed Central

Murphy, S. E.; Downham, C.; Cowen, P. J.

2008-01-01

Rationale Pharmacological agents used in the treatment of anxiety have been reported to decrease threat relevant processing in patients and healthy controls, suggesting a potentially relevant mechanism of action. However, the effects of the anxiolytic diazepam have typically been examined at sedative doses, which do not allow the direct actions on emotional processing to be fully separated from global effects of the drug on cognition and alertness. Objectives The aim of this study was to investigate the effect of a lower, but still clinically effective, dose of diazepam on emotional processing in healthy volunteers. Materials and methods Twenty-four participants were randomised to receive a single dose of diazepam (5 mg) or placebo. Sixty minutes later, participants completed a battery of psychological tests, including measures of non-emotional cognitive performance (reaction time and sustained attention) and emotional processing (affective modulation of the startle reflex, attentional dot probe, facial expression recognition, and emotional memory). Mood and subjective experience were also measured. Results Diazepam significantly modulated attentional vigilance to masked emotional faces and significantly decreased overall startle reactivity. Diazepam did not significantly affect mood, alertness, response times, facial expression recognition, or sustained attention. Conclusions At non-sedating doses, diazepam produces effects on attentional vigilance and startle responsivity that are consistent with its anxiolytic action. This may be an underlying mechanism through which benzodiazepines exert their therapeutic effects in clinical anxiety. PMID:18581100

Anxiolytic effects of orcinol glucoside and orcinol monohydrate in mice.

PubMed

Wang, Xiaohong; Li, Guiyun; Li, Peng; Huang, Linyuan; Huang, Jianmei; Zhai, Haifeng

2015-06-01

Anxiety is a common psychological disorder, often occurring in combination with depression, but therapeutic drugs with high efficacy and safety are lacking. Orcinol glucoside (OG) was recently found to have an antidepressive action. To study the therapeutic potential of OG and orcinol monohydrate (OM) as anxiolytic agents. Anxiolytic effects in mice were measured using the elevated plus-maze, hole-board, and open-field tests. Eight groups of mice were included in each test. Thirty minutes before each test, mice in each group received one oral administration of OG (5, 10, or 20 mg/kg), OM (2.5, 5, or 10 mg/kg), the positive control diazepam (1 or 5 mg/kg), or control vehicle. Each mouse underwent only one test. Uptake of orcinol (5 mg/kg) in the brain was qualitatively detected using the HPLC-MS method. OG (5, 10, and 20 mg/kg) and OM (2.5 and 5 mg/kg) increased the time spent in open arms and the number of entries into open arms in the elevated plus-maze test. OG (5 and 10 mg/kg) and OM (2.5 and 5 mg/kg) increased the number of head-dips in the hole-board test. At all tested doses, OG and OM did not significantly affect the locomotion of mice in the open-field test. Orcinol could be detected in the mouse brain homogenates 30 min after oral OM administration, having confirmed that OM is centrally active. The results demonstrated that OG and OM are anxiolytic agents without sedative effects, indicating their therapeutic potential for anxiety.

Evaluation of the Anxiolytic Activity of NR-ANX-C (a Polyherbal Formulation) in Ethanol Withdrawal-Induced Anxiety Behavior in Rats.

PubMed

Mohan, L; Rao, U S C; Gopalakrishna, H N; Nair, V

2011-01-01

The present study investigates the anxiolytic activity of NR-ANX-C, a standardized polyherbal formulation containing the extracts of Withania somnifera, Ocimum sanctum, Camellia sinensis, Triphala, and Shilajit in ethanol withdrawal- (EW-) induced anxiety behavior in rats. Ethanol dependence in rats was produced by substitution of drinking water with 7.5% v/v alcohol for 10 days. Then, ethanol withdrawal was induced by replacing alcohol with drinking water, 12 hours prior to experimentation. After confirming induction of withdrawal symptoms in the alcohol deprived animals, the anxiolytic activity of the test compound in graded doses (10, 20, and 40 mg/kg) was compared to the standard drug alprazolam (0.08 mg/kg) in the elevated plus maze and bright and dark arena paradigms. In our study, single and repeated dose administration of NR-ANX-C reduced EW-induced anxiety in a dose-dependent manner. Even though the anxiolytic activity was not significant at lower doses, NR-ANX-C at the highest dose tested (40 mg/kg) produced significant anxiolytic activity that was comparable to the standard drug alprazolam. Based on our findings we believe that NR-ANX-C has the potential to be used as an alternative to benzodiazepines in the treatment of EW-induced anxiety.

Evaluation of the Anxiolytic Activity of NR-ANX-C (a Polyherbal Formulation) in Ethanol Withdrawal-Induced Anxiety Behavior in Rats

PubMed Central

Mohan, L.; Rao, U. S. C.; Gopalakrishna, H. N.; Nair, V.

2011-01-01

The present study investigates the anxiolytic activity of NR-ANX-C, a standardized polyherbal formulation containing the extracts of Withania somnifera, Ocimum sanctum, Camellia sinensis, Triphala, and Shilajit in ethanol withdrawal- (EW-) induced anxiety behavior in rats. Ethanol dependence in rats was produced by substitution of drinking water with 7.5% v/v alcohol for 10 days. Then, ethanol withdrawal was induced by replacing alcohol with drinking water, 12 hours prior to experimentation. After confirming induction of withdrawal symptoms in the alcohol deprived animals, the anxiolytic activity of the test compound in graded doses (10, 20, and 40 mg/kg) was compared to the standard drug alprazolam (0.08 mg/kg) in the elevated plus maze and bright and dark arena paradigms. In our study, single and repeated dose administration of NR-ANX-C reduced EW-induced anxiety in a dose-dependent manner. Even though the anxiolytic activity was not significant at lower doses, NR-ANX-C at the highest dose tested (40 mg/kg) produced significant anxiolytic activity that was comparable to the standard drug alprazolam. Based on our findings we believe that NR-ANX-C has the potential to be used as an alternative to benzodiazepines in the treatment of EW-induced anxiety. PMID:20953426

Koumine exhibits anxiolytic properties without inducing adverse neurological effects on functional observation battery, open-field and Vogel conflict tests in rodents.

PubMed

Chen, Chao-Jie; Zhong, Zhi-Feng; Xin, Zhi-Ming; Hong, Long-Hui; Su, Yan-Ping; Yu, Chang-Xi

2017-04-01

Koumine, an active alkaloid of neurotoxic plant Gelsemium, has been focused on its therapeutic uses, especially in central nervous system. Nevertheless, less is known about the neurological effects of koumine, which hampers its potential therapeutic exploitation. Moreover, as the anxiolytic potential of Gelsemium has raised many critical issues, its active principles on the anxiolytic and other neurological effects need to be further investigated. Here, we used functional observation battery (FOB) of mice to systematically measure the neurological effects of koumine at the effective doses, and then further confirmed its anxiolytic properties in open-field test (OFT) of mice and Vogel conflict test (VCT) of rats. Koumine exhibited anxiolytic-like activities but did not affect other autonomic, neurological and physical functions in FOB. Furthermore, koumine released anxiolytic responses and anti-punishment action in a manner similar to diazepam in OFT and VCT, respectively. The results constitutes solid set of fundamental data further demonstrating anxiolytic properties of koumine at the therapeutic doses without inducing adverse neurological effects, which supports the perspectives for the development of safe and effective koumine medicine against pathological anxiety.

Interactions between ifenprodil and dizocilpine on mouse behaviour in models of anxiety and working memory.

PubMed

Fraser, C M; Cooke, M J; Fisher, A; Thompson, I D; Stone, T W

1996-11-01

The N-methyl-D-aspartate (NMDA) receptor polyamine site antagonist, ifenprodil, had no effect on spontaneous alteration or locomotor activity in the Y-maze when given alone. The NMDA receptor/ion channel blocker, dizocilpine, induced a deficit in spontaneous alteration, but when ifenprodil was co-administered with dizocilpine, it showed a strong tendency to attenuate the dizocilpine-induced deficit. In the plus-maze, ifenprodil had an anxiolytic profile which was accompanied by an increase in locomotion. Dizocilpine had an anxiolytic profile in this model and increased locomotor activity. When co-administered with dizocilpine, ifenprodil reduced both the anxiolytic and locomotor effects of dizocilpine. When co-administered with ifenprodil, cyclopentyladenosine (CPA) and 1,3-dipropyl-8-cyclopentylxanthine (CPX) reduced the anxiolytic effect of ifenprodil. CPA and CPX in combination did not reverse the anxiolytic effect of ifenpropil. It is concluded that NMDA antagonists with different sites of action can show distinct behavioural profiles, with dizocilpine but not ifenprodil inducing a deficit in working memory, while both are anxiolytic. Blockade of NMDA receptors by ifenprodil, however, can preclude any response to dizocilpine. The anxiolytic activity of ifenprodil may involve the release of purines acting at adenosine receptors.

Interaction between Antagonist of Cannabinoid Receptor and Antagonist of Adrenergic Receptor on Anxiety in Male Rat.

PubMed

Komaki, Alireza; Abdollahzadeh, Fatemeh; Sarihi, Abdolrahman; Shahidi, Siamak; Salehi, Iraj

2014-01-01

Anxiety is among the most common and treatable mental disorders. Adrenergic and cannabinoid systems have an important role in the neurobiology of anxiety. The elevated plus-maze (EPM) has broadly been used to investigate anxiolytic and anxiogenic compounds. The present study investigated the effects of intraperitoneal (IP) injection of cannabinoid CB1 receptor antagonist (AM251) in the presence of alpha-1 adrenergic antagonist (Prazosin) on rat behavior in the EPM. In this study, the data were obtained from male Wistar rat, which weighing 200- 250 g. Animal behavior in EPM were videotaped and saved in computer for 10 min after IP injection of saline, AM251 (0.3 mg/kg), Prazosin (0.3 mg/kg) and AM251 + Prazosin, subsequently scored for conventional indices of anxiety. During the test period, the number of open and closed arms entries, the percentage of entries into the open arms of the EPM, and the spent time in open and closed arms were recorded. Diazepam was considered as a positive control drug with anxiolytic effect (0.3, 0.6, 1.2 mg/kg). Diazepam increased the number of open arm entries and the percentage of spent time on the open arms. IP injection of AM251 before EPM trial decreased open arms exploration and open arm entry. Whereas, Prazosin increased open arms exploration and open arm entry. This study showed that both substances in simultaneous injection have conflicting effects on the responses of each of these two compounds in a single injection. Injection of CB1 receptor antagonist may have an anxiogenic profile in rat, whereas adrenergic antagonist has an anxiolytic effect. Further investigations are essential for better understanding of anxiolytic and anxiogenic properties and neurobiological mechanisms of action and probable interactions of the two systems.

Anxiolytic, antidepressant, and antistress activities of the aqueous extract of Cinnamomum tamala Nees and Eberm in rats

PubMed Central

Upadhyay, Gayaprasad; Khoshla, Sarvesh; Kosuru, Ramoji; Singh, Sanjay

2016-01-01

Objective: The current study was designed to explore anxiolytic, antidepressant, and antistress actions of Cinnamomum tamala (CT) leaves (aqueous extract) in rats. Materials and Methods: Behavioral procedures of anxiety, depression, and stress were assessed in rats. CT (100, 200, and 400 mg/kg) was given once a daily for 7 days via oral route and the efficacy was matched by those elicited by lorazepam (1 mg/kg, p.o.), imipramine (10 mg/kg, p.o.), and Withania somnifera (100 mg/kg, p.o.) for anxiolytic, antidepressant, and antistress studies, respectively. Standard drugs were given 1 time, 30 min preceding the behavioral trials. Results: One-way analysis of variance followed by Newman–Keuls multiple comparison test was employed to analyze the results. P < 0.05 was considered statistically significant as compared to control. CT at 400 mg/kg produced an antianxiety effect equivalent to lorazepam, in the elevated plus maze, open field, and social interaction tests among selected doses of the CT. CT at 400 mg/kg also induced an antidepressant activity similar to imipramine, in the behavioral despair, learned helplessness test, and tail suspension among selected doses of the CT. Moreover, CT at 400 mg/kg produced a significant antistress effect comparable to W. somnifera in water immersion-restraint stress by decreasing ulcer index, adrenal gland weight, and by normalizing the plasma levels of corticosterone, glucose, cholesterol, and triglyceride levels when related to stress control. Conclusion: The study shows that among the different CT doses, CT at 400 mg/kg possesses significant anxiolytic, antidepressant, and anti-stress effects and has therapeutic beneficial for the management of psychological ailments. PMID:27721543

Antipsychotic drugs prevent the motor hyperactivity induced by psychotomimetic MK-801 in zebrafish (Danio rerio).

PubMed

Seibt, Kelly Juliana; Oliveira, Renata da Luz; Zimmermann, Fernanda Francine; Capiotti, Katiúcia Marques; Bogo, Maurício Reis; Ghisleni, Gabriele; Bonan, Carla Denise

2010-12-25

Glutamate N-methyl-d-aspartate (NMDA) receptor antagonists, such as dizocilpine (MK-801), elicit schizophrenia-like symptoms in humans and a behavioral syndrome in rodents, characterized by hyperlocomotion and stereotyped actions, which is antagonized by antipsychotic drugs. Animal models of schizophrenia have been established and used for the development of new antipsychotic drugs. In this work we characterized the behavioral effects of MK-801 and investigated the effect of typical and atypical antipsychotic treatments on locomotor activity as well on the hyperlocomotion induced by MK-801 in zebrafish. MK-801 (20 microM) increased the locomotor behavior as measured by the number of line crossings, distance traveled, and the mean speed in the tank test after 15, 30, and 60 min of exposure. All tested antipsychotics counteracted MK-801-induced hyperactivity on all parameters analyzed and at doses that, given alone, had no effect on spontaneous locomotor activity. The results suggest a similar profile between typical and atypical antipsychotics in the reversal of locomotor disorders induced by MK-801. Moreover, an anxiolytic effect was verified at 30 and 60 min of MK-801 exposure, which was not reversed by antipsychotics tested in this work. In addition, olanzapine, which alone caused an anxiolytic response, when given with MK-801 potentiated the latter's effect on anxiety. In this work we demonstrated the value of the zebrafish, a simple to use animal model, in developing some behavioral features observed in schizophrenia, which may indicate a new approach for drug screening. Copyright (c) 2010 Elsevier B.V. All rights reserved.

Anxiolytic and Anticonvulsant Effects on Mice of Flavonoids, Linalool, and α-Tocopherol Presents in the Extract of Leaves of Cissus sicyoides L. (Vitaceae)

PubMed Central

de Almeida, Edvaldo Rodrigues; de Oliveira Rafael, Krissia Rayane; Couto, Geraldo Bosco Lindoso; Ishigami, Ana Beatriz Matos

2009-01-01

The aim of the present study is to demonstrate the anxiolytic and anticonvulsant effects of a hydroalcoholic extract obtained from the aerial parts of Cissus sicyoides L. (CS) (Vitaceae) on male and female mice using several behavioral assays. Groups of males and females treated via intraperitoneal (IP) with doses of 300, 600, and 1000 mg/kg of the extract showed significant action in the elevated plus-maze (EPM), time spent in the open arms, and number of entries in the open arms. The board-hole test also showed a significant increase in the time spent in head-dipping and in marble-burying test of the number of marbles buried. The same treatment increased the duration of sleeping time induced by sodium pentobarbital and also showed a significant increase in protection against pentylenotetrazole-induced convulsions. These results indicate an anxiolytic and anticonvulsant-like action from C. sicyoides L. extract on mice, probably due to the action of flavonoid(s), Linalool, and α-tocopherol present in the C. sicyoides leaves. PMID:19300520

Antidepressant drugs can modify cytotoxic action of temozolomide.

PubMed

Bielecka, A M; Obuchowicz, E

2017-09-01

Cancer patients often require antidepressant treatment due to comorbid depressive disorder. However, recent studies have demonstrated that antidepressant drugs affect the efficacy of chemotherapy and promote progression of cancer. Apart from the main mood-improving effect, antidepressant drugs also produce analgesic, anxiolytic, hypnotic and pro-cognitive actions. Patients suffering from brain cancer constitute the greatest percentage of depressive cancer patients. However, vital safety and efficacy issues related to combined therapy with temozolomide, the first-line cytostatic in patients diagnosed with glioblastoma multiforme, and antidepressant drugs have yet to be addressed. The aim of the present studies was to evaluate the effect of three antidepressant drugs (imipramine, fluoxetine and tranylcypromine) on the cytotoxic efficacy of temozolomide on T98G cells, a human glioblastoma cell line. In our experiments, we used a complex experimental in vitro system to mimic the instability of a tumour's oxygen supply, thereby reproducing conditions that occur inside the tumour. The effect of the interaction between temozolomide and antidepressant drugs on viability, apoptosis and intensity of divisions of glioblastoma cells was evaluated under different oxygen conditions. The results of our studies demonstrated that imipramine and tranylcypromine reduced the cytotoxic efficacy of temozolomide under some oxygen conditions while fluoxetine did not demonstrate such effects. © 2016 John Wiley & Sons Ltd.

The effects of central administration of physostigmine in two models of anxiety.

PubMed

Sienkiewicz-Jarosz, H; Maciejak, Piotr; Krzaścik, Paweł; Członkowska, Agnieszka I; Szyndler, Janusz; Bidziński, Andrzej; Kostowski, Wojciech; Płaźnik, Adam

2003-05-01

The effects of intracerebroventricular and intraseptal (the medial septum) administration of a prototypical acetylcholinesterase inhibitor (AChE-I), physostigmine, and a classic benzodiazepine midazolam on rat behavior in the open field test of neophobia and in the conditioned fear test (freezing reaction) were examined in rats. In the open field test of neophobia midazolam and physostigmine increased at a limited dose range, rat exploratory activity, after intracerebroventricular injection. Physostigmine produced in addition the hyperlocomotory effect. Following intraseptal injections, only physostigmine selectively prolonged the time spent by animals in the central sector of the open field. In the model of a conditioned fear, both midazolam and physostigmine inhibited rat freezing reaction to the aversively conditioned context after intracerebroventricular, but not after intraseptal, pretrial drug administration. The presented data support the notion about the selective anxiolytic-like effects of some AChE-Is. It appears, therefore, that the calming and sedative effects of AChE-Is observed in patients with Alzheimer's disease may be directly related to their anxiolytic action, independent of an improvement in cognitive functions, which in turn may decrease disorientation-induced distress and anxiety.

Investigation of antidepressant-like and anxiolytic-like actions and cognitive and motor side effects of four N-methyl-D-aspartate receptor antagonists in mice.

PubMed

Refsgaard, Louise K; Pickering, Darryl S; Andreasen, Jesper T

2017-02-01

Evidence suggests that N-methyl-D-aspartate receptor (NMDAR) antagonists could be efficacious in treating depression and anxiety, but side effects constitute a challenge. This study evaluated the antidepressant-like and anxiolytic-like actions, and cognitive and motor side effects of four NMDAR antagonists. MK-801, ketamine, S-ketamine, RO 25-6981 and the positive control, citalopram, were tested for antidepressant-like and anxiolytic-like effects in mice using the forced-swim test, the elevated zero maze and the novelty-induced hypophagia test. Side effects were assessed using a locomotor activity test, the modified Y-maze and the rotarod test. All compounds increased swim distance in the forced-swim test. In the elevated zero maze, the GluN2B subtype-selective RO 25-6981 affected none of the measured parameters, whereas all other compounds showed anxiolytic-like effects. In the novelty-induced hypophagia test, citalopram and MK-801 showed anxiogenic-like action. All NMDAR antagonists induced hyperactivity. The high doses of ketamine and MK-801 impaired performance in the modified Y-maze test, whereas S-ketamine and RO 25-6891 showed no effects in this test. Only MK-801 impaired rotarod performance. The study supports that NMDARs could be a possible therapeutic target for treating depression and anxiety. However, selective antagonism of GluN2B subunit-containing NMDARs showed no effect on anxiety-like behaviours in this study.

Anxiolytic effects of aniracetam in three different mouse models of anxiety and the underlying mechanism.

PubMed

Nakamura, K; Kurasawa, M

2001-05-18

The anxiolytic effects of aniracetam have not been proven in animals despite its clinical usefulness for post-stroke anxiety. This study, therefore, aimed to characterize the anxiolytic effects of aniracetam in different anxiety models using mice and to examine the mode of action. In a social interaction test in which all classes (serotonergic, cholinergic and dopaminergic) of compounds were effective, aniracetam (10-100 mg/kg) increased total social interaction scores (time and frequency), and the increase in the total social interaction time mainly reflected an increase in trunk sniffing and following. The anxiolytic effects were completely blocked by haloperidol and nearly completely by mecamylamine or ketanserin, suggesting an involvement of nicotinic acetylcholine, 5-HT2A and dopamine D2 receptors in the anxiolytic mechanism. Aniracetam also showed anti-anxiety effects in two other anxiety models (elevated plus-maze and conditioned fear stress tests), whereas diazepam as a positive control was anxiolytic only in the elevated plus-maze and social interaction tests. The anxiolytic effects of aniracetam in each model were mimicked by different metabolites (i.e., p-anisic acid in the elevated plus-maze test) or specific combinations of metabolites. These results indicate that aniracetam possesses a wide range of anxiolytic properties, which may be mediated by an interaction between cholinergic, dopaminergic and serotonergic systems. Thus, our findings suggest the potential usefulness of aniracetam against various types of anxiety-related disorders and social failure/impairments.

Essential oil of Lippia alba and its main constituent citral block the excitability of rat sciatic nerves

PubMed Central

Sousa, D.G.; Sousa, S.D.G.; Silva, R.E.R.; Silva-Alves, K.S.; Ferreira-da-Silva, F.W.; Kerntopf, M.R.; Menezes, I.R.A.; Leal-Cardoso, J.H.; Barbosa, R.

2015-01-01

Lippia alba is empirically used for infusions, teas, macerates, and hydroalcoholic extracts because of its antispasmodic, analgesic, sedative, and anxiolytic effects. Citral is a mixture of trans-geranial and cis-neral and is the main constituent of L. alba essential oil and possesses analgesic, anxiolytic, anticonvulsant, and sedative effects. The present study evaluated the effects of the essential oil of L. alba (EOLa) and citral on compound action potentials (CAPs) in Wistar rat sciatic nerves. Both drugs inhibited CAP in a concentration-dependent manner. The calculated half-maximal inhibitory concentrations (IC50) of peak-to-peak amplitude were 53.2 µg/mL and 35.00 µg/mL (or 230 µM) for EOLa and citral, respectively. Peak-to-peak amplitude of the CAP was significantly reduced by 30 µg/mL EOLa and 10 µg/mL citral. EOLa and citral (at 60 and 30 µg/mL, values close to their respective IC50 for CAP blockade) significantly increased chronaxy and rheobase. The conduction velocity of the first and second CAP components was statistically reduced to ∼86% of control with 10 µg/mL EOLa and ∼90% of control with 3 µg/mL citral. This study showed that EOLa inhibited nerve excitability and this effect can be explained by the presence of citral in its composition. Both EOLa and citral showed inhibitory actions at lower concentrations compared with other essential oils and constituents with local anesthetic activity. In conclusion, these data demonstrate that EOLa and citral are promising agents in the development of new drugs with local anesthetic activity. PMID:26132093

Essential oil of Lippia alba and its main constituent citral block the excitability of rat sciatic nerves.

PubMed

Sousa, D G; Sousa, S D G; Silva, R E R; Silva-Alves, K S; Ferreira-da-Silva, F W; Kerntopf, M R; Menezes, I R A; Leal-Cardoso, J H; Barbosa, R

2015-08-01

Lippia alba is empirically used for infusions, teas, macerates, and hydroalcoholic extracts because of its antispasmodic, analgesic, sedative, and anxiolytic effects. Citral is a mixture of trans-geranial and cis-neral and is the main constituent of L. alba essential oil and possesses analgesic, anxiolytic, anticonvulsant, and sedative effects. The present study evaluated the effects of the essential oil of L. alba (EOLa) and citral on compound action potentials (CAPs) in Wistar rat sciatic nerves. Both drugs inhibited CAP in a concentration-dependent manner. The calculated half-maximal inhibitory concentrations (IC50) of peak-to-peak amplitude were 53.2 µg/mL and 35.00 µg/mL (or 230 µM) for EOLa and citral, respectively. Peak-to-peak amplitude of the CAP was significantly reduced by 30 µg/mL EOLa and 10 µg/mL citral. EOLa and citral (at 60 and 30 µg/mL, values close to their respective IC50 for CAP blockade) significantly increased chronaxy and rheobase. The conduction velocity of the first and second CAP components was statistically reduced to ∼86% of control with 10 µg/mL EOLa and ∼90% of control with 3 µg/mL citral. This study showed that EOLa inhibited nerve excitability and this effect can be explained by the presence of citral in its composition. Both EOLa and citral showed inhibitory actions at lower concentrations compared with other essential oils and constituents with local anesthetic activity. In conclusion, these data demonstrate that EOLa and citral are promising agents in the development of new drugs with local anesthetic activity.

Effects of reference analgesics and psychoactive drugs on the noxious heat threshold of mice measured by an increasing-temperature water bath.

PubMed

Boros, Melinda; Benkó, Rita; Bölcskei, Kata; Szolcsányi, János; Barthó, Loránd; Pethő, Gábor

2013-12-01

The study aimed at validating an increasing-temperature water bath suitable for determining the noxious heat threshold for use in mice. The noxious heat threshold was determined by immersing the tail of the gently held awake mouse into a water container whose temperature was near-linearly increased at a rate of 24°C/min. until the animal withdrew its tail, that is, heating attained the noxious threshold. The effects of standard analgesic, neuroleptic and anxiolytic drugs were investigated in a parallel way on both the noxious heat threshold and the psychomotor activity assessed by the open field test. Morphine, diclofenac and metamizol (dipyrone) elevated the heat threshold of mice with minimum effective doses of 6, 30 and 1000 mg/kg i.p., respectively. These doses of morphine and diclofenac failed to induce any remarkable effect on psychomotor activity in the open field test while that of metamizol exerted a profound inhibition. The anxiolytic diazepam and the neuroleptic droperidol at doses evoking a mild and moderate, respectively, psychomotor inhibition failed to alter the heat threshold. Combination of a subliminal dose of morphine (regarding both antinociceptive and psychomotor inhibitory action) with diclofenac, metamizol, diazepam or droperidol at doses also subliminal regarding the thermal antinociceptive effect elevated the noxious heat threshold without major additional effects in the open field test. It is concluded that the increasing-temperature water bath is suitable for studying the thermal antinociceptive effects of morphine and diclofenac as well as the morphine-sparing action of diclofenac, metamizol, droperidol and diazepam. Behavioural testing is recommended when testing analgesics. © 2013 Nordic Pharmacological Society. Published by John Wiley & Sons Ltd.

Elucidating the mechanism of action of pregabalin: α(2)δ as a therapeutic target in anxiety.

PubMed

Micó, Juan-Antonio; Prieto, Rita

2012-08-01

This review provides a brief summary of what is known about the anxiolytic mechanism of action of pregabalin, a highly selective, high-affinity ligand of the P/Q type of voltage-gated calcium channel (CaV). Evidence from in vivo models of neuronal hyperexcitability suggests that pregabalin reduces synaptic release of neurotransmitters in selected CNS regions including the cortex, olfactory bulb, hypothalamus, amygdala, hippocampus, cerebellum and dorsal horn of the spinal cord. Release of neurotransmitters from the synaptic vesicle, and propagation of neurotransmission, requires the vesicle to fuse with the presynaptic membrane. Pregabalin binding to the α(2)δ type 1 protein of the P/Q type CaV reduces the availability of Ca2+ required for membrane fusion and exocytosis of neurotransmitters. Evidence that the anxiolytic mechanism of action of pregabalin is mediated by binding to the α(2)δ type 1 protein comes from animal models, which have demonstrated a structure-activity relationship between the affinity of ligands for the α(2)δ type 1 protein and their potency in models of anxiety such as the Vogel conflict test. Furthermore, the anxiolytic activity of pregabalin is lost in transgenic mice with specific point mutations in the CaV α(2)δ type 1 protein. Pregabalin-mediated reduction in calcium currents has also been shown to result in a significant inhibition of the release of neurotransmitters implicated in pathological anxiety such as glutamate and monoamine neurotransmitters. However, further research is needed to confirm that these effects contribute to the anxiolytic mechanism of action of pregabalin. Finally, pregabalin may also act by inhibiting synaptogenesis of excitatory neurons formed in response to chronic stress or anxiety, or more acutely inhibit the trafficking of CaV to the plasma membrane.

Drugs in Mental Retardation: Treatment or Tragedy?

ERIC Educational Resources Information Center

Aman, Michael G.

1985-01-01

Treatment of mentally retarded persons with psychotropic and anticonvulsant drugs is discussed in terms of drug classification, rationale for use, attitudes toward use, and clinical research findings. The literature on neuroleptic, anticonvulsant, anxiolytic, and cerebral stimulant drugs is summarized. Controversial reports that some medications…

DOR(2)-selective but not DOR(1)-selective antagonist abolishes anxiolytic-like effects of the δ opioid receptor agonist KNT-127.

PubMed

Sugiyama, Azusa; Nagase, Hiroshi; Oka, Jun-Ichiro; Yamada, Mitsuhiko; Saitoh, Akiyoshi

2014-04-01

Recently, we reported that the δ opioid receptor (DOR) agonist KNT-127 produces anxiolytic-like effects in behaving rats. Here, we report on the roles of DOR subtypes ( DOR(1) and DOR(2)) play in mediating KNT-127-induced anxiolytic-like effects. Pretreatment with the DOR(2)-selective antagonist naltriben (NTB; 0.05mg/kg, s.c.) completely abolished KNT-127 (3.0mg/kg, s.c.)-induced anxiolytic-like effects in rats performing the elevated plus-maze task. By contrast, the DOR(1)-selective antagonist 7-benzylidenenaltrexone (BNTX; 0.5mg/kg, s.c.) produced no effect at a dose that completely blocked the antinociceptive effects of KNT-127. These findings were also supported by results from a light/dark test and open-field test. We clearly demonstrated that the DOR(2)-selective antagonist, but not the DOR(1)-selective antagonist, abolishes the anxiolytic-like effects of the DOR agonist KNT-127, suggesting different roles of these DOR subtypes in anxiety. We propose that DOR(2)-selective agonists would be good candidates for future development of anxiolytic drugs. Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.

Anticonvulsant and antipunishment effects of toluene.

PubMed

Wood, R W; Coleman, J B; Schuler, R; Cox, C

1984-08-01

Toluene can have striking acute behavioral effects and is subject to abuse by inhalation. To determine if its actions resemble those of drugs used in the treatment of anxiety ("anxiolytics"), two sets of experiments were undertaken. Inasmuch as prevention of pentylenetetrazol-induced convulsions is an identifying property of this class of agents, we first demonstrated that pretreatment with injections of toluene delayed the onset of convulsive signs and prevented the tonic extension phase of the convulsant activity in a dose-related manner. Injections of another alkyl benzene, m-xylene, were of comparable potency to toluene. Inhalation of toluene delayed the time to death after pentylenetetrazol injection in a manner related to the duration and concentration of exposure; at lower convulsant doses, inhalation of moderate concentrations (EC50, 1311 ppm) prevented death. Treatment with a benzodiazepine receptor antagonist (Ro 15-1788) failed to reduce the anticonvulsant activity of inhaled toluene. Anxiolytics also attenuate the reduction in response rate produced by punishment with electric shock. Toluene increased rates of responding suppressed by punishment when responding was maintained under a multiple fixed-interval fixed-interval punishment schedule of reinforcement. Distinct antipunishment effects were observed after 2 hr of exposure to 1780 and 3000 ppm of toluene; the rate-increasing effects of toluene were related to concentration and to time after the termination of exposure. Thus, toluene and m-xylene resemble in several respects clinically useful drugs such as the benzodiazepines.

Effects of the brain-penetrant and selective 5-HT6 receptor antagonist SB-399885 in animal models of anxiety and depression.

PubMed

Wesołowska, Anna; Nikiforuk, Agnieszka

2007-04-01

The effects of a selective 5-HT(6) receptor antagonist, SB-399885 (N-[3,5-dichloro-2-(methoxy)phenyl]-4-(methoxy)-3-(1-piperazinyl)benzenesulfonamide), were evaluated in behavioural tests sensitive to clinically effective anxiolytic- and antidepressant-compounds using diazepam and imipramine as reference drugs. In the Vogel conflict drinking test in rats, SB-399885 (1-3mg/kg i.p.) caused an anxiolytic-like activity comparable to that of diazepam (2.5-5mg/kg i.p.). An anxiolytic-like effect was also seen in the elevated plus-maze test in rats, where SB-399885 (0.3-3mg/kg i.p.) was slightly weaker than diazepam (2.5-5mg/kg i.p.). In the four-plate test in mice, SB-399885 (3-20mg/kg i.p.) showed an anxiolytic-like effect which was weaker than that produced by diazepam (2.5-5mg/kg i.p.). In the forced swim test in rats, SB-399885 (10mg/kg i.p.) significantly shortened the immobility time and the effect was stronger than that of imipramine (30mg/kg i.p.). In the forced swim test in mice, SB-399885 (20-30mg/kg i.p.) had an anti-immobility action, comparable to imipramine (30mg/kg i.p.) and also in the tail suspension test in mice, SB-399885 (10-30mg/kg i.p.) had an antidepressant-like effect, though was weaker than imipramine (10-20mg/kg i.p.). The tested 5-HT(6) antagonist (3-20mg/kg i.p.) shortened the walking time of rats in the open field test and, at a dose of 30mg/kg i.p. reduced the locomotor activity of mice. SB-399885 (in doses up to 30mg/kg i.p.) did not affect motor coordination in mice and rats tested in the rota-rod test. Such data indicate that the selective 5-HT(6) receptor antagonist SB-399885had specific effects, indicative of this compound's anxiolytic and antidepressant potential.

Psychotropic medication use in French children and adolescents.

PubMed

Kovess, Viviane; Choppin, Sabine; Gao, Fei; Pivette, Mathilde; Husky, Mathilde; Leray, Emmanuelle

2015-03-01

The purpose of this study was to describe the patterns of psychotropic drug use in a large representative population of children and adolescents drawn from the French National Health Insurance databank. Data were drawn from a sample of 1% of the beneficiaries of the French national health insurance, selecting those 0-17 years old in 2010 (n=128,298). In addition to age and gender, data included the identification number of each drug allowing a European Pharmaceutical Marketing Research Association (EphMRA) classification, as well as the type of the prescriber. Overall, 2.5% of children and adolescents had been prescribed psychotropic medication. A majority were prescribed anxiolytics (1.9%), followed by antidepressants (0.3%), antipsychotics (0.3%), and stimulants (0.2%). Between the ages of 15 and 17, 6.1% of girls were prescribed anxiolytics and 1.1% were prescribed antidepressants. For boys, the anxiolytics remained the most prescribed psychotropic medication; however, between the ages of 11 and 14, and between the ages of 15 and 17 they received more antipsychotics (0.7% and 0.8%) and between the ages of 6 and 10, and between the ages of 11 and 14 (0.7% and 0.6%), they were prescribed more stimulants than were girls. Among those who received a prescription, a majority of youth (84.6%) received only one class of drugs, and general practitioners were found to be prescribing most of these prescriptions (81.7%). The prevalence of psychotropic drug use in France is similar to that of the Netherlands and much lower than what is observed in the United States. Stimulants are less frequently prescribed in France than in other European countries, but anxiolytics are prescribed considerably more in France than in any other country.

Neuronal nicotinic receptor antagonist reduces anxiety-like behavior in mice.

PubMed

Roni, Monzurul Amin; Rahman, Shafiqur

2011-10-31

Brain cholinergic neurotransmission has been implicated in the modulation of anxiety in humans and evidence suggests that drugs targeting neuronal nicotinic acetylcholine receptor (nAChR) could have potential for the treatment of anxiety. The objective of present study was to examine anxiolytic effects of lobeline (0.04 or 0.1 mg/kg), a nAChR antagonist, in C57BL/6J mice using elevated plus-maze (EPM) and marble-burying test. Lobeline (0.04 mg/kg) significantly increased open arm time on EPM and reduced number of marbles buried. Similarly, mecamylamine (0.3 mg/kg) produced anxiolytic effects, while peripherally acting hexamethonium (0.3 mg/kg) failed to produce any response. These results provide evidence that lobeline has anxiolytic potential and nAChR antagonists may represent a new class of anxiolytics in humans. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Maerua angolensis stem bark extract reverses anxiety and related behaviours in zebrafish-Involvement of GABAergic and 5-HT systems.

PubMed

Benneh, Charles Kwaku; Biney, Robert Peter; Mante, Priscilla Kolibea; Tandoh, Augustine; Adongo, Donatus Wewura; Woode, Eric

2017-07-31

Maerua angolensis DC (Capparaceae) has been employed in the management of several central nervous system (CNS) disorders including anxiety. This study evaluated the anxiolytic effects of the petroleum ether/ethyl acetate fraction stem bark extract and its possible mechanism(s) using zebrafish anxiety models. Adult zebrafish, tested in the novel tank and light dark tests, have shown by previous authors to be sensitive to the anxiolytic effects of known anxiolytic drugs. Adult zebrafish were treated with M. angolensis extract, fluoxetine, desipramine, and diazepam followed by testing in the novel tank and light dark tests. We further assessed the effect of the extract on anxiety after inducing an anxiogenic phenotype using the ethanol-withdrawal and chronic unpredictable stress (CUS) tests. The anxiolytic effect was further investigated after pretreatment with flumazenil, granisetron, cyproheptadine, methysergide and pizotifen. M. angolensis extract, similar to fluoxetine and desipramine, demonstrated significant anxiolytic behaviour at doses that did not reduce locomotor activity significantly. Similar anxiolytic effects were recorded in the ethanol withdrawal-induced anxiety test. Furthermore, the anxiogenic effects induced by the CUS paradigm were significantly reversed by treatment M. angolensis extract and fluoxetine. The anxiolytic effects of M. angolensis extract were however reversed after pre-treatment with flumazenil, granisetron, cyproheptadine, methysergide and pizotifen. Taken together, this suggests that the petroleum ether/ ethyl acetate fraction of M. angolensis possesses significant anxiolytic activity, which could partly be accounted for by an interaction with the serotoninergic system and the GABA A receptor. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Effect of anxiolytics on cognitive flexibility in problem solving.

PubMed

Silver, Jennifer A; Hughes, John D; Bornstein, Robert A; Beversdorf, David Q

2004-06-01

Our purpose is to examine the effect of different classes of anxiolytics on cognitive flexibility. Situational stressors and anxiety impede performance on "creativity" tests requiring cognitive flexibility. Noradrenergic agents have been shown to modulate cognitive flexibility as assessed by performance on anagrams. To determine whether these findings on noradrenergic modulation of cognitive flexibility are specific to the noradrenergic system or are a nonspecific anxiety effect, we compared the effects of propranolol, lorazepam, and placebo on the anagram task. Subjects attended 3 test sessions. Prior to each session, subjects were given 1 of the 3 drugs. As in previous research, the natural log of the solution latency of each test item was summed for each test session and compared across drug conditions. For subjects able to solve the anagrams, solution times after propranolol, but not lorazepam, were significantly lower than after placebo. Therefore, this suggests that the phenomenon of noradrenergic modulation of cognitive flexibility does not result from a nonspecific anxiolytic effect, but rather is specific to the noradrenergic system.

Preclinical evidence of the anxiolytic and sedative-like activities of Tagetes erecta L. reinforces its ethnobotanical approach.

PubMed

Pérez-Ortega, Gimena; Angeles-López, Guadalupe Esther; Argueta-Villamar, Arturo; González-Trujano, María Eva

2017-09-01

Morelos State is one of the regions of Mexico where several plant species are used in traditional medicine. Species from Tagetes genus (Asteraceae) are reported as useful in infusion to treat stomachache and intestinal diseases, but also as tranquilizers. In this study, medicinal uses of T. erecta including its depressant effect on the central nervous system (CNS) were explored by interviewing healers and merchants of local markets of Morelos State, and by investigation of the phytochemical and pharmacological tranquilizing properties. Specific anxiolytic and/or sedative-like responses of different doses of T. erecta (10, 30 and 100 or 300mg/kg, i.p.) were investigated using experimental models in mice such as: open-field, exploration cylinder, hole-board, and the barbituric-induced hypnosis potentiation. The possible anxiolytic mechanism of action was assessed in the presence of WAY100635 (0.32mg/kg, i.p.) and flumazenil (10mg/kg, i.p.), antagonists of 5-HT 1A and GABA/BDZs receptors, respectively. Individual flavonoids reported in this species were also evaluated in these experimental models. As a result of this study, healers and merchants from ten local regions of Morelos State recommended T. erecta flowers as an infusion or as a tincture for several culture-bound syndromes associated with CNS, among others. Anxiolytic and sedative-like activities of the T. erecta aqueous and organic polar extracts were corroborated in these models associated to a participation of rutin, kaempferol, quercetin, kaempferitrin, and β-sitosterol constituents; where 5-HT 1A , but not BDZs, receptors were involved as anxiolytic mechanism of action. These data support the anxiolytic and sedative-like properties of T. erecta in traditional medicine by involving mainly serotonergic neurotransmission because of the presence in part of flavonoids and the terpenoid β-sitosterol. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Effects of single and combined gabapentin use in elevated plus maze and forced swimming tests.

PubMed

Kilic, Fatma Sultan; Ismailoglu, Sule; Kaygisiz, Bilgin; Oner, Setenay

2014-10-01

Gabapentin, a third-generation antiepileptic drug, is a structural analogue of γ-aminobutyric acid, which is an important mediator of central nervous system. There is clinical data indicating its effectiveness in the treatment of psychiatric illnesses such as bipolar disorder and anxiety disorders. We aimed to investigate the antidepressant and anxiolytic-like effects and mechanisms of gabapentin in rats. Female Spraque-Dawley rats weighing 250±20 g were used. A total of 13 groups were formed, each containing 8 rats: gabapentin (5, 10, 20, 40 mg/kg), amitriptyline (10 mg/kg), sertraline (5 mg/kg), diazepam (5 mg/kg), ketamine (10 mg/kg), gabapentin 20 mg/kg was also combined with amitriptyline (10 mg/kg), sertraline (5 mg/kg), diazepam (5 mg/kg) and ketamine (10 mg/kg). All the drugs were used intraperitoneally as single dose. Saline was administered to the control group. Elevated plus maze and forced swimming tests were used as experimental models of anxiety and depression, respectively. It was observed that gabapentin showed an anxiolytic-like and antidepressant-like effect in all doses in rats. Its antidepressant effect was found to be the same as the antidepressant effects of amitriptyline and sertraline. There was no change in the antidepressant effect when gabapentin was combined with amitriptyline and ketamine, but there was an increase when combined with sertraline and diazepam. Gabapentin and amitriptyline showed similar anxiolytic effect, whereas ketamine and diazepam had more potent anxiolytic effect compared with them. These data suggest that gabapentin may possess antidepressant- and anxiolytic-like effects.

Stressful life events and social health factors in women using anxiolytics and antidepressants: an Italian observational study in community pharmacies.

PubMed

D'Incau, Paola; Barbui, Corrado; Tubini, Jacopo; Conforti, Anita

2011-04-01

In Italy, as in all of Europe, women differ from men in that they are somewhat more sensitive to the depressogenic effects of stressful life events related to their social networks and emotional sphere. Women are more likely than men to have experienced poverty, gender discrimination, and physical and sexual abuse. The purpose of this study was to expand the knowledge about the occurrence of stressful life events in women exposed and not exposed to anxiolytics and antidepressants in a community pharmacy setting. Women attending 100 community pharmacies in the Italian Veneto region were surveyed by pharmacists with regard to a number of general features of their current pharmacologic treatment. Women independently completed a written self-assessment questionnaire that focused on stressful life events. Unconditional logistic regression analysis was performed to investigate the association between anxiolytics and antidepressants use and potential factors, including stressful life events. The study population comprised 11,357 women. One or more stressful life events occurred in 90% of the women treated with anxiolytics and/or antidepressants (users [n = 3848]) and in 74% of the women not treated with these drugs (nonusers [n = 7509]) (odds ratio = 3.19; 95% CI, 2.83-3.60). On average, the life events occurred during the previous 6 months and the women considered the influence of these events on their well-being to be severe. After the unconditional logistic regression analysis, the association between anxiolytics and/or antidepressants use remained positive for most of the stressful life events studied as well as for other factors: separation/divorce, living alone or with others (family or friends), unemployment, whether currently being seen by a psychologist/psychiatrist, and treatment with drugs for the alimentary tract and metabolism, cardiovascular system, or nervous system. A significant association between stressful life events and anxiolytics and/or antidepressants use was observed. Further efforts are needed to increase our knowledge of the use of anxiolytics or antidepressants in relation to the occurrence of life events. Copyright © 2011 Elsevier HS Journals, Inc. All rights reserved.

[The original novel nootropic and neuroprotective agent noopept].

PubMed

Ostrovskaia, R U; Gudasheva, T A; Voronina, T A; Seredenin, S B

2002-01-01

The paper describes pharmacological properties of the new nootropic drug noopept created using an original approach based on the imitation of a nonpeptide nootrope structure by means of the short-peptide design. In particular, the structure of pyracetam was designed using dipeptide nootropes. Experimental investigations of noopept (N-phenylacetyl-L-polyglycine ethyl ester) showed that the new drug exceeds pyracetam both with respect to the effective dose level (1000 times lower for noopept than for pyracetam) and in the spectrum of mnemotropic activity. In contrast to pyracetam facilitating only the early stages of the memory process, noopept positively influences the memory consolidation and retrieval steps as well. The new drug produces an additional selective anxiolytic action. The pronounced neuroprotective effect of noopept was demonstrated both in vivo (in cases of various forms of brain ischemia) and in vitro (on various neuronal models). The drug action is based on the antioxidant effect, the antiinflammatory action, and the ability to inhibit the neurotoxicity of excess calcium and glutamate, and to improve the blood rheology. It was established for the first time that the activity of noopept is retained both upon parenteral introduction and upon peroral administration, which is a principal advantage of this proline-containing dipeptide over other, more complex peptides. This property provided a basis for the development of a medicinal form of noopept for peroral usage. At present, noopept tablets (noopept 5 and 10 mg) are under clinical assessment as a means of treating cognitive deficiency of cerebrovascular and post-traumatic origin.

FG7142, yohimbine, and βCCE produce anxiogenic-like effects in the elevated plus-maze but do not affect brainstem activated hippocampal theta.

PubMed

Yeung, Michelle; Lu, Lily; Hughes, Adam M; Treit, Dallas; Dickson, Clayton T

2013-12-01

The neurobiological underpinnings of anxiety are of paramount importance to selective and efficacious pharmaceutical intervention. Hippocampal theta frequency in urethane anaesthetized rats is suppressed by all known (and some previously unknown) anti-anxiety (anxiolytic) drugs. Although these findings support the predictive validity of this assay, its construct validity (i.e., whether theta frequency actually indexes anxiety per se) has not been a subject of systematic investigation. We reasoned that if anxiolytic drugs suppress hippocampal theta frequency, then drugs that increase anxiety (i.e., anxiogenic agents) should increase theta frequency, thus providing evidence of construct validity. We used three proven anxiogenic drugs--two benzodiazepine receptor inverse agonists, N-methyl-β-carboline-3-carboxamide (FG7142) and β-carboline-3-carboxylate ethyl ester (βCCE), and one α2 noradrenergic receptor antagonist, 17α-hydroxy-yohimban-16α-carboxylic acid methyl ester (yohimbine) as pharmacological probes to assess the construct validity of the theta model. Although all three anxiogenic drugs significantly increased behavioural measures of anxiety in the elevated plus-maze, none of the three increased the frequency of hippocampal theta oscillations in the neurophysiological model. As a positive control, we demonstrated that diazepam, a proven anxiolytic drug, decreased the frequency of hippocampal theta, as in all other studies using this model. Given this discrepancy between the significant effects of anxiogenic drugs in the behavioural model and the null effects of these drugs in the neurophysiological model, we conclude that the construct validity of the hippocampal theta model of anxiety is questionable. Copyright © 2013 Elsevier Ltd. All rights reserved.

Oral dosing in adult zebrafish: proof-of-concept using pharmacokinetics and pharmacological evaluation of carbamazepine.

PubMed

Kulkarni, Pushkar; Chaudhari, Girish Hari; Sripuram, Vijaykumar; Banote, Rakesh Kumar; Kirla, Krishna Tulasi; Sultana, Razia; Rao, Pallavi; Oruganti, Srinivas; Chatti, Kiranam

2014-02-01

We describe a method for obtaining pharmacokinetics (PK) and pharmacology data from adult zebrafish in terms of mg/kg using a novel method of oral administration. Using carbamazepine (CBZ) as a test drug, we employed dried blood spot (DBS) cards to enable drug quantification for PK; and we evaluated the pharmacological anxiolytic effect using novel tank test. The PK study confirmed the presence of CBZ in both blood and brain and the behavioural study showed dose dependent anxiolytic effect. The reproducibility of oral dosing was confirmed by the fact that the results obtained in both the experiments had negligible errors. This report enables a novel approach for optimizing the utility of zebrafish in drug discovery and drug delivery research. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Oxidative metabolism of limbic structures after acute administration of diazepam, alprazolam and zolpidem.

PubMed

González-Pardo, Héctor; Conejo, Nélida M; Arias, Jorge L

2006-08-30

The effects of acute administration of two benzodiazepines and a non-benzodiazepine hypnotic on behavior and brain metabolism were evaluated in rats. After testing the behavioral action of the benzodiazepines on the open field and the elevated plus-maze, the effects of the three drugs on neuronal metabolism of particular limbic regions were measured using cytochrome c oxidase (CO) histochemistry. Diazepam (5 mg/kg i.p.) and alprazolam (0.5 mg/kg i.p.) induced clear anxiolytic effects and a decrease in locomotion, whereas zolpidem (2 mg/kg i.p.) caused an intense hypnotic effect. The anxiolytic effects of alprazolam were distinguishable from diazepam due to the pharmacological and clinical profile of this triazolobenzodiazepine. CO activity decreased significantly in almost all the limbic regions evaluated after zolpidem administration. However, significant prominent decreases in CO activity were found after diazepam treatment in the medial mammillary nucleus, anteroventral thalamus, cingulate cortex, dentate gyrus and basolateral amygdala. Alprazolam caused similar decreases in CO activity, with the exception of the prelimbic and cingulate cortices, where significant increases were detected. In agreement with previous studies using other functional mapping techniques, our results indicate that particular benzodiazepines and non-benzodiazepine hypnotics induce selective changes in brain oxidative metabolism.

Involvement of the GABAergic system in the anxiolytic-like effect of the flavonoid ellagic acid in mice.

PubMed

Girish, Chandrashekaran; Raj, Vishnu; Arya, Jayasree; Balakrishnan, Sadasivam

2013-06-15

Anxiolytic-like effects of dietary flavonoids are relatively well known. Ellagic acid is a naturally occurring flavonoid compound which is abundant in many plants and fruits. The present study was designed to investigate the antianxiety-like effect of ellagic acid in mice using an elevated plus-maze test. The involvement of the GABAergic and serotonergic systems in the antianxiety-like activity of ellagic acid was also studied. Our results showed that ellagic acid treatment (25, 50 and 100 mg/kg, p.o.), produced a significant increase in the percentage of time spent and entry into the open arms, with a profile comparable to that of diazepam (1 mg/kg, p.o.). Unlike diazepam, the anxiolytic doses of ellagic acid did not prolong the duration of sodium thiopental-induced loss of righting reflex, indicating that this flavonoid is non-hypnotic. The anxiolytic effect observed with ellagic acid treatment (25 mg/kg, p.o.) was antagonized by pretreatment with picrotoxin (a non-competitive GABAA receptor antagonist, 1 mg/kg, i.p.) and flumazenil (a benzodiazepine site antagonist, 1 mg/kg, i.p.) but not with p-chlorophenylalanine (a serotonin synthesis inhibitor, 100 mg/kg, i.p.) and pindolol (a β-adrenoceptors blocker/5-HT1A/1B receptor antagonist, 10 mg/kg, i.p.). Taken together, the data demonstrated that acute and chronic administration of ellagic acid to mice has produced antianxiety-like effect when tested in the elevated plus-maze. The experiments with different receptor blockers suggest an involvement of GABAergic system in the anxiolytic action of this bioflavonoid. However, this action is not seems to be mediated through serotonergic system. Copyright © 2013 Elsevier B.V. All rights reserved.

Central nervous system activity of Illicium verum fruit extracts.

PubMed

Chouksey, Divya; Upmanyu, Neeraj; Pawar, R S

2013-11-01

To research the acute toxicity of Illicium verum (I. verum) fruit extracts and its action on central nervous system. The TLC and HPTLC techniques were used as fingerprints to determine the chemical components present in I. verum. Male albino rats and mice were utilized for study. The powdered material was successively extracted with n-hexane, ethyl acetate and methanol using a Soxhlet extractor. Acute toxicity studies were performed as per OECD guidelines. The CNS activity was evaluated on parameters of general behavior, sleeping pattern, locomotor activity, anxiety and myocoordination activity. The animals were trained for seven days prior to experiments and the divided into five groups with six animals in each. The drug was administered by intraperitoneal route according to body weight. The dosing was done as prescribed in each protocol. Toxicity studies reported 2 000 mg/kg as toxicological dose and 1/10 of the same dose was taken as therapeutic dose Intraperitoneal injection of all extracts at dose of 200 mg prolonged phenobarbitone induced sleeping time, produced alteration in general behavior pattern, reduced locomotor activity and produced anxiolytic effects but the extracts do not significantly alter muscles coordination activity. The three extracts of I. verum at the dose of 200 mg, methanol extract was found to produce more prominent effects, then hexane and ethylacetate extracts. The observation suggested that the extracts of I. verum possess potent CNS depressant action and anxiolytic effect without interfering with motor coordination. Copyright © 2013 Hainan Medical College. Published by Elsevier B.V. All rights reserved.

Survey on the use of psychotropic drugs by twelve military police units in the municipalities of Goiânia and Aparecida de Goiânia, state of Goiás, Brazil.

PubMed

Costa, Sérgio Henrique Nascente; Cunha, Luiz Carlos da; Yonamine, Maurício; Pucci, Liuba Laxor; Oliveira, Fernando Gomes Ferreira; Souza, Camila Gabriela de; Mesquita, Guilherme Alves; Vieira, Ana Paula de Toledo; Vinhal, Ludmilla Barros; Dalastra, Janayna; Leles, Cláudio Rodrigues

2010-12-01

To determine the prevalence of psychotropic drug use among military police officers in the state of Goiás, Brazil. Study carried out at twelve military police units located in the municipalities of Goiânia and Aparecida de Goiânia between March to October 2008. Volunteers (n=221) were interviewed about drug use using a questionnaire especially designed by the Centro Brasileiro de Informações sobre Drogas Psicotrópicas (CEBRID). Descriptive statistics was used to determine the prevalence of licit and illicit drug use in the study sample. The frequency of use was divided into: 1) lifetime use: tobacco-39.9%, alcohol-87.8%, cannabis-8.1%, cocaine-1.8%, stimulants-7.2%, solvents-10.0%, sedatives, anxiolytics, antidepressants-6.8%, LSD-0.5%, Bentyl®-0.5%, anabolic steroids-5.4%; 2) use in the previous year: tobacco-15.4%, alcohol-72.9%, stimulants-6.3%, solvents-0.5%, sedatives, anxiolytics, antidepressants-3.7%; 3) use in the previous 30 days: tobacco-14.5%, alcohol-57.5%, stimulants-5.0%, solvents-0.5, sedatives, anxiolytics, antidepressants-3.7%. The high prevalence rate of psychotropic drug use found amoung military police officers in two cities of the state of Goiás in Brazil can be considered an important factor with potential influence on job activities.

Anxiolytic Effects and Neuroanatomical Targets of Estrogen Receptor-β (ERβ) Activation by a Selective ERβ Agonist in Female Mice

PubMed Central

Oyola, Mario G.; Portillo, Wendy; Reyna, Andrea; Foradori, Chad D.; Kudwa, Andrea; Hinds, Laura; Handa, Robert J.

2012-01-01

The dichotomous anxiogenic and anxiolytic properties of estrogens have been reported to be mediated by two distinct neural estrogen receptors (ER), ERα and ERβ, respectively. Using a combination of pharmacological and genetic approaches, we confirmed that the anxiolytic actions of estradiol are mediated by ERβ and extended and these observations to demonstrate the neuroanatomical targets involved in ERβ activation in these behavioral responses. We examined the effects of the biologically active S-enantiomer of diarylpropionitrile (S-DPN) on anxiety-related behavioral measures, the corresponding stress hormonal response to hypothalamo-pituitary-adrenal axis reactivity, and potential sites of neuronal activation in mutant female mice carrying a null mutation for ERβ gene (βERKO). S-DPN administration significantly reduced anxiety-like behaviors in the open field, light-dark exploration, and the elevated plus maze (EPM) in ovariectomized wild-type (WT) mice, but not in their βERKO littermates. Stress-induced corticosterone (CORT) and ACTH were also attenuated by S-DPN in the WT mice but not in the βERKO mice. Using c-fos induction after elevated plus maze, as a marker of stress-induced neuronal activation, we identified the anterodorsal medial amygdala and bed nucleus of the stria terminalis as the neuronal targets of S-DPN action. Both areas showed elevated c-fos mRNA expression with S-DPN treatment in the WT but not βERKO females. These studies provide compelling evidence for anxiolytic effects mediated by ERβ, and its neuroanatomical targets, that send or receive projections to/from the paraventricular nucleus, providing potential indirect mode of action for the control of hypothalamo-pituitary-adrenal axis function and behaviors. PMID:22186418

Validating a human model for anxiety using startle potentiated by cue and context: the effects of alprazolam, pregabalin, and diphenhydramine

PubMed Central

Mol, N.; Kenemans, J. L.; Prinssen, E. P.; Niklson, I.; Xia-Chen, C.; Broeyer, F.; van Gerven, J.

2009-01-01

Background Fear-potentiated startle has been suggested as a translational model for evaluating efficacy of anxiolytic compounds in humans. Several known anxiolytic compounds have been tested as well as several putative anxiolytics. Because results of these studies have been equivocal, the aim of the present study was to examine another pharmacological permutation of the human potentiated startle model by comparing two anxiolytic agents to a non-anxiolytic sedative and placebo. Methods Twenty healthy volunteers participated in a double-blind, placebo-controlled, cross-over study with four sessions in which they received single doses of the anxiolytics alprazolam (1 mg) and pregabalin (200 mg), as well as diphenhydramine (50 mg) as a non-anxiolytic sedative control and placebo. The design included a cued shock condition that presumably evokes fear and an unpredictable shock context condition presumably evoking anxiety. Results None of the treatments reliably reduced either fear- or anxiety-potentiated startle. Alprazolam and diphenhydramine reduced overall baseline startle. Alprazolam was found to only affect contextual anxiety in a statistical significant way after two subjects who failed to show a contextual anxiety effect in the placebo condition were excluded from the analysis. Pregabalin did not significantly affect any of the physiological measures. Discussion The negative findings from this study are discussed in terms of methodological differences between designs and in variability of startle both between and within study participants. Conclusion Even though fear-potentiated startle may be used to translate preclinical evidence to human populations, methodological issues still hamper the application of this model to early screening of putative anxiolytic drugs. PMID:19415242

First Trimester Exposure to Anxiolytic and Hypnotic Drugs and the Risks of Major Congenital Anomalies: A United Kingdom Population-Based Cohort Study

PubMed Central

Ban, Lu; West, Joe; Gibson, Jack E.; Fiaschi, Linda; Sokal, Rachel; Doyle, Pat; Hubbard, Richard; Smeeth, Liam; Tata, Laila J.

2014-01-01

Background Despite their widespread use the effects of taking benzodiazepines and non-benzodiazepine hypnotics during pregnancy on the risk of major congenital anomaly (MCA) are uncertain. The objectives were to estimate absolute and relative risks of MCAs in children exposed to specific anxiolytic and hypnotic drugs taken in the first trimester of pregnancy, compared with children of mothers with depression and/or anxiety but not treated with medication and children of mothers without diagnosed mental illness during pregnancy. Methods We identified singleton children born to women aged 15–45 years between 1990 and 2010 from a large United Kingdom primary care database. We calculated absolute risks of MCAs for children with first trimester exposures of different anxiolytic and hypnotic drugs and used logistic regression with a generalised estimating equation to compare risks adjusted for year of childbirth, maternal age, smoking, body mass index, and socioeconomic status. Results Overall MCA prevalence was 2.7% in 1,159 children of mothers prescribed diazepam, 2.9% in 379 children with temazepam, 2.5% in 406 children with zopiclone, and 2.7% in 19,193 children whose mothers had diagnosed depression and/or anxiety but no first trimester drug exposures. When compared with 2.7% in 351,785 children with no diagnosed depression/anxiety nor medication use, the adjusted odds ratios were 1.02 (99% confidence interval 0.63–1.64) for diazepam, 1.07 (0.49–2.37) for temazepam, 0.96 (0.42–2.20) for zopiclone and 1.27 (0.43–3.75) for other anxiolytic/hypnotic drugs and 1.01 (0.90–1.14) for un-medicated depression/anxiety. Risks of system-specific MCAs were generally similar in children exposed and not exposed to such medications. Conclusions We found no evidence for an increase in MCAs in children exposed to benzodiazepines and non-benzodiazepine hypnotics in the first trimester of pregnancy. These findings suggest that prescription of these drugs during early pregnancy may be safe in terms of MCA risk, but findings from other studies are required before safety can be confirmed. PMID:24963627

Anticonvulsant and antipunishment effects of toluene

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wood, R.W.; Coleman, J.B.; Schuler, R.

1984-01-01

Toluene can have striking acute behavioral effects and is subject to abuse by inhalation. To determine if its actions resemble those of drugs used in the treatment of anxiety (anxiolytics), two sets of experiments were undertaken. Inasmuch as prevention of pentylenetetrazol-induced convulsions is an identifying property of this class of agents, the authors first demonstrated that pretreatment of mice with injections of toluene delayed the onset of convulsive signs and prevented the tonic extension phase of the convulsant activity in a dose-related manner. Injections of another alkyl benzene, m-xylene, were of comparable potency to toluene. Inhalation of toluene delayed themore » time of death after pentylenetetrazol injection in a manner related to the duration and concentration of exposure; at lower convulsant doses, inhalation of moderate concentrations (EC/sub 58/, 1300 ppm) prevented death. Treatment with a benzodiazepine receptor antagonist (Ro 15-1788) failed to reduce the anticonvulsant activity of inhaled toluene. Anxiolytics also attenuate the reduction in response rate produced by punishment with electric shock. Toluene increased rates of responding suppressed by punishment when responding was maintained under a multiple fixed-interval fixed-interval punishment schedule of reinforcement. Distinct antipunishment effects were observed in rats after 2 hr of exposure to 1780 and 3000 ppm of toluene; the rate-increasing effects of toluene were related to concentration and to time after the termination of exposure. Thus, toluene and m-xylene resemble in several respects clinically useful drugs such as the benzodiazepines. 51 references, 3 figures, 2 tables.« less

Montanoa frutescens and Montanoa grandiflora extracts reduce anxiety-like behavior during the metestrus-diestrus phase of the ovarian cycle in Wistar rats.

PubMed

Rodríguez-Landa, Juan Francisco; Vicente-Serna, Julio; Rodríguez-Blanco, Luis Alfredo; Rovirosa-Hernández, María de Jesús; García-Orduña, Francisco; Carro-Juárez, Miguel

2014-01-01

In previous studies, the anxiolytic-like effects of Montanoa tomentosa and Montanoa frutescens were reported in male rats, but the potential anxiolytic-like effects of Montanoa plants during the different phases of the ovarian cycle in rats remain to be explored. The anxiolytic-like effects of the aqueous crude extracts of M. frutescens (25 and 50 mg/kg) and M. grandiflora (25 and 50 mg/kg) in the elevated plus maze were investigated in Wistar rats during the estrous cycle and compared with 2 mg/kg diazepam as a reference anxiolytic drug. To investigate any motor effect (i.e., hyperactivity, no changes, or hypoactivity) associated with the treatments, the rats were evaluated in the open field test. The M. frutescens (25 and 50 mg/kg) and M. grandiflora (50 mg/kg) extracts exerted anxiolytic-like effects during the metestrus-diestrus phase, similar to diazepam, without disrupting spontaneous motor activity. No significant effects of the extracts were detected in either behavioral test during the proestrus-estrus phase, whereas diazepam produced motor hypoactivity in the open field test. These results indicate that the M. frutescens and M. grandiflora extracts possess anxiolytic-like effects that depend on the ovarian cycle phase, supporting the Mexican ancient medicinal use of these plants to ameliorate anxiety disorders.

Montanoa frutescens and Montanoa grandiflora Extracts Reduce Anxiety-Like Behavior during the Metestrus-Diestrus Phase of the Ovarian Cycle in Wistar Rats

PubMed Central

Rodríguez-Landa, Juan Francisco; Vicente-Serna, Julio; Rodríguez-Blanco, Luis Alfredo; Rovirosa-Hernández, María de Jesús; García-Orduña, Francisco; Carro-Juárez, Miguel

2014-01-01

In previous studies, the anxiolytic-like effects of Montanoa tomentosa and Montanoa frutescens were reported in male rats, but the potential anxiolytic-like effects of Montanoa plants during the different phases of the ovarian cycle in rats remain to be explored. The anxiolytic-like effects of the aqueous crude extracts of M. frutescens (25 and 50 mg/kg) and M. grandiflora (25 and 50 mg/kg) in the elevated plus maze were investigated in Wistar rats during the estrous cycle and compared with 2 mg/kg diazepam as a reference anxiolytic drug. To investigate any motor effect (i.e., hyperactivity, no changes, or hypoactivity) associated with the treatments, the rats were evaluated in the open field test. The M. frutescens (25 and 50 mg/kg) and M. grandiflora (50 mg/kg) extracts exerted anxiolytic-like effects during the metestrus-diestrus phase, similar to diazepam, without disrupting spontaneous motor activity. No significant effects of the extracts were detected in either behavioral test during the proestrus-estrus phase, whereas diazepam produced motor hypoactivity in the open field test. These results indicate that the M. frutescens and M. grandiflora extracts possess anxiolytic-like effects that depend on the ovarian cycle phase, supporting the Mexican ancient medicinal use of these plants to ameliorate anxiety disorders. PMID:24800255

Drug Usage in Pilots Involved in Aviation Accidents Compared With Drug Usage in the General Population: From 1990 to 2005

DTIC Science & Technology

2008-04-01

Unclassified 11 Form DOT F 1700.7 (8-72) Reproduction of completed page authorized 1 DRUG USAGE IN PILOTS INVOLVED IN AVIATION ACCIDENTS COMPARED WITH DRUG...0.01% during the examined time period (5192 accidents). Benzodiazepines Psychotherapeutic agents, anxiolytics, sedatives, and hypnotics occurred in

[Effects of noopept and cortexin on the behavior of matured rats treated with corticoliberin or 70-kDa heat shock proteins in early ontogeny].

PubMed

Shabanov, P D; Lebedev, A A; Stetsenko, V P; Lavrov, N V; Sablina, G V; Gudasheva, T A; Ostrovaskaia, R U

2007-01-01

Young Wistar rats aged 4 days were injected intraperitoneally with corticotropin releasing hormone (CRH), which is an agent activating the stress system, or 70-kDa heat shock proteins (HSP-70)--intracellular shaperons, possessing antistress properties. In grown adult rats aged 90-100 days, the effects of nootropic drugs noopept and cortexin (1 mg/kg, i.p.) were assessed. The activation of stress or antistress systems with CRH or HSP-70 significantly altered the drug action. The effects were different in males and females and depended on animal gender. The spectrum of pharmacological activity of noopept and cortexin changed: noopept demonstrated preferable psychoactivating and antiaggressive effects, whereas cortexin showed mild anxiolytic and antidepressant activity. It is suggested that the behavioral effects of nootropes depend on the conditions of the stress system formation in early ontogeny.

Concomitant medication of psychoses in a lifetime perspective.

PubMed

Vares, Maria; Saetre, Peter; Strålin, Pontus; Levander, Sten; Lindström, Eva; Jönsson, Erik G

2011-01-01

Patients treated with antipsychotic drugs often receive concomitant psychotropic compounds. Few studies address this issue from a lifetime perspective. Here, an analysis is presented of the prescription pattern of such concomitant medication from the first contact with psychiatry until the last written note in the case history documents, in patients with a diagnosis of psychotic illness. A retrospective descriptive analysis of all case history data of 66 patients diagnosed with schizophrenia or schizophrenia-like psychotic disorders. Benzodiazepines and benzodiazepine-related anxiolytic drugs had been prescribed to 95% of the patients, other anxiolytics, sedatives or hypnotic drugs to 61%, anti-parkinsonism drugs to 86%, and antidepressants to 56% of the patients. However, lifetime doses were small and most of the time patients had no concomitant medication. The prescribed lifetime dose of anti-parkinsonism drugs was associated with that of prescribed first-generation but not second-generation antipsychotics. Most psychosis patients are sometimes treated with concomitant drugs but mainly over short periods. Lifetime concomitant add-on medication at the individual patient level is variable and complex but not extensive. Copyright © 2011 John Wiley & Sons, Ltd.

Psychotropic drugs in patients with Alzheimer's Disease: a longitudinal study by the Registry of Dementias of Girona (ReDeGi) in Catalonia, Spain.

PubMed

Calvó-Perxas, Laia; Turró-Garriga, Oriol; Aguirregomozcorta, Maria; Bisbe, Josep; Hernández, Erélido; López-Pousa, Secundino; Manzano, Anna; Palacios, Mónica; Pericot-Nierga, Imma; Perkal, Héctor; Ramió, Lluís; Vilalta-Franch, Joan; Garre-Olmo, Josep

2014-07-01

Psychotropic drugs are usually prescribed to deal with behavioral and psychological symptoms of dementia, especially when nonpharmacologic approaches are not available or have limited efficacy. Poor outcomes and serious adverse events of the drugs used must be addressed, and risk-benefit ratios need to be considered. The aim of this longitudinal study was to describe the evolution of dispensation of psychotropic drugs in patients with Alzheimer's disease (AD) and to identify the associated demographic and clinical variables. Longitudinal study using 698 cases with AD included in the Registry of Dementias of Girona in 2007 and 2008 and followed up during 3 years. Drugs were categorized according to the Anatomical Therapeutic Chemical classification. Binary logistic regression analyses were used to detect the variables associated with the use of antipsychotics, selective serotonin reuptake inhibitors (SSRIs), anxiolytics, and hypnotics. Of the patients, 51.2% consumed antipsychotics at least once during the three years of the study, whereas 73.3% and 58.2% consumed SSRIs and anxiolytics, respectively; 32.8% used hypnotics. Antipsychotic use was associated with a diagnosis of AD with delusions) [odds ratio (OR) = 5.7] and with increased behavior disorders (OR = 1.2). Patients with AD with depressed mood were more likely to be treated with SSRIs (OR = 3.1), while being a woman was associated with increased dispensation of anxiolytics (OR = 1.9) and SSRIs (OR = 2.2). Consumption of psychotropic drugs by the patients with AD registered in the Registry of Dementias of Girona is very high. Despite all the described adverse effects and recommendations of caution in their use, antipsychotics still are extensively used. Copyright © 2014 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.

GABAergic anxiolytic drug in water increases migration behaviour in salmon

NASA Astrophysics Data System (ADS)

Hellström, Gustav; Klaminder, Jonatan; Finn, Fia; Persson, Lo; Alanärä, Anders; Jonsson, Micael; Fick, Jerker; Brodin, Tomas

2016-12-01

Migration is an important life-history event in a wide range of taxa, yet many migrations are influenced by anthropogenic change. Although migration dynamics are extensively studied, the potential effects of environmental contaminants on migratory physiology are poorly understood. In this study we show that an anxiolytic drug in water can promote downward migratory behaviour of Atlantic salmon (Salmo salar) in both laboratory setting and in a natural river tributary. Exposing salmon smolt to a dilute concentration of a GABAA receptor agonist (oxazepam) increased migration intensity compared with untreated smolt. These results implicate that salmon migration may be affected by human-induced changes in water chemical properties, such as acidification and pharmaceutical residues in wastewater effluent, via alterations in the GABAA receptor function.

Anxiolytic-like effect of inhalation of essential oil from Lavandula officinalis: investigation of changes in 5-HT turnover and involvement of olfactory stimulation.

PubMed

Takahashi, Mizuho; Yamanaka, Ayako; Asanuma, Chihiro; Asano, Hiroko; Satou, Tadaaki; Koike, Kazuo

2014-07-01

Essential oil extracted from Lavandula officinalis (LvEO) has a long history of usage in anxiety alleviation with good evidence to support its use. However, findings and information regarding the exact pathway involved and mechanism of action remain inconclusive. Therefore, we aimed to (1) reveal the influence of olfactory stimulation, and (2) determine whether the serotonergic system is involved in the anxiolytic effect of LvEO when it is inhaled. To this end, we first compared the anxiety-related behaviors of normosmic and anosmic mice. LvEO inhalation caused notable elevation in anxiety-related parameters with or without olfactory perception, indicating that olfactory stimulation is not necessarily required for LvEO to be effective. Neurochemical analysis of the serotonin (5-HT) turnover rate, accompanied by EPM testing, was then performed. LvEO significantly increased the striatal and hippocampal levels of 5-HT and decreased turnover rates in accordance with the anxiolytic behavioral changes. These results, together with previous findings, support the hypothesis that serotonergic neurotransmission plays a certain role in the anxiolytic properties of LvEO.

Anxiolytic effects of repeated treatment with an essential oil from Lippia alba and (R)-(-)-carvone in the elevated T-maze.

PubMed

Hatano, V Y; Torricelli, A S; Giassi, A C C; Coslope, L A; Viana, M B

2012-03-01

Lippia alba (Mill.) N.E. Brown (Verbenaceae) is widely used in different regions of Central and South America as a tranquilizer. The plant's anxiolytic properties, however, merit investigation. The present study evaluated the effects of repeated daily (14 days) intraperitoneal (ip) treatment with an essential oil (EO) from a chemotype of L. alba (LA, chemotype II, 12.5 and 25 mg/kg; N = 6-8) and (R)-(-)-carvone (25 mg/kg; N = 8-12), the main constituent of this chemotype, on male Wistar rats (weighing 250 g at the beginning of the experiments) submitted to the elevated T-maze (ETM). The ETM allows the measurement of two defensive responses: inhibitory avoidance and one-way escape. In terms of psychopathology, these responses have been related to generalized anxiety and panic disorder, respectively. Treatment with the EO impaired ETM avoidance latencies, without altering escape, in a way similar to the reference drug diazepam (P < 0.05) (avoidance 2: control = 84.6 ± 35.2; EO 12.5 mg/kg = 11.8 ± 3.8; EO 25 mg/kg = 14.6 ± 2.7; diazepam = 7 ± 2.1). (R)-(-)-carvone also significantly altered this same response (P < 0.05; avoidance 1: control = 91.9 ± 31.5; carvone = 11.6 ± 1.8; diazepam = 8.1 ± 3.3). These results were not due to motor changes since no significant effects were detected in an open field. These observations suggest that LA exerts anxiolytic-like effects on a specific subset of defensive behaviors that have been implicated in generalized anxiety disorder, and suggest that carvone is one of the constituents of LA responsible for its action as a tranquilizer.

Anxiolytic effects of repeated treatment with an essential oil from Lippia alba and (R)-(-)-carvone in the elevated T-maze

PubMed Central

Hatano, V.Y.; Torricelli, A.S.; Giassi, A.C.C.; Coslope, L.A.; Viana, M.B.

2012-01-01

Lippia alba (Mill.) N.E. Brown (Verbenaceae) is widely used in different regions of Central and South America as a tranquilizer. The plant's anxiolytic properties, however, merit investigation. The present study evaluated the effects of repeated daily (14 days) intraperitoneal (ip) treatment with an essential oil (EO) from a chemotype of L. alba (LA, chemotype II, 12.5 and 25 mg/kg; N = 6-8) and (R)-(-)-carvone (25 mg/kg; N = 8-12), the main constituent of this chemotype, on male Wistar rats (weighing 250 g at the beginning of the experiments) submitted to the elevated T-maze (ETM). The ETM allows the measurement of two defensive responses: inhibitory avoidance and one-way escape. In terms of psychopathology, these responses have been related to generalized anxiety and panic disorder, respectively. Treatment with the EO impaired ETM avoidance latencies, without altering escape, in a way similar to the reference drug diazepam (P < 0.05) (avoidance 2: control = 84.6 ± 35.2; EO 12.5 mg/kg = 11.8 ± 3.8; EO 25 mg/kg = 14.6 ± 2.7; diazepam = 7 ± 2.1). (R)-(-)-carvone also significantly altered this same response (P < 0.05; avoidance 1: control = 91.9 ± 31.5; carvone = 11.6 ± 1.8; diazepam = 8.1 ± 3.3). These results were not due to motor changes since no significant effects were detected in an open field. These observations suggest that LA exerts anxiolytic-like effects on a specific subset of defensive behaviors that have been implicated in generalized anxiety disorder, and suggest that carvone is one of the constituents of LA responsible for its action as a tranquilizer. PMID:22358424

Anxiolytic activity of Nymphaea alba Linn. in mice as experimental models of anxiety

PubMed Central

Thippeswamy, B.S.; Mishra, Brijesh; Veerapur, V.P.; Gupta, Gourav

2011-01-01

Objective: The aim of the present work was to evaluate the anxiolytic effect of an ethanolic extract of Nymphaea alba Linn. in mice. Materials and Methods: The elevated plus maze test (EPMT), light and dark test (L and DT) and open field test (OFT) were used to assess the anxiolytic activity of the ethanolic extract of N. alba Linn. in mice. In addition, aggressive behavior and motor coordination was also assessed by foot shock induced aggression test (FSIAT) and rota rod test (RRT). Diazepam 1 mg/kg served as a standard anxiolytic drug, administered orally. Results: The ethanolic extract of N. alba (100 and 200 mg/kg, p.o.) significantly increased the percentage of time spent and number of entries in open arm in EPMT. In L and DT, the extract produced significant increase in time spent, number of crossing and decrease in the duration of immobility in light box. In OFT, the extract showed significant increase in number of rearings, assisted rearings and number of square crossed, all of which are demonstrations of exploratory behavior. In FSIAT, N. alba extract attenuated aggressive behavior related to anxiolytic activity, such as number of vocalization, leaps, rearing, biting/attacks and facing each other in paired mice. Furthermore, the extract produced skeletal muscle relaxant effect assessed by RRT. Conclusion: The results of the present study suggest that an ethanolic extract of N. alba may possess anxiolytic activity and provide a scientific evidence for its traditional claim. PMID:21455422

Anxiolytic property of hydro-alcohol extract of Lactuca sativa and its effect on behavioral activities of mice.

PubMed

Harsha, Singapura Nagesh; Anilakumar, Kandangath Raghavan

2013-01-01

Lactuca sativa, belonging to the Asteraceae family, is a leafy vegetable known for its medicinal properties. This study aimed to understand the mechanism of Lactuca sativa extract with respect to pharmacological action.We investigated the anxiolytic effects of hydro-alcoholic extract of leaves of Lactuca sativa on mice. The behavioral tests performed on mice models to assess anti-anxiety properties were: open field test (OFT), elevated plus maze test (EPM), elevated T maze test, and marble burying test. Increased locomotor activity and time spent in the "open-arm" were observed in extract fed group. Malondialdehyde (MDA) and nitrite levels were decreased, catalase and glutathione levels were increased in Lactuca sativa treated mice. The data obtained in the present study suggests that the extract of Lactuca sativa can afford significant protection against anxiolytic activity.

Anxiolytic-like effect of Shigyakusan extract with low side effects in mice.

PubMed

Tanaka, Machiko; Satou, Tadaaki; Koike, Kazuo

2013-10-01

Shigyakusan is a traditional Japanese herbal (Kampo) medicine used to treat inflammatory conditions such as cholecystitis and gastritis as well as psychiatric disorders. This study examined the anxiolytic-like effect of Shigyakusan extract (SS), and evaluated the activity of the main compound. Three behavioral tests in mice were used to evaluate the activity of SS. Samples were administered orally over a 10-day period. A light and dark box (LDB) test was performed on the 8th day, while an open field (OF) test was done on the 9th day, and an elevated plus maze (EPM) test was performed on the 10th day. Diazepam (DZ), a typical anxiolytic drug, was used as the positive control. Administration of 10 mg/kg DZ resulted in a significant anxiolytic-like effect in the LDB and EPM tests, while administration of 0.3 g/kg SS resulted in a weak anxiolytic-like effect. In the OF test, while DZ caused a significant reduction of locomotor activity, SS did not cause any changes compared to the water controls. This suggests that locomotor activity may be a side effect of DZ, and thus SS, which lacks this response, may be a more useful treatment. Quantitative analysis performed to clarify the activity of the main compound also determined that SS contained 51.4 mg/g naringin, which also has been reported to have anxiolytic-like activity. Since these results suggested that this compound might be responsible for the activity of SS, we subsequently examined the oral administration of a similar dose of naringin. Although we observed a tendency for a weak anxiolytic-like effect, this effect was not greater than that seen for SS.

Effects of repeated asenapine in a battery of tests for anxiety-like behaviours in mice.

PubMed

Ene, Hila M; Kara, Nirit Z; Barak, Noa; Reshef Ben-Mordechai, Tal; Einat, Haim

2016-04-01

A number of atypical antipsychotic drugs were demonstrated to have anxiolytic effects in patients and in animal models. These effects were mostly suggested to be the consequence of the drugs' affinity to the serotonin system and its receptors. Asenapine is a relatively new atypical antipsychotic that is prescribed for schizophrenia and for bipolar mania. Asenapine has a broad pharmacological profile with significant effects on serotonergic receptors, hence it is reasonable to expect that asenapine may have some anxiolytic effects. The present study was therefore designed to examine possible effects of asenapine on anxiety-like behaviour of mice. Male ICR mice were repeatedly treated with 0.1 or 0.3 mg/kg injections of asenapine and then tested in a battery of behavioural tests related to anxiety including the open-field test, elevated plus-maze (EPM), defensive marble burying and hyponeophagia tests. In an adjunct experiment, we tested the effects of acute diazepam in the same test battery. The results show that diazepam reduced anxiety-like behaviour in the EPM, the defensive marble burying test and the hyponeophagia test but not in the open field. Asenapine has anxiolytic-like effects in the EPM and the defensive marble burying tests but had no effects in the open-field or the hyponeophagia tests. Asenapine had no effects on locomotor activity. The results suggest that asenapine may have anxiolytic-like properties and recommends that clinical trials examining such effects should be performed.

Anxiolytic-like effect of Sonchus oleraceus L. in mice.

PubMed

Cardoso Vilela, Fabiana; Soncini, Roseli; Giusti-Paiva, Alexandre

2009-07-15

Sonchus oleraceus L. has been used as a general tonic in Brazilian folk medicine. Nevertheless, available scientific information regarding this species is scarce; there are no reports related to its possible effect on the central nervous system. This study was conducted to establish the anxiolytic effect of extracts from the aerial parts of Sonchus oleraceus. This study evaluated the effect of hydroethanolic and dichloromethane extracts of Sonchus oleraceus in mice submitted to the elevated plus-maze and open-field tests. Clonazepam was used as the standard drug. In the elevated plus-maze test, the Sonchus oleraceus extracts increased the percentage of open arm entries (P<0.05) and time spent in the open-arm portions of the maze (P<0.05). The extracts induce an anti-thigmotactic effect, evidenced by increased locomotor activity into the central part of the open field set-up (P<0.05). The extracts administered at 30-300 mg/kg, p.o. had a similar anxiolytic effect to clonazepam (0.5 mg/kg, p.o.). These data indicate that Sonchus oleraceus extract exerts an anxiolytic-like effect on mice.

Is chlordiazepoxide the rational choice among benzodiazepines?

PubMed

Baskin, S I; Esdale, A

1982-01-01

Diazepam is frequently the subject of review by various agencies and institutions charged with determining whether or not to substitute another, more economical drug--in most instances, chlordiazepoxide. A review of the comparative literature has shown that, on clinical and pharmacokinetic grounds, chlordiazepoxide is not the drug of choice for all clinical indications recommended for the benzodiazepines as a class, particularly for use as an antianxiety agent. There is evidence that the antianxiety effect of chlordiazepoxide is related to the appearance of its two active metabolites, which may explain the observed delay in its onset of action. When chlordiazepoxide's reduced clearance in the elderly and in patients with liver disease is considered along with its limited range of indications, substitution of diazepam with chlordiazepoxide is clearly not reasonable. Diazepam and lorazepam are preferred choices in acute anxiety because they are themselves active anxiolytics. Oxazepam is recommended in alcoholic cirrhotics because its plasma clearance does not seem to be significantly affected by liver disease. Diazepam is recommended for chronic anxiety because of the rapid onset of action of diazepam itself and the smooth transition to the nondrug state via its longer-acting active metabolite.

The antidepressant- and anxiolytic-like effects following co-treatment with escitalopram and risperidone in rats.

PubMed

Kaminska, K; Rogoz, Z

2016-06-01

Several clinical reports have documented a beneficial effect of the addition of a low dose of risperidone to the ongoing treatment with antidepressants, in particular selective serotonin reuptake inhibitors (SSRI), in the treatment of drug-resistant depression and treatment-resistant anxiety disorders. In the present study, we investigated the effect of treatment with the antidepressant escitalopram (SSRI) given separately or jointly with a low dose of risperidone (an atypical antipsychotic) in the forced swim test and in the elevated plus-maze test in rats. The obtained results showed that escitalopram at doses of 2.5 or 5 mg/kg evoked antidepressant-like effect in the forced swim test. Moreover, risperidone at low doses (0.05 or 0.1 mg/kg) enhanced the antidepressant-like activity of escitalopram (1 mg/kg) in this test by increasing the swimming time and decreasing the immobility time in those animals. WAY 100635 (a serotonin 5-HT1A receptor antagonist) at a dose of 0.1 mg/kg abolished the antidepressant-like effect induced by co-administration of escitalopram and risperidone. The active behavior in that test did not reflect an increase in general activity, since the combined treatment with escitalopram and risperidone failed to enhance the exploratory activity of rats. In the following experiment, we showed that escitalopram (5 mg/kg) and mirtazapine (5 or 10 mg/kg) or risperidone (0.1 mg/kg) induced an anxiolytic-like effect in the elevated plus-maze test, and the combined treatment with an ineffective dose of risperidone (0.05 mg/kg) enhanced the anxiolytic-like effects of escitalopram (2.5 mg/kg) or mirtazapine (1 and 2.5 mg/kg) in this test. The obtained results suggest that risperidone applied at a low dose enhances the antidepressant-like activity of escitalopram in the forced swim test, and that 5-HT1A receptors may play some role in these effects. Moreover, a low dose of risperidone may also enhance the anxiolytic-like action of the studied antidepressants.

Anxiolytic property of hydro-alcohol extract of Lactuca sativa and its effect on behavioral activities of mice

PubMed Central

Harsha, Singapura Nagesh; Anilakumar, Kandangath Raghavan

2013-01-01

Lactuca sativa, belonging to the Asteraceae family, is a leafy vegetable known for its medicinal properties. This study aimed to understand the mechanism of Lactuca sativa extract with respect to pharmacological action.We investigated the anxiolytic effects of hydro-alcoholic extract of leaves of Lactuca sativa on mice. The behavioral tests performed on mice models to assess anti-anxiety properties were: open field test (OFT), elevated plus maze test (EPM), elevated T maze test, and marble burying test. Increased locomotor activity and time spent in the “open-arm” were observed in extract fed group. Malondialdehyde (MDA) and nitrite levels were decreased, catalase and glutathione levels were increased in Lactuca sativa treated mice. The data obtained in the present study suggests that the extract of Lactuca sativa can afford significant protection against anxiolytic activity. PMID:23554792

Exposure to benzodiazepines (anxiolytics, hypnotics and related drugs) in seven European electronic healthcare databases: a cross-national descriptive study from the PROTECT-EU Project.

PubMed

Huerta, Consuelo; Abbing-Karahagopian, Victoria; Requena, Gema; Oliva, Belén; Alvarez, Yolanda; Gardarsdottir, Helga; Miret, Montserrat; Schneider, Cornelia; Gil, Miguel; Souverein, Patrick C; De Bruin, Marie L; Slattery, Jim; De Groot, Mark C H; Hesse, Ulrik; Rottenkolber, Marietta; Schmiedl, Sven; Montero, Dolores; Bate, Andrew; Ruigomez, Ana; García-Rodríguez, Luis Alberto; Johansson, Saga; de Vries, Frank; Schlienger, Raymond G; Reynolds, Robert F; Klungel, Olaf H; de Abajo, Francisco José

2016-03-01

Studies on drug utilization usually do not allow direct cross-national comparisons because of differences in the respective applied methods. This study aimed to compare time trends in BZDs prescribing by applying a common protocol and analyses plan in seven European electronic healthcare databases. Crude and standardized prevalence rates of drug prescribing from 2001-2009 were calculated in databases from Spain, United Kingdon (UK), The Netherlands, Germany and Denmark. Prevalence was stratified by age, sex, BZD type [(using ATC codes), i.e. BZD-anxiolytics BZD-hypnotics, BZD-related drugs and clomethiazole], indication and number of prescription. Crude prevalence rates of BZDs prescribing ranged from 570 to 1700 per 10,000 person-years over the study period. Standardization by age and sex did not substantially change the differences. Standardized prevalence rates increased in the Spanish (+13%) and UK databases (+2% and +8%) over the study period, while they decreased in the Dutch databases (-4% and -22%), the German (-12%) and Danish (-26%) database. Prevalence of anxiolytics outweighed that of hypnotics in the Spanish, Dutch and Bavarian databases, but the reverse was shown in the UK and Danish databases. Prevalence rates consistently increased with age and were two-fold higher in women than in men in all databases. A median of 18% of users received 10 or more prescriptions in 2008. Although similar methods were applied, the prevalence of BZD prescribing varied considerably across different populations. Clinical factors related to BZDs and characteristics of the databases may explain these differences. Copyright © 2015 John Wiley & Sons, Ltd.

Chronic sazetidine-A maintains anxiolytic effects and slower weight gain following chronic nicotine without maintaining increased density of nicotinic receptors in rodent brain.

PubMed

Hussmann, G Patrick; DeDominicis, Kristen E; Turner, Jill R; Yasuda, Robert P; Klehm, Jacquelyn; Forcelli, Patrick A; Xiao, Yingxian; Richardson, Janell R; Sahibzada, Niaz; Wolfe, Barry B; Lindstrom, Jon; Blendy, Julie A; Kellar, Kenneth J

2014-05-01

Chronic nicotine administration increases the density of brain α4β2* nicotinic acetylcholine receptors (nAChRs), which may contribute to nicotine addiction by exacerbating withdrawal symptoms associated with smoking cessation. Varenicline, a smoking cessation drug, also increases these receptors in rodent brain. The maintenance of this increase by varenicline as well as nicotine replacement may contribute to the high rate of relapse during the first year after smoking cessation. Recently, we found that sazetidine-A (saz-A), a potent partial agonist that desensitizes α4β2* nAChRs, does not increase the density of these receptors in brain at doses that decrease nicotine self-administration, increase attention in rats, and produce anxiolytic effects in mice. Here, we investigated whether chronic saz-A and varenicline maintain the density of nAChRs after their up-regulation by nicotine. In addition, we examined the effects of these drugs on a measure of anxiety in mice and weight gain in rats. After increasing nAChRs in the rodent brain with chronic nicotine, replacing nicotine with chronic varenicline maintained the increased nAChR binding, as well as the α4β2 subunit proteins measured by western blots. In contrast, replacing nicotine treatments with chronic saz-A resulted in the return of the density of nAChRs to the levels seen in saline controls. Nicotine, saz-A and varenicline each demonstrated anxiolytic effects in mice, but only saz-A and nicotine attenuated the gain of weight over a 6-week period in rats. These findings suggest that apart from its modest anxiolytic and weight control effects, saz-A, or drugs like it, may be useful in achieving long-term abstinence from smoking. © 2014 International Society for Neurochemistry.

Modulation of CYPs, P-gp, and PXR by Eschscholzia californica (California poppy) and its alkaloids

USDA-ARS?s Scientific Manuscript database

Eschscholzia californica Cham., a native US plant, is traditionally used as a sedative, analgesic and anxiolytic herb. With the rapid rise in the use of herbal supplements together with over the counter (OTC) and prescription drugs, the risk for potential herb-drug interactions is also increasing. M...

An HDAC-dependent epigenetic mechanism that enhances the efficacy of the antidepressant drug fluoxetine

PubMed Central

Schmauss, C.

2015-01-01

Depression is a prevalent and debilitating psychiatric illnesses. However, currently prescribed antidepressant drugs are only efficacious in a limited group of patients. Studies on Balb/c mice suggested that histone deacetylase (HDAC) inhibition may enhance the efficacy of the widely-prescribed antidepressant drug fluoxetine. This study shows that reducing HDAC activity in fluoxetine-treated Balb/c mice leads to robust antidepressant and anxiolytic effects. While reducing the activity of class I HDACs 1 and 3 led to antidepressant effects, additional class II HDAC inhibition was necessary to exert anxiolytic effects. In fluoxetine-treated mice, HDAC inhibitors increased enrichment of acetylated histone H4 protein and RNA polymerase II at promotor 3 of the brain-derived neurotrophic factor (Bdnf) gene and increased Bdnf transcription from this promotor. Reducing Bdnf-stimulated tropomyosin kinase B receptor activation in fluoxetine-treated mice with low HDAC activity abolished the behavioral effects of fluoxetine, suggesting that the HDAC-triggered epigenetic stimulation of Bdnf expression is critical for therapeutic efficacy. PMID:25639887

Cognition, emotion, and the alcohol--aggression relationship: comment on Giancola (2000).

PubMed

Lyvers, M

2000-11-01

P. R. Giancola's (2000) thesis that the alcohol-aggression relationship can be explained by alcohol-induced disruption of executive cognitive functions mediated by the prefrontal cortex is critically examined. At moderate doses, alcohol has been reported to increase aggression in animals as diverse as fish, rats, cats, monkeys, and humans. Although alcohol depresses prefrontal cortex activity and disrupts executive cognitive performance in humans, alcohol's anxiolytic actions, and its disinhibiting effects on subcortical structures implicated in anger and aggression, may be at least as important as the higher cognitive functions cited by Giancola in accounting for the alcohol-aggression relationship. Other drugs that alter prefrontal cortex activity have also been reported to influence aggressive responding in humans and other animals, and implications of this are briefly discussed.

Antidepressant and anxiolytic properties of the methanolic extract of Momordica charantia Linn (Cucurbitaceae) and its mechanism of action.

PubMed

Ishola, I O; Akinyede, A A; Sholarin, A M

2014-07-01

The whole plant of Momordica charantia Linn (Cucurbitaceae) is used in traditional African medicine in the management of depressive illness. Momordica charantia (MC) (50-400 mg/kg, p.o.) was administered 1 h before behavioural studies using the forced swimming test (FST) and tail suspension test (TST) to investigate antidepressant-like effect while the anxiolytic-like effect was evaluated with elevated plus maze test (EPM), hole-board test (HBT), and light-dark test (LDT). Acute treatment with MC (50-400 mg/kg) significantly increased swimming time (86.51%) and reduced the duration of immobility (52.35%) in FST and TST with peak effects observed at 200 mg/kg, respectively, in comparison to control. The pretreatment of mice with either sulpiride (dopamine D2 receptor antagonist), or metergoline (5-HT2 receptor antagonist), or cyproheptadine (5-HT2 receptor antagonist), or prazosin (α1-adrenoceptor antagonist), or yohimbine (α2-adrenoceptor antagonist), and atropine (muscarinic cholinergic receptor antagonist) 15 min before oral administration of MC (200 mg/kg) significantly blocked its anti-immobility effect. Similarly, MC (200 mg/kg) significantly reduced anxiety by increasing the open arm exploration (64.27%) in EPM, number of head-dips in HBT (34.38%), and time spent in light compartment (29.38%) in the LDT. However, pretreatment with flumazenil (GABAA receptor antagonist) 15 min before MC (200 mg/kg) significantly blocked (54.76%) its anxiolytic effect. The findings in this study showed that MC possesses antidepressant-like effect that is dependent on the serotonergic (5-HT2 receptor), noradrenergic (α1- and α2-adrenoceptors), dopaminergic (D2 receptor), and muscarinic cholinergic systems and an anxiolytic-like effect that might involve an action on benzodiazepine-type receptor. © Georg Thieme Verlag KG Stuttgart · New York.

Anxiolytic effect of saponins from Panax quinquefolium in mice.

PubMed

Wei, Xiu-Yan; Yang, Jing-Yu; Wang, Jin-Hui; Wu, Chun-Fu

2007-05-22

The anxiolytic effect of the saponins from Aniliaeea Panax quinquefolium L. (PQS) was studied in male mice by using a number of experimental paradigms of anxiety and compared with that of the known anxiolytic compound diazepam. Use of the elevated plus-maze test revealed that PQS (50 mg/kg, p.o.) and diazepam (2.5 mg/kg, p.o.) increased the percentage of time and entries spent in open arms. In the light/dark test, PQS (50 and 100 mg/kg, p.o.) and diazepam (2.5 mg/kg, p.o.) prolonged the time spent in the light area. In the hole-board test, PQS (50 and 100 mg/kg, p.o.) and diazepam (2.5 mg/kg, p.o.) significantly increased both head-dip counts and head-dip duration. Both PQS (50 and 100 mg/kg, p.o.) and diazepam (2.5 mg/kg, p.o.) decreased the total fighting time in the isolation-induced aggressive test. Since PQS, in contrast to diazepam, had no effect on locomotion in these tests, its side-effect profile might be considered superior to the benzodiazepines. Thus, the present findings suggest that PQS might be a potential candidate for use as an anxiolytic drug.

Anxiolytic- and antidepressant-like effects of an aqueous extract of Tanacetum parthenium L. Schultz-Bip (Asteraceae) in mice.

PubMed

Cárdenas, Jorge; Reyes-Pérez, Valeria; Hernández-Navarro, María Dolores; Dorantes-Barrón, Ana María; Almazán, Salvador; Estrada-Reyes, Rosa

2017-03-22

Tanacetum parthenium L. Schultz-Bip (Asteraceae) is widely used worldwide in traditional medicine for the treatment of convulsions and culture-bound syndromes such as susto (fear). The aim of this work was to evaluate the anxiolytic- and antidepressant-like effects of an aqueous extract of T. parthenium in behavioral paradigms in mice. The effects of T. parthenium were compared with those produced by anxiolytic and antidepressant drugs. We carried out the chemical characterization of the main constituents of T. parthenium. The involvement with the GABAergic and serotoninergic neurotransmitter systems were explored be means of synergic and antagonist experiments. The anxiolytic-like effect was evaluated using the Burying Behavior Test (BBT) and the Elevated Plus-Maze Test (PMT). The antidepressant-like effect was evaluated in the Forced Swimming Test (FST), and ambulatory activity was assessed in the Open Field Test (OFT). Employing the behavioral tests, synergism and antagonism experiments with Alprazolam, Muscimol, and Picrotoxin were carried out in the PMT. In a series of independent experiments, concomitant administration of T. parthenium and Alprazolam, Fluoxetine, or p-chlorophenylalanine were conducted in the FST. For chemical characterization, High-Performance Liquid Chromatography-Electro Spray Ionization-Mass Spectrometry (HPLC-ESI-MS) analysis was performed. T. parthenium exerts clear anxiolytic- and antidepressant-like effects in mice, without affecting the ambulatory activity of the experimental subjects. Anxiolytic- and antidepressant-like T. parthenium effects result, at least part from the involvement of the GABAergic system. Our results support the use of Tanacetum parthenium in traditional medicine and suggest its therapeutic potential in the comorbid anxiety and depression. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Antidepressant, anxiolytic and procognitive effects of subacute and chronic ketamine in the chronic mild stress model of depression.

PubMed

Papp, Mariusz; Gruca, Piotr; Lason-Tyburkiewicz, Magdalena; Willner, Paul

2017-02-01

Ketamine is the prototype of a new generation of antidepressant drugs, which is reported in clinical studies to be effective in treatment-resistant patients, with an effect that appears within hours and lasts for a few days. Chronic mild stress (CMS) is a well-established and widely used animal model of depression, in which anhedonia, anxiogenesis and cognitive dysfunction can be observed reliably. Studies using acute or brief ketamine treatment following withdrawal from CMS have replicated the clinical finding of a rapid onset of antidepressant action. However, there have been no CMS studies of chronic daily ketamine treatment or continued stress following ketamine treatment, which would have greater translational potential in relation to the long-term maintenance of antidepressant effects. Wistar rats were drug treated following an initial 2 weeks of CMS exposure, which continued alongside daily drug treatment. A first experiment tested a range of chronic (5 weeks) ketamine doses (5-30 mg/kg); a second compared the effects of subacute (3-5 days) and chronic (5 weeks) treatment. CMS-induced anhedonic, anxiogenic and dyscognitive effects, as measured, respectively, by decreased sucrose intake, avoidance of open arms in the elevated plus maze and loss of discrimination in the novel object recognition test. A sustained antidepressant-like effect of ketamine in the sucrose intake test was observed in both experiments, with an onset at around 1 week, faster than imipramine, and an optimum dose of 10 mg/kg. Anxiogenic and dyscognitive effects of CMS, in the elevated plus maze and novel object recognition test, respectively, were fully reversed by both subacute and chronic ketamine treatment. Daily treatment with ketamine in the CMS model causes sustained long-term antidepressant, anxiolytic and procognitive effects. The demonstration of a procognitive effect of ketamine may have particular translational value.

Functional expression of the GABAA receptor α2 and α3 subunits at synapses between intercalated medial paracapsular neurons of mouse amygdala

PubMed Central

Geracitano, Raffaella; Fischer, David; Kasugai, Yu; Ferraguti, Francesco; Capogna, Marco

2012-01-01

In the amygdala, GABAergic neurons in the intercalated medial paracapsular cluster (Imp) have been suggested to play a key role in fear learning and extinction. These neurons project to the central (CE) amygdaloid nucleus and to other areas within and outside the amygdala. In addition, they give rise to local collaterals that innervate other neurons in the Imp. Several drugs, including benzodiazepines (BZ), are allosteric modulators of GABAA receptors. BZ has both anxiolytic and sedative actions, which are mediated through GABAA receptors containing α2/α3 and α1 subunits, respectively. To establish whether α1 or α2/α3 subunits are expressed at Imp cell synapses, we used paired recordings of anatomically identified Imp neurons and high resolution immunocytochemistry in the mouse. We observed that a selective α3 subunit agonist, TP003 (100 nM), significantly increased the decay time constant of the unitary IPSCs. A similar effect was also induced by zolpidem (10 μM) or by diazepam (1 μM). In contrast, lower doses of zolpidem (0.1–1 μM) did not significantly alter the kinetics of the unitary IPSCs. Accordingly, immunocytochemical experiments established that the α2 and α3, but not the α1 subunits of the GABAA receptors, were present at Imp cell synapses of the mouse amygdala. These results define, for the first time, some of the functional GABAA receptor subunits expressed at synapses of Imp cells. The data also provide an additional rationale to prompt the search of GABAA receptor α3 selective ligands as improved anxiolytic drugs. PMID:22666188

Amygdala Lesions Reduce Anxiety-like Behavior in a Human Benzodiazepine-Sensitive Approach-Avoidance Conflict Test.

PubMed

Korn, Christoph W; Vunder, Johanna; Miró, Júlia; Fuentemilla, Lluís; Hurlemann, Rene; Bach, Dominik R

2017-10-01

Rodent approach-avoidance conflict tests are common preclinical models of human anxiety disorder. Their translational validity mainly rests on the observation that anxiolytic drugs reduce rodent anxiety-like behavior. Here, we capitalized on a recently developed approach-avoidance conflict computer game to investigate the impact of benzodiazepines and of amygdala lesions on putative human anxiety-like behavior. In successive epochs of this game, participants collect monetary tokens on a spatial grid while under threat of virtual predation. In a preregistered, randomized, double-blind, placebo-controlled trial, we tested the effect of a single dose (1 mg) of lorazepam (n = 59). We then compared 2 patients with bilateral amygdala lesions due to Urbach-Wiethe syndrome with age- and gender-matched control participants (n = 17). Based on a previous report, the primary outcome measure was the effect of intra-epoch time (i.e., an adaptation to increasing potential loss) on presence in the safe quadrant of the spatial grid. We hypothesized reduced loss adaptation in this measure under lorazepam and in patients with amygdala lesions. Lorazepam and amygdala lesions reduced loss adaptation in the primary outcome measure. We found similar results in several secondary outcome measures. The relative reduction of anxiety-like behavior in patients with amygdala lesions was qualitatively and quantitatively indistinguishable from an impact of anterior hippocampus lesions found in a previous report. Our results establish the translational validity of human approach-avoidance conflict tests in terms of anxiolytic drug action. We identified the amygdala, in addition to the hippocampus, as a critical structure in human anxiety-like behavior. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Respiratory and mental health effects of wildfires: an ecological study in Galician municipalities (north-west Spain).

PubMed

Caamano-Isorna, Francisco; Figueiras, Adolfo; Sastre, Isabel; Montes-Martínez, Agustín; Taracido, Margarita; Piñeiro-Lamas, María

2011-05-21

During the summer of 2006, a wave of wildfires struck Galicia (north-west Spain), giving rise to a disaster situation in which a great deal of the territory was destroyed. Unlike other occasions, the wildfires in this case also threatened farms, houses and even human lives, with the result that the perception of disaster and helplessness was the most acute experienced in recent years. This study sought to analyse the respiratory and mental health effects of the August-2006 fires, using consumption of anxiolytics-hypnotics and drugs for obstructive airway diseases as indicators. We conducted an analytical, ecological geographical- and temporal-cluster study, using municipality-month as the study unit. The independent variable was exposure to wildfires in August 2006, with municipalities thus being classified into the following three categories: no exposure; medium exposure; and high exposure. Dependent variables were: (1) anxiolytics-hypnotics; and (2) drugs for obstructive airway diseases consumption. These variables were calculated for the two 12-month periods before and after August 2006. Additive models for time series were used for statistical analysis purposes. The results revealed a higher consumption of drugs for obstructive airway diseases among pensioners during the months following the wildfires, in municipalities affected versus those unaffected by fire. In terms of consumption of anxiolytics-hypnotics, the results showed a significant increase among men among men overall -pensioners and non-pensioners- in fire-affected municipalities. Our study indicates that wildfires have a significant effect on population health. The coherence of these results suggests that drug utilisation research is a useful tool for studying morbidity associated with environmental incidents.

Comparison of Psychotropic Drug Prescribing Quality between Zagreb, Croatia and Sarajevo, B&H.

PubMed

Polić-Vižintin, Marina; Štimac, Danijela; Čatić, Tarik; Šostar, Zvonimir; Zelić, Ana; Živković, Krešimir; Draganić, Pero

2014-12-01

The purpose of this paper was to compare outpatient consumption and quality of psychotropic drug prescribing between Croatia and Bosnia & Herzegovina 2006-2010. Data on drug utilization from Zagreb Municipal Pharmacy and Sarajevo Public Pharmacy were used to calculate the number of defined daily doses (DDD) and DDD per 1000 inhabitants per day (DDD/TID) using the WHO Anatomical-Therapeutic-Chemical methodology. Total utilization of psychopharmaceuticals increased in both cities; however, it was higher in Zagreb than in Sarajevo throughout the study period. The utilization of psycholeptics increased in Zagreb by 2.4% (from 74.5 to 76.3 DDD/TID) and in Sarajevo by 3.8% (from 62.4 to 64.8 DDD/TID). The utilization of anxiolytics decreased in Zagreb by 2.1% and in Sarajevo by even 18.7%. The utilization of antidepressants increased in both cities with predominance of SSRI over TCA utilization, greater in Sarajevo (96.6%) than in Zagreb (10.2%). The anxiolytic/antidepressant ratio decreased by 11.1% in Zagreb (from 2.87 to 2.55) and by 58.7% in Sarajevo (from 5.66 to 2.34). Outpatient utilization of antipsychotics increased significantly in Sarajevo, predominated by typical ones, whereas in Zagreb the utilization of antipsychotics was stable, predominated by atypical ones. In Croatia and Bosnia & Herzegovina, there was an obvious tendency to follow western trends in drug prescribing, as demonstrated by the increased use of antidepressants and reduced use of anxiolytics. Despite some improvement observed in the prescribing quality, high use of antipsychotics with dominance of typical antipsychotics in Sarajevo points to the need of prescribing guidelines for antipsychotics.

Respiratory and mental health effects of wildfires: an ecological study in Galician municipalities (north-west Spain)

PubMed Central

2011-01-01

Background During the summer of 2006, a wave of wildfires struck Galicia (north-west Spain), giving rise to a disaster situation in which a great deal of the territory was destroyed. Unlike other occasions, the wildfires in this case also threatened farms, houses and even human lives, with the result that the perception of disaster and helplessness was the most acute experienced in recent years. This study sought to analyse the respiratory and mental health effects of the August-2006 fires, using consumption of anxiolytics-hypnotics and drugs for obstructive airway diseases as indicators. Methods We conducted an analytical, ecological geographical- and temporal-cluster study, using municipality-month as the study unit. The independent variable was exposure to wildfires in August 2006, with municipalities thus being classified into the following three categories: no exposure; medium exposure; and high exposure. Dependent variables were: (1) anxiolytics-hypnotics; and (2) drugs for obstructive airway diseases consumption. These variables were calculated for the two 12-month periods before and after August 2006. Additive models for time series were used for statistical analysis purposes. Results The results revealed a higher consumption of drugs for obstructive airway diseases among pensioners during the months following the wildfires, in municipalities affected versus those unaffected by fire. In terms of consumption of anxiolytics-hypnotics, the results showed a significant increase among men among men overall -pensioners and non-pensioners- in fire-affected municipalities. Conclusions Our study indicates that wildfires have a significant effect on population health. The coherence of these results suggests that drug utilisation research is a useful tool for studying morbidity associated with environmental incidents. PMID:21600035

Comparison of the Effects of Typical and Atypical Anxiolytics on Learning in Monkeys and Rats,

DTIC Science & Technology

kg) and alprazolam (0.032-0.32 mg/kg) produced dose-dependent decreases in overall response rate in all subjects. However, with buspirone and 8-OH-DPAT...monkeys were variable across drugs and drug classes. Both 8-OH-DPAT and alprazolam produced large increases in percent errors in acquisition at doses

Potential antianxiety activity of Fumaria indica: A preclinical study

PubMed Central

Singh, Gireesh K.; Chauhan, Sudhir K.; Rai, Geeta; Chatterjee, Shyam S.; Kumar, Vikas

2013-01-01

Background: In the view of diverse CNS modulating properties of Fumaria indica, present study was planned to evaluate its putative anxiolytic activity in behavioural models of rats, followed by elucidation of mechanism of observed activity through biochemical estimations. Materials and Methods: Effects of seven daily 100, 200 and 400 mg/kg oral doses of a Fumaria indica extract (FI) was compared with those of an acute oral dose (5 mg/kg) of lorazepam in a battery of rat models consisting of open-field, elevated plus and zero maze, social interaction, and novelty induced feeding tests. Results: Dose dependant antianxiety effects of FI observed in all tests were qualitatively similar to those of the reference anxiolytic drug. Although FI treatments did not alter the concentrations of noradrenaline and serotonin in hippocampus and hypothalamus, concentrations of both these monoamines were dose dependently elevated in prefrontal cortex of FI treated animals. Flunitrazepam binding in brain frontal cortex was also elevated by the extract. Moreover, higher levels of brain expressions of the cytokines TNF-α, IL-1β, and IL-10 observed in animals with prior experience on elevated plus maze were almost completely reversed by the lowest dose of FI tested in the behavioral models. Conclusion: Taken together, these observations strongly suggest that FI is a functionally novel type of antianxiety agent, and that inhibition of cytokine expressions in the brain could be involved in its mode of action. PMID:23661988

Pharmacological Evaluation of Naproxen Metal Complexes on Antinociceptive, Anxiolytic, CNS Depressant, and Hypoglycemic Properties

PubMed Central

Das, Narhari; Abdur Rahman, S. M.

2016-01-01

Purpose. The present study was designed to investigate the antinociceptive, anxiolytic, CNS depressant, and hypoglycemic effects of the naproxen metal complexes. Methods. The antinociceptive activity was evaluated by acetic acid-induced writhing method and radiant heat tail-flick method while anxiolytic activity was evaluated by elevated plus maze model. The CNS depressant activity of naproxen metal complexes was assessed using phenobarbitone-induced sleeping time test and the hypoglycemic test was performed using oral glucose tolerance test. Results. Metal complexes significantly (P < 0.001) reduced the number of abdominal muscle contractions induced by 0.7% acetic acid solution in a dose dependent manner. At the dose of 25 mg/kg body weight p.o. copper, cobalt, and zinc complexes exhibited higher antinociceptive activity having 59.15%, 60.56%, and 57.75% of writhing inhibition, respectively, than the parent ligand naproxen (54.93%). In tail-flick test, at both doses of 25 and 50 mg/kg, the copper, cobalt, silver, and zinc complexes showed higher antinociceptive activity after 90 minutes than the parent drug naproxen. In elevated plus maze (EPM) model the cobalt and zinc complexes of naproxen showed significant anxiolytic effects in dose dependent manner, while the copper, cobalt, and zinc complexes showed significant CNS depressant and hypoglycemic activity. Conclusion. The present study demonstrated that copper, cobalt, and zinc complexes possess higher antinociceptive, anxiolytic, CNS depressant, and hypoglycemic properties than the parent ligand. PMID:27478435

Anxiolytic- and Antidepressant-like Effects of the Methadone Metabolite 2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline (EMDP)

PubMed Central

Lee, Bridgin G.; Olson, Thao T.; Xie, Teresa; Xiao, Yingxian; Blendy, Julie A.; Kellar, Kenneth J.

2015-01-01

The enhancement of GABAergic and monoaminergic neurotransmission has been the mainstay of pharmacotherapy and the focus of drug-discovery for anxiety and depressive disorders for several decades. However, the significant limitations of drugs used for these disorders underscores the need for novel therapeutic targets. Neuronal nicotinic acetylcholine receptors (nAChRs) may represent one such target. For example, mecamylamine, a non-competitive antagonist of nAChRs, displays positive effects in preclinical tests for anxiolytic and antidepressant activity in rodents. In addition, nicotine elicits similar effects in rodent models, possibly by receptor desensitization. Previous studies (Xiao et al., 2001) have identified two metabolites of methadone, EMDP (2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline) and EDDP (2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine), which are considered to be inactive at opiate receptors, as relatively potent noncompetitive channel blockers of rat α3β4 nAChRs. Here, we show that these compounds are likewise highly effective blockers of human α3β4 and α4β2 nAChRs. Moreover, we show that they display relatively low affinity for opiate binding sites labeled by [3H]-naloxone. We then evaluated these compounds in rats and mice in preclinical behavioral models predictive of potential anxiolytic and antidepressant efficacy. We found that EMDP, but not EDDP, displayed robust effects predictive of anxiolytic and antidepressant efficacy without significant effects on locomotor activity. Moreover, EMDP at behaviorally active doses, unlike mecamylamine, did not produce eyelid ptosis, suggesting it may produce fewer autonomic side effects than mecamylamine. Thus, the methadone metabolite EMDP may represent a novel therapeutic avenue for the treatment of some affective disorders. PMID:26365569

A Computational Drug-Target Network for Yuanhu Zhitong Prescription

PubMed Central

Lu, Peng; Zhang, Fangbo; Yuan, Yuan; Wang, Songsong

2013-01-01

Yuanhu Zhitong prescription (YZP) is a typical and relatively simple traditional Chinese medicine (TCM), widely used in the clinical treatment of headache, gastralgia, and dysmenorrhea. However, the underlying molecular mechanism of action of YZP is not clear. In this study, based on the previous chemical and metabolite analysis, a complex approach including the prediction of the structure of metabolite, high-throughput in silico screening, and network reconstruction and analysis was developed to obtain a computational drug-target network for YZP. This was followed by a functional and pathway analysis by ClueGO to determine some of the pharmacologic activities. Further, two new pharmacologic actions, antidepressant and antianxiety, of YZP were validated by animal experiments using zebrafish and mice models. The forced swimming test and the tail suspension test demonstrated that YZP at the doses of 4 mg/kg and 8 mg/kg had better antidepressive activity when compared with the control group. The anxiolytic activity experiment showed that YZP at the doses of 100 mg/L, 150 mg/L, and 200 mg/L had significant decrease in diving compared to controls. These results not only shed light on the better understanding of the molecular mechanisms of YZP for curing diseases, but also provide some evidence for exploring the classic TCM formulas for new clinical application. PMID:23762151

Drug discrimination: A versatile tool for characterization of CNS safety pharmacology and potential for drug abuse.

PubMed

Swedberg, Michael D B

2016-01-01

Drug discrimination studies for assessment of psychoactive properties of drugs in safety pharmacology and drug abuse and drug dependence potential evaluation have traditionally been focused on testing novel compounds against standard drugs for which drug abuse has been documented, e.g. opioids, CNS stimulants, cannabinoids etc. (e.g. Swedberg & Giarola, 2015), and results are interpreted such that the extent to which the test drug causes discriminative effects similar to those of the standard training drug, the test drug would be further characterized as a potential drug of abuse. Regulatory guidance for preclinical assessment of abuse liability by the European Medicines Agency (EMA, 2006), the U.S. Food and Drug Administration (FDA, 2010), the International Conference of Harmonization (ICH, 2009), and the Japanese Ministry of Health Education and Welfare (MHLW, 1994) detail that compounds with central nervous system (CNS) activity, whether by design or not, need abuse and dependence liability assessment. Therefore, drugs with peripheral targets and a potential to enter the CNS, as parent or metabolite, are also within scope (see Swedberg, 2013, for a recent review and strategy). Compounds with novel mechanisms of action present a special challenge due to unknown abuse potential, and should be carefully assessed against defined risk criteria. Apart from compounds sharing mechanisms of action with known drugs of abuse, compounds intended for indications currently treated with drugs with potential for abuse and or dependence are also within scope, regardless of mechanism of action. Examples of such compounds are analgesics, anxiolytics, cognition enhancers, appetite control drugs, sleep control drugs and drugs for psychiatric indications. Recent results (Swedberg et al., 2014; Swedberg & Raboisson, 2014; Swedberg, 2015) on the metabotropic glutamate receptor type 5 (mGluR5) antagonists demonstrate that compounds causing hallucinatory effects in humans did not exhibit clear discriminative effects when tested against classical drugs of abuse in drug discrimination studies, and were not self-administered by rats. However, these compounds did cause salient discriminative effects of their own in animals trained to discriminate them from no drug. Therefore, from a safety pharmacology perspective, novel compounds that do not cause discriminative effects similar to classical drugs of abuse, may still cause psychoactive effects in humans and carry the potential to maintain drug abuse, suggesting that proactive investigation of drug abuse potential is warranted (Swedberg, 2013). These and other findings will be discussed, and the application of drug discrimination procedures beyond the typical standard application of testing novel compounds against known and well characterized reference drugs will be addressed. Copyright © 2016 Elsevier Inc. All rights reserved.

Relations between open-field, elevated plus-maze, and emergence tests in C57BL/6J and BALB/c mice injected with GABA- and 5HT-anxiolytic agents.

PubMed

Lalonde, Robert; Strazielle, Catherine

2010-06-01

Two 5HT(1A) receptor agonists and chlordiazepoxide were examined in open-field, elevated plus maze, and emergence tests. At doses with no effect in the open-field, chlordiazepoxide increased open and open/total arm visits as well as open arm duration in the elevated plus maze, whereas 5HT(1A) receptor agonists showed an anxiolytic response on a single measure. The anxiolytic action of chlordiazepoxide was limited to the less active BALB/c strain. Unlike the 5HT(1A) receptor agonists, chlordiazepoxide was also anxiolytic in the emergence test, once again only in BALB/c and not C57BL/6J mice. Significant correlations were found between emergence latencies and specific indicators of anxiety in the elevated plus-maze in chlordiazepoxide-treated but not in mice treated with buspirone and 8-OH-DPAT. These results indicate that elevated plus-maze and emergence tests depend on benzodiazepine receptors. In contrast, 5HT(1A) receptor agonists were ineffective in the emergence test and no correlation was found between emergence latencies and specific indicators of anxiety in the elevated plus-maze. Though superficially similar, the emergence test seems to tap into a partially separate facet of anxiety.

Antioxidant and anxiolytic activities of Crataegus nigra Wald. et Kit. berries.

PubMed

Popovic-Milenkovic, Marija T; Tomovic, Marina T; Brankovic, Snezana R; Ljujic, Biljana T; Jankovic, Slobodan M

2014-01-01

Hawthorn has been present for a long time in traditional medicine as antihypertensive, hypolipidemic, anti-inflammatory, gastroprotective, antimicrobial agent. Hawthorn can be used for the cure of stress, nervousness but there is no published paper about actions of Crataegus nigra Wald. et Kit. fruits. The present study was carried out to test free-radical-scavenging and anxiolytic activity of C. nigra fruits. DPPH (alpha,alpha-diphenyl-beta-picrylhydrazyl) assay was used to measure antioxidant activity. BHT, BHA, PG, quercetin and rutin were used as standards. The total amount of phenolic compounds, procyanidins, and flavonoids in the extracts, was determined spectrophotometrically. Results were expressed as equivalents of gallic acid, cyanidin chloride and quercetin equivalents, respectively. LC-MS/MS was used for identification and quantification of phenolic composition. The anxiety effect, expressed as the difference in time spent in the open and closed arms, was measured and compared between groups. Phenolic compound content of Crataegus nigra fruits was 72.7 mg/g. Yield of total flavonoid aglycones was 0.115 mg/g. Procyanidins were 5.6 mg/g. DPPH radical-scavenging capacity of the extracts showed linear concentration dependency, IC50 value were 27.33 microg/mL. Anxiolytic effect was observed. Species Crataegus nigra fruits hydroalcoholic extract showed antioxidant and anxiolytic activity.

Investigation of the Anxiolytic and Antidepressant Effects of Curcumin, a Compound From Turmeric (Curcuma longa), in the Adult Male Sprague-Dawley Rat.

PubMed

Ceremuga, Tomás Eduardo; Helmrick, Katie; Kufahl, Zachary; Kelley, Jesse; Keller, Brian; Philippe, Fabiola; Golder, James; Padrón, Gina

As the use of herbal medications continues to increase in America, the potential interaction between herbal and prescription medications necessitates the discovery of their mechanisms of action. The purpose of this study was to investigate the anxiolytic and antidepressant effects of curcumin, a compound from turmeric (Curcuma longa), and its effects on the benzodiazepine site of the γ-aminobutyric acid receptor A (GABAA) receptor. Utilizing a prospective, between-subjects group design, 55 male Sprague-Dawley rats were randomly assigned to 1 of the 5 intraperitoneally injected treatment groups: vehicle, curcumin, curcumin + flumazenil, midazolam, and midazolam + curcumin. Behavioral testing was performed using the elevated plus maze, open field test, and forced swim test. A 2-tailed multivariate analysis of variance and least significant difference post hoc tests were used for data analysis. In our models, curcumin did not demonstrate anxiolytic effects or changes in behavioral despair. An interaction of curcumin at the benzodiazepine site of the GABAA receptor was also not observed. Additional studies are recommended that examine the anxiolytic and antidepressant effects of curcumin through alternate dosing regimens, modulation of other subunits on the GABAA receptor, and interactions with other central nervous system neurotransmitter systems.

Unmanned Aircraft Pilot Medical Certification Requirements

DTIC Science & Technology

2007-02-01

Security Classif. (of this page) 21. No. of Pages 22. Price Unclassified Unclassified 14 Form DOT F 1700.7 (8-72) Reproduction of completed...and hypnotics , anxiolytics, marijuana, cocaine, opiods, amphetamines, hallucinogens, and other psychoactive drugs or chemicals.) Disqualifying

Deletion of Dlk2 increases the vulnerability to anxiety-like behaviors and impairs the anxiolytic action of alprazolam.

PubMed

Navarrete, Francisco; García-Gutiérrez, María S; Laborda, Jorge; Manzanares, Jorge

2017-11-01

The purpose of this study was to evaluate the role of the non-canonical DLK2 NOTCH ligand in the regulation of emotional behavior. To this aim, anxiety and depressive-like behaviors were examined in Dlk2 knock-out (Dlk2 -/- ) and its corresponding wild-type (WT) mice. Furthermore, relative gene expression analyses of corticotropin releasing hormone (Crh) in the paraventricular nucleus (PVN), glucocorticoid receptor (NR3C1) and FK506 binding protein 5 (FKBP5) in the hippocampus (HIPP), and the transcription factors Hes1, Hes5 and Hey1 in the PVN, HIPP and amygdala (AMY) were carried out in Dlk2 -/- and WT mice under basal conditions and after exposure to restraint stress. The anxiolytic action of alprazolam and the relative gene expression levels of the GABA-A alpha 2 and gamma 2 receptor subunits (Gabra2 and Gabrg2) were also evaluated in the HIPP and AMY of WT and Dlk2 -/- mice. The results reveal that deletion of Dlk2 increased anxiety and depressive-like behaviors and altered the vulnerability to restraint stress on Crh gene expression in the PVN, Nr3c1 and Fkbp5 gene expression in the HIPP, and Hes1, Hes5 and Hey1 gene expression in the PVN, HIPP and AMY. Interestingly, the administration of alprazolam failed to produce an anxiolytic action in Dlk2 -/- mice. Indeed, Gabra2 and Gabrg2 gene expression levels were significantly affected under basal conditions and after stress exposure in Dlk2 -/- mice compared with WT mice. In conclusion, the results suggest that DLK2 plays an important role in the regulation of emotional behaviors and relevant targets of the stress axis, NOTCH pathway and GABAergic neurotransmission. In addition, the deletion of Dlk2 blocked the anxiolytic response to alprazolam. Future studies are needed to determine the relevance of DLK2 as a potential therapeutic target for the treatment of neuropsychiatric disorders with anxiety or depressive-like behaviors. Copyright © 2017 Elsevier Ltd. All rights reserved.

[Determining factors for the use of anxiolytic and hypnotic drugs in the elderly].

PubMed

Téllez-Lapeira, Juan M; López-Torres Hidalgo, Jesús; Gálvez-Alcaraz, Luis; Párraga-Martínez, Ignacio; Boix-Gras, Clotilde; García-Ruiz, Antonio

To estimate the prevalence of self-reported anxiety/hypnotics use in adults 65 years and older and identify potential factors that determine the use of these drugs. Cross-sectional study conducted on a study population of 1,161 non-institutionalised adults 65 years old and older with enough ability to conduct a personal interview. Participants were randomly selected from health care registers. The main outcomes of interest included consumption of anxiolytics, hypnotics and other drugs (filed by ATC classification system), mood (based on the Yesavage geriatric depression scale), cognitive status (Pfeiffer questionnaire), physical-functional assessment of basic activities of daily living (Katz index), health problems (ICPC-2 classification WONCA), and sociodemographic variables. The prevalence of self-reported anxiety/hypnotics consumption was 16.6% (95% CI: 14.5 - 18.7), of which 90.5% were benzodiazepines (BZD), mainly lorazepam (39.4% of BZD). Long half-life BZD accounted for 24.7% of BZD. Hypnotics accounted for 27.5% of anxiolytics/hypnotics. The use of sedatives/hypnotics was independently associated with other drugs (non-psychotropics) consumption (OR 6.8, 95% CI: 2.1-22.0), presence of established depression (OR: 2.5; 95% CI: 1.0 -5.9), presence of 4 or more comorbidities (OR: 2.0; 95% CI: 1.4-2.9), being female (OR 2.1, 95% CI: 1.5-3.1) and being dependent for basic activities of daily living (OR: 1.8, 95% CI: 1.1-2.9). The prevalence of sedatives/hypnotics use in the elderly from Albacete is high. Several factors were identified as potential determinants of sedatives/hypnotics use in our study population. It will be important to evaluate the misuse of these drugs in order to develop effective, efficient and safe prescription strategies. Copyright © 2016 SEGG. Publicado por Elsevier España, S.L.U. All rights reserved.

Relationship between xerostomia and psychotropic drugs in patients with schizophrenia: evaluation using an oral moisture meter.

PubMed

Okamoto, A; Miyachi, H; Tanaka, K; Chikazu, D; Miyaoka, H

2016-12-01

Patients with schizophrenia are most commonly treated with antipsychotic medications, often with the addition of anxiolytics. This study used an oral moisture meter to evaluate xerostomia in patients with schizophrenia taking typical and atypical antipsychotics, anxiolytics and non-psychotropic medications. Patients diagnosed with schizophrenia according to ICD-10 criteria in the Department of Psychiatry, Kitasato University East, and affiliated hospitals were studied. All patients were on psychotropic medications. Patients with diseases associated with xerostomia, such as Sjögren's syndrome I, were excluded. A total of 127 patients were enrolled. Mean oral moisture was 27·81 ± 2·27% (normal, ≥30·0%). A significant association was observed between objective oral moisture and the subjective sense of dry mouth. Multivariate analysis revealed a negative correlation between the number of antipsychotics and, especially, anxiolytics, and the degree of oral moisture. Drug dosages themselves were not significantly correlated with dry mouth. These findings suggest that objective oral moisture measurements show decreased moisture in patients on these medications and that the degree of moisture shows a greater negative correlation with the number, as opposed to the dosages, of psychotropic drugs administered. When patients with schizophrenia visit a dental clinic, it is important for the dentist to accurately assess the degree of oral moisture and to determine the medications being taken. Based on these findings of the association of polypharmacy with xerostomia, dentists are encouraged to inform the psychiatrist of the need to actively manage patients' xerostomia. © 2016 John Wiley & Sons Ltd.

Anxiolytic-like effects of ursolic acid in mice.

PubMed

Colla, André R S; Rosa, Julia M; Cunha, Mauricio P; Rodrigues, Ana Lúcia S

2015-07-05

Ursolic acid is a pentacyclic triterpenoid that possesses several biological and neuropharmacological effects including antidepressant-like activity. Anxiety disorders represent common and disability psychiatric conditions that are often associated with depressive symptoms. This work investigated the anxiolytic-like effects of ursolic acid administration in different behavioral paradigms that evaluate anxiety in mice: open field test, elevated plus maze test, light/dark box test and marble burying test. To this end, mice were administered with ursolic acid (0.1, 1 and 10mg/kg, p.o.) or diazepam (2mg/kg, p.o.), positive control, and submitted to the behavioral tests. The results show that ursolic acid (10mg/kg) elicited an anxiolytic-like effect observed by the increased total time in the center and decreased number of rearings responses in the open field test and an increased percentage of entries and total time spent in the open arms of elevated plus maze, similarly to diazepam. No significant effects of ursolic acid were shown in the light/dark box and marble burying test. These data indicate that ursolic acid exhibits anxiolytic-like effects in the open field and elevated plus maze test, but not in the light/dark box and marble burying test, showing the relevance of testing several behavioral paradigms in the evaluation of anxiolytic-like actions. Of note, the results extend the understanding on the effects of ursolic acid in the central nervous system and suggest that it may be a novel approach for the management of anxiety-related disorders. Copyright © 2015. Published by Elsevier B.V.

Antidepressive and anxiolytic effects of ayahuasca: a systematic literature review of animal and human studies.

PubMed

Dos Santos, Rafael G; Osório, Flávia L; Crippa, José Alexandre S; Hallak, Jaime E C

2016-03-01

To conduct a systematic literature review of animal and human studies reporting anxiolytic or antidepressive effects of ayahuasca or some of its isolated alkaloids (dimethyltryptamine, harmine, tetrahydroharmine, and harmaline). Papers published until 3 April 2015 were retrieved from the PubMed, LILACS and SciELO databases following a comprehensive search strategy and using a predetermined set of criteria for article selection. Five hundred and fourteen studies were identified, of which 21 met the established criteria. Studies in animals have shown anxiolytic and antidepressive effects of ayahuasca, harmine, and harmaline, and experimental studies in humans and mental health assessments of experienced ayahuasca consumers also suggest that ayahuasca is associated with reductions in anxiety and depressive symptoms. A pilot study reported rapid antidepressive effects of a single ayahuasca dose in six patients with recurrent depression. Considering the need for new drugs that produce fewer adverse effects and are more effective in reducing anxiety and depression symptomatology, the described effects of ayahuasca and its alkaloids should be further investigated.

Female Wistar rats tested during late proestrus or during pregnancy and ovariectomized rats tested after receiving progesterone or allopregnanolone displayed reduced conflict behavior.

PubMed

Molina-Hernandez, Miguel; Perez, Julian Garcia; Olivera Lopez, Jorge Ivan

2002-06-01

In a conflict test based on the rat's choice between an immediate punished reinforcer or a delayed nonpunished reinforcer, anxiolytic drugs increase the number of immediate punished reinforcers. In this study, two hypotheses were tested: first, during late proestrus or during midpregnancy, female rats will display an elevated amount of immediate punished reinforcers; second, ovariectomized rats will display an elevated amount of immediate punished reinforcers when they receive anxiolytic doses of neurosteroids. Thus, female rats (n = 15) were tested repeatedly during late proestrus, diestrus, and pregnancy in the aforementioned conflict task. They displayed an elevated amount of immediate punished reinforcers during late proestrus (P < .05) and during the 14th (P < .05) and 17th (P < .05) days of pregnancy compared to diestrus or 3rd, 7th, or 20th days of pregnancy. Likewise, ovariectomized rats (n = 90) displayed an elevated amount of immediate punished reinforcers compared to control rats only when they received anxiolytic doses of progesterone (1.0-2.0 mg/kg, P < .05) or allopregnanolone (1.0-2.0 mg/kg, P < .05). In conclusion, female rats displayed reduced conflict behavior during late proestrus and pregnancy, or after received anxiolytic doses of neurosteroids.

Phytochemical and biological assessments on Lipidium meyenii (maca) and Epimidium sagittatum (horny goat weed).

PubMed

Qureshi, Mahmood; Mehjabeen, -; Noorjahan, -; Muhammad, Shafi; Siddiqui, Faheem Ahmed; Baig, Iftikhar; Ahmad, Mansoor

2017-01-01

The effects of Lipidium meyenii (maca, LM) and Epimidium sagittatum (horny goat weed, ES) have been investigated due to their involvement in fertilization. Both of the drugs showed good results before, during and after fertilization in male and female mice. The results revealed that the crude extract of Lipidium meyenii caused a significant decrease in the no. of writhes at 300 and 500mg/kg (p<0.05) as compare to control, Epimidium sagittatum and standard drug. The gross behavioral, open field, exploratory behaviour, forced swimming test for stress, diuretic activity, chronic toxicity with the effect on reproduction of both male and female and change in body weight were also studied. The phytochemical study showed the presence of tannin, alkaloid, carbohydrate, rich protein and absence of sterol in LM, whereas ES shows presence of sterol and less protein. LS improve in muscle activity and exploratory behaviours without any toxic effects on mice and their pups. It does not have diuretic effect for first two hour but act normally after initial phase of drug therapy. Epimidium sagittatum has dual action that is at low dose it has slight stimulation action and at high dose little depressive effect. ES also has some diuretic effect. Overall these results suggest that LM is highly effective remedy for treatment of impotency and reduces stress and depression, because of dual effect ES not only suggested as an anxiolytic medicine but also effective in female hormonal disorder.

Anxiogenic-like effects of chronic nicotine exposure in zebrafish.

PubMed

Stewart, Adam Michael; Grossman, Leah; Collier, Adam D; Echevarria, David J; Kalueff, Allan V

2015-12-01

Nicotine is one of the most widely used and abused legal drugs. Although its pharmacological profile has been extensively investigated in humans and rodents, nicotine CNS action remains poorly understood. The importance of finding evolutionarily conserved signaling pathways, and the need to apply high-throughput in vivo screens for CNS drug discovery, necessitate novel efficient experimental models for nicotine research. Zebrafish (Danio rerio) are rapidly emerging as an excellent organism for studying drug abuse, neuropharmacology and toxicology and have recently been applied to testing nicotine. Anxiolytic, rewarding and memory-modulating effects of acute nicotine treatment in zebrafish are consistently reported in the literature. However, while nicotine abuse is more relevant to long-term exposure models, little is known about chronic effects of nicotine on zebrafish behavior. In the present study, chronic 4-day exposure to 1-2mg/L nicotine mildly increased adult zebrafish shoaling but did not alter baseline cortisol levels. We also found that chronic exposure to nicotine evokes robust anxiogenic behavioral responses in zebrafish tested in the novel tank test paradigm. Generally paralleling clinical and rodent data on anxiogenic effects of chronic nicotine, our study supports the developing utility of zebrafish for nicotine research. Copyright © 2015 Elsevier Inc. All rights reserved.

Plant-based medicines for anxiety disorders, Part 1: a review of preclinical studies.

PubMed

Sarris, Jerome; McIntyre, Erica; Camfield, David A

2013-03-01

Research in the area of herbal psychopharmacology has revealed a variety of promising medicines that may provide benefit in the treatment of general anxiety and specific anxiety disorders. However, a comprehensive review of plant-based anxiolytics has been absent to date. This article (part 1) reviews herbal medicines for which only preclinical investigations for anxiolytic activity have been performed. In part 2, we review herbal medicines for which there have been clinical investigations for anxiolytic activity. An open-ended, language-restricted (English) search of MEDLINE (PubMed), CINAHL, Scopus and the Cochrane Library databases was conducted (up to 28 October 2012) using specific search criteria to identify herbal medicines that have been investigated for anxiolytic activity. This search of the literature revealed 1,525 papers, from which 53 herbal medicines were included in the full review (having at least one study using the whole plant extract). Of these plants, 21 had human clinical trial evidence (reviewed in part 2), with another 32 having solely preclinical studies (reviewed here in part 1). Preclinical evidence of anxiolytic activity (without human clinical trials) was found for Albizia julibrissin, Sonchus oleraceus, Uncaria rhynchophylla, Stachys lavandulifolia, Cecropia glazioui, Magnolia spp., Eschscholzia californica, Erythrina spp., Annona spp., Rubus brasiliensis, Apocynum venetum, Nauclea latifolia, Equisetum arvense, Tilia spp., Securidaca longepedunculata, Achillea millefolium, Leea indica, Juncus effusus, Coriandrum sativum, Eurycoma longifolia, Turnera diffusa, Euphorbia hirta, Justicia spp., Crocus sativus, Aloysia polystachya, Albies pindrow, Casimiroa edulis, Davilla rugosa, Gastrodia elata, Sphaerathus indicus, Zizyphus jujuba and Panax ginseng. Common mechanisms of action for the majority of botanicals reviewed primarily involve GABA, either via direct receptor binding or ionic channel or cell membrane modulation; GABA transaminase or glutamic acid decarboxylase inhibition; a range of monoaminergic effects; and potential cannabinoid receptor modulation. Future research should focus on conducting human clinical trials on the plants reviewed with promising anxiolytic activity.

Development and evaluation of fixed dose bi therapy sublingual tablets for treatment stress hypertension and anxiety

PubMed Central

El-Nabarawi, Mohamed A.; Tayel, Saadia A.; Soliman, Nadia A.; Abo Enin, Hadel A.

2013-01-01

Objective: A stress induced rise in the blood pressure. Some believe that patients with hypertension are characterized by a generalized state of increased anxiety. Aim: The purpose of this study is to prepare a fixed dose bi therapy using bisoprolol hemifumarate (BH) as antihypertensive drug and buspirone hydrochloride (BuHCl) as anxiolytic drug, which can be used to treat both diseases concomitantly. Using sublingual tablets is hopeful to improve the BuHCl poor oral bioavailability and to facilitate administration to patients experiencing problems with swallowing. Materials and Methods: A total of 5mg BH and 10mg BuHCl were selected based on compatibility study. A 3×22 full factorial design was adopted for the optimization of the tablets prepared by direct compression method. The effects of the filler type, the binder molecular weight, and the binder type were studied. The prepared formulae were evaluated according to their physical characters as hardness, friability, disintegration time (new modified method and in vivo disintegration time) and wetting properties. In vitro drugs dissolute, permeation through the buccal mucosa and the effect of storage were analyzed by a new valid high pressure liquid chromatography (HPLC) method. Bioavailability study of the selected formula study was carried out and followed by the clinical. Results: The optimized tablet formulation showed accepted average weight, hardness, wetting time, friability, content uniformity, disintegration time (less than 3 min). Maximum drug release could be achieved with in 10 min. In addition enhancing drug permeation through the buccal mucosa and, the maximum concentration of the drug that reached the blood was in the first 10 min which means a rapid onset of action and improved the extent of both drug's absorption. Conclusion: The results revealed that sublingual (F6) tablets containing both drugs would maintain rapid onset of action, and increase bioavailability. BuHCl with BH can be attributed to the marked decline in DBP and SBP. That led to a reduction in the MAP. PMID:24082695

Secondary metabolites from three Florida sponges with antidepressant activity.

PubMed

Kochanowska, Anna J; Rao, Karumanchi V; Childress, Suzanne; El-Alfy, Abir; Matsumoto, Rae R; Kelly, Michelle; Stewart, Gina S; Sufka, Kenneth J; Hamann, Mark T

2008-02-01

Brominated indole alkaloids are a common class of metabolites reported from sponges of the order Verongida. Herein we report the isolation, structure determination, and activity of metabolites from three Florida sponges, namely, Verongula rigida (order Verongida, family Aplysinidae), Smenospongia aurea, and S. cerebriformis (order Dictyoceratida, family Thorectidae). All three species were investigated chemically, revealing similarities in secondary metabolites. Brominated compounds, as well as sesquiterpene quinones and hydroquinones, were identified from both V. rigida and S. aurea despite their apparent taxonomic differences at the ordinal level. Similar metabolites found in these distinct sponge species of two different genera provide evidence for a microbial origin of the metabolites. Isolated compounds were evaluated in the Porsolt forced swim test (FST) and the chick anxiety-depression continuum model. Among the isolated compounds, 5,6-dibromo- N,N-dimethyltryptamine ( 1) exhibited significant antidepressant-like action in the rodent FST model, while 5-bromo- N,N-dimethyltryptamine ( 2) caused significant reduction of locomotor activity indicative of a potential sedative action. The current study provides ample evidence that marine natural products with the diversity of brominated marine alkaloids will provide potential leads for antidepressant and anxiolytic drugs.

Clozapine and Olanzapine Exhibit an Intrinsic Anxiolytic Property in Two Conditioned Fear Paradigms: Contrast with Haloperidol and Chlordiazepoxide

PubMed Central

Mead, Alexa; Li, Ming; Kapur, Shitij

2008-01-01

Psychotic fear and anxiety disturbances are seen at a relatively high frequency in patients with schizophrenia. Atypical antipsychotics are believed to show superior efficacy in reducing these symptoms. However, clinical and preclinical evidence regarding their anxiolytic efficacy has been mixed. In this study, we evaluated the possible anxiolytic property of two atypicals clozapine and olanzapine and compared them with typical haloperidol and chlordiazepoxide (a prototype of sedative-anxiolytic drug) in two preclinical models of fear. In Experiment 1, we used a fear-induced passive avoidance and conditioned place aversion paradigm and examined the effects of clozapine (20 mg/kg, sc), haloperidol (0.05 mg/kg, sc) and chlordiazepoxide (10 mg/kg, ip). In Experiments 2 and 3, we used a two-way active avoidance conditioning paradigm and further compared the effects of clozapine (20 mg/kg, sc), haloperidol (0.05 mg/kg, sc), chlordiazepoxide (10 mg/kg, ip) and three doses of olanzapine (0.5, 1.0, and 2.0 mg/kg, sc). Results show that clozapine and chlordiazepoxide, but not haloperidol, significantly attenuated the shock conditioning-induced place aversion, decreased the amount of defecations and the number of the 22 kHz vocalizations. Clozapine also reduced the shock conditioning-induced hyperthermia. Similar to clozapine, olanzapine also significantly decreased the amount of defecations and reduced the shock conditioning-induced hyperthermia, but it did not inhibit the 22 kHz vocalizations. This study demonstrates that clozapine and olanzapine possess an intrinsic anxiolytic property, which is not attributable to its superior anti-“psychotic” effect or its favorable effects on motor functions or learning and memory processes. These findings also suggest that the combined use of passive avoidance and active avoidance conditioning models can be useful in better differentiating typical and atypical antipsychotics as well as anxiolytics. PMID:18547622

Studies into the anxiolytic actions of agomelatine in social isolation reared rats: Role of corticosterone and sex.

PubMed

Regenass, Wilmie; Möller, Marisa; Harvey, Brian H

2018-02-01

Anxiety disorders are severely disabling, while current pharmacological treatments are complicated by delayed onset, low remission rates and side-effects. Sex is also noted to contribute towards illness severity and treatment response. Agomelatine is a melatonin (MT 1 /MT 2 ) agonist and serotonin (5-HT 2C ) antagonist purported to be anxiolytic in clinical and some pre-clinical studies. We undertook a detailed analysis of agomelatine's anxiolytic activity in a neurodevelopmental model of anxiety, the social isolation reared rat. Rats received sub-chronic treatment with vehicle or agomelatine (40 mg/kg per day intraperitoneally at 16:00 h for 16 days), with behaviour analysed in the open field test, social interaction test and elevated plus maze. The contribution of corticosterone and sex was also studied. Social isolation rearing increased locomotor activity and reduced social interaction in the social interaction test, and was anxiogenic in the elevated plus maze in males and females. Agomelatine reversed these behaviours. Male and female social isolation reared rats developed anxiety-like behaviours to a similar degree, although response to agomelatine was superior in male rats. Social isolation rearing decreased plasma corticosterone in both sexes and tended to higher levels in females, although agomelatine did not affect corticosterone in either sex. Concluding, agomelatine is anxiolytic in SIR rats, although correcting altered corticosterone could not be implicated. Sex-related differences in the response to agomelatine are evident.

Ritanserin-sensitive receptors modulate the prosocial and the anxiolytic effect of MDMA derivatives, DOB and PMA, in zebrafish.

PubMed

Ponzoni, Luisa; Sala, Mariaelvina; Braida, Daniela

2016-11-01

Little is known about the pharmacological effects of amphetamine derivatives. In the present study, the effect on social preference and anxiety-like behavior of 2,5-dimetoxy-4-bromo-amphetamine hydrobromide (DOB) and para-methoxyamphetamine (PMA), in comparison with 3,4 methylenedioxymethamphetamine (MDMA) was investigated in zebrafish, an emerging model to study emotional behavior in an inexpensive and quick manner. DOB (0.05-2mg/kg), PMA (0.0005-2mg/kg) or MDMA (0.25-20mg/kg), given i.m. to adult zebrafish, progressively increased the time spent in the proximity of nacre fish picture in a social preference test. However, high doses were ineffective. Similarly, in the novel tank diving and light-dark tests the compounds elicited a progressive anxiolytic effect in terms of time spent in the upper half of the tank and in the light compartment, respectively. All the above effects were interpolated by symmetrical parabolas. The 5-HT2A/C antagonist ritanserin (0.025-2.5mg/kg) in association with the maximal effective dose of MDMA, DOB and PMA blocked both the social and anxiolytic effect. Taken together these findings demonstrate for the first time the prosocial and anxiolytic properties of DOB and PMA and focus on the mechanisms of their action through the serotonergic-like system suggesting a potential clinical application. Copyright © 2016 Elsevier B.V. All rights reserved.

Sedative-hypnotic and anxiolytic effects and the mechanism of action of aqueous extracts of peanut stems and leaves in mice.

PubMed

Deng, Lei; Shi, Ai-Min; Wang, Qiang

2018-03-24

Peanut stems and leaves (PSL) have traditionally been used as both a special food and a herbal medicine in Asia. The sedative-hypnotic and anxiolytic effects of PSL have been recorded in classical traditional Chinese literature, and more recently by many other researchers. In a previous study, four sleep-related ingredients (linalool, 5-hydroxy-4',7-dimethoxyflavanone, 2'-O-methylisoliquiritigenin and ferulic acid), among which 5-hydroxy-4',7-dimethoxyflavanone and 2'-O-methylisoliquiritigenin were newly found in Arachis species, were screened by ultrahigh-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC/QTOF-MS). In the current study, quantitative examination of the above four ingredients was conducted. Serious fundamental functional studies were done in mice, including locomotor activity, direct sleep tests, pentobarbital-induced sleeping time tests, subthreshold dose of pentobarbital tests and barbital sodium sleep incubation period tests, to determine the material base for the sedative-hypnotic and anxiolytic effects of aqueous extracts of PSL. Furthermore, neurotransmitter levels in three brain regions (cerebrum, cerebellum and brain stem) were determined using UHPLC coupled with triple-quadrupole mass spectrometry (UHPLC/QQQ-MS) in order to elucidate the exact mechanism of action. Aqueous extract of PSL at a dose of 500 mg kg -1 (based on previous experience), along with different concentrations of the above four functional ingredients (189.86 µg kg -1 linalool, 114.75 mg kg -1 5-hydroxy-4',7-dimethoxyflavanone, 32.4mg kg -1 2'-O-methylisoliquiritigenin and 44.44 mg kg -1 ferulic acid), had a sedative-hypnotic effect by affecting neurotransmitter levels in mice. The data demonstrate that these four ingredients are the key functional factors for the sedative-hypnotic and anxiolytic effects of PSL aqueous extracts and that these effects occur via changes in neurotransmitter levels and pathways. © 2018 Society of Chemical Industry. © 2018 Society of Chemical Industry.

[Analysis of the binding capacity of the benzodiazepine site of gabaa receptor in mice C57BL/6 and BALB/C pretreated with anxiolytics].

PubMed

Iarkova, M A

2011-01-01

The level of specific 3H-flunitrazepam binding in synaptosomal membranes of C57BL/6 and BALB/c mice brain underwent to the stress of different types has been studied. Mild stress (Elevated Plus Maze) was shown to induce the decrease of benzodiazepine binding in BALB/c mice only, while the strong one (Exposure to a predator) was revealed to cause this decrease in both strains. Behavioral effects of different non-benzodiazepine drugs possessing anxiolytic properties (Afobazol, Ladasten and Noopept) was accompanied with the normalization of the level of benzodiazepine reception, reduced by the stress of both modalities.

Neuropeptide Y in the central nucleus of amygdala regulates the anxiolytic effect of agmatine in rats.

PubMed

Taksande, Brijesh G; Kotagale, Nandkishor R; Gawande, Dinesh Y; Bharne, Ashish P; Chopde, Chandrabhan T; Kokare, Dadasaheb M

2014-06-01

In the present study, modulation of anxiolytic action of agmatine by neuropeptide Y (NPY) in the central nucleus of amygdala (CeA) is evaluated employing Vogel's conflict test (VCT) in rats. The intra-CeA administration of agmatine (0.6 and 1.2µmol/rat), NPY (10 and 20pmol/rat) or NPY Y1/Y5 receptors agonist [Leu(31), Pro(34)]-NPY (30 and 60pmol/rat) significantly increased the number of punished drinking licks following 15min of treatment. Combination treatment of subeffective dose of NPY (5pmol/rat) or [Leu(31), Pro(34)]-NPY (15pmol/rat) and agmatine (0.3µmol/rat) produced synergistic anxiolytic-like effect. However, intra-CeA administration of selective NPY Y1 receptor antagonist, BIBP3226 (0.25 and 0.5mmol/rat) produced anxiogenic effect. In separate set of experiment, pretreatment with BIBP3226 (0.12mmol/rat) reversed the anxiolytic effect of agmatine (0.6µmol/rat). Furthermore, we evaluated the effect of intraperitoneal injection of agmatine (40mg/kg) on NPY-immunoreactivity in the nucleus accumbens shell (AcbSh), lateral part of bed nucleus of stria terminalis (BNSTl) and CeA. While agmatine treatment significantly decreased the fibers density in BNSTl, increase was noticed in AcbSh. In addition, agmatine reduced NPY-immunoreactive cells in the AcbSh and CeA. Immunohistochemical data suggest the enhanced transmission of NPY from the AcbSh and CeA. Taken together, this study suggests that agmatine produced anxiolytic effect which might be regulated via modulation of NPYergic system particularly in the CeA. Copyright © 2013 Elsevier B.V. and ECNP. All rights reserved.

Evaluation of n-hexane extract of Viola betonicifolia for its neuropharmacological properties.

PubMed

Muhammad, Naveed; Saeed, Muhammad; Khan, Haroon; Haq, Ikramul

2013-01-01

Viola betonicifolia (whole plant) has been used as a sedative and in various nervous disorders in Pakistani traditional medicines. The n-hexane extract of the whole plant of V. betonicifolia (HEVB) was investigated for neuropharmacological properties such as anxiolytic, muscle relaxant, sleep induction, antidepressant and sedative to ascertain its folk use. Anxiolytic activity was tested using the staircase test, while the muscle relaxing property of the extract was tested in various muscle relaxant paradigms, i.e. chimney test, traction test, rota rod and inclined plane. In anxiolytic and muscle relaxant tests, HEVB (0.3, 0.4 and 0.5 g/kg, i.p.), diazepam (1 mg/kg, i.p.) or distilled water (10 ml/kg i.p.) were administered 30, 60 and 90 min before performing the tests in mice. HEVB was also screened for a sleep-inducing effect. The antidepressant activity was determined by using the forced swimming test (FST), while line crossing in a special box was used for locomotor activity. HEVB showed a significant (P < 0.05) dose-dependent anxiolytic action in the staircase test. In muscle relaxant paradigms, a dose-dependent muscle relaxation was observed. For the phenobarbitone sleep induction test, HEVB notably (P < 0.05) reduced the latency time and increased the total sleeping duration. However, HEVB was devoid of any antidepressant activity, while the movements of mice were reduced significantly (P < 0.05) in locomotor activity. The results suggest that HEVB has anxiolytic, muscle relaxant, sleep-inducing (sedative) activity and, thus, provides pharmacological justification for the use of this plant as a sedative and for the relief of various nervous disorders.

Effects of Psychological Stress and Alprazolam on Development of Oral Candidiasis in Rats

PubMed Central

Núñez, M. J.; Balboa, J.; Riveiro, P.; Liñares, D.; Mañá, P.; Rey-Méndez, M.; Rodríguez-Cobos, A.; Suárez-Quintanilla, J. A.; García-Vallejo, L. A.; Freire-Garabal, M.

2002-01-01

Psychological stress has been found to suppress cell-mediated immune responses that are important in limiting the proliferation of Candida albicans. Since anxiolytic drugs can restore cellular immunity in rodents exposed to stress conditions, we designed experiments conducted to evaluate the effects of alprazolam (1 mg/kg of body weight/day), a central benzodiazepine anxiolytic agonist, on the development of oral candidiasis in Sprague-Dawley rats exposed to a chronic auditory stressor. Animals were submitted to surgical hyposalivation in order to facilitate the establishment and persistence of C. albicans infection. Application of stress and treatment with drugs (placebo or alprazolam) were initiated 7 days before C. albicans inoculation and lasted until the end of the experiments (day 15 postinoculation). Establishment of C. albicans infection was evaluated by swabbing the inoculated oral cavity with a sterile cotton applicator on days 2 and 15 after inoculation, followed by plating on YEPD (yeast extract-peptone-dextrose) agar. Tissue injury was determined by the quantification of the number and type (normal or abnormal) of papillae on the dorsal tongue per microscopic field. A semiquantitative scale was devised to assess the degree of colonization of the epithelium by fungal hyphae. Our results show that stress exacerbates C. albicans infection of the tongues of rats. Significant increases in Candida counts, the percentage of the tongue's surface covered with clinical lesions, the percentage of abnormal papillae, and the colonization of the epithelium by fungal hyphae were found in stressed rats compared to those found in the unstressed rats. Treatment with alprazolam significantly reversed these adverse effects of stress, showing that, besides the psychopharmacological properties of this anxiolytic drug against stress, it has consequences for Candida infection. PMID:12093685

Assessing anxiety in C57BL/6J mice: a pharmacological characterization of the open-field and light/dark tests.

PubMed

Heredia, Luis; Torrente, Margarita; Colomina, María T; Domingo, José L

2014-01-01

In order to assess anxiety in mammals various tests and species are currently available. These current assays measure changes in anxiety-like behaviors. The open-field and the light/dark are anxiety tests based on the spontaneous behavior of the animals, with C57BL/6J mice being a frequently used strain in behavioral studies. However, the suitability of this strain as a choice in anxiety studies has been questioned. In this study, we performed two pharmacological characterizations of this strain in both the open-field and the light/dark tests. We examined the changes in the anxiety-like behaviors of C57BL/6J mice exposed to chlordiazepoxide (CDP), an anxiolytic drug, at doses of 5 and 10 mg/kg, picrotoxine (PTX), an anxiogenic drug, at doses of 0.5 and 1 mg/kg, and methylphenidate (MPH), a psychomotor stimulant drug, at doses of 5 and 10 mg/kg, in a first experiment. In a second experiment, we tested CDP at 2.5 mg/kg, PTX at 2 mg/kg and MPH at 2.5 mg/kg. Results showed an absence of anxiolytic-like effects of CDP in open-field and light/dark tests. Light/dark test was more sensitive to the anxiogenic effects of PTX than the open-field test. Finally, a clear anxiogenic effect of MPH was observed in the two tests. Although C57BL/6J mice could not be a sensitive model to study anxiolytic effects in pharmacological or behavioral interventions, it might be a suitable model to test anxiogenic effects. Further studies are necessary to corroborate these results. Copyright © 2013 Elsevier Inc. All rights reserved.

Ultra-high-pressure liquid chromatography tandem mass spectrometry determination of antidepressant and anxiolytic drugs in neonatal meconium and maternal hair.

PubMed

Pichini, Simona; Cortes, Laura; Marchei, Emilia; Solimini, Renata; Pacifici, Roberta; Gomez-Roig, Mª Dolores; García-Algar, Oscar

2016-01-25

A procedure based on ultra-high-pressure liquid chromatography tandem mass spectrometry has been developed for the determination of 22 antidepressant and anxiolytic drugs ad metabolites in the three consecutive maternal hair segments representing the pregnancy trimesters and paired neonatal meconium samples. After hair washing with methyl alcohol and diethyl ether and subsequent addition of internal standards, hair samples were treated with 500 μl VMA-T M3 reagent for 1h at 100 °C. After cooling, 100 μl M3 extract were diluted with 400 μl water and a volume of 10 μl was injected into chromatographic system. Meconium samples were firstly treated with 1 ml methyl alcohol and the organic layer back-extracted twice with 1.5 ml of a mixture of ethylacetate:hexane (80:20, v/v). Chromatographic separation was achieved at ambient temperature using a reverse-phase column and a linear gradient elution with two solvents: 0.3% formic acid in acetonitrile and 5mM ammonium formate pH 3. The mass spectrometer was operated in positive ion mode, using multiple reaction monitoring via positive electrospray ionization. The method was linear from the limit of quantification (0.05-1 ng/mg hair and 5-25 ng/g meconium depending on analyte under investigation;) to 10 ng/mg hair and 1000 ng/g meconium, with an intra- and inter-assay imprecision and inaccuracy always less than 20% and an analytical recovery between 66.6% and 95.3%, depending on the considered analyte and biological matrix. Using the validated method, 7 mothers were found positive to one or more hair segments and 5 meconium samples were found positive to one or more antidepressant and anxiolytic drugs, assessing prenatal exposure to these drugs following maternal consumption in one or more pregnancy trimesters. Copyright © 2015 Elsevier B.V. All rights reserved.

Stopping Antidepressants and Anxiolytics as Major Concerns Reported in Online Health Communities: A Text Mining Approach.

PubMed

Abbe, Adeline; Falissard, Bruno

2017-10-23

Internet is a particularly dynamic way to quickly capture the perceptions of a population in real time. Complementary to traditional face-to-face communication, online social networks help patients to improve self-esteem and self-help. The aim of this study was to use text mining on material from an online forum exploring patients' concerns about treatment (antidepressants and anxiolytics). Concerns about treatment were collected from discussion titles in patients' online community related to antidepressants and anxiolytics. To examine the content of these titles automatically, we used text mining methods, such as word frequency in a document-term matrix and co-occurrence of words using a network analysis. It was thus possible to identify topics discussed on the forum. The forum included 2415 discussions on antidepressants and anxiolytics over a period of 3 years. After a preprocessing step, the text mining algorithm identified the 99 most frequently occurring words in titles, among which were escitalopram, withdrawal, antidepressant, venlafaxine, paroxetine, and effect. Patients' concerns were related to antidepressant withdrawal, the need to share experience about symptoms, effects, and questions on weight gain with some drugs. Patients' expression on the Internet is a potential additional resource in addressing patients' concerns about treatment. Patient profiles are close to that of patients treated in psychiatry. ©Adeline Abbe, Bruno Falissard. Originally published in JMIR Mental Health (http://mental.jmir.org), 23.10.2017.

Impact of hospital type II violent events: use of psychotropic drugs and mental health services.

PubMed

Dement, John M; Lipscomb, Hester J; Schoenfisch, Ashley L; Pompeii, Lisa A

2014-06-01

While violence can adversely affect mental health of victims, repercussions of violence against workers is not as well characterized. We explored relationships between workplace violent events perpetrated by patients or visitors (Type II) against hospital employees and the employee use of psychotropic medications or mental health services using a data system that linked violent events with health claims. Significant associations were observed between reported Type II workplace violent events and employee prescription claims for anti-depressants and anxiolytics combined (RR = 1.45, 95% CI = 1.01-2.33) and anti-depressants alone (RR = 1.65, 95% CI = 1.10-2.48). No significant association between reported violent events and health claims for treatment of depression or anxiety was observed. Type II violence experienced by hospital workers may lead to increased use of psychotropic drugs, particularly anti-depressants but also anxiolytics. Our results suggest an important role of employee assistance programs in mitigating the psychological consequences of workplace violent events. © 2014 Wiley Periodicals, Inc.

Involvement of the CA1 GABAA receptors in MK-801-induced anxiolytic-like effects: an isobologram analysis.

PubMed

Naseri, Mohammad-Hasan; Hesami-Tackallou, Saeed; Torabi-Nami, Mohammad; Zarrindast, Mohammad-Reza; Nasehi, Mohammad

2014-06-01

There seems to be a close relationship between hippocampal N-methyl-D-aspartic acid (NMDA) and GABAA receptors with respect to the modulation of behavior that occurs in the CA1 region of the hippocampus. This study investigated the possible involvement of the CA1 GABAA receptors in anxiolytic-like effects induced by (+)-MK-801 (a noncompetitive antagonist of the NMDA subtype of the glutamate receptor). Male Wistar rats were subjected to the elevated plus-maze apparatus and open arm time (%OAT), and open arm entries (%OAE) for anxiety-related behaviors, and closed arm entries that correspond to the locomotor activity were assessed. An intra-CA1 injection of (+)-MK-801 (2 μg/rat) and muscimol (0.5 μg/rat; a GABAA receptor agonist) increased %OAT and %OAE by themselves while not altering the closed arm entries, indicating an anxiolytic-like effect of these drugs. Injection of bicuculline (0.1, 0.25, and 0.5 μg/rat; a GABAA receptor antagonist) did not alter any of the anxiety-related parameters. An intra-CA1 injection of a subthreshold dose of muscimol (0.1 μg/rat) or bicuculline (0.5 μg/rat), 5 min before injection of subthreshold and effective doses of (+)-MK-801 (0.5, 1 and 2 μg/rat), increased and decreased the anxiolytic-like effect of (+)-MK-801, respectively. The isobologram analysis of these findings suggested a synergistic anxiety-like effect of intra-CA1 (+)-MK-801 and muscimol. In conclusion, the CA1 GABAA receptors appear to be involved in anxiolytic-like behaviors induced by (+)-MK-801.

[Characteristics of clinical effects of paxil in the treatment of endogenous depression].

PubMed

Panteleeva, G P; Korenev, A N; Khananashvili, M M; Oleĭchik, I V; Kaleda, V G

1998-01-01

47 patients with endogenous depressions were treated with paxil (paroxetine) during 4 weeks in the daily dose of 30-40 mg. Improvement of psychical state was observed in 89.3% of the patients; improvement was significant in 78.7%. Severity of the depression reduced from 28.9 to 6.0 scores according to Hamilton Depression Rating Scale. Antidepressive activity of paxil was observed at the third day of the therapy. Symptoms of depression disappeared completely in 46.7% of the patients 2 weeks after the beginning of treatment and in 62.8% of the cases in 4 weeks. Thymoleptic and sedative-anxiolytic effects prevailed in the spectrum of antidepressive activity of paxil; while its stimulating effect was expressed smaller. Mentioned peculiarities of paxil action, its small toxicity and positive subjective attitude of the patients towards the drug make this preparation quite valuable, especially in the treatment of classic melancholic and anxious depressions.

The pattern of anxiolytic and hypnotic management by Australian general practice trainees.

PubMed

Holliday, Simon M; Morgan, Simon; Tapley, Amanda; Henderson, Kim M; Dunlop, Adrian J; van Driel, Mieke L; Spike, Neil A; McArthur, Lawrence A; Ball, Jean; Oldmeadow, Christopher J; Magin, Parker J

2017-03-01

Guidelines recommend anxiolytics and hypnotics (A/H) as second-line, short-term medications. We aimed to establish prevalence and associations of A/H prescribing by Australian general practice (GP) trainees. A cross-sectional analysis from a cohort study of vocational trainees from four GP Regional Training Providers during 2010-2013. General practice trainees act as independent practitioners (including for prescribing purposes) while having recourse to advice from a GP supervisor. Practice and trainee demographic data were collected as well as patient, clinical and educational data from 60 consecutive consultations of each trainee each training term. Analysis was at the level of individual problem managed, with the outcome factor being prescription of any anxiolytic or hypnotic. Overall, 645 registrars (response rate 94.0%) prescribed 68 582 medications in 69 621 consultations (with 112 890 problems managed). A/Hs were prescribed for 1.3% of problems managed and comprised 2.2% of all prescriptions. They were prescribed particularly for insomnia (28.2%) or anxiety (21.8%), but also for many 'off-label' indications. Significant associations of A/H prescriptions were: patient-level (greater age, Aboriginal and Torres Strait Islander status, English-speaking background, being new to the trainee but not to the practice); trainee-level (male) and consultation-level (longer duration, pre-existing problem, specialist referral not being made). Prescribing was significantly lower in one of the four Regional Training Providers. GP trainees, inconsistent with most guideline recommendations, prescribe A/Hs mainly as maintenance therapy to unfamiliar and older patients. Our results suggest that changes in management approaches are needed which may be facilitated by support for psychotherapeutic training. [Holliday SM, Morgan S, Tapley A, Henderson KM, Dunlop AJ, van Driel ML, Spike NA, McArthur LA, Ball J, Oldmeadow CJ, Magin PJ. The pattern of anxiolytic and hypnotic management by Australian general practice trainees. Drug Alcohol Rev 2017;36:261-269]. © 2016 Australasian Professional Society on Alcohol and other Drugs.

Differences in psychotropic drug prescriptions among ethnic groups in the Netherlands.

PubMed

Wittkampf, Laura Christina; Smeets, Hugo M; Knol, Mirjam J; Geerlings, Mirjam I; Braam, Arjan W; De Wit, Niek J

2010-08-01

Psychotropic drug use in Europe and the USA has increased in the past 20 years. The rise in mental health-care use instigated a debate about possible differences in prevalence rates between different ethnic groups in the Netherlands, although the exact differences were unknown. The aim of this study was to determine whether these minority groups were more or less likely than the native population to receive psychotropic drugs. A descriptive population study was conducted using the Agis Health Database, containing demographic and health-care consumption data of approximately 1.5 million inhabitants of the Netherlands. Rates of prescriptions of psychotropic drugs from 2001 to 2006 and adjusted odds ratios for psychotropic drug prescriptions among native Dutch, Turkish and Moroccan ethnic groups were calculated. These data were analysed using logistic regression, after being adjusted for age, gender and socioeconomic status. The mean year prevalence of psychotropic drug prescriptions from 2001 to 2006 was 14.0%. Except for a decrease in anxiolytic drugs, the prescriptions of psychotropic drugs increased from 2001 to 2006. These trends were the same for all of the ethnic groups considered. Among both the Moroccan and Turkish populations, there was a higher risk of antidepressant and antipsychotic drug prescriptions, and a pronounced lower risk of ADHD medication and lithium prescriptions compared to the native population. Among the Turkish population, the risk of anxiolytic drug prescriptions was greater than in the native population. Compared to the native population in the Netherlands, first- and second-generation Turkish and Moroccan immigrants had an increased risk of antidepressant and antipsychotic drug prescriptions and a decreased risk of ADHD medication and Lithium prescriptions. Further research is needed to clarify whether patients of different ethnic backgrounds with the same symptoms receive similar diagnosis and adequate treatment.

Organisational downsizing and increased use of psychotropic drugs among employees who remain in employment.

PubMed

Kivimäki, Mika; Honkonen, Teija; Wahlbeck, Kristian; Elovainio, Marko; Pentti, Jaana; Klaukka, Timo; Virtanen, Marianna; Vahtera, Jussi

2007-02-01

Organisational downsizing is common in modern work life, but its effect on employees' mental health is not known. The authors examined whether working in downsizing organisations predicts use of psychotropic drugs among employees who remain in employment. Prospective cohort study of municipal employees in Finland. 4783 employees worked in downsized units but kept their jobs after downsizing in 1993, 4271 employees lost their jobs during the downsizing, and 17 599 employees did not experience downsizing. The outcome was psychotropic drug prescriptions (antidepressants, anxiolytics and hypnotics) during 1994-2000 extracted from nationwide registers and linked to the data by means of each participant's personal identification number. After adjustment for predownsizing characteristics, employees who were exposed to downsizing but kept their jobs were at a higher risk of being prescribed psychotropic drugs (rate ratio 1.49, 95% CI 1.10 to 2.02 in men and 1.12, 95% CI 1.00 to 1.27 in women) than those not exposed to downsizing. The association of downsizing was strongest with hypnotics among the men and with anxiolytics among the women. An increased rate of psychotropic prescriptions after downsizing was also seen in male workers who lost their job (rate ratio 1.64, 95% CI 1.19 to 2.25). The association between organisational downsizing and increased use of psychotropic drugs suggests that this managerial strategy may pose mental health risks among employees.

Acute behavioural and neurotoxic effects of MDMA plus cocaine in adolescent mice.

PubMed

Daza-Losada, M; Rodríguez-Arias, M; Maldonado, C; Aguilar, M A; Guerri, C; Miñarro, J

2009-01-01

The poly-drug pattern is the most common among those observed in MDMA users, with cocaine being a frequently associated drug. This study evaluates the acute effects of MDMA (5, 10 and 20 mg/kg), alone or in combination with cocaine (25 mg/kg), on motor activity, anxiety (elevated plus maze and social interaction test), memory and brain monoamines in adolescent mice. Both drugs, administered alone or concurrently, produced hyperactivity and a decrease in social contacts. However, an anxiolytic effect, studied by means of the elevated plus maze and expressed as an increase in the time spent on the open arms, was observed only in those animals treated with cocaine and MDMA. The passive avoidance task was affected only with the highest MDMA dose (20 mg/kg). Mice treated with MDMA did not present significant changes in brain monoamines, while those receiving MDMA and cocaine showed a decrease in DA in the striatum, which was accompanied by an increase in the serotonin concentration in the striatum and cortex 30 min after acute administration. In conclusion, the combined use of MDMA and cocaine produces a predominance of serotonin over DA, which is associated with an anxiolytic profile, defensive behaviours and fewer social contacts.

Acute and subchronic effects of MDMA ("ecstasy") on anxiety in male mice tested in the elevated plus-maze.

PubMed

Navarro, José Francisco; Maldonado, Enrique

2002-10-01

3,4-Methylenedioxymethamphetamine (MDMA) is a compound structurally similar to methamphetamine, which has become one of the most widely used illicit substances. Animal studies investigating acute effects of MDMA on anxiety are unclear since, although an anxiogenic-like action of MDMA in different animal models of anxiety has been mainly described, there is also evidence supporting an anxiolytic-like effect for this drug. An attempt was made to clarify the possible anxiogenic-like profile of MDMA (1, 8 and 15 mg/kg i.p.) by analyzing its effect on behavior of male mice in the elevated plus-maze test. Moreover, the possible development of tolerance to the effects of MDMA on anxiety after its subchronic administration for 5 consecutive days was examined. The parameters evaluated included: (1) total time in open arms, (2) total time in closed arms, (3) total time in central area, (4) number of open arm entries, (5) number of closed arm entries and (6) number of central area entries. Acute treatment with MDMA (8 mg/kg) significantly reduced the time spent in the open arms, as well as markedly increasing the number of entries in the closed arms and in the central area, as compared with the control group, suggesting that MDMA, at this dose, has an anxiogenic-like activity. Mice subchronically treated with the drug (1 and 8 mg/kg) displayed a notable reduction in the time spent in the open arms, accompanied by an increase in the time spent in the closed arms and in the central platform. These results indicate that the anxiogenic-like effect found after acute treatment is not only maintained but also more marked after subchronic treatment. In contrast, mice treated subchronically with the highest dose of MDMA (15 mg/kg) exhibited a significant increase in the time spent in the open arms as well as a marked reduction in the time spent in the closed arms, supporting an anxiolytic-like activity of the drug. A possible dual pharmacological property of MDMA on anxiety is suggested.

Multi-psychotropic drug prescription and the association to neuropsychiatric symptoms in three Norwegian nursing home cohorts between 2004 and 2011.

PubMed

Gulla, Christine; Selbaek, Geir; Flo, Elisabeth; Kjome, Reidun; Kirkevold, Øyvind; Husebo, Bettina S

2016-06-01

Neuropsychiatric symptoms, such as affective symptoms, psychosis, agitation, and apathy are common among nursing home patients with and without dementia. Treatment with one or more psychotropic drug is often without explicit clinical indication, despite low treatment efficacy, and potential side effects. We aim to investigate the multi-psychotropic drug use to identify factors and patient characteristics associated with multi-use. We analysed three cohorts from 129 Norwegian nursing homes, collected between 2004 and 2011. Patients (N = 4739) were assessed with the Neuropsychiatric Inventory - Nursing Home version (NPI-NH), Clinical Dementia Rating scale, and Physical Self Maintenance Scale. We used ordinal logistic regression to analyse associations between psychotropics (antidepressants, antipsychotics, anxiolytics, hypnotics, and anti-dementia drugs), patient characteristics, and neuropsychiatric symptoms. Patients used on average 6.6 drugs; 27 % used no psychotropics, 32 % one, and 41 % multiple psychotropic drugs (24 % two, 17 % ≥3). Thirty-nine percent were prescribed antidepressants, 30 % sedatives, 24 % anxiolytics, and 20 % antipsychotics. The total NPI-NH score was associated with multi-use (OR 1.02, 95 % CI 1.02-1.03), and increased from a mean of 13.5 (SD 16.3) for patients using none, to 25.5 (21.8) for patients using ≥3 psychotropics. Affective symptoms (depression and anxiety) were most strongly associated with multi-psychotropic drug use (OR 1.10, 95 % CI: 1.09-1.12). Female gender, independency in daily living, younger age, dementia, and many regular drugs were also associated with multi-use. Forty-one percent were exposed to multi-psychotropic drug prescriptions. Contrary to current evidence and guidelines, there is an extensive use of multiple psychotropic drugs in patients with severe NPS and dementia.

Mexican medicinal plants with anxiolytic or antidepressant activity: Focus on preclinical research.

PubMed

López-Rubalcava, Carolina; Estrada-Camarena, Erika

2016-06-20

Anxiety and depression are considered the most prevalent psychiatric disorders worldwide. In Mexico, the use of medicinal plants to alleviate the symptoms associated with these psychiatric disorders is increasing. However, there is little scientific evidence that validates the efficacy of these plants. This evidence needs to be critically revised, and further studied to provided scientific support for their use. To identify the plants that are used in Mexico for the treatment of disorders related to anxiety and depression, and to review the current preclinical and when available, clinical information of these plants. We searched in scientific databases (Pubmed, Web of Science, Scopus and other web sources such as "Biblioteca digital de la medicina tradicional Mexicana" ) for Mexican plants used for the treatment of anxiety and depression that have been analyzed in preclinical studies. Additional information was obtained from published books. For this review, we also consider those plants used in Mexican traditional medicine for the treatment of "nervios," "susto" or "espanto;" common terms that describe symptoms related to anxiety and depression disorders. The bibliographic search identified 49 plants used in Mexican traditional medicine for the treatment of disorders related to anxiety and depression. From all these plants, 59% were analyzed in preclinical research, and only 8% were tested in clinical studies; only a few of these studies tried to elucidate their mechanism of action. In general, it is proposed that the plant extracts interact with the GABAergic system. However, only part of these studies attempted to analyze other neurotransmitter systems. Finally, in some cases, drug-herbal interactions were reported. There is a large number of Mexican medicinal plants used as a treatment for anxiety and depression disorders. Although some of these plants have been studied in preclinical research, in most cases these studies are preliminary, and the understanding of the mechanism of action is inconclusive. The need for systematic studies in preclinical and clinical research is evident, and efforts should be done to fulfill these research. Finally, it is important also to study possible drug-herbal interactions to establish specific recommendations for people that use these plants as anxiolytic or antidepressant treatments either alone or in combination with another type of medicine. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Making Sense of Fear Testing - Validating Common Behavioral Tests used in Swine

USDA-ARS?s Scientific Manuscript database

Tests to assess fear are commonly used in laboratory animals, such as mice and rats, when researchers wish to understand the implications of specific drugs, such as anxiolytics, or specific environments which may be used to house experimental animals. Researchers who study the welfare of livestock ...

The anxiolytic-like effect of 6-styryl-2-pyrone in mice involves GABAergic mechanism of action.

PubMed

Chaves, Edna Maria Camelo; Honório-Júnior, Jose Eduardo Ribeiro; Sousa, Caren Nádia Soares; Monteiro, Valdécio Silveira; Nonato, Dayanne Terra Tenório; Dantas, Leonardo Pimentel; Lúcio, Ana Silvia Suassuna Carneiro; Barbosa-Filho, José Maria; Patrocínio, Manoel Cláudio Azevedo; Viana, Glauce Socorro Barros; Vasconcelos, Silvânia Maria Mendes

2018-02-01

The present work aims to investigate the anxiolytic activity of 6-styryl-2-pyrone (STY), obtained from Aniba panurensis, in behavioral tests and amino acids dosage on male Swiss mice. The animals were treated with STY (1, 10 or 20 mg), diazepam (DZP 1 or 2 mg/kg) or imipramine (IMI 30 mg/kg). Some groups were administered with flumazenil, 30 min before administration of the STYor DZP. The behavioral tests performed were open field, rota rod, elevated plus maze (EPM), hole-board (HB) and tail suspension test (TST). After behavioral tests, these animals were sacrificed and had their prefrontal cortex (PFC), hippocampus (HC) and striatum (ST) dissected for assaying amino acids (aspartate- ASP, glutamate- GLU, glycine- GLY, taurine- TAU and Gamma-aminobutyric acid- GABA). In EPM test, STY or DZP increased the number of entries and the time of permanence in the open arms, but these effects were reverted by flumazenil. In the HB test, STY increased the number of head dips however this effect was blocked by flumazenil. The effects of the STY on amino acid concentration in PFC showed increased GLU, GABA and TAU concentrations. In hippocampus, STY increased the concentrations of all amino acids studied. In striatum, STY administration at lowest dose reduced GLU concentrations, while the highest dosage caused the opposite effect. GLI, TAU and GABA concentrations increased with STY administration at highest doses. In conclusion, this study showed that STY presents an anxiolytic-like effect in behavioral tests that probably is related to GABAergic mechanism of action.

Central nervous system effects and chemical composition of two subspecies of Agastache mexicana; an ethnomedicine of Mexico.

PubMed

Estrada-Reyes, Rosa; López-Rubalcava, C; Ferreyra-Cruz, Octavio Alberto; Dorantes-Barrón, Ana María; Heinze, G; Moreno Aguilar, Julia; Martínez-Vázquez, Mariano

2014-04-11

Agastache mexicana subspecies mexicana (Amm) and xolocotziana (Amx) are used in Mexican traditional medicine to relief cultural affiliation syndromes known as "susto" or "espanto", for "nervous" condition, and as a sleep aid. Despite its intensive use, neuropharmacological studies are scarce, and the chemical composition of the aqueous extracts has not been described. Aims of the study are: (1) To analyze the chemical composition of aqueous extracts from aerial parts of Amm and Amx. (2) To evaluate the anxiolytic-like, sedative, antidepressant-like effects. (3) Analyze the general toxic effects of different doses. Anxiolytic-like and sedative effects were measured in the avoidance exploratory behavior, burying behavior and the hole-board tests. The antidepressant-like actions were studied in the forced swimming and tail suspension tests. Finally, general activity and motor coordination disturbances were evaluated in the open field, inverted screen and rota-rod tests. The acute toxicity of Amm and Amx was determined by calculating their LD50 (mean lethal dose). The chemical analyses were performed employing chromatographic, photometric and HPLC-ESI-MS techniques. Low doses of Amm and Amx (0.1σ1.0mg/kg) induced anxiolytic-like actions; while higher doses (over 10mg/kg) induced sedation and reduced the locomotor activity, exerting a general inhibition in the central nervous system (CNS). Results support the use of Amm and Amx in traditional medicine as tranquilizers and sleep inducers. Additionally, this paper contributes to the knowledge of the chemical composition of the aqueous extracts of these plants. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Dose-dependent effects of β-phenylglutamic acid hydrochloride (RGPU-135, neuroglutam) on animal behavior.

PubMed

Tyurenkov, I N; Bagmetova, V V; Chernyshova, Yu V; Merkushenkova, O V

2014-12-01

β-Phenylglutamic acid hydrochloride (RGPU-135, neuroglutam) in doses of 13-650 mg/kg suppressed depressive behavior of animals in the Porsolt test (i.e. produced antidepressant properties), reduced anxiety in the open-field, elevated plus maze, and Vogel conflict tests (i.e. produced anxiolytic effects). RGPU-135 in doses of 26-130 mg/kg exhibited more pronounced antidepressant action and in doses of 26 and 52 mg/kg had more pronounced anxiolytic effects. RGPU-135 in doses of 13-78 mg/kg increased locomotor and exploratory activity of animals in the open-field test. Activating effects of this agent decreased with increasing the dose. RGPU-135 in the subtoxic dose (650 mg/kg) suppressed locomotor activity of animals (produced sedative effect).

Minocycline does not evoke anxiolytic and antidepressant-like effects in C57BL/6 mice.

PubMed

Vogt, M A; Mallien, A S; Pfeiffer, N; Inta, I; Gass, P; Inta, D

2016-03-15

Minocycline is a broad-spectrum tetracycline antibiotic with multiple actions, including anti-inflammatory and neuroprotective effects, that was proposed as novel treatment for several psychiatric disorders including schizophrenia and depression. However, there are contradictory results regarding antidepressant effects of minocycline in rodent models. Additionally, the possible anxiolytic effect of minocycline is still poorly investigated. Therefore, we aimed to clarify in the present study the influence of minocycline on behavioral correlates of mood disorders in standard tests for depression and anxiety, the Porsolt Forced Swim Test (FST), Elevated O-Maze, Dark-Light Box Test and Openfield Test in adult C57BL/6 mice. We found, unexpectedly, that mice treated with minocycline (20-40mg/kg, i.p.) did not display antidepressant- or anxiolytic-like behavioral changes in contrast to mice treated with diazepam (0.5mg/kg, anxiety tests) or imipramine (20mg/kg, depressive-like behavior). These results are relevant for future studies, considering that C57BL/6 mice, the most widely used strain in pharmacological and genetic animal models, did not react as expected to the treatment regime applied. Copyright © 2015 Elsevier B.V. All rights reserved.

Pregnanolone Glutamate, a Novel Use-Dependent NMDA Receptor Inhibitor, Exerts Antidepressant-Like Properties in Animal Models.

PubMed

Holubova, Kristina; Nekovarova, Tereza; Pistovcakova, Jana; Sulcova, Alexandra; Stuchlík, Ales; Vales, Karel

2014-01-01

A number of studies demonstrated a rapid onset of an antidepressant effect of non-competitive N-methyl-d-aspartic acid receptor (NMDAR) antagonists. Nonetheless, its therapeutic potential is rather limited, due to a high coincidence of negative side-effects. Therefore, the challenge seems to be in the development of NMDAR antagonists displaying antidepressant properties, and at the same time maintaining regular physiological function of the NMDAR. Previous results demonstrated that naturally occurring neurosteroid 3α5β-pregnanolone sulfate shows pronounced inhibitory action by a use-dependent mechanism on the tonically active NMDAR. The aim of the present experiments is to find out whether the treatment with pregnanolone 3αC derivatives affects behavioral response to chronic and acute stress in an animal model of depression. Adult male mice were used throughout the study. Repeated social defeat and forced swimming tests were used as animal models of depression. The effect of the drugs on the locomotor/exploratory activity in the open-field test was also tested together with an effect on anxiety in the elevated plus maze. Results showed that pregnanolone glutamate (PG) did not induce hyperlocomotion, whereas both dizocilpine and ketamine significantly increased spontaneous locomotor activity in the open field. In the elevated plus maze, PG displayed anxiolytic-like properties. In forced swimming, PG prolonged time to the first floating. Acute treatment of PG disinhibited suppressed locomotor activity in the repeatedly defeated group-housed mice. Aggressive behavior of isolated mice was reduced after the chronic 30-day administration of PG. PG showed antidepressant-like and anxiolytic-like properties in the used tests, with minimal side-effects. Since PG combines GABAA receptor potentiation and use-dependent NMDAR inhibition, synthetic derivatives of neuroactive steroids present a promising strategy for the treatment of mood disorders. -3α5β-pregnanolone glutamate (PG) is a use-dependent antagonist of NMDA receptors.-We demonstrated that PG did not induce significant hyperlocomotion.-We showed that PG displayed anxiolytic-like and antidepressant-like properties.

A possible mechanism for anxiolytic and antidepressant effects of alpha- and beta-amyrin from Protium heptaphyllum (Aubl.) March.

PubMed

Aragão, G F; Carneiro, L M V; Junior, A P F; Vieira, L C; Bandeira, P N; Lemos, T L G; Viana, G S de B

2006-12-01

In the present study, we examined the anxiolytic and antidepressant effects of the mixture of alpha- and beta-amyrin (AMY), pentacyclic triterpenes isolated from the stem bark resin of Protium heptaphyllum. These effects of AMY were demonstrated by the open-field, elevated-plus-maze, rota rod, forced swimming, and pentobarbital-induced sleeping time tests, in mice. In the open-field test, AMY at the doses of 10, 25 and 50 mg/kg, after intraperitoneal or oral administrations, significantly decreased the number of crossings, grooming, and rearing. All these effects were reversed by the pre-treatment with flumazenil (2.5 mg/kg, i.p.), similarly to those observed with diazepam used as a positive standard. In the elevated-plus-maze test, AMY increased the time of permanence and the number of entrances in the open arms. On the contrary, the time of permanence and the number of entrances in the closed arms were decreased. All these effects were also completely reversed by flumazenil, an antagonist of benzodiazepine receptors. In the pentobarbital-induced sleeping time test, AMY at the same doses significantly increased the animals sleeping time duration. In the rota rod test, AMY did not alter motor coordination and, thus, was devoid of effects, as related to controls. Since AMY, at the doses of 10 and 25 mg/kg, showed a sedative effect in the open field test, lower doses (2.5 and 5.0 mg/kg) were used in the forced swimming test, producing a decrease in the immobility time, similarly to that of imipramine, the positive control. The effect of AMI was greater when it was administered 15 min after imipramine (10 mg/kg). However, the antidepressant AMY effects were not altered by the previous administration of paroxetine, a selective blocker of serotonin uptake. In addition, AMY effects in the forced swimming test were totally blocked by reserpine pretreatment, a drug known to induce depletion of biogenic amines. In conclusion, the present work evidenced sedative and anxiolytic effects of AMY that might involve an action on benzodiazepine-type receptors, and also an antidepressant effect where noradrenergic mechanisms will probably play a role.

[Psychoactive drugs and costs in the Madrid III (Valdemoro) prison].

PubMed

Algora-Donoso, I; Varela-González, O

2008-01-01

Annual pharmaceutical expenditures in prisons increases dramatically and the rising costs of psychoactive drugs have especially contributed to this. These drugs are often prescribed in order to find therapeutic uses in the field of personality disorders, addictions, and dysfunctional behaviours that are not included in the authorized indications (compassionate use). This study has enabled a detailed description of the use of psychoactive drugs at the Madrid III prison, a centre with one of the lowest levels of pharmaceutical expenditure in this autonomous community. During a two-week period, all prescriptions of psychoactive drugs were collected and registered along with data of several possible conditioning factors. 20.5% of the population was receiving some kind of psychoactive drug; 76% of those inmates undergoing treatment were receiving one or two substances; 65% were taking anxiolytics, 38% antidepressants and 27% antipsychotics. The total amount of psychoactive drugs consumed was 9,840 defined daily doses, 46% of which were anxiolytics, 17% antidepressants and 14% antipsychotics. The total cost of the fortnight's treatment was euros 5,379 with a saving of euro 611 due to requesting and selecting offers carried out by the pharmacist. 72% of the costs were spent on anti-psychotics and the newer psychoactive drugs, representing 66% of the prescriptions, accounted for 98% of expenditure. The prescriber was one of the key influential factors over the amount, type and cost of the treatments. There are signs that compassionate use of current antipsychotics and antiepileptics, and newer antidepressants are a main cause of the dramatic increase in the costs, with cost-efficiency not always clearly demonstrated. These results are not an isolated fact restricted only to prisons, as demonstrated by consumption data published by the National Health System in the same year.

Long-term alterations in vulnerability to addiction to drugs of abuse and in brain gene expression after early life ethanol exposure.

PubMed

Barbier, Estelle; Pierrefiche, Olivier; Vaudry, David; Vaudry, Hubert; Daoust, Martine; Naassila, Mickaël

2008-12-01

Exposure to ethanol early in life can have long-lasting implications on brain function and drug of abuse response later in life. The present study investigated in rats, the long-term consequences of pre- and postnatal (early life) ethanol exposure on drug consumption/reward and the molecular targets potentially associated with these behavioral alterations. Since a relationship has been demonstrated between heightened drugs intake and susceptibility to drugs-induced locomotor activity/sensitization, anxiolysis, we tested these behavioral responses, depending on the drug, in control and early life ethanol-exposed animals. Our results show that progeny exposed to early life ethanol displayed increased consumption of ethanol solutions and increased sensitivity to cocaine rewarding effects assessed in the conditioned place preference test. Offspring exposed to ethanol were more sensitive to the anxiolytic effect of ethanol and the increased sensitivity could, at least in part, explain the alteration in the consumption of ethanol for its anxiolytic effects. In addition, the sensitivity to hypothermic effects of ethanol and ethanol metabolism were not altered by early life ethanol exposure. The sensitization to cocaine (20 mg/kg) and to amphetamine (1.2 mg/kg) was increased after early life ethanol exposure and, could partly explain, an increase in the rewarding properties of psychostimulants. Gene expression analysis revealed that expression of a large number of genes was altered in brain regions involved in the reinforcing effects of drugs of abuse. Dopaminergic receptors and transporter binding sites were also down-regulated in the striatum of ethanol-exposed offspring. Such long-term neurochemical alterations in transmitter systems and in the behavioral responses to ethanol and other drugs of abuse may confer an increased liability for addiction in exposed offspring.

Organisational downsizing and increased use of psychotropic drugs among employees who remain in employment

PubMed Central

Kivimäki, Mika; Honkonen, Teija; Wahlbeck, Kristian; Elovainio, Marko; Pentti, Jaana; Klaukka, Timo; Virtanen, Marianna; Vahtera, Jussi

2007-01-01

Objective Organisational downsizing is common in modern work life, but its effect on employees' mental health is not known. The authors examined whether working in downsizing organisations predicts use of psychotropic drugs among employees who remain in employment. Design, setting and participants Prospective cohort study of municipal employees in Finland. 4783 employees worked in downsized units but kept their jobs after downsizing in 1993, 4271 employees lost their jobs during the downsizing, and 17 599 employees did not experience downsizing. The outcome was psychotropic drug prescriptions (antidepressants, anxiolytics and hypnotics) during 1994–2000 extracted from nationwide registers and linked to the data by means of each participant's personal identification number. Main results After adjustment for predownsizing characteristics, employees who were exposed to downsizing but kept their jobs were at a higher risk of being prescribed psychotropic drugs (rate ratio 1.49, 95% CI 1.10 to 2.02 in men and 1.12, 95% CI 1.00 to 1.27 in women) than those not exposed to downsizing. The association of downsizing was strongest with hypnotics among the men and with anxiolytics among the women. An increased rate of psychotropic prescriptions after downsizing was also seen in male workers who lost their job (rate ratio 1.64, 95% CI 1.19 to 2.25). Conclusions The association between organisational downsizing and increased use of psychotropic drugs suggests that this managerial strategy may pose mental health risks among employees. PMID:17234876

Riluzole in the prelimbic medial prefrontal cortex attenuates veratrine-induced anxiety-like behaviors in mice.

PubMed

Ohashi, Masanori; Saitoh, Akiyoshi; Yamada, Misa; Oka, Jun-Ichiro; Yamada, Mitsuhiko

2015-01-01

We previously demonstrated in mice that the activation of prelimbic medial prefrontal cortex (PL) with the sodium channel activator veratrine induces anxiety-like behaviors via NMDA receptor-mediated glutamatergic neurotransmission. Riluzole directly affects the glutamatergic system and has recently been suggested to have an anxiolytic-like effect in both experimental animals and patients with anxiety disorders. We investigated the effects of co-perfusion of riluzole on veratrine-induced anxiety-like behaviors in mice. Extracellular glutamate levels were measured in 7-week-old male C57BL6 mice by using an in vivo microdialysis-HPLC/ECD system, and behaviors were assessed simultaneously in an open field (OF) test. Basal levels of glutamate were measured by collecting samples every 10 min for 60 min. The medium containing drugs was perfused for 30 min, and the OF test was performed during the last 10 min of drug perfusion. After the drug treatments, the drug-containing medium was switched to perfusion of control medium lacking drugs, and then samples were collected for another 90 min. Riluzole co-perfusion attenuated veratrine-induced increase in extracellular glutamate levels in the PL and completely diminished veratrine-induced anxiety-like behaviors. Interestingly, riluzole perfusion alone in the PL did not affect the basal levels of glutamate and anxiety-like behaviors. Our results suggest that compounds like riluzole that inhibit glutamatergic function in the PL are possible candidates for novel anxiolytics.

Antidepressive, anxiolytic, and antiaddictive effects of ayahuasca, psilocybin and lysergic acid diethylamide (LSD): a systematic review of clinical trials published in the last 25 years.

PubMed

Dos Santos, Rafael G; Osório, Flávia L; Crippa, José Alexandre S; Riba, Jordi; Zuardi, Antônio W; Hallak, Jaime E C

2016-06-01

To date, pharmacological treatments for mood and anxiety disorders and for drug dependence show limited efficacy, leaving a large number of patients suffering severe and persistent symptoms. Preliminary studies in animals and humans suggest that ayahuasca, psilocybin and lysergic acid diethylamide (LSD) may have antidepressive, anxiolytic, and antiaddictive properties. Thus, we conducted a systematic review of clinical trials published from 1990 until 2015, assessing these therapeutic properties. Electronic searches were performed using the PubMed, LILACS, and SciELO databases. Only clinical trials published in peer-reviewed journals were included. Of these, 151 studies were identified, of which six met the established criteria. Reviewed studies suggest beneficial effects for treatment-resistant depression, anxiety and depression associated with life-threatening diseases, and tobacco and alcohol dependence. All drugs were well tolerated. In conclusion, ayahuasca, psilocybin and LSD may be useful pharmacological tools for the treatment of drug dependence, and anxiety and mood disorders, especially in treatment-resistant patients. These drugs may also be useful pharmacological tools to understand psychiatric disorders and to develop new therapeutic agents. However, all studies reviewed had small sample sizes, and half of them were open-label, proof-of-concept studies. Randomized, double-blind, placebo-controlled studies with more patients are needed to replicate these preliminary findings.

Antidepressive, anxiolytic, and antiaddictive effects of ayahuasca, psilocybin and lysergic acid diethylamide (LSD): a systematic review of clinical trials published in the last 25 years

PubMed Central

dos Santos, Rafael G.; Osório, Flávia L.; Crippa, José Alexandre S.; Riba, Jordi; Zuardi, Antônio W.; Hallak, Jaime E. C.

2016-01-01

To date, pharmacological treatments for mood and anxiety disorders and for drug dependence show limited efficacy, leaving a large number of patients suffering severe and persistent symptoms. Preliminary studies in animals and humans suggest that ayahuasca, psilocybin and lysergic acid diethylamide (LSD) may have antidepressive, anxiolytic, and antiaddictive properties. Thus, we conducted a systematic review of clinical trials published from 1990 until 2015, assessing these therapeutic properties. Electronic searches were performed using the PubMed, LILACS, and SciELO databases. Only clinical trials published in peer-reviewed journals were included. Of these, 151 studies were identified, of which six met the established criteria. Reviewed studies suggest beneficial effects for treatment-resistant depression, anxiety and depression associated with life-threatening diseases, and tobacco and alcohol dependence. All drugs were well tolerated. In conclusion, ayahuasca, psilocybin and LSD may be useful pharmacological tools for the treatment of drug dependence, and anxiety and mood disorders, especially in treatment-resistant patients. These drugs may also be useful pharmacological tools to understand psychiatric disorders and to develop new therapeutic agents. However, all studies reviewed had small sample sizes, and half of them were open-label, proof-of-concept studies. Randomized, double-blind, placebo-controlled studies with more patients are needed to replicate these preliminary findings. PMID:27354908

Secondary Metabolites from Three Florida Sponges with Antidepressant Activity

PubMed Central

Kochanowska, Anna J.; Rao, Karumanchi V.; Childress, Suzanne; El-Alfy, Abir; Matsumoto, Rae R.; Kelly, Michelle; Stewart, Gina S.; Sufka, Kenneth J.; Hamann, Mark T.

2016-01-01

Brominated indole alkaloids are a common class of metabolites reported from sponges of the order Verongida. Herein we report the isolation, structure determination, and activity of metabolites from three Florida sponges, namely, Verongula rigida (order Verongida, family Aplysinidae), Smenospongia aurea, and S. cerebriformis (order Dictyoceratida, family Thorectidae). All three species were investigated chemically, revealing similarities in secondary metabolites. Brominated compounds, as well as sesquiterpene quinones and hydroquinones, were identified from both V. rigida and S. aurea despite their apparent taxonomic differences at the ordinal level. Similar metabolites found in these distinct sponge species of two different genera provide evidence for a microbial origin of the metabolites. Isolated compounds were evaluated in the Porsolt forced swim test (FST) and the chick anxiety–depression continuum model. Among the isolated compounds, 5,6-dibromo-N,N-dimethyltryptamine (1) exhibited significant antidepressant-like action in the rodent FST model, while 5-bromo-N,N-dimethyltryptamine (2) caused significant reduction of locomotor activity indicative of a potential sedative action. The current study provides ample evidence that marine natural products with the diversity of brominated marine alkaloids will provide potential leads for antidepressant and anxiolytic drugs. PMID:18217716

Pharmacological properties of cannabidiol in the treatment of psychiatric disorders: a critical overview.

PubMed

Mandolini, G M; Lazzaretti, M; Pigoni, A; Oldani, L; Delvecchio, G; Brambilla, P

2018-05-23

Cannabidiol (CBD) represents a new promising drug due to a wide spectrum of pharmacological actions. In order to relate CBD clinical efficacy to its pharmacological mechanisms of action, we performed a bibliographic search on PUBMED about all clinical studies investigating the use of CBD as a treatment of psychiatric symptoms. Findings to date suggest that (a) CBD may exert antipsychotic effects in schizophrenia mainly through facilitation of endocannabinoid signalling and cannabinoid receptor type 1 antagonism; (b) CBD administration may exhibit acute anxiolytic effects in patients with generalised social anxiety disorder through modification of cerebral blood flow in specific brain sites and serotonin 1A receptor agonism; (c) CBD may reduce withdrawal symptoms and cannabis/tobacco dependence through modulation of endocannabinoid, serotoninergic and glutamatergic systems; (d) the preclinical pro-cognitive effects of CBD still lack significant results in psychiatric disorders. In conclusion, current evidences suggest that CBD has the ability to reduce psychotic, anxiety and withdrawal symptoms by means of several hypothesised pharmacological properties. However, further studies should include larger randomised controlled samples and investigate the impact of CBD on biological measures in order to correlate CBD's clinical effects to potential modifications of neurotransmitters signalling and structural and functional cerebral changes.

Anxiolytic-Like Effects and Increase in Locomotor Activity Induced by Infusions of NMDA into the Ventral Hippocampus in Rat: Interaction with GABAergic System.

PubMed

Bina, Payvand; Rezvanfard, Mehrnaz; Ahmadi, Shamseddin; Zarrindast, Mohammad Reza

2014-10-01

In this study, we investigated the role of N-Methyl-D-Aspartate (NMDA) receptors in the ventral hippocampus (VH) and their possible interactions with GABAA system on anxiety-like behaviors. We used an elevated-plus maze test (EPM) to assess anxiety-like behaviors and locomotor activity in male Wistar rats. The results showed that intra-VH infusions of different doses of NMDA (0.25 and 0.5 μg/rat) increased locomotor activity, and also induced anxiolytic-like behaviors, as revealed by a tendency to increase percentage of open arm time (%OAT), and a significant increase in percentage of open arm entries (%OAE). The results also showed that intra-VH infusions of muscimol (0.5 and 1 μg/rat) or bicuculline (0.5 and 1 μg/rat) did not significantly affect anxiety-like behaviors, but bicuculline at dose of 1 μg/rat increased locomotor activity. Intra-VH co-infusions of muscimol (0.5 μg/rat) along with low doses of NMDA (0.0625 and 0.125 μg/rat) showed a tendency to increase %OAT, %OAE and locomotor activity; however, no interaction was observed between the drugs. Interestingly, intra-VH co-infusions of bicuculline (0.5 μg/rat) along with effective doses of NMDA (0.25 and 0.5 μg/rat) decreased %OAT, %OAE and locomotor activity, and a significant interaction between two drugs was observed. It can be concluded that GABAergic system may mediate the anxiolytic-like effects and increase in locomotor activity induced by NMDA in the VH.

[Pharmacotherapy of panic disorder].

PubMed

Bougerol, T; Farisse, J

1996-12-01

The concept of Panic Disorders has itself been developed on the strength of therapeutic effects of drug treatments and it is therefore not surprising that psychotropic medications are currently the main therapeutic tool for this condition. Their use may be indicated in two differing circumstances, as treatment for Panic Attack itself or as a long-term treatment for what is properly called Panic Disorder. The latter scenario is that which has been most actively studied and represents the more original side of the question. Treatment of acute Panic Attack involves administration of sedative anxiolytics, principally benzodiazepines (BZD). Long-term treatment aiming to prevent repeated attacks is the core strategy for treatment for Panic Disorder. For the past fifteen years, a large number of research projects have shown the elective anti-panic efficacy of a number of drugs, principally antidepressants and anxiolytics. The response profile to anti-depressant treatment is characterized by a lag time which is sometimes longer than that observed when they are used solely as antidepressants; frequently they are also less well tolerated which necessitates a very gradual step-up in dosage. The "classic" MAOI (non-selective and irreversible) have a proven anti-panic effect. Selective serotonin reuptake inhibitor (SSRI) anti-depressants are currently drugs of choice in the treatment of Panic Disorder. Although the anti-panic effect appears to be common to all the various SSRI drugs available, and directly attributable to their mechanism of action, not all of them however have undergone controlled studies. In France, paroxetine is the first anti-depressant in this group to obtain a marketing authorization for this particular indication. The advantages of the SSRI drugs are principally related to their limited adverse effects and lack of toxicity, thereby making them particularly straightforward to use. Benzodiazepines (BZD) are the second group of psychotropic medications which have been shown to be effective in the treatment of Panic Disorder. The major disadvantage of the BZD for this indication is chiefly related to the major risk of promoting a dependency state with the corresponding appearance of a withdrawal syndrome when treatment is stopped. This risk constitutes a major stumbling block to the use of BZD as a first-line treatment for Panic Disorder. Various other drugs have been evaluated in the treatment of Panic Disorder with varying success. The current anti-panic pharmacopoeia therefore appears to be relatively well stocked. In this context, antidepressants-especially the SSRI drugs-are the first-line treatment of choice for Panic Disorders. In all cases, it appears useful to integrate pharmacological treatment within an overall management plan for the patient with Panic Disorder, especially if it is hoped to maintain therapeutic benefit long-term.

Quantification of Ethanol's Anti-Punishment Effect in Humans Using the Generalized Matching Equation

ERIC Educational Resources Information Center

Rasmussen, Erin B.; Newland, M. Christopher

2009-01-01

Increases in rates of punished behavior by the administration of drugs with anxiolytic effects (called antipunishment effects) are well established in animals but not humans. The present study examined antipunishment effects of ethanol in humans using a choice procedure. The behavior of 5 participants was placed under six concurrent…

The rational use of anxiolytics.

PubMed

Bianchi, G N

1976-05-12

The prescribing of anxiolytics is often a hit-and-miss process. Current knowledge is examined to encourage a more rational use of such drugs. Because the common symptoms occur in a great array of illnesses, diagnosis is of first importance. For the transient situational disturbance drugs may be unnecessary or may be used merely for a day or two. If the anxiety state persists for a month or so the illness might be termed an anxiety neurosis and if there is no accompanying depression, a short course of benzodiazepine may be of value. With depression present to more than a mild degree as part of the neurosis the tricyclic antidepressant doxepin usually achieves better results than a benzodiazepine. Imipramine can be helpful for the phobic anxiety syndrome and monoamine-oxidase inhibitors can be of separate utility. If the anxiety and depression occur in the context of alcoholism, thioridazine and amitriptyline have certain advantages. There is very little place for phenothiazines or other antipsychotic agents in low doses in the therapy of anxiety except for thioridazine in the above indication.

An orally administered lavandula oil preparation (Silexan) for anxiety disorder and related conditions: an evidence based review.

PubMed

Kasper, Siegfried

2013-11-01

Silexan is a lavender oil preparation in gelatine capsules containing 80 mg. We reviewed the clinical trials investigating the anxiolytic efficacy and tolerability of Silexan as well as its safety and potential for drug interactions. Seven trials were included, among which four therapeutic trials had a treatment duration of 6 or 10 weeks. In patients with subsyndromal anxiety or generalised anxiety disorder (GAD) an anxiolytic effect of Silexan was evident after 2 weeks. Patients treated with Silexan showed Hamilton Anxiety Scale (HAMA) total score decreases between 10.4 ± 7.1 and 12.0 ± 7.2 points at Week 6 and between 11.8 ± 7.7 and 16.0 ± 8.3 points at Week 10. HAMA total score reductions between baseline and end of treatment were significantly superior to placebo in patients with subsyndromal anxiety and comparable to lorazepam in its starting dose in patients with GAD. Silexan had beneficial effects on typical co-morbidity symptoms of anxiety disorders, for example, disturbed sleep, somatic complaints, or decreased quality of life. Except for mild gastrointestinal symptoms, the drug was devoid of adverse effects and did not cause drug interactions or withdrawal symptoms at daily doses of 80 or 160 mg.

Drug-, dose- and sex-dependent effects of chronic fluoxetine, reboxetine and venlafaxine on open-field behavior and spatial memory in rats.

PubMed

Gray, Vanessa C; Hughes, Robert N

2015-03-15

In an effort to address the need to include both sexes in studies of effects of the SSRI fluoxetine, the NRI reboxetine and the SNRI venlafaxine on anxiety-related behavior and memory along with the use of chronic drug administration, male and female PVG/c rats were fed diets containing two doses of each drug for 21 days. The rats' anxiety level was then assessed in an open field. Short-term spatial memory for a brightness change in a Y maze was also measured. While there was little evidence of anxiolytic effects of any of the drugs, both fluoxetine and, to a lesser extent, venlafaxine appeared to be mainly anxiogenic in their action depending on both dose and sex. Reboxetine was relatively ineffective in this respect. Ability to locate the Y-maze arm that had changed (from white to black) seemed to be impaired for male (but not female) rats by both fluoxetine and venlafaxine and, to a much lesser extent, by reboxetine. Given the relative ineffectiveness of reboxetine in either test, it is possible that the effects of the other two drugs on both anxiety and memory were mainly due to their serotonin reuptake inhibiting properties. The differences that occurred between males and females in responsiveness to all three drugs supported the long-held view that both sexes should be investigated in studies of this sort, especially in view of reports of sex differences in effects of clinically prescribed antidepressants. Copyright © 2014 Elsevier B.V. All rights reserved.

Hip/femur fractures associated with the use of benzodiazepines (anxiolytics, hypnotics and related drugs): a methodological approach to assess consistencies across databases from the PROTECT-EU project.

PubMed

Requena, Gema; Huerta, Consuelo; Gardarsdottir, Helga; Logie, John; González-González, Rocío; Abbing-Karahagopian, Victoria; Miret, Montserrat; Schneider, Cornelia; Souverein, Patrick C; Webb, Dave; Afonso, Ana; Boudiaf, Nada; Martin, Elisa; Oliva, Belén; Alvarez, Arturo; De Groot, Mark C H; Bate, Andrew; Johansson, Saga; Schlienger, Raymond; Reynolds, Robert; Klungel, Olaf H; de Abajo, Francisco J

2016-03-01

Results from observational studies may be inconsistent because of variations in methodological and clinical factors that may be intrinsically related to the database (DB) where the study is performed. The objectives of this paper were to evaluate the impact of applying a common study protocol to study benzodiazepines (BZDs) (anxiolytics, hypnotics, and related drugs) and the risk of hip/femur fracture (HFF) across three European primary care DBs and to investigate any resulting discrepancies. To measure the risk of HFF among adult users of BZDs during 2001-2009, three cohort and nested case control (NCC) studies were performed in Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP) (Spain), Clinical Practice Research Datalink (CPRD) (UK), and Mondriaan (The Netherlands). Four different models (A-D) with increasing levels of adjustment were analyzed. The risk according to duration and type of BZD was also explored. Adjusted hazard ratios (cohort), odds ratios (NCC), and their 95% confidence intervals were estimated. Adjusted hazard ratios (Model C) were 1.34 (1.23-1.47) in BIFAP, 1.66 (1.54-1.78) in CPRD, and 2.22 (1.55-3.29) in Mondriaan in cohort studies. Adjusted odds ratios (Model C) were 1.28 (1.16-1.42) in BIFAP, 1.60 (1.49-1.72) in CPRD, and 1.48 (0.89-2.48) in Mondriaan in NCC studies. A short-term effect was suggested in Mondriaan, but not in CPRD or BIFAP. All DBs showed an increased risk with the concomitant use of anxiolytic and hypnotic drugs. Applying similar study methods to different populations and DBs showed an increased risk of HFF in BZDs users but differed in the magnitude of the risk, which may be because of inherent differences between DBs. Copyright © 2015 John Wiley & Sons, Ltd.

Imidazenil prevention of alprazolam-induced acquisition deficit in patas monkeys is devoid of tolerance

PubMed Central

Auta, James; Guidotti, Alessandro; Costa, Erminio

2000-01-01

The partial allosteric modulators (PAMs) of γ-aminobutyric acid-gated Cl− current intensities at γ-aminobutyric acid type A receptors have high affinity but low intrinsic efficacy on benzodiazepine recognition sites. Unlike the full allosteric modulators (FAM), like alprazolam, triazolam, and diazepam, PAMs are virtually devoid of unwanted side effects, including tolerance. Imidazenil (IMD) is a PAM that elicits potent anxiolytic and anticonvulsant actions in rodents and nonhuman primates and retains its anticonvulsant and anxiolytic effects, even in rodents that are tolerant to FAMs. IMD antagonizes the side effects of FAMs in rodents and nonhuman primates. Using patas monkeys and a multiple schedule with repeated acquisition and performance of chain responses, we report that IMD administration for 17 days antagonized without showing tolerance ALP-induced disruption of acquisition. PMID:10696114

Antidepressant-like activity of venlafaxine and clonidine in mice exposed to single prolonged stress - A model of post-traumatic stress disorder. Pharmacodynamic and molecular docking studies.

PubMed

Malikowska, Natalia; Fijałkowski, Łukasz; Nowaczyk, Alicja; Popik, Piotr; Sałat, Kinga

2017-10-15

Post-traumatic stress disorder (PTSD) is a growing issue worldwide characterized by stress and anxiety in response to re-experiencing traumatic events which strongly impair patient's quality of life and social functions. Available antidepressant and anxiolytic drugs are not efficacious in the majority of treated individuals. This necessitates a significant medical demand to develop novel therapeutic strategies for PTSD. Animal model of PTSD was induced using a mouse single prolonged stress protocol (mSPS). To assess the activity of venlafaxine and clonidine, the forced swim test (FST) was used repeatedly 24h, 3days, 8days, 15days and 25days after mSPS. To get insight into a possible mechanism of anti-PTSD action, molecular docking procedure was utilized for the most active drug. This in silico part comprised molecular docking of enantiomers of venlafaxine to human transporters for serotonin (hSERT), norepinephrine (hNET) and dopamine (hDAT). In mSPS-subjected mice FST revealed the effectiveness of venlafaxine, however in non SPS-subjected mice both venlafaxine and clonidine were active. Molecular docking studies indicated that the affinity of venlafaxine to monoamine transporters is growing in the following rank order: hDAT

Involvement of monoaminergic systems in anxiolytic and antidepressive activities of the standardized extract of Cocos nucifera L.

PubMed

Lima, Eliane Brito Cortez; de Sousa, Caren Nádia Soares; Meneses, Lucas Nascimento; E Silva Pereira, Yuri Freitas; Matos, Natália Castelo Branco; de Freitas, Rayanne Brito; Lima, Nycole Brito Cortez; Patrocínio, Manoel Cláudio Azevedo; Leal, Luzia Kalyne Almeida Moreira; Viana, Glauce Socorro Barros; Vasconcelos, Silvânia Maria Mendes

2017-01-01

Extracts from the husk fiber of Cocos nucifera are used in folk medicine, but their actions on the central nervous system have not been studied. Here, the anxiolytic and antidepressant effects of the standardized hydroalcoholic extract of C. nucifera husk fiber (HECN) were evaluated. Male Swiss mice were treated with HECN (50, 100, or 200 mg/kg) 60 min before experiments involving the plus maze test, hole-board test, tail suspension test, and forced swimming test (FST). HECN was administered orally (p.o.) in acute and repeated-dose treatments. The forced swimming test was performed with dopaminergic and noradrenergic antagonists, as well as a serotonin release inhibitor. Administration of HECN in the FST after intraperitoneal (i.p.) pretreatment of mice with sulpiride (50 mg/kg), prazosin (1 mg/kg), or p-chlorophenylalanine (PCPA, 100 mg/kg) caused the actions of these three agents to be reversed. However, this effect was not observed after pretreating the animals with SCH23390 (15 µg/kg, i.p.) or yohimbine (1 mg/kg, i.p.) The dose chosen for HECN was 100 mg/kg, p.o., which increased the number of entries as well as the permanence in the open arms of the maze after acute and repeated doses. In both the forced swimming and the tail suspension tests, the same dose decreased the time spent immobile but did not disturb locomotor activity in an open-field test. The anxiolytic effect of HECN appears to be related to the GABAergic system, while its antidepressant effect depends upon its interaction with the serotoninergic, noradrenergic (α1 receptors), and dopaminergic (D2 dopamine receptors) systems.

Bud extracts from Tilia tomentosa Moench inhibit hippocampal neuronal firing through GABAA and benzodiazepine receptors activation.

PubMed

Allio, Arianna; Calorio, Chiara; Franchino, Claudio; Gavello, Daniela; Carbone, Emilio; Marcantoni, Andrea

2015-08-22

Tilia tomentosa Moench bud extracts (TTBEs) is used in traditional medicine for centuries as sedative compound. Different plants belonging to the Tilia genus have shown their efficacy in the treatment of anxiety but still little is known about the mechanism of action of their bud extracts. To evaluate the action of TTBEs as anxiolytic and sedative compound on in vitro hippocampal neurons. The anxiolytic effect of TTBEs was assayed by testing the effects of these compounds on GABAA receptor-activated chloride current of hippocampal neurons by means of the patch-clamp technique and microelectrode-arrays (MEAs). TTBEs acutely administered on mouse hippocampal neurons, activated a chloride current comparable to that measured in the presence of GABA (100 µM). Bicuculline (100 µM) and picrotoxin (100 µM) blocked about 90% of this current, while the remaining 10% was blocked by adding the benzodiazepine (BDZ) antagonist flumazenil (30 µM). Flumazenil alone blocked nearly 60% of the TTBEs activated current, suggesting that TTBEs binds to both GABAA and BDZ receptor sites. Application of high-doses of TTBEs on spontaneous active hippocampal neurons grown for 3 weeks on MEAs blocked the synchronous activity of these neurons. The effects were mimicked by GABA and prevented by picrotoxin (100µM) and flumazenil (30 µM). At minimal doses, TTBEs reduced the frequency of synchronized bursts and increased the cross-correlation index of synchronized neuronal firing. Our data suggest that TTBEs mimics GABA and BDZ agonists by targeting hippocampal GABAergic synapses and inhibiting network excitability by increasing the strength of inhibitory synaptic outputs. Our results contribute toward the validation of TTBEs as effective sedative and anxiolytic compound. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

The mGlu5 receptor antagonist MPEP activates specific stress-related brain regions and lacks neurotoxic effects of the NMDA receptor antagonist MK-801: significance for the use as anxiolytic/antidepressant drug.

PubMed

Inta, Dragos; Filipovic, Dragana; Lima-Ojeda, Juan M; Dormann, Christof; Pfeiffer, Natascha; Gasparini, Fabrizio; Gass, Peter

2012-04-01

Glutamatergic agents have been conceptualized as powerful, fast-acting alternatives to monoaminergic-based antidepressants. NMDA receptor antagonists such as ketamine or MK-801 are therapeutically effective, but their clinical use is hampered by psychotomimetic effects, accompanied by neurotoxicity in the retrosplenial and cingulate cortex. Antagonists of metabotropic mGlu5 receptors like MPEP elicit both robust antidepressant and anxiolytic effects; however, the underlying mechanisms are yet unknown. mGlu5 receptors closely interact with NMDA receptors, but whether MPEP induces neurotoxicity similar to NMDA receptor antagonists has not been elucidated. We show here using c-Fos brain mapping that MPEP administration results in a restricted activation of distinct stress-related brain areas, including the bed nucleus of stria terminalis (BNST), central nucleus of the amygdala, and paraventricular nucleus of the hypothalamus (PVNH), in a pattern similar to that induced by classical antidepressants and anxiolytics. Unlike the NMDA antagonist MK-801, MPEP does not injure the adult retrosplenial cortex, in which it fails to induce heat shock protein 70 (Hsp70). Moreover, MPEP does not elicit to the same extent as MK-801 apoptosis in cortical areas at perinatal stages, as revealed by caspase 3 expression. These data identify new cellular targets for the anxiolytic and antidepressant effect of MPEP, indicating also in addition that in contrast to MK-801, it lacks the cortical neurotoxicity associated with psychotomimetic side-effects. Copyright © 2012 Elsevier Ltd. All rights reserved.

Marijuana and cannabinoid regulation of brain reward circuits.

PubMed

Lupica, Carl R; Riegel, Arthur C; Hoffman, Alexander F

2004-09-01

The reward circuitry of the brain consists of neurons that synaptically connect a wide variety of nuclei. Of these brain regions, the ventral tegmental area (VTA) and the nucleus accumbens (NAc) play central roles in the processing of rewarding environmental stimuli and in drug addiction. The psychoactive properties of marijuana are mediated by the active constituent, Delta(9)-THC, interacting primarily with CB1 cannabinoid receptors in a large number of brain areas. However, it is the activation of these receptors located within the central brain reward circuits that is thought to play an important role in sustaining the self-administration of marijuana in humans, and in mediating the anxiolytic and pleasurable effects of the drug. Here we describe the cellular circuitry of the VTA and the NAc, define the sites within these areas at which cannabinoids alter synaptic processes, and discuss the relevance of these actions to the regulation of reinforcement and reward. In addition, we compare the effects of Delta(9)-THC with those of other commonly abused drugs on these reward circuits, and we discuss the roles that endogenous cannabinoids may play within these brain pathways, and their possible involvement in regulating ongoing brain function, independently of marijuana consumption. We conclude that, whereas Delta(9)-THC alters the activity of these central reward pathways in a manner that is consistent with other abused drugs, the cellular mechanism through which this occurs is likely different, relying upon the combined regulation of several afferent pathways to the VTA.

The Aqueous Crude Extracts of Montanoa frutescens and Montanoa grandiflora Reduce Immobility Faster Than Fluoxetine Through GABAA Receptors in Rats Forced to Swim.

PubMed

Rodríguez-Landa, Juan Francisco; Cueto-Escobedo, Jonathan; Flores-Aguilar, Luis Ángel; Rosas-Sánchez, Gilberto Uriel; Rovirosa-Hernández, María de Jesús; García-Orduña, Francisco; Carro-Juárez, Miguel

2018-01-01

Montanoa frutescens and Montanoa grandiflora have been indistinctly used for centuries in traditional Mexican medicine for reproductive impairments, anxiety, and mood disorders. Preclinical studies support their aphrodisiac and anxiolytic properties, but their effects on mood are still unexplored. The effects of 25 and 50 mg/kg of M frutescens and M grandiflora extracts were evaluated on days 1, 7, 14, 21, and 28 of treatment, and compared with fluoxetine (1 mg/kg) and Remotiv (7.14 mg/kg) in Wistar rats. The participation of GABA A receptor in the effects produced by the treatments was explored. Montanoa extracts reduced immobility since day 1 of treatment, while fluoxetine and Remotiv required 14 days. The GABA A antagonism blocked the effects of Montanoa extracts, but not of fluoxetine or Remotiv. Montanoa extracts prevented quickly the stress-induced behaviors in the swimming test through action at the GABA A receptor, exerting a protective effect different to the typical antidepressants drugs.

Outpatient utilization of psychopharmaceuticals in the City of Zagreb 2001-2006.

PubMed

Stimac, Danijela; Culig, Josip

2009-03-01

A comprehensive insight into drug utilization as an economic and primarily a public health issue can only be acquired in the context of overall health state of the respective population. The objectives of the study were: 1) to determine the real outpatient utilization of psychopharmaceuticals in Zagreb, 2) to determine the psychopharmaceutical prescribing quality during the study period; and 3) to propose appropriate interventions in Zagreb on the basis of the results obtained. Data on drug utilization were obtained from all Zagreb pharmacies. The number of defined daily doses (DDD) and number of DDD per 1000 inhabitants per day (DDD/1000/day) were calculated from the number of particular drug packages. The Drug Utilization 90% (DU90%) method was used as a criterion of prescribing quality. Outpatient utilization of psychopharmaceuticals showed a declining pattern from 115.40 DDD/1000/day in 2001 to 93.15 DDD/1000/day in 2006. Anxiolytics accounted for the majority of this drug group utilization in the City of Zagreb, although the anxiolytic/antidepressant ratio decreased from 7.19 in 2001 to 3.86 in 2006. The utilization of selective serotonin reuptake inhibitors showed a 2.5-fold increase and accounted for 90% of overall antidepressant utilization. A 2.5-fold decrease was recorded in the utilization of antipsychotics, while the atypical/typical antipsychotic ratio changed from 1:2 in 2001 to 1.1:1 in 2006. Despite some improvement observed in the prescribing quality, the predominance of benzodiazepines in the utilization of psychopharmaceuticals points to the need of additional rationalization in the field.

Antidepressant, anxiolytic and procognitive effects of rivastigmine and donepezil in the chronic mild stress model in rats.

PubMed

Papp, Mariusz; Gruca, Piotr; Lason-Tyburkiewicz, Magdalena; Willner, Paul

2016-04-01

The treatment of depression in old age is complicated by frequent co-morbidity with cognitive impairment. Anti-dementia drugs have some efficacy to improve cognitive performance and there is an inconsistent literature regarding the effect of such drugs on depressive symptoms. Here, we have investigated whether anti-dementia drugs would have antidepressant-like and pro-cognitive effects in a well-validated animal model of depression and cognitive impairment, chronic mild stress (CMS). Rats were subjected to CMS for a total of 8 weeks. After 2 weeks, subgroups of stressed and non-stressed animals were treated daily, for 5 weeks followed by 1 week of drug withdrawal, with vehicle, imipramine (10 mg/kg), rivastigmine (2 mg/kg), donepezil (0.3 mg/kg) or memantine (5 mg/kg). Sucrose intake was tested weekly, and animals were also tested in the elevated plus maze (at week 7) and in an object recognition task (at weeks 7 and 8). CMS decreased sucrose intake, had an anxiogenic effect in the elevated plus maze, and impaired performance in the object recognition test. Imipramine, rivastigmine and donepezil normalized performance in all three tests. Memantine had anxiolytic and pro-cognitive effects, but did not reverse CMS-induced anhedonia. The fact that all three anti-dementia drugs reversed CMS-induced cognitive impairment and that cholinesterase inhibitors, but not memantine, have antidepressant-like effects in this model suggest that different mechanisms may underlie CMS-induced anhedonia and cognitive impairment. We discuss the clinical implications of these findings.

GABA-A Receptor Modulation and Anticonvulsant, Anxiolytic, and Antidepressant Activities of Constituents from Artemisia indica Linn

PubMed Central

Khan, Imran; Karim, Nasiara; Ahmad, Waqar; Abdelhalim, Abeer; Chebib, Mary

2016-01-01

Artemisia indica, also known as “Mugwort,” has been widely used in traditional medicines. However, few studies have investigated the effects of nonvolatile components of Artemisia indica on central nervous system's function. Fractionation of Artemisia indica led to the isolation of carnosol, ursolic acid, and oleanolic acid which were evaluated for their effects on GABA-A receptors in electrophysiological studies in Xenopus oocytes and were subsequently investigated in mouse models of acute toxicity, convulsions (pentylenetetrazole induced seizures), depression (tail suspension and forced swim tests), and anxiety (elevated plus maze and light/dark box paradigms). Carnosol, ursolic acid, and oleanolic acid were found to be positive modulators of α1β2γ2L GABA-A receptors and the modulation was antagonized by flumazenil. Carnosol, ursolic acid, and oleanolic acid were found to be devoid of any signs of acute toxicity (50–200 mg/kg) but elicited anticonvulsant, antidepressant, and anxiolytic activities. Thus carnosol, ursolic acid, and oleanolic acid demonstrated CNS activity in mouse models of anticonvulsant, antidepressant, and anxiolysis. The anxiolytic activity of all three compounds was ameliorated by flumazenil suggesting a mode of action via the benzodiazepine binding site of GABA-A receptors. PMID:27143980

Anxiolytic and antidepressant-like effects of the hydroalcoholic extract from Aloysia polystachya in rats.

PubMed

Mora, S; Díaz-Véliz, G; Millán, R; Lungenstrass, H; Quirós, S; Coto-Morales, T; Hellión-Ibarrola, M C

2005-10-01

Behavioral effects of a hydroalcoholic extract from leaves of Aloysia polystachya (Griseb.) Moldenke (Verbenaceae) were studied in female Sprague-Dawley rats. The extract was administered intraperitoneally and its effects on spontaneous motor activity (total motility, locomotion, rearing and grooming behavior) were monitored. Anxiolytic-like properties were studied in the elevated plus-maze (EPM) test and the possible antidepressant-like actions were evaluated in the forced swimming test (FST). The results revealed that high doses of the extract (25 and 50 mg/kg, i.p.) caused a significant decrease in total motility, locomotion, rearing and grooming behavior. All doses injected (from 1.56 to 50 mg/kg) increased the exploration of the EPM open arms in a similar way to that of diazepam (1 mg/kg, i.p.). In the FST, the extract (12.5, 25 and 50 mg/kg) was as effective as fluoxetine (10 mg/kg, i.p.) and imipramine (12.5 mg/kg, i.p.) in reducing immobility, along with a significant increase in swimming and climbing, respectively. These results suggest that some of the components of the hydroalcoholic extract of A. polystachya, such as thujone and carvone among others, may have sedative, anxiolytic and antidepressant-like properties which deserve further investigation.

GABAA-benzodiazepine receptors in the dorsomedial (Dm) telencephalon modulate restraint-induced antinociception in the fish Leporinus macrocephalus.

PubMed

Wolkers, Carla Patricia Bejo; Barbosa Junior, Augusto; Menescal-de-Oliveira, Leda; Hoffmann, Anette

2015-08-01

The possibility that fish experience pain has been denied based on the absence of the neural substrates to support this "experience". In this context, the identification of brain regions involved in nociception modulation could provide important insights regarding the processing of nociceptive information in fish. Our study evaluated the participation of the GABAA-benzodiazepine receptor in the dorsomedial (Dm) telencephalon in restraint-induced antinociception in the fish Leporinus macrocephalus through the microinjection of the anxiolytic drug midazolam. The microinjection of midazolam in the Dm did not alter the nocifensive response; however, this drug did block the inhibition of the nocifensive response to formaldehyde promoted by restraint stress. The fish that received midazolam (40nmol) microinjection prior to restraint (3 or 5min), followed by subcutaneous injection with formaldehyde presented a higher distance traveled than the fish that received saline microinjection. This effect might reflect the specific action of midazolam on benzodiazepine receptors in the Dm telencephalon, as pre-treatment with flumazenil, a benzodiazepine receptor antagonist, inhibited the effects of this drug. In the present study, we present the first evidence demonstrating a role for the dorsomedial telencephalic region in the modulation of stress-induced antinociception in fish, revealing new perspectives in the understanding of nociceptive information processing in this group. Copyright © 2015 Elsevier Inc. All rights reserved.

Classification and determination of cerebral biovailability of psychotropic drugs by quantitative "pharmaco-EEG" and psychometric investigations (studies with AX-A411-BS).

PubMed

Saletu, B; Grünberger, J; Linzmayer, L

1977-10-01

Utilizing computerized quantitative analysis of the human scalp recorded electroencephalogram (EEG), it is possible to classify psychotropic drugs. While neuroleptic compounds produce an increase of slow and decrease of fast activities, anxiolytic substances induce an augmentation of fast waves, decrease of alpha waves and--according to the sedative properties of the drug--an increase or decrease of slow waves. Antidepressants produce a concomitant augmentation of slow and fast activities as well as an attenuation of alpha waves. Nootropic substances attenuate slow activities, augment alpha and slow beta waves and decrease fast beta waves. The latter alterations are quite opposite to age-related changes. Since the main psychopharmacological classes seem to have characteristic pharmaco-EEG profiles, the method proved to be useful for determination of psychoactivity and cerebral bioavailability of newly developed substances as for instance AX-A411-BS, a new benzodiazepine. The latter substance was found to be CNS-active and was classified as anxiolytic. It induced dosedependent changes, which were barely visible in the 2nd hour post-drug, became quite obvious in the 4th hour and increased until the 8th hour after oral administration of one single dose. In the higher dosage range, slow activities came to the fore, indicating aoditional sedative properties. Psychometric tests measuring attention, psychomotor activity. mood, vigilance, extroversion, concentration aith a long-lasting effect. The implications of these methods are discussed.

No Acute Effects of Cannabidiol on the Sleep-Wake Cycle of Healthy Subjects: A Randomized, Double-Blind, Placebo-Controlled, Crossover Study

PubMed Central

Linares, Ila M. P.; Guimaraes, Francisco S.; Eckeli, Alan; Crippa, Ana C. S.; Zuardi, Antonio W.; Souza, Jose D. S.; Hallak, Jaime E.; Crippa, José A. S.

2018-01-01

Cannabidiol (CBD) is a component of Cannabis sativa that has a broad spectrum of potential therapeutic effects in neuropsychiatric and other disorders. However, few studies have investigated the possible interference of CBD on the sleep-wake cycle. The aim of the present study was to evaluate the effect of a clinically anxiolytic dose of CBD on the sleep-wake cycle of healthy subjects in a crossover, double-blind design. Twenty-seven healthy volunteers that fulfilled the eligibility criteria were selected and allocated to receive either CBD (300 mg) or placebo in the first night in a double-blind randomized design (one volunteer withdrew from the study). In the second night, the same procedure was performed using the substance that had not been administered in the previous occasion. CBD or placebo were administered 30 min before the start of polysomnography recordings that lasted 8 h. Cognitive and subjective measures were performed immediately after polysomnography to assess possible residual effects of CBD. The drug did not induce any significant effect (p > 0.05). Different from anxiolytic and antidepressant drugs such as benzodiazepines and selective serotonin reuptake inhibitors, acute administration of an anxiolytic dose of CBD does not seem to interfere with the sleep cycle of healthy volunteers. The present findings support the proposal that CBD do not alter normal sleep architecture. Future studies should address the effects of CBD on the sleep-wake cycle of patient populations as well as in clinical trials with larger samples and chronic use of different doses of CBD. Such studies are desirable and opportune. PMID:29674967

Safety of ipsapirone treatment compared with lorazepam: discontinuation effects.

PubMed Central

Busto, U E; Naranjo, C A; Bremner, K E; Peachey, J E; Bologa, M

1998-01-01

OBJECTIVE: To determine discontinuation effects of ipsapirone, a novel azapirone and partial 5-HTIA agonist that has anxiolytic effects clinically and has not caused dependence or withdrawal symptoms in animals, and to compare these effects with those of the benzodiazepine lorazepam, owing to concern about dependence or withdrawal symptoms following use of these drugs. DESIGN: Prospective, randomized, double-blind, placebo-controlled trial. SETTING: Outpatient and inpatient treatment. PARTICIPANTS: Sixty-five healthy male volunteers who had experience with sedative-hypnotics or anxiolytics and did not meet DSM-III-R criteria for abuse or dependence. INTERVENTIONS: Participants were randomized to receive ipsapirone 15 mg per day (n = 17), ipsapirone 22.5 mg per day (n = 16), lorazepam 3 mg per day (n = 16), or placebo (n = 16) as outpatients for 36 days (treatment) followed by single-blind placebo as inpatients for 3 days and as outpatients for 6 days (withdrawal). OUTCOME MEASURES: Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Scale (HAM-D), Spielberger State Anxiety Scale, Sleep Quality Questionnaire, General Symptom Checklist, self-rated intoxication, Clinical Institute Withdrawal Assessment--Benzodiazepines (CIWA-Benzo), psychomotor testing and urine drug screen. RESULTS: Only 45 subjects completed the study; discontinuation rates did not significantly differ among treatment groups. At day 39, fewer and less severe symptoms (e.g., insomnia and fatigue) were found on the CIWA-Benzo scale after treatment with ipsapirone or placebo than after treatment with lorazepam (p < 0.05). Subjects reported longer sleep latency and poorer sleep quality after receiving lorazepam than after receiving ipsapirone or placebo. Scores on the HAM-D, Spielberger State Anxiety and HAM-A scales did not change from baseline. CONCLUSIONS: Withdrawal symptoms were detected after discontinuation of therapeutic doses of lorazepam. Significantly fewer symptoms were observed after withdrawal from anxiolytic doses of ipsapirone. PMID:9505058

Safety of ipsapirone treatment compared with lorazepam: discontinuation effects.

PubMed

Busto, U E; Naranjo, C A; Bremner, K E; Peachey, J E; Bologa, M

1998-01-01

To determine discontinuation effects of ipsapirone, a novel azapirone and partial 5-HTIA agonist that has anxiolytic effects clinically and has not caused dependence or withdrawal symptoms in animals, and to compare these effects with those of the benzodiazepine lorazepam, owing to concern about dependence or withdrawal symptoms following use of these drugs. Prospective, randomized, double-blind, placebo-controlled trial. Outpatient and inpatient treatment. Sixty-five healthy male volunteers who had experience with sedative-hypnotics or anxiolytics and did not meet DSM-III-R criteria for abuse or dependence. Participants were randomized to receive ipsapirone 15 mg per day (n = 17), ipsapirone 22.5 mg per day (n = 16), lorazepam 3 mg per day (n = 16), or placebo (n = 16) as outpatients for 36 days (treatment) followed by single-blind placebo as inpatients for 3 days and as outpatients for 6 days (withdrawal). Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Scale (HAM-D), Spielberger State Anxiety Scale, Sleep Quality Questionnaire, General Symptom Checklist, self-rated intoxication, Clinical Institute Withdrawal Assessment--Benzodiazepines (CIWA-Benzo), psychomotor testing and urine drug screen. Only 45 subjects completed the study; discontinuation rates did not significantly differ among treatment groups. At day 39, fewer and less severe symptoms (e.g., insomnia and fatigue) were found on the CIWA-Benzo scale after treatment with ipsapirone or placebo than after treatment with lorazepam (p < 0.05). Subjects reported longer sleep latency and poorer sleep quality after receiving lorazepam than after receiving ipsapirone or placebo. Scores on the HAM-D, Spielberger State Anxiety and HAM-A scales did not change from baseline. Withdrawal symptoms were detected after discontinuation of therapeutic doses of lorazepam. Significantly fewer symptoms were observed after withdrawal from anxiolytic doses of ipsapirone.

Behavioral studies with anxiolytic drugs. IV. Serotonergic involvement in the effects of buspirone on punished behavior of pigeons

DOE Office of Scientific and Technical Information (OSTI.GOV)

Witkin, J.M.; Mansbach, R.S.; Barrett, J.E.

1987-12-01

Interactions of the nonbenzodiazepine anxiolytic, buspirone, with serotonin (5-HT) were studied using behavioral and neurochemical procedures. Punished responding was studied in pigeons as this behavior is a generally acknowledged preclinical predictor of anxiolytic activity and because buspirone increases punished responding of pigeons with greater potency and efficacy than in other species. Keypeck responses were maintained under either fixed-interval or fixed-ratio schedules of food presentation; every 30th response produced a brief electric shock and suppressed responding (punishment). Buspirone (0.1-5.6 mg/kg i.m.) produced dose-related increases in punished responding which reached a maximum at 1 mg/kg. A serotonin agonist, MK-212 (0.01 mg/kg), antagonizedmore » whereas the 5-HT antagonist, cyproheptadine (0.01 mg/kg), potentiated the effects of buspirone without having behavioral effects of their own. The characteristics of (/sup 3/H)-5-HT binding in pigeon brain membranes were similar to results reported in mammalian brain. Neither buspirone, MJ-13805 (gepirone, a related analog), nor MJ-13653 (a buspirone metabolite), significantly affected (/sup 3/H)-5-HT binding and none of the compounds appreciably inhibited uptake of (/sup 3/H)-5-HT into pigeon cerebral synaptosomes. Hill coefficients significantly less than unity for all drugs except 5-HT suggested multiple serotonergic binding sites for buspirone and analogs. Buspirone and MJ-13805 (1 nM) inhibited (/sup 3/H)ketanserin binding (a measure of 5-HT2 binding sites) in pigeon cerebrum with Ki values above 10(-6) M. The number of (/sup 3/H)ketanserin binding sites was estimated to be 109 fmol/mg of protein in pigeon cerebrum compared to 400 fmol/mg of protein in rat cerebrum.« less

Do preclinical seizure models preselect certain adverse effects of antiepileptic drugs.

PubMed

Meldrum, Brian

2002-06-01

Classical screening tests (maximal electroshock, MES, and threshold pentylenetetrazol, PTZ) employ non-epileptic rodents and identify antiepileptic drugs (AEDs) with mechanisms of action associated with significant CNS side effects. Thus MES identifies drugs acting on Na+ channels that produce cerebellar toxicity. It may be possible to produce novel AEDs more selectively targeted at voltage-sensitive (VS) ion channels. There is little specific evidence for the likely success of this strategy with subunit selective agents targeted at the different VS Na+ channels. Drugs targeted at specific VS Ca++ channels (T, N, P/Q types) may be useful in generalised seizures. There are many as yet unexplored possibilities relating to K+ channels. GABA related drugs acting on PTZ clonic seizures tend to induce sedation and muscle hypotonia. Studies in mice, particularly with knock-in mutations, but also with subunit selective agents acting via the GABA(A) benzodiazepine site, suggest that it is possible to produce agents which do or do not induce particular side effects (sedative, hypnotic, anxiolytic, muscle relaxant, amnesia, anaesthesia). Whether these findings transfer to man has yet to be established. Acquired epilepsy in rodents (e.g. kindling or spontaneous seizures following chemically- or electrically-induced status epilepticus) or acquired epilepsy in man (following prolonged febrile seizures or traumatic brain injury) is associated with multiple changes in the function and subunit composition of ion channels and receptor molecules. Optimal screening of novel AEDs, both for efficacy and side effects, requires models with receptor and ion channel changes similar to those in the target human syndrome.

Extracts of Valeriana officinalis L. s.l. show anxiolytic and antidepressant effects but neither sedative nor myorelaxant properties.

PubMed

Hattesohl, Miguel; Feistel, Björn; Sievers, Hartwig; Lehnfeld, Romanus; Hegger, Mirjam; Winterhoff, Hilke

2008-01-01

Extracts of Valeriana officinalis L. s.l. are used for treating mild sleep disorders and nervous tension. Despite intensive research efforts, the pharmacological actions accounting for the clinical efficacy of valerian remain unclear. Thus, it was the aim of this study to evaluate CNS-related effects of different valerian extracts using behavioral paradigms (mice and rats). Following oral administration two commercially available preparations (extraction solvents: 45% methanol m/m and 70% ethanol v/v), a 35% ethanolic v/v extract and a refined extract derived from it (patented special extract phytofin Valerian 368) were tested for sedative (locomotor activity, ether-induced anaesthesia) and anxiolytic (elevated plus maze) activity. Using the forced swimming and the horizontal wire test the latter two extracts were additionally tested for antidepressant and myorelaxant properties. Up to maximum dosages of 500 or 1000 mg/kg bw none of the valerian extracts displayed sedative effects. Neither spontaneous activity was reduced nor the duration of ether-induced narcosis was prolonged. In contrast, results obtained in the elevated plus maze test revealed a pronounced anxiolytic effect of the 45% methanolic and 35% ethanolic extract as well as of phyotofin Valerian 368 in a dose range of 100-500 mg/kg bw. Additionally and different from its primary extract (35% ethanolic extract) phytofin Valerian 368 showed antidepressant activity in the forced swimming test after subacute treatment. Myorelaxant effects were not observed in dosages up to 1000 mg/kg bw. Due to these findings it is proposed that not sedative but anxiolytic and antidepressant activity, which was elaborated particularly in the special extract phytofin Valerian 368, considerably contribute to the sleep-enhancing properties of valerian.

Ropren® treatment reverses anxiety-like behavior and monoamines levels in gonadectomized rat model of Alzheimer's disease.

PubMed

Fedotova, Julia; Soultanov, Vagif; Nikitina, Tamara; Roschin, Victor; Ordyan, Natalia; Hritcu, Lucian

2016-10-01

Previous studies indicated that reduced androgen levels may contribute to both physical and cognitive disorders in men, including Alzheimer's disease. New drug candidates for Alzheimer's disease in patients with androgen deficiency should ideally be able to act not only on multiple brain targets but also to correct impaired endocrine functions in hypogonadal men with Alzheimer's disease. Ropren ® is one such candidate for the treatment of Alzheimer's disease in men with an imbalance of androgens. Accordingly, the aim of the current study was to examine the effects of long-term Ropren ® administration (8.6mg/kg, orally, once daily, for 28 days) on the anxiety-like behavior and monoamines levels in the rat hippocampus using a β-amyloid (25-35) rat model of Alzheimer's disease following gonadectomy. Ropren ® was administered to the gonadectomized (GDX) rats and GDX rats treated with testosterone propionate (TP, 0.5mg/kg, subcutaneous, once daily, for 28 days). Anxiety-like behavior was assessed in the elevated plus maze (EPM) and the light-dark test (LDT), locomotor and grooming activities were assessed in the open field test (OFT). Ropren ® alone or in combination with TP-induced anxiolytic effects as evidenced in the EPM and in the LDT and increased locomotor activity in the OFT. Additionally, it was observed that dopamine (DA) and serotonin (5-HT) levels increased while 5-hydroxyindoleacetic acid (5-HIAA)/5-HT ratio in the hippocampus decreased. Our results indicate that Ropren ® has a marked anxiolytic-like action due to an increase in the monoamines levels in the experimental rat model of Alzheimer's disease with altered levels of androgens. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Essential oil of lavender in anxiety disorders: Ready for prime time?

PubMed Central

2017-01-01

Anxiety disorders are some of the most common psychiatric disorders, with potentially debilitating consequences on individual function. Existing pharmacotherapies for anxiety disorders are limited by delay to therapeutic effect, dependence, tolerance, withdrawal, and abuse potential. Therefore, safe and evidence-based complementary or alternative therapies may be important allies in the care of patients with anxiety disorders. Essential oils are lipophilic and concentrated botanical extracts that exhibit many properties of drugs, although they are not Food and Drug Administration approved and have limitations characteristic of herbal preparations. Lavender essential oil has an extensive anecdotal history of anxiolytic benefit that has recently been supported by clinical efficacy studies. The 2 primary terpenoid constituents of lavender essential oil, linalool and linalyl acetate, may produce an anxiolytic effect in combination via inhibition of voltage-gated calcium channels, reduction of 5HT1A receptor activity, and increased parasympathetic tone. The objectives of this article are to provide a brief overview of lavender oil in aromatherapy, explore variability in the constituents of lavender oil, summarize its pharmacology and safety profile, as well as describe its body of research that has been conducted for anxiety.

Evaluation of anxiolytic activity of aqueous extract of Coriandrum sativum Linn. in mice: A preliminary experimental study

PubMed Central

Latha, K.; Rammohan, B.; Sunanda, B. P. V.; Maheswari, M. S. Uma; Mohan, Surapaneni Krishna

2015-01-01

Objectives: To evaluate the anxiolytic effect of Coriandrum sativum (CS) aqueous extract in mice. To compare the antianxiety activity of CS against standard drug diazepam (3 mg/kg). Materials and Methods: After obtaining Institutional Animal Ethics Committee approval, Swiss albino mice (18–25 g) of either sex were randomly divided into five groups of six animals each. Dried powder of CS leaves was boiled with distilled water, cooled, filtered, placed on a hotplate for complete evaporation, finally weighed and stored. The control group, test group, and standard drugs group received saline, CS extract (50, 100, and 200 mg/kg), diazepam (3 mg/kg), respectively, by oral feeding. The antianxiety effect was assessed by elevated plus maze (EPM) in mice. Results: In EPM, it implied that CS 50 mg/kg (Group III), 100 mg/kg (Group IV), and 200 mg/kg (Group V) significantly (P < 0.001) increases the number of entries in open arms compared to control. The time spent in open arms also increased in all the doses of CS extract significantly. Conclusion: The current study demonstrates statistically significant dose-dependent antianxiety activity of CS leaves. PMID:26109787

Parenteral poppy seed tea packs a powerful punch.

PubMed

Monaghan, Dominic; Peckler, Brad

2013-12-13

Poppy seed tea (PST) has a long history of use for its medicinal (analgesic, anti-diarrhoeal, anxiolytic) effects. It is also commonly used as a recreational drug in its oral form throughout the world, but reports of intravenous use are very rare. We present two cases of intravenously injected PST with dramatic effects in order to create awareness among health professionals of this method of drug use and its potential complications, as well as to help clinicians dealing with opiate-dependent patients to warn them of the risk.

Dissociating anxiolytic and sedative effects of GABAAergic drugs using temperature and locomotor responses to acute stress

PubMed Central

Klanker, Marianne; Groenink, Lucianne; Korte, S. Mechiel; Cook, James M.; Van Linn, Michael L.; Hopkins, Seth C.; Olivier, Berend

2009-01-01

Rationale The stress-induced hyperthermia (SIH) model is an anxiety model that uses the transient rise in body temperature in response to acute stress. Benzodiazepines produce anxiolytic as well as sedative side effects through nonselective binding to GABAA receptor subunits. The GABAA receptor α1 subunit is associated with sedation, whereas the GABAA receptor α2 and α3 subunits are involved in anxiolytic effects. Objectives We therefore examined the effects of (non) subunit-selective GABAA receptor agonists on temperature and locomotor responses to novel cage stress. Results Using telemetric monitoring of temperature and locomotor activity, we found that nonsubunit-selective GABAA receptor agonist diazepam as well as the α3 subunit-selective receptor agonist TP003 dose-dependently attenuated SIH and locomotor responses. Administration of GABAA receptor α1-selective agonist zolpidem resulted in profound hypothermia and locomotor sedation. The GABAA receptor α1-selective antagonist βCCt antagonized the hypothermia, but did not reverse the SIH response attenuation caused by diazepam and zolpidem. These results suggest an important regulating role for the α1 subunit in thermoregulation and sedation. Ligands of extrasynaptic GABAA receptors such as alcohol and nonbenzodiazepine THIP attenuated the SIH response only at high doses. Conclusions The present study confirms a putative role for the GABAA receptor α1 subunit in hypothermia and sedation and supports a role for α2/3 subunit GABAA receptor agonists in anxiety processes. In conclusion, we show that home cage temperature and locomotor responses to novel home cage stress provide an excellent tool to assess both anxiolytic and sedative effects of various (subunit-selective) GABAAergic compounds. PMID:19169673

Childhood adversities predict strongly the use of psychotropic drugs in adulthood: a population-based cohort study of 24,284 Finns.

PubMed

Koskenvuo, Karoliina; Koskenvuo, Markku

2015-04-01

Exposure to adverse childhood experiences has been shown to be associated with negative health outcomes including mental health problems, but only a few studies with register-based data have used psychotropic drugs as an outcome variable. The purpose of this study is to examine whether adverse emotional childhood experiences, such as serious conflicts in the family and frequent fear of a family member, predict the use of psychotropic drugs in adulthood. In addition, the association of a child-parent relationship during childhood with the use of psychotropic drugs is studied. The participants of the population-based Health and Social Support Study (24,284 working aged Finns) were followed up for 9 years. The information on childhood experiences and child-parent relationships was obtained from the questionnaires in 1998 and 2003. The number of psychotropic purchases (antipsychotics, drugs for bipolar disorder, antidepressants, anxiolytics, hypnotics and sedatives) was obtained from the National-Drug-Prescription-Register. Logistic and multinomial regression models were used. A graded association between childhood adversities and the use of psychotropic drugs was found, even after adjustments for occupational training, work status, recent life events and health behaviour. Frequent fear of a family member showed the strongest association: the OR for multiple use of antidepressants was 3.08 (95% CI 2.72 to 3.49) and 2.69 (2.27 to 3.20) for multiple use of anxiolytics. Use of psychotropic drugs was clearly increased among those with poor child-parent relationship and multiple childhood adversities. The results highlight the effect of environmental factors during childhood on mental health and the need for early recognition of families at risk. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Safety and side effects of cannabidiol, a Cannabis sativa constituent.

PubMed

Bergamaschi, Mateus Machado; Queiroz, Regina Helena Costa; Zuardi, Antonio Waldo; Crippa, José Alexandre S

2011-09-01

Cannabidiol (CBD), a major nonpsychotropic constituent of Cannabis, has multiple pharmacological actions, including anxiolytic, antipsychotic, antiemetic and anti-inflammatory properties. However, little is known about its safety and side effect profile in animals and humans. This review describes in vivo and in vitro reports of CBD administration across a wide range of concentrations, based on reports retrieved from Web of Science, Scielo and Medline. The keywords searched were "cannabinoids", "cannabidiol" and "side effects". Several studies suggest that CBD is non-toxic in non-transformed cells and does not induce changes on food intake, does not induce catalepsy, does not affect physiological parameters (heart rate, blood pressure and body temperature), does not affect gastrointestinal transit and does not alter psychomotor or psychological functions. Also, chronic use and high doses up to 1,500 mg/day of CBD are reportedly well tolerated in humans. Conversely, some studies reported that this cannabinoid can induce some side effects, including inhibition of hepatic drug metabolism, alterations of in vitro cell viability, decreased fertilization capacity, and decreased activities of p-glycoprotein and other drug transporters. Based on recent advances in cannabinoid administration in humans, controlled CBD may be safe in humans and animals. However, further studies are needed to clarify these reported in vitro and in vivo side effects.

Pharmacology of midazolam.

PubMed

Pieri, L; Schaffner, R; Scherschlicht, R; Polc, P; Sepinwall, J; Davidson, A; Möhler, H; Cumin, R; Da Prada, M; Burkard, W P; Keller, H H; Müller, R K; Gerold, M; Pieri, M; Cook, L; Haefely, W

1981-01-01

8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine (midazolam, Ro 21-3981, Dormicum) is an imidazobenzodiazepine whose salts are soluble and stable in aqueous solution. It has a quick onset and, due to rapid metabolic inactivation, a rather short duration of action in all species studied. Midazolam has a similar pharmacologic potency and broad therapeutic range as diazepam. It produces all the characteristic effects of the benzodiazepine class, i.e., anticonvulsant, anxiolytic, sleep-inducing, muscle relaxant, and "sedative" effects. The magnitude of the anticonflict effect of midazolam is smaller than that of diazepam in rats and squirrel monkeys, probably because a more pronounced sedative component interferes with the increase of punished responses. In rodents, surgical anaesthesia is not attained with midazolam alone even in high i.v. doses, whereas this state is obtained in monkeys. The drug potentiates the effect of various central depressant agents. Midazolam is virtually free of effects on the cardiovascular system in conscious animals and produces only slight decreases in cardiac performance in dogs anaesthetized with barbiturates. No direct effects of the drugs on autonomic functions were found, however, stress-induced autonomic disturbances are prevented, probably by an effect on central regulatory systems. All animal data suggest the usefulness of midazolam as a sleep-inducer and i.v. anaesthetic of rapid onset and short duration.

Diazepam-stress interactions in the rat: effects on autoanalgesia and a plus-maze model of anxiety.

PubMed

Taukulis, H K; Goggin, C E

1990-03-01

On six occasions spaced at least a week apart, two groups of rats were subjected to a variety of stressful conditions consisting of a restraint/bright light complex, either alone or in combination with a tail pinch, whole-body inversion, or partial immersion in cold water. One of these groups was injected with diazepam (2.0 mg/kg) 30 min prior to the stressors, while the other group experienced the drug in their home cages the following day. A third group also received the diazepam but was not exposed to the stressors. In three test sessions all animals were injected with either diazepam or saline and were then exposed to a novel stressor: a plus-maze used as a screening device for anxiolytic drugs. This was immediately followed by a tail-flick measure of analgesia. The longest tail-flick latencies, indicating stress-induced analgesia ("autoanalgesia"), were observed in the group that had not been exposed to stress prior to testing. The other two groups exhibited substantially shorter latencies but did not differ from one another, thus showing a "stress inoculation" effect that was uninfluenced by diazepam. In the plus-maze, diazepam tends to increase the amount of time rats will spend in the two exposed arms of the maze relative to the two enclosed arms. This effect was significantly attenuated in the group that had previously experienced the variety of stressors after a diazepam injection, suggesting a learned association between drug and stress that resulted in a diminution of the drug's anxiolytic property.

[Prevalence of psychoactive drug consumption in an obese population].

PubMed

Cerdá Esteve, Maria A; Barral Tafalla, Diego; Gudelis, Mindaugas; Goday, Albert; Farre Albaladejo, Magi; Cano, Juan F

2010-04-01

To establish the prevalence of psychoactive drug consumption in an obese population. We collected data from the clinical records of obese patients attending the Endocrinology and Nutrition Department and Psychiatry Department of Hospital del Mar between June 2005 and May 2006 (n=259). We recorded anthropometric, epidemiological and toxicological data. We also investigated the prevalence of concomitant diseases in this population. Psychoactive drugs were consumed by 37% of obese patients, mainly antidepressants (27%), anxiolytics, sedatives and hypnotics, and anticonvulsants. Moreover, 15% of all patients received combination treatment with two or more psychoactive drugs, mostly the association of an antidepressant and an antiepileptic drug. The prevalence of psychoactive drug consumption in our sample was higher than prevalence data observed in the general population, with antidepressant consumption being three-fold higher. Copyright 2009 SEEN. Published by Elsevier Espana. All rights reserved.

Kappa-Opioid Antagonists for Psychiatric Disorders: From Bench to Clinical Trials.

PubMed

Carlezon, William A; Krystal, Andrew D

2016-10-01

Kappa-opioid receptor (KOR) antagonists are currently being considered for the treatment of a variety of neuropsychiatric conditions, including depressive, anxiety, and substance abuse disorders. A general ability to mitigate the effects of stress, which can trigger or exacerbate these conditions, may explain their putative efficacy across such a broad array of conditions. The discovery of their potentially therapeutic effects evolved from preclinical research designed to characterize the molecular mechanisms by which experience causes neuroadaptations in the nucleus accumbens (NAc), a key element of brain reward circuitry. This research established that exposure to drugs of abuse or stress increases the activity of the transcription factor CREB (cAMP response element binding protein) in the NAc, which leads to elevated expression of the opioid peptide dynorphin that in turn causes core signs of depressive- and anxiety-related disorders. Disruption of KORs-the endogenous receptors for dynorphin-produces antidepressant- and anxiolytic-like actions in screening procedures that identify standard drugs of these classes, and reduces stress effects in tests used to study addiction and stress-related disorders. Although interest in this target is high, prototypical KOR antagonists have extraordinarily persistent pharmacodynamic effects that complicate clinical trials. The development of shorter acting KOR antagonists together with more rapid designs for clinical trials may soon provide insight on whether these drugs are efficacious as would be predicted by preclinical work. If successful, KOR antagonists would represent a unique example in psychiatry where the therapeutic mechanism of a drug class is understood before it is shown to be efficacious in humans. © 2016 Wiley Periodicals, Inc.

Participation of mitochondrial diazepam binding inhibitor receptors in the anticonflict, antineophobic and anticonvulsant action of 2-aryl-3-indoleacetamide and imidazopyridine derivatives.

PubMed

Auta, J; Romeo, E; Kozikowski, A; Ma, D; Costa, E; Guidotti, A

1993-05-01

The 2-hexyl-indoleacetamide derivative, FGIN-1-27 [N,N-di-n-hexyl-2- (4-fluorophenyl)indole-3-acetamide], and the imidazopyridine derivative, alpidem, both bind with high affinity to glial mitochondrial diazepam binding inhibitor receptors (MDR) and increase mitochondrial steroidogenesis. Although FGIN-1-27 is selective for the MDR, alpidem also binds to the allosteric modulatory site of the gamma-aminobutyric acidA receptor where the benzodiazepines bind. FGIN-1-27 and alpidem, like the neurosteroid 3 alpha,21-dehydroxy-5 alpha-pregnane-20-one (THDOC), clonazepam and zolpidem (the direct allosteric modulators of gamma-aminobutyric acidA receptors) delay the onset of isoniazid and metrazol-induced convulsions. The anti-isoniazid convulsant action of FGIN-1-27 and alpidem, but not that of THDOC, is blocked by PK 11195. In contrast, flumazenil blocked completely the anticonvulsant action of clonazepam and zolpidem and partially blocked that of alpidem, but it did not affect the anticonvulsant action of THDOC and FGIN-1-27. Alpidem, like clonazepam, zolpidem and diazepam, but not THDOC or FGIN-1-27, delay the onset of bicuculline-induced convulsions. In two animal models of anxiety, the neophobic behavior in the elevated plus maze test and the conflict-punishment behavior in the Vogel conflict test, THDOC and FGIN-1-27 elicited anxiolytic-like effects in a manner that is flumazenil insensitive, whereas alpidem elicited a similar anxiolytic effect, but is partially blocked by flumazenil. Whereas PK 11195 blocked the effect of FGIN-1-27 and partially blocked alpidem, it did not affect THDOC in both animal models of anxiety.(ABSTRACT TRUNCATED AT 250 WORDS)

Religious treatments for drug addiction: an exploratory study in Brazil.

PubMed

van der Meer Sanchez, Zila; Nappo, Solange A

2008-08-01

The main objective of the present work is to understand the processes used in emerging Catholic and Protestant religious interventions for recovery from drug dependence, from the vantage point of individuals subjected to them. A qualitative method and an intentional sample selected by criteria were adopted for this investigation, which was conducted in São Paulo, Brazil. An in-depth semi-structured interview was conducted with 57 predominantly male former drug users who fit the criteria: they had been submitted to non-medical religious treatments to treat dependence and were abstinent for at least 6 months. Crisis was found to be the main reason leading interviewees to seek treatment; this includes, losing family, losing employment, and experiencing severe humiliation. Evangelicals most used religious resources exclusively as treatment, showing strong aversion to the role of doctors and to any type of pharmacological treatment. A common feature of Catholic and Protestant groups is the importance ascribed to praying and talking to God, described by subjects as strongly anxiolytic, and a means to control drug craving. Confession and forgiveness, through faith conversion or penitences, respectively, appeal strongly to the restructuring of life and increase of self-esteem. Religious interventions were considered effective by the individuals who underwent them and were seen as attractive for the humane, respectful treatment they delivered. The key aspects of this type of treatment are social support provided by the receiving group, equal treatment, and instant, judgment-free acceptance. The success of these actions, then, is not only due to some "supernatural" aspect, as might be assumed, but also more to the unconditional dedication of human beings to their peers. Given the difficulty in treating drug dependence, religious interventions could be used as a complementary treatment for conventional therapies.

Targeting ligand-operated chaperone sigma-1 receptors in the treatment of neuropsychiatric disorders

PubMed Central

Teruo, Hayashi; Shang-Yi, Tsai; Tomohisa, Mori; Michiko, Fujimoto; Tsung-Ping, Su

2011-01-01

Introduction Current conventional therapeutic drugs for the treatment of psychiatric or neurodegenerative disorders have certain limitations of use. Psychotherapeutic drugs such as typical and atypical antipsychotics, tricyclic antidepressants, and selective monoamine reuptake inhibitors, aim to normalize the hyper- or hypo-neurotransmission of monoaminergic systems. Despite their great contribution to the outcomes of psychiatric patients, these agents often exert severe side effects and require chronic treatments to promote amelioration of symptoms. Furthermore, drugs available for the treatment of neurodegenerative disorders are severely limited. Areas covered This review discusses recent evidence that has shed light on sigma-1 receptor ligands, which may serve as a new class of antidepressants or neuroprotective agents. Sigma-1 receptors are novel ligand-operated molecular chaperones regulating a variety of signal transduction, ER stress, cellular redox, cellular survival, and synaptogenesis. Selective sigma-1 receptor ligands exert rapid antidepressant-like, anxiolytic, antinociceptive and robust neuroprotective actions in preclinical studies. The review also looks at recent studies which suggest that reactive oxygen species might play a crucial role as signal integrators at the downstream of Sig-1Rs Expert opinion The significant advances in sigma receptor research in the last decade have begun to elucidate the intracellular signal cascades upstream and downstream of sigma-1 receptors. The novel ligand-operated properties of the sigma-1 receptor chaperone may enable a variety of interventions by which stress-related cellular systems are pharmacologically controlled. PMID:21375464

Anxiolytic-like effect of Carvacrol (5-isopropyl-2-methylphenol) in mice: involvement with GABAergic transmission.

PubMed

Melo, Francisca Helvira Cavalcante; Venâncio, Edith Teles; de Sousa, Damião Pergentino; de França Fonteles, Marta Maria; de Vasconcelos, Silvânia Maria Mendes; Viana, Glauce Socorro Barros; de Sousa, Francisca Cléa Florenço

2010-08-01

Carvacrol (5-isopropyl-2-methylphenol) is a monoterpenic phenol present in the essencial oil of many plants. It is the major component of the essential oil fraction of oregano and thyme. This work presents the behavioral effects of carvacrol in animal models of elevated plus maze (EPM), open field, Rotarod and barbiturate-induced sleeping time tests in mice. Carvacrol (CVC) was administered orally, in male mice, at single doses of 12.5; 25 and 50 mg/kg while diazepam 1 or 2 mg/kg was used as standard drug and flumazenil (2.5 mg/kg) was used to elucidate the possible anxiolytic mechanism of CVC on the plus maze test. The results showed that CVC, at three doses, had no effect on the spontaneous motor activity in the Rotarod test nor in the number of squares crossed in the open-field test. However, CVC decreased the number of groomings in the open-field test. In the plus maze test, CVC, at three doses significantly increased all the observed parameters in the EPM test and flumazenil was able to reverse the effects of diazepam and CVC. Therefore, CVC did not alter the sleep latency and sleeping time in the barbiturate-induced sleeping time test. These results show that CVC presents anxiolytic effects in the plus maze test which are not influenced by the locomotor activity in the open-field test.

Behavioural studies on BR-16A (Mentat), a herbal psychotropic formulation.

PubMed

Bhattacharya, S K

1994-01-01

The anxiolytic, antidepressant and anti-aggression activities of Mentat were investigated in rats and mice, using standard behavioural paradigms. Single acute administration of Mentat, up to a dose of 200 mg/kg, ip, induced insignificant behavioural effects on the test parameters. However, when Mentat was administered subchronically for 7 days at two dose levels (50 and 100 mg/kg, intragastrically), the drug induced dose-related behavioural effects. Thus, it exhibited anxiolytic effect, as assessed by paradigms like the open-field test and elevated plus-maze tests in mice, and the social interaction test and Vogel's drink conflict test in rats. Furthermore, Mentat attenuated the increase in rat brain tribulin, a putative endocoid marker of anxiety, levels induced by pentylenetetrazole (20 mg/kg, sc), a known anxiogenic agent. Mentat attenuated footshock-induced aggressive behaviour in paired rats but failed to affect clonidine-induced automutilative behaviour. The observed aggression-attenuating effect of Mentat may be related to its anxiolytic activity. Mentat exhibited significant antidepressant effect as indicated by its ability to reduce swim stress induced immobility in Porsolt's behavioural despair test, reduction in escape failures concomitant with an increase in avoidance response in the learned helplessness test, and attenuation of muricidal behaviour, in rats. The observed behavioural effects are consonant with the reported clinical utility of Mentat as an adjuvant in the treatment of anxiety and depression.

Diverse antidepressants increase CDP-diacylglycerol production and phosphatidylinositide resynthesis in depression-relevant regions of the rat brain.

PubMed

Tyeryar, Kimberly R; Vongtau, Habiba O U; Undieh, Ashiwel S

2008-01-24

Major depression is a serious mood disorder affecting millions of adults and children worldwide. While the etiopathology of depression remains obscure, antidepressant medications increase synaptic levels of monoamine neurotransmitters in brain regions associated with the disease. Monoamine transmitters activate multiple signaling cascades some of which have been investigated as potential mediators of depression or antidepressant drug action. However, the diacylglycerol arm of phosphoinositide signaling cascades has not been systematically investigated, even though downstream targets of this cascade have been implicated in depression. With the ultimate goal of uncovering the primary postsynaptic actions that may initiate cellular antidepressive signaling, we have examined the antidepressant-induced production of CDP-diacylglycerol which is both a product of diacylglycerol phosphorylation and a precursor for the synthesis of physiologically critical glycerophospholipids such as the phosphatidylinositides. For this, drug effects on [3H]cytidine-labeled CDP-diacylglycerol and [3H]inositol-labeled phosphatidylinositides were measured in response to the tricyclics desipramine and imipramine, the selective serotonin reuptake inhibitors fluoxetine and paroxetine, the atypical antidepressants maprotiline and nomifensine, and several monoamine oxidase inhibitors. Multiple compounds from each antidepressant category significantly stimulated [3H]CDP-diacylglycerol accumulation in cerebrocortical, hippocampal, and striatal tissues, and also enhanced the resynthesis of inositol phospholipids. Conversely, various antipsychotics, anxiolytics, and non-antidepressant psychotropic agents failed to significantly induce CDP-diacylglycerol or phosphoinositide synthesis. Drug-induced CDP-diacylglycerol accumulation was independent of lithium and only partially dependent on phosphoinositide hydrolysis, thus indicating that antidepressants can mobilize CDP-diacylglycerol from additional pools lying outside of the inositol cycle. Further, unlike direct serotonergic, muscarinic, or alpha-adrenergic agonists that elicited comparable or lower effects on CDP-diacylglycerol versus inositol phosphates, the antidepressants dose-dependently induced significantly greater accumulations of CDP-diacylglycerol. Chemically divergent antidepressant agents commonly and significantly enhanced the accumulation of CDP-diacylglycerol. The latter is not only a derived product of phosphoinositide hydrolysis but is also a crucial intermediate in the biosynthesis of several signaling substrates. Hence, altered CDP-diacylglycerol signaling might be implicated in the pathophysiology of depression or the mechanism of action of diverse antidepressant medications.

Diverse antidepressants increase CDP-diacylglycerol production and phosphatidylinositide resynthesis in depression-relevant regions of the rat brain

PubMed Central

Tyeryar, Kimberly R; Vongtau, Habiba OU; Undieh, Ashiwel S

2008-01-01

Background Major depression is a serious mood disorder affecting millions of adults and children worldwide. While the etiopathology of depression remains obscure, antidepressant medications increase synaptic levels of monoamine neurotransmitters in brain regions associated with the disease. Monoamine transmitters activate multiple signaling cascades some of which have been investigated as potential mediators of depression or antidepressant drug action. However, the diacylglycerol arm of phosphoinositide signaling cascades has not been systematically investigated, even though downstream targets of this cascade have been implicated in depression. With the ultimate goal of uncovering the primary postsynaptic actions that may initiate cellular antidepressive signaling, we have examined the antidepressant-induced production of CDP-diacylglycerol which is both a product of diacylglycerol phosphorylation and a precursor for the synthesis of physiologically critical glycerophospholipids such as the phosphatidylinositides. For this, drug effects on [3H]cytidine-labeled CDP-diacylglycerol and [3H]inositol-labeled phosphatidylinositides were measured in response to the tricyclics desipramine and imipramine, the selective serotonin reuptake inhibitors fluoxetine and paroxetine, the atypical antidepressants maprotiline and nomifensine, and several monoamine oxidase inhibitors. Results Multiple compounds from each antidepressant category significantly stimulated [3H]CDP-diacylglycerol accumulation in cerebrocortical, hippocampal, and striatal tissues, and also enhanced the resynthesis of inositol phospholipids. Conversely, various antipsychotics, anxiolytics, and non-antidepressant psychotropic agents failed to significantly induce CDP-diacylglycerol or phosphoinositide synthesis. Drug-induced CDP-diacylglycerol accumulation was independent of lithium and only partially dependent on phosphoinositide hydrolysis, thus indicating that antidepressants can mobilize CDP-diacylglycerol from additional pools lying outside of the inositol cycle. Further, unlike direct serotonergic, muscarinic, or α-adrenergic agonists that elicited comparable or lower effects on CDP-diacylglycerol versus inositol phosphates, the antidepressants dose-dependently induced significantly greater accumulations of CDP-diacylglycerol. Conclusion Chemically divergent antidepressant agents commonly and significantly enhanced the accumulation of CDP-diacylglycerol. The latter is not only a derived product of phosphoinositide hydrolysis but is also a crucial intermediate in the biosynthesis of several signaling substrates. Hence, altered CDP-diacylglycerol signaling might be implicated in the pathophysiology of depression or the mechanism of action of diverse antidepressant medications. PMID:18218113

The clinical implications of mouse models of enhanced anxiety

PubMed Central

Sartori, Simone B; Landgraf, Rainer; Singewald, Nicolas

2011-01-01

Mice are increasingly overtaking the rat model organism in important aspects of anxiety research, including drug development. However, translating the results obtained in mouse studies into information that can be applied in clinics remains challenging. One reason may be that most of the studies so far have used animals displaying ‘normal’ anxiety rather than ‘psychopathological’ animal models with abnormal (elevated) anxiety, which more closely reflect core features and sensitivities to therapeutic interventions of human anxiety disorders, and which would, thus, narrow the translational gap. Here, we discuss manipulations aimed at persistently enhancing anxiety-related behavior in the laboratory mouse using phenotypic selection, genetic techniques and/or environmental manipulations. It is hoped that such models with enhanced construct validity will provide improved ways of studying the neurobiology and treatment of pathological anxiety. Examples of findings from mouse models of enhanced anxiety-related behavior will be discussed, as well as their relation to findings in anxiety disorder patients regarding neuroanatomy, neurobiology, genetic involvement and epigenetic modifications. Finally, we highlight novel targets for potential anxiolytic pharmacotherapeutics that have been established with the help of research involving mice. Since the use of psychopathological mouse models is only just beginning to increase, it is still unclear as to the extent to which such approaches will enhance the success rate of drug development in translating identified therapeutic targets into clinical trials and, thus, helping to introduce the next anxiolytic class of drugs. PMID:21901080

[Effect of autogenic training with cognitive and symbol therapy on the treatment of patients with primary headache].

PubMed

Zsombók, Terézia; Juhász, Gabriella; Gonda, Xénia; Vitrai, József; Bagdy, György

2005-01-01

Only a minor part of headaches are associated with an organic abnormality in the nervous system. In case of migraine and tension headache, the main provoking factor is psychological stress. Furthermore, these syndromes often occur together with depression and anxiety disorders, and when these comorbid conditions are present headache attacks tend to be more frequent, longer and stronger, causing an increase in the consumption of antimigraine agents, and at the same time increase the consumption of antidepressant and anxiolytic agents. Further to drugs, modified versions of Schultz-type autogenic training is also frequently used for anxiolysis. The aim of our research was to study the effect of the cognitive and symbol therapy enhanced autogenic training on headache and related drug consumption in three different types of primary headaches. Twenty five female patients with migraine, tension-type headache or mixed headache participated in an eight-month follow-up study. Headache frequency, analgesic, antimigraine and anxiolytic consumption were measured by means of a headache diary. During the first four months (observation phase) patients became familiar with using the diary, and in the second four months they participated in autogenic training. The data of the second, third and fourth months were considered as baseline data. Our method decreased headache frequency and drug consumption in all three headache groups. This means that the cognitive and symbol therapy enhanced autogenic training is an effective alternative for medications in the treatment of primary headaches.

The association of peptic ulcer and schizophrenia: a population-based study.

PubMed

Liao, Chun-Hui; Chang, Chen-Shu; Chang, Shih-Ni; Muo, Chih-Hsin; Lane, Hsien-Yuan; Sung, Fung-Chang; Kao, Chia-Hung

2014-12-01

The association of schizophrenia with peptic ulcer is not conclusive. In the last 30years, there has been little evaluation of peptic ulcer among schizophrenia patients. To explore the relation of peptic ulcer and schizophrenia during this new phase, we used the data from Taiwan insurance claims, identified 1496 schizophrenia patients (ICD-9-CM: 295) and selected 5984 non-schizophrenia controls that were frequency-matched by sex, age, and index year with schizophrenia patients during the years 1998-2001. All subjects were free of peptic ulcer at baseline. We measured incidences of peptic ulcer (ICD-9-CM: 531-534) until the end of 2009. The incidence of peptic ulcer was 1.27 times higher in schizophrenia patients than in the control group (12.1vs. 9.52 per 1000 person-years). Patients are at higher risk taking anti-depression, anxiolytic and hypnotics or non-steroidal anti-inflammatory drugs. After controlling the confounding factors, schizophrenia patients had no significant increase incidence of peptic ulcer. Schizophrenia patients have a slightly higher risk of peptic ulcer compared to the general population. This might be due to a higher rate of taking anti-depression, anxiolytic and hypnotics or non-steroidal anti-inflammatory drugs and alcoholism among this group. Copyright © 2014 Elsevier Inc. All rights reserved.

Skeletal effects of central nervous system active drugs: anxiolytics, sedatives, antidepressants, lithium and neuroleptics.

PubMed

Vestergaard, Peter

2008-09-01

Many central nervous system active drugs can alter postural balance, increasing the risk of fractures. Anxiolytics and sedatives include the benzodiazepines, and these have been associated with a limited increase in the risk of fractures, even at low doses, probably from an increased risk of falls. No systematic differences have been shown between benzodiazepines with long and short half-lives. Although the increase in risk of fractures was limited, care must still be taken when prescribing for older fall-prone subjects at risk of osteoporosis. Neuroleptics may be associated with a decrease in bone mineral density and a very limited increase in fracture risk. Antidepressants are associated with a dose-dependent increase in the risk of fractures. The increase in relative risk of fractures seems to be larger with selective serotonin reuptake inhibitors (SSRIs) than with tricyclic antidepressants. The reason for this is not known but may be linked to serotonin effects on bone cells and the risk of falls. With the wide use of SSRIs, more research is needed. Lithium is associated with a decrease in the risk of fractures. This may be linked to its effects on the Wnt glycoprotein family, which is a specialised signalling system for certain cell types.

Periodical reactivation under the effect of caffeine attenuates fear memory expression in rats.

PubMed

Pedraza, Lizeth K; Sierra, Rodrigo O; Lotz, Fernanda N; Alvares, Lucas de Oliveira

2018-05-08

In the last decade, several studies have shown that fear memories can be attenuated by interfering with reconsolidation. However, most of the pharmacological agents used in preclinical studies cannot be administered to humans. Caffeine is one of the world's most popular psychoactive drugs and its effects on cognitive and mood states are well documented. Nevertheless, the influence of caffeine administration on fear memory processing is not as clear. We employed contextual fear conditioning in rats and acute caffeine administration under a standard memory reconsolidation protocol or periodical memory reactivation. Additionally, potential rewarding/aversion and anxiety effects induced by caffeine were evaluated by conditioning place preference or open field, respectively. Caffeine administration was able to attenuate weak fear memories in a standard memory reconsolidation protocol; however, periodical memory reactivation under caffeine effect was necessary to attenuate strong and remote memories. Moreover, caffeine promoted conditioned place preference and anxiolytic-like behavior, suggesting that caffeine weakens the initial learning during reactivation through counterconditioning mechanisms. Thus, our study shows that rewarding and anxiolytic effects of caffeine during fear reactivation can change the emotional valence of fear memory. It brings a new promising pharmacological approach based on drugs widely used such as caffeine to treat fear-related disorders.

Long-term treatment with haloperidol affects neuropeptide S and NPSR mRNA levels in the rat brain.

PubMed

Palasz, Artur; Rojczyk, Ewa; Golyszny, Milosz; Filipczyk, Lukasz; Worthington, John J; Wiaderkiewicz, Ryszard

2016-04-01

The brainstem-derived neuropeptide S (NPS) has a multidirectional regulatory activity, especially as a potent anxiolytic factor. Accumulating data suggests that neuroleptics affect peptidergic signalling in various brain structures. However, there is no information regarding the influence of haloperidol on NPS and NPS receptor (NPSR) expression. We assessed NPS and NPSR mRNA levels in brains of rats treated with haloperidol using quantitative real-time polymerase chain reaction. Chronic haloperidol treatment (4 weeks) led to a striking upregulation of NPS and NPSR expression in the rat brainstem. Conversely, the NPSR mRNA expression was decreased in the hippocampus and striatum. This stark increase of NPS in response to haloperidol treatment supports the hypothesis that this neuropeptide is involved in the dopamine-dependent anxiolytic actions of neuroleptics and possibly also in the pathophysiology of mental disorders. Furthermore, our findings underline the complex nature of potential interactions between dopamine receptors and brain peptidergic pathways, which has potential clinical applications.

Planning for Bioterrorism. Behavioral & Mental Health Responses to Weapons of Mass Destruction & Mass Disruption

DTIC Science & Technology

2000-07-16

Specifically, the management of the acute situation will set the tone for societal responses. The accurate portrayal of ongoing efforts and successful...their comments and actions. Specifically, the management of the acute situation will set the tone for societal responses. The accurate portrayal of...casualties. In the acute phase, anxiolytics may help acutely anxious individuals who do not respond to reassurance and education. In the chronic phase

[Pharmacological possibilities for the prevention of complications following myocardial infarction].

PubMed

Szekeres, L

1986-01-01

Sudden cardiac death (SCD) due to acute myocardial infarction (AMI) is mostly the result of ventricular fibrillation (VP) which is an electrical accident appearing on the basis of electrical instability of the myocardium. In addition to the chronic electrical instability predisposing to ventricular arrhythmias the trigger effect of a precipitating factor also seems necessary which may disrupt the normal sequence of cardiac contractions. In view of this hypothesis the following strategy of therapeutic interventions aimed at preventing SCD from AMI seems to be logical: Prophylactic measures to prevent pathological processes underlying chronic electrical instability of the heart i.e. elimination of identified risk factors of ischemic heart disease. Protection from SCD due to AMI: by using drugs which could, prevent further electrical destabilization as shifts in myocardial and plasma ionic balance, in pH, in pCO2, accumulation of potentially arrhythmogenic metabolites: Inhibit the trigger effect of sudden changes: in hemodynamics, in the autonomic nervous outflow and balance. The general supportive measures include therapeutic interventions which are not directly connected with appearance of lethal arrhythmias but may indirectly contribute to their development as pain, arterial Hb desaturation, deep vein thrombosis. Some of the measures listed above are capable of limiting the size of the developing infarct, a major determinant of the future conditions of life and prognosis of the patient. In the prehospital phase of AMI when two thirds of all coronary deaths occur general supportive measures and drug treatment of life threatening arrhythmias should be applied simultaneously. Sedatives and anxiolytics, furthermore analgetics are widely used. They are however often associated with bradycardia and sometimes with hypotension. This latter is dominant in patients with inferior infarction, showing a parasympathetic hyperactivity, when atropine treatment is needed. Sympathetic hyperactivity responds to analgesia and sedation but beta blockers may be required to reduce increased MVO2. These agents belong to the group of anti-ischemic drugs. The beneficial anti-ischemic action of beta-blockers is mostly due to their negative chronotropic and inotropic effect. A direct metabolic action was shown by use as well as the presence of a positive steal phenomenon in the experimental angina model in dogs. Anti-ischemic action of coronary vasodilators. The most reliable drug for preventing or abolishing anginal attack is still the classic nitroglycerin. On the other hand persantine a potent coronary dilator failed to protect against anginal attack in man.

Behavioural profiles in the mouse defence test battery suggest anxiolytic potential of 5-HT(1A) receptor antagonists.

PubMed

Griebel, G; Rodgers, R J; Perrault, G; Sanger, D J

1999-05-01

Compounds varying in selectivity as 5-HT1A receptor antagonists have recently been reported to produce anxiolytic-like effects comparable to those of benzodiazepines in the mouse elevated plus-maze procedure. In view of the potential clinical significance of these findings, the present experiments compared the behavioural effects of diazepam (0.5-3.0 mg/kg) with those of several non-selective 5-HT1A receptor antagonists [NAN-190, 0.1-3.0 mg/kg, MM-77, 0.03-1.0 mg/kg, (S)-UH-301, 0.3-3.0 mg/kg and pindobind-5-HT1A, 0.03-1.0 mg/kg], and three selective 5-HT1A receptor antagonists (WAY100635, 0.01-3.0 mg/kg, p-MPPI, 0.1-3.0 mg/kg and SL88.0338, 0.3-3.0 mg/kg) in the mouse defence test battery (MDTB). In this well-validated anxiolytic screening test, Swiss mice are directly confronted with a natural threat (a rat) as well as situations associated with this threat. Primary measures taken during and after rat confrontation were flight, risk assessment (RA), defensive threat/attack and escape attempts. Diazepam significantly decreased flight reactions after the rat was introduced into the runway, reduced RA activities of mice chased by the rat, increased RA responses displayed when subjects were constrained in a straight alley and reduced defensive upright postures and biting upon forced contact. All the selective 5-HT1A receptor antagonists and NAN-190 also reduced flight, RA in the chase test, and defensive threat and attack behaviours. (S)-UH-301 and pindobind-5-HT1A reduced RA in the chase test, but only partially modified defensive threat and attack. Unlike the other drugs tested, MM-77 produced significant effects only at doses which also markedly reduced spontaneous locomotor activity, suggesting a behaviourally non-specific action. In contrast to diazepam, the 5-HT1A receptor ligands failed to affect RA in the straight alley test. Following removal of the rat from the test area, only diazepam and (S)-UH-301 reduced escape behaviour (contextual defence) at doses which did not decrease locomotion. Overall, the present findings indicate that except for one RA behaviour and escape responses, the 5-HT1A receptor ligands studied modified the same defensive behaviours as diazepam, suggesting potential therapeutic efficacy in the management of anxiety disorders. However, the magnitude of the effects of the 5-HT1A compounds on defence was generally smaller than that of the benzodiazepine. As all of the 5-HT1A compounds tested in this series share antagonistic activity in models of postsynaptic 5-HT1A receptor function, it is proposed that this action accounts for their effects on defence.

[Identification and evaluation of the neuroleptic activity of phenotropil].

PubMed

Akhapkina, V I; Akhapkin, R V

2013-01-01

The neuroleptic (antipsychotic) activity of phenotropil was studied in an experimental animal model. Phenotropil had a marked neuroleptic activity in models of positive (apomorphine-induced verticalization test) and negative (5-HTP-induced hyperkinesis test) symptoms of psychoses as well as in the m-cholinergic pathway hyperactivation (arecoline-induced tremor test). The compound markedly antagonized haloperidol catalepsy. Used in a single dose or as a course treatment, phenotropil did not provoke aggression nor intensify it. In contrast to typical and atypical antipsychotics, phenotropil had no sedative action and other adverse effects. It exhibited a positive effect on exploratory behavior and motor activity, had anxiolytic and antidepressant action.

Antipsychotics increase vesicular glutamate transporter 2 (VGLUT2) expression in thalamolimbic pathways.

PubMed

Moutsimilli, Larissa; Farley, Severine; El Khoury, Marie-Anne; Chamot, Christophe; Sibarita, Jean-Baptiste; Racine, Victor; El Mestikawy, Salah; Mathieu, Flavie; Dumas, Sylvie; Giros, Bruno; Tzavara, Eleni T

2008-03-01

Recently the two vesicular-glutamate-transporters VGLUT1 and VGLUT2 have been cloned and characterized. VGLUT1 and VGLUT2 together label all glutamatergic neurons, but because of their distinct expression patterns in the brain they facilitate our ability to define between a VGLUT1-positive cortical and a VGLUT2-positive subcortical glutamatergic systems. We have previously demonstrated an increased cortical VGLUT1 expression as marker of antidepressant activity. Here, we assessed the effects of different psychotropic drugs on brain VGLUT2 mRNA and protein expression. The typical antipsychotic haloperidol, and the atypicals clozapine and risperidone increased VGLUT2 mRNA selectively in the central medial/medial parafascicular, paraventricular and intermediodorsal thalamic nuclei; VGLUT2 protein was accordingly amplified in paraventricular and ventral striatum and in prefrontal cortex. The antidepressants fluoxetine and desipramine and the sedative anxiolytic diazepam had no effect. These results highlight the implication of thalamo-limbic glutamatergic pathways in the action of antipsychotics. Increased VGLUT2 expression in these neurons might constitute a marker for antipsychotic activity and subcortical glutamate neurotransmission might be a possible novel target for future generation antipsychotics.

Effect of autogenic training on drug consumption in patients with primary headache: an 8-month follow-up study.

PubMed

Zsombok, Terezia; Juhasz, Gabriella; Budavari, Agota; Vitrai, Jozsef; Bagdy, Gyorgy

2003-03-01

To examine the effects of Schultz-type autogenic training on headache-related drug consumption and headache frequency in patients with migraine, tension-type, or mixed (migraine plus tension-type) headache over an 8-month period. Behavioral treatments often are used alone or adjunctively for different types of headache. There are, however, only a few studies that have compared the efficacy and durability of the same treatment in different types of primary headache, and the effects of treatment on headache-related drug consumption rarely have been assessed even in these studies. Twenty-five women with primary headache (11 with mixed headache, 8 with migraine, and 6 with tension-type headache) were evaluated via an open-label, self-controlled, 8-month, follow-up study design. After an initial 4 months of observation, patients began learning Schultz-type autogenic training as modified for patients with headache. They practiced autogenic training on a regular basis for 4 months. Based on data from headache diaries and daily medication records, headache frequencies and the amounts of analgesics, "migraine-specific" drugs (ergots and triptans), and anxiolytics taken by the patients were compared in the three subgroups over the 8-month period. Results.-From the first month of implementation of autogenic training, headache frequencies were significantly reduced in patients with tension-type and mixed headache. Significant reduction in frequency was achieved in patients with migraine only from the third month of autogenic training. Decreases in headache frequencies were accompanied by decreases in consumption of migraine drugs and analgesics resulting in significant correlations among these parameters. Reduction in consumption of anxiolytic drugs was more rapid and robust in patients with tension-type headache compared to patients with migraine, and this outcome failed to show any correlation with change in headache frequency. Schultz-type autogenic training is an effective therapeutic approach that may lead to a reduction in both headache frequency and the use of headache medication.

Anxiolytic effects of phosphodiesterase-2 inhibitors associated with increased cGMP signaling.

PubMed

Masood, Anbrin; Huang, Ying; Hajjhussein, Hassan; Xiao, Lan; Li, Hao; Wang, Wei; Hamza, Adel; Zhan, Chang-Guo; O'Donnell, James M

2009-11-01

Phosphodiesterase (PDE)-2 is a component of the nitric-oxide synthase (NOS)/guanylyl cyclase signaling pathway in the brain. Given recent evidence that pharmacologically induced changes in NO-cGMP signaling can affect anxiety-related behaviors, the effects of the PDE2 inhibitors (2-(3,4-dimethoxybenzyl)-7-det-5-methylimidazo-[5,1-f][1,2,4]triazin-4(3H)-one) (Bay 60-7550) and 3-(8-methoxy-1-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)benzamide (ND7001), as well as modulators of NO, were assessed on cGMP signaling in neurons and on the behavior of mice in the elevated plus-maze, hole-board, and open-field tests, well established procedures for the evaluation of anxiolytics. Bay 60-7550 (1 microM) and ND7001 (10 microM) increased basal and N-methyl-d-aspartate- or detanonoate-stimulated cGMP in primary cultures of rat cerebral cortical neurons; Bay 60-7550, but not ND7001, also increased cAMP. Increased cGMP signaling, either by administration of the PDE2 inhibitors Bay 60-7550 (0.5, 1, and 3 mg/kg) or ND7001 (1 mg/kg), or the NO donor detanonoate (0.5 mg/kg), antagonized the anxiogenic effects of restraint stress on behavior in the three tests. These drugs also produced anxiolytic effects on behavior in nonstressed mice in the elevated plus-maze and hole-board tests; these effects were antagonized by the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (20 mg/kg). By contrast, the NOS inhibitor N(omega)-nitro-l-arginine methyl ester (50 mg/kg), which reduces cGMP signaling, produced anxiogenic effects similar to restraint stress. Overall, the present behavioral and neurochemical data suggest that PDE2 may be a novel pharmacological target for the development of drugs for the treatment of anxiety disorders.

Polymethoxyflavones from Nicotiana plumbaginifolia (Solanaceae) Exert Antinociceptive and Neuropharmacological Effects in Mice

PubMed Central

Shajib, Md. Shafiullah; Rashid, Ridwan B.; Ming, Long C.; Islam, Shanta; Sarker, Md. Moklesur R.; Nahar, Lutfun; Sarker, Satyajit D.; Datta, Bidyut K.; Rashid, Mohammad A.

2018-01-01

Polymethoxylavones (PMFs) are known to exhibit significant anti-inflammatory and neuroprotective properties. Nicotiana plumbaginifolia, an annual Bangladeshi herb, is rich in polymethoxyflavones that possess significant analgesic and anxiolytic activities. The present study aimed to determine the antinociceptive and neuropharmacological activities of polyoxygenated flavonoids namely- 3,3′,5,6,7,8-hexamethoxy-4′,5′-methylenedioxyflavone (1), 3,3′,4′,5′,5,6,7,8-octamethoxyflavone (exoticin) (2), 6,7,4′,5′-dimethylenedioxy-3,5,3′-trimethoxyflavone (3), and 3,3′,4′,5,5′,8-hexamethoxy-6,7-methylenedioxyflavone (4), isolated and identified from N. plumbaginifolia. Antinociceptive activity was assessed using the acetic-acid induced writhing, hot plate, tail immersion, formalin and carrageenan-induced paw edema tests, whereas neuropharmacological effects were evaluated in the hole cross, open field and elevated plus maze test. Oral treatment of compounds 1, 3, and 4 (12.5–25 mg/kg b.w.) exhibited dose-dependent and significant (p < 0.01) antinociceptive activity in the acetic-acid, formalin, carrageenan, and thermal (hot plate)-induced pain models. The association of ATP-sensitive K+ channel and opioid systems in their antinociceptive effect was obvious from the antagonist effect of glibenclamide and naloxone, respectively. These findings suggested central and peripheral antinociceptive activities of the compounds. Compound 1, 3, and 4 (12.5 mg/kg b.w.) demonstrated significant (p < 0.05) anxiolytic-like activity in the elevated plus-maze test, while the involvement of GABAA receptor in the action of compound 3 and 4 was evident from the reversal effects of flumazenil. In addition, compounds 1 and 4 (12.5–25 mg/kg b.w) exhibited anxiolytic activity without altering the locomotor responses. The present study suggested that the polymethoxyflavones (1–4) from N. Plumbaginifolia could be considered as suitable candidates for the development of analgesic and anxiolytic agents. PMID:29515437

Polymethoxyflavones from Nicotiana plumbaginifolia (Solanaceae) Exert Antinociceptive and Neuropharmacological Effects in Mice.

PubMed

Shajib, Md Shafiullah; Rashid, Ridwan B; Ming, Long C; Islam, Shanta; Sarker, Md Moklesur R; Nahar, Lutfun; Sarker, Satyajit D; Datta, Bidyut K; Rashid, Mohammad A

2018-01-01

Polymethoxylavones (PMFs) are known to exhibit significant anti-inflammatory and neuroprotective properties. Nicotiana plumbaginifolia , an annual Bangladeshi herb, is rich in polymethoxyflavones that possess significant analgesic and anxiolytic activities. The present study aimed to determine the antinociceptive and neuropharmacological activities of polyoxygenated flavonoids namely- 3,3',5,6,7,8-hexamethoxy-4',5'-methylenedioxyflavone ( 1 ), 3,3',4',5',5,6,7,8-octamethoxyflavone (exoticin) ( 2 ), 6,7,4',5'-dimethylenedioxy-3,5,3'-trimethoxyflavone ( 3 ), and 3,3',4',5,5',8-hexamethoxy-6,7-methylenedioxyflavone ( 4 ), isolated and identified from N. plumbaginifolia . Antinociceptive activity was assessed using the acetic-acid induced writhing, hot plate, tail immersion, formalin and carrageenan-induced paw edema tests, whereas neuropharmacological effects were evaluated in the hole cross, open field and elevated plus maze test. Oral treatment of compounds 1 , 3 , and 4 (12.5-25 mg/kg b.w.) exhibited dose-dependent and significant ( p < 0.01) antinociceptive activity in the acetic-acid, formalin, carrageenan, and thermal (hot plate)-induced pain models. The association of ATP-sensitive K + channel and opioid systems in their antinociceptive effect was obvious from the antagonist effect of glibenclamide and naloxone, respectively. These findings suggested central and peripheral antinociceptive activities of the compounds. Compound 1 , 3 , and 4 (12.5 mg/kg b.w.) demonstrated significant ( p < 0.05) anxiolytic-like activity in the elevated plus-maze test, while the involvement of GABA A receptor in the action of compound 3 and 4 was evident from the reversal effects of flumazenil. In addition, compounds 1 and 4 (12.5-25 mg/kg b.w) exhibited anxiolytic activity without altering the locomotor responses. The present study suggested that the polymethoxyflavones ( 1-4 ) from N. Plumbaginifolia could be considered as suitable candidates for the development of analgesic and anxiolytic agents.

Rational identification of a novel soy-derived anxiolytic-like undecapeptide acting via gut-brain axis after oral administration.

PubMed

Ota, Ami; Yamamoto, Akane; Kimura, Saeko; Mori, Yukiha; Mizushige, Takafumi; Nagashima, Yoshiki; Sato, Masaru; Suzuki, Hideyuki; Odagiri, Saori; Yamada, Daisuke; Sekiguchi, Masayuki; Wada, Keiji; Kanamoto, Ryuhei; Ohinata, Kousaku

2017-05-01

Here we found that the chymotryptic digest of soy β-conglycinin, a major storage protein, exhibited anxiolytic-like effects in mice. We then searched for anxiolytic-like peptides in the digest. Based on a comprehensive peptide analysis of the chymotryptic digest by high performance liquid chromatograph connected to an LTQ Orbitrap mass spectrometer and the structure-activity relationship of known peptides, we explored anxiolytic-like peptides present in the digest. FLSSTEAQQSY, which corresponds to 323-333 of the β-conglycinin α subunit [βCGα(323-333)] emerged as a candidate. Oral administration of synthetic βCGα(323-333) exhibited anxiolytic-like effects in the elevated plus-maze and open-field test in male mice. Orally administered βCGα(323-333) exhibited anxiolytic-like effects in sham-operated control mice but not in vagotomized mice. In addition, oral administration of βCGα(323-333) increased the expression of c-Fos, a marker of neuronal activity, in the nucleus of the solitary tract, which receives inputs from the vagus nerve. These results suggest that the anxiolytic-like effects were mediated by the vagus nerve. The anxiolytic-like effects of βCGα(323-333) were also blocked by antagonists of the serotonin 5-HT 1A , dopamine D 1 and GABA A receptors. However βCGα(323-333) had no affinity for these receptors, suggesting it stimulates the release of endogenous neurotransmitters to activate the receptors. Taken together, a soy-derived undecapeptide, βCGα(323-333), may exhibit anxiolytic-like effects after oral administration via the vagus nerve and 5-HT 1A , D 1 and GABA A systems. Copyright © 2017 Elsevier Ltd. All rights reserved.

Psychiatric disease in late adolescence and young adulthood. Foetal programming by maternal hypothyroidism?

PubMed

Andersen, Stine Linding; Olsen, Jørn; Wu, Chun Sen; Laurberg, Peter

2014-07-01

Lack of maternal thyroid hormones during foetal brain development may lead to structural abnormalities in the brain. We hypothesized that maternal hypothyroidism during the pregnancy could programme the foetus to development of psychiatric disease later in life. Danish nationwide register study. Singletons live-born 1980-1990. Cox proportional hazards model was used to estimate adjusted hazard ratio (aHR) with 95% confidence interval for offspring redemption of ≥2 prescriptions of a psychiatric drug from age 15 to 31 years. Among 542 100 adolescents and young adults included, altogether 3979 (0·7%) were born to mothers with hypothyroidism registered before 1996. In crude analyses, the use of a psychiatric drug was more frequent in late adolescence and young adulthood when the mother had hypothyroidism (P < 0·001); however, several possible confounders had to be taken into account. For example, mothers with hypothyroidism often also had a psychiatric registration (38·5% vs 27·7%, P < 0·001) and the use of psychiatric drugs changed over time. After adjustment for confounders including birth year, maternal age and maternal psychiatric history, maternal hypothyroidism was associated with an increased risk of having redeemed prescriptions of anxiolytics [aHR 1·23 (1·03-1·48)] and antipsychotics [aHR 1·22 (1·03-1·44)] in late adolescence and young adulthood. For antidepressants, aHR was 1·07 (0·98-1·17). The association between maternal hypothyroidism and the use of a psychiatric drug in late adolescence and young adulthood was partly confounded by maternal psychiatric history, but foetal programming by maternal hypothyroidism may be part of the mechanisms leading to the use of anxiolytics and antipsychotics. © 2014 John Wiley & Sons Ltd.

The Phytoestrogen Genistein Produces Similar Effects as 17β-Estradiol on Anxiety-Like Behavior in Rats at 12 Weeks after Ovariectomy

PubMed Central

Rivadeneyra-Domínguez, Eduardo; Herrera-Huerta, Emma Virginia; Santos-Torres, Andrea

2017-01-01

The phytoestrogen genistein produces anxiolytic-like effects in ovariectomized rats, which highlights its potential therapeutic effect in ameliorating anxiety in surgical menopausal women. However, no studies have directly compared the effects of identical doses of genistein and 17β-estradiol, the main estrogen used in hormone replacement therapy in menopausal women. The present study evaluated the anxiolytic-like effects of identical doses of genistein and 17β-estradiol (0.045, 0.09, and 0.18 mg/kg/7 days, s.c.) in a surgical menopause model in rats in the elevated plus maze and locomotor activity tests at 12 weeks after ovariectomy. Additionally, the participation of estrogen receptor-β in the anxiolytic-like effect of genistein and 17β-estradiol was explored by previous administration of the 5 mg/kg tamoxifen antagonist. Genistein and 17β-estradiol (0.09 and 0.18 mg/kg) similarly reduced anxiety-like behavior in the elevated plus maze and also increased the time spent grooming and rearing, without affecting crossing in locomotor activity test. These effects were blocked by tamoxifen. Present results indicate that the phytoestrogen genistein has a similar behavioral profile as 17β-estradiol in rats at 12 weeks after ovariectomy through action at the estrogen receptor-β. Thus genistein has potential for reducing anxiety-like behavior associated with low concentrations of ovarian hormones, which normally occurs during natural and surgical menopause. PMID:29226152

Pharmacokinetics of dietary kaempferol and its metabolite 4-hydroxyphenylacetic acid in rats.

PubMed

Zabela, Volha; Sampath, Chethan; Oufir, Mouhssin; Moradi-Afrapoli, Fahimeh; Butterweck, Veronika; Hamburger, Matthias

2016-12-01

Kaempferol is a major flavonoid in the human diet and in medicinal plants. The compound exerts anxiolytic activity when administered orally in mice, while no behavioural changes were observed upon intraperitoneal administration, or upon oral administration in gut sterilized animals. 4-Hydroxyphenylacetic acid (4-HPAA), which possesses anxiolytic effects when administered intraperitoneally, is a major intestinal metabolite of kaempferol. Pharmacokinetic properties of the compounds are currently not clear. UHPLC-MS/MS methods were validated to support pharmacokinetic studies of kaempferol and 4-HPAA in rats. Non-compartmental and compartmental analyses were performed. After intravenous administration, kaempferol followed a one-compartment model, with a rapid clearance (4.40-6.44l/h/kg) and an extremely short half-life of 2.93-3.79min. After oral gavage it was not possible to obtain full plasma concentration-time profiles of kaempferol. Pharmacokinetics of 4-HPAA was characterized by a two-compartment model, consisting of a quick distribution phase (half-life 3.04-6.20min) followed by a fast elimination phase (half-life 19.3-21.1min). Plasma exposure of kaempferol is limited by poor oral bioavailability and extensive metabolism. Both compounds are rapidly eliminated, so that effective concentrations at the site of action do not appear to be reached. At present, it is not clear how the anxiolytic-like effects reported for the compounds can be explained. Copyright © 2016 Elsevier B.V. All rights reserved.

Neuropharmacological effects of essential oil from the leaves of Croton conduplicatus Kunth and possible mechanisms of action involved.

PubMed

Oliveira Júnior, Raimundo Gonçalves de; Ferraz, Christiane Adrielly Alves; Silva, Juliane Cabral; de Andrade Teles, Roxana Braga; Silva, Mariana Gama; Diniz, Tâmara Coimbra; Dos Santos, Uiliane Soares; de Souza, Ana Valéria Vieira; Nunes, Carlos Eduardo Pereira; Salvador, Marcos José; Lorenzo, Vitor Prates; Quintans Júnior, Lucindo José; Almeida, Jackson Roberto Guedes da Silva

2018-07-15

Croton conduplicatus Kunth (Euphorbiaceae) is a Brazilian aromatic medicinal plant, widely known as "quebra-faca". In folk medicine, its leaves and stem-barks are used as a natural analgesic for the treatment of headaches. In this study, we describe for the first time the neuropharmacological potential of the essential oil obtained from the leaves of Croton conduplicatus (EO) in experimental models of pain, anxiety and insomnia. The mechanisms of action involved in these activities were also investigated. Different experimental models were used to evaluate the antinociceptive (acetic acid, formalin-induced nociception and hot plate tests), anxiolytic (elevated plus maze and hole board tests) and sedative (thiopental-induced sleeping time) effects of EO in mice. EO was evaluated in three different doses (25, 50 and 100 mg/kg, i.p.) and compared with positive and negative controls in all experimental protocols. When appropriate, animals were pretreated with pharmacological antagonists (naloxone, atropine and flumazenil) in order to evaluate the mechanisms of action involved. A docking study also was performed to identify possible targets involved. EO (25, 50 and 100 mg/kg, i.p.) demonstrated a significant antinociceptive activity in all experimental models. Pretreatment with naloxone or atropine reversed the antinociceptive response (p < 0.05), suggesting the involvement of opioid and muscarinic receptors, respectively. A docking study was performed with the major components identified in EO (1,8 cineole - 21.42%, spathulenol - 15.47%, p-cymene - 12.41% and caryophyllene oxide - 12.15%), demonstrating favorable interaction profile with different subtypes of muscarinic (M2, M3 and M4) and opioids (delta and mu) receptors. EO also showed anxiolytic (mainly at doses of 25 and 50 mg/kg, i.p.) and sedative (only at the dose of 100 mg/kg, i.p.) effects in mice. These pharmacological responses were reversed by flumazenil (p < 0.05), indicating possible involvement of GABA A receptors. Our findings support the traditional use of this plant as a natural analgesic and suggest that EO is a multi-target natural product, presenting not only antinociceptive effect but also anxiolytic and sedative activities depending on the dose used. Copyright © 2018 Elsevier B.V. All rights reserved.

Is lavender an anxiolytic drug? A systematic review of randomised clinical trials.

PubMed

Perry, R; Terry, R; Watson, L K; Ernst, E

2012-06-15

Lavender (Lavandula angustifolia) is often recommended for stress/anxiety relief and believed to possess anxiolytic effects. To critically evaluate the efficacy/effectiveness of lavender for the reduction of stress/anxiety. Seven electronic databases were searched to identify all relevant studies. All methods of lavender administration were included. Data extraction and the assessment of the methodological quality of all included trials were conducted by two independent reviewers. Fifteen RCTs met the inclusion criteria. Two trials scored 4 points on the 5-point Jadad scale, the remaining 13 scored two or less. Results from seven trials appeared to favour lavender over controls for at least one relevant outcome. Methodological issues limit the extent to which any conclusions can be drawn regarding the efficacy/effectiveness of lavender. The best evidence suggests that oral lavender supplements may have some therapeutic effects. However, further independent replications are needed before firm conclusions can be drawn. Copyright © 2012 Elsevier GmbH. All rights reserved.

A beta-blocker as anxiolytic and haemostatic in tonsillectomy.

PubMed

Basjrah, R; Lubis, H R; Tann, G

1983-01-01

Administration of a beta-blocker, pindolol, was utilized in the premedication of patients selected for tonsillectomies (dissection), to study anxiolytic effects. A curious result observed was that bleeding during and after operation in patients on pindolol was remarkably reduced compared to those not on beta-blocker treatment. This effect was further explored in a small controlled study. Nineteen patients were given pindolol, 5 mg the evening before and on the morning, an hour prior to surgery. Seventeen controls were on placebos. The amount of bleeding was measured in both groups. Patients on pindolol show significantly reduced bleeding when compared to controls (1.77 +/- 1.15 ml versus 7.30 +/- 6.05 ml; p less than 0.005). Coagulation and fibrinolytic profiles were studied in a number of patients in both groups attempting to clarify the cause of the reduced bleeding. The results will be reported. This preliminary study shows that pindolol is a useful drug for controlling bleeding in tonsillectomies. To our knowledge the haemostatic properties of pindolol have been reported before.

Anxiolytic effects of muscarinic acetylcholine receptors agonist oxotremorine in chronically stressed rats and related changes in BDNF and FGF2 levels in the hippocampus and prefrontal cortex.

PubMed

Di Liberto, Valentina; Frinchi, Monica; Verdi, Vincenzo; Vitale, Angela; Plescia, Fulvio; Cannizzaro, Carla; Massenti, Maria F; Belluardo, Natale; Mudò, Giuseppa

2017-02-01

In depressive disorders, one of the mechanisms proposed for antidepressant drugs is the enhancement of synaptic plasticity in the hippocampus and cerebral cortex. Previously, we showed that the muscarinic acetylcholine receptor (mAChR) agonist oxotremorine (Oxo) increases neuronal plasticity in hippocampal neurons via FGFR1 transactivation. Here, we aimed to explore (a) whether Oxo exerts anxiolytic effect in the rat model of anxiety-depression-like behavior induced by chronic restraint stress (CRS), and (b) if the anxiolytic effect of Oxo is associated with the modulation of neurotrophic factors, brain-derived neurotrophic factor (BDNF) and fibroblast growth factor-2 (FGF2), and phosphorylated Erk1/2 (p-Erk1/2) levels in the dorsal or ventral hippocampus and in the medial prefrontal cortex. The rats were randomly divided into four groups: control unstressed, CRS group, CRS group treated with 0.2 mg/kg Oxo, and unstressed group treated with Oxo. After 21 days of CRS, the groups were treated for 10 days with Oxo or saline. The anxiolytic role of Oxo was tested by using the following: forced swimming test, novelty suppressed feeding test, elevated plus maze test, and light/dark box test. The hippocampi and prefrontal cortex were used to evaluate BDNF and FGF2 protein levels and p-Erk1/2 levels. Oxo treatment significantly attenuated anxiety induced by CRS. Moreover, Oxo treatment counteracted the CRS-induced reduction of BDNF and FGF2 levels in the ventral hippocampus and medial prefrontal cerebral cortex CONCLUSIONS: The present study showed that Oxo treatment ameliorates the stress-induced anxiety-like behavior and rescues FGF2 and BDNF levels in two brain regions involved in CRS-induced anxiety, ventral hippocampal formation, and medial prefrontal cortex.

Acute Stress Affects the Expression of Hippocampal Mu Oscillations in an Age-Dependent Manner

PubMed Central

Takillah, Samir; Naudé, Jérémie; Didienne, Steve; Sebban, Claude; Decros, Brigitte; Schenker, Esther; Spedding, Michael; Mourot, Alexandre; Mariani, Jean; Faure, Philippe

2017-01-01

Anxiolytic drugs are widely used in the elderly, a population particularly sensitive to stress. Stress, aging and anxiolytics all affect low-frequency oscillations in the hippocampus and prefrontal cortex (PFC) independently, but the interactions between these factors remain unclear. Here, we compared the effects of stress (elevated platform, EP) and anxiolytics (diazepam, DZP) on extracellular field potentials (EFP) in the PFC, parietal cortex and hippocampus (dorsal and ventral parts) of adult (8 months) and aged (18 months) Wistar rats. A potential source of confusion in the experimental studies in rodents comes from locomotion-related theta (6–12 Hz) oscillations, which may overshadow the direct effects of anxiety on low-frequency and especially on the high-amplitude oscillations in the Mu range (7–12 Hz), related to arousal. Animals were restrained to avoid any confound and isolate the direct effects of stress from theta oscillations related to stress-induced locomotion. We identified transient, high-amplitude oscillations in the 7–12 Hz range (“Mu-bursts”) in the PFC, parietal cortex and only in the dorsal part of hippocampus. At rest, aged rats displayed more Mu-bursts than adults. Stress acted differently on Mu-bursts depending on age: it increases vs. decreases burst, in adult and aged animals, respectively. In contrast DZP (1 mg/kg) acted the same way in stressed adult and age animal: it decreased the occurrence of Mu-bursts, as well as their co-occurrence. This is consistent with DZP acting as a positive allosteric modulator of GABAA receptors, which globally potentiates inhibition and has anxiolytic effects. Overall, the effect of benzodiazepines on stressed animals was to restore Mu burst activity in adults but to strongly diminish them in aged rats. This work suggests Mu-bursts as a neural marker to study the impact of stress and DZP on age. PMID:29033825

Early Phase in the Development of Cannabidiol as a Treatment for Addiction: Opioid Relapse Takes Initial Center Stage.

PubMed

Hurd, Yasmin L; Yoon, Michelle; Manini, Alex F; Hernandez, Stephanie; Olmedo, Ruben; Ostman, Maria; Jutras-Aswad, Didier

2015-10-01

Multiple cannabinoids derived from the marijuana plant have potential therapeutic benefits but most have not been well investigated, despite the widespread legalization of medical marijuana in the USA and other countries. Therapeutic indications will depend on determinations as to which of the multiple cannabinoids, and other biologically active chemicals that are present in the marijuana plant, can be developed to treat specific symptoms and/or diseases. Such insights are particularly critical for addiction disorders, where different phytocannabinoids appear to induce opposing actions that can confound the development of treatment interventions. Whereas Δ(9)-tetracannabinol has been well documented to be rewarding and to enhance sensitivity to other drugs, cannabidiol (CBD), in contrast, appears to have low reinforcing properties with limited abuse potential and to inhibit drug-seeking behavior. Other considerations such as CBD's anxiolytic properties and minimal adverse side effects also support its potential viability as a treatment option for a variety of symptoms associated with drug addiction. However, significant research is still needed as CBD investigations published to date primarily relate to its effects on opioid drugs, and CBD's efficacy at different phases of the abuse cycle for different classes of addictive substances remain largely understudied. Our paper provides an overview of preclinical animal and human clinical investigations, and presents preliminary clinical data that collectively sets a strong foundation in support of the further exploration of CBD as a therapeutic intervention against opioid relapse. As the legal landscape for medical marijuana unfolds, it is important to distinguish it from "medical CBD" and other specific cannabinoids, that can more appropriately be used to maximize the medicinal potential of the marijuana plant.

[The original nootropic and neuroprotective drug noopept potentiates the anticonvulsant activity of valproate in mice].

PubMed

Kravchenko, E V; Ponteleeva, I V; Trofimov, S S; Lapa, V I; Ostrovskaia, R U; Voronina, T A

2009-01-01

The influence of the original dipeptide drug noopept, known to possess nootrope, neuroprotector, and anxiolytic properties, on the anticonvulsant activity of the antiepileptic drug valproate has been studied on the model of corazole-induced convulsions in mice. Neither a single administration of noopept (0.5 mg/kg, i.p.) nor its repeated introduction in 10 or 35 days enhanced the convulsant effect of corazole, which is evidence that noopept alone does not possess anticonvulsant properties. Prolonged (five weeks) preliminary administration of noopept enhanced the anticonvulsant activity of valproate. This result justifies the joint chronic administration of noopept in combination with valproate in order to potentiate the anticonvulsant effect of the latter drug. In addition, the administration of noopept favorably influences the cognitive functions and suppresses the development of neurodegenerative processes.

[Strategy for the development of dipeptide drugs].

PubMed

Gudasheva, T A

2011-01-01

The author describes an original approach to the development of dipeptide drugs based on the concept of the leading role of the beta-bend in the interaction of biologically active endogenous peptides with their receptors. The approach called "peptide-based drug design" includes both developments from the structure of a known psychotropic agent toward its topological peptide analog and developments from the active dipeptide site of a neuropeptide toward its mimetic. This strategy has been worked out at the V.V. Zakusov Research Institute of Pharmacology for 25 years. Results of investigations that discovered endogenous peptide prototypes of the known non-peptidic drugs (piracetam and sulpiride) are presented. They provided a basis for the creation of highly active non-toxic oral dipeptide preparations, such as nootrop Noopept, potential anti psychotic Dilept, and potential selective anxiolytic GB-115.

Comparison of the effects of the GABAB receptor positive modulator BHF177 and the GABAB receptor agonist baclofen on anxiety-like behavior, learning, and memory in mice

PubMed Central

Li, Xia; Risbrough, Victoria B.; Cates-Gatto, Chelsea; Kaczanowska, Katarzyna; Finn, M. G.; Roberts, Amanda J; Markou, Athina

2013-01-01

γ-Aminobutyric acid B (GABAB) receptor activation is a potential therapeutic approach for the treatment of drug addiction, pain, anxiety, and depression. However, full agonists of this receptor induce side-effects, such as sedation, muscle relaxation, tolerance, and cognitive disruption. Positive allosteric modulators (PAMs) of the GABAB receptor may have similar therapeutic effects as agonists with superior side-effect profiles. The present study behaviorally characterized N-([1R,2R,4S]-bicyclo[2.2.1]hept-2-yl)-2-methyl-5-(4-[trifluoromethyl]phenyl)-4-pyrimidinamine (BHF177), a GABAB receptor PAM, in mouse models of anxiety-like behavior, learning and memory. In addition, the effects of BHF177 were compared with the agonist baclofen. Unlike the anxiolytic chlordiazepoxide, baclofen (0.5, 1.5, and 2.5 mg/kg, intraperitoneally) and BHF177 (10, 20, and 40 mg/kg, orally) had no effect on anxiety-like behavior in the elevated plus maze, light/dark box, or the Vogel conflict test. Baclofen increased punished drinking in the Vogel conflict test, however this effect may be attributable to analgesic actions of baclofen. At the highest dose tested (2.5 mg/kg), baclofen-treated mice exhibited sedation-like effects (i.e., reduced locomotor activity) across many of the tests, whereas BHF177-treated mice exhibited no sedation-like effects. BHF177 exhibited pro-convulsion properties only in mice, but not in rats, indicating that this effect may be species-specific. At doses that were not sedative or pro-convulsant, baclofen and BHF177 had no selective effects on fear memory retrieval in contextual and cued fear conditioning or spatial learning and memory in the Barnes maze. These data suggest that BHF177 has little sedative activity, no anxiolytic-like profile, and minimal impairment of learning and memory in mice. PMID:23376712

In vitro screening of major neurotransmitter systems possibly involved in the mechanism of action of antibodies to S100 protein in released-active form

PubMed Central

Gorbunov, Evgeniy A; Ertuzun, Irina A; Kachaeva, Evgeniya V; Tarasov, Sergey A; Epstein, Oleg I

2015-01-01

Experimentally and clinically, it was shown that released-active form of antibodies to S100 protein (RAF of Abs to S100) exerts a wide range of pharmacological activities: anxiolytic, antiasthenic, antiaggressive, stress-protective, antihypoxic, antiischemic, neuroprotective, and nootropic. The purpose of this study was to determine the influence of RAF of Abs to S100 on major neurotransmitter systems (serotoninergic, GABAergic, dopaminergic, and on sigma receptors as well) which are possibly involved in its mechanism of pharmacological activity. Radioligand binding assays were used for assessment of the drug influence on ligand–receptor interaction. [35S]GTPγS binding assay, cyclic adenosine monophosphate HTRF™, cellular dielectric spectroscopy assays, and assays based on measurement of intracellular concentration of Ca2+ ions were used for assessment of agonist or antagonist properties of the drug toward receptors. RAF of Abs to S100 increased radioligand binding to 5-HT1F, 5-HT2B, 5-HT2Cedited, 5-HT3, and to D3 receptors by 142.0%, 131.9%, 149.3%, 120.7%, and 126.3%, respectively. Also, the drug significantly inhibited specific binding of radioligands to GABAB1A/B2 receptors by 25.8%, and to both native and recombinant human sigma1 receptors by 75.3% and 40.32%, respectively. In the functional assays, it was shown that the drug exerted antagonism at 5-HT1B, D3, and GABAB1A/B2 receptors inhibiting agonist-induced responses by 23.24%, 32.76%, and 30.2%, respectively. On the contrary, the drug exerted an agonist effect at 5-HT1A receptors enhancing receptor functional activity by 28.0%. The pharmacological profiling of RAF of Abs to S100 among 27 receptor provides evidence for drug-related modification of major neurotransmitter systems. PMID:26604768

Quality of life and social determinants of anxiolytics and hypnotics use in women in Poland: a population-based study.

PubMed

Zagozdzon, Pawel; Kolarzyk, Emilia; Marcinkowski, Jerzy T

2013-05-01

The majority of studies show a substantially higher consumption of anxiolytics and antidepressants among women than among men and in the age bracket above 45 years. To analyse association between the use of hypnotics/anxiolytics, and various characteristics of Polish women, including health-related quality of life. One thousand, five hundred and sixty (1,560) women aged 45-60 years completed a questionnaire dealing with the use of hypnotics/anxiolytics, demographic characteristics, environmental and work stress exposure, and self-reported quality of life (SF-36 form). The following variables were revealed as the predictors of hypnotic/anxiolytic use on univariate analysis: age; social pension; stress at work and environmental stress; hormone replacement therapy; headache; palpitations; mood swings or increased muscular tension; anger; duration of symptoms longer than one week; consulting a specialist; and low physical and mental health-related quality of life. The significant protective factors included: vocational and tertiary education; job satisfaction; and home as place of rest. The independent predictors of anxiolytic/hypnotic use included consulting a specialist and symptoms lasting more than one week, while job satisfaction and home as place of rest were the independent protective factors. The use of hypnotic/anxiolytic medication is strongly associated with environmental and psychosocial characteristics of women between 40 and 65 years of age.

Effects of bupropion, alone or coadministered with nicotine, on social behavior in mice.

PubMed

Gómez, Carmen; Carrasco, Carmen; Redolat, Rosa

2008-09-01

Bupropion, administered alone or combined with nicotine, is presently used to treat nicotine dependence. Despite experimental evidence of the complex behavioral actions of this drug, there have been little data reported about its effects on social behavior. Our main aim was to investigate the effects of acute administration of bupropion, alone or plus nicotine, on social interaction in mice. OF1 group-housed male mice were confronted in a neutral cage with an anosmic opponent during a 10 minutes encounter. Time allocated to body care and digging was reduced by administration of bupropion (40 mg/kg) both when administered alone and with nicotine (1 and 0.5 mg/kg). The lowest dose of bupropion (10 mg/kg) also reduced digging when combined with 1 mg/kg of nicotine. Time spent on non-social exploration and exploration from a distance was significantly higher in mice treated with bupropion (40 mg/kg) alone or combined with nicotine (1 and 0.5 mg/kg). The lowest dose of bupropion (10 mg/kg) increased non-social exploration when combined with 0.5 mg/kg of nicotine and exploration from a distance when combined with 1 mg/kg of nicotine. Ethopharmacological assessment of the behavior of groups of mice treated with different combinations of the two drugs indicates that nicotine can potentiate some of the behavioral effects of low doses of bupropion. Results also indicate that bupropion, either alone or combined with nicotine, has no significant effects on social investigation, suggesting that this drug does not induce a clear anxiolytic profile in OF1 mice.

Effect of Cholinergic Perturbations on Neuromotor-Cognitive Performance

DTIC Science & Technology

1986-09-01

the effects of 1.0 and 2.0 rrg of alprazolam (Xanax), a standard anxiolytic drug commonly used with clinical populations (Figures 1 to 3). The 1.0 mg...procedure and results of the study that generated the alprazolam data have been presented previously by Ellinwood et al. (26). As clearly shown in Figures 1...for either dose of alprazolam . Since the atropine and alprazolam studies were accomplished with different subjects and the sample size of the atropine

GABA homeostasis contributes to the developmental programming of anxiety-related behavior.

PubMed

Depino, Amaicha Mara; Tsetsenis, Theodoros; Gross, Cornelius

2008-05-19

During development, when inhibitory and excitatory synapses are formed and refined, homeostatic mechanisms act to adjust inhibitory input in order to maintain neural activity within a normal range. As the brain matures, synaptogenesis slows and a relatively stable level of inhibition is achieved. Deficits in inhibitory neurotransmission are associated with increased anxiety-related behavior and drugs that potentiate GABA function, the major inhibitory neurotransmitter in the brain, are effective anxiolytics. These observations raise the possibility that transient perturbations in the activity of neural circuits during development might induce compensatory changes in inhibition that could persist into adulthood and contribute to changes in anxiety-related behavior. To test this hypothesis, we treated mice continuously during the major period of forebrain synaptogenesis (P14-28) with the GABA-A receptor positive modulator diazepam and assessed anxiety-related behavior in adulthood. Control experiments confirmed anxiolytic effects of the drug following one day of treatment and the development of tolerance following two weeks of treatment. When tested in adulthood, one month after the end of treatment, diazepam-treated mice exhibited significantly increased behavioral inhibition in the open-field, elevated-plus maze, and novel object behavioral paradigms. Levels of benzodiazepine binding sites in amygdala and frontal cortex were specifically decreased in diazepam-treated mice demonstrating that homeostatic adjustments in GABA function persist into adulthood. Our results show that increased GABAergic activity can affect the developmental programming of anxiety-related behavior.

Critical neuropsychobiological analysis of panic attack- and anticipatory anxiety-like behaviors in rodents confronted with snakes in polygonal arenas and complex labyrinths: a comparison to the elevated plus- and T-maze behavioral tests.

PubMed

Coimbra, Norberto C; Paschoalin-Maurin, Tatiana; Bassi, Gabriel S; Kanashiro, Alexandre; Biagioni, Audrey F; Felippotti, Tatiana T; Elias-Filho, Daoud H; Mendes-Gomes, Joyce; Cysne-Coimbra, Jade P; Almada, Rafael C; Lobão-Soares, Bruno

2017-01-01

To compare prey and snake paradigms performed in complex environments to the elevated plus-maze (EPM) and T-maze (ETM) tests for the study of panic attack- and anticipatory anxiety-like behaviors in rodents. PubMed was reviewed in search of articles focusing on the plus maze test, EPM, and ETM, as well as on defensive behaviors displayed by threatened rodents. In addition, the authors' research with polygonal arenas and complex labyrinth (designed by the first author for confrontation between snakes and small rodents) was examined. The EPM and ETM tests evoke anxiety/fear-related defensive responses that are pharmacologically validated, whereas the confrontation between rodents and snakes in polygonal arenas with or without shelters or in the complex labyrinth offers ethological conditions for studying more complex defensive behaviors and the effects of anxiolytic and panicolytic drugs. Prey vs. predator paradigms also allow discrimination between non-oriented and oriented escape behavior. Both EPM and ETM simple labyrinths are excellent apparatuses for the study of anxiety- and instinctive fear-related responses, respectively. The confrontation between rodents and snakes in polygonal arenas, however, offers a more ethological environment for addressing both unconditioned and conditioned fear-induced behaviors and the effects of anxiolytic and panicolytic drugs.

Childhood bullying behavior and later psychiatric hospital and psychopharmacologic treatment: findings from the Finnish 1981 birth cohort study.

PubMed

Sourander, Andre; Ronning, John; Brunstein-Klomek, Anat; Gyllenberg, David; Kumpulainen, Kirsti; Niemelä, Solja; Helenius, Hans; Sillanmäki, Lauri; Ristkari, Terja; Tamminen, Tuula; Moilanen, Irma; Piha, Jorma; Almqvist, Fredrik

2009-09-01

No prospective population-based study examining predictive associations between childhood bullying behavior and long-term mental health outcomes in both males and females exists. To study predictive associations between bullying and victimization in childhood and later psychiatric hospital and psychopharmacologic treatment. Nationwide birth cohort study from age 8 to 24 years. Five thousand thirty-eight Finnish children born in 1981 with complete information about bullying and victimization at age 8 years from parents, teachers, and self-reports. National register-based lifetime information about psychiatric hospital treatments and psychopharmacologic medication prescriptions. When controlled for psychopathology score, frequent victim status at age 8 years among females independently predicted psychiatric hospital treatment and use of antipsychotic, antidepressant, and anxiolytic drugs. Among males, frequent bully-victim and bully-only statuses predicted use of antidepressant and anxiolytic drugs. Frequent bully-victim status among males also predicted psychiatric hospital treatment and use of antipsychotics. However, when the analysis was controlled with total psychopathology score at age 8 years, frequent bully, victim, or bully-victim status did not predict any psychiatric outcomes among males. Boys and girls who display frequent bullying behavior should be evaluated for possible psychiatric problems, as bullying behaviors in concert with psychiatric symptoms are early markers of risk of psychiatric outcome. Among females, frequent childhood victimization predicts later psychiatric problems irrespective of psychiatric problems at baseline.

SH-I-048A, AN IN VITRO NONSELECTIVE SUPER-AGONIST AT THE BENZODIAZEPINE SITE OF GABAA RECEPTORS: THE APPROXIMATED ACTIVATION OF RECEPTOR SUBTYPES MAY EXPLAIN BEHAVIORAL EFFECTS

PubMed Central

Obradović, Aleksandar Lj.; Joksimović, Srđan; Poe, Michael M.; Ramerstorfer, Joachim; Varagic, Zdravko; Namjoshi, Ojas; Batinić, Bojan; Radulović, Tamara; Marković, Bojan; Roth, Brian; Sieghart, Werner; Cook, James M.; Savić, Miroslav M.

2014-01-01

Enormous progress in understanding the role of four populations of benzodiazepine-sensitive GABAA receptors was paralleled by the puzzling findings suggesting that substantial separation of behavioral effects may be accomplished by apparently non-selective modulators. We report on SH-I-048A, a newly-synthesized chiral positive modulator of GABAA receptors characterized by exceptional subnanomolar affinity, high efficacy and non-selectivity. Its influence on behavior was assessed in Wistar rats and contrasted to that obtained with 2 mg/kg diazepam. SH-I-048A reached micromolar concentrations in brain tissue, while the unbound fraction in brain homogenate was around 1.5%. The approximated electrophysiological responses, which estimated free concentrations of SH-I-048A or diazepam are able to elicit, suggested a similarity between the 10 mg/kg dose of the novel ligand and 2 mg/kg diazepam; however, SH-I-048A was relatively more active at α1- and α5-containing GABAA receptors. Behaviorally, SH-I-048A induced sedative, muscle relaxant and ataxic effects, reversed mechanical hyperalgesia 24 hours after injury, while it was devoid of clear anxiolytic actions and did not affect water-maze performance. While lack of clear anxiolytic actions may be connected with an enhanced potentiation at α1-containing GABAA receptors, the observed behavior in the rotarod, water maze and peripheral nerve injury tests was possibly affected by its prominent action at receptors containing the α5 subunit. The current results encourage further innovative approaches aimed at linking in vitro and in vivo data in order to help define fine-tuning mechanisms at four sensitive receptor populations that underlie subtle differences in behavioral profiles of benzodiazepine site ligands. PMID:24472579

Long-Lasting Increase of Corticosterone After Fear Memory Reactivation: Anxiolytic Effects and Network Activity Modulation in the Ventral Hippocampus

PubMed Central

Albrecht, Anne; Çalışkan, Gürsel; Oitzl, Melly S; Heinemann, Uwe; Stork, Oliver

2013-01-01

Pathological fear and anxiety can be studied, in rodents, with fear conditioning and exposure to reminder cues. These paradigms are thought to critically involve the ventral hippocampus, which also serves as key site of glucocorticoid action in the brain. Here, we demonstrate a long-lasting reduction of kainate-induced gamma oscillations in slice preparations of the ventral hippocampal area CA3, 30 days after a single fear conditioning training. Reduction of gamma power was sensitive to corticosterone application and associated with a decrease in glucocorticoid and mineralocorticoid receptor mRNA expression across strata of the ventral hippocampal CA3. A fear reactivation session 24 h after the initial conditioning normalized receptor expression levels and attenuated the corticosterone-mediated recovery of gamma oscillations. It moreover increased both baseline and stimulus-induced corticosterone plasma levels and evoked a generalization of fear memory to the background context. Reduced ventral hippocampal gamma oscillation in both fear reactivated and non-reactivated mice were associated with a decrease of anxiety-like behavior in an elevated plus maze. Taking advantage of the circadian fluctuation in corticosterone, we demonstrated the association of high endogenous basal corticosterone plasma concentrations during morning hours with reduced anxiety-like behavior in fear reactivated mice. The anxiolytic effect of the hormone was verified with local applications to the ventral hippocampus. Our data suggest that corticosterone acting on ventral hippocampal network activity has anxiolytic-like effects following fear exposure, highlighting its potential therapeutic value for anxiety disorders. PMID:22968818

Loss of hypothalamic corticotropin-releasing hormone markedly reduces anxiety behaviors in mice.

PubMed

Zhang, R; Asai, M; Mahoney, C E; Joachim, M; Shen, Y; Gunner, G; Majzoub, J A

2017-05-01

A long-standing paradigm posits that hypothalamic corticotropin-releasing hormone (CRH) regulates neuroendocrine functions such as adrenal glucocorticoid release, whereas extra-hypothalamic CRH has a key role in stressor-triggered behaviors. Here we report that hypothalamus-specific Crh knockout mice (Sim1CrhKO mice, created by crossing Crhflox with Sim1Cre mice) have absent Crh mRNA and peptide mainly in the paraventricular nucleus of the hypothalamus (PVH) but preserved Crh expression in other brain regions including amygdala and cerebral cortex. As expected, Sim1CrhKO mice exhibit adrenal atrophy as well as decreased basal, diurnal and stressor-stimulated plasma corticosterone secretion and basal plasma adrenocorticotropic hormone, but surprisingly, have a profound anxiolytic phenotype when evaluated using multiple stressors including open-field, elevated plus maze, holeboard, light-dark box and novel object recognition task. Restoring plasma corticosterone did not reverse the anxiolytic phenotype of Sim1CrhKO mice. Crh-Cre driver mice revealed that PVHCrh fibers project abundantly to cingulate cortex and the nucleus accumbens shell, and moderately to medial amygdala, locus coeruleus and solitary tract, consistent with the existence of PVHCrh-dependent behavioral pathways. Although previous, nonselective attenuation of CRH production or action, genetically in mice and pharmacologically in humans, respectively, has not produced the anticipated anxiolytic effects, our data show that targeted interference specifically with hypothalamic Crh expression results in anxiolysis. Our data identify neurons that express both Sim1 and Crh as a cellular entry point into the study of CRH-mediated, anxiety-like behaviors and their therapeutic attenuation.

Loss of hypothalamic corticotropin-releasing hormone markedly reduces anxiety behaviors in mice

PubMed Central

Zhang, Rong; Asai, Masato; Mahoney, Carrie E; Joachim, Maria; Shen, Yuan; Gunner, Georgia; Majzoub, Joseph A

2016-01-01

A long-standing paradigm posits that hypothalamic corticotropin-releasing hormone (CRH) regulates neuroendocrine functions such as adrenal glucocorticoid release, while extra-hypothalamic CRH plays a key role in stressor-triggered behaviors. Here we report that hypothalamus-specific Crh knockout mice (Sim1CrhKO mice, created by crossing Crhflox with Sim1Cre mice) have absent Crh mRNA and peptide mainly in the paraventricular nucleus of the hypothalamus (PVH) but preserved Crh expression in other brain regions including amygdala and cerebral cortex. As expected, Sim1CrhKO mice exhibit adrenal atrophy as well as decreased basal, diurnal and stressor-stimulated plasma corticosterone secretion and basal plasma ACTH, but surprisingly, have a profound anxiolytic phenotype when evaluated using multiple stressors including open field, elevated plus maze, holeboard, light-dark box, and novel object recognition task. Restoring plasma corticosterone did not reverse the anxiolytic phenotype of Sim1CrhKO mice. Crh-Cre driver mice revealed that PVHCrh fibers project abundantly to cingulate cortex and the nucleus accumbens shell, and moderately to medial amygdala, locus coeruleus, and solitary tract, consistent with the existence of PVHCrh-dependent behavioral pathways. Although previous, nonselective attenuation of CRH production or action, genetically in mice and pharmacologically in humans, respectively, has not produced the anticipated anxiolytic effects, our data show that targeted interference specifically with hypothalamic Crh expression results in anxiolysis. Our data identify neurons that express both Sim1 and Crh as a cellular entry point into the study of CRH-mediated, anxiety-like behaviors and their therapeutic attenuation. PMID:27595593

[Psychotropic drugs in the Family Health Strategy: profile of use, access and strategies to promote rational use].

PubMed

da Rocha, Bruno Simas; Werlang, Maria Cristina

2013-11-01

The use of psychotropic drugs is on the increase, and there are few studies in Brazil investigating their use in the population and in Primary Health Care (PHC). This study aimed to determine the prevalence and patterns of psychotropic drug use by patients of a Family Health Unit in Porto Alegre, through an observational, descriptive, retrospective and cross-sectional study. The sample consisted of patients who received prescriptions for controlled psychotropic drugs and the data collected from medical records. The study included 329 patients, with prevalence of the use of psychotropic drugs of 7.30%, mean age of 53.14 (SD = 18.58) years and 72% female. The average number of prescribed drugs and psychotropic drugs per user was 3.56 (SD = 2.36) and 1.66 (SD = 0.90), respectively. The most widely used class was antidepressants, followed by antiepileptics, anxiolytics and antipsychotics. It is necessary to develop strategies to improve access, treatment of patients and rational use of psychotropic drugs, including the revision of lists of essential drugs and training of professionals in PHC.

Anxiolytic-like effect of 2-(4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)ethan-1-ol is mediated through the benzodiazepine and nicotinic pathways.

PubMed

Brito, Adriane F; Fajemiroye, James O; Neri, Hiasmin F S; Silva, Dayane M; Silva, Daiany P B; Sanz, Germán; Vaz, Boniek G; de Carvalho, Flávio S; Ghedini, Paulo C; Lião, Luciano M; Menegatti, Ricardo; Costa, Elson A

2017-09-01

In this study, we proposed the design, synthesis of a new compound 2-(4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)ethan-1-ol (LQFM032), and pharmacological evaluation of its anxiolytic-like effect. This new compound was subjected to pharmacological screening referred to as Irwin test, prior to sodium pentobarbital-induced sleep, open-field and wire tests. The anxiolytic-like effect of this compound was evaluated using elevated plus maze and light-dark box tests. In addition, the mnemonic activity was evaluated through step-down test. In sodium pentobarbital-induced sleep test, LQFM032 decreased latency and increased duration of sleep. In the open-field test, LQFM032 altered behavioral parameter, that suggested anxiolytic-like activity, as increased in crossings and time spent at the center of open field. In the plus maze test and light-dark box test, the LQFM032 showed anxiolytic-like activity, increased entries and time spent on open arms, and increased in number of transitions and time spent on light area, respectively. Those effects was antagonized by flumazenil but not with 1-(2-Methoxyphenyl)-4-(4-phthalimidobutyl)piperazine (NAN-190). The LQFM032 did not alter mnemonic activity. Moreover, the anxiolytic-like activity of LQFM032 was antagonized by mecamylamine. In summary, LQFM032 showed benzodiazepine and nicotinic pathways mediated anxiolytic-like activity without altering the mnemonic activity. © 2017 John Wiley & Sons A/S.

High doses alprazolam induced amenorrhoea and galactorrhoea.

PubMed

Petrić, Daniela; Peitl, Marija Vučić; Peitl, Vjekoslav

2011-03-01

Alprazolam belongs in the group of anxiolytics, medicaments used for reducing anxiety. As most other drugs, it can cause various adverse events, including hormonal disturbances and imbalance. Prolactin elevation is one such hormonal adverse event that can lead to galactorrhoea, or abnormal milk discharge from the breast and amenorrhoea. In this case report we will present the case of a female patient that developed galactorrhoea while treated with alprazolam, after all physical factors that can also cause these symptoms were excluded.

Prosocial effects of nicotine and ethanol in adolescent rats through partially dissociable neurobehavioral mechanisms

PubMed Central

Trezza, Viviana; Baarendse, Petra J.J.; Vanderschuren, Louk J.M.J.

2009-01-01

The widespread use of tobacco and alcohol among adolescents might be related to the ability of nicotine and ethanol to facilitate social interactions. To investigate the neurobehavioral mechanisms underlying the prosocial effects of nicotine and ethanol, we focused on social play behavior, the most characteristic social activity in adolescent rats. Social play behavior is rewarding, and it is modulated through opioid, cannabinoid and dopaminergic neurotransmission, which are also involved in the reinforcing properties of nicotine and ethanol. We found that nicotine and ethanol increased social play, without affecting locomotion or social exploration. Their effects depended on the level of social activity of the partner, and were comparable in familiar and unfamiliar environments. At doses that increased social play, nicotine and ethanol had no anxiolytic effects in the elevated plus-maze. By contrast, the prototypical anxiolytic drug diazepam reduced social play at doses that reduced anxiety. The effects of nicotine on social play were blocked by the opioid receptor antagonist naloxone, the CB1 cannabinoid receptor antagonist SR141716A, and the dopamine receptor antagonist alpha-flupenthixol. The effects of ethanol were blocked by SR141716A and alpha-flupenthixol, but not by naloxone. Combined administration of subeffective doses of nicotine and ethanol only modestly enhanced social play. These results show that the facilitatory effects of nicotine and ethanol on social play are behaviorally specific and mediated through neurotransmitter systems involved in positive emotions and motivation, through partially dissociable mechanisms. Furthermore, the stimulating effects of nicotine and ethanol on social play behavior are independent of their anxiolytic-like properties. PMID:19657330

Unstimulated whole salivary flow rate and anxiolytics intake are independently associated with oral Candida infection in patients with oral lichen planus.

PubMed

Bokor-Bratic, Marija; Cankovic, Milos; Dragnic, Natasa

2013-10-01

Many factors have been proposed to influence oral infection with yeast. The aim of this study was to determine the prevalence of oral yeasts in oral lichen planus (OLP) patients and control subjects, and to perform a multiple logistic regression analysis to identify factors that influence oral Candida infection in OLP patients. In this cross-sectional study, 90 new patients with OLP and 90 sex- and age-matched control subjects with no mucosal lesions were interviewed about their health status, use of medication, and smoking and alcohol habits. Swab and unstimulated whole saliva samples were collected and salivary pH was measured. A positive Candida culture was more prevalent among OLP patients (48.9%) than among control subjects (26.7%). Candida albicans was the most frequently isolated species in both groups. By logistic regression analysis, unstimulated whole salivary flow rates of 0.11-0.24 ml min(-1) (OR = 5.90) and 0.25-0.32 ml min(-1) (OR = 3.51) and benzodiazepine anxiolytics intake (OR = 8.30) were independently associated with the presence of Candida among OLP patients. Age, denture wearing, levels of dentition, decreased salivary pH, antihypertensive drugs, and alcohol consumption were not associated with oral Candida infection in OLP patients. The results indicate that data on benzodiazepine anxiolytics intake and evaluation of unstimulated whole salivary flow rate should be considered as part of the clinical evaluation to identify OLP patients at risk for Candida infection. © 2013 Eur J Oral Sci.

A mouse model of high trait anxiety shows reduced heart rate variability that can be reversed by anxiolytic drug treatment.

PubMed

Gaburro, Stefano; Stiedl, Oliver; Giusti, Pietro; Sartori, Simone B; Landgraf, Rainer; Singewald, Nicolas

2011-11-01

Increasing evidence suggests that specific physiological measures may serve as biomarkers for successful treatment to alleviate symptoms of pathological anxiety. Studies of autonomic function investigating parameters such as heart rate (HR), HR variability and blood pressure (BP) indicated that HR variability is consistently reduced in anxious patients, whereas HR and BP data show inconsistent results. Therefore, HR and HR variability were measured under various emotionally challenging conditions in a mouse model of high innate anxiety (high anxiety behaviour; HAB) vs. control normal anxiety-like behaviour (NAB) mice. Baseline HR, HR variability and activity did not differ between mouse lines. However, after cued Pavlovian fear conditioning, both elevated tachycardia and increased fear responses were observed in HAB mice compared to NAB mice upon re-exposure to the conditioning stimulus serving as the emotional stressor. When retention of conditioned fear was tested in the home cage, HAB mice again displayed higher fear responses than NAB mice, while the HR responses were similar. Conversely, in both experimental settings HAB mice consistently exhibited reduced HR variability. Repeated administration of the anxiolytic NK1 receptor antagonist L-822429 lowered the conditioned fear response and shifted HR dynamics in HAB mice to a more regular pattern, similar to that in NAB mice. Additional receiver-operating characteristic (ROC) analysis demonstrated the high specificity and sensitivity of HR variability to distinguish between normal and high anxiety trait. These findings indicate that assessment of autonomic response in addition to freezing might be a useful indicator of the efficacy of novel anxiolytic treatments.

Prosocial effects of nicotine and ethanol in adolescent rats through partially dissociable neurobehavioral mechanisms.

PubMed

Trezza, Viviana; Baarendse, Petra J J; Vanderschuren, Louk J M J

2009-11-01

The widespread use of tobacco and alcohol among adolescents might be related to the ability of nicotine and ethanol to facilitate social interactions. To investigate the neurobehavioral mechanisms underlying the prosocial effects of nicotine and ethanol, we focused on social play behavior, the most characteristic social activity in adolescent rats. Social play behavior is rewarding, and it is modulated through opioid, cannabinoid and dopaminergic neurotransmission, which are also involved in the reinforcing properties of nicotine and ethanol. We found that nicotine and ethanol increased social play, without affecting locomotion or social exploration. Their effects depended on the level of social activity of the partner, and were comparable in familiar and unfamiliar environments. At doses that increased social play, nicotine and ethanol had no anxiolytic effects in the elevated plus-maze. By contrast, the prototypical anxiolytic drug diazepam reduced social play at doses that reduced anxiety. The effects of nicotine on social play were blocked by the opioid receptor antagonist naloxone, the CB(1) cannabinoid receptor antagonist SR141716A, and the dopamine receptor antagonist alpha-flupenthixol. The effects of ethanol were blocked by SR141716A and alpha-flupenthixol, but not by naloxone. Combined administration of subeffective doses of nicotine and ethanol only modestly enhanced social play. These results show that the facilitatory effects of nicotine and ethanol on social play are behaviorally specific and mediated through neurotransmitter systems involved in positive emotions and motivation, through partially dissociable mechanisms. Furthermore, the stimulating effects of nicotine and ethanol on social play behavior are independent of their anxiolytic-like properties.

The GABAergic system contributes to the anxiolytic-like effect of essential oil from Cymbopogon citratus (lemongrass).

PubMed

Costa, Celso A Rodrigues de Almeida; Kohn, Daniele Oliveira; de Lima, Valéria Martins; Gargano, André Costa; Flório, Jorge Camilo; Costa, Mirtes

2011-09-01

The essential oil (EO) from Cymbopogon citratus (DC) Stapf is reported to have a wide range of biological activities and is widely used in traditional medicine as an infusion or decoction. However, despite this widely use, there are few controlled studies confirming its biological activity in central nervous system. The anxiolytic-like activity of the EO was investigated in light/dark box (LDB) and marble-burying test (MBT) and the antidepressant activity was investigated in forced-swimming test (FST) in mice. Flumazenil, a competitive antagonist of benzodiazepine binding and the selective 5-HT(1A) receptor antagonist WAY100635 was used in experimental procedures to determine the action mechanism of EO. To exclude any false positive results in experimental procedures, mice were submitted to the rota-rod test. We also quantified some neurotransmitters at specific brain regions after EO oral acute treatment. The present work found anxiolytic-like activity of the EO at the dose of 10mg/kg in a LDB. Flumazenil, but not WAY100635, was able to reverse the effect of the EO in the LDB, indicating that the EO activity occurs via the GABA(A) receptor-benzodiazepine complex. Only at higher doses did the EO potentiate diethyl-ether-induced sleeping time in mice. In the FST and MBT, EO showed no effect. Finally, the increase in time spent in the light chamber, demonstrated by concomitant treatment with ineffective doses of diazepam (DZP) and the EO, revealed a synergistic effect of the two compounds. The lack of activity after long-term treatment in the LDB test might be related to tolerance induction, even in the DZP-treated group. Furthermore, there were no significant differences between groups after either acute or repeated treatments with the EO in the rota-rod test. Neurochemical evaluation showed no amendments in neurotransmitter levels evaluated in cortex, striatum, pons, and hypothalamus. The results corroborate the use of Cymbopogon citratus in folk medicine and suggest that the anxiolytic-like effect of its EO is mediated by the GABA(A) receptor-benzodiazepine complex. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Risk mitigation for children exposed to drugs during gestation: A critical role for animal preclinical behavioral testing.

PubMed

Zucker, Irving

2017-06-01

Many drugs with unknown safety profiles are administered to pregnant women, placing their offspring at risk. I assessed whether behavioral outcomes for children exposed during gestation to antidepressants, anxiolytics, anti-seizure, analgesic, anti-nausea and sedative medications can be predicted by more extensive animal studies than are part of the FDA approval process. Human plus rodent data were available for only 8 of 33 CNS-active drugs examined. Similar behavioral and cognitive deficits, including autism and ADHD emerged in human offspring and in animal models of these disorders after exposure to fluoxetine, valproic acid, carbamazepine, phenytoin, phenobarbital and acetaminophen. Rodent data helpful in identifying and predicting adverse effects of prenatal drug exposure in children were first generated many years after drugs were FDA-approved and administered to pregnant women. I recommend that enhanced behavioral testing of rodent offspring exposed to drugs prenatally should begin during preclinical drug evaluation and continue during Phase I clinical trials, with findings communicated to physicians and patients in drug labels. Copyright © 2017 Elsevier Ltd. All rights reserved.

A Novel 1,4-Dihydropyridine Derivative Improves Spatial Learning and Memory and Modifies Brain Protein Expression in Wild Type and Transgenic APPSweDI Mice.

PubMed

Jansone, Baiba; Kadish, Inga; van Groen, Thomas; Beitnere, Ulrika; Moore, Doyle Ray; Plotniece, Aiva; Pajuste, Karlis; Klusa, Vija

2015-01-01

Ca2+ blockers, particularly those capable of crossing the blood-brain barrier (BBB), have been suggested as a possible treatment or disease modifying agents for neurodegenerative disorders, e.g., Alzheimer's disease. The present study investigated the effects of a novel 4-(N-dodecyl) pyridinium group-containing 1,4-dihydropyridine derivative (AP-12) on cognition and synaptic protein expression in the brain. Treatment of AP-12 was investigated in wild type C57BL/6J mice and transgenic Alzheimer's disease model mice (Tg APPSweDI) using behavioral tests and immunohistochemistry, as well as mass spectrometry to assess the blood-brain barrier (BBB) penetration. The data demonstrated the ability of AP-12 to cross the BBB, improve spatial learning and memory in both mice strains, induce anxiolytic action in transgenic mice, and increase expression of hippocampal and cortical proteins (GAD67, Homer-1) related to synaptic plasticity. The compound AP-12 can be seen as a prototype molecule for use in the design of novel drugs useful to halt progression of clinical symptoms (more specifically, anxiety and decline in memory) of neurodegenerative diseases, particularly Alzheimer's disease.

A review of Neuropharmacology Effects of Nigella sativa and Its Main Component, Thymoquinone.

PubMed

Javidi, Soheila; Razavi, Bibi Marjan; Hosseinzadeh, Hossein

2016-08-01

Neuropharmacology is the scientific study of drug effect on nervous system. In the last few years, different natural plants and their active constituents have been used in neurological therapy. The availability, lower price, and less toxic effects of herbal medicines compared with synthetic agents make them as simple and excellent choice in the treatment of nervous diseases. Nigella sativa, which belongs to the botanical family of Ranunculaceae, is a widely used medicinal plant all over the world. In traditional and modern medicines several beneficial properties have been attributed to N. sativa and its main component, thymoquinone (TQ). In this review, various studies in scientific databases regarding the neuropharmacological aspects of N. sativa and TQ have been introduced. Results of these studies showed that N. sativa and TQ have several properties including anticonvulsant, antidepressant, anxiolytic, anti-ischemic, analgesic, antipsychotic, and memory enhancer. Furthermore, its protective effects against neurodegenerative diseases such as Alzheimer, Parkinson and multiple sclerosis have been discussed. Although there are many studies indicating the beneficial actions of this plant in nervous system, the number of research projects relating to the human reports is rare. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Psychotropic drug use among persons with mental distress symptoms: a population-based study in Norway.

PubMed

Hausken, Anne M; Skurtveit, Svetlana; Rosvold, Elin O; Bramness, Jørgen G; Furu, Kari

2007-01-01

To explore psychotropic drug use in the general population and in particular among non-institutionalized persons with mental distress symptoms. A total of 14,139 women and 11,665 men participating in the Oslo Health Study or the Oppland/Hedmark Study 2000-2001 submitted a self-administered questionnaire on health status and drug use, lifestyle, and socioeconomic factors. Respondents using antidepressants, hypnotics, and/or anxiolytics during the last four weeks were defined as users. A high Hopkins Symptoms Checklist-10 score indicated mental distress. The 15% with the highest score in each gender and age group (adults: 30/40/45 years; elderly: 60 years) were studied. The prevalence of antidepressant use among those with mental distress was, for women: adults 21%; elderly 30%; and for men, adults 15%; elderly 15%. These figures were nearly four times higher than in the general population. Not participating in the labour market was the main factor associated with use of antidepressants for subjects with mental distress: adult women (odds ratio (OR) 3.5; 95% confidence interval (CI) 2.5-5.0); elderly women (OR 5.2; CI 2.7-10.2); adult men (OR 4.7; CI 3.0-7.3); and elderly men (OR 2.9; CI 1.4-6.0). Use of analgesics was the main factor associated with use of anxiolytics/hypnotics: adult women (OR 2.4; CI 1.7-3.4); elderly women (OR 2.3; CI 1.4-3.8); adult men (OR 2.1; CI 1.3-3.3); and elderly men (OR 3.4; CI 1.9-6.0). Among individuals with mental distress, not participating in the labour market and regular use of analgesics were the main factors associated with use of psychotropics in both genders regardless of age.

Pharmacological blockade or genetic deletion of substance P (NK(1)) receptors attenuates neonatal vocalisation in guinea-pigs and mice.

PubMed

Rupniak, N M; Carlson, E C; Harrison, T; Oates, B; Seward, E; Owen, S; de Felipe, C; Hunt, S; Wheeldon, A

2000-06-08

The regulation of stress-induced vocalisations by central NK(1) receptors was investigated using pharmacological antagonists in guinea-pigs, a species with human-like NK(1) receptors, and transgenic NK1R-/- mice. In guinea-pigs, i.c.v. infusion of the selective substance P agonist GR73632 (0.1 nmol) elicited a pronounced vocalisation response that was blocked enantioselectively by the NK(1) receptor antagonists CP-99,994 and L-733,060 (0.1-10 mg/kg). GR73632-induced vocalisations were also markedly attenuated by the antidepressant drugs imipramine and fluoxetine (30 mg/kg), but not by the benzodiazepine anxiolytic diazepam (3 mg/kg) or the 5-HT(1A) agonist buspirone (10 mg/kg). Similarly, vocalisations in guinea-pig pups separated from their mothers were blocked enantioselectively by the highly brain-penetrant NK(1) receptor antagonists L-733,060 and GR205171 (ID(50) 3 mg/kg), but not by the poorly brain-penetrant compounds LY303870 and CGP49823 (30 mg/kg). Separation-induced vocalisations were also blocked by the anxiolytic drugs diazepam, chlordiazepoxide and buspirone (ID(50) 0.5-1 mg/kg), and by the antidepressant drugs phenelzine, imipramine, fluoxetine and venlafaxine (ID(50) 3-8 mg/kg). In normal mouse pups, GR205171 attenuated neonatal vocalisations when administered at a high dose (30 mg/kg) only, consistent with its lower affinity for the rat than the guinea-pig NK(1) receptor. Ultrasound calls in NK1R-/- mouse pups were markedly reduced compared with those in WT pups, confirming the specific involvement of NK(1) receptors in the regulation of vocalisation. These observations suggest that centrally-acting NK(1) receptor antagonists may have clinical utility in the treatment of a range of anxiety and mood disorders.

AVN-101: A Multi-Target Drug Candidate for the Treatment of CNS Disorders.

PubMed

Ivachtchenko, Alexandre V; Lavrovsky, Yan; Okun, Ilya

2016-05-25

Lack of efficacy of many new highly selective and specific drug candidates in treating diseases with poorly understood or complex etiology, as are many of central nervous system (CNS) diseases, encouraged an idea of developing multi-modal (multi-targeted) drugs. In this manuscript, we describe molecular pharmacology, in vitro ADME, pharmacokinetics in animals and humans (part of the Phase I clinical studies), bio-distribution, bioavailability, in vivo efficacy, and safety profile of the multimodal drug candidate, AVN-101. We have carried out development of a next generation drug candidate with a multi-targeted mechanism of action, to treat CNS disorders. AVN-101 is a very potent 5-HT7 receptor antagonist (Ki = 153 pM), with slightly lesser potency toward 5-HT6, 5-HT2A, and 5HT-2C receptors (Ki = 1.2-2.0 nM). AVN-101 also exhibits a rather high affinity toward histamine H1 (Ki = 0.58 nM) and adrenergic α2A, α2B, and α2C (Ki = 0.41-3.6 nM) receptors. AVN-101 shows a good oral bioavailability and facilitated brain-blood barrier permeability, low toxicity, and reasonable efficacy in animal models of CNS diseases. The Phase I clinical study indicates the AVN-101 to be well tolerated when taken orally at doses of up to 20 mg daily. It does not dramatically influence plasma and urine biochemistry, nor does it prolong QT ECG interval, thus indicating low safety concerns. The primary therapeutic area for AVN-101 to be tested in clinical trials would be Alzheimer's disease. However, due to its anxiolytic and anti-depressive activities, there is a strong rational for it to also be studied in such diseases as general anxiety disorders, depression, schizophrenia, and multiple sclerosis.

AVN-101: A Multi-Target Drug Candidate for the Treatment of CNS Disorders

PubMed Central

Ivachtchenko, Alexandre V.; Lavrovsky, Yan; Okun, Ilya

2016-01-01

Lack of efficacy of many new highly selective and specific drug candidates in treating diseases with poorly understood or complex etiology, as are many of central nervous system (CNS) diseases, encouraged an idea of developing multi-modal (multi-targeted) drugs. In this manuscript, we describe molecular pharmacology, in vitro ADME, pharmacokinetics in animals and humans (part of the Phase I clinical studies), bio-distribution, bioavailability, in vivo efficacy, and safety profile of the multimodal drug candidate, AVN-101. We have carried out development of a next generation drug candidate with a multi-targeted mechanism of action, to treat CNS disorders. AVN-101 is a very potent 5-HT7 receptor antagonist (Ki = 153 pM), with slightly lesser potency toward 5-HT6, 5-HT2A, and 5HT-2C receptors (Ki = 1.2–2.0 nM). AVN-101 also exhibits a rather high affinity toward histamine H1 (Ki = 0.58 nM) and adrenergic α2A, α2B, and α2C (Ki = 0.41–3.6 nM) receptors. AVN-101 shows a good oral bioavailability and facilitated brain-blood barrier permeability, low toxicity, and reasonable efficacy in animal models of CNS diseases. The Phase I clinical study indicates the AVN-101 to be well tolerated when taken orally at doses of up to 20 mg daily. It does not dramatically influence plasma and urine biochemistry, nor does it prolong QT ECG interval, thus indicating low safety concerns. The primary therapeutic area for AVN-101 to be tested in clinical trials would be Alzheimer’s disease. However, due to its anxiolytic and anti-depressive activities, there is a strong rational for it to also be studied in such diseases as general anxiety disorders, depression, schizophrenia, and multiple sclerosis. PMID:27232215

Coriandrum sativum: evaluation of its anxiolytic effect in the elevated plus-maze.

PubMed

Emamghoreishi, Masoumeh; Khasaki, Mohammad; Aazam, Maryam Fath

2005-01-15

The clinical applications of benzodiazepines as anxiolytics are limited by their unwanted side effects. Therefore, the development of new pharmacological agents is well justified. Among medicinal plants, Coriandrum sativum L. has been recommended for relief of anxiety and insomnia in Iranian folk medicine. Nevertheless, no pharmacological studies have thus far evaluated its effects on central nervous system. Therefore, the aim of this study was to examine if the aqueous extract of Coriandrum sativum seed has anxiolytic effect in mice. Additionally, its effect on spontaneous activity and neuromuscular coordination were evaluated. The anxiolytic effect of aqueous extract (10, 25, 50, 100 mg/kg, i.p.) was examined in male albino mice using elevated plus-maze as an animal model of anxiety. The effects of the extract on spontaneous activity and neuromuscular coordination were assessed using Animex Activity Meter and rotarod, respectively. In the elevated plus-maze, aqueous extract at 100 mg/kg showed an anxiolytic effect by increasing the time spent on open arms and the percentage of open arm entries, compared to control group. Aqueous extract at 50, 100 and 500 mg/kg significantly reduced spontaneous activity and neuromuscular coordination, compared to control group. These results suggest that the aqueous extract of Coriandrum sativum seed has anxiolytic effect and may have potential sedative and muscle relaxant effects.

Involvement of l-arginine-nitric oxide pathway in anxiolytic-like effects of zinc chloride in rats.

PubMed

Navabi, Seyedeh Parisa; Eshagh Harooni, Hooman; Moazedi, Ahmad Ali; Khajepour, Lotfolah; Fathinia, Kosar

2016-10-01

Zinc is crucial for normal development of the brain, and Zinc deficiency has been shown to associate with neurological disorders (e.g. anxiety) through interactions with several neurotransmitter systems such as nitric oxide (NO). In this regard, our study aimed to evaluate the possible involvement of l-arginine NO pathway on anxiolytic effects of zinc in adult male rats. Zinc chloride at doses of 2.5 and 10mg/kg (intraperitoneal or ip) or saline (1ml/kg, ip) were injected 30min before the anxiety test. Zinc administrated rats (10mg/kg) were pre-treated with intra-CA1 microinjection of l-arginine in sub-effective dose of 1μg/rat (dorsal hippocampus, vehicle: saline1μl/rat). In addition, zinc chloride and NG-nitro-l-arginine methyl ester (l-NAME) were intraperitoneally co-administrated in sub-effective doses of 2.5mg/kg and 80mg/kg, respectively. The percentage of open arm time (OAT%), percentage of open arm entry (OAE%), as measures of anxiety, and total number of arm entries, as measures of locomotor activity, were recorded. Treatment with zinc (10mg/kg) markedly produced an increase in OAT% and OAE% in the Elevated plus maze test (EPM). A decrease of OAT% and OAE% was shown in groups which received zinc (10mg/kg) and l-arginine (1μg/rat) concomitantly as compared to the control group. Moreover, an increase of OAE% was revealed in the group exposed to Zinc (2.5mg/kg) and l-NAME (80mg/kg) co-administration. Although, Two-way ANOVA showed no significant differences of anxiety indices in rats received drug+zinc chloride in compare to the zinc pretreated with saline group. Anxiolytic- like effect of zinc reversed by nitric oxide precursor l-arginine. Additionally, the synergistic effects of l-NAME and ZnCl 2 were shown in the EPM. Thus our findings suggest that at least in part the anxiolytic effects of zinc can be mediated through the nitric oxide system. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Functional Selectivity and Antidepressant Activity of Serotonin 1A Receptor Ligands

PubMed Central

Chilmonczyk, Zdzisław; Bojarski, Andrzej Jacek; Pilc, Andrzej; Sylte, Ingebrigt

2015-01-01

Serotonin (5-HT) is a monoamine neurotransmitter that plays an important role in physiological functions. 5-HT has been implicated in sleep, feeding, sexual behavior, temperature regulation, pain, and cognition as well as in pathological states including disorders connected to mood, anxiety, psychosis and pain. 5-HT1A receptors have for a long time been considered as an interesting target for the action of antidepressant drugs. It was postulated that postsynaptic 5-HT1A agonists could form a new class of antidepressant drugs, and mixed 5-HT1A receptor ligands/serotonin transporter (SERT) inhibitors seem to possess an interesting pharmacological profile. It should, however, be noted that 5-HT1A receptors can activate several different biochemical pathways and signal through both G protein-dependent and G protein-independent pathways. The variables that affect the multiplicity of 5-HT1A receptor signaling pathways would thus result from the summation of effects specific to the host cell milieu. Moreover, receptor trafficking appears different at pre- and postsynaptic sites. It should also be noted that the 5-HT1A receptor cooperates with other signal transduction systems (like the 5-HT1B or 5-HT2A/2B/2C receptors, the GABAergic and the glutaminergic systems), which also contribute to its antidepressant and/or anxiolytic activity. Thus identifying brain specific molecular targets for 5-HT1A receptor ligands may result in a better targeting, raising a hope for more effective medicines for various pathologies. PMID:26262615

Characterization of the rat exploratory behavior in the elevated plus-maze with Markov chains.

PubMed

Tejada, Julián; Bosco, Geraldine G; Morato, Silvio; Roque, Antonio C

2010-11-30

The elevated plus-maze is an animal model of anxiety used to study the effect of different drugs on the behavior of the animal. It consists of a plus-shaped maze with two open and two closed arms elevated 50cm from the floor. The standard measures used to characterize exploratory behavior in the elevated plus-maze are the time spent and the number of entries in the open arms. In this work, we use Markov chains to characterize the exploratory behavior of the rat in the elevated plus-maze under three different conditions: normal and under the effects of anxiogenic and anxiolytic drugs. The spatial structure of the elevated plus-maze is divided into squares, which are associated with states of a Markov chain. By counting the frequencies of transitions between states during 5-min sessions in the elevated plus-maze, we constructed stochastic matrices for the three conditions studied. The stochastic matrices show specific patterns, which correspond to the observed behaviors of the rat under the three different conditions. For the control group, the stochastic matrix shows a clear preference for places in the closed arms. This preference is enhanced for the anxiogenic group. For the anxiolytic group, the stochastic matrix shows a pattern similar to a random walk. Our results suggest that Markov chains can be used together with the standard measures to characterize the rat behavior in the elevated plus-maze. Copyright © 2010 Elsevier B.V. All rights reserved.

Effects of NMDA receptor blockade during the early development period on the retest performance of adult Wistar rats in the elevated plus maze.

PubMed

Kocahan, Sayad; Akillioglu, Kubra

2013-07-01

The elevated plus maze (EPM) is an animal model of anxiety used to test the effects of anxioselective drugs. The loss of the anxiolytic effect of drugs during the second exposure to the EPM is called the "one trial tolerance" (OTT) phenomenon. The present study was designed to investigate the relationship between the OTT phenomenon and N-methyl-D-aspartate (NMDA) receptor blockade in the early developmental period of rats. NMDA receptor blockade was accomplished using MK-801 treatment given between postnatal days 20-30. Beginning on postnatal day 20, the rats were subcutaneously injected with MK-801 twice a day at the nape of the neck for a period of 10 days (0.25 mg/kg). Increased open arm exploration was observed in MK-801-treated rats during trial 1 (p = 0.001) and trial 2 (p = 0.003). The rats spent less time in the closed arms as compared to the saline animals in trial 1 (p = 0.006), and this time decreased further in trial 2 (p = 0.02). The fecal boli of the MK-801 group was decreased in trial 1 as compared to the saline group (p = 0.01), but was not significantly different in trial 2 (p = 0.08). In conclusion, NMDA receptor blockade using MK-801 produced an anxiolytic-like effect in trials 1 and 2. Furthermore, OTT was not affected by NMDA receptor blockade.

Chronic fluoxetine treatment induces anxiolytic responses and altered social behaviors in medaka, Oryzias latipes.

PubMed

Ansai, Satoshi; Hosokawa, Hiroshi; Maegawa, Shingo; Kinoshita, Masato

2016-04-15

Medaka (Oryzias latipes) is a small freshwater teleost that is an emerging model system for neurobehavioral research and toxicological testing. The selective serotonin reuptake inhibitor class of antidepressants such as fluoxetine is one of the widely prescribed drugs, but little is known about the effects of these drugs on medaka behaviors. To assess the behavioral effects of fluoxetine, we chronically administrated fluoxetine to medaka adult fish and analyzed the anxiety-related and social behaviors using five behavioral paradigms (diving, open-field, light-dark transition, mirror-biting, and social interaction) with an automated behavioral testing system. Fish chronically treated with fluoxetine exhibited anxiolytic responses such as an overall increased time spent in the top area in the diving test and an increased time spent in center area in the open-field test. Analysis of socially evoked behavior showed that chronic fluoxetine administration decreased the number of mirror biting times in the mirror-biting test and increased latency to first contact in the social interaction test. Additionally, chronic fluoxetine administration reduced the horizontal locomotor activity in the open-field test but not the vertical activity in the diving test. These investigations are mostly consistent with previous reports in the other teleost species and rodent models. These results indicate that behavioral assessment in medaka adult fish will become useful for screening of effects of pharmaceutical and toxicological compounds in animal behaviors. Copyright © 2016 Elsevier B.V. All rights reserved.

Kampo Medicine: Evaluation of the Pharmacological Activity of 121 Herbal Drugs on GABAA and 5-HT3A Receptors

PubMed Central

Hoffmann, Katrin M.; Herbrechter, Robin; Ziemba, Paul M.; Lepke, Peter; Beltrán, Leopoldo; Hatt, Hanns; Werner, Markus; Gisselmann, Günter

2016-01-01

Kampo medicine is a form of Japanese phytotherapy originating from traditional Chinese medicine (TCM). During the last several decades, much attention has been paid to the pharmacological effects of these medical plants and their constituents. However, in many cases, a systematic screening of Kampo remedies to determine pharmacologically relevant targets is still lacking. In this study, a broad screening of Kampo remedies was performed to look for pharmacologically relevant 5-HT3A and GABAA receptor ligands. Several of the Kampo remedies are currently used for symptoms such as nausea, emesis, gastrointestinal motility disorders, anxiety, restlessness, or insomnia. Therefore, the pharmacological effects of 121 herbal drugs from Kampo medicine were analyzed as ethanol tinctures on heterologously expressed 5-HT3A and GABAA receptors, due to the involvement of these receptors in such pathophysiological processes. The tinctures of Lindera aggregata (radix) and Leonurus japonicus (herba) were the most effective inhibitory compounds on the 5-HT3A receptor. Further investigation of known ingredients in these compounds led to the identification of leonurine from Leonurus as a new natural 5-HT3A receptor antagonist. Several potentiating herbs (e.g., Magnolia officinalis (cortex), Syzygium aromaticum (flos), and Panax ginseng (radix)) were also identified for the GABAA receptor, which are all traditionally used for their sedative or anxiolytic effects. A variety of tinctures with antagonistic effects Salvia miltiorrhiza (radix) were also detected. Therefore, this study reveals new insights into the pharmacological action of a broad spectrum of herbal drugs from Kampo, allowing for a better understanding of their physiological effects and clinical applications. PMID:27524967

THE ROLE OF AMYGDALAR MU OPIOID RECEPTORS IN ANXIETY-RELATED RESPONSES IN TWO RAT MODELS

PubMed Central

Wilson, Marlene A.; Junor, Lorain

2009-01-01

Amygdala opioids such as enkephalin appear to play some role in the control of anxiety and the anxiolytic effects of benzodiazepines, although the opioid receptor subtypes mediating such effects are unclear. This study compared the influences of mu opioid receptor (MOR) activation in the central nucleus of the amygdala (CEA) on unconditioned fear or anxiety-like responses in two models, the elevated plus maze and the defensive burying test. The role of MOR in the anxiolytic actions of the benzodiazepine agonist diazepam was also examined using both models. Either the MOR agonist [D-Ala2, NMe-Phe4, Gly-ol5]-enkephalin (DAMGO) or the MOR antagonists Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) or β-funaltrexamine (FNA) were bilaterally infused into the CEA of rats prior to testing. The results show that microinjection of DAMGO in the CEA decreased open arm time in the plus maze, while CTAP increased open arm behaviors. In contrast, DAMGO injections in the CEA reduced burying behaviors and increased rearing following exposure to a predator odor, suggesting a shift in the behavioral response in this context. Amygdala injections of the MOR agonist DAMGO or the MOR antagonist CTAP failed to change the anxiolytic effects of diazepam in either test. Our results demonstrate that MOR activation in the central amygdala exerts distinctive effects in two different models of unconditioned fear or anxiety-like responses, and suggest that opioids may exert context-specific regulation of amygdala output circuits and behavioral responses during exposure to potential threats (open arms of the maze) versus discrete threats (predator odor). PMID:18216773

Targeted deletion of the GABRA2 gene encoding alpha2-subunits of GABA(A) receptors facilitates performance of a conditioned emotional response, and abolishes anxiolytic effects of benzodiazepines and barbiturates.

PubMed

Dixon, C I; Rosahl, T W; Stephens, D N

2008-07-01

Mice with point-mutated alpha2 GABA(A) receptor subunits (rendering them diazepam insensitive) are resistant to the anxiolytic-like effects of benzodiazepines (BZs) in the conditioned emotional response (CER) test, but show normal anxiolytic effects of a barbiturate. We investigated the consequence of deleting the alpha2-subunit on acquisition of the CER with increasing intensity of footshock, and on the anxiolytic efficacy of a benzodiazepine, diazepam, and a barbiturate, pentobarbital. alpha2 knockout (KO) and wildtype (WT) mice were trained in a conditioned emotional response (CER) task, in which lever pressing for food on a variable interval (VI) schedule was suppressed during the presentation of a compound light/tone conditioned stimulus (CS+) that predicted footshock. The ability of diazepam and of pentobarbital to reduce suppression during the CS+ was interpreted as an anxiolytic response. There were no differences between the genotypes in shock sensitivity, as assessed by their flinch responses to increasing levels of shock. However, alpha2 KO mice showed a greater suppression of lever pressing than WT littermates in the presence of a compound cue signalling footshock. Diazepam (0, 0.5, 1 and 2 mg/kg) induced a dose-dependent anxiolytic-like effect in WT mice but no such effect was seen in KO mice. Similarly, although pentobarbital (20 mg/kg) reduced the ability of the CS+ to reduce lever pressing rates in WT mice, this effect was not seen in the KO. These findings suggest that alpha2-containing GABA(A) receptors mediate the anxiolytic effects of barbiturates, as well as benzodiazepines, and that they may be involved in neuronal circuits underlying conditioned anxiety.

Interactions between environmental aversiveness and the anxiolytic effects of enhanced cannabinoid signaling by FAAH inhibition in rats.

PubMed

Haller, J; Barna, I; Barsvari, B; Gyimesi Pelczer, K; Yasar, S; Panlilio, L V; Goldberg, S

2009-07-01

Since the discovery of endogenous cannabinoid signaling, the number of studies exploring its role in health and disease has increased exponentially. Fatty acid amide hydrolase (FAAH), the enzyme responsible for degradation of the endocannabinoid anandamide, has emerged as a promising target for anxiety-related disorders. FAAH inhibitors (e.g., URB597) increase brain levels of anandamide and induce anxiolytic-like effects in rodents. Recent findings, however, questioned the efficacy of URB597 as an anxiolytic. We tested here the hypothesis that conflicting findings are due to variations in the stressfulness of experimental conditions employed in various studies. We found that URB597 (0.1-0.3 mg/kg) did not produce anxiolytic effects when the aversiveness of testing procedures was minimized by handling rats daily before experimentation, by habituating them to the experimental room, or by employing low illumination during testing. In contrast, URB597 had robust anxiolytic effects when the aversiveness of the testing environment was increased by eliminating habituation to the experimental room or by employing bright lighting conditions. Unlike URB597, the benzodiazepine chlordiazepoxide (5 mg/kg) had anxiolytic effects under all testing conditions. The anxiolytic effects of URB597 were abolished by the cannabinoid CB1-receptor antagonist AM251, showing that they were mediated by CB1 receptors. Close inspection of experimental conditions employed in earlier reports suggests that conflicting findings with URB597 can be explained by different testing conditions, such as those manipulated in the present study. Our findings show that FAAH inhibition does not affect anxiety under mildly stressful circumstances but protects against the anxiogenic effects of aversive stimuli.

Selegiline Ameliorates Depression-Like Behavior in Mice Lacking the CD157/BST1 Gene, a Risk Factor for Parkinson’s Disease

PubMed Central

Kasai, Satoka; Yoshihara, Toru; Lopatina, Olga; Ishihara, Katsuhiko; Higashida, Haruhiro

2017-01-01

Parkinson’s disease (PD), a neurodegenerative disorder, is accompanied by various non-motor symptoms including depression and anxiety, which may precede the onset of motor symptoms. Selegiline is an irreversible monoamine oxidase-B (MAO-B) inhibitor, and is widely used in the treatment of PD and major depression. However, there are few reports about the effects of selegiline on non-motor symptoms in PD. The aim of this study was to explore the antidepressant and anxiolytic effects of selegiline, using CD157/BST1 knockout (CD157 KO) mouse, a PD-related genetic model displaying depression and anxiety, compared with other antiparkinsonian drugs and an antidepressant, and was to investigate the effects of selegiline on biochemical parameters in emotion-related brain regions. A single administration of selegiline (1–10 mg/kg) dose-dependently reduced immobility time in the forced swimming test (FST) in CD157 KO mice, but not C57BL/6N wild-type (WT) mice. At 10 mg/kg, but not 3 mg/kg, selegiline significantly increased climbing time in CD157 KO mice. A single administration of the antiparkinsonian drugs pramipexole (a dopamine (DA) D2/D3 receptor agonist) or rasagiline (another MAO-B inhibitor), and repeated injections of a noradrenergic and specific serotonergic antidepressant (NaSSA), mirtazapine, also decreased immobility time, but did not increase climbing time, in CD157 KO mice. The antidepressant-like effects of 10 mg/kg selegiline were comparable to those of 10 mg/kg rasagiline, and tended to be stronger than those of 1 mg/kg rasagiline. After the FST, CD157 KO mice showed decreases in striatal and hippocampal serotonin (5-HT) content, cortical norepinephrine (NE) content, and plasma corticosterone concentration. A single administration of selegiline at 10 mg/kg returned striatal 5-HT, cortical NE, and plasma corticosterone levels to those observed in WT mice. In the open field test (OFT), repeated administration of mirtazapine had anxiolytic effects, and selegiline nonsignificantly ameliorated anxiety-like behaviors in CD157 KO mice. In the social interaction and preference tests, repeated mirtazapine ameliorated the high anxiety and low sociability of CD157 KO mice, whereas selegiline did not. These results indicate that selegiline has antidepressant and mild anxiolytic effects in CD157 KO mice, and suggest that it is an effective antiparkinsonian drug for depressive and anxiety symptoms in PD patients with a CD157 single nucleotide polymorphism (SNP). PMID:28515684

Antidepressant activity of standardized extract of Bacopa monniera in experimental models of depression in rats.

PubMed

Sairam, K; Dorababu, M; Goel, R K; Bhattacharya, S K

2002-04-01

Bacopa monniera Wettst. (syn. Herpestis monniera L.; Scrophulariaceae) is a commonly used Ayurvedic drug for mental disorders. The standardized extract was reported earlier to have significant anti-oxidant effect, anxiolytic activity and improve memory retention in Alzheimer's disease. Presently, the standardized methanolic extract of Bacopa monniera (bacoside A - 38.0+/-0.9) was investigated for potential antidepressant activity in rodent models of depression. The effect was compared with the standard antidepressant drug imipramine (15 mg/kg, ip). The extract when given in the dose of 20 and 40 mg/kg, orally once daily for 5 days was found to have significant antidepressant activity in forced swim and learned helplessness models of depression and was comparable to that of imipramine.

[Relationship of Anxiety and Depression in the Development of Mixed Anxiety/Depression Disorder. An Experimental Study of Comorbidity Mechanisms (Review)].

PubMed

Galyamina, A G; Kovalenko, I L; Smagin, D A; Kudryavtseva, N N

2016-01-01

As clinical practice and experimental studies show, symptoms of depression and anxiety often accompany each other. It is well known that combination of anxiety and depression in patients is treated more slowly, requires large doses of drugs, increases the likelihood of suicide and often leads to relapse. Furthermore, antidepressants and anxiolytics exert its therapeutic effect in limited cases even in monopolar anxiety or depression state. In this review of literature and our own data the relationship of anxiety and depression is analyzed. It has been shown with using the model of mixed anxiety/depression disorder caused by chronic social defeat stress, that the anxiety and depression are changed under the influence of psychotropic drugs independently.

Experimental neuropharmacology of Gelsemium sempervirens: Recent advances and debated issues.

PubMed

Bellavite, Paolo; Bonafini, Clara; Marzotto, Marta

Gelsemium sempervirens L. (Gelsemium) is traditionally used for its anxiolytic-like properties and its action mechanism in laboratory models are under scrutiny. Evidence from rodent models was reported suggesting the existence of a high sensitivity of central nervous system to anxiolytic power of Gelsemium extracts and Homeopathic dilutions. In vitro investigation of extremely low doses of this plant extract showed a modulation of gene expression of human neurocytes. These studies were criticized in a few commentaries, generated a debate in literature and were followed by further experimental studies from various laboratories. Toxic doses of Gelsemium cause neurological signs characterized by marked weakness and convulsions, while ultra-low doses or high Homeopathic dilutions counteract seizures induced by lithium and pilocarpine, decrease anxiety after stress and increases the anti-stress allopregnanolone hormone, through glycine receptors. Low (non-Homeopathic) doses of this plant or its alkaloids decrease neuropathic pain and c-Fos expression in mice brain and oxidative stress. Due to the complexity of the matter, several aspects deserve interpretation and the main controversial topics, with a focus on the issues of high dilution pharmacology, are discussed and clarified. Copyright © 2017 Transdisciplinary University, Bangalore and World Ayurveda Foundation. Published by Elsevier B.V. All rights reserved.

Chronic administration of parecoxib exerts anxiolytic-like and memory enhancing effects and modulates synaptophysin expression in mice.

PubMed

Wang, Bo; Jin, Xin; Kuang, Xin; Tian, Shaowen

2017-11-13

Previous studies have shown that cyclooxygenase-2, a key enzyme that converts arachidonic acid to prostaglandins, is involved in anxiety and cognitive processes, but few studies have investigated the effects of chronic administration of cyclooxygenase-2 inhibitors on anxiety, learning and memory under normal physiological conditions. The aim of the study was to investigate the effects of chronic administration of parecoxib, a cyclooxygenase-2 inhibitor, on anxiety behavior and memory performance under normal physiological conditions and to explore the possible neural mechanism underlying parecoxib-mediated effects. Adult male ICR mice were randomly divided into four groups: the control group and three parecoxib groups. Mice received normal saline or parecoxib (2.5, 5.0 or 10 mg/kg) intraperitoneal injection once a day for 21 days, respectively. Elevated plus-maze, novel object recognition and Y maze tests were conducted on day 23, 24 and 26, respectively. Four additional groups that received same drug treatment were used to measure synaptophysin protein levels by western blot and prostaglandin E2 (PGE2) levels by ELISA in the amygdala and hippocampus on day 26. Chronic parecoxib exerted an anxiolytic-like effect in the plus-maze test test, and enhanced memory performance in the novel object recognition and Y maze tests. Western blot analysis showed that chronic parecoxib down-regulated synaptophysin levels in the amygdala and up-regulated synaptophysin levels in the hippocampus. ELISA assay showed that chronic parecoxib inhibited PGE2 in the hippocampus but not amygdala. Chronic parecoxib exerts anxiolytic-like and memory enhancing effects, which might be mediated through differential modulation of synaptophysin and PGE2 in the amygdala and hippocampus.

Activation of cannabinoid CB1 receptors in the dorsolateral periaqueductal gray induces anxiolytic effects in rats submitted to the Vogel conflict test.

PubMed

Lisboa, Sabrina F; Resstel, Leonardo B M; Aguiar, Daniele C; Guimarães, Francisco S

2008-09-28

There are contradictory results concerning the effects of systemic injections of cannabinoid agonists in anxiety-induced behavioral changes. Direct drug administration into brain structures related to defensive responses could help to clarify the role of cannabinoids in these changes. Activation of cannabinoid CB(1) receptors in the dorsolateral periaqueductal gray induces anxiolytic-like effects in the elevated plus maze. The aim of this work was to verify if facilitation of endocannabinoid-mediated neurotransmission in this region would also produce anxiolytic-like effects in another model of anxiety, the Vogel conflict test. Male Wistar rats (n=5-9/group) with cannulae aimed at the dorsolateral periaqueductal gray were water deprived for 24 h and pre-exposed to the apparatus where they were allowed to drink for 3 min. After another 24 h-period of water deprivation, they received the microinjections and, 10 min later, were placed into the experimental box. In this box an electrical shock (0.5 mA, 2 s) was delivered in the spout of a drinking bottle at every twenty licks. The animals received a first microinjection of vehicle (0.2 microl) or AM251 (a cannabinoid CB(1) receptor antagonist; 100 pmol) followed, 5 min later, by a second microinjection of vehicle, anandamide (an endocannabinoid, 5 pmol), AM404 (an inhibitor of anandamide uptake, 50 pmol) or URB597 (an inhibitor of Fatty Acid Amide Hydrolase, 0.01 or 0.1 nmol). Anandamide, AM404 and URB597 (0.01 nmol) increased the total number of punished licks. These effects were prevented by AM251. The results give further support to the proposal that facilitation of CB(1) receptor-mediated endocannabinoid neurotransmission in the dorsolateral periaqueductal gray modulates defensive responses.

Attention deficit and hyperactivity disorder: a therapeutic option

PubMed Central

Topczewski, Abram

2014-01-01

Objective To evaluate the use of a therapeutic regimen to treat attention deficit hyperactivity disorder patients. Methods A total of 140 patients initially underwent physical, neurological and laboratory evaluation. Thereafter, treatment was initiated with a compounding product consisting of a tricyclic antidepressant and an anxiolytic. Results The response was positive in 71.43% of patients in controlling hyperactivity and improving dispersion and attention deficit. Conclusion The therapeutic regimen utilized proved to be an effective therapeutic alternative, especially for patients who do not adapt to psychostimulant drugs. PMID:25295451

[Use of psychoactive drugs by health sciences undergraduate students at the Federal University in Amazonas, Brazil].

PubMed

Lucas, Ana Cyra dos Santos; Parente, Rosana Cristina Pereira; Picanço, Neila Soares; Conceição, Denis Alvaci; Costa, Karen Regina Carim da; Magalhães, Igor Rafael dos Santos; Siqueira, João Cladirson Alves

2006-03-01

A survey was conducted with 521 undergraduate health sciences students from the Federal University in Amazonas, Manaus, Brazil. Lifetime alcohol consumption was reported by 87.7% students, as compared to 30.7% for tobacco, with the latter reported more frequently by males (39.7%). The most common illicit drugs were solvents (11.9%), marijuana (9.4%), amphetamines and anxiolytics (9.2% each), cocaine (2.1%), and hallucinogens (1.2%). The main reason for illicit drug use was curiosity. Lifetime use of anabolic steroids was reported by 2.1% of the students. Alcohol abuse in the previous 30 days was reported by 12.4% of the students. Events following drinking included: fights (4.7%), accidents (2.4%), classroom absenteeism (33.7%), and job absenteeism (11.8%). Another important finding was that 47.3% of students drove after drinking. Opinions on drug abuse and patterns agree with those from similar studies in other regions of Brazil.

Health status and drug use 1 year before and 1 year after skilled nursing home admission during the first quarter of 2013 in France: a study based on the French National Health Insurance Information System.

PubMed

Atramont, Alice; Bonnet-Zamponi, Dominique; Bourdel-Marchasson, Isabelle; Tangre, Isabelle; Fagot-Campagna, Anne; Tuppin, Philippe

2018-01-01

Changes in prescribing practices following skilled nursing home (SNH) admission have not been clearly described in France. The study aimed to evaluate health status and drug use 1 year before and 1 year after admission to SNH. People ≥ 65 years old admitted to SNH in the first quarter of 2013, covered by the national health insurance general scheme (69% of the population of this age) and still alive 1 year after admission were identified in a specific database (Resid-ehpad). Linking with the National Health Insurance Information System (SNIIRAM) allowed analysis of their health status, identified by algorithms, and changes in their use of reimbursed drugs. In a population of 11,687 residents (mean age: 86 years, women: 76%), the most prevalent diseases were cardiovascular/neurovascular diseases (45%) and dementias (35%). The use of certain chronic treatments (≥ 3 reimbursements/year) increased significantly (p < 0.001) after nursing home admission: antidepressants: 34 to 46%, anxiolytics: 32 to 42%, hypnotics/sedatives: 18 to 24%, antipsychotics: 10 to 21% (14 to 30% in patients with dementia). The use of lipid-modifying agents and agents acting on the renin-angiotensin system decreased significantly (33 to 24% and 44 to 37%, respectively, p < 0.001). The use of antibacterials (≥ 1 reimbursement/year) increased also significantly (p < 0.001): 45 to 61%, including quinolones (13 to 20%) and third-generation cephalosporins (10 to 18%). These results reveal increased prescribing of psychotropic drugs and antibacterials in SNH, requiring the development or sustainability of actions designed to improve prescribing practices in older people targeted by these treatments.

Complexities in understanding and addressing the serious public health issues related to the nonmedical use of prescription drugs

PubMed Central

Arria, Amelia M.; Compton, Wilson M.

2016-01-01

The nonmedical use of prescription drugs (NMUPD) is not only a serious public health problem, but also a complex one. The articles presented in this special issue underscore that complexity by describing multiple classes of prescription drugs (e.g., opioid analgesics, benzodiazepines, stimulants, anxiolytics, and sedatives) and examining multiple aspects of their patterns of use. Collectively, the articles examine epidemiologic use patterns in the United States, risk factors, clinical characteristics of individuals in treatment for dependence, and consequences. The key to addressing NMUPD is to construct a solid understanding of the issues through scientific research, and to translate the scientific evidence into action. The articles in this issue build upon a large body of literature that has accumulated during the last two decades. Dramatic increases in overdoses from prescription opioids and the transition to heroin use among nonmedical users of prescription opioids has captured the attention of community leaders across the nation. Yet, less well known is the co-occurrence of multiple substances among those using prescription drug nonmedically. This represents a common theme across these articles which document that nonmedical users were observed to have a history of using alcohol, marijuana, tobacco, and other psychoactive substances. In addition, the articles dispel certain ideas that appear to have gained traction in the popular discourse that have little scientific evidence behind them. First, the notion that prescription drug problems arise in cases of drug naïve individuals who are first exposed through a physician’s prescription for pain medication is widespread, but is not rooted in scientific evidence. Second, despite the popular notion that nonmedical use of stimulants confers an “academic edge”, nonmedical users have lower grade point averages (GPAs) than non-users. NMUPD was also shown to be associated with sexual aggression victimization and perpetration and regretted sex. In addition, several of the articles in this issue point to innovative targets for prevention of NMUPD. It is only through high-quality research can we gain a clearer understanding of the problem and how to address it. PMID:27639956

Exploring diazepam’s effect on hemodynamic responses of mouse brain tissue by optical spectroscopic imaging

PubMed Central

Abookasis, David; Shochat, Ariel; Nesher, Elimelech; Pinhasov, Albert

2014-01-01

In this study, a simple duel-optical spectroscopic imaging apparatus capable of simultaneously determining relative changes in brain oxy-and deoxy-hemoglobin concentrations was used following administration of the anxiolytic compound diazepam in mice with strong dominant (Dom) and submissive (Sub) behavioral traits. Three month old mice (n = 30) were anesthetized and after 10 min of baseline imaging, diazepam (1.5 mg/kg) was administered and measurements were taken for 80 min. The mouse head was illuminated by white light based LED's and diffused reflected light passing through different channels, consisting of a bandpass filter and a CCD camera, respectively, was collected and analyzed to measure the hemodynamic response. This work’s major findings are threefold: first, Dom and Sub animals showed statistically significant differences in hemodynamic response to diazepam administration. Secondly, diazepam was found to more strongly affect the Sub group. Thirdly, different time-series profiles were observed post-injection, which can serve as a possible marker for the groups’ differentiation. To the best of our knowledge, this is the first report on the effects of an anxiolytic drug on brain hemodynamic responses in mice using diffused light optical imaging. PMID:25071958

Anticonflict effect of alpidem as compared with the benzodiazepine alprazolam in rats.

PubMed

Hascoët, M; Bourin, M

1997-02-01

A comparative study between two drugs acting on the GABAA receptor, alprazolam and alpidem was undertaken, using simple tests such as measurement of spontaneous locomotor activity, four plates test and rotarod in mice. Additional conflict test was further performed using a new conflict paradigm where the opportunity existed for rats to choose during punished periods between immediate, punished reinforcement and delayed non-punished reinforcement. The benzodiazepine alprazolam, demonstrated, as expected, strong anxiolytic effects in mice and increased punished response in rats at non sedative doses (0.5, 1 mg/kg). High doses of alprazolam decreased spontaneous locomotor activity and induced myorelaxant effects in mice. Alpidem, an imidazopyridine derivative, induced motor impairment in mice and only very weak anxiolytic effects in the four plates test in mice (4 mg/kg) and in punished procedure in rats (32 mg/kg). As alprazolam is a full agonist for the GABAA receptor complex and alpidem is a partial agonist acting with specificity on omega 1 GABAA receptor subtypes, the results are discussed. Activity on omega 1 receptor subtypes is perhaps not sufficient in order to obtain a true anti-conflict effect and compounds such as alpidem only relieve some of the symptoms of anxiety disorders.

Oxytocin Stimulates Extracellular Ca2+ Influx Through TRPV2 Channels in Hypothalamic Neurons to Exert Its Anxiolytic Effects.

PubMed

van den Burg, Erwin H; Stindl, Julia; Grund, Thomas; Neumann, Inga D; Strauss, Olaf

2015-12-01

There is growing interest in anxiolytic and pro-social effects of the neuropeptide oxytocin (OXT), but the underlying intraneuronal mechanisms are largely unknown. Here we examined OXT-mediated anxiolysis in the hypothalamic paraventricular nucleus (PVN) of rats and effects of OXT administration on signaling events in hypothalamic primary and immortalized cells. In vivo, the application of SKF96365 prevented the anxiolytic activity of OXT in the PVN, suggesting that changes in intracellular Ca(2+) mediate the acute OXT behavioral effects. In vitro, mainly in the neurons with autonomous Ca(2+) oscillations, OXT increased intracellular Ca(2+) concentration and oscillation amplitude. Pharmacological intervention revealed OXT-dependent changes in Ca(2+) signaling that required activation of transient receptor potential vanilloid type-2 channel (TRPV2), mediated by phosphoinositide 3-kinase. TRPV2 induced the activation of the anxiolytic mitogen-activated protein kinase kinase (MEK1/2). In situ, immunohistochemistry revealed co-localization of TRPV2 and OXT in the PVN. Thus, functional and pharmacological analyses identified TRPV2 as a mediator of anxiolytic effects of OXT, conveying the OXT signal to MEK1/2 via modulation of intracellular Ca(2+).

Oxytocin Stimulates Extracellular Ca2+ Influx Through TRPV2 Channels in Hypothalamic Neurons to Exert Its Anxiolytic Effects

PubMed Central

van den Burg, Erwin H; Stindl, Julia; Grund, Thomas; Neumann, Inga D; Strauss, Olaf

2015-01-01

There is growing interest in anxiolytic and pro-social effects of the neuropeptide oxytocin (OXT), but the underlying intraneuronal mechanisms are largely unknown. Here we examined OXT-mediated anxiolysis in the hypothalamic paraventricular nucleus (PVN) of rats and effects of OXT administration on signaling events in hypothalamic primary and immortalized cells. In vivo, the application of SKF96365 prevented the anxiolytic activity of OXT in the PVN, suggesting that changes in intracellular Ca2+ mediate the acute OXT behavioral effects. In vitro, mainly in the neurons with autonomous Ca2+ oscillations, OXT increased intracellular Ca2+ concentration and oscillation amplitude. Pharmacological intervention revealed OXT-dependent changes in Ca2+ signaling that required activation of transient receptor potential vanilloid type-2 channel (TRPV2), mediated by phosphoinositide 3-kinase. TRPV2 induced the activation of the anxiolytic mitogen-activated protein kinase kinase (MEK1/2). In situ, immunohistochemistry revealed co-localization of TRPV2 and OXT in the PVN. Thus, functional and pharmacological analyses identified TRPV2 as a mediator of anxiolytic effects of OXT, conveying the OXT signal to MEK1/2 via modulation of intracellular Ca2+. PMID:26013963

Similar anxiolytic effects of agonists targeting serotonin 5-HT1A or cannabinoid CB receptors on zebrafish behavior in novel environments

PubMed Central

Connors, Kristin A.; Valenti, Theodore W.; Lawless, Kelly; Sackerman, James; Onaivi, Emmanuel S.; Brooks, Bryan W.; Gould, Georgianna G.

2014-01-01

The discovery that selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine are present and bioaccumulate in aquatic ecosystems have spurred studies of fish serotonin transporters (SERTs) and changes in SSRI-sensitive behaviors as adverse outcomes relevant for risk assessment. Many SSRIs also act at serotonin 5-HT1A receptors. Since capitolizing on this action may improve treatments of clinical depression and other psychiatric disorders, novel multimodal drugs that agonize 5-HT1A and block SERT were introduced. In mammals both 5-HT1A and CB agonists, such as buspirone and WIN55,212-2, reduce anxious behaviors. Immunological and behavioral evidence suggests that 5-HT1A-like receptors may function similarly in zebrafish (Danio rerio), yet their pharmacological properties are not well characterized. Herein we compared the density of [3H] 8-hydroxy-2-di-n-propylamino tetralin (8-OH-DPAT) binding to 5-HT1A-like sites in the zebrafish brain, to that of simalarly Gαi/o-coupled cannabinoid receptors. [3H] 8-OH-DPAT specific binding was 176 ± 8, 275 ± 32, and 230 ± 36 fmol/mg protein in the hypothalamus, optic tectum, and telencephalon. [3H] WIN55,212-2 binding density was higher in those same brain regions at 6 ± 0.3, 5.5 ± 0.4 and 7.3 ± 0.3 pm/mg protein. The aquatic light-dark plus maze was used to examine behavioral effects of 5-HT1A and CB receptor agonists on zebrafish novelty-based anxiety. With acute exposure to the 5-HT1A partial-agonist buspirone (50 mg/L), or dietary exposure to WIN55,212-2 (7 μg/week) zebrafish spent more time in and/or entered white arms more often than controls (p < 0.05). Acute exposure to WIN55,212-2 at 0.5-50 mg/L, reduced mobility. These behavioral findings suggest that azipirones, like cannabinoid agonists, have anxiolytic and/or sedative properties on fish in novel environments. These observations highlight the need to consider potential ecological risks of azapirones and multimodal antidepressants in the future. PMID:24411165

The anxiolytic effect of Juniperus virginiana L. essential oil and determination of its active constituents.

PubMed

Zhang, Kai; Yao, Lei

2018-05-15

Essential oil from Juniperus virginiana L. (eastern red cedarwood essential oil, CWO) has been used to relax mind and enhance comfort for medical purposes. Few reports showed its effect on anxiety behaviors in animal models. The present study investigated the anxiolytic effect of CWO using two anxiety tests in mice, then determined the major active constituents, examined the change of neurotransmitters after intraperitoneal (i.p.) administration. Analysis using GC/MS revealed that the CWO contained (-)-α-cedrene (28.11%), (+)-β-cedrene (7.81%), (-)-thujopsene (17.71%) and (+)-cedrol (24.58%). CWO at 400-800mg/kg increased the percentage of open arm entries and the percentage of the time spent in open arms in the elevated plus maze (EPM), suggesting that the oil has anxiolytic effect. However, it didn't show anxiolytic effect in the light-dark box (LDB) test. Tests of the cedrene did not show anxiolytic effect in either test, but rather induced anxiety-related behaviors and inhibited the locomotor activity in EPM and LDB. Cedrol produced significant anxiolytic effect in both EPM and LDB tests at 400-1600mg/kg and 800-1600mg/kg, respectively. A more significant increase in locomotor activity was observed in cedrol at 200-1600mg/kg administration than CWO. CWO increased the 5-hydroxytryptamine (5-HT) concentration at 800mg/kg, whereas it didn't affect the dopamine (DA) concentration. Cedrol significantly reduced the DA level at 100-200mg/kg and elevated the 5-HT level at 1200-1600mg/kg. Moreover, it changed the ratio of 5-hydroxyindoleacetic acid/5-HT and 3, 4-dihydroxyphenyl acetic acid/DA at 1200-1600mg/kg. CWO and cedrol, in particular might act in an anxiolytic effect through the 5-HTnergic and DAnergic pathways. Copyright © 2018. Published by Elsevier Inc.

Sedative and sleep-enhancing properties of linarin, a flavonoid-isolated from Valeriana officinalis.

PubMed

Fernández, Sebastián; Wasowski, Cristina; Paladini, Alejandro C; Marder, Mariel

2004-02-01

We have recently reported the presence of the anxiolytic flavone 6-methylapigenin (MA) and of the sedative and sleep-enhancing flavanone glycoside 2S (-) hesperidin (HN) in Valeriana officinalis and Valeriana wallichii. MA, in turn, was able to potentiate the sleep-inducing properties of HN. The present paper reports the identification in V. officinalis of the flavone glycoside linarin (LN) and the discovery that it has, like HN, sedative and sleep-enhancing properties that are potentiated by simultaneous administration of valerenic acid (VA). These effects should be taken into account when considering the pharmacological actions of valeriana extracts.

Parecoxib Possesses Anxiolytic Properties in Patients Undergoing Total Knee Arthroplasty: A Prospective, Randomized, Double-Blind, Placebo-Controlled, Clinical Study.

PubMed

Sarridou, Despoina G; Chalmouki, Georgia; Braoudaki, Maria; Siafaka, Ioanna; Asmatzi, Chrisi; Vadalouka, Athina

2016-06-01

Intravenous administration of parecoxib could provide significant pain relief in surgical operations that require additional forms of analgesia. However, very little is known about its effects on the anxiety levels of patients before a surgical procedure. The aim of this prospective study was to investigate whether intravenous parecoxib, pre-emptively administered, has an effect on anxiety levels experienced post-surgically after total knee arthroplasty (TKA) and if it influences the reported pain of the procedure itself. A total of 90 patients who underwent TKA under spinal anesthesia were included in the study. Prior to TKA, all patients received continuous femoral nerve block (CFNB) and were randomized into two groups: Group D consisted of 45 patients who received the drug parecoxib intravenously in addition to CFNB, whereas Group P consisted of 45 patients who received a placebo drug (N/S 0.9 %) intravenously instead of parecoxib. All patients were asked to fill in the questionnaires STAI1 and STAI2 in order to evaluate anxiety levels pre- and post-surgically, respectively. One of the main aims was to distinguish personality-trait anxiety from state anxiety, i.e., anxiety experience due to the actual perioperative events and the actual pain endured. The group receiving parecoxib had statistically significant lower anxiety levels both for personality trait anxiety and state anxiety, as compared to the placebo group. Based on our findings, parecoxib had both analgesic and anxiolytic effects in patients undergoing TKA with CFNB. Current Controlled Trials: NCT02185924.

Use of a platform in an automated open-field to enhance assessment of anxiety-like behaviors in mice.

PubMed

Pogorelov, Vladimir M; Lanthorn, Thomas H; Savelieva, Katerina V

2007-05-15

The present report describes a setup for simultaneously measuring anxiety-like behaviors and locomotor activity in mice. Animals are placed in a brightly lit, standard automated open-field (OF) in which a rectangular ceramic platform 8 cm high covers one quadrant of the floor. Mice preferred to stay under the platform, avoiding the area with bright illumination. Activities under and outside the platform were measured for 5 min. Chlordiazepoxide and buspirone dose-dependently increased time spent outside the platform (L-Time) and the light distance to total OF distance ratio (L:T-TD) in both genders without changing total OF distance. By contrast, amphetamine decreased L-Time and L:T-TD in males, thus displaying an anxiogenic effect. Imipramine was without selective effect on L-Time or L:T-TD, but decreased total OF distance at the highest dose indicative of a sedative effect. Drug effects were also evaluated in the OF without platform using conventional anxiety measures. Introduction of the platform into the OF apparatus strongly enhanced the sensitivity to anxiolytics. Comparison of strains differing in activity or anxiety levels showed that L-Time and L:T-TD can be used as measures of anxiety-like behavior independent of locomotor activity. Changes in motor activity are reflected in the total distance traveled under and outside the platform. Therefore, the platform test is fully automated, sensitive to both anxiolytic and anxiogenic effects of drugs and genetic phenotypes with little evidence of gender-specific responses, and can be easily utilized by most laboratories measuring behavior.

Benzodiazepine-site pharmacology on GABAA receptors in histaminergic neurons.

PubMed

May, A C; Fleischer, W; Kletke, O; Haas, H L; Sergeeva, O A

2013-09-01

The histaminergic tuberomamillary nucleus (TMN) of the posterior hypothalamus controls the cognitive aspects of vigilance which is reduced by common sedatives and anxiolytics. The receptors targeted by these drugs in histaminergic neurons are unknown. TMN neurons express nine different subunits of the GABAA receptor (GABAA R) with three α- (α1, α2 and α5) and two γ- (γ1, γ 2) subunits, which confer different pharmacologies of the benzodiazepine-binding site. We investigated the actions of zolpidem, midazolam, diazepam, chlordiazepoxide, flumazenil (Ro15-1788) and methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM) in TMN neurons using mouse genetics, electrophysiological and molecular biological methods. We find the sensitivity of GABAA R to zolpidem, midazolam and DMCM significantly reduced in TMN neurons from γ2F77I mice, but modulatory activities of diazepam, chlordiazepoxide and flumazenil not affected. Potencies and efficacies of these compounds are in line with the dominance of α2- and α1-subunit containing receptors associated with γ2- or γ1-subunits. Functional expression of the γ1-subunit is supported by siRNA-based knock-down experiments in γ2F77I mice. GABAA R of TMN neurons respond to a variety of common sedatives with a high affinity binding site (γ2F77I) involved. The γ1-subunit likely contributes to the action of common sedatives in TMN neurons. This study is relevant for understanding the role of neuronal histamine and benzodiazepines in disorders of sleep and metabolism. © 2013 The British Pharmacological Society.

[Benzodiazepines in the treatment of anxiety].

PubMed

Boulenger, J P; Pellet, V; Zarifian, E

1991-09-28

During the last ten years, the treatment of anxiety disorders has changed considerably. Cognitive-behavioural therapies and new chemotherapies have been added to benzodiazepine therapy and psychotherapy which for a long time had been the only treatment of these frequent and invalidating disorders. Recent reports of possible drawbacks in prolonged benzodiazepine therapy provide another reason to reconsider the indications of these drugs now that other drugs are available. Benzodiazepines remain the treatment of choice for recent anxiety states requiring some degree of sedation and rapid relief, but their long-term administration should be reserved to patients who did not respond to other treatments. The authors propose several guidelines for a better prescription of these anxiolytic agents and for more rational indications taking into account the advantages of other available treatments.

Zolpidem, a clinical hypnotic that affects electronic transfer, alters synaptic activity through potential GABA receptors in the nervous system without significant free radical generation.

PubMed

Kovacic, Peter; Somanathan, Ratnasamy

2009-01-01

Zolpidem (trade name Ambien) has attracted much interest as a sleep-inducing agent and also in research. Attention has been centered mainly on receptor binding and electrochemistry in the central nervous system which are briefly addressed herein. A novel integrated approach to mode of action is presented. The pathways to be discussed involve basicity, reduction potential, electrostatics, cell signaling, GABA receptor binding, electron transfer (ET), pharmacodynamics, structure activity relationships (SAR) and side effects. The highly conjugated pyridinium salt formed by protonation of the amidine moiety is proposed to be the active form acting as an ET agent. Extrapolation of reduction potentials for related compounds supports the premise that zolpidem may act as an ET species in vivo. From recent literature reports, electrostatics is believed to play a significant role in drug action. The pyridinium cation displays molecular electrostatic potential which may well play a role energetically or as a bridging mechanism. An SAR analysis points to analogy with other physiologically active xenobiotics, namely benzodiazepines and paraquat in the conjugated iminium category. Inactivity of metabolites indicates that the parent is the active form of zolpidem. Absence of reactive oxygen species and oxidative stress is in line with minor side effects. In contrast, generally, the prior literature contains essentially no discussion of these fundamental biochemical relationships. Pharmacodynamics may play an important role. Concerning behavior at the blood-brain barrier, useful insight can be gained from investigations of the related cationic anesthetics that are structurally related to acetyl choline. Evidently, the neutral form of the drug penetrates the neuronal membrane, with the salt form operating at the receptor. The pathways of zolpidem have several clinical implications since the agent affects sedation, electroencephalographic activity, oxidative metabolites and receptors in the central nervous system. The drug acts at the GABA(A) receptor benzodiazepine site, displaying high and intermediate affinities to various receptor regions. Structural features for tight binding were determined. The sedative and anticonvulsant activities are due to its action on the alpha-1-GABA(A) receptors. One of the common adverse responses to zolpidem is hallucinations. Proposed mechanisms comprise changes in the GABA(A) receptor, pharmacodynamic interactions involving serotonin and neuronal-weak photon emission processes entailing redox phenomena. Reports cite cases of abuse with cravings based on anxiolytic and stimulating actions. It is important to recognize that insight concerning processes at the fundamental, molecular level can translate into beneficial results involving both positive and adverse side effects. In order for this to occur, interdisciplinary interaction is necessary. Suggestions are made for future research aimed at testing the various hypotheses.

Anxiolytic-like effects and toxicological studies of Brickellia cavanillesii (Cass.) A. Gray in experimental mice models.

PubMed

Ávila-Villarreal, Gabriela; González-Trujano, María Eva; Carballo-Villalobos, Azucena Ibeth; Aguilar-Guadarrama, Berenice; García-Jiménez, Sara; Giles-Rivas, Diana Elizabeth; Castillo-España, Patricia; Villalobos-Molina, Rafael; Estrada-Soto, Samuel

2016-11-04

Brickellia cavanillesii (Asteraceae) (Cass.) A. Gray is one of the popular plants consumed in Central America and Mexico for the treatment of several diseases such as hypertension, diabetes and anxiety, among others. To determine the anxiolytic-like effect of B. Cavanillesii and the safety of its use through toxicological studies. Anxiolytic-like effects of soluble-methanol extract of B. cavanillesii (MEBc) were evaluated in ambulatory activity (open-field test), hole-board test, cylinder of exploration, the elevated plus-maze and the potentiation of the sodium pentobarbital-induced hypnosis mice models. On the other hand, in vivo toxicological studies were conducted on acute and sub-acute mice models recommended by OECD. Active MEBc was subjected to phytochemical studies through conventional chromatographic techniques to isolate bioactive compounds. MEBc (100mg/Kg) showed significant anxiolytic-like effect on animal model used (p<0.05). The phytochemical analysis of MEBc allowed the isolation of two major compounds nicotiflorin and acacetin, among others. Both compounds were found to be partially responsible for the anxiolytic-like effects. Moreover, a median lethal dose (LD 50 ) higher than 2000mg/Kg was determined in mice and sub-acute oral administration of MEBc (100mg/Kg) did not alter body weight, clinical chemistry parameters (ALT and AST) and it did not induce any toxic nor alteration in the liver, kidney and heart functions. In current investigation, we have shown that MEBc has a wide range of pharmacology-toxicology patterns. The results support further investigation of MEBc as a potential anxiolytic phytomedicinal agent. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Animal models of 'anxiety': where next?

PubMed

Rodgers, R J

1997-11-01

Numerous procedures have been developed to facilitate preclinical research on the behavioural pharmacology of anxiety and, as a result of this application, are often referred to as animal models of 'anxiety'. This is an unfortunate misnomer, not only because of the apparent inability of many tests to detect novel anxiolytics consistently, but also because the term implies that anxiety is a unitary emotion. Such difficulties have arisen largely as a consequence of test development strategies which, by emphasizing pharmacological (i.e. benzodiazepine) validation, have yielded models predictive of a specific type of anxiolytic activity. The present review argues that the refinement of existing tests as well as the development of new procedures requires urgent attention to the much neglected issue of behavioural validation. From an evolutionary perspective, normal human anxiety may be conceptualized as a repertoire of defence reactions tailored to meet different forms of threats, and disorders of anxiety as the inappropriate activation or exaggeration of these usually adaptive response patterns. In this context, consideration of the defensive reactions typically observed in our animal models reveals substantially greater commonality in the behavioural effects of benzodiazepine and 5-HT1A anxiolytics than would otherwise be apparent. Therefore, with the exception of the conventional plus-maze paradigm (discussed at some length), better correspondence is seen in tests involving unconditioned response to potential threat (e.g. social interaction, distress vocalizations and light/dark exploration) than in tests of conditioned fear reactions. Even within the latter grouping, however, greater commonality is seen in procedures based on reactions to proximal threat (e.g. freezing, startle, ultrasonic vocalizations, burying) than those involving reactions to distal threat (e.g. avoidance/flight). Significantly, very similar findings have been reported in tests specifically designed to study defensive reactions (e.g. rat and mouse defence test batteries) or which incorporate a more detailed knowledge of defence into established procedures (e.g. ethological plus-maze and defensive burying paradigms). Furthermore, recent evidence also suggests that drugs with proved clinical efficacy in panic attacks/panic disorder have reliably stronger effects on flight responses than other components of the defensive repertoire. It is concluded that a focus on defensive behaviour patterns improves test validity (predictive/face/construct), offers a more rational basis for test selection in drug development programmes, and provides a firmer theoretical framework for future methodological and therapeutic advance.

Voluntary Exercise Produces Antidepressant and Anxiolytic Behavioral Effects in Mice

PubMed Central

Duman, Catharine H.; Schlesinger, Lee; Russell, David S.; Duman, Ronald S.

2008-01-01

Reports of beneficial effects of exercise on psychological health in humans are increasingly supported by basic research studies. Exercise is hypothesized to regulate antidepressant-related mechanisms and we therefore characterized the effects of chronic exercise in mouse behavioral paradigms relevant to antidepressant actions. Mice given free access to running wheels showed antidepressant-like behavior in learned helplessness, forced-swim (FST) and tail suspension paradigms. These responses were similar to responses of antidepressant drug-treated animals. When tested under conditions where locomotor activity was not altered, exercising mice also showed reduced anxiety compared to sedentary control mice. In situ hybridization analysis showed that BDNF mRNA was increased in specific subfields of hippocampus after wheel running. We chose one paradigm, the FST, in which to investigate a functional role for brain-derived neurotrophic factor (BDNF) in the behavioral response to exercise. We tested mice heterozygous for a deletion of the BDNF gene in the FST after wheel-running. Exercising wild-type mice showed the expected antidepressant-like behavioral response in the FST but exercise was ineffective in improving FST performance in heterozygous BDNF knockout mice. A possible functional contribution of a BDNF signaling pathway to FST performance in exercising mice was investigated using the specific MEK inhibitor PD184161 to block the MAPK signaling pathway. Subchronic administration of PD184161 to exercising mice blocked the antidepressant-like behavioral response seen in vehicle-treated exercising mice in the FST. In summary, chronic wheel-running exercise in mice results in antidepressant-like behavioral changes that may involve a BDNF related mechanism similar to that hypothesized for antidepressant drug treatment. PMID:18267317

Cannabidiol: from an inactive cannabinoid to a drug with wide spectrum of action.

PubMed

Zuardi, Antonio Waldo

2008-09-01

The aim of this review is to describe the historical development of research on cannabidiol. This review was carried out on reports drawn from Medline, Web of Science and SciELO. After the elucidation of the chemical structure of cannabidiol in 1963, the initial studies showed that cannabidiol was unable to mimic the effects of Cannabis. In the 1970's the number of publications on cannabidiol reached a first peak, having the research focused mainly on the interaction with delta9-THC and its antiepileptic and sedative effects. The following two decades showed lower degree of interest, and the potential therapeutic properties of cannabidiol investigated were mainly the anxiolytic, antipsychotic and on motor diseases effects. The last five years have shown a remarkable increase in publications on cannabidiol mainly stimulated by the discovery of its anti-inflammatory, anti-oxidative and neuroprotective effects. These studies have suggested a wide range of possible therapeutic effects of cannabidiol on several conditions, including Parkinson's disease, Alzheimer's disease, cerebral ischemia, diabetes, rheumatoid arthritis, other inflammatory diseases, nausea and cancer. In the last 45 years it has been possible to demonstrate that CBD has a wide range of pharmacological effects, many of which being of great therapeutic interest, but still waiting to be confirmed by clinical trials.

Synthesis and Characterization of a Novel γ-Aminobutyric Acid Type A (GABAA) Receptor Ligand That Combines Outstanding Metabolic Stability, Pharmacokinetics, and Anxiolytic Efficacy.

PubMed

Poe, Michael M; Methuku, Kashi Reddy; Li, Guanguan; Verma, Ashwini R; Teske, Kelly A; Stafford, Douglas C; Arnold, Leggy A; Cramer, Jeffrey W; Jones, Timothy M; Cerne, Rok; Krambis, Michael J; Witkin, Jeffrey M; Jambrina, Enrique; Rehman, Sabah; Ernst, Margot; Cook, James M; Schkeryantz, Jeffrey M

2016-12-08

1,4-Benzodiazepines are used in the treatment of anxiety disorders but have limited long-term use due to adverse effects. HZ-166 (2) has been shown to have anxiolytic-like effects with reduced sedative/ataxic liabilities. A 1,3-oxazole KRM-II-81 (9) was discovered from a series of six bioisosteres with significantly improved pharmacokinetic and pharmacodynamic properties as compared to 2. Oxazole 9 was further characterized and exhibited improved anxiolytic-like effects in a mouse marble burying assay and a rat Vogel conflict test.

Antidepressant and anxiolytic-like activity of sodium selenite after acute treatment in mice.

PubMed

Kędzierska, Ewa; Dudka, Jarosław; Poleszak, Ewa; Kotlińska, Jolanta H

2017-04-01

Selenium (Se) is an essential trace element for humans and animals, that is needed for a broad variety of physiological functions including thyroid hormone metabolism, protection against oxidative stress, and immunity associated functions. Human nutritional Se deficiencies are associated with neuropsychiatric diseases, like Alzheimer's disease, Parkinson's disease, obsessive - compulsive disorder, stroke, epilepsy as well as depressive behaviours. In this study we examined antidepressant- and anxiolytic-like activity of Se in the inorganic form of sodium selenite and investigated whether Se influence on the locomotor activity in mice. The antidepressant-like and anxiolytic-like activity of Se was assessed using forced swim test (FST) and elevated plus-maze test (EPM), respectively. Spontaneous locomotor activity was measured using photoresistor actimeters. Sodium selenite administered at the doses of 0.5, 1, and 2mg/kg, ip reduced immobility time in the FST exerting antidepressant-like activity. In the EPM test, sodium selenite at the same doses, produced anxiolytic-like effect; the doses active in both tests did not affect locomotor activity, indicating that these effects of Se are specific. These potential antidepressant- and anxiolytic-like effects of Se require more detailed experimental study using animal models to approach a clear conclusion regarding the potential mechanism of the observed effect. Copyright © 2016. Published by Elsevier Urban & Partner Sp. z o.o.

Anxiolytic properties of Valeriana officinalis in the zebrafish: a possible role for metabotropic glutamate receptors.

PubMed

Del Valle-Mojica, Lisa M; Ortíz, José G

2012-11-01

Valerian extract is used in complementary and alternative medicine for its anxiolytic and sedative properties. Our previous research demonstrated valerian interactions with glutamate receptors. The purpose of this study was to determine if valerian anxiolytic properties are mediated by metabotropic glutamate receptors (mGluR) such as mGluR (1/5) (mGluR I) and mGluR (2/3) (mGluR II). Adult wild-type zebrafish (Danio rerio) prefer the black compartment and avoid the white compartment in the dark/light preference task. Zebrafish exposed to 1 mg/mL of valerian extract or 0.00117 mg/mL valerenic acid increased their residence time in the white side by 84.61 ± 6.55 % and 58.30 ± 8.97 %, respectively. LAP3 (mGluR I antagonist) and EGLU (mGluR II antagonist) significantly inhibited the effects of valerian and valerenic acid. These results demonstrated that valerian and valerenic acid have anxiolytic properties in the zebrafish. Moreover, the selective interaction of valerian with mGluR I and II represent an alternative explanation for the anxiolytic properties of this plant and support the role of mGluR in anxiety. Georg Thieme Verlag KG Stuttgart · New York.

Selective Mitochondrial Targeting Exerts Anxiolytic Effects In Vivo

PubMed Central

Nussbaumer, Markus; Asara, John M; Teplytska, Larysa; Murphy, Michael P; Logan, Angela; Turck, Christoph W; Filiou, Michaela D

2016-01-01

Current treatment strategies for anxiety disorders are predominantly symptom-based. However, a third of anxiety patients remain unresponsive to anxiolytics highlighting the need for more effective, mechanism-based therapeutic approaches. We have previously compared high vs low anxiety mice and identified changes in mitochondrial pathways, including oxidative phosphorylation and oxidative stress. In this work, we show that selective pharmacological targeting of these mitochondrial pathways exerts anxiolytic effects in vivo. We treated high anxiety-related behavior (HAB) mice with MitoQ, an antioxidant that selectively targets mitochondria. MitoQ administration resulted in decreased anxiety-related behavior in HAB mice. This anxiolytic effect was specific for high anxiety as MitoQ treatment did not affect the anxiety phenotype of C57BL/6N and DBA/2J mouse strains. We furthermore investigated the molecular underpinnings of the MitoQ-driven anxiolytic effect and found that MitoQ treatment alters the brain metabolome and that the response to MitoQ treatment is characterized by distinct molecular signatures. These results indicate that a mechanism-driven approach based on selective mitochondrial targeting has the potential to attenuate the high anxiety phenotype in vivo, thus paving the way for translational implementation as long-term MitoQ administration is well-tolerated with no reported side effects in mice and humans. PMID:26567514

Selective Mitochondrial Targeting Exerts Anxiolytic Effects In Vivo.

PubMed

Nussbaumer, Markus; Asara, John M; Teplytska, Larysa; Murphy, Michael P; Logan, Angela; Turck, Christoph W; Filiou, Michaela D

2016-06-01

Current treatment strategies for anxiety disorders are predominantly symptom-based. However, a third of anxiety patients remain unresponsive to anxiolytics highlighting the need for more effective, mechanism-based therapeutic approaches. We have previously compared high vs low anxiety mice and identified changes in mitochondrial pathways, including oxidative phosphorylation and oxidative stress. In this work, we show that selective pharmacological targeting of these mitochondrial pathways exerts anxiolytic effects in vivo. We treated high anxiety-related behavior (HAB) mice with MitoQ, an antioxidant that selectively targets mitochondria. MitoQ administration resulted in decreased anxiety-related behavior in HAB mice. This anxiolytic effect was specific for high anxiety as MitoQ treatment did not affect the anxiety phenotype of C57BL/6N and DBA/2J mouse strains. We furthermore investigated the molecular underpinnings of the MitoQ-driven anxiolytic effect and found that MitoQ treatment alters the brain metabolome and that the response to MitoQ treatment is characterized by distinct molecular signatures. These results indicate that a mechanism-driven approach based on selective mitochondrial targeting has the potential to attenuate the high anxiety phenotype in vivo, thus paving the way for translational implementation as long-term MitoQ administration is well-tolerated with no reported side effects in mice and humans.

Short-term open-label chamomile (Matricaria chamomilla L.) therapy of moderate to severe generalized anxiety disorder.

PubMed

Keefe, John R; Mao, Jun J; Soeller, Irene; Li, Qing S; Amsterdam, Jay D

2016-12-15

Conventional drug treatments for Generalized Anxiety Disorder (GAD) are often accompanied by substantial side effects, dependence, and/or withdrawal syndrome. A prior controlled study of oral chamomile (Matricaria chamomilla L.) extract showed significant efficacy versus placebo, and suggested that chamomile may have anxiolytic activity for individuals with GAD. We hypothesized that treatment with chamomile extract would result in a significant reduction in GAD severity ratings, and would be associated with a favorable adverse event and tolerability profile. We report on the open-label phase of a two-phase randomized controlled trial of chamomile versus placebo for relapse-prevention of recurrent GAD. Subjects with moderate to severe GAD received open-label treatment with pharmaceutical-grade chamomile extract 1500mg/day for up to 8 weeks. Primary outcomes were the frequency of clinical response and change in GAD-7 symptom scores by week 8. Secondary outcomes included the change over time on the Hamilton Rating Scale for Anxiety, the Beck Anxiety Inventory, and the Psychological General Well Being Index. Frequency of treatment-emergent adverse events and premature treatment discontinuation were also examined. Of 179 subjects, 58.1% (95% CI: 50.9% to 65.5%) met criteria for response, while 15.6% prematurely discontinued treatment. Significant improvement over time was also observed on the GAD-7 rating (β=-8.4 [95% CI=-9.1 to -7.7]). A similar proportion of subjects demonstrated statistically significant and clinically meaningful reductions in secondary outcome ratings of anxiety and well-being. Adverse events occurred in 11.7% of subjects, although no serious adverse events occurred. Chamomile extract produced a clinically meaningful reduction in GAD symptoms over 8 weeks, with a response rate comparable to those observed during conventional anxiolytic drug therapy and a favorable adverse event profile. Future comparative effectiveness trials between chamomile and conventional drugs may help determine the optimal risk/benefit of these therapies for patients suffering from GAD. Copyright © 2016 Elsevier GmbH. All rights reserved.

Estrogen Receptor-β Agonist Diarylpropionitrile: Biological Activities of R- and S-Enantiomers on Behavior and Hormonal Response to Stress

PubMed Central

Weiser, Michael J.; Wu, T. John; Handa, Robert J.

2009-01-01

Estrogens have been shown to have positive and negative effects on anxiety and depressive-like behaviors, perhaps explained by the existence of two distinct estrogen receptor (ER) systems, ERα and ERβ. The ERβ agonist, diarylpropionitrile (DPN) has been shown to have anxiolytic properties in rats. DPN exists as a racemic mixture of two enantiomers, R-DPN and S-DPN. In this study, we compared R-DPN and S-DPN for their in vitro binding affinity, ability to activate transcription in vitro at an estrogen response element, and in vivo endocrine and behavioral responses. In vitro binding studies using recombinant rat ERβ revealed that S-DPN has a severalfold greater relative binding affinity for ERβ than does R-DPN. Furthermore, cotransfection of N-38 immortalized hypothalamic cells with an estrogen response element-luc reporter and ERβ revealed that S-DPN is a potent activator of transcription in vitro, whereas R-DPN is not. Subsequently, we examined anxiety-like behaviors using the open-field test and elevated plus maze or depressive-like behaviors, using the forced swim test. Ovariectomized young adult female Sprague Dawley rats treated with racemic DPN, S-DPN, and the ERβ agonist, WAY-200070, showed significantly decreased anxiety-like behaviors in both the open-field and elevated plus maze and significantly less depressive-like behaviors in the forced swim test compared with vehicle-, R-DPN-, or propylpyrazoletriol (ERα agonist)-treated animals. In concordance with the relative binding affinity and transcriptional potency, these results demonstrate that the S-enantiomer is the biologically active form of DPN. These studies also indicate that estrogen's positive effects on mood, including its anxiolytic and antidepressive actions, are due to its actions at ERβ. PMID:19074580

An Overview on Medicinal Chemistry of Synthetic and Natural Derivatives of Cannabidiol.

PubMed

Morales, Paula; Reggio, Patricia H; Jagerovic, Nadine

2017-01-01

Cannabidiol (CBD) has been traditionally used in Cannabis -based preparation, however historically, it has received far less interest as a single drug than the other components of Cannabis . Currently, CBD generates considerable interest due to its beneficial neuroprotective, antiepileptic, anxiolytic, antipsychotic, and anti-inflammatory properties. Therefore, the CBD scaffold becomes of increasing interest for medicinal chemists. This review provides an overview of the chemical structure of natural and synthetic CBD derivatives including the molecular targets associated with these compounds. A clear identification of their biological targets has been shown to be still very challenging.

An Overview on Medicinal Chemistry of Synthetic and Natural Derivatives of Cannabidiol

PubMed Central

Morales, Paula; Reggio, Patricia H.; Jagerovic, Nadine

2017-01-01

Cannabidiol (CBD) has been traditionally used in Cannabis-based preparation, however historically, it has received far less interest as a single drug than the other components of Cannabis. Currently, CBD generates considerable interest due to its beneficial neuroprotective, antiepileptic, anxiolytic, antipsychotic, and anti-inflammatory properties. Therefore, the CBD scaffold becomes of increasing interest for medicinal chemists. This review provides an overview of the chemical structure of natural and synthetic CBD derivatives including the molecular targets associated with these compounds. A clear identification of their biological targets has been shown to be still very challenging. PMID:28701957

Case report: polyuria related to dexmedetomidine.

PubMed

Pratt, Alexandra; Aboudara, Matthew; Lung, Linn

2013-07-01

Dexmedetomidine has become a popular sedative in the intensive care unit for patients undergoing mechanical ventilation because of its highly selective α-2 agonism, which exerts a combination of anesthetic, analgesic, and anxiolytic effects. Bradycardia and hypotension have been reported as the most common side effects of its use in large studies. Dexmedetomidine has been reported to induce polyuria by suppressing vasopressin secretion and increasing permeability of the collecting ducts in a dose-dependent fashion. We report a case of dexmedetomidine-related polyuria that occurred with a high-dose continuous infusion and subsequently resolved with discontinuation of the drug. (Anesth Analg 2013;117:150-2).

Analytical methodologies for the determination of benzodiazepines in biological samples.

PubMed

Persona, Karolina; Madej, Katarzyna; Knihnicki, Paweł; Piekoszewski, Wojciech

2015-09-10

Benzodiazepine drugs belong to important and most widely used medicaments. They demonstrate such therapeutic properties as anxiolytic, sedative, somnifacient, anticonvulsant, diastolic and muscle relaxant effects. However, despite the fact that benzodiazepines possess high therapeutic index and are considered to be relatively safe, their use can be dangerous when: (1) co-administered with alcohol, (2) co-administered with other medicaments like sedatives, antidepressants, neuroleptics or morphine like substances, (3) driving under their influence, (4) using benzodiazepines non-therapeutically as drugs of abuse or in drug-facilitated crimes. For these reasons benzodiazepines are still studied and determined in a variety of biological materials. In this article, sample preparation techniques which have been applied in analysis of benzodiazepine drugs in biological samples have been reviewed and presented. The next part of the article is focused on a review of analytical methods which have been employed for pharmacological, toxicological or forensic study of this group of drugs in the biological matrices. The review was preceded by a description of the physicochemical properties of the selected benzodiazepines and two, very often coexisting in the same analyzed samples, sedative-hypnotic drugs. Copyright © 2015. Published by Elsevier B.V.

SENSITIZATION TO SOCIAL ANXIOLYTIC EFFECTS OF ETHANOL IN ADOLESCENT AND ADULT SPRAGUE-DAWLEY RATS FOLLOWING REPEATED ETHANOL EXPOSURE

PubMed Central

Varlinskaya, Elena; Spear, Linda Patia

2009-01-01

Ontogenetic studies using a social interaction paradigm have shown that adolescent rats are less sensitive to anxiolytic properties of acute ethanol than their adult counterparts. It is not known, however, whether adaptations to these anxiolytic effects upon repeated experiences with ethanol would be similar in adolescents and adults. The present study investigated sensitivity to the anxiolytic effects of ethanol in adolescent and adult male and female Sprague-Dawley rats following 7 days of exposure [postnatal day (P) 27–33 for adolescents and P62–68 for adults] to 1 g/kg ethanol or saline (i.p.), as well as in animals left non-manipulated during this time. Anxiolytic effects of ethanol (0, 0.75, 1.0, 1.25, and 1.5 g/kg for adolescents and 0, 0.25, 0.5, 0.75, 1.0, and 1.25 g/kg for adults in Experiments 1 and 2, respectively) were examined 48 hours after the last exposure using a modified social interaction test under unfamiliar test circumstances. At both ages, repeated ethanol exposure resulted in the development of apparent sensitization to anxiolytic effects of ethanol indexed via enhancement of social investigation and transformation of social avoidance into social indifference or preference, as well as expression of tolerance to the socially inhibiting effects induced by higher ethanol doses. Evidence for the emergence of sensitization in adults and tolerance at both ages was seen not only following chronic ethanol, but also after chronic saline exposure, suggesting that chronic manipulation per se may be sufficient to alter the sensitivity of both adolescents and adults to socially-relevant effects of ethanol. PMID:20113878

Nootropic and anxiolytic activity of saponins of Albizzia lebbeck leaves.

PubMed

Une, H D; Sarveiya, V P; Pal, S C; Kasture, V S; Kasture, S B

2001-01-01

The effect of saponin containing, n-butanolic fraction (BF), extracted from dried leaves of Albizzia lebbeck, was studied on cognitive behavior and anxiety in albino mice. The elevated plus maze was used for assessment of both nootropic and anxiolytic activity. The nootropic activity was evaluated by recording the effect of BF (0, 10, 25, and 50 mg/kg) on the transfer latency, whereas anxiolytic activity was assessed by studying its effect on the duration of occupancy in the closed arm. Results showed significant improvement in the retention ability of the normal and amnesic mice as compared to their respective controls. Animals treated with BF (25 mg/kg) spent more time in the open arm in a dose-dependent manner. The BF was without any significant effect on motor coordination. However, it significantly inhibited passivity and hypothermia induced by baclofen (10 mg/kg), a GABA(B) agonist. The data emanated in the present study suggests involvement of gamma-aminobutyric acid (GABA) in the nootropic and anxiolytic activity of saponins obtained from A. lebbeck.

A systematic review on the anxiolytic effects of aromatherapy on rodents under experimentally induced anxiety models.

PubMed

Tsang, Hector W H; Ho, Timothy Y C

2010-01-01

We reviewed studies from 1999 to 2009 on anxiolytic effects of different essential oils toward rodents in anxiety-related behavioral models. Journal papers that evaluated the anxiolytic effects of essential oils for rodents were extracted from available electronic data bases. The results based on 14 studies showed that different rodent species were recruited including ICR mice and Swiss mice. Most of studies applied the Elevated Plus Maze (EPM) as the animal behavioral model. Lavender oil was the most popular within the 14 studies. Lavender and rose oils were found to be effective in some of the studies. Only one study reported the underlying neurophysiological mechanism in terms of concentrations of emotionally related neuro-transmitters such as dopamine, serotonin, and their derivatives, in various brain regions. Some essential oils are found to be effective to induce anxiolytic effect in rodents under different animal anxiety models. However, more standardized experimental procedures and outcome measures are needed in future studies. Translational research to human subjects is also recommended.

Evaluation of anxiolytic and sedative effects of 80% ethanolic Carica papaya L. (Caricaceae) pulp extract in mice.

PubMed

Kebebew, Zerihun; Shibeshi, Workineh

2013-11-25

Carica papaya has been used in the Ethiopian traditional medicine to relieve stress and other disease conditions. The present study was undertaken to evaluate the anxiolytic and sedative effects of 80% ethanolic Carica papaya (Caricaceae) pulp extract in mice. Carica papaya pulp extract was screened for anxiolytic effect by using elevated plus maze, staircase and open field tests, and ketamine-induced sleeping time test for sedation at doses of 50, 100, 200, 400 mg/kg. Distilled water and Diazepam were employed as negative and positive control groups, respectively. Carica papaya pulp extract 100 mg/kg significantly increased the percentage of open arm time and entry, and reduced the percentage of entry and time spent in closed arm in elevated plus maze test; reduced the number of rearing in the staircase test; and increased the time spent and entries in the central squares while the total number of entries into the open field were not significantly affected, suggesting anxiolytic activity without altering locomotor and sedative effects. A synergistic reduction in the number of rearing and an inverted U-shaped dose response curves were obtained with important parameters of anxiety The results of this study established a support for the traditional usage of Carica papaya as anxiolytic medicinal plant. © 2013 Elsevier Ireland Ltd. All rights reserved.

Evaluation of antidepressant-like and anxiolytic-like activity of purinedione-derivatives with affinity for adenosine A2A receptors in mice.

PubMed

Dziubina, Anna; Szmyd, Karina; Zygmunt, Małgorzata; Sapa, Jacek; Dudek, Magdalena; Filipek, Barbara; Drabczyńska, Anna; Załuski, Michał; Pytka, Karolina; Kieć-Kononowicz, Katarzyna

2016-12-01

It has recently been suggested that the adenosine A 2A receptor plays a role in several animal models of depression. Additionally, A 2A antagonists have reversed behavioral deficits and exhibited a profile similar to classical antidepressants. In the present study, imidazo- and pyrimido[2,1-f]purinedione derivatives (KD 66, KD 167, KD 206) with affinity to A 2A receptors but poor A 1 affinity were evaluated for their antidepressant- and anxiolytic-like activity. The activity of these derivatives was tested using a tail suspension and forced swim test, two widely-used behavioral paradigms for the evaluation of antidepressant-like activity. In turn, the anxiolytic activity was evaluated using the four-plate test. The results showed the antidepressant-like activity of pyrimido- and imidazopurinedione derivatives (i.e. KD 66, KD 167 and KD 206) in acute and chronic behavioral tests in mice. KD 66 revealed an anxiolytic-like effect, while KD 167 increased anxiety behaviors. KD 206 had no effect on anxiety. Furthermore, none of the tested compounds increased locomotor activity. Available data support the proposition that the examined compounds with adenosine A 2A receptor affinity may be an interesting target for the development of antidepressant and/or anxiolytic agents. Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report.

PubMed

Crippa, José Alexandre S; Derenusson, Guilherme Nogueira; Ferrari, Thiago Borduqui; Wichert-Ana, Lauro; Duran, Fábio L S; Martin-Santos, Rocio; Simões, Marcus Vinícius; Bhattacharyya, Sagnik; Fusar-Poli, Paolo; Atakan, Zerrin; Santos Filho, Alaor; Freitas-Ferrari, Maria Cecília; McGuire, Philip K; Zuardi, Antonio Waldo; Busatto, Geraldo F; Hallak, Jaime Eduardo Cecílio

2011-01-01

Animal and human studies indicate that cannabidiol (CBD), a major constituent of cannabis, has anxiolytic properties. However, no study to date has investigated the effects of this compound on human pathological anxiety and its underlying brain mechanisms. The aim of the present study was to investigate this in patients with generalized social anxiety disorder (SAD) using functional neuroimaging. Regional cerebral blood flow (rCBF) at rest was measured twice using (99m)Tc-ECD SPECT in 10 treatment-naïve patients with SAD. In the first session, subjects were given an oral dose of CBD (400 mg) or placebo, in a double-blind procedure. In the second session, the same procedure was performed using the drug that had not been administered in the previous session. Within-subject between-condition rCBF comparisons were performed using statistical parametric mapping. Relative to placebo, CBD was associated with significantly decreased subjective anxiety (p < 0.001), reduced ECD uptake in the left parahippocampal gyrus, hippocampus, and inferior temporal gyrus (p < 0.001, uncorrected), and increased ECD uptake in the right posterior cingulate gyrus (p < 0.001, uncorrected). These results suggest that CBD reduces anxiety in SAD and that this is related to its effects on activity in limbic and paralimbic brain areas.

Alcoholism: the role of different motivational systems.

PubMed Central

Pihl, R O; Peterson, J B

1995-01-01

Individuals use and misuse alcohol (and other drugs) because of the pharmacologically mediated effects these substances have on the operation of 4 psychobiological systems, mediating response to motivationally relevant unconditioned and conditioned stimuli. These 4 systems have unique neuroanatomical structure, biochemical modes of operation, association with affect, behavior and cognition, and responsiveness to drugs of abuse. Individual variation in the operation of these systems determines individual susceptibility to initiation and maintenance of drug use and abuse. Sources of such variation differ, in a vitally important fashion, in various specific populations of individuals at heightened risk for drug abuse. Nonalcoholic sons of male alcoholics, with multigenerational family histories of male alcoholism, appear to be at heightened risk for the development of alcohol abuse because alcohol eliminates their heightened response to threat, and because they are hypersensitive to ethanol's psychomotor stimulant effects. Anxiety-sensitive individuals also appear attracted to alcohol for its anxiolytic properties. Many other important sources of idiosyncratic variability exist. Detailed analysis of such sources may lead to the development of more effective prevention and treatment programs. Images Figure 7 PMID:8527424

Further Characterization of the Predictive Validity of the Brattleboro Rat Model for Antipsychotic Efficacy

PubMed Central

Feifel, D.; Shilling, P. D.; Melendez, G.

2014-01-01

Our laboratory and others have reported that Brattleboro (BRAT) rats, a Long Evans (LE) strain with a single gene mutation, have inherent deficits in prepulse inhibition (PPI) homologous to those observed in schizophrenia patients and that these deficits are reversed by antipsychotic drugs (APDs). To further evaluate the potential predictive validity of BRAT rat PPI for APDs, we compared the effects of acute subcutaneous administration of the typical APD chlorpromazine to that of three psychotropic drugs without antipsychotic efficacy, the antidepressant imipramine, the anxiolytic diazepam and the anticonvulsant mood stabilizer valproic acid on male and female BRAT rat PPI. Male and female BRAT rats exhibited baseline (saline treatment) PPI that was not different from each other (21.1 % and 21.3 %, respectively) and low compared to those historically exhibited by LE rats (approximately 59 %). Chlorpromazine facilitated PPI in male and female BRAT rats, whereas imipramine, diazepam, and valproic acid had no significant effect on PPI. These results suggest that PPI in the BRAT rat responds specifically to drugs with APD efficacy but not psychotropic drugs of different therapeutic families. PMID:21106605

Opposing acute and chronic behavioural effects of a beta-blocker, propranolol, in the rat.

PubMed

Salmon, P; Gray, J A

1985-01-01

Rats were trained over 40 days to lever-press for food reward under a schedule of differential reinforcement of low rates of response with a 20-s criterion (DRL 20), following seven sessions of continuous reinforcement. The effect of injecting a beta-adrenergic blocker, propranolol (5 mg/kg IP), before and at two different delays after each daily session of DRL were investigated. In Experiment I, rats drugged 5-8 min before every session earned fewer reinforcements compared to controls, and showed impaired temporal discrimination. In Experiment II, this result was not replicated, but similar effects were clear in animals drugged pre-session from the 15th day of acquisition. By contrast, an improved temporal discrimination, and increased number of reinforcements were seen in rats drugged 5-8 min after every session. In Experiment III, the post-session effects were replicated and found also in rats drugged 4-5.5 h after each session. These results suggest that propranolol has an acute effect on DRL responding which resembles that of anxiolytics, and a chronic effect which opposes the acute one.

A new piperazine derivative: 1-(4-(3,5-di-tert-butyl-4-hydroxybenzyl) piperazin-1-yl)-2-methoxyethan-1-one with antioxidant and central activity.

PubMed

Brito, Adriane F; Braga, Patrícia C C S; Moreira, Lorrane K S; Silva, Dayane M; Silva, Daiany P B; Sanz, Germán; Vaz, Boniek G; de Carvalho, Flávio S; Lião, Luciano M; Silva, Rafaela R; Noël, François; Neri, Hiasmin F S; Ghedini, Paulo C; de Carvalho, Murilo F; de S Gil, Eric; Costa, Elson A; Menegatti, Ricardo

2018-03-01

In the scope of a research program aimed at developing new drugs for the treatment of central nervous system diseases, we describe herein the synthesis and pharmacological evaluation of 1-(4-(3,5-di-tert-butyl-4-hydroxybenzyl) piperazin-1-yl)-2-methoxyethan-1-one (LQFM180). This compound showed antioxidant activity in two models, electroanalytical assays, and DPPH activity. Moreover, in behavioral tests as the open field test LQFM180 (9.4, 18.8, and 37.6 mg/kg, per oral (p.o.)), we detected anxiolytic-like activity. In the sodium pentobarbital-induced sleep test, LQFM180, in all doses, decreased the latency to sleep and increased sleep duration, indicating central depressant activity; moreover, in the chimney test, LQFM180 did not alter motor activity. LQFM180 (18.8 mg/kg, p.o.) increased the time and number of entries on open arms in the elevated plus maze test, suggesting anxiolytic-like activity, which was reversed by NAN-190 and p-chlorophenylalanine, indicating a role of the serotonergic pathway on this effect. In the forced swimming test, LFQM180 (18.8 mg/kg, p.o.) decreased immobility time, suggesting antidepressant-like activity, which was reversed by monoaminergic antagonists, indicating a role for the serotonergic, noradrenergic, and dopaminergic pathways. Competition binding assays showed that LQFM180 was able to bind to the α 1B , 5-HT 1A , and D 2 receptors, however, within the low micromolar range. We conclude that LQFM180 should be considered as a scaffold for drug candidate development.

Evaluation of the effect of acute sibutramine in female rats in the elevated T-maze and elevated plus-maze tests.

PubMed

Santos, Raliny O; de Assunção, Gabriela L M; de Medeiros, Diogo M B; de Sousa Pinto, Icaro A; de Barros, Keizianny S; Soares, Bruno L; André, Eunice; Gavioli, Elaine C; de Paula Soares-Rachetti, Vanessa

2014-02-01

Sibutramine is a serotonin and norepinephrine reuptake inhibitor indicated for the treatment of obesity. A pre-clinical study showed that acute administration of sibutramine promoted anxiolytic- and panicolytic-like effects in male rats. However, in clinical reports, sibutramine favoured the onset of panic attacks in women. In this study, the effect of sibutramine on experimental anxiety in females and the relevance of different oestrous cycle phases for this effect were analysed. In experiment 1, both male and female rats were submitted to acute intraperitoneal injection of sibutramine or vehicle 30 min. before testing in the elevated T-maze (ETM) and in the open-field test (OF). Females in the pro-oestrus (P), oestrus (E), early dioestrus (ED) and late dioestrus (LD) phases were tested in the ETM and OF (experiment 2) or in the elevated plus-maze (EPM) 30 min. after the injection of sibutramine. Sibutramine impaired the escape response in the ETM in both males and females. This effect was observed for P, E and ED, but not for LD females. Sibutramine altered neither the inhibitory avoidance in the ETM nor the behaviour of females in the EPM. Thus, sibutramine promoted a panicolytic-like effect in female rats cycling at P, E and ED, but not in the LD phase and did not alter behaviours related to anxiety in both ETM and EPM. Considering that pre-clinical studies aiming the screening of anxiolytic drugs employ male rodents, data here obtained reinforce the importance of better understanding the effects of drugs in females. © 2013 Nordic Pharmacological Society. Published by John Wiley & Sons Ltd.

Anxiety and 10-Year Risk of Incident Dementia—An Association Shaped by Depressive Symptoms: Results of the Prospective Three-City Study

PubMed Central

Mortamais, Marion; Abdennour, Meriem; Bergua, Valérie; Tzourio, Christophe; Berr, Claudine; Gabelle, Audrey; Akbaraly, Tasnime N.

2018-01-01

Background: Anxiety is common in patients with cognitive impairment and dementia. However, whether anxiety is a risk factor for dementia is still not known. We aimed to examine the association between trait anxiety at baseline and the 10-year risk of incident dementia to determine to which extent depressive symptoms influence this relationship in the general population. Methods: Data came from 5,234 community-dwelling participants from the Three-City prospective cohort study, aged 65 years at baseline and followed over 10 years. At baseline, anxiety trait was assessed using the Spielberger State-Trait Anxiety Inventory (STAI), and depressive symptoms using Center for Epidemiologic Studies-Depression Scale (CESD). Use of anxiolytic drugs was also considered. Diagnoses of dementia were made at baseline and every 2 years. To examine the relationship between anxiety exposures and risk of incident dementia, Cox proportional hazard regression models were performed. Results: Taking anxiolytic drugs or having high trait anxiety (STAI score ≥ 44) increased the risk of dementia assessed over 10 years of follow-up [Hazard Ratio (HR) = 1.39, 95%CI: 1.08–1.80, p = 0.01 and HR = 1.26, 95%CI: 1.01–1.57, p = 0.04, respectively], independently of a large panel of socio-demographic variables, health behaviors, cardio-metabolic disorders, and additional age-related disorders such as cardiovascular diseases, activity limitations, and cognitive deficit. However, the associations were substantially attenuated after further adjustment for depressive symptoms. Conclusion: Our findings suggest that depressive symptoms shape the association between anxiety trait and dementia. Further research is needed to replicate our findings and extrapolate our results to anxiety disorders. PMID:29719498

Trends in prescriptions and costs of drugs for mental disorders in England, 1998-2010.

PubMed

Ilyas, Stephen; Moncrieff, Joanna

2012-05-01

Increasing rates of prescriptions for antidepressants, antipsychotics and stimulants have been reported from various countries. To examine trends in prescriptions and the costs of all classes of psychiatric medication in England. Data from the Prescription Cost Analysis 1998-2010 was examined, using linear regression analysis to examine trends. Prescriptions of drugs used for mental disorders increased by 6.8% (95% CI 6.3-7.4) per year on average, in line with other drugs, but made up an increasing proportion of all prescription drug costs (P = 0.001). There were rising trends in prescriptions of all classes of psychiatric drugs, except anxiolytics and hypnotics (which did not change). Antidepressant prescriptions increased by 10% (95% CI 9.0-11) per year on average, and antipsychotics by 5.1% (95% CI 4.3-5.9). Antipsychotics overtook antidepressants as the most costly class of psychiatric medication, with costs rising 22% (95% CI 17-27) per year. Rising prescriptions may be partly explained by longer-term treatment and increasing population. Nevertheless, it appears that psychiatric drugs make an increasing contribution to total prescription drug costs, with antipsychotics becoming the most costly. Low-dose prescribing of some antipsychotics is consistent with other evidence that their use may not be restricted to those with severe mental illness.

Antidepressant and anxiolytic activity of Lavandula officinalis aerial parts hydroalcoholic extract in scopolamine-treated rats.

PubMed

Rahmati, Batool; Kiasalari, Zahra; Roghani, Mehrdad; Khalili, Mohsen; Ansari, Fariba

2017-12-01

Anxiety and depression are common in Alzheimer's disease (AD). Despite some evidence, it is difficult to confirm Lavandula officinalis Chaix ex Vill (Lamiaceae) as an anxiolytic and antidepressant drug. The effects of L. officinalis extract were studied in scopolamine-induced memory impairment, anxiety and depression-like behaviour. Male NMRI rats were divided into control, scopolamine alone-treated group received scopolamine (0.1 mg/kg) intraperitoneally (i.p.), daily and 30 min prior to performing behavioural testing on test day, for 12 continuous days and extract pretreated groups received aerial parts hydro alcoholic extract (i.p.) (100, 200 and 400 mg/kg), 30 min before each scopolamine injection. Memory impairment was assessed by Y-maze task, while, elevated plus maze and forced swimming test were used to measure anxiolytic and antidepressive-like activity. Spontaneous alternation percentage in Y maze is reduced by scopolamine (36.42 ± 2.60) (p ≤ 0.001), whereas lavender (200 and 400 mg/kg) enhanced it (83.12 ± 5.20 and 95 ± 11.08, respectively) (p ≤ 0.05). Also, lavender pretreatment in 200 and 400 mg/kg enhanced time spent on the open arms (15.4 ± 3.37 and 32.1 ± 3.46, respectively) (p ≤ 0.001). On the contrary, while immobility time was enhanced by scopolamine (296 ± 4.70), 100, 200 and 400 mg/kg lavender reduced it (193.88 ± 22.42, 73.3 ± 8.25 and 35.2 ± 4.22, respectively) in a dose-dependent manner (p ≤ 0.001). Lavender extracts improved scopolamine-induced memory impairment and also reduced anxiety and depression-like behaviour in a dose-dependent manner.

Inverted U-Shaped Dose-Response Curve of the Anxiolytic Effect of Cannabidiol during Public Speaking in Real Life.

PubMed

Zuardi, Antonio W; Rodrigues, Natália P; Silva, Angélica L; Bernardo, Sandra A; Hallak, Jaime E C; Guimarães, Francisco S; Crippa, José A S

2017-01-01

The purpose of this study was to investigate whether the anxiolytic effect of cannabidiol (CBD) in humans follows the same pattern of an inverted U-shaped dose-effect curve observed in many animal studies. Sixty healthy subjects of both sexes aged between 18 and 35 years were randomly assigned to five groups that received placebo, clonazepam (1 mg), and CBD (100, 300, and 900 mg). The subjects were underwent a test of public speaking in a real situation (TPSRS) where each subject had to speak in front of a group formed by the remaining participants. Each subject completed the anxiety and sedation factors of the Visual Analog Mood Scale and had their blood pressure and heart rate recorded. These measures were obtained in five experimental sessions with 12 volunteers each. Each session had four steps at the following times (minutes) after administration of the drug/placebo, as time 0: -5 (baseline), 80 (pre-test), 153 (speech), and 216 (post-speech). Repeated-measures analyses of variance showed that the TPSRS increased the subjective measures of anxiety, heart rate, and blood pressure. Student-Newman-Keuls test comparisons among the groups in each phase showed significant attenuation in anxiety scores relative to the placebo group in the group treated with clonazepam during the speech phase, and in the clonazepam and CBD 300 mg groups in the post-speech phase. Clonazepam was more sedative than CBD 300 and 900 mg and induced a smaller increase in systolic and diastolic blood pressure than CBD 300 mg. The results confirmed that the acute administration of CBD induced anxiolytic effects with a dose-dependent inverted U-shaped curve in healthy subjects, since the subjective anxiety measures were reduced with CBD 300 mg, but not with CBD 100 and 900 mg, in the post-speech phase.

Inverted U-Shaped Dose-Response Curve of the Anxiolytic Effect of Cannabidiol during Public Speaking in Real Life

PubMed Central

Zuardi, Antonio W.; Rodrigues, Natália P.; Silva, Angélica L.; Bernardo, Sandra A.; Hallak, Jaime E. C.; Guimarães, Francisco S.; Crippa, José A. S.

2017-01-01

The purpose of this study was to investigate whether the anxiolytic effect of cannabidiol (CBD) in humans follows the same pattern of an inverted U-shaped dose-effect curve observed in many animal studies. Sixty healthy subjects of both sexes aged between 18 and 35 years were randomly assigned to five groups that received placebo, clonazepam (1 mg), and CBD (100, 300, and 900 mg). The subjects were underwent a test of public speaking in a real situation (TPSRS) where each subject had to speak in front of a group formed by the remaining participants. Each subject completed the anxiety and sedation factors of the Visual Analog Mood Scale and had their blood pressure and heart rate recorded. These measures were obtained in five experimental sessions with 12 volunteers each. Each session had four steps at the following times (minutes) after administration of the drug/placebo, as time 0: -5 (baseline), 80 (pre-test), 153 (speech), and 216 (post-speech). Repeated-measures analyses of variance showed that the TPSRS increased the subjective measures of anxiety, heart rate, and blood pressure. Student-Newman-Keuls test comparisons among the groups in each phase showed significant attenuation in anxiety scores relative to the placebo group in the group treated with clonazepam during the speech phase, and in the clonazepam and CBD 300 mg groups in the post-speech phase. Clonazepam was more sedative than CBD 300 and 900 mg and induced a smaller increase in systolic and diastolic blood pressure than CBD 300 mg. The results confirmed that the acute administration of CBD induced anxiolytic effects with a dose-dependent inverted U-shaped curve in healthy subjects, since the subjective anxiety measures were reduced with CBD 300 mg, but not with CBD 100 and 900 mg, in the post-speech phase. PMID:28553229

Gender specific influence of endogenous glutamate release on stress-induced fear in rats.

PubMed

Jain, S K; Zelena, D

2011-01-01

Stress, fear and anxiety are among major public health concerns. The role of glutamate in these processes is becoming more recognized with promising new drug targets. The aim of this study was to establish the gender specificity of a possible treatment of fear by glutamate antagonists in correspondence with changes in stress-hormone release. Footshock-induced fear was used as an anxiogenic situation in rats. A combination of two ionotrop receptor antagonists such as MK-801 (dizocilpine; 0.2 mg/kg) for NMDA (N-methyl-D-aspartic acid) and GYKI 52466 (benzodiazepine derivative; 10 mg/kg) for AMPA/kainate receptors were used for 5 days following the hypothesis that they potentiate each other the main action, but at the same time the side effects may be minimized. Female rats tried to avoid the electrical stimulus more actively than males, as they spent more time with exploration and jumping and less time with freezing or rest. Ionotropic glutamate receptor antagonists have anxiolytic action. MK-801 was more effective in females, as it prevented the footshock-induced freezing per se, while in males it was effective only in combination with GyKI 52466. The locomotor side effect of MK-801 was not visible after repeated administration. The freezing behavior was positively correlated with the changes in prolactin but not with adrenocorticotropin levels. We proved the involvement of endogenous glutamate neurotransmission in stress-induced fear. Therapeutical usage may involve a combination of different receptor antagonists. Special attention should be paid to the gender, as females seem to be more sensitive, therefore they require smaller doses. During the treatment the prolactin levels should be monitored.

A study on the quality of outpatient prescription of psychopharmaceuticals in the City of Zagreb 2006-2009.

PubMed

Zivković, Kresimir; Zelić-Kerep, Ana; Stimac, Danijela; Ozić, Sanja; Zivković, Nikica

2014-06-01

The lack of Croatian studies which could determine the justifiability of excessive psychopharmaceutical utilization was an encouragement to conduct this research. Furthermore, regarding the conduction of this study, it would be possible to determine whether the trend of drug utilization has increased, decreased or perhaps stabilized. The data on the outpatient utilization of psycholeptics and psychoanaleptics were collected from all Zagreb pharmacies, 2006-2009. Based on the collected data for all N05 and N06 groups of drugs, the defined daily doses (DDD) and DDD per thousand inhabitants per day (DDD/TID) have been calculated using the Anatomical-Therapeutic-Chemical classification (ATC) for 2006, 2007, 2008 and 2009. To indicate the quality of drug prescription the Drug Utilization 90% (DU 90%) method was used. Moreover, in order to determine a more precise quality of individual drug group prescriptions, the indicators have been calculated by determining the proportion of the total utilization of individual therapeutic and pharmacological therapeutic subgroups in DDD/TID a day. The utilization of anxiolytics (N05B) accounts for most of the psycholeptic utilization in the City of Zagreb throughout the entire study period. In the study period, the utilization of antidepressants has slightly increased, by 10.5%, taking the first and the last years of the period into account. In 2006, 5 benzodiazepines and the hypnotic zolpidem, as well as 5 selective serotonin reuptake inhibitors (SSRIs) and 1 third generation antipsychotic (olanzapin) were found in the DU 90% segment. In 2009, the DU 90% segment also comprised 5 benzodiazepines and the hypnotic zolpidem, as well as 6 SSRIs and 1 third generation antipsychotic (olanzapin). In the City of Zagreb, a general insight into the quality of psychopharmaceutical prescriptions indicates stability in comparison to earlier studies. The ratio index of the first generation antipsychotic utilization, compared to the third generation antipsychotics, shows an increase in the quality of prescription. Also, the ratio index of total tricyclic antidepressants (TCA) and SSRI utilization indicates improvement in quality of prescription. The ratio index of the entire outpatient utilization of anxiolytics and antidepressants expressed in DDD/TID unfortunately shows a very mild increase of prescription quality. Benzodiazepines accounted for more than 50% of the outpatient utilization of psychopharmaceuticals throughout the study period, which proves the need for precise guidelines as the most significant means of drug rationalization and utilization. It is necessary to identify priorities and problems in order to solve them successfully, by monitoring drug utilization and prescription on a national level. Results demonstrate that within the primary health care system, there is a need for constant education on rational prescription of this drug group.

Benzodiazepine-induced anxiolysis and reduction of conditioned fear are mediated by distinct GABAA receptor subtypes in mice

PubMed Central

Smith, Kiersten S.; Engin, Elif; Meloni, Edward G.; Rudolph, Uwe

2012-01-01

GABAA receptor modulating drugs such as benzodiazepines (BZs) have been used to treat anxiety disorders for over five decades. In order to determine whether the same or different GABAA receptor subtypes are necessary for the anxiolytic-like action of BZs in unconditioned anxiety and conditioned fear models, we investigated the role of different GABAA receptor subtypes by challenging wild type, α1(H101R), α2(H101R) and α3(H126R) mice bred on the C57BL/6J background with diazepam or chlordiazepoxide in the elevated plus maze and the fear-potentiated startle paradigms. Both drugs significantly increased open arm exploration in the elevated plus maze in wild type, α1(H101R) and α3(H126R), but this effect was abolished in α2(H101R) mice; these were expected results based on previous published results. In contrast, while administration of diazepam and chlordiazepoxide significantly attenuated fear-potentiated startle (FPS) in wild type mice and α3(H126R) mice, the fear-reducing effects of these drugs were absent in both α1(H101R) and α2(H101R) point mutants, indicating that both α1- and α2-containing GABAA receptors are necessary for BZs to exert their effects on conditioned fear responses.. Our findings illustrate both an overlap and a divergence between the GABAA receptor subtype requirements for the impact of BZs, specifically that both α1- and α2-containing GABAA receptors are necessary for BZs to reduce conditioned fear whereas only α2-containing GABAA receptors are needed for BZ-induced anxiolysis in unconditioned tests of anxiety. This raises the possibility that GABAergic pharmacological interventions for specific anxiety disorders can be differentially tailored. PMID:22465203

p-Coumaric acid activates the GABA-A receptor in vitro and is orally anxiolytic in vivo.

PubMed

Scheepens, Arjan; Bisson, Jean-Francois; Skinner, Margot

2014-02-01

The increasing prevalence and social burden of subclinical anxiety in the western world represents a significant psychosocial and financial cost. Consumers are favouring a more natural and nonpharmacological approach for alleviating the effects of everyday stress and anxiety. The gamma-aminobutyric acid (GABA) receptor is the primary mediator of central inhibitory neurotransmission, and GABA-receptor agonists are well known to convey anxiolytic effects. Using an in vitro screening approach to identify naturally occurring phytochemical GABA agonists, we discovered the plant secondary metabolite p-coumaric acid to have significant GABAergic activity, an effect that could be blocked by co-administration of the specific GABA-receptor antagonist, picrotoxin. Oral administration of p-coumaric acid to rodents induced a significant anxiolytic effect in vivo as measured using the elevated plus paradigm, in line with the effects of oral diazepam. Given that p-coumaric acid is reasonably well absorbed following oral consumption in man and is relatively nontoxic, it may be suitable for the formulation of a safe and effective anxiolytic functional food. Copyright © 2013 John Wiley & Sons, Ltd.

Lotus Leaf Alkaloid Extract Displays Sedative-Hypnotic and Anxiolytic Effects through GABAA Receptor.

PubMed

Yan, Ming-Zhu; Chang, Qi; Zhong, Yu; Xiao, Bing-Xin; Feng, Li; Cao, Fang-Rui; Pan, Rei-Le; Zhang, Ze-Sheng; Liao, Yong-Hong; Liu, Xin-Min

2015-10-28

Lotus leaves have been used traditionally as both food and herbal medicine in Asia. Open-field, sodium pentobarbital-induced sleeping and light/dark box tests were used to evaluate sedative-hypnotic and anxiolytic effects of the total alkaloids (TA) extracted from the herb, and the neurotransmitter levels in the brain were determined by ultrafast liquid chromatography-tandem mass spectrometry. The effects of picrotoxin, flumazenil, and bicuculline on the hypnotic activity of TA, as well as the influence of TA on Cl(-) influx in cerebellar granule cells, were also investigated. TA showed a sedative-hypnotic effect by increasing the brain level of γ-aminobutyric acid (GABA), and the hypnotic effect could be blocked by picrotoxin and bicuculline, but could not be antagonized by flumazenil. Additionally, TA could increase Cl(-) influx in cerebellar granule cells. TA at 20 mg/kg induced anxiolytic-like effects and significantly increased the concentrations of serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), and dopamine (DA). These data demonstrated that TA exerts sedative-hypnotic and anxiolytic effects via binding to the GABAA receptor and activating the monoaminergic system.

NMDA/glutamate mechanism of magnesium-induced anxiolytic-like behavior in mice.

PubMed

Poleszak, Ewa; Wlaź, Piotr; Wróbel, Andrzej; Fidecka, Sylwia; Nowak, Gabriel

2008-01-01

The anxiolytic-like activity of magnesium in mice during the elevated plus maze (EPM) has been demonstrated previously. In the present study, we examined the involvement of NMDA/glutamate receptor ligands on the magnesium effect on the EPM. We demonstrated that low, ineffective doses of NMDA antagonists (the competitive NMDA antagonist CGP 37849, 0.3 mg/kg; an antagonist of the glycineB sites, L-701,324, 1 mg/kg; a partial agonist of the glycineB sites, D-cycloserine, 2.5 mg/kg; and the non-competitive NMDA antagonist MK-801, 0.05 mg/kg) administered together with an ineffective dose of magnesium (10 mg/kg) evoked a significant increase in the percentage of time spent in the open arm of the maze (an index of anxiety). Moreover, magnesium-induced anxiolytic-like activity (20 mg/kg) was antagonized by D-serine (100 nmol/mouse), an agonist of glycineB site of the NMDA receptor complex. The present study demonstrates the involvement of the NMDA/glutamate pathway in the magnesium anxiolytic-like activity in the EPM in mice, and that this activity particularly involves the glycineB sites.

Bioactive peptides derived from natural proteins with respect to diversity of their receptors and physiological effects.

PubMed

Yoshikawa, Masaaki

2015-10-01

We have found various bioactive peptides derived from animal and plant proteins, which interact with receptors for endogenous bioactive peptides such as opioids, neurotensin, complements C3a and C5a, oxytocin, and formyl peptides etc. Among them, rubiscolin, a δ opioid peptide derived from plant RuBisCO, showed memory-consolidating, anxiolytic-like, and food intake-modulating effects. Soymorphin, a μ opioid peptide derived from β-conglycinin showed anxiolytic-like, anorexigenic, hypoglycemic, and hypotriglyceridemic effects. β-Lactotensin derived from β-lactoglobulin, the first natural ligand for the NTS2 receptor, showed memory-consolidating, anxiolytic-like, and hypocholesterolemic effects. Weak agonist peptides for the complements C3a and C5a receptors were released from many proteins and exerted various central effects. Peptides showing anxiolytic-like antihypertensive and anti-alopecia effects via different types of receptors such as OT, FPR and AT2 were also obtained. Based on these study, new functions and post-receptor mechanisms of receptor commom to endogenous and exogenous bioactive peptides have been clarified. Copyright © 2015 Elsevier Inc. All rights reserved.

Pharmacology of basimglurant (RO4917523, RG7090), a unique metabotropic glutamate receptor 5 negative allosteric modulator in clinical development for depression.

PubMed

Lindemann, Lothar; Porter, Richard H; Scharf, Sebastian H; Kuennecke, Basil; Bruns, Andreas; von Kienlin, Markus; Harrison, Anthony C; Paehler, Axel; Funk, Christoph; Gloge, Andreas; Schneider, Manfred; Parrott, Neil J; Polonchuk, Liudmila; Niederhauser, Urs; Morairty, Stephen R; Kilduff, Thomas S; Vieira, Eric; Kolczewski, Sabine; Wichmann, Juergen; Hartung, Thomas; Honer, Michael; Borroni, Edilio; Moreau, Jean-Luc; Prinssen, Eric; Spooren, Will; Wettstein, Joseph G; Jaeschke, Georg

2015-04-01

Major depressive disorder (MDD) is a serious public health burden and a leading cause of disability. Its pharmacotherapy is currently limited to modulators of monoamine neurotransmitters and second-generation antipsychotics. Recently, glutamatergic approaches for the treatment of MDD have increasingly received attention, and preclinical research suggests that metabotropic glutamate receptor 5 (mGlu5) inhibitors have antidepressant-like properties. Basimglurant (2-chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine) is a novel mGlu5 negative allosteric modulator currently in phase 2 clinical development for MDD and fragile X syndrome. Here, the comprehensive preclinical pharmacological profile of basimglurant is presented with a focus on its therapeutic potential for MDD and drug-like properties. Basimglurant is a potent, selective, and safe mGlu5 inhibitor with good oral bioavailability and long half-life supportive of once-daily administration, good brain penetration, and high in vivo potency. It has antidepressant properties that are corroborated by its functional magnetic imaging profile as well as anxiolytic-like and antinociceptive features. In electroencephalography recordings, basimglurant shows wake-promoting effects followed by increased delta power during subsequent non-rapid eye movement sleep. In microdialysis studies, basimglurant had no effect on monoamine transmitter levels in the frontal cortex or nucleus accumbens except for a moderate increase of accumbal dopamine, which is in line with its lack of pharmacological activity on monoamine reuptake transporters. These data taken together, basimglurant has favorable drug-like properties, a differentiated molecular mechanism of action, and antidepressant-like features that suggest the possibility of also addressing important comorbidities of MDD including anxiety and pain as well as daytime sleepiness and apathy or lethargy. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Anxiety- rather than depression-like behavior is associated with adult neurogenesis in a female mouse model of higher trait anxiety- and comorbid depression-like behavior

PubMed Central

Sah, A; Schmuckermair, C; Sartori, S B; Gaburro, S; Kandasamy, M; Irschick, R; Klimaschewski, L; Landgraf, R; Aigner, L; Singewald, N

2012-01-01

Adult neurogenesis has been implicated in affective disorders and the action of antidepressants (ADs) although the functional significance of this association is still unclear. The use of animal models closely mimicking human comorbid affective and anxiety disorders seen in the majority of patients should provide relevant novel information. Here, we used a unique genetic mouse model displaying higher trait anxiety (HAB) and comorbid depression-like behavior. We demonstrate that HABs have a lower rate of hippocampal neurogenesis and impaired functional integration of newly born neurons as compared with their normal anxiety/depression-like behavior (NAB) controls. In HABs, chronic treatment with the AD fluoxetine alleviated their higher depression-like behavior and protected them from relapse for 3 but not 7 weeks after discontinuation of the treatment without affecting neurogenesis. Similar to what has been observed in depressed patients, fluoxetine treatment induced anxiogenic-like effects during the early treatment phase in NABs along with a reduction in neurogenesis. On the other hand, treatment with AD drugs with a particularly strong anxiolytic component, namely the neurokinin-1-receptor-antagonist L-822 429 or tianeptine, increased the reduced rate of neurogenesis in HABs up to NAB levels. In addition, challenge-induced hypoactivation of dentate gyrus (DG) neurons in HABs was normalized by all three drugs. Overall, these data suggest that AD-like effects in a psychopathological mouse model are commonly associated with modulation of DG hypoactivity but not neurogenesis, suggesting normalization of hippocampal hypoactivity as a neurobiological marker indicating successful remission. Finally, rather than to higher depression-related behavior, neurogenesis seems to be linked to pathological anxiety. PMID:23047242

Anxiogenic-like activity of 3,4-methylenedioxy-methamphetamine ("Ecstasy") in the social interaction test is accompanied by an increase of c-fos expression in mice amygdala.

PubMed

Navarro, José Francisco; Rivera, Alicia; Maldonado, Enrique; Cavas, María; de la Calle, Adelaida

2004-03-01

3,4-Methylenedioxymethamphetamine (MDMA) is a synthetic amphetamine popularly known as "Ecstasy." Animal studies examining acute effects of MDMA on anxiety are unclear because although an anxiolytic-like action of MDMA in different animal models of anxiety has been described, there is also substantial evidence supporting an anxiogenic-like effect of this drug. To date, several studies have examined c-fos expression following MDMA administration in rats. However, there is no information about the MDMA-induced c-fos expression in mice previously tested in an animal model of anxiety. In this study, male mice were injected with MDMA (1, 8 and 15 mg/kg ip) and assessed for changes on anxiety and for the expression of the immediate early gene c-fos in the amygdala (central, basolateral and basomedial). Anxiety was evaluated by the "social interaction test." Ten behavioral categories were recorded: body care, digging, nonsocial exploration, exploration from a distance, social investigation, threat, attack, avoidance/flee, defense/submission and immobility. As compared with the control group, mice treated with MDMA (all doses) showed a decrease in mean duration and total time spent in social investigation behaviors, whereas avoidance/flee behaviors were significantly increased after treatment with this compound (8 and 15 mg/kg). Likewise, a significant increase in c-fos expression was found in the basolateral (all doses) and central (15 mg/kg) amygdala after MDMA administration. Overall, these findings indicate that MDMA exhibits an anxiogenic-like profile in the social interaction test in mice, and that central and basolateral amygdala might be involved in these anxiogenic-like effects of the drug.

Anxiolytic and Hypnotic Effects of Aqueous and Ethanolic Extracts of Aerial Parts of Echium italicum L. in Mice

PubMed Central

Hosseinzadeh, Hossein; Shahandeh, Shabnam; Shahsavand, Shabnam

2012-01-01

Background Research in the area of herbal psychopharmacology has clearly improved in recent decades. Self-administration of herbal medicines has been the most popular therapeutic alternative to standard medicine. Objectives Since the extract of Echium amoenum exhibits an anxiolytic effect, the aim of this study is to evaluate the anxiolytic and hypnotic effects in mice of the aqueous and ethanolic extracts of aerial parts of E. italicum, a member of the Boraginaceae family. Materials and Methods Mice were administered the agents intraperitoneally before the start of the experiments for evaluation of hypnotic activity (induced by sodium pentobarbital, 30 mg/kg, i.p.), anxiolytic activity (elevated plus-maze [EPM] test), locomotor activity (open field test), and motor coordination (rotarod test). Result The ethanolic and aqueous extracts of E. italicum, at doses of 1.2 and 2.1 g/kg, increased the percentage of time-spent and the percentage of arm entries in the open arms of the EPM and decreased the percentage of time-spent in the closed arms of the EPM. Moreover, both extracts decreased the pentobarbital-induced latency to sleep and significantly increased the total sleeping time induced by pentobarbital. In addition, locomotor activity was affected by aqueous extracts and ethanolic extract (at higher doses). Both extracts showed no effect in the rotarod test. Conclusions These results suggest that both ethanolic and aqueous extracts of E. italicum may have anxiolytic effects and sedative activity but no effect on muscle relaxation. PMID:24624158

Comparison of anxiety between smokers and nonsmokers with acute myocardial infarction.

PubMed

Sheahan, Sharon L; Rayens, Mary K; An, Kyungeh; Riegel, Barbara; McKinley, Sharon; Doering, Lynn; Garvin, Bonnie J; Moser, Debra K

2006-11-01

Increased anxiety correlates with increased complications after acute myocardial infarction. Anxiety levels and use of anxiolytic agents have not been compared between smokers and nonsmokers hospitalized because of acute myocardial infarction. To compare anxiety level, sociodemographic factors, and clinical variables between smokers and nonsmokers hospitalized with acute myocardial infarction and to examine predictors of use of beta-blockers and anxiolytic agents among smokers and nonsmokers. Secondary data analysis of a prospective multisite study on anxiety in 181 smokers and 351 nonsmokers with acute myocardial infarction. Anxiety was measured by using the State Trait Anxiety Inventory and the anxiety subscale of the Basic Symptom Inventory within 72 hours of admission. Smokers reported higher anxiety levels than nonsmokers reported on both anxiety scales. Female smokers reported the highest anxiety and peak pain levels of all, yet women were the least likely to receive anxiolytic agents. Smoking status was not a predictor for anxiety level when sex, peak pain, use of beta-blockers in the hospital, and age were controlled for. However, smokers were twice as likely as nonsmokers to receive an anxiolytic agent and 60% more likely to receive a beta-blocker in the emergency department, and smokers were 80% more likely than nonsmokers to receive an anxiolytic agent during hospitalization when these variables were controlled. Older female smokers are at risk for complications because they are older than their male counterparts and less likely to receive beta-blockers and antianxiety medications in the emergency department.

An imidazopyridine anxiolytic alters glucose tolerance in patients: a pilot investigation.

PubMed

Bottaï, T; Cartault, F; Pouget, R; Blayac, J P; Petit, P

1995-02-01

We have recently shown that compounds with high affinity for peripheral-type benzodiazepine receptors inhibited glucose-induced insulin secretion in vitro. We therefore performed an oral glucose tolerance test in anxious inpatients treated with the imidazopyridine derivative alpidem, which has been shown to display high affinity for these binding sites. The test was performed before and after 1 week of daily administration of the drug. As compared with pretreatment values, a significant alteration of the insulin response to glucose was observed. It is suggested that daily administration of alpidem, at therapeutically effective doses for the treatment of anxiety, may alter glucose tolerance.

Intraperitoneal injection of neuropeptide Y (NPY) alters neurotrophin rat hypothalamic levels: Implications for NPY potential role in stress-related disorders.

PubMed

Gelfo, Francesca; De Bartolo, Paola; Tirassa, Paola; Croce, Nicoletta; Caltagirone, Carlo; Petrosini, Laura; Angelucci, Francesco

2011-06-01

Neuropeptide Y (NPY) is a 36-amino acid peptide which exerts several regulatory actions within peripheral and central nervous systems. Among NPY actions preclinical and clinical data have suggested that the anxiolytic and antidepressant actions of NPY may be related to its antagonist action on the hypothalamic-pituitary-adrenal (HPA) axis. The neurotrophins brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are proteins involved in the growth, survival and function of neurons. In addition to this, a possible role of neurotrophins, particularly BDNF, in HPA axis hyperactivation has been proposed. To characterize the effect of NPY on the production of neurotrophins in the hypothalamus we exposed young adult rats to NPY intraperitoneal administration for three consecutive days and then evaluated BDNF and NGF synthesis in this brain region. We found that NPY treatment decreased BDNF and increased NGF production in the hypothalamus. Given the role of neurotrophins in the hypothalamus, these findings, although preliminary, provide evidence for a role of NPY as inhibitor of HPA axis and support the idea that NPY might be involved in pathologies characterized by HPA axis dysfunctions. Copyright © 2011 Elsevier Inc. All rights reserved.

Dopaminergic system in CA1 modulates MK-801 induced anxiolytic-like responses.

PubMed

Zarrindast, Mohammad Reza; Nasehi, Mohammad; Pournaghshband, Mahnaz; Yekta, Batool Ghorbani

2012-11-01

Today, there is relatively no debate on the notion that NMDA receptor antagonist agents in the hippocampus induce anxiolytic-like effects through distinct mechanisms. There is also a bulk of studies showing the involvement of the dopaminergic system in NMDA induced behaviors. Thus, on the basis of the involvement of dopaminergic system in anxiety-related behaviors, the present study aimed to investigate the involvement of the dorsal hippocampal (CA1) dopaminergic system in anxiolytic-like responses induced by MK801 (NMDA receptor antagonist) in male Wistar rats. We used the elevated plus maze to test anxiety. This apparatus has widely been employed to test parameters of anxiety-related behaviors including the open arm time percentage (%OAT), open arm entries percentage (%OAE), locomotor activity, grooming (the rat rubs its face), rearing (the rat maintains an erect posture) and defecation (the number of boli defection). The data showed that, intra-CA1 injection of MK801 (2 μg/rat) increases %OAT and %OAE but not other exploratory behaviors, indicating an anxiolytic-like effect. Moreover, sole intra-CA1 injection of SCH23390, dopamine D1 receptor antagonist, (0.25, 0.5 and 1 μg/rat) and sulpiride, dopamine D2 receptor antagonist, (0.25,0.5 and 0.75 μg/rat) did not alter anxiety-like behaviors. Co-administration of subthreshold doses of SCH23390 (0.5 μg/rat) and MK801 (0.5 g/rat), induced anxiolytic-like behaviors. Furthermore, intra-CA1 administration of different doses of sulpiride (0.12, 0.5 and 0.75 μg/rat), 5 min before the injection of an effective dose of MK801 (2 μg/rat), decreased %OAT and %OAE, however did not alter other exploratory behaviors induced by MK801. Our results suggested a modulatory effect of the CA1 dopaminergic system on the anxiolytic-like effects induced by MK801.

The use of temazepam elixir in surgical dental sedation: a comparison with intravenous midazolam.

PubMed

Skelly, A M; Girdler, N M; File, S E

1992-02-22

Out-patients attending for removal of at least one lower third molar were randomly allocated to treatment with temazepam elixir (n = 7) or intravenous midazolam (n = 8), as well as local analgesia. Patients were tested prior to drug administration and at the end of surgery. Both drugs increased heart rate and midazolam also decreased diastolic blood pressure. The two drugs caused significant, equal increases in ratings of sedation, but the reduction of anxiety was significant only for midazolam. There was significant amnesia for material presented after drug administration, as well as for dental events and this was significantly greater for midazolam. The effects of these drugs in dental patients were compared with those in normal volunteers treated in an identical manner, but without oral surgery. The drugs had similar significant cardiovascular and amnesic effects in the volunteers and the same effects on mood ratings, even though volunteers and patients differed in their pretreatment levels of anxiety and discontent. The dentist's ratings of the sedation and operating conditions were excellent in both cases. Thus temazepam elixir provided a useful sedative for oral surgery, avoiding the complications of intravenous administration. However, for equivalent levels of sedation, midazolam had greater anxiolytic and amnesic effects than temazepam.

Effects of alprazolam and clonidine on carbon dioxide-induced increases in anxiety rating in healthy human subjects

DOE Office of Scientific and Technical Information (OSTI.GOV)

Woods, S.W.; Krystal, J.H.; Heninger, G.R.

1989-01-01

In order to investigate possible neurobiologic mechanisms underlying carbon dioxide-induced anxiety, the effects of oral alprazolam 0.75 mg and intravenous clonidine 2 mcg/kg on CO/sub 2/-induced increases in ratings of subjective anxiety, pulse rate, and ventilation were measured in healthy human subjects. Pretreatment with alprazolam but not with clonidine significantly reduced the CO/sub 2/-induced increases in ratings of anxiety. Neither drug altered CO/sub 2/-induced increases in pulse rate or ventilatory responses. Clonidine did produce potent sedative and hypotensive effects. The behavioral data suggest that the mechanisms through which CO/sub 2/ induces anxiety-like effects involve neural systems regulated by benzodiazepine receptorsmore » and, secondly, that they appear not to require normal functioning of noradrenergic systems. Carbon dioxide may provide a useful model system for identification of new drugs with anxiolytic properties.« less

The long-term value of the selected list as a method of controlling drug costs in a district general hospital.

PubMed

Upton, D R; Holmes, G K; Fox, P D; Cullen, A M; Poston, J W

1989-02-01

The results of a study aimed at evaluating the long-term effects of the Limited List (now officially referred to as the Selected List Scheme) on inpatient drug costs in a district general hospital (DGH) are presented. Study periods of six months duration were examined before, shortly after, and a further year after implementation of the List on 1 April 1985. Eight therapeutic classes affected by the regulations were examined; in four of these (antacids, expectorants, mucolytics and anxiolytics, hypnotics and sedatives) statistically significant reductions in costs were demonstrated over the study periods. There was no significant change in the costs of the other four classes (vitamins, laxatives, nasal preparations and analgesics). Overall, inpatient expenditure for the hospital showed no significant change. The changes in cost demonstrated can be attributed to the Selected List and occurred despite the prior existence of a local formulary.

Parent Report of Antidepressant, Anxiolytic, and Antipsychotic Medication Use in Individuals with Williams Syndrome: Effectiveness and Adverse Effects

ERIC Educational Resources Information Center

Martens, Marilee A.; Seyfer, Daisha L.; Andridge, Rebecca R.; Foster, Jessica E. A.; Chowdhury, Monali; McClure, Kelsey E.; Coury, Daniel L.

2012-01-01

Williams syndrome (WS) is a neurodevelopmental genetic disorder characterized in part by anxiety and behavioral difficulties. We examine the effectiveness and adverse effects of antidepressant, anxiolytic, and antipsychotic medications in individuals with WS. A total of 513 parents/caregivers completed a survey of psychotropic medication usage…

Effects of traditionally used anxiolytic botanicals on enzymes of the gamma-aminobutyric acid (GABA) system.

PubMed

Awad, R; Levac, D; Cybulska, P; Merali, Z; Trudeau, V L; Arnason, J T

2007-09-01

In Canada, the use of botanical natural health products (NHPs) for anxiety disorders is on the rise, and a critical evaluation of their safety and efficacy is required. The purpose of this study was to determine whether commercially available botanicals directly affect the primary brain enzymes responsible for gamma-aminobutyric acid (GABA) metabolism. Anxiolytic plants may interact with either glutamic acid decarboxylase (GAD) or GABA transaminase (GABA-T) and ultimately influence brain GABA levels and neurotransmission. Two in vitro rat brain homogenate assays were developed to determine the inhibitory concentrations (IC50) of aqueous and ethanolic plant extracts. Approximately 70% of all extracts that were tested showed little or no inhibitory effect (IC50 values greater than 1 mg/mL) and are therefore unlikely to affect GABA metabolism as tested. The aqueous extract of Melissa officinalis (lemon balm) exhibited the greatest inhibition of GABA-T activity (IC50 = 0.35 mg/mL). Extracts from Centella asiatica (gotu kola) and Valeriana officinalis (valerian) stimulated GAD activity by over 40% at a dose of 1 mg/mL. On the other hand, both Matricaria recutita (German chamomile) and Humulus lupulus (hops) showed significant inhibition of GAD activity (0.11-0.65 mg/mL). Several of these species may therefore warrant further pharmacological investigation. The relation between enzyme activity and possible in vivo mode of action is discussed.

Antipsychotic profile of cannabidiol and rimonabant in an animal model of emotional context processing in schizophrenia.

PubMed

Levin, Raquel; Almeida, Valeria; Peres, Fernanda Fiel; Calzavara, Mariana Bendlin; da Silva, Neide Derci; Suiama, Mayra Akimi; Niigaki, Suzy Tamie; Zuardi, Antonio Waldo; Hallak, Jaime Eduardo Cecilio; Crippa, Jose Alexandre; Abílio, Vanessa Costhek

2012-01-01

Clinical and neurobiological findings suggest that cannabinoids and their receptors are implicated in schizophrenia. Cannabidiol (CBD), a non-psychotomimetic compound of the Cannabis sativa plant, has been reported to have central therapeutic actions, such as antipsychotic and anxiolytic effects. We have recently reported that spontaneously hypertensive rats (SHR) present a deficit in contextual fear conditioning (CFC) that is specifically ameliorated by antipsychotics and aggravated by proschizophrenia manipulations. These results led us to suggest that the CFC deficit presented by SHR could be used as a model to study emotional processing impairment in schizophrenia. The aim of this study is to evaluate the effects of CBD and rimonabant (CB1 receptor antagonist) on the contextual fear conditioning in SHR and Wistar rats (WR). Rats were submitted to CFC task after treatment with different doses of CBD (experiment 1) and rimonabant (experiment 2). In experiment 1, SHR showed a decreased freezing response when compared to WR that was attenuated by 1 mg/kg CBD. Moreover, all CBD-treated WR presented a decreased freezing response when compared to control rats. In experiment 2, SHR showed a decreased freezing response when compared to WR that was attenuated by 3 mg/kg rimonabant. Our results suggest a potential therapeutical effect of CBD and rimonabant to treat the emotional processing impairment presented in schizophrenia. In addition, our results reinforce the anxiolytic profile of CBD.

GABAergic modulation with classical benzodiazepines prevent stress-induced neuro-immune dysregulation and behavioral alterations.

PubMed

Ramirez, Karol; Niraula, Anzela; Sheridan, John F

2016-01-01

Psychosocial stress is associated with altered immunity, anxiety, and depression. Repeated social defeat (RSD), a model of social stress, triggers egress of inflammatory myeloid progenitor cells (MPCs; CD11b(+)/Ly6C(hi)) that traffic to the brain, promoting anxiety-like behavior. In parallel, RSD enhances neuroinflammatory signaling and long-lasting social avoidant behavior. Lorazepam and clonazepam are routinely prescribed anxiolytics that act by enhancing GABAergic activity in the brain. Besides binding to the central benzodiazepine binding site (CBBS) in the central nervous system (CNS), lorazepam binds to the translocator protein (TSPO) with high affinity causing immunomodulation. Clonazepam targets the CBBS and has low affinity for the TSPO. Here the aims were to determine if lorazepam and clonazepam would: (1) prevent stress-induced peripheral and central inflammatory responses, and (2) block anxiety and social avoidance behavior in mice subjected to RSD. C57/BL6 mice were divided into experimental groups, and treated with either lorazepam (0.10mg/kg), clonazepam (0.25mg/kg) or vehicle (0.9% NaCl). Behavioral data and tissues were collected the morning after the last cycle of RSD. Lorazepam and clonazepam were effective in attenuating mRNA expression of CRH in the hypothalamus and corticosterone in plasma in mice subjected to RSD. Both drugs blocked stress-induced levels of IL-6 in plasma. Lorazepam and clonazepam had different effects on stress-induced enhancement of myelopoiesis and inhibited trafficking of monocytes and granulocytes in circulation. Furthermore, lorazepam, but not clonazepam, inhibited splenomegaly and the production of pro-inflammatory cytokines in the spleen following RSD. Additionally, lorazepam and clonazepam, blocked stress-induced accumulation of macrophages (CD11b(+)/CD45(high)) in the CNS. In a similar manner, both lorazepam and clonazepam prevented neuroinflammatory signaling and reversed anxiety-like and depressive-like behavior in mice exposed to RSD. These data support the notion that lorazepam and clonazepam, aside from exerting anxiolytic and antidepressant effects, may have therapeutic potential as neuroimmunomodulators during psychosocial stress. The reversal of RSD-induced behavioral outcomes may be due to the enhancement of GABAergic neurotransmission, or some other off-target effect. The peripheral actions of lorazepam, but not clonazepam, seem to be mediated by TSPO activation. Copyright © 2015 Elsevier Inc. All rights reserved.

GABAergic modulation with classical benzodiazepines prevent stress-induced neuro-immune dysregulation and behavioral alterations

PubMed Central

Ramirez, Karol; Niraula, Anzela; Sheridan, John F.

2015-01-01

Objective Psychosocial stress is associated with altered immunity, anxiety, and depression. Repeated social defeat (RSD), a model of social stress, triggers egress of inflammatory myeloid progenitor cells (MPCs; CD11b+ /Ly6Chi) that traffic to the brain, promoting anxiety-like behavior. In parallel, RSD enhances neuroinflammatory signaling and long-lasting social avoidant behavior. Lorazepam and clonazepam are routinely prescribed anxiolytics that act by enhancing GABAergic activity in the brain. Besides binding to the central benzodiazepine binding site (CBBS) in the central nervous system (CNS), lorazepam binds to the translocator protein (TSPO) with high affinity causing immunomodulation. Clonazepam targets the CBBS and has low affinity for the TSPO. Here the aims were to determine if lorazepam and clonazepam would: 1) prevent stress-induced peripheral and central inflammatory responses, and 2) block anxiety and social avoidance behavior in mice subjected to RSD. Methods C57/BL6 mice were divided into experimental groups, and treated with either lorazepam (0.10mg/kg), clonazepam (0.25 mg/kg) or vehicle (0.9%NaCl). Behavioral data and tissues were collected the morning after the last cycle of RSD. Results Lorazepam and clonazepam were effective in attenuating mRNA expression of CRH in the hypothalamus and corticosterone in plasma in mice subjected to RSD. Both drugs blocked stress-induced levels of IL-6 in plasma. Lorazepam and clonazepam had different effects on stress-induced enhancement of myelopoiesis and inhibited trafficking of monocytes and granulocytes in circulation. Furthermore, lorazepam, but not clonazepam, inhibited splenomegaly and the production of pro-inflammatory cytokines in the spleen following RSD. Additionally, lorazepam and clonazepam, blocked stress-induced accumulation of macrophages (CD11b+/CD45high) in the CNS. In a similar manner, both lorazepam and clonazepam prevented neuroinflammatory signaling and reversed anxiety-like and depressive-like behavior in mice exposed to RSD. Conclusion These data support the notion that lorazepam and clonazepam, aside from exerting anxiolytic and antidepressant effects, may have therapeutic potential as neuroimmunomodulators during psychosocial stress. The reversal of RSD-induced behavioral outcomes may be due to the enhancement of GABAergic neurotransmission, or some other off-target effect. The peripheral actions of lorazepam, but not clonazepam, seem to be mediated by TSPO activation. PMID:26342944

Campania Region (Italy) spontaneous reporting system and preventability assessment through a case-by-case approach: a pilot study on psychotropic drugs.

PubMed

Sessa, Maurizio; Rafaniello, Concetta; Sportiello, Liberata; Mascolo, Annamaria; Scavone, Cristina; Maccariello, Alessandra; Iannaccone, Teresa; Fabrazzo, Michele; Berrino, Liberato; Rossi, Francesco; Capuano, Annalisa

2016-12-01

We conducted the first pilot Italian study to assess the preventability of adverse drug reactions involving psychotropic drugs reported through spontaneous reporting system from 01/07/2012 to 31/12/2014 in Campania Region. Preventability was assessed, case-by-case, using an adapted version of the P-method. The evaluation was performed only for those reports that had, as suspected drug, antipsychotics, mood stabilizers, antidepressants, anxiolytic and/or sedative-hypnotic. Eighty-one cases (19.2%) out of 421 reported during the study period were preventable. In seventy-seven (95.1%) out of 81 preventable cases, the underlying mechanism of the adverse drug reactions was dose-related, in four (4.9%) preventable cases the underlying mechanism of the adverse drug reactions was respectively susceptibility- (1; 1.2%), unknown- (1; 1.2%) and time-related (2; 2.5%). In the 81 preventable cases, 97 critical criteria were detected of which 29/97 (29.9%) related to healthcare professionals' practices, 0/97 (0.0%) to drug quality and 68/97 (70.1%) to patient behaviour. We proved that it was possible to apply and adapt the P-Method to assess the preventability of the adverse drug reactions involving psychotropic drugs, analysing individual case safety report sent through Campania Region spontaneous reporting system. Information acquired will be used to organize educational activities for both physicians and patients to promote a more appropriate drug use.

State/Trait Anxiety and Anxiolytic Effects of Acute Physical Exercises

ERIC Educational Resources Information Center

Guszkowska, Monika

2009-01-01

Study aim: To determine anxiolytic effects of acute physical exertions in relation to the initial anxiety state and trait in women. Material and methods: A group of 163 women aged 16-56 years, attending fitness clubs in Warsaw, participated in the study. They selected a single exercise to perform--strength, aerobic or mixed, lasting 30 to over 60…

Mental health and substance use among self-employed lawyers and pharmacists.

PubMed

Leignel, S; Schuster, J-P; Hoertel, N; Poulain, X; Limosin, F

2014-04-01

Self-employed workers experience occupational stress and may suffer from various mental health disorders. To assess the mental health, substance use and risk factors for psychological distress in a sample of self-employed lawyers and pharmacists. A cross-sectional study, using self-completion postal questionnaires, of lawyers and pharmacists. The General Health Questionnaire-28 (GHQ-28) was used as a measure of current mental health, and some additional questions evaluated alcohol, tobacco and psychotropic drug use and somatic morbidity. A multiple regression model was used to analyse the respective impact of the different risk factors on psychological suffering. A total of 1282 lawyers and 1153 pharmacists participated representing response rates of 36 and 35%, respectively. According to the GHQ-28 score, the rate of psychological distress was high in the sample overall, especially in lawyers (52 versus 47% in pharmacists, P < 0.05). According to the mean number of drinks per day, 16% of the lawyers and 13% of the pharmacists reported alcohol misuse, and lawyers were twice as likely as pharmacists to smoke (26 versus 13%, P < 0.001). Higher GHQ-28 scores were associated in lawyers with female gender, being widowed or divorced, smoking and using anxiolytic medication and in pharmacists with being younger, smoking, alcohol abuse and anxiolytic and hypnotic use. In our sample of these self-employed groups, both pharmacists and lawyers reported a high rate of psychological distress.

Behavioral consequences of predator stress in the rat elevated T-maze.

PubMed

Bulos, Erika Mondin; Pobbe, Roger Luis Henschel; Zangrossi, Helio

2015-07-01

Analyses of the behavioral reactions of rodents to predators have greatly contributed to the understanding of defense-related human psychopathologies such as anxiety and panic.We here investigated the behavioral consequences of exposing male Wistar rats to a live cat using the elevated T-maze test of anxiety. This test allows the measurement of two defensive responses: inhibitory avoidance and escape, which in terms of pathology have been associated with generalized anxiety and panic disorders, respectively. For comparative reasons, the effects of exposure to the cat were also assessed in the elevated plus-maze. The results showed that a 5-min exposure to the cat selectively facilitated inhibitory avoidance acquisition, an anxiogenic effect, without affecting escape expression in the elevated T-maze. This was seen immediately but not 30 min after contact with the predator. This short-lived anxiogenic effect was also detected in the elevated plus-maze. Previous administration of the benzodiazepine anxiolytic diazepam (2 mg/kg) decreased the immediate avoidance response to the predator and the neophobic reaction to a dummy cat used as a control stimulus. The drug also impaired inhibitory avoidance acquisition in the elevated T-maze, indicating an anxiolytic effect, without affecting escape performance. The results indicate that the state of anxiety evoked during contact with the predator generalizes to both elevated plus- and T-mazes, impacting on defensive responses associated with generalized anxiety disorder.

Acute and subchronic effects of Org 2305 and diazepam on psychomotor performance in man.

PubMed

Mattila, M J; Koski, J; Strömberg, C

1987-02-01

Three doses (15, 30 and 60 mg) of Org 2305 (O 15, O 30 and O 60 respectively), a novel anxiolytic drug chemically related to mianserin, were compared with placebo and 15 mg diazepam (DZ) on human psychomotor performance in a double-blind, cross-over study with 15 healthy volunteers. Objective measurements (choice reaction, tracking, flicker fusion, Maddox wing, digit symbol substitution, memory recall) and subjective assessments (visual analogue scales) were done at baseline and 2 and 13 h after the first dose. This testing procedure was repeated on day 7 when administering the seventh consecutive daily night-time dose. After the first dose O 15 did not differ from placebo and O 30 rarely differed from placebo. O 60 impaired various objective functions similarly to, or less than DZ. Subjectively, DZ and O 60 were felt as sedative. During subchronic treatment, DZ caused some impairment of baseline due to accumulation of bioassayable benzodiazepines, but significant responses to the last DZ dose were less than those to the first dose. DZ but not O 60 was reported to have caused lethargy and clumsiness during subchronic treatment. In the doses used Org 2305 impaired psychomotor performance less than diazepam did. A dose of 60 mg Org 2305 may offer some advantage over 15 mg diazepam, provided that their anxiolytic effects are about similar.

[Adaptations of psychotropic drugs in patients aged 75 years and older in a departement of geriatric internal medecine: report of 100 cases].

PubMed

Couderc, Anne-Laure; Bailly-Agaledes, Cindy; Camalet, Joëlle; Capriz-Ribière, Françoise; Gary, André; Robert, Philippe; Brocker, Patrice; Guérin, Olivier

2011-06-01

The elderly often with multiple diseases are particularly at risk from adverse drug reactions. Nearly half of iatrogenic drug in the elderly are preventable. Some medications such as psychotropic drugs are particularly involved in iatrogenic accidents. We wanted to know if the tools of the comprehensive geriatric assessment or other factors could influence the changes of psychotropic drugs in a geriatric departement. Our prospective study of four months in 100 patients aged 75 years and older hospitalized in the Geriatric Internal Medecine Departement of University Hospital of Nice investigated what were the clinical or biological reasons and tools used during changes of psychotropic drugs. We compared these changes according to the comprehensive geriatric assessment tools and we analyzed the changes based on lists of potentially inappropriate medications by Laroche et al. and from the instrument STOPP/START. The Mini Mental State Examination (MMSE) was the tool that has most influenced the changes in psychotropic including a tendency to increase and the introduction of anxiolytics when MMSE < 20 (p = 0.007) while neuroleptics instead arrested and decreased (p = 0.012). The comprehensive geriatric assessment has its place in decision support during the potentially iatrogenic prescriptions of drugs such as psychotropic and new tools such as STOPP/START can also be a help to the prescriber informed.

Contrasting effects of acute and chronic treatment with imipramine and fluoxetine on inhibitory avoidance and escape responses in mice exposed to the elevated T-maze.

PubMed

Gomes, Karina Santos; de Carvalho-Netto, Eduardo Ferreira; Monte, Kátia Cristina Da Silva; Acco, Bruno; Nogueira, Paulo José de Campos; Nunes-de-Souza, Ricardo Luiz

2009-03-30

The elevated T-maze (ETM) is an animal model of anxiety-like behavior that assesses two different defensive behavioral tasks in the same animal-acquisition of inhibitory avoidance and latency to escape from an open and elevated arm. In rats, cute and chronic treatments with anxiolytic-like drugs impair avoidance acquisition while only chronic administration of panicolytic-like drugs impairs open arm withdrawal. To date, only the acute effects of anxiolytic/anxiogenic or panicolytic/panicogenic drugs have been tested in the mouse ETM and the results have partially corroborated those found in the rat ETM. This study investigated the effects of acute (a single intraperitoneal injection 30 min before testing) and chronic (daily i.p. injections for 15 consecutive days) treatment with imipramine or fluoxetine, non-selective and selective serotonin reuptake inhibitors, respectively, on inhibitory avoidance and escape tasks in the mouse ETM. Neither acute nor chronic treatment with imipramine (0, 1, 5 or 10 mg/kg, i.p.) significantly changed the behavioral profile of mice in the two ETM tasks. Interestingly, while acute fluoxetine (0, 5, 10, 20 or 40 mg/kg, i.p.) facilitated inhibitory avoidance and impaired escape latency, chronic treatment (0, 5, 20 or 40 mg/kg, i.p.) with this selective serotonin reuptake inhibitor (SSRI) produced an opposite effect, i.e., it impaired inhibitory avoidance acquisition and facilitated open arm withdrawal. Importantly, acute or chronic treatment with imipramine (except at the highest dose that increased locomotion when given acutely) or fluoxetine failed to alter general locomotor activity in mice as assessed in an ETM in which all arms were enclosed by lateral walls (eETM). These results suggest that inhibitory avoidance acquisition is a useful task for the evaluation of acute and chronic effects of SSRI treatment on anxiety in mice. However, as open arm latency was actually increased and reduced by acute and chronic fluoxetine, respectively, this does not seem to be a useful measure of escape from a proximal threat in this species.

Comparative Analyses of Zebrafish Anxiety-Like Behavior Using Conflict-Based Novelty Tests.

PubMed

Kysil, Elana V; Meshalkina, Darya A; Frick, Erin E; Echevarria, David J; Rosemberg, Denis B; Maximino, Caio; Lima, Monica Gomes; Abreu, Murilo S; Giacomini, Ana C; Barcellos, Leonardo J G; Song, Cai; Kalueff, Allan V

2017-06-01

Modeling of stress and anxiety in adult zebrafish (Danio rerio) is increasingly utilized in neuroscience research and central nervous system (CNS) drug discovery. Representing the most commonly used zebrafish anxiety models, the novel tank test (NTT) focuses on zebrafish diving in response to potentially threatening stimuli, whereas the light-dark test (LDT) is based on fish scototaxis (innate preference for dark vs. bright areas). Here, we systematically evaluate the utility of these two tests, combining meta-analyses of published literature with comparative in vivo behavioral and whole-body endocrine (cortisol) testing. Overall, the NTT and LDT behaviors demonstrate a generally good cross-test correlation in vivo, whereas meta-analyses of published literature show that both tests have similar sensitivity to zebrafish anxiety-like states. Finally, NTT evokes higher levels of cortisol, likely representing a more stressful procedure than LDT. Collectively, our study reappraises NTT and LDT for studying anxiety-like states in zebrafish, and emphasizes their developing utility for neurobehavioral research. These findings can help optimize drug screening procedures by choosing more appropriate models for testing anxiolytic or anxiogenic drugs.

[Hospital pharmaceutical practice in prison].

PubMed

Harcouët, L

2010-09-01

Since 1994, hospital pharmaceutical teams have been in charge of pharmaceutical tasks in "unités de consultation et de soins ambulatoires" (UCSA), which are hospital consulting care units in French prisons. In 2008, pharmaceutical team in Parisian prisons received 6500 prescriptions and prepared 85,000 nominative bags containing drugs. Prisoners were 1.3% to receive treatments against HIV, 8.2% cardiovascular drugs, 7.2% opioid substitution treatments, and 52.9% psychoactive drugs, including 39.3% hypnotics, 40.5% anxiolytics, 11.3% antidepressants and 12.2% neuroleptics. In prison, the dichotomy between somatic and mental care is marked, attitudes of prisoners about their medicines are complex (important claims, embezzlement, etc.) and it is difficult for law defendants to maintain treatment confidentiality and to prepare prison outing in terms of health. To attenuate the heterogeneity of drug distribution systems in French prisons, we propose pharmaceutical analysis of prescriptions and nominative dispensation, computerization in UCSA in coordination with hospitals, a better contribution of prison medical and pharmaceutical staff in hospital "drug committees" and the redaction of pharmaceutical guidelines. Acting in concert with multidisciplinary medical staff in UCSA, pharmaceutical teams have to develop epidemiological studies to improve knowledge in prisoner's health and also prevention and health care in prison. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

Personnel-General: Army Substance Abuse Program Civilian Services

DTIC Science & Technology

2001-10-15

destroyed. Additional reproduction and distribution of completed records is prohibited. c. SECTION I. IDENTIFICATION. (1) Block I. Date of Report. Enter...AMPHETAMINE B BARBITUATES C COCAINE H HALLUCINOGENS (LSD) M METHAQUALONE, SEDATIVE, HYPNOTIC , OR ANXIOLYTIC O OPIATES P PHENCYCLIDINE (PCP) T CANNABIS...Table 5–6 Codes for TABLE F (T-DIAG-CODE) Code Rejection Reason 30390 ALCOHOL DEPENDENCE 30400 OPIOID DEPENDENCE 30410 SEDATIVE, HYPNOTIC , OR ANXIOLYTIC

Cyanide Suicide After Deep Web Shopping: A Case Report.

PubMed

Le Garff, Erwan; Delannoy, Yann; Mesli, Vadim; Allorge, Delphine; Hédouin, Valéry; Tournel, Gilles

2016-09-01

Cyanide is a product that is known for its use in industrial or laboratory processes, as well as for intentional intoxication. The toxicity of cyanide is well described in humans with rapid inhibition of cellular aerobic metabolism after ingestion or inhalation, leading to severe clinical effects that are frequently lethal. We report the case of a young white man found dead in a hotel room after self-poisoning with cyanide ordered in the deep Web. This case shows a probable complex suicide kit use including cyanide, as a lethal tool, and dextromethorphan, as a sedative and anxiolytic substance. This case is an original example of the emerging deep Web shopping in illegal drug procurement.

[Psychopharmacology in aviation and astronautics].

PubMed

Vasil'ev, P V; Glod, G D

1977-01-01

Flights aboard modern vehicles are associated with high nervous-emotional and physical stresses. This may induce depletion of reserve capabilities, development of fatigue and, consequently, reduction of work capacity of crewmembers. The paper discusses approaches and results of the use of drugs by pilots and cosmonauts in order to alleviate their fatigue and emotional stress. It gives indications and contraindications for the adminstration of stimulants and tranquilizers. On the basis of a comprehensive analysis of the literature data and their own findings, the authors draw the conclusion that the use of stimulants and anxiolytics may increase the level of reliability and performance of air- and spacecraft pilots during programmed and, particularly, contigent situations of the flight.

Room-temperature super-extraction system (RTSES) optimizes the anxiolytic- and antidepressant-like behavioural effects of traditional Xiao-Yao-San in mice

PubMed Central

2012-01-01

Background Xiao-Yao-San (XYS) is a Chinese medicinal formula for treating anxiety and depression. This study aims to evaluate the use of a room-temperature super-extraction system (RTSES) to extract the major active components of XYS and enhance their psycho-pharmacological effects. Methods The neuroprotective roles of XYS/RTSES against reserpine-derived neurotoxicity were evaluated using a glial cell injury system (in vitro) and a depression-like C57BL/6 J mouse model (in vivo). The anxiolytic-behavioural effects were measured by the elevated plus-maze (EPM) test and the antidepressant effects were evaluated by the forced swimming test (FST) and tail suspension test (TST). Glucose tolerance and insulin resistance were assayed by ELISA. The expression of 5-HT1A receptors in the prefrontal cortex was examined by western blotting. Results XYS/RTSES (300 μg/mL) diminished reserpine-induced glial cell death more effectively than either XYS (300 μg/mL) or fluoxetine (30 μM) at 24 h (P = 0.0481 and P = 0.054, respectively). Oral administration of XYS/RTSES (500 mg/kg/day) for 4 consecutive weeks significantly elevated the ratios of entries (open arms/closed arms; P = 0.0177) and shuttle activity (P = 0.00149) on the EPM test, and reduced the immobility time by 90% on the TST (P = 0.00000538) and FST (P = 0.0000053839). XYS/RTSES also improved the regulation of blood glucose (P = 0.0305) and increased the insulin sensitivity (P = 0.0093). The Western blot results indicated that the activation of cerebral 5-HT1A receptors may be involved in the mechanisms of XYS/RTSES actions. Conclusion The RTSES could provide a novel method for extracting effective anxiolytic- and antidepressant-like substances. XYS/RTSES improved the regulation of blood glucose and increased the insulin sensitivity in reserpine-induced anxiety and depression. Neuroprotection of glial cells and activation of cerebral 5-HT1A receptors were also involved. PMID:23134744

[Psychotropic medication use by French active self-employed workers].

PubMed

Ha-Vinh, Philippe; Régnard, Pierre; Sauze, Laurent

2011-04-01

INTERESTS OF THE STUDY: In the self-employed workers population (shop keepers, craft men, industrialists and liberal professions), psychotropic medications use and discrepancies between occupational situations have never been evaluated before. It is nevertheless a prerequisite in preventive actions against addictions, stress and injuries caused by disorders of attentiveness at work. The French Self Employed Workers Health Care Insurance Fund affiliate members data base was analysed for active workers from 18 to 60 years of age living in the Provence Alpes Côte d'Azur Region. From this population the cases were defined as having refunded ambulatory prescription of behind the counter psychotropic treatment during the year 2009 (anxiolytic, antidepressant, hypnotic, neuroleptic, lithium, alcoholic or opioid dependance therapy) and the randomised control sample was constituted by drawing the key of the social security number. A case-control multivariate logistic regression adjusted for gender, age and place of abode was used for searching discrepancy between occupational situations. Anxiolytic, antidepressant or hypnotic consumers are the most numerous (906; 557 and 446 consumers per 10 000 persons-year respectively). Antidepressant, neuroleptic and opioid dependance therapy are the three main posts of expense for the health insurance (584 505; 169 947 and 151 201 € per year respectively). When compared to workers of the construction sector, workers of retail trade of clothes had an Odd Ratio of 2,04 [95%CI 1,46-2,85] for anxiolytics consumption and 2,29 [95%CI 1,67-3,14] for antidepressants consumption, workers in the sector of the hotel and catering had an Odd Ratio of 1,62 [95%CI 1,19-2,22] for alcoholic dependance therapy medicines consumption, workers in the accountant, legal and financial sector had an Odd Ratio of 0,05 [95%CI 0,01-0,32] for opioid dependence therapy medicines consumption. Occupations associated with increased psychotropic medicines consumption are important to consider when assessing or fighting against psychotropic or addictive substance consumption, psychological stress and vigilance or attention perturbation at work. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

Acute anxiolytic effects of quetiapine during virtual reality exposure--a double-blind placebo-controlled trial in patients with specific phobia.

PubMed

Diemer, Julia; Domschke, Katharina; Mühlberger, Andreas; Winter, Bernward; Zavorotnyy, Maxim; Notzon, Swantje; Silling, Karen; Arolt, Volker; Zwanzger, Peter

2013-11-01

Anxiety disorders are among the most frequent psychiatric disorders. With regard to pharmacological treatment, antidepressants, the calcium modulator pregabalin and benzodiazepines are recommended according to current treatment guidelines. With regard to acute states of anxiety, so far practically only benzodiazepines provide an immediate anxiolytic effect. However, the risk of tolerance and dependency limits the use of this class of medication. Therefore, there is still a need for alternative pharmacologic strategies. Increasing evidence points towards anxiety-reducing properties of atypical antipsychotics, particularly quetiapine. Therefore, we aimed to evaluate the putative acute anxiolytic effects of this compound, choosing the induction of acute anxiety in patients with specific phobia as a model for the evaluation of ad-hoc anxiolytic properties in a proof-of-concept approach. In a randomized, double-blind, placebo-controlled study, 58 patients with arachnophobia were treated with a single dose of quetiapine XR or placebo prior to a virtual reality spider challenge procedure. Treatment effects were monitored using rating scales for acute anxiety as well as measurements of heart rate and skin conductance. Overall, quetiapine showed significant anxiolytic effects compared to placebo. However, effects were not seen on the primary outcome measure (VAS Anxiety), but were limited to somatic anxiety symptoms. Additionally, a significant reduction of skin conductance was observed. Further exploratory analyses hint towards a mediating role of the (COMT) val158met genotype on treatment response. The present results thus suggest a possible suitability of quetiapine in the acute treatment of anxiety, particularly with regard to somatic symptoms. Copyright © 2013 Elsevier B.V. and ECNP. All rights reserved.

Anti-anxiety activity of successive extracts of Angelica archangelica Linn. on the elevated T-maze and forced swimming tests in rats.

PubMed

Kumar, Dinesh; Bhat, Zulfiqar Ali; Shah, M Y

2012-09-01

Angelica archangelica Linn. is widely used in food and liquor preparations and also in Kashmiri folk medicine to reduce anxiety. We evaluated the anxiolytic effect of successive extracts of A. archangelica linn. (SAE) on rats tested in the elevated T-maze test (an animal model of generalized anxiety) at doses that exhibit antidepressant-like activity in humans. A. archangelica (1 kg) was subjected to successive extraction in a soxhlet apparatus with solvents [petroleum ether (40-60 degrees C), chloroform, ethyl acetate, methanol and decoction with water] in order of increasing polarity (yield: 6.9%, 7.3%, 5.1%, 11.88% and 8.2% w/w, respectively). SAE were evaluated for anxiolytic effects using the elevated T-maze and forced swimming tests in rats. Oral dosing of diazepam (1 mg/kg) and extracts (50, 100 and 200 mg/kg) clearly showed an anxiolytic-like profile in the elevated T-maze test: it increased one-way escape and decreased inhibitory avoidance on the first, third and seventh day. In the forced swimming test, imipramine and SAE showed antidepressant- and anxiolytic-like effects as reflected by increased climbing time, swimming time and decreased immobility time on the first, third and seventh day. Aqueous and methanol extracts showed the most, petroleum ether (40-60 degrees C) and chloroform intermediate, and ethyl acetate the least anxiolytic activity (*P<0.05, **P<0.01, ***P< 0.001) in both models. These results suggest the anti-anxiety activity of various extracts of A. archangelica and strongly justify its use in traditional Indian medicine for the treatment of anxiety.

Neuromotor tolerability and behavioural characterisation of cannabidiolic acid, a phytocannabinoid with therapeutic potential for anticipatory nausea.

PubMed

Brierley, Daniel I; Samuels, James; Duncan, Marnie; Whalley, Benjamin J; Williams, Claire M

2016-01-01

Anticipatory nausea (AN) is a poorly controlled side effect experienced by chemotherapy patients. Currently, pharmacotherapy is restricted to benzodiazepine anxiolytics, which have limited efficacy, have significant sedative effects and induce dependency. The non-psychoactive phytocannabinoid, cannabidiolic acid (CBDA), has shown considerable efficacy in pre-clinical AN models, however determination of its neuromotor tolerability profile is crucial to justify clinical investigation. Provisional evidence for appetite-stimulating properties also requires detailed investigation. This study aims to assess the tolerability of CBDA in locomotor activity, motor coordination and muscular strength tests, and additionally for ability to modulate feeding behaviours. Male Lister Hooded rats administered CBDA (0.05-5 mg/kg; p.o.) were assessed in habituated open field (for locomotor activity), static beam and grip strength tests. A further study investigated whether these CBDA doses modulated normal feeding behaviour. Finally, evidence of anxiolytic-like effects in the habituated open field prompted testing of 5 mg/kg CBDA for anxiolytic-like activity in unhabituated open field, light/dark box and novelty-suppressed feeding (NSF) tests. CBDA had no adverse effects upon performance in any neuromotor tolerability test, however anxiolytic-like behaviour was observed in the habituated open field. Normal feeding behaviours were unaffected by any dose. CBDA (5 mg/kg) abolished the increased feeding latency in the NSF test induced by the 5-HT1AR antagonist, WAY-100,635, indicative of anxiolytic-like effects, but had no effect on anxiety-like behaviour in the novel open field or light/dark box. CBDA is very well tolerated and devoid of the sedative side effect profile of benzodiazepines, justifying its clinical investigation as a novel AN treatment.

Dipeptidyl-peptidase IV (DPP-IV) inhibitor delays tolerance to anxiolytic effect of ethanol and withdrawal-induced anxiety in rats.

PubMed

Sharma, Ajaykumar N; Pise, Ashish; Sharma, Jay N; Shukla, Praveen

2015-06-01

Dipeptidyl-peptidase IV (DPP-IV) is an enzyme responsible for the metabolism of endogenous gut-derived hormone, glucagon-like peptide-1 (GLP-1). DPP-IV is known for its role in energy homeostasis and pharmacological blockade of this enzyme is a recently approved clinical strategy for the management of type II diabetes. Accumulating evidences suggest that enzyme DPP-IV can affect spectrum of central nervous system (CNS) functions. However, little is known about the role of this enzyme in ethanol-mediated neurobehavioral complications. The objective of the present study was to examine the impact of DPP-IV inhibitor, sitagliptin on the development of tolerance to anxiolytic effect of ethanol and anxiety associated with ethanol withdrawal in rats. A dose-response study revealed that sitaglitpin (20 mg/kg, p.o.) per se exhibit anxiolytic effect in the elevated plus maze (EPM) test in rats. Tolerance to anxiolytic effect of ethanol (2 g/kg, i.p.; 8 % w/v) was observed from 7(th) day of ethanol-diet (6 % v/v) consumption. In contrast, tolerance to anxiolytic effect of ethanol was delayed in rats that were treated daily with sitagliptin (20 mg/kg, p.o.) as tolerance was observed from 13(th)day since commencement of ethanol-diet consumption. Discontinuation of rats from ethanol-diet after 15-days of ethanol consumption resulted in withdrawal anxiety between 8 h and 12 h post-abstinence. However, rats on 15-day ethanol-diet with concomitant sitagliptin (20 mg/kg, p.o.) treatment exhibited delay in appearance (24 h post-withdrawal) of withdrawal anxiety. In summary, DPP-IV inhibitors may prove as an attractive research strategy against ethanol tolerance and dependence.

Effect of prior foot shock stress and Δ9-tetrahydrocannabinol, cannabidiolic acid, and cannabidiol on anxiety-like responding in the light-dark emergence test in rats.

PubMed

Rock, Erin M; Limebeer, Cheryl L; Petrie, Gavin N; Williams, Lauren A; Mechoulam, Raphael; Parker, Linda A

2017-07-01

Cannabis is commonly used by humans to relieve stress. Here, we evaluate the potential of intraperitoneally (i.p.) administered Δ 9 -tetrahydrocannabiol (THC) and cannabidiolic acid (CBDA, the precursor of cannabidiol [CBD]) to produce dose-dependent effects on anxiety-like responding in the light-dark (LD) emergence test of anxiety-like responding in rats, when administered acutely or chronically (21 days). As well, we evaluate the potential of THC, CBDA, and CBD to reduce anxiogenic responding produced by foot shock (FS) stress 24 h prior to the LD test. In the absence of the explicit FS stressor, THC (1 and 10 mg/kg) produced anxiogenic-like responding when administered acutely or chronically, but CBDA produced neither anxiogenic- nor anxiolytic-like responding. Administration of FS stress 24 h prior to the LD test enhanced anxiogenic-like responding (reduced time spent and increased latency to enter the light compartment) in rats pretreated with either vehicle (VEH) or THC (1 mg/kg); however, administration of CBDA (0.1-100 μg/kg) or CBD (5 mg/kg) prevented the FS-induced anxiogenic-like responding (an anxiolytic-like effect). The 5-hydroxytryptamine 1A (5-HT 1A ) receptor antagonist, WAY100635, reversed CBDA's anxiolytic effect (1 μg/kg). Combining an anxiolytic dose of CBDA (1 μg/kg) or CBD (5 mg/kg) with an anxiogenic dose of THC (1 mg/kg) did not modify THC's anxiogenic effect. These results suggest the anxiolytic effects of CBDA and CBD may require the presence of a specific stressor.

Effects of cholinergic system of dorsal hippocampus of rats on MK-801 induced anxiolytic-like behavior.

PubMed

Zarrindast, Mohammad Reza; Nasehi, Mohammad; Piri, Morteza; Heidari, Negar

2011-11-14

Some investigations have shown that the glutamate receptors play a critical role in cognitive processes such as learning and anxiety. The possible involvement of the cholinergic system of the dorsal hippocampus in the anxiolytic-like response induced by MK-801, NMDA receptor antagonist, was investigated in the present study. Male Wistar rats were used in the elevated plus maze apparatus to test the parameters: open arm time (%OAT), open arm entries (%OAE), close arm time (%CAT), close arm entries (%CAE) and other exploratory behaviors (locomotor activity, grooming, rearing and defecation) of anxiety-like response. The data indicated that intra-CA1 administration of MK-801 increased %OAT (2μg/rat) and %OAE (1 and 2μg/rat) while decreased %CAT and %CAE and did not alter other exploratory behaviors, indicating an anxiolytic-like effect. Moreover, intra-hippocampal injections of mecamylamine, a cholinergic receptor antagonists (2μg/rat) and scopolamine (4μg/rat), by themselves, 5min before testing, increased %OAT and %OAE but decreased %CAT and %CAE and did not alter locomotor activity and other exploratory behaviors, suggesting an anxiolytic-like effect. On the other hand, intra-CA1 co-administration of an ineffective dose of scopolamine (3μg/rat), but not mecamylamine (1μg/rat), with an ineffective dose of MK-801 (0.5μg/rat) increased %OAT and %OAE and decreased %CAT and %CAE. The data may indicate the possible involvement of the cholinergic system of the CA1 in the anxiolytic-like response induced by MK-801. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Pharmaceutical services in a Mexican pain relief and palliative care institute

PubMed Central

Escutia Gutiérrez, Raymundo; Cortéz Álvarez, César R.; Álvarez Álvarez, Rosa M.; Flores Hernández, Jorge LV.; Gutiérrez Godínez, Jéssica; López Y López, José G.

Neither the purchase nor the distribution of pharmaceuticals in hospitals and community pharmacies in Mexico is under the care of pharmacists. Some are under control of physicians. This report presents the results of the implementation of somef pharmaceutical services for the Jalisco Pain Relief, and Palliative Care Institute (Palia Institute), under the direction of the Secretary of Health, Government of Jalisco. The services implemented were drug distribution system, Drug Information Service, Pharmacovigilance Program, and home pharmacotherapy follow-up pilot program for patients with advanced illness, with the ultimate using the appropriate medication. The drug distribution system included dispensing of opioid pain medications, antidepressants, anticonvulsants, NSAIDs, anxiolytic drugs, steroid drugs, laxatives, and anti-emetics. The frequently used drugs were morphine sulfate (62%), amitriptyline (6.4%), and dextropropoxyphene (5.8%). The Drug Information Service answered 114 consultations, mainly asked by a physician (71%) concerned with adverse drug reactions and contraindications (21%). The pharmacovigilance program identified 146 suspected adverse drug reactions and classified them reasonably as possible (27%), probable (69%), and certain (4%). These were attributed mainly to pregabalin and tramadol. The home pharmacotherapy follow-up pilot program cared patients with different cancer diagnoses and drug-related problems (DRP), which were identified and classified (according to second Granada Consensus) for pharmaceutical intervention as DRP 1 (5%), DRP 2 (10%), DRP 3 (14%), DRP 4 (19%), DRP 5 (24%), or DRP 6 (28%). This report provides information concerning the accurate use of medication and, above all, an opportunity for Mexican pharmacists to become an part of health teams seeking to resolve drug-related problems. PMID:25170355

Working conditions and psychotropic drug use: cross-sectional and prospective results from the French national SIP study.

PubMed

Lassalle, Marion; Chastang, Jean-François; Niedhammer, Isabelle

2015-04-01

Prospective studies exploring the associations between a large range of occupational factors and psychotropic drug use among national samples of workers are seldom. This study investigates the cross-sectional and prospective associations between occupational factors, including a large set of psychosocial work factors, and psychotropic drug use in the national French working population. The study sample comprised 7542 workers for the cross-sectional analysis and 4213 workers followed up for a 4-year period for the prospective analysis. Psychotropic drug use was measured within the last 12 months and defined by the use of antidepressants, anxiolytics or hypnotics. Three groups of occupational factors were explored: classical and emergent psychosocial work factors, working time/hours and physical work exposures. Weighted Poisson regression analyses were performed to adjust for covariates. In the cross-sectional analysis, psychological demands, low social support and hiding emotions were associated with psychotropic drug use. Job insecurity for men and night work for women were associated with psychotropic drug use. In the prospective analysis, hiding emotions and physical exposure were predictive of psychotropic drug use. Dose-response associations were observed for the frequency/intensity of exposure and repeated exposure to occupational factors. This study underlines the role of psychosocial work factors, including emergent factors, in psychotropic drug use. Prevention policies oriented toward psychosocial work factors comprehensively may be useful to reduce this use. Copyright © 2015 Elsevier Ltd. All rights reserved.

Caffeine prevents high-intensity exercise-induced increase in enzymatic antioxidant and Na+-K+-ATPase activities and reduction of anxiolytic like-behaviour in rats.

PubMed

Vieira, Juliano M; Carvalho, Fabiano B; Gutierres, Jessié M; Soares, Mayara S P; Oliveira, Pathise S; Rubin, Maribel A; Morsch, Vera M; Schetinger, Maria Rosa; Spanevello, Roselia M

2017-11-01

Here we investigated the impact of chronic high-intensity interval training (HIIT) and caffeine consumption on the activities of Na + -K + -ATPase and enzymes of the antioxidant system, as well as anxiolytic-like behaviour in the rat brain. Animals were divided into groups: control, caffeine (4 mg/kg), caffeine (8 mg/kg), HIIT, HIIT plus caffeine (4 mg/kg) and HIIT plus caffeine (8 mg/kg). Rats were trained three times per week for 6 weeks, and caffeine was administered 30 minutes before training. We assessed the anxiolytic-like behaviour, Na + -K + -ATPase, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities, levels of reduced glutathione (GSH) and thiobarbituric acid reactive substances (TBARS) in the brain. HIIT-induced anxiolytic-like behaviour increased Na + -K + -ATPase and GPx activities and TBARS levels, altered the activities of SOD and CAT in different brain regions, and decreased GSH levels. Caffeine, however, elicited anxiogenic-like behaviour and blocked HIIT effects. The combination of caffeine and HIIT prevented the increase in SOD activity in the cerebral cortex and GPx activity in three brain regions. Our results show that caffeine promoted anxiogenic behaviour and prevented HIIT-induced changes in the antioxidant system and Na + -K + -ATPase activities.

Anxiolytic effects of the aqueous extract of Uncaria rhynchophylla.

PubMed

Jung, Ji Wook; Ahn, Nam Yoon; Oh, Hye Rim; Lee, Bo Kyung; Lee, Kang Jin; Kim, Sun Yeou; Cheong, Jae Hoon; Ryu, Jong Hoon

2006-11-24

The purpose of this study was to characterize the putative anxiolytic-like effects of the aqueous extract of hooks with stem of Uncaria rhynchophylla using the elevated plus maze (EPM) and the hole-board apparatus in rats and mice. Control rats were treated with an equal volume of saline, and positive control rats with buspirone (1 mg/kg). Single or repeated treatments of the aqueous extract of Uncaria rhynchophylla (200 mg/kg/day, p.o.) for 7 days significantly increased the time-spent and entries into open arms of the EPM, and reduced the time-spent and entries into the closed arms versus saline controls (P<0.05). However, no changes in spontaneous locomotor activity or myorelaxant effects were observed versus saline controls. In the hole-board test, repeated treatment with the aqueous extract of Uncaria rhynchophylla (100 or 200 mg/kg/day, p.o.) significantly increased the number of head-dips (P<0.05). In addition, the anxiolytic-like effects of Uncaria rhynchophylla extract as assessed using the EPM test were abolished by WAY 100635 (0.3 mg/kg, i.p.), a 5-HT(1A) receptor antagonist. These results suggest that Uncaria rhynchophylla is an effective anxiolytic agent, and acts via the serotonergic nervous system.

Pharmacological characterization of stress-induced hyperthermia in DBA/2 mice using metabotropic and ionotropic glutamate receptor ligands.

PubMed

Rorick-Kehn, Linda M; Hart, John C; McKinzie, David L

2005-12-01

Accumulating evidence suggests that drugs acting on the glutamatergic system may represent promising novel therapeutic targets for the treatment of anxiety disorders. The stress-induced hyperthermia paradigm has been used widely to model some of the physiological symptoms associated with anxiety disorders and has produced results that are predictive of clinical efficacy. We have modified this paradigm to measure the autonomic consequences of stress induced by the fear of predation in mice. To evaluate the efficacy of several classes of metabotropic and ionotropic glutamate receptor ligands, as well as known anxiolytics and psychotropic comparators, in attenuating predatory-stress-induced hyperthermia. Male DBA/2 mice were implanted with radiotelemetric transmitters in the peritoneal cavity to measure stress-related increases in core body temperature, following placement in a novel cage containing soiled rat shavings. Clinically active compounds such as chlordiazepoxide (5-10 mg/kg), alprazolam (0.3-3 mg/kg), and buspirone (10-30 mg/kg) exhibited an anxiolytic profile. Assessment of glutamatergic agents indicated that the mGlu1 receptor antagonist LY456236 (10-30 mg/kg), mGlu5 receptor antagonist MPEP (10-30 mg/kg), mGlu2/3 receptor agonist LY354740 (3-10 mg/kg), mGlu2 receptor potentiator LY566332 (30 and 100 mg/kg), mGlu8 receptor agonist (S)-3,4-dicarboxyphenylglycine (30-60 mg/kg), competitive NMDA receptor antagonist LY235959 (1 mg/kg), AMPA receptor antagonist GYKI-52466 (10-20 mg/kg), and glycine transporter-1 (GlyT-1) inhibitor ALX-5407 (3-10 mg/kg) dose-dependently attenuated stress-induced hyperthermia. The AMPA receptor potentiator LY451646, iGlu5 kainate receptor antagonist LY382884, glycine(B) receptor partial agonist D: -cycloserine, and GlyT-1 inhibitor ORG-24461 were ineffective in this model. Select metabotropic and ionotropic glutamate receptor ligands exhibited an anxiolytic profile, as measured by the attenuation of stress-induced hyperthermia, and may represent viable targets for the development of pharmacological treatments for anxiety-related disorders.

Anxiolytic effects of buspirone and MTEP in the Porsolt Forced Swim Test.

PubMed

Lee, Kaziya M; Coelho, Michal A; Sern, Kimberly R; Class, MacKayla A; Bocz, Mark D; Szumlinski, Karen K

2017-01-01

Traditionally, a reduction in floating behavior or immobility in the Porsolt forced swim test (FST) is employed as a predictor of antidepressant efficacy. However, over the past several years, our studies of alcohol withdrawal-induced negative affect consistently indicate the coincidence of increased anxiety-related behaviors on various behavioral tests with reduced immobility in the FST. Further, this behavioral profile correlates with increased mGlu5 protein expression within limbic brain regions. As the role for mGlu5 in anxiety is well established, we hypothesized that the reduced immobility exhibited by alcohol-withdrawn mice when tested in the FST might reflect anxiety, possibly a hyper-reactivity to the acute swim stressor. Herein, we evaluated whether or not the decreased FST immobility during alcohol withdrawal responds to systemic treatment with a behaviorally-effective dose of the prototypical anxiolytic, buspirone (5 mg/kg). We also determined the functional relevance of the withdrawal-induced increase in mGlu5 expression for FST behavior by comparing the effects of buspirone to a behaviorally effective dose of the mGlu5 negative allosteric modulator MTEP (3 mg/kg). Adult male C57BL/6J mice were subjected to a 14-day, multi-bottle, binge-drinking protocol that elicits hyper-anxiety and increases glutamate-related protein expression during early withdrawal. Control animals received only water. At 24hr withdrawal, animals from each drinking condition were subdivided into groups and treated with an IP injection of buspirone, MTEP, or vehicle, 30min prior to the FST. Drug effects on general locomotor activity were also assessed. As we reported previously, alcohol-withdrawn animals exhibited significantly reduced immobility in the FST compared to water controls. Both buspirone and MTEP significantly increased immobility in alcohol-withdrawn animals, with a modest increase also seen in water controls. No significant group differences were observed for locomotor activity, indicating that neither anxiolytic was sedating. These results provide predictive validity for increased swimming/reduced immobility in the FST as a model of anxiety and provide novel evidence in favor of mGlu5 inhibition as an effective therapeutic strategy for treating hyperanxiety during alcohol withdrawal.

NOVEL POSITIVE ALLOSTERIC MODULATORS OF GABAA RECEPTORS: DO SUBTLE DIFFERENCES IN ACTIVITY AT α1 PLUS α5 VERSUS α2 PLUS α3 SUBUNITS ACCOUNT FOR DISSIMILARITIES IN BEHAVIORAL EFFECTS IN RATS?

PubMed Central

Savić, Miroslav M.; Majumder, Samarpan; Huang, Shengming; Edwankar, Rahul V.; Furtmüller, Roman; Joksimović, Srđan; Clayton, Terry; Ramerstorfer, Joachim; Milinković, Marija M.; Roth, Bryan L.; Sieghart, Werner; Cook, James M.

2010-01-01

Over the last years, genetic studies have greatly improved our knowledge on the receptor subtypes mediating various pharmacological effects of positive allosteric modulators at GABAA receptors. This stimulated the development of new benzodiazepine (BZ)-like ligands, especially those inactive/low-active at GABAA receptors containing the α1 subunit, with the aim of generating more selective drugs. Hereby, the affinity and efficacy of four recently-synthesized BZ site ligands: SH-053-2’N, SH-053-S-CH3-2’F, SH-053-R-CH3-2’F and JY-XHe-053 were assessed. They were also studied in behavioral tests of spontaneous locomotor activity, elevated plus maze, and water maze in rats, which are considered predictive of, respectively, the sedative, anxiolytic, and amnesic influence of BZs. The novel ligands had moderately low to low affinity and mild to partial agonistic efficacy at GABAA receptors containing the α1 subunit, with variable, but more pronounced efficacy at other BZ-sensitive binding sites. While presumably α1 receptor-mediated sedative effects of GABAA modulation were not fully eliminated with any of the ligands tested, only SH-053-2’N and SH-053-S-CH3-2’F, both dosed at 30 mg/kg, exerted anxiolytic effects. The lack of clear anxiolytic-like activity of JY-XHe-053, despite its efficacy at α2- and α3-GABAA receptors, may have been partly connected with its preferential affinity at α5-GABAA receptors coupled with weak agonist activity at α1-containing subtypes. The memory impairment in water-maze experiments, generally reported with BZ site agonists, was completely circumvented with all four ligands. The results suggest that a substantial amount of activity at α1 GABAA receptors is needed for effecting spatial learning and memory impairments, while much weaker activity at α1- and α5-GABAA receptors is sufficient for eliciting sedation. PMID:20074611

Psychotropic and Opioid Medication Use in Older Patients With Breast Cancer Across the Care Trajectory: A Population-Based Cohort Study.

PubMed

Syrowatka, Ania; Chang, Sue-Ling; Tamblyn, Robyn; Mayo, Nancy E; Meguerditchian, Ari N

2016-11-01

Older patients with breast cancer represent a vulnerable population at higher risk of experiencing distress and pain, as well as medication-related adverse events from pharmacological treatment of these symptoms. The purpose of this study is to estimate the prevalence of psychotropic (anxiolytic, antidepressant, and antipsychotic) and opioid medication use by older women diagnosed with breast cancer. This population-based cohort study followed 19,353 women older than 65 years diagnosed with incident, nonmetastatic breast cancer in Quebec, Canada. Data were obtained from provincial, universal health and drug insurance plans covering all medical and pharmaceutical care. Descriptive statistics were calculated for demographic information, breast cancer characteristics, and treatments. Psychotropic and opioid medication use was assessed across the care trajectory: precancer baseline, active care, and first-year survivorship. There was a marked increase in the prevalence of medication use from precancer baseline to active care, followed by a decrease into first-year survivorship. Anxiolytics were used most often across the care trajectory (36.3%, 50.6%, and 44.4% at baseline, active care, and survivorship, respectively). In contrast, antipsychotic and opioid medications were sought primarily during active care (4.5- and 7-fold increases from baseline, respectively), with opioid use during active care increasing dramatically over the study period (9.0% to 40.9% from 1998 to 2010). Unlike other drugs, antidepressant use peaked in active care but persisted into survivorship (14.7%, 22.4%, and 22.3% at baseline, active care, and survivorship, respectively). A substantial proportion of older patients with breast cancer use psychotropic and opioid medications. The different patterns of medication use represent distress and pain experienced by patients across the care trajectory. Given that medication use in this vulnerable population is associated with an increased risk of adverse events, a multidimensional approach integrating psychological interventions in cancer care may better address psychosocial needs of older patients with breast cancer. Copyright © 2016 by the National Comprehensive Cancer Network.

Towards a more practical attention bias test to assess affective state in sheep

PubMed Central

Doyle, Rebecca E.; Colditz, Ian G.; Belson, Sue; Cronin, Greg M.; Lee, Caroline

2018-01-01

Tests for attention bias potentially offer more rapid assessment of affective state in animals than existing cognitive methods. An attention bias test has previously been developed for sheep and validated as a measure of anxious states. The 3 minute test assessed behavioural responses of sheep in an enclosed arena after brief exposure to the threat of a dog. Experiment 1 of the current study aimed to refine the previously developed method, removing the need for a habituation period and shortening the test duration. Sheep were given either an anxiolytic drug, an anxiogenic drug or a control treatment prior to testing to induce contrasting affective states. Differences in behaviour were found between the treatment groups within the first 45s of the test, indicating the original test duration could be shortened from 180 s. During testing, 36 of 40 animals in the control and anxiolytic groups ate the novel feed offered in the test, indicating it is not necessary to habituate animals to a feed container. Experiment 2 aimed to confirm the responses measured in the test were primarily towards the dog rather than other aspects of the test environment. Sheep exposed to an empty window at the beginning of the test behaved differently to those which were exposed to a dog, indicating sheep behaviour in the test is at least partially a response to the dog. A third group of sheep were also tested with the dog immediately after having small data loggers attached to their necks. Behaviour of these sheep did not differ from the sheep tested without loggers, indicating data logger attachment did not impact their behaviour in the test. In both experiments, treatments did not appear to modify activity (zones crossed), which we propose indicates the test was primarily detecting valence of the affective state rather than arousal. PMID:29293636

Cellular and behavioural profile of the novel, selective neurokinin1 receptor antagonist, vestipitant: a comparison to other agents.

PubMed

Brocco, Mauricette; Dekeyne, Anne; Mannoury la Cour, Clotilde; Touzard, Manuelle; Girardon, Sylvie; Veiga, Sylvie; de Nanteuil, Guillaume; deJong, Trynke R; Olivier, Berend; Millan, Mark J

2008-10-01

This study characterized the novel neurokinin (NK)(1) antagonist, vestipitant, under clinical evaluation for treatment of anxiety and depression. Vestipitant possessed high affinity for human NK(1) receptors (pK(i), 9.4), and potently blocked Substance P-mediated phosphorylation of Extracellular-Regulated-Kinase. In vivo, it occupied central NK(1) receptors in gerbils (Inhibitory Dose(50), 0.11 mg/kg). At similar doses, it abrogated nociception elicited by formalin in gerbils, and blocked foot-tapping and locomotion elicited by the NK(1) agonist, GR73632, in gerbils and guinea pigs, respectively. Further, vestipitant attenuated fear-induced foot-tapping in gerbils, separation-induced distress-vocalizations in guinea pigs, marble-burying behaviour in mice, and displayed anxiolytic actions in Vogel conflict and fear-induced ultrasonic vocalization procedures in rats. These actions were mimicked by CP99,994, L733,060 and GR205,171 which acted stereoselectively vs its less active isomer, GR226,206. In conclusion, vestipitant is a potent NK(1) receptor antagonist: its actions support the utility of NK(1) receptor blockade in the alleviation of anxiety and, possibly, depression.

Anxiolytic-like effects of oleamide in group-housed and socially isolated mice.

PubMed

Wei, Xiu Yan; Yang, Jing Yu; Dong, Ying Xu; Wu, Chun Fu

2007-08-15

Oleamide (cis-9,10-octadecenoamide) is an endogenous sleep-inducing lipid and prototypic member of a new class of biological signaling molecules identified in recent years. In the present study, the anxiolytic-like effect of oleamide was studied in several experimental models of anxiety in group-housed and socially isolated mice. As the results show, socially isolated mice exhibited an anxiogenic-like profile in the elevated plus-maze test, the light/dark test, and the hole-board test, which could be significantly reversed by oleamide (10 or 20 mg/kg, i.p.). Moreover, oleamide significantly reduced the anxiety levels in grouped-housed mice. In the isolation-induced aggressive test, oleamide markedly reduced the attacking duration and increased the attacking latency. It is concluded that oleamide has an anxiolytic-like effect in socially isolated or group-housed mice, which suggests that fatty acid amides might be involved in the regulation of anxiety-related behavior in mice.

Antidepressant-like and anxiolytic-like effects of cannabidiol: a chemical compound of Cannabis sativa.

PubMed

de Mello Schier, Alexandre R; de Oliveira Ribeiro, Natalia P; Coutinho, Danielle S; Machado, Sergio; Arias-Carrión, Oscar; Crippa, Jose A; Zuardi, Antonio W; Nardi, Antonio E; Silva, Adriana C

2014-01-01

Anxiety and depression are pathologies that affect human beings in many aspects of life, including social life, productivity and health. Cannabidiol (CBD) is a constituent non-psychotomimetic of Cannabis sativa with great psychiatric potential, including uses as an antidepressant-like and anxiolytic-like compound. The aim of this study is to review studies of animal models using CBD as an anxiolytic-like and antidepressant-like compound. Studies involving animal models, performing a variety of experiments on the above-mentioned disorders, such as the forced swimming test (FST), elevated plus maze (EPM) and Vogel conflict test (VCT), suggest that CBD exhibited an anti-anxiety and antidepressant effects in animal models discussed. Experiments with CBD demonstrated non-activation of neuroreceptors CB1 and CB2. Most of the studies demonstrated a good interaction between CBD and the 5-HT1A neuro-receptor.

Consistency of psychotropic drug-drug interactions listed in drug monographs.

PubMed

Liu, Xinyue; Hatton, Randy C; Zhu, Yanmin; Hincapie-Castillo, Juan M; Bussing, Regina; Barnicoat, Marie; Winterstein, Almut G

With an increasing prevalence of psychotropic polypharmacy, clinicians depend on drug-drug interaction (DDI) references to ensure safe regimens, but the consistency of such information is frequently questioned. To evaluate the consistency of psychotropic DDIs documented in Clinical Pharmacology (CP), Micromedex (MM), and Lexicomp (LC) and summarize consistent psychotropic DDIs. In May 2016, we extracted severe or major psychotropic DDIs for 102 psychotropic drugs, including central nervous system (CNS) stimulants, antidepressants, an antimanic agent (lithium), antipsychotics, anticonvulsants, and anxiolytics-sedatives-hypnotics from CP, MM, and LC. We then summarized the psychotropic DDIs that were included in all 3 references and with evidence quality of "excellent" or "good" based on MM. We identified 1496, 938, and 1006 unique severe or major psychotropic DDIs from CP, MM, and LC, respectively. Common adverse effects related to psychotropic DDIs include increased or decreased effectiveness, CNS depression, neurotoxicity, QT prolongation, serotonin syndrome, and multiple adverse effects. Among these interactions, only 371 psychotropic DDIs were documented in all 3 references, 59 of which had "excellent" or "good" quality of evidence based on MM. The consistency of psychotropic DDI documentation across CP, MM, and LC is poor. DDI documentations need standards that would encourage consistency among drug information references. The list of the 59 DDIs may be useful in the assessment of psychotropic polypharmacy and highlighting DDI alerts in clinical practice. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

The natural products magnolol and honokiol are positive allosteric modulators of both synaptic and extra-synaptic GABAA receptors

PubMed Central

Alexeev, Mikhail; Grosenbaugh, Denise K.; Mott, David D.; Fisher, Janet L.

2012-01-01

The National Center for Complementary and Alternative Medicine (NCCAM) estimates that nearly 40% of adults in the United States use alternative medicines, often in the form of an herbal supplement. Extracts from the tree bark of magnolia species have been used for centuries in traditional Chinese and Japanese medicines to treat a variety of neurological diseases, including anxiety, depression, and seizures. The active ingredients in the extracts have been identified as the bi-phenolic isomers magnolol and honokiol. These compounds were shown to enhance the activity of GABAA receptors, consistent with their biological effects. The GABAA receptors exhibit substantial subunit heterogeneity, which influences both their functional and pharmacological properties. We examined the activity of magnolol and honokiol at different populations of both neuronal and recombinant GABAA receptors to characterize their mechanism of action and to determine whether sensitivity to modulation was dependent upon the receptor’s subunit composition. We found that magnolol and honokiol enhanced both phasic and tonic GABAergic neurotransmission in hippocampal dentate granule neurons. In addition, all recombinant receptors examined were sensitive to modulation, regardless of the identity of the α, β, or γ subunit subtype, although the compounds showed particularly high efficacy at δ-containing receptors. This direct positive modulation of both synaptic and extra-synaptic populations of GABAA receptors suggests that supplements containing magnolol and/or honokiol would be effective anxiolytics, sedatives, and anti-convulsants. However, significant side-effects and risk of drug interactions would also be expected. PMID:22445602

Serotonin and stress: protective or malevolent actions in the biobehavioral response to repeated trauma?

PubMed

Harvey, Brian H; Naciti, Carla; Brand, Linda; Stein, Dan J

2004-12-01

Structural hippocampus and prefrontal cortex changes occur in patients with posttraumatic stress disorder (PTSD) that appears correlated with cognitive dysfunction. In these brain regions, serotonin (5HT) plays a prominent role in symptom presentation and treatment of PTSD. However, 5HT is both anxiogenic and anxiolytic, and while 5HT reuptake inhibitors are effective in treatment, the role of 5HT in the development of PTSD remains uncertain. Using a model of repeated trauma in rats, we observed significant spatial memory impairment together with significantly increased 5HT(1A) receptor density (B(max)), decreased 5HT(1A) receptor affinity (K(d)), and significantly increased 5HT(2A) receptor affinity on day 7 poststress. The serotonergic agent fluoxetine (FLX; 10 mg/kg/d ip) administered 1 week before stress and continuing throughout the stress procedure, but not the 5HT depleter p-chloro-phenylalanine (PCPA; 300/100/50 mg/kg/d ip), prevented stress-induced cognitive dysfunction. PCPA, however, reversed stress-induced hippocampal 5HT(1A) receptor affinity changes, with FLX narrowly missing significance. Neither drug reversed stress effects on 5HT(2A) receptor affinity. Thus, 5HT plays an important part in the cognitive-behavioral changes evoked by repeated trauma. That raised 5HT activity may mediate hippocampal 5HT(1A) receptor changes evoked by stress suggests a bidirectional role for 5HT in the development of PTSD.

Endogenous psychoactive tryptamines reconsidered: an anxiolytic role for dimethyltryptamine.

PubMed

Jacob, Michael S; Presti, David E

2005-01-01

The presence of the potent hallucinogenic psychoactive chemical N,N-dimethyltryptamine (DMT) in the human body has puzzled scientists for decades. Endogenous DMT was investigated in the 1960s and 1970s and it was proposed that DMT was involved in psychosis and schizophrenia. This hypothesis developed from comparisons of the blood and urine of schizophrenic and control subjects. However, much of this research proved inconclusive and conventional thinking has since held that trace levels of DMT, and other endogenous psychoactive tryptamines, are insignificant metabolic byproducts. The recent discovery of a G-protein-coupled, human trace amine receptor has triggered a reappraisal of the role of compounds present in limited concentrations in biological systems. Interestingly enough, DMT and other psychoactive tryptamine hallucinogens elicit a robust response at the trace amine receptor. While it is currently accepted that serotonin 5-HT(2A) receptors play a pivotal role in the activity of hallucinogenic/psychedelic compounds, we propose that the effects induced by exogenous DMT administration, especially at low doses, are due in part to activity at the trace amine receptor. Furthermore, we suggest that endogenous DMT interacts with the TA receptor to produce a calm and relaxed mental state, which may suppress, rather than promote, symptoms of psychosis. This hypothesis may help explain the inconsistency in the early analysis of endogenous DMT in humans. Finally, we propose that amphetamine action at the TA receptor may contribute to the calming effects of amphetamine and related drugs, especially at low doses.

Alkaloids in Erythrina by UPLC-ESI-MS and In Vivo Hypotensive Potential of Extractive Preparations

PubMed Central

Merlugo, Liara; Santos, Marí C.; Sant'Anna, Liane S.; Cordeiro, Everson W. F.; Batista, Luiz A. C.; Miotto, Silvia T. S.; Garcia, Cássia V.; Moreira, Cleci M.; Mendez, Andreas S. L.

2015-01-01

Erythrina species are used in popular medicine as sedative, anxiolytic, anti-inflammatory, and antihypertensive. In this work, we investigated the chemical composition of extracts obtained from leaves of E. falcata and E. crista-galli. The hypotensive potential of E. falcata and the mechanism of action were also studied. The extracts were obtained by maceration and infusion. The total content of phenolic compounds and flavonoids was estimated by spectrophotometric methods. The chemical constituents were studied performing a chromatographic analysis by UPLC-ESI-MS. For in vivo protocols, blood pressure and heart rate were measured by the invasive hemodynamic monitoring method. Different concentrations of extracts and drugs such as L-NAME, losartan, hexamethonium, and propranolol were administrated i.v. The results of total phenolic contents for E. falcata and E. crista-galli were 1.3193–1.4989 mgGAE/mL for maceration and 0.8771–0.9506 mgGAE/mL for infusion. In total flavonoids, the content was 7.7829–8.1976 mg RE/g for maceration and 9.3471–10.4765 RE mg/g for infusion. The chemical composition was based on alkaloids, suggesting the presence of erythristemine, 11β-methoxyglucoerysodine, erysothiopine, 11β-hydroxyerysodine-glucose, and 11-hydroxyerysotinone-rhamnoside. A potent dose-dependent hypotensive effect was observed for E. falcata, which may be related to the route of β-adrenergic receptors. PMID:26356581

Discriminative stimulus properties of intragastrically administered d-amphetamine and pentobarbital in rhesus monkeys.

PubMed

de la Garza, R; Johanson, C E

1987-12-01

Rhesus monkeys were trained to discriminate intragastrically administered d-amphetamine (AMPH) or pentobarbital (PENTO) from saline using a signaled shock-avoidance trail procedure. All monkeys maintained criterion levels (greater than 90% drug-appropriate responding) throughout the duration of the study during training sessions. In the AMPH experiment, the anorectics diethylpropion, mazindol, phendimetrazine, phenmetrazine and phentermine completely substituted for the training dose of AMPH. The atypical antidepressant bupropion and the psychomotor stimulant methylphenidate also completely substituted for AMPH. Other anorectics including benzphetamine, clortermine, fenetylline, mefenorex and the psychomotor stimulant pemoline that share some pharmacological properties with AMPH substituted for AMPH in some, but not all, of the monkeys tested. The anorectics fenfluramine and chlorphentermine failed to substitute for AMPH. Drugs from other pharmacological classes such as morphine, diazepam, nortripyline and PENTO also failed to substitute for AMPH, indicating pharmacological specificity. In the PENTO experiment, the benzodiazepines alprazolam, bromazepam, diazepam, flurazepam, halazepam, lorazepam, midazolam, oxazepam, temazepam and triazolam and the sedatives methaqualone and phenobarbital completely substituted for the training dose of PENTO. The nonbenzodiazepine anxiolytic CL 218,872 only partially substituted for PENTO. In addition, morphine and AMPH failed to substitute for PENTO, indicating pharmacological specificity. In summary, drugs delivered intragastrically functioned as discriminative stimuli in a drug-class specific manner. The ability to use drugs delivered by this route as discriminative stimuli provides a way to compare anorectic drugs to AMPH or sedative drugs to PENTO under conditions that resemble the mode of human consumption to determine whether these drugs are likely to be associated with AMPH-like or PENTO-like drug dependence.

Psychiatric effects of antiepileptic drugs in adults.

PubMed

Dussaule, Claire; Bouilleret, Viviane

2018-06-01

Epileptic and psychiatric diseases share overlaps. Indeed, anxiety and depression are common comorbidities in epilepsy, and patients with psychiatric disease are at risk of epilepsy. Some antiepileptic drugs (AED) have psychiatric side effects; conversely, some AED could be used to treat psychiatric pathologies. Based on current literature data, the aim of this study is to determine the psychiatric effects induced by the most frequently prescribed AED in epileptic adults. Some AED will have positive mood or anxiolytic effects like sodium channel blockers, valproate and benzodiazepines; conversely, others might induce negative psychiatric effect, especially depression, anxiety or aggression, like levetiracetam, perampanel, topiramate, zonisamide, and barbiturates. The main risk factor for presenting these side effects is a personal history of psychiatric pathology. We therefore recommend monitoring the occurrence of psychiatric side effects, especially when using the most at risk AED and/or in case of psychiatric history. Moreover, in this latter case, it is preferable to use AED with positive psychiatric effects. The use of anxiety and depression scales could be useful detection tools.

Risk factors for fractures in the elderly.

PubMed

Jacqmin-Gadda, H; Fourrier, A; Commenges, D; Dartigues, J F

1998-07-01

We report the results of a 5-year prospective cohort study of risk factors for fractures, including drinking fluoridated water, in a cohort of 3,216 men and women aged 65 years and older. We studied risk factors for hip fracture and fractures at other locations separately. We found a higher risk of hip fractures for subjects exposed to fluorine concentrations over 0.11 mg per liter but without a dose-effect relation (odds ratio (OR) = 3.25 for a concentration of 0.11-0.25 mg per liter; OR = 2.43 for > or = 0.25 mg per liter]. For higher thresholds (0.7 and 1 mg per liter), however, the OR was less than 1. We found no association between fluorine and non-hip fractures. Non-hip fractures were associated with polymedication rather than with specific drug use, whereas fracture was associated with polymedication and use of anxiolytic and antidepressive drugs. Subjects drinking spirits every day were more likely to have hip fractures. Tobacco consumption increased the risk for non-hip fractures.

Synthesis and biological evaluation of 2-fluoro and 3-trifluoromethyl-phenyl-piperazinylalkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione as potential antidepressant agents.

PubMed

Zagórska, Agnieszka; Bucki, Adam; Kołaczkowski, Marcin; Siwek, Agata; Głuch-Lutwin, Monika; Starowicz, Gabriela; Kazek, Grzegorz; Partyka, Anna; Wesołowska, Anna; Słoczyńska, Karolina; Pękala, Elżbieta; Pawłowski, Maciej

2016-01-01

A series of 2-fluoro and 3-trifluoromethylphenylpiperazinylalkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione (4-21) were synthesized and evaluated for their serotonin (5-HT 1A /5-HT 7 ) receptor affinity and phosphodiesterase (PDE4B and PDE10A) inhibitor activity. The study enabled the identification of potent 5-HT 1A , 5-HT 7 and mixed 5-HT 1A /5-HT 7 receptor ligands with weak inhibitory potencies for PDE4B and PDE10A. The tests have been completed with the determination of lipophilicity and metabolic stability using micellar electrokinetic chromatography (MEKC) system and human liver microsomes (HLM) model. In preliminary pharmacological in vivo studies, selected compound 8-(5-(4-(2-fluorophenyl)piperazin-1-yl)pentyl)-1,3,7-trimethyl-1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione (9) behaved as a potential antidepressant in forced swim test (FST) in mice. Moreover, potency of antianxiety effects evoked by 9 (2.5 mg/kg) is greater than that of the reference anxiolytic drug, diazepam. Molecular modeling revealed that fluorinated arylpiperazinylalkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione have major significance for the provision of lead compounds for antidepressant and/or anxiolytic application.

Effect of early trauma on the sleep quality of euthymic bipolar patients.

PubMed

Aubert, E; Jaussent, I; Olié, E; Ducasse, D; Azorin, J M; Bellivier, F; Belzeaux, R; Bougerol, T; Etain, B; Gard, S; Henry, C; Kahn, J P; Leboyer, M; Loftus, J; Passerieux, C; Lopez-Castroman, J; Courtet, Ph

2016-12-01

Poor quality of sleep is frequent in euthymic bipolar patients and conveys worse clinical outcomes. We investigated the features of euthymic bipolar patients associated with poor sleep quality, with a focus on the effect of childhood trauma. 493 euthymic patients with DSM-IV-defined bipolar disorders were recruited in FondaMental Advanced Centers of Expertize for Bipolar Disorders (FACE-BD) between 2009 and 2014. Clinical variables were recorded. Subjective sleep quality and history of childhood trauma were respectively measured by the Pittsburgh Sleep Quality Index (PSQI) and the Childhood Trauma Questionnaire (CTQ). Poor sleepers were older, less professionally active, had significantly higher anxiety levels, took more anxiolytic drugs and did endorse more suicide attempts and suicidal ideas than good sleepers after adjusting for anxiety levels and age. Emotional abuse was associated with poor sleep quality after adjustment for BMI, age, professional activity, and bipolar disorders (BD) type (OR=1.83; 95% CI [1.30; 3.10]; p=0.02). However, this association was lost after adjustment for anxiety levels, anxiolytic treatment and suicide ideation/attempts. The main limitation was the type of sleep assessment, which only measured the subjective part of sleep complaints. A history of emotional abuse might underlie sleep problems in many bipolar patients but anxiety seems to act as a confounding factor in this relationship. New studies are needed to elucidate the role of childhood maltreatment on poor sleep among bipolar patients. Copyright © 2016 Elsevier B.V. All rights reserved.

[Comparison of in vitro model examinaitons with respect to drug release from suppositories].

PubMed

Regdon, G; Vágó, I; Mándi, E; Regdon, G; Erós, I

2000-04-01

9 lipophilic suppository bases with different physical-chemical parameters were examined. Buspiron-hydrochloride, an anxiolytic drug with good water-solubility was used--partly as a model--as a pharmacon, in a concentration of 10.0 mg/2.00 g. The rate and extent of in vitro drug release was monitored with static and dynamic methods. Kidney-dialysing membranes with various surfaces were used. The quantitative measurements were carried out spectrophotometrically and the amount of the diffused drug was determined at lambda = 298 nm. The mean values were calculated from 5 parallel measurements each time. The percentage values of in vitro relative availability revealed that the results of the two static diffusion studies did not differ significantly (p < 0.05) and were almost independent of the size of the membrane surface. The results of the dynamic diffusion method were well-reproducible but were vehicle-dependent. The process of release was characterized by the mathematical transformation of the release curves, while the correlation coefficients described the closeness of the relation. Two German vehicles, namely Witepsol H 15 with a medium hydroxyl value and Massa Estarinum 299, and a French vehicle, Suppocire AS2X were found to be excellent for the formulation of suppositories containing Buspiron-hydrochloride.

Relationship Between Emotional Behavior in Mice and the Concentration of (+)-α-Santalol in the Brain.

PubMed

Satou, Tadaaki; Ogawa, Yuko; Koike, Kazuo

2015-08-01

We previously reported finding anxiolytic-like activity for sandalwood oil after administration in mice. In this report, we further investigated the emotional behavior associated with inhaled or intraperitoneally administered (+)-α-santalol, the main component of sandalwood oil, in addition to examining whether pharmacological or neurological transfers are responsible for this behavior. After administration of (+)-α-santalol by inhalation or intraperitoneal injection, we assessed anxiolytic-like and locomotor activities using elevated-plus maze tests. We also examined the relationship between the emotional behavior and the (+)-α-santalol brain concentration. Anxiolytic-like activity was not observed immediately after administration or after water-immersion stress for 24 h for either the (+)-α-santalol 2 μL/L air inhalation or the (+)-α-santalol 0.03 mL/kg (i.p.) administration. However, mice administered (+)-α-santalol 0.03 mL/kg intraperitoneally exhibited a significant decrease in the locomotor activity after exposure to water-immersion stress for 24 h. The brain (+)-α-santalol concentration was 2.6 µg/g tissue after (+)-α-santalol 0.03 mL/kg (i.p.) administration. The observed shift of (+)-α-santalol to the brain suggests that this component acts via pharmacological transfer and is responsible for the sedative effect but not the anxiolytic-like activity. Copyright © 2015 John Wiley & Sons, Ltd.

No association between prenatal exposure to psychotropics and intelligence at age five.

PubMed

Eriksen, Hanne-Lise Falgreen; Kesmodel, Ulrik Schiøler; Pedersen, Lars Henning; Mortensen, Erik Lykke

2015-05-01

To examine associations between prenatal exposure to selective serotonin reuptake inhibitors (SSRIs)/anxiolytics and intelligence assessed with a standard clinical intelligence test at age 5 years. Longitudinal follow-up study. Denmark, 2003-2008. A total of 1780 women and their children sampled from the Danish National Birth Cohort. Self-reported information on use of SSRI and anxiolytics was obtained from the Danish National Birth Cohort at the time of consent and from two prenatal interviews. Intelligence was assessed at age 5 years, and parental education, maternal intelligence quotient (IQ), maternal smoking and alcohol consumption in pregnancy, the child's age at testing, sex, and tester were included in the full model. The IQ of 13 medication-exposed children was compared with the IQ of 19 children whose mothers had untreated depression and 1748 control children. Wechsler Preschool and Primary Scale of Intelligence - Revised. In unadjusted analyses, children of mothers who used antidepressants or anxiolytics during pregnancy had higher verbal IQ; this association, however, was insignificant after adjustment for potentially confounding maternal and child factors. No consistent associations between IQ and fetal exposure to antidepressants and anxiolytics were observed, but the study had low statistical power, and there is an obvious need to conduct long-term follow-up studies with comprehensive cognitive assessment and sufficiently large samples of adolescent or adult offspring. © 2015 Nordic Federation of Societies of Obstetrics and Gynecology.

The anxiolytic activity of n-3 PUFAs enriched egg yolk phospholipids in rat behavioral studies.

PubMed

Rutkowska, M; Słupski, W; Trocha, M; Szandruk, M; Rymaszewska, J

2016-11-02

Phospholipids play an important role in the biochemical and physiological processes of cells. An association between disturbed phospholipids metabolism in neuronal tissue and anxiety it was shown. The aim of this study was to examine the anxiolytic properties of phospholipids obtained from a new generation of eggs enriched in n-3 PUFA and its effect on locomotor activity in rat behavioral studies N-3 PUFA-enriched egg yolk phospholipids ("super lecithin") were added to the standard feed. Rats were fed by chow without (control group) or with (experimental group) addition of phospholipids. After six weeks of supplementation, the effect of phospholipids on locomotor activity in the open field test and anxiolytic properties in elevated plus maze and Vogel conflict test were examined. In the open field test the total distance traveled in the experimental group was similar to the control group. In the elevated plus maze test a six weeks phospholipids' administration significantly prolonged the time spent on the open arms by rats from experimental group compared to control group. The number of entries into the open arms was also increased but the difference was not statistically significant. The number of punished drinking water in the Vogel conflict test increased significantly in experimental versus control group. The obtained results suggest that the phospholipids isolated from n-3 PUFA enriched egg yolk have a specific anxiolytic effect, without general sedative influence.

Anxiolytic and neuroprotective effects of the Traditional Chinese Medicinal formulation Dan-zhi-xiao-yao-san in a rat model of chronic stress.

PubMed

Cao, Guo-Ping; Gui, Dan; Fu, Lu-Di; Guo, Zhou-Ke; Fu, Wen-Jun

2016-08-01

Dan-zhi-xiao-yao-san is a Traditional Chinese Medicinal formulation widely used for the treatment of neuropsychological disorders. The present study examined the anxiolytic and neuroprotective effects of Dan-zhi-xiao-yao-san in a rat model of chronic stress. The results of an elevated plus maze test showed that Dan‑zhi‑xiao‑yao‑san significantly attenuated the levels of anxiety-induced stress as evidenced by increases in the time spent in the open arm region, as well as the percentage of entries into this area. In addition, Dan-zhi-xiao-yao-san alleviated stress‑induced neuronal death, as indicated by histological examination. Furthermore, mechanistic studies suggested that the anxiolytic and neuroprotective effects of Dan-zhi-xiao-yao-san may be mediated via attenuation of chronic stress‑induced upregulation of α‑synuclein and corticosterone, and downregulation of protein phosphatase 2A (PP2A) in the hippocampal region of the brain at the mRNA and protein level. In addition, Dan‑zhi‑xiao‑yao‑san decreased the serum levels of stress‑induced corticosterone in the model animals. In conclusion, the present study demonstrated that Dan‑zhi‑xiao‑yao‑san exerted anxiolytic and neuroprotective effects in a rat model of chronic stress via attenuation of stress‑induced upregulation of α‑synuclein and corticosterone, and downregulation of PP2A in the hippocampus.

Psychotropic Drug Prescription in Adolescents: A Retrospective Study in a Swiss Psychiatric University Hospital.

PubMed

Ansermot, Nicolas; Jordanov, Véronique; Smogur, Michal; Holzer, Laurent; Eap, Chin B

2018-04-01

This retrospective study aims to evaluate off-label prescriptions and administrations of psychotropic medications in adolescents in a university psychiatric hospital in Switzerland. Data were collected during the entire stays from the electronic database for 76 inpatients in 2008 and 76 inpatients in 2014. Data collected included gender, age, psychiatric diagnosis, duration of hospitalization, and psychotropic drug prescriptions and administrations. A total of 224 psychotropic drugs (mean 2.9 drugs/patient) were prescribed in 2008 and 268 (mean 3.5 drugs/patient) in 2014. Due to the prescriptions of some drugs as required, only 76% of the prescriptions were actually administered in 2008 (mean 2.3 drugs/patient) and 55% in 2014 (mean 1.9 drugs/patient). Antipsychotics were the most frequently prescribed drugs in 2008 (74% of patients) and 2014 (86% of patients). Anxiolytics were also highly prescribed in 2008 (54% of patients) and 2014 (66% of patients), as well as antidepressants in 2008 (30% of patients), but less in 2014 (13% of patients). Overall, 69% of prescriptions were found to be off label in 2008 and 68% in 2014, according to age, diagnosis, dose, or formulation as approved by Swissmedic. The medication classes with the highest rate of off-label prescriptions were antidepressants (100% for both years), antipsychotics (94% in 2008 and 92% in 2014), and hypnotics (67% in 2008 and 100% in 2014). For both study periods, at least one off-label psychotropic drug prescription and administration was recorded in 96% and 79% of the patients, respectively. The high rate of off-label psychotropic drug use strengthens the need for clinical trials to better evaluate the efficacy and safety of these treatments in adolescents.

Effects of propranolol on conversational reciprocity in autism spectrum disorder: a pilot, double-blind, single-dose psychopharmacological challenge study.

PubMed

Zamzow, Rachel M; Ferguson, Bradley J; Stichter, Janine P; Porges, Eric C; Ragsdale, Alexandra S; Lewis, Morgan L; Beversdorf, David Q

2016-04-01

Pharmacological intervention for autism spectrum disorder (ASD) is an important addition to treatment, yet currently available agents target co-morbid psychiatric concerns, such as aggression and irritability. Propranolol, a beta-adrenergic antagonist with anxiolytic effects, has been shown to improve verbal fluency and working memory in adults and adolescents with ASD in single-dose challenges. The present pilot study explores the acute effects of propranolol on a measure of conversational reciprocity in this population. We also examined whether autonomic activity and anxiety moderate or mediate response to the drug, given relationships between these variables and ASD, as well as the drug's effects. In a within-subject crossover design, 20 individuals with ASD received a single dose of propranolol or placebo during two sessions in a double-blinded, counterbalanced manner. After drug administration, participants performed a conversational reciprocity task by engaging in a short conversation with the researcher. Measurements of autonomic activity and anxiety were obtained before and after drug administration. Propranolol significantly improved performance on the conversational reciprocity task total [d = 0.40] and nonverbal communication domain scores when compared to the placebo condition. However, neither autonomic activity nor anxiety was significantly associated with drug response. Acute propranolol administration improved conversational reciprocity in ASD. Further exploration of these preliminary findings, as well as other potential treatment response predictors, with serial doses is warranted.

Antibiotic use in children and the use of medicines by parents.

PubMed

de Jong, Josta; Bos, Jens H J; de Vries, Tjalling W; de Jong-van den Berg, Lolkje T W

2012-06-01

Antibiotic drugs are frequently used for viral infections in children. It is probable that health beliefs and parental concern have great influence on the use of drugs in children. This study, performed in The Netherlands, investigates whether the use of antibiotics in children is associated with the use of medicines by parents. In this observational cohort study, the authors selected 6731 children from the prescription database IADB.nl who did not receive antibiotics until their fifth birthday and 1479 children who received at least one antibiotic prescription every year. The authors then selected parents for each group of children (5790 mothers and 4250 fathers for the children who did not receive antibiotics and 1234 mothers and 1032 fathers for the children who regularly received antibiotics). The authors compared the use of antibiotics and other medicines between the two groups of parents. Parents of children who received antibiotics recurrently were found to use more antibiotics themselves compared with parents of children who did not receive antibiotics. Moreover, this group also showed a higher percentage of chronic medication use: (11.3 vs 6.2% (mothers) and 13.1% vs 9.5% (fathers)). Mothers more often use antacids, non-steroidal anti-inflammatory drugs (NSAIDs), analgesics, anxiolytics, hypnotics, antidepressants, drugs for treatment of asthma and antihistamines. Fathers use more antacids, cardiovascular drugs, NSAIDs and asthma drugs. The parents of children who receive antibiotic drugs regularly use more medicines compared with the parents of children who use no antibiotic drugs. Parents' medicine use may influence that of children and is a factor physicians and pharmacists should take into account.

[Mechanism of action of antidepressants and therapeutic perspectives].

PubMed

Bourin, M; David, D J P; Jolliet, P; Gardier, A

2002-01-01

Depression is an incapacitating disease which needs appropriate treatment. This article reviews the pharmacology of antidepressant drugs and the future perspectives of treating mood disorders such as depression. The foremost theory for explaining the biological basis of depression has been the monoamine hypothesis. Depression is due to a deficiency in one or other biogenic monoamines (serotonin, 5-HT; noradrenaline, NA; dopamine, DA). Antidepressant drugs are therefore classified according to their ability to improve monoaminergic transmission. Since this first theory, other explanations based on abnormal function of monoamine receptors or associated with impaired signalling pathways have been suggested. Notable progress has been accomplished in the treatment of major depressive disorders with new compounds recently discovered (selective serotonin reuptake inhibitors: SSRI; serotonin noradrenaline reuptake inhibitors: SNRI). Behavioural, electrophysiological and microdialysis studies have shown that serotonin (5-HT) receptors, mainly 5-HT1A, 5-HT1B and 5-HT2C sub-types, exert a key role in modulating antidepressant activity. Indirect activation of neurotransmitter receptors by antidepressants may also lead, via increases in endogenous levels of serotonin in synapses in specific brain regions, to activation of various G proteins coupled to a receptor, signal of transduction, transcription factors and neurotrophic factors such as brain-derived neurotrophic factor (BDNF). Thus, depression may be considered as a transduction mechanism anomaly. This hypothesis needs to be clarified by molecular biology. Although antidepressants have improved the therapeutic potential compared to tricyclics (TCA) in terms of reduced side effects, a number of problems still occur with these drugs. Clinical effects are not always observed until after this time has elapsed (4-6 weeks) and a substantial proportion of depressed patients show only partial or no response to antidepressants. Knowledge of the existence of links between neurotransmitter systems and the discovery of the most specific target, 5-HT receptors, should lead to improvements in antidepressant therapy. Developing drugs using innovative mechanisms such as directly acting on 5-HT receptors (5-HT1A agonists or 5-HT2 antagonists), would appear to be useful in the treatment of depression. The use of antidepressants in anxiety disorders such as obsessional compulsive disorders and even generalised anxiety, highlights the distinction between antidepressants and classic anxiolytics such as benzodiazepines, or even buspirone.

Targeted analysis of 116 drugs in hair by UHPLC-MS/MS and its application to forensic cases.

PubMed

Wang, Xin; Johansen, Sys Stybe; Nielsen, Marie Katrine Klose; Linnet, Kristian

2017-08-01

A multi-target method that can detect a broad range of drugs in human hair, such as hypnotics, anxiolytics, analgesics, benzodiazepines, antihistamines, antidepressants, antipsychotics, and anticonvulsants, was developed based on ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The drugs were extracted from 10 mg of washed hair by incubation for 18 h in a 25:25:50 (v/v/v) mixture of methanol/acetonitrile/2 mM ammonium formate (8% acetonitrile, pH 5.3). For 51% of the basic drugs, the lower limits of quantification (LLOQs) were in the range of 0.05-0.5 pg/mg, and the majority (98%) were ≤ 5 pg/mg. Linearity ranged from LLOQs to 100-500 pg/mg for all the basic drugs. For acid and neutral drugs, the LLOQs ranged from 0.4 to 500 pg/mg, and linearity ranged from LLOQs to 80-40 000 pg/mg. According to published reports on concentrations attained in single dose control studies, the present method is sensitive enough to detect single-dose drug exposure for many of the drugs. The accuracy was within 75-125% for the majority of drugs. Good precision was observed (relative standard deviations [RSD%] < 25%) for most of the compounds, including the prepared quality control (QC) hair samples. The method was applied to forensic cases and concentrations of rarely reported drugs in hair in 25 post-mortem forensic cases were presented. Hair concentrations of amisulpride, gabapentin, mianserin, mepyramine, orphenadrine, and xylometazoline have not been previously reported. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Music therapy as a non-pharmacological anxiolytic for paediatric radiotherapy patients.

PubMed

O'Callaghan, C; Sexton, M; Wheeler, G

2007-04-01

Outpatient radiotherapy treatment in the paediatric cancer patient can be a traumatic and an anxiety-provoking experience for both the patient and the family. Music therapy has been widely reported to have psychosocial, educational and physical benefits for the paediatric cancer patient. Using individual case reports, this paper shows the successful use of music therapy as a non-pharmacological anxiolytic in the paediatric radiotherapy, outpatient waiting room setting, by providing the patient and the family with a means of communication, self-expression and creativity.

Convergence and divergence, a concept for explaining drug actions.

PubMed

Watanabe, Takehiko; Kamisaki, Yoshinori; Timmerman, Henk

2004-10-01

For the teaching and/or learning about drug actions and for the discovery and development of new drugs, it is important to understand how drugs act on living bodies. So far, there has been no clear description on the general principle of drug action in pharmacology textbooks. We propose two principles to depict the action mechanism of drugs. The first is that most, if not all, drugs act on proteins at the molecular level, that is, enzymes, receptors, ion channels, and transporters. The second is that a drug may cause divergent or convergent responses, resulting in changes of a physiological or pathological function of the human body. The concept of divergence and convergence can be used to explain the complex individuality of drug actions.

Sedation and analgesia in gastrointestinal endoscopy: What’s new?

PubMed Central

Fanti, Lorella; Testoni, Pier Alberto

2010-01-01

Various types of sedation and analgesia technique have been used during gastrointestinal endoscopy procedures. The best methods for analgesia and sedation during gastrointestinal endoscopy are still debated. Providing an adequate regimen of sedation/analgesia might be considered an art, influencing several aspects of endoscopic procedures: the quality of the examination, the patient’s cooperation and the patient’s and physician’s satisfaction with the sedation. The properties of a model sedative agent for endoscopy would include rapid onset and offset of action, analgesic and anxiolytic effects, ease of titration to desired level of sedation, rapid recovery and an excellent safety profile. Therefore there is an impulse for development of new approaches to endoscopic sedation. This article provides an update on the methods of sedation today available and future directions in endoscopic sedation. PMID:20503443

Behavioral evidence for the interaction of oleamide with multiple neurotransmitter systems.

PubMed

Fedorova, I; Hashimoto, A; Fecik, R A; Hedrick, M P; Hanus, L O; Boger, D L; Rice, K C; Basile, A S

2001-10-01

While the endogenous fatty acid amide oleamide has hypnotic properties, neither the breadth of its behavioral actions nor the mechanism(s) by which these behaviors may be mediated has been elucidated. Therefore, the effects of oleamide on the performance of rats in tests of motor function, analgesia, and anxiety were investigated. Oleamide reduced the distance traveled in the open field (ED50 = 14, 10-19 mg/kg, mean, 95% confidence interval), induced analgesia and hypothermia, but did not cause catalepsy. Moreover, a dose of oleamide without effect on motor function was anxiolytic in the social interaction test and elevated plus-maze. These actions of a single dose of oleamide lasted for 30 to 60 min. While rats became tolerant to oleamide following 8 days of repeated administration, oleamide is a poor inducer of physical dependence. Pretreatment with antagonists of the serotonin (5HT)1A, 5HT2C, and vanilloid receptors did not modify oleamide's effects. However, the cannabinoid receptor antagonist SR 141716A inhibited oleamide-induced analgesia in the tail-flick assay, the gamma-aminobutyric acid (GABA)A receptor antagonist bicuculline reversed the analgesia and hypothermia, and the dopamine D2 receptor antagonist L 741626 blocked oleamide's locomotor and analgesic actions. Interestingly, oleamide analogs resistant to hydrolysis by fatty acid amide hydrolase (FAAH) maintained but did not show increased behavioral potency or duration of action, whereas two FAAH inhibitors produced analogous behavioral effects. Thus, oleamide induces behaviors reminiscent of the actions of endogenous cannabinoids, but the involvement of GABAergic and dopaminergic systems, either directly or indirectly, in the actions of oleamide cannot be ruled out.

Retrospective Chart Review of Skin-to-Skin Contact in the Operating Room and Administration of Analgesic and Anxiolytic Medication to Women After Cesarean Birth.

PubMed

Wagner, Debra L; Lawrence, Stephen; Xu, Jing; Melsom, Janice

2018-04-01

Transporting a newborn out of the operating room after cesarean birth can contribute to maternal awareness of discomfort, anxiety, and the need for administration of analgesics and anxiolytics for relief. This retrospective study analyzed the association between skin-to-skin contact in the operating room and administration of analgesics and anxiolytics to women in the operating and recovery rooms after cesarean birth. Our results indicated a trend toward decreased medication administration for women who experienced skin-to-skin contact and add to evidence supporting the incorporation of skin-to-skin contact in the operating room as the standard of care for cesarean birth. This practice has the potential to enhance the birth experience, promote breastfeeding, and provide greater safety with less exposure to opioids and benzodiazepines for women and their newborns. © 2018 AWHONN, the Association of Women’s Health, Obstetric and Neonatal Nurses.

Anxiolytic effect of Kami-Shoyo-San (TJ-24) in mice: possible mediation of neurosteroid synthesis.

PubMed

Mizowaki, M; Toriizuka, K; Hanawa, T

2001-09-21

We assessed the anxiolytic effect of Kami-Shoyo-San (Jia-wei-xiao-yao-san; TJ-24), one of a traditional Chinese herbal medicine used for the treatment of menopausal anxiety, by the social interaction (SI) test in male mice. Acute administration of TJ-24 (25-100 mg/kg, p.o.), as well as the gamma-amino-butyric acidA/benzodiazepine (GABA(A)/BZP) receptor agonist diazepam (1-3 mg/kg, i.p.), dose dependently increased the SI time, respectively. The GABA(A) receptor antagonist picrotoxin blocked the effects of TJ-24 and diazepam. TJ-24-induced SI behavior was significantly blocked by the GABA(A)/BZP receptor inverse agonist Ro 15-4513 and the GABA(A)/BZP receptor antagonist flumazenil. In addition, 5alpha-reductase inhibitor finasteride potently blocked the effect of TJ-24 without attenuating the basal level by itself. These findings suggest that TJ-24 shows the anxiolytic effect through the neurosteroid synthesis followed by GABA(A)/BDZ receptor stimulations.

Home tank water versus novel water differentially affect alcohol-induced locomotor activity and anxiety related behaviours in zebrafish.

PubMed

Tran, Steven; Facciol, Amanda; Gerlai, Robert

2016-05-01

The zebrafish may be uniquely well suited for studying alcohol's mechanisms of action in vivo, since alcohol can be administered via immersion in a non-invasive manner. Despite the robust behavioural effects of alcohol administration in mammals, studies reporting the locomotor stimulant and anxiolytic effects of alcohol in zebrafish have been inconsistent. In the current study, we examined whether differences in the type of water used for alcohol exposure and behavioural testing contribute to these inconsistencies. To answer this question, we exposed zebrafish to either home water from their housing tanks or novel water from an isolated reservoir (i.e. water lacking zebrafish chemosensory and olfactory cues) with 0% or 1% v/v alcohol for 30 min, a 2 × 2 between subject experimental designs. Behavioural responses were quantified throughout the 30-minute exposure session via a video tracking system. Although control zebrafish exposed to home water and novel water were virtually indistinguishable in their behavioural responses, alcohol's effect on locomotor activity and anxiety-like behavioural responses were dependent on the type of water used for testing. Alcohol exposure in home tank water produced a mild anxiolytic and locomotor stimulant effect, whereas alcohol exposure in novel water produced an anxiogenic effect without altering locomotor activity. These results represent a dissociation between alcohol's effects on locomotor and anxiety related responses, and also illustrate how environmental factors, in this case familiarity with the water, may interact with such effects. In light of these findings, we urge researchers to explicitly state the type of water used. Copyright © 2016 Elsevier Inc. All rights reserved.

Sex and Exercise Interact to Alter the Expression of Anabolic Androgenic Steroid-Induced Anxiety-Like Behaviors in the Mouse

PubMed Central

Onakomaiya, Marie M.; Porter, Donna M.; Oberlander, Joseph G.; Henderson, Leslie P.

2014-01-01

Anabolic androgenic steroids (AAS) are taken by both sexes to enhance athletic performance and body image, nearly always in conjunction with an exercise regime. Although taken to improve physical attributes, chronic AAS use can promote negative behavior, including anxiety. Few studies have directly compared the impact of AAS use in males versus females or assessed the interaction of exercise and AAS. We show that AAS increase anxiety-like behaviors in female but not male mice and that voluntary exercise accentuates these sex-specific differences. We also show that levels of the anxiogenic peptide corticotrophin releasing factor (CRF) are significantly greater in males, but that AAS selectively increase CRF levels in females, thus abrogating this sex-specific difference. Exercise did not ameliorate AAS-induced anxiety or alter CRF levels in females. Exercise was anxiolytic in males, but this behavioral outcome did not correlate with CRF levels. Brain-derived neurotrophic factor (BDNF) has also been implicated in the expression of anxiety. As with CRF, levels of hippocampal BDNF mRNA were significantly greater in males than females. AAS and exercise were without effect on BDNF mRNA in females. In males, anxiolytic effects of exercise correlated with increased BDNF mRNA, however AAS-induced changes in BDNF mRNA and anxiety did not. In sum, we find that AAS elicit sex-specific differences in anxiety and that voluntary exercise accentuates these differences. In addition, our data suggest that these behavioral outcomes may reflect convergent actions of AAS and exercise on a sexually differentiated CRF signaling system within the extended amygdala. PMID:24768711

Revealing chemical processes and kinetics of drug action within single living cells via plasmonic Raman probes.

PubMed

Li, Shan-Shan; Guan, Qi-Yuan; Meng, Gang; Chang, Xiao-Feng; Wei, Ji-Wu; Wang, Peng; Kang, Bin; Xu, Jing-Juan; Chen, Hong-Yuan

2017-05-23

Better understanding the drug action within cells may extend our knowledge on drug action mechanisms and promote new drugs discovery. Herein, we studied the processes of drug induced chemical changes on proteins and nucleic acids in human breast adenocarcinoma (MCF-7) cells via time-resolved plasmonic-enhanced Raman spectroscopy (PERS) in combination with principal component analysis (PCA). Using three popular chemotherapy drugs (fluorouracil, cisplatin and camptothecin) as models, chemical changes during drug action process were clearly discriminated. Reaction kinetics related to protein denaturation, conformational modification, DNA damage and their associated biomolecular events were calculated. Through rate constants and reaction delay times, the different action modes of these drugs could be distinguished. These results may provide vital insights into understanding the chemical reactions associated with drug-cell interactions.

Psychiatric services in primary care settings: a survey of general practitioners in Thailand

PubMed Central

Lotrakul, Manote; Saipanish, Ratana

2006-01-01

Background General Practitioners (GPs) in Thailand play an important role in treating psychiatric disorders since there is a shortage of psychiatrists in the country. Our aim was to examine GP's perception of psychiatric problems, drug treatment and service problems encountered in primary care settings. Methods We distributed 1,193 postal questionnaires inquiring about psychiatric practices and service problems to doctors in primary care settings throughout Thailand. Results Four hundred and thirty-four questionnaires (36.4%) were returned. Sixty-seven of the respondents (15.4%) who had taken further special training in various fields were excluded from the analysis, giving a total of 367 GPs in this study. Fifty-six per cent of respondents were males and they had worked for 4.6 years on average (median = 3 years). 65.6% (SD = 19.3) of the total patients examined had physical problems, 10.7% (SD = 7.9) had psychiatric problems and 23.9% (SD = 16.0) had both problems. The most common psychiatric diagnoses were anxiety disorders (37.5%), alcohol and drugs abuse (28.1%), and depressive disorders (29.2%). Commonly prescribed psychotropic drugs were anxiolytics and antidepressants. The psychotropic drugs most frequently prescribed were diazepam among anti-anxiety drugs, amitriptyline among antidepressant drugs, and haloperidol among antipsychotic drugs. Conclusion Most drugs available through primary care were the same as what existed 3 decades ago. There should be adequate supply of new and appropriate psychotropic drugs in primary care. Case-finding instruments for common mental disorders might be helpful for GPs whose quality of practice was limited by large numbers of patients. However, the service delivery system should be modified in order to maintain successful care for a large number of psychiatric patients. PMID:16867187

Treatment with HC-070, a potent inhibitor of TRPC4 and TRPC5, leads to anxiolytic and antidepressant effects in mice

PubMed Central

Ceci, Angelo; Strassmaier, Timothy; Chong, Jayhong A.; Blair, Nathaniel T.; Gallaschun, Randall J.; del Camino, Donato; Cantin, Susan; D’Amours, Marc; Eickmeier, Christian; Fanger, Christopher M.; Hecker, Carsten; Hessler, David P.; Hengerer, Bastian; Kroker, Katja S.; Malekiani, Sam; Mihalek, Robert; McLaughlin, Joseph; Rast, Georg; Witek, JoAnn; Sauer, Achim; Pryce, Christopher R.

2018-01-01

Background Forty million adults in the US suffer from anxiety disorders, making these the most common forms of mental illness. Transient receptor potential channel canonical subfamily (TRPC) members 4 and 5 are non-selective cation channels highly expressed in regions of the cortex and amygdala, areas thought to be important in regulating anxiety. Previous work with null mice suggests that inhibition of TRPC4 and TRPC5 may have anxiolytic effects. HC-070 in vitro To assess the potential of TRPC4/5 inhibitors as an avenue for treatment, we invented a highly potent, small molecule antagonist of TRPC4 and TRPC5 which we call HC-070. HC-070 inhibits recombinant TRPC4 and TRPC5 homomultimers in heterologous expression systems with nanomolar potency. It also inhibits TRPC1/5 and TRPC1/4 heteromultimers with similar potency and reduces responses evoked by cholecystokinin tetrapeptide (CCK-4) in the amygdala. The compound is >400-fold selective over a wide range of molecular targets including ion channels, receptors, and kinases. HC-070 in vivo Upon oral dosing in mice, HC-070 achieves exposure levels in the brain and plasma deemed sufficient to test behavioral activity. Treatment with HC-070 attenuates the anxiogenic effect of CCK-4 in the elevated plus maze (EPM). The compound recapitulates the phenotype observed in both null TRPC4 and TRPC5 mice in a standard EPM. Anxiolytic and anti-depressant effects of HC-070 are also observed in pharmacological in vivo tests including marble burying, tail suspension and forced swim. Furthermore, HC-070 ameliorates the increased fear memory induced by chronic social stress. A careful evaluation of the pharmacokinetic-pharmacodynamic relationship reveals that substantial efficacy is observed at unbound brain levels similar to, or even lower than, the 50% inhibitory concentration (IC50) recorded in vitro, increasing confidence that the observed effects are indeed mediated by TRPC4 and/or TRPC5 inhibition. Together, this experimental data set introduces a novel, high quality, small molecule antagonist of TRPC4 and TRPC5 containing channels and supports the targeting of TRPC4 and TRPC5 channels as a new mechanism of action for the treatment of psychiatric symptoms. PMID:29385160

Prevalence of Drug-Induced Xerostomia in Older Adults with Cognitive Impairment or Dementia: An Observational Study.

PubMed

Gil-Montoya, José Antonio; Barrios, Rocío; Sánchez-Lara, Inés; Carnero-Pardo, Cristobal; Fornieles-Rubio, Francisco; Montes, Juan; Gonzalez-Moles, Miguel Angel; Bravo, Manuel

2016-08-01

Older adults, especially those with cognitive impairment or dementia, frequently consume drugs with potential xerostomic effects that impair their quality of life and oral health. The objective of this study was to determine the prevalence and analyze the possible pharmacological etiology of xerostomia in older people with or without cognitive impairment. Individuals with cognitive impairment were recruited from patients diagnosed using standardized criteria in two neurology departments in Southern Spain. A comparison group was recruited from healthcare centers in the same city after ruling out cognitive impairment. Data on oral health, xerostomia, and drug consumption were recorded in both groups. Dry mouth was evaluated using a 1-item questionnaire and recording clinical signs of oral dryness. All drugs consumed by the participants were recorded, including memantine, anticholinesterases, antipsychotics, antidepressants, and anxiolytics. The final sample comprised 200 individuals with mild cognitive impairment or dementia and 156 without. Xerostomia was present in 70.5 % of participants with cognitive impairment versus 36.5 % of those without, regardless of the drug consumed. Memantine consumption was the only variable significantly related to xerostomia in the multivariate model (OR 3.1; 95 % CI 1.1-8.7), and this relationship persisted after adjusting for possible confounders and forcing the inclusion of drugs with xerostomic potential. More than 70 % of participants diagnosed with cognitive impairment or dementia had xerostomia. Anticholinesterases and memantine were both associated with the presence of xerostomia. In the case of memantine, this association was independent of the consumption of the other drugs considered.

Central nervous system medications and falls risk in men aged 60-75 years: the Study on Male Osteoporosis and Aging (SOMA).

PubMed

Masud, Tahir; Frost, Morten; Ryg, Jesper; Matzen, Lars; Ibsen, Marlene; Abrahamsen, Bo; Brixen, Kim

2013-01-01

drugs acting on the central nervous system (CNS) increase falls risk. Most data on CNS drugs and falls are in women/mixed-sex populations. This study assessed the relationship between CNS drugs and falls in men aged 60-75 years. a questionnaire was sent to randomly selected Danish men aged 60-75 years. Cross-sectional data on CNS drugs and falls in the previous year were available for 4,696 men. Logistic regression investigated the relationship between falls and CNS drugs. the median age was 66.3 (IQR = 63.1-70.0) years; 21.7% were fallers. The following were associated with fallers (OR; 95% CI): opiates (2.4; 1.5-3.7), other analgesics (1.7; 1.4-2.1), antiepileptics (2.8; 1.5-5.1), antidepressants (2.8; 1.9-4.1) and anxiolytics/hypnotics (1.5; 0.9-2.6). Effects of opiates interacted strongly and significantly with age, with a marked association with falls in the older half of the subjects only. No significant associations were found between antipsychotics and fallers. Selective serotonin reuptake inhibitors and tricyclics were significantly associated with fallers (3.1; 2.0-5.0 and 2.2; 1.0-4.7, respectively). several CNS drug classes are associated with an approximately 2-3-fold increase risk of falls in men aged 60-75 years randomly selected from the population. Further longitudinal data are now required to confirm and further investigate the role of CNS drugs in falls causation in men.

Plant-based medicines for anxiety disorders, part 2: a review of clinical studies with supporting preclinical evidence.

PubMed

Sarris, Jerome; McIntyre, Erica; Camfield, David A

2013-04-01

Research in the area of herbal psychopharmacology has revealed a variety of promising medicines that may provide benefit in the treatment of general anxiety and specific anxiety disorders. However, a comprehensive review of plant-based anxiolytics has been absent to date. Thus, our aim was to provide a comprehensive narrative review of plant-based medicines that have clinical and/or preclinical evidence of anxiolytic activity. We present the article in two parts. In part one, we reviewed herbal medicines for which only preclinical investigations for anxiolytic activity have been performed. In this current article (part two), we review herbal medicines for which there have been both preclinical and clinical investigations of anxiolytic activity. A search of MEDLINE (PubMed), CINAHL, Scopus and the Cochrane Library databases was conducted (up to 28 October 2012) for English language papers using the search terms 'anxiety' OR 'anxiety disorder' OR 'generalized anxiety disorder' OR 'social phobia' OR 'post-traumatic stress disorder' OR 'panic disorder' OR 'agoraphobia' OR 'obsessive compulsive disorder' in combination with the search terms 'Herb*' OR 'Medicinal Plants' OR 'Botanical Medicine' OR 'Chinese herb*', in addition to individual herbal medicines. This search of the literature revealed 1,525 papers, of which 53 plants were included in the review (having at least one study using the whole plant extract). Of these plants, 21 had human clinical trial evidence (reviewed here in part two), with the other 32 having solely preclinical evidence (reviewed in part one). Support for efficacy was found for chronic use (i.e. greater than one day) of the following herbs in treating a range of anxiety disorders in human clinical trials: Piper methysticum, Matricaria recutita, Ginkgo biloba, Scutellaria lateriflora, Silybum marianum, Passiflora incarnata, Withania somniferum, Galphimia glauca, Centella asiatica, Rhodiola rosea, Echinacea spp., Melissa officinalis and Echium amoenum. For several of the plants studied, conclusions need to be tempered due to methodological issues such as small sample sizes, brief intervention durations and non-replication. Current evidence does not support Hypericum perforatum or Valeriana spp. for any anxiety disorder. Acute anxiolytic activity was found for Centella asiatica, Salvia spp., Melissa officinalis, Passiflora incarnata and Citrus aurantium. Bacopa monnieri has shown anxiolytic effects in people with cognitive decline. The therapeutic application of psychotropic plant-based treatments for anxiety disorders is also discussed, specifically Psychotria viridis and Banisteriopsis caarti (ayahuasca), Psilocybe spp. and cannabidiol-enriched (low tetrahydrocannabinol (Δ(9)-THC)) Cannabis spp.

21 CFR 201.66 - Format and content requirements for over-the-counter (OTC) drug product labeling.

Code of Federal Regulations, 2010 CFR

2010-04-01

... general pharmacological category(ies) or the principal intended action(s) of the drug or, where the drug... actions of each active ingredient. When an OTC drug monograph contains a statement of identity, the pharmacological action described in the statement of identity shall also be stated as the purpose of the active...

Neuropeptide S Activates Paraventricular Oxytocin Neurons to Induce Anxiolysis.

PubMed

Grund, Thomas; Goyon, Stephanie; Li, Yuting; Eliava, Marina; Liu, Haikun; Charlet, Alexandre; Grinevich, Valery; Neumann, Inga D

2017-12-13

Neuropeptides, such as neuropeptide S (NPS) and oxytocin (OXT), represent potential options for the treatment of anxiety disorders due to their potent anxiolytic profile. In this study, we aimed to reveal the mechanisms underlying the behavioral action of NPS, and present a chain of evidence that the effects of NPS within the hypothalamic paraventricular nucleus (PVN) are mediated via actions on local OXT neurons in male Wistar rats. First, retrograde studies identified NPS fibers originating in the brainstem locus coeruleus, and projecting to the PVN. FACS identified prominent NPS receptor expression in PVN-OXT neurons. Using genetically encoded calcium indicators, we further demonstrated that NPS reliably induces a transient increase in intracellular Ca 2+ concentration in a subpopulation of OXT neurons, an effect mediated by NPS receptor. In addition, intracerebroventricular (i.c.v.) NPS evoked a significant somatodendritic release of OXT within the PVN as assessed by microdialysis in combination with a highly sensitive radioimmunoassay. Finally, we could show that the anxiolytic effect of NPS seen after i.c.v. or intra-PVN infusion requires responsive OXT neurons of the PVN and locally released OXT. Thus, pharmacological blockade of OXT receptors as well as chemogenetic silencing of OXT neurons within the PVN prevented the effect of synthetic NPS. In conclusion, our results indicate a significant role of the OXT system in mediating the effects of NPS on anxiety, and fill an important gap in our understanding of brain neuropeptide interactions in the context of regulation of emotional behavior within the hypothalamus. SIGNIFICANCE STATEMENT Given the rising scientific interest in neuropeptide research in the context of emotional and stress-related behaviors, our findings demonstrate a novel intrahypothalamic mechanism involving paraventricular oxytocin neurons that express the neuropeptide S receptor. These neurons respond with transient Ca 2+ increase and somatodendritic oxytocin release following neuropeptide S stimulation. Thereby, oxytocin neurons seem essential for neuropeptide S-induced anxiolysis, as this effect was blocked by pharmacological and chemogenetic inhibition of the oxytocin system. Copyright © 2017 the authors 0270-6474/17/3712215-12$15.00/0.

Does Pregabalin Have Neuropsychotropic Effects?: A Short Perspective

PubMed Central

Marks, David M.; Patkar, Ashwin A.; Masand, Prakash S.

2009-01-01

Pregabalin is a newly developed synthetic gamma-aminobutyric acid (GABA) that is approved for the treatment of fibromyalgia and several neuropathy. It has been proven to show analgesic, anxiolytic, anticonvulsant and sleep enhancement effects, which could be applicable in the treatment of a variety of psychiatric disorders. There have been consistent reports that unexplained somatic symptoms (i.e., pain) may be a part of psychiatric disorders such as major depressive disorder (MDD) and anxiety disorders. Previous researches have also suggested the possible therapeutic potential of anticonvulsants as augmentation therapy or monotherapy in the treatment of mood disorders and anxiety disorders. Hence this short perspective tries to prompt and facilitate a shifting of researchers' attention to potential neuropsychotropic drug role of pregabalin to treat a wide range of neuropsychiatric disorders. PMID:20046375

Strychnine and taurine modulation of amygdala-associated anxiety-like behavior is 'state' dependent.

PubMed

McCool, Brian A; Chappell, Ann

2007-03-12

Strychnine-sensitive glycine receptors are expressed in many adult forebrain regions, yet the biological function of these receptors outside the spinal cord/brainstem is poorly understood. We have recently shown that rat lateral/basolateral amygdala neurons express strychnine-sensitive glycine-gated currents whose pharmacological and molecular characteristics are consistent with those established for classic ligand-gated chloride channels. The current studies were undertaken to establish the behavioral role, if any, of these strychnine-sensitive glycine receptors. Adult Long-Evans male rats were implanted with guide cannulae targeted at the lateral amygdala and were microinjected with standard artificial cerebrospinal fluid with or without various doses of strychnine or taurine. Anxiety-like behaviors were assessed with the elevated plus maze or the light/dark box. In the elevated plus maze, strychnine decreased closed-arm time and increased open-arm time, suggestive of an anxiolytic effect. Similarly, strychnine produced a modest anxiolytic effect in the light/dark box. Post hoc analysis of 'open-arm' time and 'light-side' time indicated that aCSF-treated animals were distributed into two apparent groups that displayed either high or low amounts of anxiety-like behavior in a given apparatus. Surprisingly, the pharmacological effects of both strychnine and taurine in these assays were dependent upon a given animal's behavioral phenotype. Together, these findings are significant because they suggest that the basal 'emotional state' of the animal could influence the behavioral outcome associated with drug application directly into the lateral/basolateral amygdala. Furthermore, our findings also suggest that compounds acting at amygdala strychnine-sensitive glycine receptors may actively modulate this basal anxiety-like state.

Determination of alpidem, an imidazopyridine anxiolytic, and its metabolites by column-switching high-performance liquid chromatography with fluorescence detection.

PubMed

Flaminio, L; Ripamonti, M; Ascalone, V

1994-05-13

Alpidem, 6-chloro-2-(4-chlorophenyl)-N,N-dipropylimidazo[1,2-a]pyridine- 3-acetamide, is an anxiolytic imidazopyridine that undergoes a first-pass elimination after oral administration to humans; it is actively metabolized and three circulating metabolites have been identified in plasma due to N-dealkylation, oxidation or a combination of both processes. For the determination of the unchanged drug and its metabolites in human plasma, a column-switching HPLC method was developed. The method, based on solid-phase extraction (performed on-line), involves the automatic injection of plasma samples (200 microliters) on to a precolumn filled with C18 material, clean-up of the sample with water in order to remove protein and salts and transfer of the analytes to the analytical column (after valve switching) by means of the mobile phase. All the processes were performed in the presence of an internal standard, a compound chemically related to alpidem. During the analytical chromatography, the precolumn was flushed with different solvents and after regeneration with water, it was ready for further injections. The analytical column was a C8 type and the mobile phase was acetonitrile-methanol-phosphate buffer solution (45:15:45, v/v/v) at a flow-rate of 1.5 ml min-1. The column was connected to a fluorimetric detector operating at excitation and emission wavelengths of 255 and 423 nm, respectively. The limits of quantitation of alpidem and three metabolites were 2.5 and 1.5 ng ml-1, respectively, in human plasma.

Differential effects of MPEP and diazepam in tests of conditioned emotional response and Pavlovian-to-instrumental transfer suggests 'anxiolytic' effects are mediated by different mechanisms.

PubMed

George, S A; Hutson, P H; Stephens, D N

2009-06-01

The selective mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) is reported to be anxiolytic in several animal models of anxiety, including the conditioned emotional response (CER) paradigm. Suppression of responding during conditioned stimulus (CS) presentation in CER may reflect behavioural competition between lever pressing and adopting a shock-avoidance posture, or it may alternatively reflect altered value of the food reward following its association with a footshock, thus reducing its ability to motivate responding. If this is the case, then drugs that reduce the CER may interfere with the mechanism by which CSs are able to motivate responding, rather than by reducing anxiety. The standard test of the ability of Pavlovian cues to motivate responding is the Pavlovian-to-instrumental transfer (PIT) paradigm and it has recently been suggested that CER may be 'negative PIT'. We compared the effect of MPEP (0, 3, 10 and 30 mg/kg) and diazepam (0, 1, 3 and 10 mg/kg) in CER and PIT. Both MPEP and diazepam significantly reduced conditioned suppression in the CER paradigm. MPEP, but not diazepam, significantly reduced PIT. The findings support the hypothesis that MPEP may reduce expression of anxiety in the CER paradigm by interfering with the way in which emotionally salient cues are able to affect behaviour, but do not support such an analysis of the effect of diazepam. Diazepam and MPEP may therefore achieve their effects in CER by influencing different psychological processes.

Therapeutic Body Wraps in Swiss public adult acute inpatient wards. A retrospective descriptive cohort study.

PubMed

Opsommer, E; Dubois, J; Bangerter, G; Panchaud, R; Martin, D; Skuza, K

2016-04-01

WHAT IS KNOWN ON THE SUBJECT?: Various expert opinions reported relational benefits and tranquilizing effects of therapeutic body wraps (TBW) in adults experiencing high anxiety in the context of psychosis. Yet, this tranquilizing effect was never investigated in larger samples and in the context of modern psychopharmacology. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: This is the first study to establish descriptive statistics of this mind-body therapy in French-speaking Switzerland where TBWs are routinely used in two public psychiatric hospitals. It brings knowledge on patients nowadays treated with TBW. Moreover, it opens a new area of investigation on the potential of this nursing technique, which may contribute to reduce anxiolytic medication in severely ill patients. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: This study sheds light on a clinical practice in mental health nursing and upon nurses' specific contribution to psychiatric clinic. It investigates a potential for TBWs to reduce the use of anxiolytic medications by patients who agreed to have TBW as part of their treatment. It may help to inform the mental health nursing practice. Introduction Many patients suffering from serious mental illness experience severe anxiety and those with psychosis often report the feeling of their bodies falling apart. While it is believed that these patients benefit from therapeutic body wraps (TBWs), the use of this adjunct therapy has rarely been studied in adult patients. Aims The aim of this study was to obtain descriptive statistics on the clinical, social-demographic and institutional reality of TBW therapy in Swiss public adult inpatient wards. Methods Retrospective data related to a cohort of 172 adult inpatients were retrieved from records of two public hospitals. Correlations between TBW and the prescriptions of lorazepam were explored. Results TBWs were primarily used for patients diagnosed with either schizophrenia, schizotypal, delusional and other non-mood psychotic disorders or mood disorders. Patients had, on average, four psychiatric hospitalizations, and in 30% of the cases, TBWs were offered during the first hospitalization. Moreover, TBWs were mostly practiced by nurses. Body wraps were potentially associated with a reduction in both anxiolytic and neuroleptic drugs. Discussion/Implication for practice Based on our results, TBW might contribute to the clinical management of anxiety by nurses. The efficacy of TWB regarding anxiety has yet to be investigated in a randomized controlled trial. © 2016 John Wiley & Sons Ltd.

The impact of psychological testing on the patients suffering from stomatopyrosis.

PubMed

Pokupec, Josipa Sanja Gruden; Gruden, Zdenka; Gruden, Vladimir

2011-12-01

Stomatopyrosis is commonly associated with stressful situations, which implies the importance of psychological conditions of the patients with this symptom. Patients suffering from burning mouth syndrome suffered from some psychical disturbances as well. The fact that depression and anxiety are closely connected with stomatopyrosis has been scientifically confirmed. The data which systematically led to this conclusion suggest the possibility of the existence of a psychogenic disturbance as an aetiological factor which leads to stomatopyrosis. Research which might be conducted in order to relate psychogenic disturbances with stomatopyrosis by means of various drugs and procedures, might provide an insight into the relatedness of these factors, which would enable us to treat the cause and not the consequence. This research has been directed towards establishing this "relatedness" by means of psychopharmatics and psychotherapy, and has been confirmed by means of psychological depression and anxiety tests. The research has been conducted on 120 respondents suffering from stomatopyrosis, who were also, as previously diagnosed, suffering from a psychical disturbance. The respondents were divided into 4 groups. Each group contained 30 respondents suffering from stomatopyrosis as the basic symptom, but with different psychogenic disturbances. These groups were: 1) antidepressants, 2) anxiolytics, 3) autogenic training and 4) control group. A detailed clinical and psychiatric check-up was conducted before the treatment started, and was repeated several times in different intervals: after a month, after two months and after four months. Respondents are still undergoing a therapy. Subjective assessment of the intensity of the burning sensation was obtained according to Visual analogue scale and two psychological questionnaires (depression test and anxiety test). Conclusion is: 1) Antidepressants and anxiolytic drugs have a prominent role in the treatment of stomatopyrosis. Psychological tests conducted after a four-month period have shown improvement--there was a decrease in anxiety--7.5%-8.8%, while depression has in some of the tested groups completely disappeared. At the same time, subjective evaluation of the intensity of the symptom has, according to VAS, showed a fall from 6.93-7.8 cm to 2.13-3.0 cm. At the beginning of the treatment, symptoms were described as "pretty often" with 36.7%-76.7% respondents, and as "permanent" with 23.3%-63.3% respondents. At the end of the treatment, the most frequent description regarding the frequency of the symptoms was "very rarely". 2) Autogenic training--psychotherapeutic anxiolytic technique--is the therapy of choice as far as stomatopyrosis is concerned, as it both eliminates the problems and emotionally rehabilitates the patient. 3) As far as the therapeutic progress is concerned, it can be taken as the "progress" of the time when the symptoms appear: during the treatment, the frequency and the duration of the symptoms have been shortened at night, while their occurrence during the day has been reported as relatively more frequent.

Risks versus benefits of medication use during pregnancy: what do women perceive?

PubMed

Mulder, Bianca; Bijlsma, Maarten J; Schuiling-Veninga, Catharina Cm; Morssink, Leonard P; van Puijenbroek, Eugene; Aarnoudse, Jan G; Hak, Eelko; de Vries, Tjalling W

2018-01-01

Understanding perception of risks and benefits is essential for informed patient choices regarding medical care. The primary aim of this study was to evaluate the perception of risks and benefits of 9 drug classes during pregnancy and associations with women's characteristics. Questionnaires were distributed to pregnant women who attended a Dutch Obstetric Care facility (first- and second-line care). Mean perceived risk and benefit scores were computed for 9 different drug classes (paracetamol, antacids, antibiotics, antifungal medication, drugs against nausea and vomiting, histamine-2 receptor antagonists/proton pump inhibitors, antidepressants, nonsteroidal anti-inflammatory drugs, and sedatives/anxiolytics). For each participant, we computed weighted risk and benefit sum scores with principal component analysis. In addition, major concerns regarding medication use were evaluated. The questionnaire was completed by 136 women (response rate 77%). Pregnant women were most concerned about having a child with a birth defect (35%), a miscarriage (35%), or their child developing an allergic disease (23%), respectively, as a result of drug use. The majority of studied drug classes were perceived relatively low in risk and high in benefit. Higher risk scores were reported if women were in their first trimesters of pregnancy ( p =0.007). Lower benefit scores were reported if women were single ( p =0.014), smoking ( p =0.028), nulliparous ( p =0.006), or did not have a family history of birth defects ( p =0.005). Pregnant women's concerns regarding potential drug adverse effects were not only focused on congenital birth defects but also included a wider range of adverse outcomes. This study showed that most of the studied drug classes were perceived relatively low in risk and high in benefit.

Nicotine and cannabinoids: parallels, contrasts and interactions.

PubMed

Viveros, Maria-Paz; Marco, Eva M; File, Sandra E

2006-01-01

After a brief outline of the nicotinic and cannabinoid systems, we review the interactions between the pharmacological effects of nicotine and cannabis, two of the most widely used drugs of dependence. These drugs are increasingly taken in combination, particularly among the adolescents and young adults. The review focuses on addiction-related processes, gateway and reverse gateway theories of addiction and therapeutic implications. It then reviews studies on the important period of adolescence, an area that is in urgent need of further investigation and in which the importance of sex differences is emerging. Three other areas of research, which might be particularly relevant to the onset and/or maintenance of dependence, are then reviewed. Firstly, the effects of the two drugs on anxiety-related behaviours are discussed and then their effects on food intake and cognition, two areas in which they have contrasting effects. Certain animal studies suggest that reinforcing effects are likely to be enhanced by joint consumption of nicotine and cannabis, as also may be anxiolytic effects. If this was the case in humans, the latter might be viewed as an advantage particularly by adolescent girls, although the increased weight gain associated with cannabis would be a disadvantage. The two drugs also have opposite effects on cognition and the possibility of long-lasting cognitive impairments resulting from adolescent consumption of cannabis is of particular concern.

The acute and long-term neurotoxic effects of MDMA on marble burying behaviour in mice.

PubMed

Saadat, Kathryn S; Elliott, J Martin; Colado, M Isabel; Green, A Richard

2006-03-01

When mice are exposed to harmless objects such as marbles in their cage they bury them, a behaviour sometimes known as defensive burying. We investigated the effect of an acute dose of MDMA (èecstasy') and other psychoactive drugs on marble burying and also examined the effect of a prior neurotoxic dose of MDMA or p-chloroamphetamine (PCA) on burying. Acute administration of MDMA produced dose-dependent inhibition of marble burying (EC50: 7.6 micro mol/kg). Other drugs that enhance monoamine function also produced dose-dependent inhibition: methamphetamine PCA paroxetine MDMA GBR 12909 methylphenidate. None of these drugs altered locomotor activity at a dose that inhibited burying. A prior neurotoxic dose of MDMA, which decreased striatal dopamine content by 60%, but left striatal 5-HT content unaltered, did not alter spontaneous marble burying 18 or 40 days later. However, a neurotoxic dose of PCA which decreased striatal dopamine by 60% and striatal 5-HT by 70% attenuated marble burying 28 days later. Overall, these data suggest that MDMA, primarily by acutely increasing 5-HT function, acts like several anxiolytic drugs in this behavioural model. Long-term loss of cerebral 5-HT content also produced a similar effect. Since this change was observed only after 28 days, it is probably due to an adaptive response in the brain.

The anticonvulsant stiripentol acts directly on the GABAA receptor as a positive allosteric modulator

PubMed Central

Fisher, Janet L.

2009-01-01

SUMMARY Stiripentol(STP) has been used as co-therapy for treatment of epilepsy for many years. Its mechanism of action has long been considered to be indirect, as it inhibits the enzymes responsible for metabolism of other anticonvulsant agents. However, a recent report suggested that STP might also act at the neuronal level, increasing inhibitory GABAergic neurotransmission. We examined the effect of STP on the functional properties of recombinant GABAA receptors (GABARs) and found that it was a positive allosteric modulator of these ion channels. Its activity showed some dependence on subunit composition, with greater potentiation of α3-containing receptors and reduced potentiation when the β1 or ε subunits were present. STP caused a leftward shift in the GABA concentration-response relationship, but did not increase the peak response of the receptors to a maximal GABA concentration. Although STP shares some functional characteristics with the neurosteroids, its activity was not inhibited by a neurosteroid site antagonist and was unaffected by a mutation in the α3 subunit that reduced positive modulation by neurosteroids. The differential effect of STP on β1- and β2/β3-containing receptors was not altered by mutations within the second transmembrane domain that affect modulation by loreclezole. These findings suggest that STP acts as a direct allosteric modulator of the GABAR at a site distinct from many commonly used anti-convulsant, sedative and anxiolytic drugs. Its higher activity at α3-containing receptors as well as its activity at δ-containing receptors may provide a unique opportunity to target selected populations of GABARs. PMID:18585399

Anxiolytic effects of environmental enrichment attenuate sex-related anxiogenic effects of scopolamine in rats.

PubMed

Hughes, Robert N; Otto, Maria T

2013-01-10

In groups of four same-sexed animals, PVG/c hooded rats were housed for 4.5 months in standard or enriched cages containing several objects that could be explored and manipulated. On separate occasions, each rat then experienced two consecutive daily trials in an open field, a light-dark box or a Y maze with arm inserts that enabled an acquisition trial comprising one black and one white arm to be changed for a retention trial consisting of two black arms. Before their trials in the open field and light-dark box, and following each acquisition trial in the Y maze, the rats received an intraperitoneal injection of 2 mg/kg scopolamine or isotonic saline. In the open field, enrichment led to higher levels of ambulation, walking, rearing and occupancy of the center of the apparatus and shorter emergence latencies from the dark into the light compartment of the light-dark box accompanied by more entries of this compartment. Enrichment also increased entries of and time spent in the changed (or novel) Y-maze arm only for male rats treated with scopolamine. The drug decreased rearing and increased grooming in the open field as well as increasing emergence latencies and decreasing entries of and the time spent on the light compartment of the light-dark box. The main results were interpreted as enrichment having attenuated anxiogenic effects of the behavioral testing and the action of scopolamine for male (but not female) rats in their choices of the novel arm in the Y maze. Copyright © 2012 Elsevier Inc. All rights reserved.

Dopamine D2-like receptors modulate freezing response, but not the activation of HPA axis, during the expression of conditioned fear.

PubMed

de Oliveira, Amanda R; Reimer, Adriano E; Reis, Fernando M C V; Brandão, Marcus L

2017-02-01

Considering the complexity of aversive information processing and defensive response expression, a combined action of stress modulators may be required for an optimal performance during threatening situations. Dopamine is now recognized as one of the most active modulators underlying states of fear and anxiety. On the other hand, activation of hypothalamic-pituitary-adrenocortical (HPA) axis, which leads to the release of corticosterone in rodents, has been considered a key part of the stress response. The current study is an extension of prior work investigating modulatory effects of dopamine and corticosterone on conditioned fear expression. We have showed that corticosterone, acting through mineralocorticoid receptors in the ventral tegmental area (VTA), upregulates dopaminergic system in the basolateral amygdala (BLA), enabling the expression of conditioned freezing response. The novel question addressed here is whether VTA-BLA dopaminergic signaling is necessary for increases in corticosterone during conditioned fear expression. Using site-specific treatment with D 2 -like agonist quinpirole (VTA) and D 2 -like antagonist sulpiride (BLA), we evaluated freezing and plasma corticosterone in rats exposed to a light used as aversive conditioned stimulus (CS). Intra-VTA quinpirole and intra-BLA sulpiride significantly decreased freezing expression in the conditioned fear test, but this anxiolytic-like effect of the dopaminergic drugs was not associated with changes in plasma corticosterone concentrations. Altogether, data suggest that interferences with the ability of the CS to activate the dopaminergic VTA-BLA pathway reduce the expression of freezing, but activation of the HPA axis seems to occur upstream of the recruitment of dopaminergic mechanisms in conditioned fear states.

Anxiolytic- and antidepressant-like activities of a methanolic extract of Morinda citrifolia Linn. (noni) fruit in mice: Involvement of benzodiazepine-GABAAergic, serotonergic and adrenergic systems.

PubMed

Narasingam, Megala; Vijeepallam, Kamini; Mohamed, Zahurin; Pandy, Vijayapandi

2017-12-01

This study presents anxiolytic- and antidepressant-like effects of a methanolic extract of Morinda citrifolia Linn. (noni) fruit (MMC) in well-established mouse models of anxiety and depression. The administration of MMC (1 g/kg, p.o.) and diazepam (1 mg/kg, i.p.) significantly attenuated anxiety-like behaviour in mice by increasing the percentage of time spent and number of entries in the open arms in the elevated plus maze (EPM), and significantly enhanced the exploration in the light box in the light/dark test (LDT). The pre-treatment with flumazenil (6 mg/kg, i.p.) or bicuculline (3 mg/kg, i.p.) or WAY 100635 (1 mg/kg, i.p.) antagonized the anxiolytic-like effect elicited by MMC (1 g/kg, p.o.). These results suggest the possible involvement of benzodiazepine-GABA A ergic and serotonergic mechanisms in the anxiolytic-like effect of noni fruit. Meanwhile, in the antidepressant study, the administration of MMC (0.5 and 0.75 g/kg, p.o.) and desipramine (30 mg/kg, i.p.) significantly reduced the duration of immobility in the tail suspension test (TST). Furthermore, pre-treatment of mice with 4-chloro-DL-phenylalanine methyl ester hydrochloride (PCPA; 100 mg/kg, i.p., an inhibitor of serotonin synthesis) for four consecutive days or a single dose of WAY 100635 (1 mg/kg, i.p., 5HT 1A receptor antagonist) or α-methyl-DL-tyrosine (AMPT; 100 mg/kg, i.p., an inhibitor of noradrenaline synthesis) significantly reversed the anti-immobility effect of MMC (0.5 g/kg, p.o.) in TST by indicating the specific involvement of the serotonergic and noradrenergic systems in the antidepressant-like effect of noni fruit. Taken together, these findings suggest that MMC has both anxiolytic- and antidepressant-like activities to be resorted as a valuable alternative therapy for comorbid anxiety and depressive conditions. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Metabolic interaction between ethanol, high-dose alprazolam and its two main metabolites using human liver microsomes in vitro.

PubMed

Tanaka, Einosuke; Nakamura, Takako; Terada, Masaru; Shinozuka, Tatsuo; Honda, Katsuya

2007-08-01

Alprazolam is widely used as a short-acting antidepressant and anxiolytic agent and its effect appears at very low doses while ethanol is used as a social drug worldwide. Sometimes, toxic interactions occur following combined administration of these two drugs. In this study we have investigated the interaction between ethanol and high-dose alprazolam using human liver microsomes in vitro. The interaction effects between ethanol and alprazolam were examined by a mixed-function oxidation reaction using a human liver microsomal preparation. Alprazolam and its two main metabolites (alpha-hydroxyalprazolam: alpha-OH alprazolam, 4-hydroxyalprazolam: 4-OH alprazolam) were measured by HPLC/UV. The production of 4-OH alprazolam, one main metabolite of alprazolam, was weakly inhibited by higher dose of ethanol, but not alpha-OH alprazolam. These results using a human liver microsomal preparation show that the production of 4-OH alprazolam is weakly inhibited by ethanol but not alpha-OH alprazolam. Toxic levels may be reached by simultaneous administration of ethanol and high-dose alprazolam.

The effects of repeated administration of diazepam, MK-801 and CGP 37849 on rat behavior in two models of anxiety.

PubMed

Jessa, M; Nazar, M; Bidzinski, A; Plaznik, A

1996-03-01

The effects of repeated administration of diazepam, MK-801 and CGP 37849 on rat behavior in the Vogel conflict test, and in the open field test of neophobia, were studied in rats. The drugs were given at doses active acutely, for 5 days, the last dose was administered 30 or 60 min prior to testing. It appeared that diazepam and MK-801 treated animals showed clear-cut signs of behavioral tolerance and motor sensitization, respectively. CGP 37849 was characterized by the best pharmacological profile, in that on repeated administration the drug not only retained its anxiolytic-like potency in the Vogel test, but even enhanced rat exploratory behavior in a new environment, independently of changes in animal motor activity. Repeated injections of the examined agents did not cause any significant modifications in monoamine levels and their turnover rates, in the striatum and limbic forebrain. It is concluded that the new class of competitive NMDA receptor antagonists, exemplified by CGP 37849, is the most promising candidate for clinical trials in anxiety disorders.

The Anxiolytic and Antidepressant-like Effects of Testosterone and Estrogen in Gonadectomized Male Rats

PubMed Central

Carrier, Nicole; Saland, Samantha K.; Duclot, Florian; He, Huan; Mercer, Roger; Kabbaj, Mohamed

2015-01-01

Background While the influence of testosterone levels on vulnerability to affective disorders is not straightforward, research suggests this hormone may confer some degree of resiliency in men. We recently demonstrated a role for the dentate gyrus in mediating testosterone’s protective effects on depressive-like behavior in gonadectomized male rats. Here, testosterone may exert its effects through androgen receptor-mediated mechanisms or via local aromatization to estradiol. Methods Gonadectomized male rats were implanted with a placebo, testosterone, or estradiol pellet, and subsequent protective anxiolytic- and antidepressant-like effects of testosterone and its aromatized metabolite, estradiol, were then investigated in the open field and sucrose preference tests, respectively. Moreover, their influence on gene expression in the hippocampus was analyzed by genome-wide cDNA microarray analysis. Finally, the contribution of testosterone’s aromatization within the dentate gyrus was assessed by local infusion of the aromatase inhibitor, fadrozole, whose efficacy was confirmed by LC-MS/MS. Results Both hormones had antidepressant-like effects associated with a substantial overlap in transcriptional regulation, particularly in synaptic plasticity- and mitogen-activated protein kinase pathway-related genes. Further, chronic aromatase inhibition within the dentate gyrus blocked the protective effects of testosterone. Conclusions Both testosterone and estradiol exhibit anxiolytic- and antidepressant-like effects in gonadectomized male rats, while similarly regulating critical mediators of these behaviors, suggesting common underlying mechanisms. Accordingly, we demonstrated that testosterone’s protective effects are mediated, in part, by its aromatization in the dentate gyrus. These findings thus provide further insight into a role for estradiol in mediating the protective anxiolytic- and antidepressant-like effects of testosterone. PMID:25683735

The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication.

PubMed

Bercik, P; Park, A J; Sinclair, D; Khoshdel, A; Lu, J; Huang, X; Deng, Y; Blennerhassett, P A; Fahnestock, M; Moine, D; Berger, B; Huizinga, J D; Kunze, W; McLean, P G; Bergonzelli, G E; Collins, S M; Verdu, E F

2011-12-01

The probiotic Bifidobacterium longum NCC3001 normalizes anxiety-like behavior and hippocampal brain derived neurotrophic factor (BDNF) in mice with infectious colitis. Using a model of chemical colitis we test whether the anxiolytic effect of B. longum involves vagal integrity, and changes in neural cell function. Methods  Mice received dextran sodium sulfate (DSS, 3%) in drinking water during three 1-week cycles. Bifidobacterium longum or placebo were gavaged daily during the last cycle. Some mice underwent subdiaphragmatic vagotomy. Behavior was assessed by step-down test, inflammation by myeloperoxidase (MPO) activity and histology. BDNF mRNA was measured in neuroblastoma SH-SY5Y cells after incubation with sera from B. longum- or placebo-treated mice. The effect of B. longum on myenteric neuron excitability was measured using intracellular microelectrodes. Chronic colitis was associated with anxiety-like behavior, which was absent in previously vagotomized mice. B. longum normalized behavior but had no effect on MPO activity or histological scores. Its anxiolytic effect was absent in mice with established anxiety that were vagotomized before the third DSS cycle. B. longum metabolites did not affect BDNF mRNA expression in SH-SY5Y cells but decreased excitability of enteric neurons. In this colitis model, anxiety-like behavior is vagally mediated. The anxiolytic effect of B. longum requires vagal integrity but does not involve gut immuno-modulation or production of BDNF by neuronal cells. As B. longum decreases excitability of enteric neurons, it may signal to the central nervous system by activating vagal pathways at the level of the enteric nervous system. © 2011 Blackwell Publishing Ltd.

Progesterone modulation of alpha5 nAChR subunits influences anxiety-related behavior during estrus cycle.

PubMed

Gangitano, D; Salas, R; Teng, Y; Perez, E; De Biasi, M

2009-06-01

Smokers often report an anxiolytic effect of cigarettes. In addition, stress-related disorders such as anxiety, post-traumatic stress syndrome and depression are often associated with chronic nicotine use. To study the role of the alpha5 nicotinic acetylcholine receptor subunit in anxiety-related responses, control and alpha5 subunit null mice (alpha5(-/-)) were subjected to the open field activity (OFA), light-dark box (LDB) and elevated plus maze (EPM) tests. In the OFA and LDB, alpha5(-/-) behaved like wild-type controls. In the EPM, female alpha5(-/-) mice displayed an anxiolytic-like phenotype, while male alpha5(-/-) mice were undistinguishable from littermate controls. We studied the hypothalamus-pituitary-adrenal axis by measuring plasma corticosterone and hypothalamic corticotropin-releasing factor. Consistent with an anxiolytic-like phenotype, female alpha5(-/-) mice displayed lower basal corticosterone levels. To test whether gonadal steroids regulate the expression of alpha5, we treated cultured NTera 2 cells with progesterone and found that alpha5 protein levels were upregulated. In addition, brain levels of alpha5 mRNA increased upon progesterone injection into ovariectomized wild-type females. Finally, we tested anxiety levels in the EPM during the estrous cycle. The estrus phase (when progesterone levels are low) is anxiolytic-like in wild-type mice, but no cycle-dependent fluctuations in anxiety levels were found in alpha5(-/-) females. Thus, alpha5-containing neuronal nicotinic acetylcholine receptors may be mediators of anxiogenic responses, and progesterone-dependent modulation of alpha5 expression may contribute to fluctuations in anxiety levels during the ovarian cycle.

Anxiolytic effects of a combination of Melissa officinalis and Valeriana officinalis during laboratory induced stress.

PubMed

Kennedy, David O; Little, Wendy; Haskell, Crystal F; Scholey, Andrew B

2006-02-01

Melissa officinalis (lemon balm) and Valeriana officinalis (valerian) have been used both traditionally and contemporaneously as mild sedatives, anxiolytics and hypnotics. Recent research has suggested that both may attenuate laboratory induced stress. As the two herbs are most often sold in combination with each other the current study assessed the anxiolytic properties of such a combination during laboratory-induced stress. In this double-blind, placebo-controlled, randomized, balanced cross-over experiment, 24 healthy volunteers received three separate single doses (600 mg, 1200 mg, 1800 mg) of a standardized product containing M. officinalis and V. officinalis extracts, plus a placebo, on separate days separated by a 7 day wash out period. Modulation of mood and anxiety were assessed during pre-dose and 1 h, 3 h and 6 h post-dose completions of a 20 min version of the Defined Intensity Stressor Simulation (DISS) battery. Cognitive performance on the four concurrent tasks of the battery was also assessed. The results showed that the 600 mg dose of the combination ameliorated the negative effects of the DISS on ratings of anxiety. However, the highest dose (1800 mg) showed an increase in anxiety that was less marked but which reached significance during one testing session. In addition, all three doses led to decrements in performance on the Stroop task module within the battery, and the two lower doses led to decrements on the overall score generated on the DISS battery. These results suggest that a combination of Melissa officinalis and Valeriana officinalis possesses anxiolytic properties that deserve further investigation. Copyright 2006 John Wiley & Sons, Ltd.

Increases in anxiety-like behavior induced by acute stress are reversed by ethanol in adolescent but not adult rats.

PubMed

Varlinskaya, Elena I; Spear, Linda P

2012-01-01

Repeated exposure to stressors has been found to increase anxiety-like behavior in laboratory rodents, with the social anxiety induced by repeated restraint being extremely sensitive to anxiolytic effects of ethanol in both adolescent and adult rats. No studies, however, have compared social anxiogenic effects of acute stress or the capacity of ethanol to reverse this anxiety in adolescent and adult animals. Therefore, the present study was designed to investigate whether adolescent [postnatal day (P35)] Sprague-Dawley rats differ from their adult counterparts (P70) in the impact of acute restraint stress on social anxiety and in their sensitivity to the social anxiolytic effects of ethanol. Animals were restrained for 90 min, followed by examination of stress- and ethanol-induced (0, 0.25, 0.5, 0.75, and 1 g/kg) alterations in social behavior using a modified social interaction test in a familiar environment. Acute restraint stress increased anxiety, as indexed by reduced levels of social investigation at both ages, and decreased social preference among adolescents. These increases in anxiety were dramatically reversed among adolescents by acute ethanol. No anxiolytic-like effects of ethanol emerged following restraint stress in adults. The social suppression seen in response to higher doses of ethanol was reversed by restraint stress in animals of both ages. To the extent that these data are applicable to humans, the results of the present study provide some experimental evidence that stressful life events may increase the attractiveness of alcohol as an anxiolytic agent for adolescents. Copyright © 2011 Elsevier Inc. All rights reserved.

Neuronal representation of individual heroin choices in the orbitofrontal cortex.

PubMed

Guillem, Karine; Brenot, Viridiana; Durand, Audrey; Ahmed, Serge H

2018-05-01

Drug addiction is a harmful preference for drug use over and at the expense of other non-drug-related activities. We previously identified in the rat orbitofrontal cortex (OFC) a mechanism that influences individual preferences between cocaine use and an alternative action rewarded by a non-drug reward (i.e. sweet water). Here, we sought to test the generality of this mechanism to a different addictive drug, heroin. OFC neuronal activity was recorded while rats responded for heroin or the alternative non-drug reward separately or while they chose between the two. First, we found that heroin-rewarded and sweet water-rewarded actions were encoded by two non-overlapping OFC neuronal populations and that the relative size of the heroin population represented individual drug choices. Second, OFC neurons encoding the preferred action-which was the non-drug action in the large majority of individuals-progressively fired more than non-preferred action-coding neurons 1 second after the onset of choice trials and around 1 second before the preferred action was actually chosen, suggesting a pre-choice neuronal competition for action selection. Together with a previous study on cocaine choice, the present study on heroin choice reveals important commonalities in how OFC neurons encode individual drug choices and preferences across different classes of drugs. It also reveals some drug-specific differences in OFC encoding activity. Notably, the proportion of neurons that non-selectively encode both the drug and the non-drug reward was higher when the drug was heroin (present study) than when it was cocaine (previous study). We will discuss the potential functional significance of these commonalities and differences in OFC neuronal activity across different drugs for understanding drug choice. © 2017 Society for the Study of Addiction.

Nuance and behavioral cogency: How the Visible Burrow System inspired the Stress-Alternatives Model and conceptualization of the continuum of anxiety.

PubMed

Robertson, James M; Prince, Melissa A; Achua, Justin K; Carpenter, Russ E; Arendt, David H; Smith, Justin P; Summers, Torrie L; Summers, Tangi R; Summers, Cliff H

2015-07-01

By creating the Visible Burrow System (VBS) Bob Blanchard found a way to study the interaction of genetics, physiology, environment, and adaptive significance in a model with broad validity. The VBS changed the way we think about anxiety and affective disorders by allowing the mechanisms which control them to be observed in a dynamic setting. Critically, Blanchard used the VBS and other models to show how behavioral systems like defense are dependent upon context and behavioral elements unique to the individual. Inspired by the VBS, we developed a Stress Alternatives Model (SAM) to further explore the multifaceted dynamics of the stress response with a dichotomous choice condition. Like the VBS, the SAM is a naturalistic model built upon risk assessment and defensive behavior, but with a choice of response: escape or submission to a large conspecific aggressor. The anxiety of novelty during the first escape must be weighed against fear of the aggressor, and a decision must be made. Both outcomes are adaptively significant, evidenced by a 50/50 split in outcome across several study systems. By manipulating the variables of the SAM, we show that a gradient of anxiety exists that spans the contextual settings of escaping an open field, escaping from aggression, and submitting to aggression. These findings correspond with increasing levels of corticosterone and increasing levels of NPS and BDNF in the central amygdala as the context changes.Whereas some anxiolytics were able to reduce the latency to escape for some animals, only with the potent anxiolytic drug antalarmin (CRF1R-blocker) and the anxiogenic drug yohimbine (α2 antagonist) were we able to reverse the outcome for a substantial proportion of individuals. Our findings promote a novel method for modeling anxiety, offering a distinction between low-and-high levels, and accounting for individual variability. The translational value of the VBS is immeasurable, and it guided us and many other researchers to seek potential clinical solutions through a deeper understanding of regional neurochemistry and gene expression in concert with an ecological behavioral model.

Mental disorders associated with benzodiazepine use among older primary care attenders--a regional survey.

PubMed

Balestrieri, Matteo; Marcon, Gabriella; Samani, Fabio; Marini, Monica; Sessa, Emiliano; Gelatti, Umberto; Donato, Francesco

2005-04-01

Benzodiazepines (BDZs) are among the most commonly prescribed drugs in the elderly and their use is often too prolonged according to current international guidelines. We investigated the pattern of use of BDZs among 65- to 84-year-old attenders at 40 Italian primary care practices who answered positively in a questionnaire on the use of anxiolytic/hypnotic drugs and successfully completed the PRIME-MD questionnaire. The survey lasted 6 months, from February to July 2001. Of the 1,156 subjects who completed the PRIME-MD, 748 subjects were positive for at least one psychiatric diagnosis. A depressive disorder was present in 36.5% of all PRIME-MD completers and in about one-third of cases represented by major depression, whereas anxiety disorders, somatoform disorders and alcohol abuse accounted for 18.2%, 8.1% and 1.7% of all PRIME-MD completers, respectively. Most patients were first prescribed BDZs by their General Practitioners (GPs) for each diagnostic group. However, patients with pure anxiety started BDZ treatment during hospitalisation more often (19.7%) than patients with depressive disorders (13.7 %). Moreover, patients with comorbid anxiety and depressive disorders (CADD) were most likely to receive their first BDZ prescription from a psychiatrist (15.7 %). Sleep disturbances were present in at least 50% of cases (and up to 86 %) in each diagnostic group. About 75% of prescriptions concerned anxiolytic BDZ or medium/long-acting BDZ. Most patients with anxiety, CADD and depression used night-time BDZ (65.2%, 56.9 % and 60.5%, respectively). The prevalence of chronic use of BDZs was equally high in all categories of psychiatric disorder (about 90 % for each), showing that the vast majority of patients, irrespective of the diagnosis, had been using BDZs for years. BDZs are widely prescribed for elderly people by their GPs, often for a considerable length of time. The evidence that many BDZ consumers suffer from a depressive or an anxiety disorder, or both, could be a starting point for encouraging a rational prescription in accordance with international guidelines.

A robust animal model of state anxiety: fear-potentiated behaviour in the elevated plus-maze.

PubMed

Korte, S Mechiel; De Boer, Sietse F

2003-02-28

Fear (i.e., decreased percentage time spent on open-arm exploration) in the elevated plus-maze can be potentiated by prior inescapable stressor exposure, but not by escapable stress. The use of fear-potentiated plus-maze behaviour has several advantages as compared to more traditional animal models of anxiety. (a) In contrast to the traditional (spontaneous) elevated plus-maze, which measures innate fear of open spaces, fear-potentiated plus-maze behaviour reflects an enhanced anxiety state (allostatic state). This "state anxiety" can be defined as an unpleasant emotional arousal in face of threatening demands or dangers. A cognitive appraisal of threat is a prerequisite for the experience of this type of emotion. (b) Depending on the stressor used (e.g., fear of shock, predator odour, swim stress, restraint, social defeat, predator stress (cat)), this enhanced anxiety state can last from 90 min to 3 weeks. Stress effects are more severe when rats are isolated in comparison to group housing. (c) Drugs can be administered in the absence of the original stressor and after stressor exposure. As a consequence, retrieval mechanisms are not affected by drug treatment. (d) Fear-potentiated plus-maze behaviour is sensitive to proven/putative anxiolytics and anxiogenics which act via mechanisms related to the benzodiazepine-gamma-aminobutyric acid receptor, but it is also sensitive to corticotropin-releasing receptor antagonists and glucocorticoid receptor antagonists and serotonin receptor agonists/antagonists complex (high predictive validity). (e) Fear-potentiated plus-maze behaviour is very robust, and experiments can easily be replicated in other labs. (f) Fear-potentiated plus-maze behaviour can be measured both in males and females. (g) Neural mechanisms involved in contextual fear conditioning, fear potentiation and state anxiety can be studied.Thus, fear-potentiated plus-maze behaviour may be a valuable measure in the understanding of neural mechanisms involved in the development of anxiety disorders and in the search for novel anxiolytics. Finally, the involvement of corticotropin-releasing factor and corticosteroid-corticotropin-releasing factor interactions in the production of fear-potentiated plus-maze behaviour are discussed.

Comparison of the phenotype of NK1R-/- mice with pharmacological blockade of the substance P (NK1 ) receptor in assays for antidepressant and anxiolytic drugs.

PubMed

Rupniak, N M; Carlson, E J; Webb, J K; Harrison, T; Porsolt, R D; Roux, S; de Felipe, C; Hunt, S P; Oates, B; Wheeldon, A

2001-11-01

The phenotype of NK1R-/- mice was compared with that of acute pharmacological blockade of the tachykinin NK1 receptor on sensorimotor function and in assays relevant to depressive illness and anxiety. The dose range for L-760735 and GR205171 that was associated with functional blockade of central NK1 receptors in the target species was established by antagonism of the behavioural effects of intracerebroventricular NK1 agonist challenge in gerbils, mice and rats. The caudal grooming and scratching response to GR73632 was absent in NK1R-/- mice, confirming that the receptor had been genetically ablated. There was no evidence of sedation or motor impairment in NK1R-/- mice or following administration of L-760735 to gerbils, even at doses in excess of those required for central NK1 receptor occupancy. In the resident-intruder and forced swim test, the behaviour of NK1R-/- mice, or animals treated acutely with L-760735 or GR205171, resembled that seen with the clinically used antidepressant drug fluoxetine. However, the effects of GR205171 were not clearly enantioselective in mice. In contrast, although NK1R-/- mice also exhibited an increase in the duration of struggle behaviour in the tail suspension test, this was not observed following pharmacological blockade with L-760735 in gerbils or GR205171 in mice, suggesting that this may reflect a developmental alteration in the knockout mouse. There was no effect of NK1 receptor blockade with L-760735 in guinea-pigs or GR205171 in rats, or deletion of the NK1 receptor in mice, on behaviour in the elevated plus-maze test for anxiolytic activity. These findings extend previous observations on the phenotype of the NK1R-/- mouse and establish a broadly similar profile following acute pharmacological blockade of the receptor. These studies also serve to underscore the limitations of currently available antagonists that are suitable for use in rat and mouse behavioural assays.

Nuance and behavioral cogency: How the Visible Burrow System inspired the Stress-Alternatives Model and conceptualization of the continuum of anxiety

PubMed Central

Robertson, James M.; Prince, Melissa A.; Achua, Justin K.; Carpenter, Russ E.; Arendt, David H.; Smith, Justin P.; Summers, Torrie L.; Summers, Tangi R.; Summers, Cliff H.

2015-01-01

By creating the Visible Burrow System (VBS) Bob Blanchard found a way to study the interaction of genetics, physiology, environment, and adaptive significance in a model with broad validity. The VBS changed the way we think about anxiety and affective disorders by allowing the mechanisms which control them to be observed in a dynamic setting. Critically, Blanchard used the VBS and other models to show how behavioral systems like defense are dependent upon context and behavioral elements unique to the individual. Inspired by the VBS, we developed a Stress Alternatives Model (SAM) to further explore the multifaceted dynamics of the stress response with a dichotomous choice condition. Like the VBS, the SAM is a naturalistic model built upon risk-assessment and defensive behavior, but with a choice of response: escape or submission to a large conspecific aggressor. The anxiety of novelty during the first escape must be weighed against fear of the aggressor, and a decision must be made. Both outcomes are adaptively significant, evidenced by a 50/50 split in outcome across several study systems. By manipulating the variables of the SAM, we show that a gradient of anxiety exists that spans the contextual settings of escaping an open field, escaping from aggression, and submitting to aggression. These findings correspond with increasing levels of corticosterone and increasing levels of NPS and BDNF in the central amygdala as the context changes. Whereas some anxiolytics were able to reduce the latency to escape for some animals, only with the potent anxiolytic drug antalarmin (CRF1R-blocker) and the anxiogenic drug yohimbine (α2 antagonist) were we able to reverse the outcome for a substantial proportion of individuals. Our findings promote a novel method for modeling anxiety, offering a distinction between low-and-high levels, and accounting for individual variability. The translational value of the VBS is immeasurable, and it guided us and many other researchers to seek potential clinical solutions through a deeper understanding of regional neurochemistry and gene expression in concert with an ecological behavioral model. PMID:26066728

[Mechanism of action of antiepileptic drugs].

PubMed

Saidón, Patricia

2003-01-01

Antiepileptic drugs (DAEs) act through different mechanisms of action: increase in central inhibition, inhibition of excitatorios mechanisms and modification of the excitability through their action on the ionic channels. Epilepsy is characterized by an abnormal and hypersynchronic unloading of a neuronal population. The activity of numerous drugs is associated to increase in gabaergic activity. Another group of drugs decreases excitatory mechanisms, through the inhibition of ionic channels, or through a decrease in the activity of the excitatory neurotransmitters. There are some of antiepileptic drugs, especially within the group of drugs of recent appearance, for wich the mechanism of action remains unknown.

Evaluation of the anxiolytic and antidepressant effects of asiatic acid, a compound from Gotu kola or Centella asiatica, in the male Sprague Dawley rat.

PubMed

Ceremuga, Tomás Eduardo; Valdivieso, Debra; Kenner, Catherine; Lucia, Amy; Lathrop, Keith; Stailey, Owen; Bailey, Heather; Criss, Jonathan; Linton, Jessica; Fried, Jordan; Taylor, Andrew; Padron, Gina; Johnson, Arthur Don

2015-04-01

Herbal medication use continues to rise and interactions with existing medications propose risks and may have significant effects and consequences on the administration of anesthesia. The purpose of this study was to investigate the anxiolytic and antidepressant effects of asiatic acid and its potential modulation of the γ-aminobutyric acid (GABAA) receptor. Fifty-five male Sprague Dawley rats were divided into 5 groups: vehicle (DMSO), asiatic acid (AA), midazolam, or a combination of flumazenil + AA or midazolam + AA, and injected intraperitoneally 30 minutes prior to testing. The rats were tested on the Elevated Plus Maze (EPM) and the Forced Swim Test (FST). Data were analyzed using a two-tailed multivariate analysis of variance (MANOVA). Significance was found regarding the ratio of open arm time, maximum speed, and time spent mobile in the AA group and the midazolam + AA group (P < .05). Flumazenil decreased the anxiolytic effects, suggesting that AA modulates the benzodiazepine site on the GABAA receptor. Further studies are recommended to determine the efficacy of prolonged treatment for anxiety and depression.

Anti-dermatitis, anxiolytic and analgesic effects of Rhazya stricta from Balochistan.

PubMed

Ahmad, Mansoor; Muhammed, Shafi; Mehjabeen; Jahan, Noor; Jan, Syed Umer; Qureshi, Zia-Ul-Rehaman

2014-05-01

Current study was carried out on Rhazya stricta. Plant material was collected from Jhalmagsi Dist. Balochistan, Pakistan. Methanolic extract of Rhazya stricta was tested for anti-dermatitis, analgesic, anxiolytic effects, insecticidal activity and Brine shrimp Bioassay. Crude extract showed significant anti-dermatitis activity, as the results of intensity score showed mild Excoriation or erosion, moderate Edema or populations and absence of Erythema or hemorrhage, Scratching time was decreased to 1.45 and histological observations of mice treated with crude extract showed mild changes and few inflammatory cells in several microscopic fields. The results of analgesic activity were significant and the percentage inhibition of writhes were 73.54% and 69.38% at 300mg/kg and 500mg/kg respectively. The overall response of crude extract in anxiolytic activities were depressive and crude extract showed sedative effects. In Brine shrimp (Artemsia salina) lethality bioassay crude extract showed dose depended significant activity, and showed positive lethality with LD(50) 3.3004μg/ml. Insecticidal activity was positive against Callosbruchus analis, the percent mortality was 40%.

The anxiolitic effects of BTG1640 and BTG1675A on ultrasonic isolation calls and locomotor activity of rat pups.

PubMed

Niculescu, M; Cagiano, R; Caprio, M; Damian, S; Boia, E; Vermesan, D; Tattoli, M; Haragus, H

2016-12-01

The aim of the present study was to evaluate the anxiolytic properties of the new isoxazoline compounds BTG1640 and BTG1675A in comparison with diazepam. We evaluated the ultrasonic distress emission in both sexes of neonatal rat pups (which seems to be a sensitive indicator of the rat emotional reactivity and represents a valuable tool to screen compounds with expected anxiolytic properties) and the locomotor activity in 30-day old rat pups. We found a significant reduction in the number of emitted ultrasonic calls only after i.p. administration of diazepam 1 mg/kg, while no significant reduction have been detected after i.p. administration of BTG 1640 and BTG 1675A. Furthermore, we found a significant reduction of locomotor activity in the first 10' of the test, only in the group treated with diazepam 0.1 mg. The tests validating the supposed anxiolytic properties of the new isoxazoline compounds BTG1640 and BTG1675A, in comparison with diazepam, gave negative results.

The impact of the Canterbury earthquakes on prescribing for mental health.

PubMed

Beaglehole, Ben; Bell, Caroline; Frampton, Christopher; Hamilton, Greg; McKean, Andrew

2015-08-01

The aim of this study is to evaluate the impact of the Canterbury earthquakes on the mental health of the local population by examining prescribing patterns of psychotropic medication. Dispensing data from community pharmacies for antidepressants, antipsychotics, anxiolytics and sedatives/hypnotics are routinely recorded in a national database. The close relationship between prescribing and dispensing provides the opportunity to assess prescribing trends for Canterbury compared to national data and therefore examines the longitudinal impact of the earthquakes on prescribing patterns. Short-term increases in the use of anxiolytics and sedatives/hypnotics were observed after the most devastating February 2011 earthquake, but this effect was not sustained. There were no observable effects of the earthquakes on antidepressant or antipsychotic dispensing. Short-term increases in dispensing were only observed for the classes of anxiolytics and sedatives/hypnotics. No sustained changes in dispensing occurred. These findings suggest that long-term detrimental effects on the mental health of the Canterbury population were either not present or have not resulted in increased prescribing of psychotropic medication. © The Royal Australian and New Zealand College of Psychiatrists 2015.

How an Age of Anxiety Became an Age of Depression

PubMed Central

Horwitz, Allan V

2010-01-01

Context: During the 1950s and 1960s, anxiety was the emblematic mental health problem in the United States, and depression was considered to be a rare condition. One of the most puzzling phenomena regarding mental health treatment, research, and policy is why depression has become the central component of the stress tradition since then. Methods: This article reviews statistical trends in diagnosis, treatment, drug prescriptions, and textual readings of diagnostic criteria and secondary literature. Findings: The association of anxiety with diffuse and amorphous conceptions of “stress” and “neuroses” became incompatible with professional norms demanding diagnostic specificity. At the same time, the contrasting nosologies of anxiety and depression in the Diagnostic and Statistical Manual of Mental Disorders III (DSM-III) extended major depressive disorder to encompass far more patients than any particular anxiety disorder. In addition, antidepressant drugs were not associated with the stigma and alleged side effects of the anxiolytic drugs. Conclusion: Various factors combined between the 1970s and the 1990s to transform conditions that had been viewed as “anxiety” into “depression.” New interests in the twenty-first century, however, might lead to the reemergence of anxiety as the signature mental health problem of American society. PMID:20377760

21 CFR 1404.635 - May the Office of National Drug Control Policy settle a debarment or suspension action?

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 9 2010-04-01 2010-04-01 false May the Office of National Drug Control Policy settle a debarment or suspension action? 1404.635 Section 1404.635 Food and Drugs OFFICE OF NATIONAL DRUG CONTROL POLICY GOVERNMENTWIDE DEBARMENT AND SUSPENSION (NONPROCUREMENT) General Principles Relating to Suspension and Debarment Actions § 1404.635...

[Antipsychotic prescription patterns in patients affiliated to the Social Security Health System in Colombia].

PubMed

Machado-Alba, Jorge E; Morales-Plaza, Cristhian David

2013-01-01

Schizophrenia alters individual perception, thought, affection and behavior. Drug therapy can improve these manifestations. To determine prescription patterns of antipsychotic drugs in a group of patients affiliated to the Social Security Health System in Colombia. This was a descriptive study with a 6.2 million people database. We selected 3,075 patients medicated with antipsychotics, of both sexes, and all ages, with continuous treatment from March to June, 2012, and residing in 57 Colombian cities. We designed a database on drug consumption, obtained by the company that distributes the drugs to the patients. A total of 3,075 patients were studied, with an age mean of 55.8 ± 21.5 years; 50.3% of the participants were women. Of all patients, 81.9% were receiving monotherapy and 18.1% two or more antipsychotics. Prescription order was 77.1% atypical and 31.9% conventional. The most frequently used drugs were: quetiapine (on 30.3% of the patients), clozapine (23.7%), levomepropamize (18.4%), and risperidone (14.9%). The most common combinations were: haloperidol + levomepromazine (n=67, 12.1%), clozapine + pipotiazine (n=54, 9.7%), clozapine + risperidone (n=45, 8.1%), and quetiapine + levomepromazine (n=40, 7.2%). The most prescribed co-medications were: antidepressants (n=998, 32.5%), anxiolytic (n=799, 26.0%), statins (n=672, 21.9%); antiparkinsonians (n=341, 11.1%), and antidiabetic drugs (n=327, 10.6%). The practice of prescribing drugs with a high therapeutic value predominates mainly in antipsychotic monotherapy. Most agents were used in higher doses than recommended. This raises the need to design educational strategies to address these prescribing habits and research for evaluating the effectiveness of the treatment.

Diphenyl diselenide ameliorates monosodium glutamate induced anxiety-like behavior in rats by modulating hippocampal BDNF-Akt pathway and uptake of GABA and serotonin neurotransmitters.

PubMed

Rosa, Suzan Gonçalves; Quines, Caroline Brandão; Stangherlin, Eluza Curte; Nogueira, Cristina Wayne

2016-03-01

Monosodium glutamate (MSG), a flavor enhancer used in food, administered to neonatal rats causes neuronal lesions and leads to anxiety when adulthood. We investigated the anxiolytic-like effect of diphenyl diselenide (PhSe)2 and its mechanisms on anxiety induced by MSG. Neonatal male and female Wistar rats received a subcutaneous injection of saline (0.9%) or MSG (4 g/kg/day) from the 1st to 10th postnatal day. At 60 days of life, the rats received (PhSe)2 (1mg/kg/day) or vehicle by the intragastric route for 7 days. The spontaneous locomotor activity (LAM), elevated plus maze test (EPM) and contextual fear conditioning test (CFC) as well as neurochemical ([(3)H]GABA and [(3)H]5-HT uptake) and molecular analyses (Akt and p-Akt and BDNF levels) were carried out after treatment with (PhSe)2. Neonatal exposure to MSG increased all anxiogenic parameters in LAM, EPM and CFC tests. MSG increased GABA and 5-HT uptake in hippocampus of rats, without changing uptake in cerebral cortex. The levels of BDNF and p-Akt were reduced in hippocampus of rats treated with MSG. The administration of (PhSe)2 to rats reversed all behavioral anxiogenic parameters altered by MSG. The increase in hippocampal GABA and 5-HT uptake induced by MSG was reversed by (PhSe)2. (PhSe)2 reversed the reduction in hippocampal BDNF and p-Akt levels induced by MSG. In conclusion, the anxiolytic-like action of (PhSe)2 in rats exposed to MSG during their neonatal period is related to its modulation of hippocampal GABA and 5-HT uptake as well as the BDNF-Akt pathway. Copyright © 2015 Elsevier Inc. All rights reserved.

An acute, double-blind, placebo-controlled cross-over study of 320 mg and 640 mg doses of Bacopa monnieri (CDRI 08) on multitasking stress reactivity and mood.

PubMed

Benson, Sarah; Downey, Luke A; Stough, Con; Wetherell, Mark; Zangara, Andrea; Scholey, Andrew

2014-04-01

Little research exists in humans concerning the anxiolytic, antidepressant, sedative, and adaptogenic actions the traditional Ayurvedic medicine Bacopa monnieri (BM) possesses in addition to its documented cognitive-enhancing effects. Preclinical work has identified a number of acute anxiolytic, nootropic, and adaptogenic effects of BM that may also co-occur in humans. The current double-blind, placebo-controlled cross-over study assessed the acute effects of a specific extract of BM (KeenMind® - CDRI 08) in normal healthy participants during completion of a multitasking framework (MTF). Seventeen healthy volunteers completed the MTF, at baseline, then 1 h and 2 h after consuming a placebo, 320 mg BM and 640 mg of BM. Treatments were separated by a 7-day washout with order determined by Latin Square. Outcome measures included cognitive outcomes from the MTF, with mood and salivary cortisol measured before and after each completion of the MTF. Change from baseline scores indicated positive cognitive effects, notably at both 1 h post and 2 h post BM consumption on the Letter Search and Stroop tasks, suggesting an earlier nootropic effect of BM than previously investigated. There were also some positive mood effects and reduction in cortisol levels, pointing to a physiological mechanism for stress reduction associated with BM consumption. It was concluded that acute BM supplementation produced some adaptogenic and nootropic effects that need to be replicated in a larger sample and in isolation from stressful cognitive tests in order to quantify the magnitude of these effects. The study was registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12612000834853). Copyright © 2013 John Wiley & Sons, Ltd.

Herbal medicine for depression, anxiety and insomnia: a review of psychopharmacology and clinical evidence.

PubMed

Sarris, Jerome; Panossian, Alexander; Schweitzer, Isaac; Stough, Con; Scholey, Andrew

2011-12-01

Research in the area of herbal psychopharmacology has increased markedly over the past decades. To date however, a comprehensive review of herbal antidepressant, anxiolytic and hypnotic psychopharmacology and applications in depression, anxiety and insomnia has been absent. A search of MEDLINE (PubMed), CINAHL, PsycINFO, and the Cochrane Library databases was conducted (up to February 21st 2011) on commonly used psychotropic herbal medicines. A review of the literature was conducted to ascertain mechanisms of action of these botanicals, in addition to a systematic review of controlled clinical trials for treatment of mood, anxiety and sleep disorders, which are common comorbid psychiatric disorders. Specific emphasis was given to emerging phytomedicines. Analysis of evidence levels was conducted, as were effect sizes (Cohen's d) where data were available. Results provided evidence of a range of neurochemical, endocrinological, and epigenetic effects for 21 individual phytomedicines, which are detailed in this paper. Sixty six controlled studies were located involving eleven phytomedicines. Several of these provide a high level of evidence, such as Hypericum perforatum for major depression, and Piper methysticum for anxiety disorders. Several human clinical trials provide preliminary positive evidence of antidepressant effects (Echium amoenum, Crocus sativus, and Rhodiola rosea) and anxiolytic activity (Matricaria recutita, Ginkgo biloba, Passiflora incanata, E. amoenum, and Scutellaria lateriflora). Caution should however be taken when interpreting the results as many studies have not been replicated. Several herbal medicines with in vitro and in vivo evidence are currently unexplored in human studies, and along with use of emerging genetic technologies "herbomics", are areas of potential future research. Copyright © 2011 Elsevier B.V. All rights reserved.

Potentials of Mangifera indica in the treatment of depressive-anxiety disorders: possible mechanisms of action.

PubMed

Ishola, Ismail O; Awodele, Olufunsho; Eluogu, Chinedum O

2016-09-01

Mangifera indica (Anacardiaceae) is an important herb in the traditional African and Ayurvedic medicines. The stem barks are used in the treatment of hypertension, insomnia, tumour, depression, rheumatism and as a tonic. This study was carried out to investigate antidepressant- and anxiolytic-like effect of the hydroethanol stem bark extract of M. indica (HeMI) in mice. HeMI (12.5-100 mg/kg, p.o.) was administered 1 h before subjecting the animal to the forced swim test (FST), tail suspension test (TST) and elevated plus maze tests (EPM). HeMI (12.5-100 mg/kg, p.o.) treatment produced significant reduction in immobility time [F(6.56)=8.35, p<0.001], [F(6,56)=7.55, p<0.001] in the FST and TST, respectively. Moreover, co-administration of sub-therapeutic doses of imipramine or fluoxetine with HeMI (3.125 mg/kg) elicited significant reduction in time spent immobile in the FST. However, pretreatment of mice with parachlorophenylalanine, metergoline, yohimbine or sulpiride abolished the antidepressant-like effect elicited by HeMI. In the EPM, HeMI produced significant [F(5,42)=8.91, p<0.001] increase in open arms exploration by 75.55 % and this effect was blocked by pretreatment of mice with flumazenil or metergoline. Findings from this study showed antidepressant-like effect of M. indica through interaction with 5-HT2 receptor, α2-adrenoceptor and dopamine D2-receptors. Also, an anxiolytic-like effect through its affinity for 5-HT2 and benzodiazepine receptors. Hence, M. indica could be a potential phytotherapeutic agent in the treatment of mixed anxiety-depressive illness.

Pharmacodynamic and pharmacokinetic effects of MK-0343, a GABA(A) alpha2,3 subtype selective agonist, compared to lorazepam and placebo in healthy male volunteers.

PubMed

de Haas, S L; de Visser, S J; van der Post, J P; Schoemaker, R C; van Dyck, K; Murphy, M G; de Smet, M; Vessey, L K; Ramakrishnan, R; Xue, L; Cohen, A F; van Gerven, J M A

2008-01-01

The use of non-selective gamma-aminobutyric acid (GABA) enhancers, such as benzodiazepines in the treatment of anxiety disorders is still widespread but hampered by unfavourable side effects. some of these may be associated with binding properties to certain subtypes of the GABA(A) receptor that are unnecessary for therapeutic effects. MK-0343 was designed to be a less sedating anxiolytic, based on reduced efficacy at the alpha1 subtype and significant efficacy at alpha2 and alpha3 subtypes of the GABA(A) receptor. This paper is a double-blind, four-way cross-over (n = 12) study to investigate the effects of MK-0343 (0.25 and 0.75 mg) in comparison to placebo and an anxiolytic dose (2 mg) of the non-selective agonist lorazepam. Effects were measured by eye movements, body sway, Visual Analogue scales (VAS) and memory tests. Lorazepam impaired saccadic peak velocity (SPV), VAs alertness scores, postural stability and memory and increased saccadic latency and inaccuracy. MK-0343 0.75 mg was equipotent with lorazepam as indicated by SPV (-42.4 deg/s), saccadic latency (0.02 s) and VAS alertness scores (1.50 ln mm), while effects on memory and postural stability were smaller. MK-0343 0.25 mg only affected postural stability to a similar extent as MK-0343 0.75 mg. The effect profile of MK-0343 0.75 mg is different from the full agonist lorazepam, which could reflect the selective actions of this compound. Although less effect on VAS alertness was expected, diminished effects on memory and postural stability were present. Clinical studies in anxiety patients should show whether this dose of MK-0343 is therapeutically effective with a different side-effect profile.

Association of Attorney Advertising and FDA Action with Prescription Claims: A Time Series Segmented Regression Analysis.

PubMed

Tippett, Elizabeth C; Chen, Brian K

2015-12-01

Attorneys sponsor television advertisements that include repeated warnings about adverse drug events to solicit consumers for lawsuits against drug manufacturers. The relationship between such advertising, safety actions by the US Food and Drug Administration (FDA), and healthcare use is unknown. To investigate the relationship between attorney advertising, FDA actions, and prescription drug claims. The study examined total users per month and prescription rates for seven drugs with substantial attorney advertising volume and FDA or other safety interventions during 2009. Segmented regression analysis was used to detect pre-intervention trends, post-intervention level changes, and changes in post-intervention trends relative to the pre-intervention trends in the use of these seven drugs, using advertising volume, media hits, and the number of Medicare enrollees as covariates. Data for these variables were obtained from the Center for Medicare and Medicaid Services, Kantar Media, and LexisNexis. Several types of safety actions were associated with reductions in drug users and/or prescription rates, particularly for fentanyl, varenicline, and paroxetine. In most cases, attorney advertising volume rose in conjunction with major safety actions. Attorney advertising volume was positively correlated with prescription rates in five of seven drugs, likely because advertising volume began rising before safety actions, when prescription rates were still increasing. On the other hand, attorney advertising had mixed associations with the number of users per month. Regulatory and safety actions likely reduced the number of users and/or prescription rates for some drugs. Attorneys may have strategically chosen to begin advertising adverse drug events prior to major safety actions, but we found little evidence that attorney advertising reduced drug use. Further research is needed to better understand how consumers and physicians respond to attorney advertising.

[In vivo study of the pharmacokinetic interaction of afobazole and losartan (cytochrome CYP2C9 substrate)].

PubMed

Gribakina, O G; Kolyvanov, G B; Litvin, A A; Zherdev, V P; Seredin, S B

2013-01-01

The influence of afobazole on isoenzyme CYP2C9 production in rats was studied using losartan as the marker drug. Single dose of losartan was administered orally without afobazole in a dose of 30 mg/kg and in the same single (30 mg/kg) on the background of 3- and 4-day administration of afobazole in a dose of 5, 25, 75, 100, and 125 mg/kg. At 5 mg/kg (effective dose for anxiolytic effect), afobazole did not cause any induction/inhibition effect on CYP2C9 isoenzyme. A multiple increase in afobazole dose was manifested by a moderate induction effect. The maximum induction effect of afobazole was achieved in a dose of 75 mg/kg. At doses above 75 mg/kg, the induction effect of afobazole was less pronounced.

Kindling and withdrawal changes at the benzodiazepine receptor.

PubMed

Little, H J; Nutt, D J; Taylor, S C

1987-01-01

Drugs acting at benzodiazepine receptors can have two types of pharmacological profile: benzodiazepine agonists are anxiolytic, anticonvulsant and sedative, whilst benzo diazepine inverse agonists cause anxiety and convulsions. In 1982 we showed that a benzo diazepine antagonist, Ro 15-1788, prevented the effects of both types of compound at doses without intrinsic activity in the tests used. We put forward the hypothesis that the benzo diazepine receptor complex could undergo two possible conformational changes, resulting in increases (benzodiazepine agonists) or decreases (benzodiazepine inverse agonists) in the effects of the inhibitory transmitter γ-aminobutyric acid (GABA). This concept has been widely accepted. We have now studied the effects of inverse agonists after chronic treatment with inverse agonists themselves and with benzodiazepine agonists, in order to see if tolerance develops (as seen with the agonists) or whether an opposite change occurs.

Society of Family Planning clinical guidelines pain control in surgical abortion part 1 - local anesthesia and minimal sedation.

PubMed

Allen, Rebecca H; Singh, Rameet

2018-06-01

Satisfactory pain control for women undergoing surgical abortion is important for patient comfort and satisfaction. Clinicians ought to be aware of the safety and efficacy of different pain control regimens. This document will focus on nonpharmacologic modalities to reduce pain and pharmacologic interventions up to the level of minimal sedation. For surgical abortion without intravenous medications, a multimodal approach to pain control may combine a dedicated emotional-support person, visual or auditory distraction, administration of local anesthesia to the cervix with buffered lidocaine and a preoperative nonsteroidal anti-inflammatory drug. Oral opioids do not decrease procedural pain. Oral anxiolytics decrease anxiety but not the experience of pain. Further research is needed on alternative options to control pain short of moderate or deep sedation. Copyright © 2018 Elsevier Inc. All rights reserved.

Does mechanism of drug action matter to inform rational polytherapy in epilepsy?

PubMed

Giussani, Giorgia; Beghi, Ettore

2013-05-01

When monotherapy for epilepsy fails, add-on therapy is an alternative option. There are several possible antiepileptic drug combinations based on their different and multiple mechanisms of action and pharmacokinetic interactions. However, only when benefits of drug combinations outweigh the harms, polytherapy can be defined as "rational". In the past 20 years, second generation AEDs have been marketed, some of which have better defined mechanisms of action and better pharmacokinetic profile. The mechanisms of action of AEDs involve, among others, blockade of voltage-gated sodium channels, blockade of voltage-gated calcium channel, activation of the ionotropic GABAA receptor and increase of GABA levels at the synaptic cleft, blockade of glutamate receptors, binding to synaptic vesicle protein 2A, and opening of KCNQ (Kv7) potassium channels. Aim of this review was to examine published reports on AEDs combinations in animal models and humans focusing on mechanisms of action and pharmacokinetic interactions. Studies in animals have shown that AED combinations are more effective when using drugs with different mechanisms of action. The most effective combination was found using a drug with a single mechanism of action and another with multiple mechanisms of action. In humans some combinations between a blocker of voltage-gated sodium channels and a drug with multiple mechanisms of action may be synergistic. Future studies are necessary to better define rational combinations and complementary mechanisms of action, considering also pharmacokinetic interactions and measures of toxicity and not only drug efficacy.

PROPER I: frequency and appropriateness of psychotropic drugs use in nursing home patients and its associations: a study protocol

PubMed Central

2013-01-01

Background Nursing home patients with dementia use psychotropic drugs longer and more frequently than recommended by guidelines implying psychotropic drugs are not always prescribed appropriately. These drugs can have many side effects and effectiveness is limited. Psychotropic drug use between nursing home units varies and is not solely related to the severity of neuropsychiatric symptoms. There is growing evidence indicating that psychotropic drug use is associated with environmental factors, suggesting that the prescription of psychotropic drugs is not only related to (objective) patient factors. However, other factors related to the patient, elderly care physician, nurse and the physical environment are only partially identified. Using a mixed method of qualitative and quantitative research, this study aims to understand the nature of psychotropic drug use and its underlying factors by identifying: 1) frequency and appropriateness of psychotropic drug use for neuropsychiatric symptoms in nursing home patients with dementia, 2) factors associated with (appropriateness of) psychotropic drug use. Methods A cross-sectional mixed methods study. For the quantitative study, patients with dementia (n = 540), nursing staff and elderly care physicians of 36 Dementia Special Care Units of 12 nursing homes throughout the Netherlands will be recruited. Six nursing homes with high average rates and six with low average rates of psychotropic drug use, based on a national survey about frequency of psychotropic drug use on units, will be included. Psychotropic drugs include antipsychotics, anxiolytics, hypnotics, antidepressants, anticonvulsants and anti-dementia drugs. Appropriateness will be measured by an instrument based on the Medication Appropriateness Index and current guidelines for treatment of neuropsychiatric symptoms. Factors associated to psychotropic drug use, related to the patient, elderly care physician, nurse and physical environment, will be explored using multilevel regression analyses. For the qualitative study, in depth interviews with staff will be held and analyzed to identify and explore other unknown factors. Discussion This study will provide insight into factors that are associated with the frequency and appropriateness of psychotropic drug use for neuropsychiatric symptoms. Understanding psychotropic drug use and its associations may contribute to better dementia care. PMID:24238392

Are Plasma Oxytocin and Vasopressin Levels Reflective of Amygdala Activation during the Processing of Negative Emotions? A Preliminary Study.

PubMed

Motoki, Kosuke; Sugiura, Motoaki; Takeuchi, Hikaru; Kotozaki, Yuka; Nakagawa, Seishu; Yokoyama, Ryoichi; Kawashima, Ryuta

2016-01-01

Plasma oxytocin (OT) and arginine vasopressin (AVP) are associated with individual differences in emotional responses and behaviors. The amygdala is considered to be an important brain region for regulating emotion-based behavior, with OT and AVP modulating activity in the amygdala during the processing of negative emotions. In particular, increased OT levels may diminish amygdala activation (anxiolytic effects) and enhanced AVP levels may augment amygdala activation (anxiogenic effects) when negative emotions are processed. A growing body of research has shown that the effects of OT and AVP are modulated by sex: the aforementioned anxiolytic effects of OT and the anxiogenic effects of AVP occur in men, but not in women. However, we have little knowledge regarding the biological mechanisms underlying OT and AVP plasma levels or their respective anxiogenic and anxiolytic effects; similarly, little is known about the causes and nature of sex differences related to these neuropeptides and their effects on emotional processing. In the current study, we focused on the neural functions associated with the biological mechanisms underlying such effects. We hypothesized that amygdala activation would correlate with trait plasma OT (anxiolytic effects) and AVP (anxiogenic effects) levels because the amygdala is thought to affect the coordinated release of these neuropeptides following affective experiences. We further hypothesized that the effects would be modulated by sex. We assessed 51 participants (male and female) using a paradigm involving negative emotion in conjunction with functional magnetic resonance imaging and measurements of plasma OT and AVP levels. We determined that increased plasma AVP levels were positively associated with amygdala activation (anxiogenic effects) in men, but not in women. These findings highlight the potential underlying neural mechanisms of plasma AVP levels in men.

Big dynorphin, a prodynorphin-derived peptide produces NMDA receptor-mediated effects on memory, anxiolytic-like and locomotor behavior in mice.

PubMed

Kuzmin, Alexander; Madjid, Nather; Terenius, Lars; Ogren, Sven Ove; Bakalkin, Georgy

2006-09-01

Effects of big dynorphin (Big Dyn), a prodynorphin-derived peptide consisting of dynorphin A (Dyn A) and dynorphin B (Dyn B) on memory function, anxiety, and locomotor activity were studied in mice and compared to those of Dyn A and Dyn B. All peptides administered i.c.v. increased step-through latency in the passive avoidance test with the maximum effective doses of 2.5, 0.005, and 0.7 nmol/animal, respectively. Effects of Big Dyn were inhibited by MK 801 (0.1 mg/kg), an NMDA ion-channel blocker whereas those of dynorphins A and B were blocked by the kappa-opioid antagonist nor-binaltorphimine (6 mg/kg). Big Dyn (2.5 nmol) enhanced locomotor activity in the open field test and induced anxiolytic-like behavior both effects blocked by MK 801. No changes in locomotor activity and no signs of anxiolytic-like behavior were produced by dynorphins A and B. Big Dyn (2.5 nmol) increased time spent in the open branches of the elevated plus maze apparatus with no changes in general locomotion. Whereas dynorphins A and B (i.c.v., 0.05 and 7 nmol/animal, respectively) produced analgesia in the hot-plate test Big Dyn did not. Thus, Big Dyn differs from its fragments dynorphins A and B in its unique pattern of memory enhancing, locomotor- and anxiolytic-like effects that are sensitive to the NMDA receptor blockade. The findings suggest that Big Dyn has its own function in the brain different from those of the prodynorphin-derived peptides acting through kappa-opioid receptors.

The GABA(B) receptor positive modulator BHF177 attenuated anxiety, but not conditioned fear, in rats.

PubMed

Li, Xia; Kaczanowska, Katarzyna; Finn, M G; Markou, Athina; Risbrough, Victoria B

2015-10-01

GABAB (γ-aminobutyric acid B) receptors may be a therapeutic target for anxiety disorders. Here we characterized the effects of the GABAB receptor positive allosteric modulator (PAM) BHF177 on conditioned and unconditioned physiological responses to threat in the light-enhanced startle (LES), stress-induced hyperthermia, and fear-potentiated startle (FPS) procedures in rats. The effects of BHF177 on LES were compared with those of the GABAB receptor agonists baclofen and CGP44532, and the positive control buspirone, a 5-HT1A receptor partial agonist with anxiolytic activity in humans. Baclofen (0.4, 0.9 and 1.25 mg/kg) and CGP44532 (0.065, 0.125 and 0.25 mg/kg) administration had significant sedative, but not anxiolytic, activity reflected in overall decrease in the startle response in the LES tests. BHF177 (10, 20 and 40 mg/kg) had no effect on LES, nor did it produce an overall sedative effect. Interesting, however, when rats were grouped by high and low LES responses, BHF177 had anxiolytic-like effects only on LES in high, but not low, LES responding rats. BHF177 also blocked stress-induced hyperthermia, but had no effect on conditioned fear responses in the FPS test. Buspirone (1 and 3 mg/kg) had an anxiolytic-like profile in both LES and FPS tests. These results indicate that BHF177 may specifically attenuate unconditioned anxiety in individuals that exhibit a high anxiety state, and has fewer sedative effects than direct agonists. Thus, BHF177 or other GABAB receptor PAMs may be promising compounds for alleviating increased anxiety seen in various psychiatric disorders with a superior side-effect profile compared to GABAB receptor agonists. Published by Elsevier Ltd.

Changes in psychosocial and physical working conditions and psychotropic medication in ageing public sector employees: a record-linkage follow-up study.

PubMed

Kouvonen, Anne; Mänty, Minna; Lallukka, Tea; Pietiläinen, Olli; Lahelma, Eero; Rahkonen, Ossi

2017-07-12

To investigate whether changes in psychosocial and physical working conditions are associated with subsequent psychotropic medication in ageing employees. Data were from the Helsinki Health Study, a cohort study of Finnish municipal employees, aged 40-60 years at phase 1 (2000-2002). Changes in psychosocial and physical working conditions were measured between phase 1 and phase 2 (2007). Survey data were longitudinally linked to data on prescribed, reimbursed psychotropic medication purchases (Anatomical Therapeutic Chemical) obtained from the registers of the Social Insurance Institution of Finland between the phase 2 survey and December 2013 (N=3587; 80% women). Outcomes were any psychotropic medication; antidepressants (N06A); anxiolytics (N05B); and sedatives and hypnotics (N05C). Cox regression analyses were performed. During the follow-up, 28% of the participants were prescribed psychotropic medication. Repeated exposures to low job control, high job demands and high physical work load were associated with an increased risk of subsequent antidepressant and anxiolytic medication. Increased and repeated exposure to high physical work load, increased job control and repeated high job demands were associated with subsequent sedative and hypnotic medication. Age and sex-adjusted HR varied from 1.18 to 1.66. Improvement in job control was associated with a lower risk of anxiolytic, but with a higher risk of sedatives and hypnotic medication. Decreased physical work load was associated with a lower risk of antidepressant and anxiolytic medications. Improvement in working conditions could lower the risk of mental ill-health indicated by psychotropic medication. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Anxiolytic and antidepressant profile of the methanolic extract of Piper nigrum fruits in beta-amyloid (1-42) rat model of Alzheimer's disease.

PubMed

Hritcu, Lucian; Noumedem, Jaurès A; Cioanca, Oana; Hancianu, Monica; Postu, Paula; Mihasan, Marius

2015-03-29

Piper nigrum L. (Piperaceae) is employed in traditional medicine of many countries as analgesic, antiinflammatory, anticonvulsant, antioxidant, antidepressant and cognitive-enhancing agent. This study was undertaken in order to evaluate the possible anxiolytic, antidepressant and antioxidant properties of the methanolic extract of Piper nigrum fruits in beta-amyloid (1-42) rat model of Alzheimer's disease. The anxiolytic- and antidepressant-like effects of the methanolic extract were studied by means of in vivo (elevated plus-maze and forced swimming tests) approaches. Also, the antioxidant activity in the amygdala was assessed using superoxide dismutase, glutathione peroxidase and catalase specific activities, the total content of the reduced glutathione, protein carbonyl and malondialdehyde levels. Statistical analyses were performed using one-way analysis of variance (ANOVA). Significant differences were determined by Tukey's post hoc test. F values for which p < 0.05 were regarded as statistically significant. Pearson's correlation coefficient and regression analysis were used in order to evaluate the connection between behavioral measures, the antioxidant defence and lipid peroxidation. The beta-amyloid (1-42)-treated rats exhibited the following: decrease of the exploratory activity, the percentage of the time spent and the number of entries in the open arm within elevated plus-maze test and decrease of swimming time and increase of immobility time within forced swimming test. Administration of the methanolic extract significantly exhibited anxiolytic- and antidepressant-like effects and also antioxidant potential. Taken together, our results suggest that the methanolic extract ameliorates beta-amyloid (1-42)-induced anxiety and depression by attenuation of the oxidative stress in the rat amygdala.

alpha2-Adrenergic agonists antagonise the anxiolytic-like effect of antidepressants in the four-plate test in mice.

PubMed

Massé, Fabienne; Hascoët, Martine; Bourin, Michel

2005-10-14

Selective serotonin reuptake inhibitors (SSRIs) and serotonin/noradrenaline reuptake inhibitors (SNRIs) has been reported to be efficient in anxiety disorders. Some animal models have demonstrated an anxiolytic-like effect following acute administration, however, it is not yet known how noradrenergic receptors are implicated in the therapeutic effects of antidepressants (ADs) in anxiety. The effects of two alpha(2)-adrenoceptor agonists (clonidine, guanabenz) on anxiolytic-like effect of two SSRIs (paroxetine and citalopram) and two SNRIs (venlafaxine and milnacipran) were evaluated in the four-plate test (FPT) in mice. Paroxetine (4 mg/kg), citalopram (8 mg/kg), venlafaxine (8 mg/kg), and milnacipran (8 mg/kg) administered intraperitoneally (i.p.) increased the number of punishments accepted by mice in the FPT. Clonidine (0.0039-0.5 mg/kg) and guanabenz (0.03-0.5mg/kg) had no effect on the number of punishments accepted by mice. Clonidine (0.03 and 0.06 mg/kg) and guanabenz (0.125 and 0.5 mg/kg) (i.p. -45 min) reversed the anti-punishment effect of paroxetine, citalopram, venlafaxine and milnacipran (i.p. -30 min). But if the antidepressants are administered 45 min before the test and alpha(2)-adrenoceptor agonists 30 min before the test, alpha(2)-adrenoceptor agonists failed to alter the anti-punishment effect of antidepressants. The results of this present study indicate that alpha(2)-adrenoceptor agonists antagonise the anxiolytic-like effect of antidepressants in mice when they are administered 15 min before the administration of antidepressant suggesting a close inter-regulation between noradrenergic and serotoninergic system in the mechanism of SSRIs and SNRIs in anxiety-like behaviour.

Prototypical anxiolytics do not reduce anxiety-like behavior in the open field in C57BL/6J mice.

PubMed

Thompson, Trey; Grabowski-Boase, Laura; Tarantino, Lisa M

2015-06-01

Understanding and effectively treating anxiety disorders are a challenge for both scientists and clinicians. Despite a variety of available therapies, the efficacy of current treatments is still not optimal and adverse side effects can result in non-compliance. Animal models have been useful for studying the underlying biology of anxiety and assessing the anxiolytic properties of potential therapeutics. The open field (OF) is a commonly used assay of anxiety-like behavior. The OF was developed and validated in rats and then transferred to use in the mouse with only limited validation. The present study tests the efficacy of prototypical benzodiazepine anxiolytics, chlordiazepoxide (CDP) and diazepam (DZ), for increasing center time in the OF in C57BL/6J (B6) mice. Multiple doses of CDP and DZ did not change time spent in the center of the OF. Increasing illumination in the OF did not alter these results. The non-benzodiazepine anxiolytic, buspirone (BUSP) also failed to increase center time in the OF while the anxiogenic meta-chlorophenylpiperazine (mCPP) increased center time. Additional inbred mouse strains, BALB/cJ (BALB) and DBA/2J (D2) did not show any change in center time in response to CDP. Moreover, evaluation of CDP in B6 mice in the elevated plus maze (EPM), elevated zero maze (EZM) and light dark assay (LD) did not reveal changes in anxiety-like behavior while stress-induced hyperthermia (SIH) was decreased by DZ. Pharmacokinetic (PK) studies suggest that adequate CDP is present to induce anxiolysis. We conclude that the measure of center time in the OF does not show predictive validity for anxiolysis in these inbred mouse strains. Copyright © 2015 Elsevier Inc. All rights reserved.

21 CFR 212.71 - What actions must I take if a batch of PET drug product does not conform to specifications?

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 4 2012-04-01 2012-04-01 false What actions must I take if a batch of PET drug... actions must I take if a batch of PET drug product does not conform to specifications? (a) Rejection of nonconforming product. You must reject a batch of a PET drug product that does not conform to specifications...

21 CFR 212.71 - What actions must I take if a batch of PET drug product does not conform to specifications?

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 4 2014-04-01 2014-04-01 false What actions must I take if a batch of PET drug... actions must I take if a batch of PET drug product does not conform to specifications? (a) Rejection of nonconforming product. You must reject a batch of a PET drug product that does not conform to specifications...

21 CFR 212.71 - What actions must I take if a batch of PET drug product does not conform to specifications?

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 4 2011-04-01 2011-04-01 false What actions must I take if a batch of PET drug... actions must I take if a batch of PET drug product does not conform to specifications? (a) Rejection of nonconforming product. You must reject a batch of a PET drug product that does not conform to specifications...

21 CFR 212.71 - What actions must I take if a batch of PET drug product does not conform to specifications?

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 4 2013-04-01 2013-04-01 false What actions must I take if a batch of PET drug... actions must I take if a batch of PET drug product does not conform to specifications? (a) Rejection of nonconforming product. You must reject a batch of a PET drug product that does not conform to specifications...

Disciplinary careers of drug-impaired physicians.

PubMed

Holtman, Matthew C

2007-02-01

Alcohol and drug abuse are among the leading reasons for disciplinary action against physicians by state licensing authorities in the United States. I use event history models to describe the longitudinal patterns in disciplinary actions taken against physicians' licenses by state medical boards in the United States, 1990-2000. Adverse licensure action episodes that included discipline for drug or alcohol abuse were more likely to be followed by license restoration than episodes that did not. However, those restorations were also more likely to be followed by subsequent disciplinary action than episodes that did not include discipline for drug abuse. Furthermore, disciplinary licensure actions for drug abuse were the category most likely to be followed by a subsequent action for the same reason over the longer term (4-11 years). The increased risk of repeat disciplinary action associated with drug abuse may result in part from intensive surveillance of physicians who complete impaired physician programs, through mechanisms that include urine screening. However, it is also likely that the chronic nature of addiction leads to continued risk of relapse even among physicians receiving appropriate treatment.

Noradrenergic facilitation of shock-probe defensive burying in lateral septum of rats, and modulation by chronic treatment with desipramine.

PubMed

Bondi, Corina O; Barrera, Gabriel; Lapiz, M Danet S; Bedard, Tania; Mahan, Amy; Morilak, David A

2007-03-30

We have previously shown that acute stress-induced release of norepinephrine (NE) facilitates anxiety-like behavioral responses to stress, such as reduction in open-arm exploration on the elevated-plus maze and in social behavior on the social interaction test. Since these responses represent inhibition of ongoing behavior, it is important to also address whether NE facilitates a response that represents an activation of behavior. Correspondingly, it is unknown how a chronic elevation in tonic steady-state noradrenergic (NA) neurotransmission induced by NE reuptake blockade might alter this acute modulatory function, a regulatory process that may be pertinent to the anxiolytic effects of NE reuptake blockers such as desipramine (DMI). Therefore, in this study, we investigated noradrenergic modulation of the shock-probe defensive burying response in the lateral septum (LS). In experiment 1, shock-probe exposure induced an acute 3-fold increase in NE levels measured in LS of male Sprague-Dawley rats by microdialysis. Shock-probe exposure also induced a modest rise in plasma ACTH, taken as an indicator of perceived stress, that returned to baseline more rapidly in rats that were allowed to bury the probe compared to rats prevented from burying by providing them with minimal bedding, indicating that the active defensive burying behavior is an effective coping strategy that reduces the impact of acute shock probe-induced stress. In experiment 2, blockade of either alpha(1)- or beta-adrenergic receptors in LS by local antagonist microinjection immediately before testing reduced defensive burying and increased immobility. In the next experiment, chronic DMI treatment increased basal extracellular NE levels in LS, and attenuated the acute shock probe-induced increase in NE release in LS relative to baseline. Chronic DMI treatment decreased shock-probe defensive burying behavior in a time-dependent manner, apparent only after 2 weeks or more of drug treatment. Moreover, rats treated chronically with DMI showed no significant rise of plasma ACTH in response to shock-probe exposure. Thus, acute stress-induced release of NE in LS facilitated defensive burying, an active, adaptive behavioral coping response. Chronic treatment with the NE reuptake blocker and antidepressant drug DMI attenuated acute noradrenergic facilitation of the active burying response, and also attenuated the level of perceived stress driving that response. These results suggest that long-term regulation of the acute modulatory function of NE by chronic treatment with reuptake blockers may contribute to the mechanisms by which such drugs exert their anxiolytic effects in the treatment of stress-related psychiatric conditions, including depression and anxiety.

75 FR 78249 - Agency Information Collection Activities; Submission for Office of Management and Budget Review...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-12-15

... 505(q) of the Federal Food, Drug, and Cosmetic Act AGENCY: Food and Drug Administration, HHS. ACTION... Petitions for Stay of Action Subject to Section 505(q) of the Federal Food, Drug, and Cosmetic Act.'' Also... Petitions for Stay of Action Subject to Section 505(q) of the Federal Food, Drug, and Cosmetic Act In the...

Strychnine and Taurine Modulation of Amygdala-associated Anxiety-like Behavior is ‘State’ Dependent

PubMed Central

McCool, Brian A.; Chappell, Ann

2007-01-01

Strychnine-sensitive glycine receptors are expressed in many adult forebrain regions, yet the biological function of these receptors outside the spinal cord/brainstem is poorly understood. We have recently shown that rat lateral/basolateral amygdala neurons express strychnine-sensitive glycine-gated currents whose pharmacological and molecular characteristics are consistent with those established for classic ligand-gated chloride channels. The current studies were undertaken to establish the behavioral role, if any, of these strychnine-sensitive glycine receptors. Adult Long-Evans male rats were implanted with guide cannulae targeted at the lateral amygdala and were micro-injected with standard artificial cerebrospinal fluid with or without various doses of strychnine or taurine. Anxiety-like behaviors were assessed with the elevated plus-maze or the light/dark box. In the elevated plus maze, strychnine decreased closed-arm time and increased open-arm time, suggestive of an anxiolytic effect. Similarly, strychnine produced a modest anxiolytic effect in the light/dark box. Post-hoc analysis of ‘open-arm’ time and ‘light-side’ time indicated that aCSF-treated animals were distributed into two apparent groups that displayed either high or low amounts of anxiety-like behavior in a given apparatus. Surprisingly, the pharmacological effects of both strychnine and taurine in these assays were dependent upon a given animal’s behavioral phenotype. Together, these findings are significant because they suggest that the basal ‘emotional state’ of the animal could influence the behavioral outcome associated with drug application directly into the lateral/basolateral amygdala. Furthermore, our findings also suggest that compounds acting at amygdala strychnine-sensitive glycine receptors may actively modulate this basal anxiety-like state. PMID:17207866

Reduced attention and increased impulsivity in mice lacking NPY Y2 receptors: relation to anxiolytic-like phenotype.

PubMed

Greco, Barbara; Carli, Mirjana

2006-05-15

Neuropeptide (NPY) Y2 receptors play an important role in some anxiety-related and stress-related behaviours in mice. Changes in the level of anxiety can affect some cognitive functions such as memory, attention and inhibitory response control. We investigated the effects of NPY Y2 receptor deletion (Y2(-/-)) in mice on visual attention and response control using the five-choice serial reaction time (5-CSRT) task in which accuracy of detection of a brief visual stimulus across five spatial locations may serve as a valid behavioural index of attentional functioning. Anticipatory and perseverative responses provide a measure of inhibitory response control. During training, the Y2(-/-) mice had lower accuracy (% correct), and made more anticipatory responses. At stimulus durations of 2 and 4s the Y2(-/-) were as accurate as the Y2(+/+) mice but still more impulsive than Y(+/+). At stimulus durations of 0.25 and 0.5s both groups performed worse but the Y2(-/-) mice made significantly fewer correct responses than the Y2(+/+) controls. The anxiolytic drug diazepam at 2mg/kg IP greatly increased the anticipatory responding of Y2(-/-) mice compared to Y2(+/+). The anxiogenic inverse benzodiazepine agonist, FG 7142, at 10mg/kg IP reduced the anticipatory responding of Y2(-/-) but not Y2(+/+) mice. These data suggest that NPY Y2 receptors make an important contribution to mechanisms controlling attentional functioning and "impulsivity". They also show that "impulsivity" of NPY Y2(-/-) mice may depend on their level of anxiety. These findings may help in understanding the pathophysiology of stress disorders and depression.

DREADD in parvalbumin interneurons of the dentate gyrus modulates anxiety, social interaction and memory extinction.

PubMed

Zou, D; Chen, L; Deng, D; Jiang, D; Dong, F; McSweeney, C; Zhou, Y; Liu, L; Chen, G; Wu, Y; Mao, Y

2016-01-01

Parvalbumin (PV)-positive interneurons in the hippocampus play a critical role in animal memory, such as spatial working memory. However, how PV-positive interneurons in the subregions of the hippocampus affect animal behaviors remains poorly defined. Here, we achieved specific and reversible activation of PV-positive interneurons using designer receptors exclusively activated by designer drugs (DREADD) technology. Inducible DREADD expression was demonstrated in vitro in cultured neurons, in which co-transfection of the hM3D-Gq-mCherry vector with a Cre plasmid resulted in a cellular response to hM3Dq ligand clozapine-N-oxide (CNO) stimulation. In addition, the dentate gyrus (DG) of PV-Cre mice received bilateral injection of control lentivirus or lentivirus expressing double floxed hM3D-Gq-mCherry. Selective activation of PV-positive interneurons in the DG did not affect locomotor activity or depression-related behavior in mice. Interestingly, stimulation of PV-positive interneurons induced an anxiolytic effect. Activation of PVpositive interneurons appears to impair social interaction to novelty, but has no effect on social motivation. However, this defect is likely due to the anxiolytic effect as the exploratory behavior of mice expressing hM3DGq is significantly increased. Mice expressing hM3D-Gq did not affect novel object recognition. Activation of PV-positive interneurons in the DG maintains intact cued and contextual fear memory but facilitates fear extinction. Collectively, our results demonstrated that proper control of PV interneurons activity in the DG is critical for regulation of the anxiety, social interaction and fear extinction. These results improve our fundamental understanding of the physiological role of PV-positive interneurons in the hippocampus.

Evaluating psychological interventions in a novel experimental human model of anxiety

PubMed Central

Ainsworth, Ben; Marshall, Jemma E.; Meron, Daniel; Baldwin, David S.; Chadwick, Paul; Munafò, Marcus R.; Garner, Matthew

2015-01-01

Inhalation of 7.5% carbon dioxide increases anxiety and autonomic arousal and provides a novel experimental model of anxiety with which to evaluate pharmacological and psychological treatments for anxiety. To date several psychotropic drugs including benzodiazepines, SSRIs and SNRIs have been evaluated using the 7.5% CO2 model; however, it has yet to be used to evaluate psychological interventions. We compared the effects of two core psychological components of mindfulness-meditation (open monitoring and focused attention) against general relaxation, on subjective, autonomic and neuropsychological outcomes in the 7.5% CO2 experimental model. 32 healthy screened adults were randomized to complete 10 min of guided open monitoring, focused attention or relaxation, immediately before inhaling 7.5% CO2 for 20 min. During CO2-challenge participants completed an eye-tracking measure of attention control and selective attention. Measures of subjective anxiety, blood pressure and heart rate were taken at baseline and immediately following intervention and CO2-challenge. OM and FA practice reduced subjective feelings of anxiety during 20-min inhalation of 7.5% CO2 compared to relaxation control. OM practice produced a strong anxiolytic effect, whereas the effect of FA was more modest. Anxiolytic OM and FA effects occurred in the absence of group differences in autonomic arousal and eye-movement measures of attention. Our findings are consistent with neuropsychological models of mindfulness-meditation that propose OM and FA activate prefrontal mechanisms that support emotion regulation during periods of anxiety and physiological hyper-arousal. Our findings complement those from pharmacological treatment studies, further supporting the use of CO2 challenge to evaluate future therapeutic interventions for anxiety. PMID:25765144

Dose-response effects of systemic anandamide administration in mice sequentially submitted to the open field and elevated plus-maze tests.

PubMed

Ribeiro, A; Ferraz-de-Paula, V; Pinheiro, M L; Palermo-Neto, J

2009-06-01

The endocannabinoid system is involved in the control of many physiological functions, including the control of emotional states. In rodents, previous exposure to an open field increases the anxiety-like behavior in the elevated plus-maze. Anxiolytic-like effects of pharmacological compounds that increase endocannabinoid levels have been well documented. However, these effects are more evident in animals with high anxiety levels. Several studies have described characteristic inverted U-shaped dose-response effects of drugs that modulate the endocannabinoid levels. However, there are no studies showing the effects of different doses of exogenous anandamide, an endocannabinoid, in animal models of anxiety. Thus, in the present study, we determined the dose-response effects of exogenous anandamide at doses of 0.01, 0.1, and 1.0 mg/kg in C57BL/6 mice (N = 10/group) sequentially submitted to the open field and elevated plus-maze. Anandamide was diluted in 0.9% saline, ethyl alcohol, Emulphor (18:1:1) and administered ip (0.1 mL/10 g body weight); control animals received the same volume of anandamide vehicle. Anandamide at the dose of 0.1 mg/kg (but not of 0.01 or 1 mg/kg) increased (P < 0.05) the time spent and the distance covered in the central zone of the open field, as well as the exploration of the open arms of the elevated plus-maze. Thus, exogenous anandamide, like pharmacological compounds that increase endocannabinoid levels, promoted a characteristic inverted U-shaped dose-response effect in animal models of anxiety. Furthermore, anandamide (0.1 mg/kg) induced an anxiolytic-like effect in the elevated plus-maze (P < 0.05) after exposing the animals to the open field test.