Frontal Traumatic Brain Injury in Rats Causes Long-Lasting Impairments in Impulse Control That Are Differentially Sensitive to Pharmacotherapeutics and Associated with Chronic Neuroinflammation.

PubMed

Vonder Haar, Cole; Lam, Frederick C W; Adams, Wendy K; Riparip, Lara-Kirstie; Kaur, Sukhbir; Muthukrishna, Michael; Rosi, Susanna; Winstanley, Catharine A

2016-11-16

Traumatic brain injury (TBI) affects millions yearly, and is increasingly associated with chronic neuropsychiatric symptoms. We assessed the long-term effects of different bilateral frontal controlled cortical impact injury severities (mild, moderate, and severe) on the five-choice serial reaction time task, a paradigm with relatively independent measurements of attention, motor impulsivity, and motivation. Moderately- and severely injured animals exhibited impairments across all cognitive domains that were still evident 14 weeks postinjury, while mild-injured animals only demonstrated persistent deficits in impulse control. However, recovery of function varied considerably between subjects such that some showed no impairment ("TBI-resilient"), some demonstrated initial deficits that recovered ("TBI-vulnerable"), and some never recovered ("chronically-impaired"). Three clinically relevant treatments for impulse-control or TBI, amphetamine, atomoxetine, and amantadine, were assessed for efficacy in treating injury-induced deficits. Susceptibility to TBI affected the response to pharmacological challenge with amphetamine. Whereas sham and TBI-resilient animals showed characteristic impairments in impulse control at higher doses, amphetamine had the opposite effect in chronically impaired rats, improving task performance. In contrast, atomoxetine and amantadine reduced premature responding but increased omissions, suggesting psychomotor slowing. Analysis of brain tissue revealed that generalized neuroinflammation was associated with impulsivity even when accounting for the degree of brain damage. This is one of the first studies to characterize psychiatric-like symptoms in experimental TBI. Our data highlight the importance of testing pharmacotherapies in TBI models in order to predict efficacy, and suggest that neuroinflammation may represent a treatment target for impulse control problems following injury.

Acetylcholine Encodes Long-Lasting Presynaptic Plasticity at Glutamatergic Synapses in the Dorsal Striatum after Repeated Amphetamine Exposure

PubMed Central

Wang, Wengang; Darvas, Martin; Storey, Granville P.; Bamford, Ian J.; Gibbs, Jeffrey T.; Palmiter, Richard D.

2013-01-01

Locomotion and cue-dependent behaviors are modified through corticostriatal signaling whereby short-term increases in dopamine availability can provoke persistent changes in glutamate release that contribute to neuropsychiatric disorders, including Parkinson's disease and drug dependence. We found that withdrawal of mice from repeated amphetamine treatment caused a chronic presynaptic depression (CPD) in glutamate release that was most pronounced in corticostriatal terminals with a low probability of release and lasted >50 d in treated mice. An amphetamine challenge reversed CPD via a dopamine D1-receptor-dependent paradoxical presynaptic potentiation (PPP) that increased corticostriatal activity in direct pathway medium spiny neurons. This PPP was correlated with locomotor responses after a drug challenge, suggesting that it may underlie the sensitization process. Experiments in brain slices and in vivo indicated that dopamine regulation of acetylcholine release from tonically active interneurons contributes to CPD, PPP, locomotor sensitization, and cognitive ability. Therefore, a chronic decrease in corticostriatal activity during withdrawal is regulated around a new physiological range by tonically active interneurons and returns to normal upon reexposure to amphetamine, suggesting that this paradoxical return of striatal activity to a more stable, normalized state may represent an additional source of drug motivation during abstinence. PMID:23785153

Preclinical Assessment of Lisdexamfetamine as an Agonist Medication Candidate for Cocaine Addiction: Effects in Rhesus Monkeys Trained to Discriminate Cocaine or to Self-Administer Cocaine in a Cocaine Versus Food Choice Procedure

PubMed Central

Hutsell, Blake A.; Blough, Bruce E.; Poklis, Justin L.; Negus, S. Stevens

2015-01-01

Background: Chronic amphetamine treatment decreases cocaine consumption in preclinical and human laboratory studies and in clinical trials. Lisdexamfetamine is an amphetamine prodrug in which L-lysine is conjugated to the terminal nitrogen of d-amphetamine. Prodrugs may be advantageous relative to their active metabolites due to slower onsets and longer durations of action; however, lisdexamfetamine treatment’s efficacy in decreasing cocaine consumption is unknown. Methods: This study compared lisdexamfetamine and d-amphetamine effects in rhesus monkeys using two behavioral procedures: (1) a cocaine discrimination procedure (training dose = 0.32mg/kg cocaine, i.m.); and (2) a cocaine-versus-food choice self-administration procedure. Results: In the cocaine-discrimination procedure, lisdexamfetamine (0.32–3.2mg/kg, i.m.) substituted for cocaine with lower potency, slower onset, and longer duration of action than d-amphetamine (0.032–0.32mg/kg, i.m.). Consistent with the function of lisdexamfetamine as an inactive prodrug for amphetamine, the time course of lisdexamfetamine effects was related to d-amphetamine plasma levels by a counter-clockwise hysteresis loop. In the choice procedure, cocaine (0–0.1mg/kg/injection, i.v.) and food (1g banana-flavored pellets) were concurrently available, and cocaine maintained a dose-dependent increase in cocaine choice under baseline conditions. Treatment for 7 consecutive days with lisdexamfetamine (0.32–3.2mg/kg/day, i.m.) or d-amphetamine (0.032–0.1mg/kg/h, i.v.) produced similar dose-dependent rightward shifts in cocaine dose-effect curves and decreases in preference for 0.032mg/kg/injection cocaine. Conclusions: Lisdexamfetamine has a slower onset and longer duration of action than amphetamine but retains amphetamine’s efficacy to reduce the choice of cocaine in rhesus monkeys. These results support further consideration of lisdexamfetamine as an agonist-based medication candidate for cocaine addiction. PMID:25618405

Cocaine versus food choice procedure in rats: environmental manipulations and effects of amphetamine.

PubMed

Thomsen, Morgane; Barrett, Andrew C; Negus, S Stevens; Caine, S Barak

2013-03-01

We have adapted a nonhuman primate model of cocaine versus food choice to the rat species. To evaluate the procedure, we tested cocaine versus food choice under a variety of environmental manipulations as well as pharmacological pretreatments. Complete cocaine-choice dose-effect curves (0-1.0 mg/kg/infusion) were obtained for each condition under concurrent fixed ratio schedules of reinforcement. Percentage of responding emitted on the cocaine-reinforced lever was not affected significantly by removal of cocaine-associated visual or auditory cues, but it was decreased after removal of response-contingent or response-independent cocaine infusions. Cocaine choice was sensitive to the magnitude and fixed ratio requirement of both the cocaine and food reinforcers. We also tested the effects of acute (0.32, 0.56, 1.0, 1.8 mg/kg) and chronic (0.1, 0.32 mg/kg/hr) d-amphetamine treatment on cocaine choice. Acute and chronic d-amphetamine had opposite effects, with acute increasing and chronic decreasing cocaine choice, similar to observations in humans and in nonhuman primates. The results suggest feasibility and utility of the choice procedure in rats and support its comparability to similar procedures used in humans and monkeys. © Society for the Experimental Analysis of Behavior.

Repeated intermittent administration of psychomotor stimulant drugs alters the acquisition of Pavlovian approach behavior in rats: differential effects of cocaine, d-amphetamine and 3,4- methylenedioxymethamphetamine ("Ecstasy").

PubMed

Taylor, J R; Jentsch, J D

2001-07-15

Psychomotor stimulant drugs can produce long-lasting changes in neurochemistry and behavior after multiple doses. In particular, neuroadaptations within corticolimbic brain structures that mediate incentive learning and motivated behavior have been demonstrated after chronic exposure to cocaine, d-amphetamine, and 3,4-methylenedioxymethamphetamine (MDMA). As stimulus-reward learning is likely relevant to addictive behavior (i.e., augmented conditioned reward and stimulus control of behavior), we have investigated whether prior repeated administration of psychomotor stimulant drugs (of abuse, including cocaine, d-amphetamine, or MDMA, would affect the acquisition of Pavlovian approach behavior. Water-deprived rats were tested for the acquisition of Pavlovian approach behavior after 5 days treatment with cocaine (15-20 mg/kg once or twice daily), d-amphetamine (2.5 mg/kg once or twice daily), or MDMA (2.5 mg/kg twice daily) followed by a 7-day, drug-free period. Prior repeated treatment with cocaine or d-amphetamine produced a significant enhancement of acquisition of Pavlovian approach behavior, indicating accelerated stimulus-reward learning, whereas MDMA administration produced increased inappropriate responding, indicating impulsivity. Abnormal drug-induced approach behavior was found to persist throughout the testing period. These studies demonstrate that psychomotor stimulant-induced sensitization can produce long-term alterations in stimulus-reward learning and impulse control that may contribute to the compulsive drug taking that typifies addiction.

Vitamin D3: A Role in Dopamine Circuit Regulation, Diet-Induced Obesity, and Drug Consumption.

PubMed

Trinko, Joseph R; Land, Benjamin B; Solecki, Wojciech B; Wickham, Robert J; Tellez, Luis A; Maldonado-Aviles, Jaime; de Araujo, Ivan E; Addy, Nii A; DiLeone, Ralph J

2016-01-01

The influence of micronutrients on dopamine systems is not well defined. Using mice, we show a potential role for reduced dietary vitamin D3 (cholecalciferol) in promoting diet-induced obesity (DIO), food intake, and drug consumption while on a high fat diet. To complement these deficiency studies, treatments with exogenous fully active vitamin D3 (calcitriol, 10 µg/kg, i.p.) were performed. Nondeficient mice that were made leptin resistant with a high fat diet displayed reduced food intake and body weight after an acute treatment with exogenous calcitriol. Dopamine neurons in the midbrain and their target neurons in the striatum were found to express vitamin D3 receptor protein. Acute calcitriol treatment led to transcriptional changes of dopamine-related genes in these regions in naive mice, enhanced amphetamine-induced dopamine release in both naive mice and rats, and increased locomotor activity after acute amphetamine treatment (2.5 mg/kg, i.p.). Alternatively, mice that were chronically fed either the reduced D3 high fat or chow diets displayed less activity after acute amphetamine treatment compared with their respective controls. Finally, high fat deficient mice that were trained to orally consume liquid amphetamine (90 mg/L) displayed increased consumption, while nondeficient mice treated with calcitriol showed reduced consumption. Our findings suggest that reduced dietary D3 may be a contributing environmental factor enhancing DIO as well as drug intake while eating a high fat diet. Moreover, these data demonstrate that dopamine circuits are modulated by D3 signaling, and may serve as direct or indirect targets for exogenous calcitriol.

Case report: Improvement in dissociative symptoms with mixed amphetamine salts.

PubMed

Scarella, Timothy M; Franzen, Jamie R

2017-01-01

Symptoms of dissociation, including dissociative amnesia, depersonalization, and derealization, commonly develop in individuals subject to chronic and repeated trauma during development. This includes the trauma of environmental inability to facilitate development of adequate cognitive strategies for coping with strong negative emotions. Dissociation likely involves dysregulated balance of prefrontal inhibition of limbic structures and inadequate regulation of attentional bias by both prefrontal and limbic systems. There is currently no established psychopharmacologic treatment for dissociative symptoms. Here the case of a woman with severe dissociative symptoms that were markedly improved with the administration of mixed amphetamine salts is discussed. Potential neurobiologic mechanisms for dissociative symptom improvement with psychostimulants are discussed.

Evidence that alpha-methyl-p-tyramine is implicated in behavioural augmentation to amphetamine.

PubMed

Dougan, D F; Labrie, S L; Paull, P D; Duffield, P H; Wade, D N

1986-01-01

Behavioural studies showed that administration of alpha-methyl-p-tyramine (AMT; 10 mg/kg i.p.) to rats 24 hr before treatment with d-amphetamine (AMPHET; 4 mg/kg i.p.) resulted in augmentation of AMPHET-induced stereotype activity. Parallel experiments involving electro-chemical estimation of dopamine metabolites in the striatum showed that the decrease in the concentration of homovanillic acid (HVA) produced by AMPHET (4 mg/kg) was enhanced in AMT (10 mg/kg) pretreated animals. These findings suggest that AMT derived from previous doses of AMPHET may play a role in the phenomena of behavioural augmentation observed after chronic administration of AMPHET.

Behavioral sensitization and cross-sensitization between methylphenidate amphetamine, and 3-4, methylenedioxymethamphetamine (MDMA) in female SD rats

PubMed Central

Yang, Pamela B.; Atkins, Kristal D.; Dafny, Nachum

2014-01-01

The psychostimulants amphetamine and methylphenidate (MPD / Ritalin) are the drugs most often used to treat attention deficit hyperactivity disorder (ADHD). In addition, students of all ages take these drugs to improve academic performance but also abuse them for pleasurable enhancement. In addition, other psychostimulants such 3,4 methylenedioxymethamphetamine (MDMA / ecstasy) are used / abused for similar objectives. One of the experimental markers for the potential of a drug to produce dependence is its ability to induce behavioral sensitization and cross sensitization with other drugs of abuse. The objective of this study is to use identical experimental protocols and behavioral assays to compare in female rats the effects of amphetamine, MPD and MDMA on locomotor activity and to determine if they induce behavioral sensitization and/or cross sensitization with each other. The main findings of this study are 1. Acute amphetamine, MPD and MDMA all elicited increases in locomotor activity. 2. Chronic administration of an intermediate dose of amphetamine or MPD elicited behavioral sensitization. 3. Chronic administration of MDMA elicited behavioral sensitization in some animals and behavioral tolerance in others. 4. Cross sensitization between MPD and amphetamine was observed. 5. MDMA did not show either cross sensitization or cross tolerance with amphetamine. In conclusion, these results suggest that MDMA act by different mechanisms compared to MPD and amphetamine. PMID:21549116

Adolescent THC exposure does not sensitize conditioned place preferences to subthreshold d-amphetamine in male and female rats.

PubMed

Keeley, Robin J; Bye, Cameron; Trow, Jan; McDonald, Robert J

2018-01-01

The acute effects of marijuana consumption on brain physiology and behaviour are well documented, but the long-term effects of its chronic use are less well known. Chronic marijuana use during adolescence is of increased interest, given that the majority of individuals first use marijuana during this developmental stage , and  adolescent marijuana use is thought to increase the susceptibility to abusing other drugs when exposed later in life. It is possible that marijuana use during critical periods in adolescence could lead to increased sensitivity to other drugs of abuse later on. To test this, we chronically administered ∆ 9 -tetrahydrocannabinol (THC) to male and female Long-Evans (LER) and Wistar (WR) rats directly after puberty onset. Rats matured to postnatal day 90 before being exposed to a conditioned place preference task (CPP). A subthreshold dose of d-amphetamine, found not to induce place preference in drug naïve rats, was used as the unconditioned stimulus. The effect of d-amphetamine on neural activity was inferred by quantifying cfos expression in the nucleus accumbens and dorsal hippocampus following CPP training. Chronic exposure to THC post-puberty had no potentiating effect on a subthreshold dose of d-amphetamine to induce CPP. No differences in cfos expression were observed. These results show that chronic exposure to THC during puberty did not increase sensitivity to d-amphetamine in adult LER and WR rats. This supports the concept that THC may not sensitize the response to all drugs of abuse.

Stuttering—The Effect of Treatment with D-Amphetamine and a Tranquilizing Agent, Trifluoperazine; A Preliminary Report on an Uncontrolled Study

PubMed Central

Fish, Charles H.; Bowling, Evelyn

1965-01-01

In an institution for the mentally retarded, an uncontrolled study was made on the effects of d-amphetamine, d-amphetamine followed by trifluoperazine, and of combined d-amphetamine and trifluoperazine on stuttering. Of 28 patients to whom d-amphetamine was given, 14 showed improvement after one month's treatment. Eight more showed improvement when trifluoperazine was given for one month to those who did not improve on d-amphetamine. In many cases, improvement was sustained at least six months after treatment was discontinued. Treatment with d-amphetamine was apparently more effective in patients with functional than with organic retardation. PMID:5836893

Characteristics of treatment provided for amphetamine use in New South Wales, Australia.

PubMed

McKetin, Rebecca; Kelly, Erin; Indig, Devon

2005-09-01

The purpose of this study was to examine the types of treatment services provided for amphetamine use, the characteristics of amphetamine treatment clients and the geographic areas most affected by amphetamine treatment provision within New South Wales (NSW), Australia. Data on completed amphetamine treatment episodes were extracted from the NSW Minimum Data Set for Alcohol and Other Drug Treatment Services for the year 2002/03 (n = 4,337). The geographic area of treatment presentations was based on the location of the treatment service, and was categorized as metropolitan, regional or rural. Treatment disproportionately affected regional and rural NSW, and treatment clients often presented with concurrent cannabis and/or alcohol problems. Clients were overwhelmingly injecting drug users with poor socio-demographic characteristics. Counselling was the most common treatment service provided, followed by detoxification and residential rehabilitation. Detoxification was usually provided in an in-patient setting, particularly within metropolitan NSW. Compliance with residential rehabilitation was notably poor. In conclusion, the development of appropriate interventions for amphetamine use needs to consider that the majority of treatment recipients will be based in a regional or rural setting, and treating amphetamine users will often involve treatment of concurrent cannabis and alcohol problems. The nature and appropriateness of treatment services provided for amphetamine use needs to be reviewed in detail, and further research is needed into the nature of problematic amphetamine use and factors affecting treatment demand in regional and rural NSW.

Treatment for amphetamine withdrawal.

PubMed

Srisurapanont, M; Jarusuraisin, N; Kittirattanapaiboon, P

2001-01-01

Amphetamine withdrawal has been less studied although it is a common problem with a prevalent rate of 87% among amphetamine users. Its symptoms, in particular intense craving, may be a critical factor leading to relapse of amphetamine use. In clinical practice, treatment for cocaine withdrawal has been recommended for the management of amphetamine withdrawal although the pharmacodynamic and pharmacokinetic properties of these two substances are not the same. To search and determine risks, benefits, and costs of a variety of treatments for the management of amphetamine withdrawal. Electronic searches of MEDLINE (1966 - December 2000), EMBASE (1980 - February 2001), CINAHL (1982 - January 2001) and Cochrane Controlled Trials Register (Cochrane Library 2000 issue 4) were undertaken. References to the articles obtained by any means were searched. All relevant randomised controlled trials (RCTs) and controlled clinical trials (CCTs) were included. Participants were people with amphetamine withdrawal, diagnosed by any set of criteria. Any kinds of biological and psychological treatments both alone and combined were examined. A variety of outcomes, for example, number of treatment responders, score changes, were considered. Two reviewers evaluated and extracted the data independently. The dichotomous data were extracted on an intention-to-treat basis in which the dropouts were assigned as participants with the worst outcomes. The Relative Risk (RR) with the 95% confidence interval (95% CI) was used to assess the dichotomous data. The Weighted Mean Difference (WMD) with 95% CI was used to assessed the continuous data. The results of two studies have shown some benefits of amineptine in the treatment of amphetamine withdrawal. Those benefits can be seen in the respects of discontinuation rate and global state, as measured by Clinical Global Impression Scale. However, no direct benefit of amineptine on amphetamine withdrawal symptoms or craving was shown. The evidence about the treatment for amphetamine withdrawal is very limited. Amineptine has limited benefits on some amphetamine withdrawal symptoms. Due to a number of reports of amineptine abuse, it has been withdrawn from the market for a few years. At present, no available treatment has been demonstrated to be effective in the treatment of amphetamine withdrawal. The medications that should be considered for further treatment studies may be those with the propensities to increase dopamine, norepinephrine and/or serotonin activities of the brain. Naturalistic studies of amphetamine withdrawal symptoms and course are also crucial for the development of study designs appropriate for further treatment studies of amphetamine withdrawal.

The neurocircuitry of illicit psychostimulant addiction: acute and chronic effects in humans

PubMed Central

Taylor, Sara B; Lewis, Candace R; Olive, M Foster

2013-01-01

Illicit psychostimulant addiction remains a significant problem worldwide, despite decades of research into the neural underpinnings and various treatment approaches. The purpose of this review is to provide a succinct overview of the neurocircuitry involved in drug addiction, as well as the acute and chronic effects of cocaine and amphetamines within this circuitry in humans. Investigational pharmacological treatments for illicit psychostimulant addiction are also reviewed. Our current knowledge base clearly demonstrates that illicit psychostimulants produce lasting adaptive neural and behavioral changes that contribute to the progression and maintenance of addiction. However, attempts at generating pharmacological treatments for psychostimulant addiction have historically focused on intervening at the level of the acute effects of these drugs. The lack of approved pharmacological treatments for psychostimulant addiction highlights the need for new treatment strategies, especially those that prevent or ameliorate the adaptive neural, cognitive, and behavioral changes caused by chronic use of this class of illicit drugs. PMID:24648786

[The medical treatment of attention deficit hyperactivity disorder (ADHD) with amphetamines in children and adolescents].

PubMed

Frölich, Jan; Banaschewski, Tobias; Spanagel, Rainer; Döpfner, Manfred; Lehmkuhl, Gerd

2012-09-01

Psychostimulants (methylphenidate and amphetamines) are the drugs of first choice in the pharmacological treatment of children and adolescents with attention deficit hyperactivity disorder (ADHD). We summarize the pharmacological characteristics of amphetamines and compare them with methylphenidate, special emphasis being given to a comparison of effects and side effects of the two substances. Finally, we analyze the abuse and addiction risks. Publications were chosen based on a Medline analysis for controlled studies and meta-analyses published between 1980 and 2011; keywords were amphetamine, amphetamine salts, lisdexamphetamine, controlled studies, and metaanalyses. Amphetamines generally exhibit some pharmacologic similarities with methylphenidate. However, besides inhibiting dopamine reuptake amphetamines also cause the release of monoamines. Moreover, plasma half-life is significantly prolonged. The clinical efficacy and tolerability of amphetamines is comparable to methylphenidate. Amphetamines can therefore be used if the individual response to methylphenidate or tolerability is insufficient before switching to a nonstimulant substance, thus improving the total response rate to psychostimulant treatment. Because of the high abuse potential of amphetamines, especially in adults, the prodrug lisdexamphetamine (Vyvanse) could become an effective treatment alternative. Available study data suggest a combination of high clinical effect size with a beneficial pharmacokinetic profile and a reduced abuse risk. In addition to methylphenidate, amphetamines serve as important complements in the psychostimulant treatment of ADHD. Future studies should focus on a differential comparison of the two substances with regard to their effects on different core symptom constellations and the presence of various comorbidities.

The effects of d-govadine on conditioned place preference with d-amphetamine or food reward.

PubMed

Nesbit, Maya O; Dias, Carine; Phillips, Anthony G

2017-03-15

Tetrahydroprotoberberines (THPB) have a high affinity for dopamine (DA) D1 and D2 receptors and may provide a novel treatment for drug addiction. We assessed the effects of the THPB d-govadine on the acquisition, expression, extinction and reinstatement of d-amphetamine-(1.5mg/kg, i.p.) induced conditioned place preference (CPP). Furthermore, the effects of d-govadine on conditioned association between contextual stimuli and a natural reward were examined using food-induced CPP. In separate experiments, rats received d-govadine (0, 0.5 or 1.0mg/kg, i.p.) before a) each d-amphetamine injection during conditioning, b) expression of amphetamine-induced CPP, c) each extinction session, d) amphetamine-induced reinstatement of CPP, or e) placement into a compartment containing food during conditioning. Although d-govadine had no effect on acquisition of amphetamine CPP, treatment with d-govadine during acquisition dose-dependently extinguished a preference for the amphetamine-associated context more quickly than vehicle treatment. Moreover, d-govadine treatment facilitated the extinction of amphetamine CPP when given repeatedly throughout the extinction phase. Although the expression of amphetamine CPP was not affected by d-govadine administered prior to the expression test, amphetamine-induced reinstatement of CPP following an extinction period was blocked by d-govadine (1.0mg/kg). The intermediate dose of d-govadine blocked the acquisition of food CPP, whereas the high dose facilitated extinction of this preference as compared to vehicle-treated animals. Therefore, d-govadine attenuates the maintenance of conditioned associations between contextual stimuli and amphetamine or food reward, as well as amphetamine-induced reinstatement of drug seeking behaviour. As such, d-govadine may be a candidate for further development as a pharmacological treatment of psychostimulant drug dependence. Copyright © 2017 Elsevier B.V. All rights reserved.

May Exercise Prevent Addiction?

PubMed Central

Fontes-Ribeiro, C. A; Marques, E; Pereira, F. C; Silva, A. P; Macedo, T. R. A

2011-01-01

Amphetamines exert their persistent addictive effects by activating brain's reward pathways, perhaps through the release of dopamine in the nucleus accumbens (and/or in other places). On the other hand, there is a relationship between dopamine and all behavioural aspects that involve motor activity and it has been demonstrated that exercise leads to an increase in the synthesis and release of dopamine, stimulates neuroplasticity and promotes feelings of well-being. Moreover, exercise and drugs of abuse activate overlapping neural systems. Thus, our aim was to study the influence of chronic exercise in the mechanism of addiction using an amphetamine-induced conditioned-place-preference in rats. Adult male Sprague-Dawley rats were randomly separated in groups with and without chronic exercise. Chronic exercise consisted in a 8 week treadmill running program, with increasing intensity. The conditioned place preference test was performed in both groups using a procedure and apparatus previously established. A 2 mg.kg-1 amphetamine or saline solution was administered intraperitonially according to the schedule of the conditioned place preference. Before conditioning none of the animals showed preference for a specific compartment of the apparatus. The used amphetamine dose in the conditioning phase was able to produce a marked preference towards the drug-associated compartment in the group without exercise. In the animals with exercise a significant preference by the compartment associated with saline was observed. These results lead us to conclude that a previous practice of regular physical activity may help preventing amphetamine addiction in the conditions used in this test. PMID:21886560

Attenuation of cocaine self-administration by chronic oral phendimetrazine in rhesus monkeys.

PubMed

Czoty, P W; Blough, B E; Fennell, T R; Snyder, R W; Nader, M A

2016-06-02

Chronic treatment with the monoamine releaser d-amphetamine has been consistently shown to decrease cocaine self-administration in laboratory studies and clinical trials. However, the abuse potential of d-amphetamine is an obstacle to widespread clinical use. Approaches are needed that exploit the efficacy of the agonist approach but avoid the abuse potential associated with dopamine releasers. The present study assessed the effectiveness of chronic oral administration of phendimetrazine (PDM), a pro-drug for the monoamine releaser phenmetrazine (PM), to decrease cocaine self-administration in four rhesus monkeys. Each day, monkeys pressed a lever to receive food pellets under a 50-response fixed-ratio (FR) schedule of reinforcement and self-administered cocaine (0.003-0.56 mg/kg per injection, i.v.) under a progressive-ratio (PR) schedule in the evening. After completing a cocaine self-administration dose-response curve, sessions were suspended and PDM was administered (1.0-9.0 mg/kg, p.o., b.i.d.). Cocaine self-administration was assessed using the PR schedule once every 7 days while food-maintained responding was studied daily. When a persistent decrease in self-administration was observed, the cocaine dose-effect curve was re-determined. Daily PDM treatment decreased cocaine self-administration by 30-90% across monkeys for at least 4 weeks. In two monkeys, effects were completely selective for cocaine. Tolerance developed to initial decreases in food-maintained responding in the third monkey and in the fourth subject, fluctuations were observed that were lower in magnitude than effects on cocaine self-administration. Cocaine dose-effect curves were shifted down and/or rightward in three monkeys. These data provide further support for the use of agonist medications for cocaine abuse, and indicate that the promising effects of d-amphetamine extend to a more clinically viable pharmacotherapy. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Early-life risperidone enhances locomotor responses to amphetamine during adulthood.

PubMed

Lee Stubbeman, Bobbie; Brown, Clifford J; Yates, Justin R; Bardgett, Mark E

2017-10-05

Antipsychotic drug prescriptions for pediatric populations have increased over the past 20 years, particularly the use of atypical antipsychotic drugs such as risperidone. Most antipsychotic drugs target forebrain dopamine systems, and early-life antipsychotic drug exposure could conceivably reset forebrain neurotransmitter function in a permanent manner that persists into adulthood. This study determined whether chronic risperidone administration during development modified locomotor responses to the dopamine/norepinephrine agonist, D-amphetamine, in adult rats. Thirty-five male Long-Evans rats received an injection of one of four doses of risperidone (vehicle, .3, 1.0, 3.0mg/kg) each day from postnatal day 14 through 42. Locomotor activity was measured for 1h on postnatal days 46 and 47, and then for 24h once a week over the next two weeks. Beginning on postnatal day 75, rats received one of four doses of amphetamine (saline, .3, 1.0, 3.0mg/kg) once a week for four weeks. Locomotor activity was measured for 27h after amphetamine injection. Rats administered risperidone early in life demonstrated increased activity during the 1 and 24h test sessions conducted prior to postnatal day 75. Taking into account baseline group differences, these same rats exhibited significantly more locomotor activity in response to the moderate dose of amphetamine relative to controls. These results suggest that early-life treatment with atypical antipsychotic drugs, like risperidone, permanently alters forebrain catecholamine function and increases sensitivity to drugs that target such function. Copyright © 2017 Elsevier B.V. All rights reserved.

Continuous, but not intermittent, antipsychotic drug delivery intensifies the pursuit of reward cues.

PubMed

Bédard, Anne-Marie; Maheux, Jérôme; Lévesque, Daniel; Samaha, Anne-Noël

2011-05-01

Chronic exposure to antipsychotic medications can persistently change brain dopamine systems. Most studies on the functional significance of these neural changes have focused on motor behavior and few have addressed how long-term antipsychotic treatment might influence dopamine-mediated reward function. We asked, therefore, whether a clinically relevant antipsychotic treatment regimen would alter the incentive motivational properties of a reward cue. We assessed the ability of a Pavlovian-conditioned stimulus to function as a conditioned reward, as well as to elicit approach behavior in rats treated with haloperidol, either continuously (achieved via subcutaneous osmotic minipump) or intermittently (achieved via daily subcutaneous injections). Continuous, but not intermittent, treatment enhanced the ability of amphetamine to potentiate the conditioned reinforcing effects of a cue associated with water. This effect was not related to differences in the ability to attribute predictive value to a conditioned stimulus (as measured by conditioned approach behavior), but was potentially linked to the development of behavioral supersensitivity to amphetamine and to augmented amphetamine-induced immediate early-gene expression (c-fos and Nur77) in dorsal striatopallidal and striatonigral cells. By enhancing the ability of reward cues to control behavior and by intensifying dopamine-mediated striatopallidal and striatonigral cell activity, standard (ie, continuous) antipsychotic treatment regimens might exacerbate drug-seeking and drug-taking behavior in schizophrenia. Achieving regular but transiently high antipsychotic levels in the brain (as modeled in the intermittent condition) might be a viable option to prevent these changes. This possibility should be explored in the clinic.

Treatment of Attention Deficit/Hyperactivity Disorder with Amphetamine: Short-Term Effects on Family Interaction

ERIC Educational Resources Information Center

Gustafsson, Peik; Hansson, Kjell; Eidevall, Lena; Thernlund, Gunilla; Svedin, Carl Goran

2008-01-01

Objective: This research seeks to study the impact on family function after 3 months of treatment with amphetamine. Method: A total of 43 children, 6 to 11 years of age, with ADHD were treated with amphetamine for 3 months. Family function was studied before and after treatment by parent self-rating and independent observer ratings of videotaped…

Treatment for amphetamine withdrawal.

PubMed

Shoptaw, Steven J; Kao, Uyen; Heinzerling, Keith; Ling, Walter

2009-04-15

Few studies examined treatments for amphetamine withdrawal, although it is a common problem among amphetamine users. Its symptoms, in particular intense craving, may be a critical factor leading to relapse to amphetamine use. In clinical practice, medications for cocaine withdrawal are commonly used to manage amphetamine withdrawal although the pharmacodynamic and pharmacokinetic properties of these two illicit substances are different. To assess the effectiveness of pharmacological alone or in combination with psychosocial treatment for amphetamine withdrawals on discontinuation rates, global state, withdrawal symptoms, craving, and other outcomes. MEDLINE (1966 - 2008), CINAHL (1982 - 2008), PsycINFO (1806 - 2008), CENTRAL (Cochrane Library 2008 issue 2), references of obtained articles. All randomised controlled and clinical trials evaluating pharmacological and or psychosocial treatments (alone or combined) for people with amphetamine withdrawal symptoms. Two authors evaluated and extracted data independently. The data were extracted from intention-to-treat analyses. The Relative Risk (RR) with the 95% confidence interval (95% CI) was used to assess dichotomous outcomes. The Weighted Mean Difference (WMD) with 95% CI was used to assess continuous outcomes. Four randomised controlled trials (involving 125 participants) met the inclusion criteria for the review. Two studies found that amineptine significantly reduced discontinuation rates and improved overall clinical presentation, but did not reduce withdrawal symptoms or craving compared to placebo. The benefits of mirtazapine over placebo for reducing amphetamine withdrawal symptoms were not as clear. One study suggested that mirtazapine may reduce hyperarousal and anxiety symptoms associated with amphetamine withdrawal. A more recent study failed to find any benefit of mirtazapine over placebo on retention or on amphetamine withdrawal symptoms. No medication is effective for treatment of amphetamine withdrawal. Amineptine showed reduction in discontinuation rates and improvement in clinical presentation compared to placebo, but had no effect on reducing withdrawal symptoms or craving. In spite of these limited benefits, amineptine is not available for use due to concerns over abuse liability when using the drug. The benefits of mirtazapine as a withdrawal agent are less clear based on findings from two randomised controlled trials: one report showed improvements in amphetamine withdrawal symptoms over placebo; a second report showed no differences in withdrawal symptoms compared to placebo. Further potential treatment studies should examine medications that increase central nervous system activity involving dopamine, norepinephrine and/or serotonin neurotransmitters, including mirtazapine.

Restorative effect of endurance exercise on behavioral deficits in the chronic mouse model of Parkinson's disease with severe neurodegeneration

PubMed Central

Pothakos, Konstantinos; Kurz, Max J; Lau, Yuen-Sum

2009-01-01

Background Animal models of Parkinson's disease have been widely used for investigating the mechanisms of neurodegenerative process and for discovering alternative strategies for treating the disease. Following 10 injections with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 25 mg/kg) and probenecid (250 mg/kg) over 5 weeks in mice, we have established and characterized a chronic mouse model of Parkinson's disease (MPD), which displays severe long-term neurological and pathological defects resembling that of the human Parkinson's disease in the advanced stage. The behavioral manifestations in this chronic mouse model of Parkinson's syndrome remain uninvestigated. The health benefit of exercise in aging and in neurodegenerative disorders including the Parkinson's disease has been implicated; however, clinical and laboratory studies in this area are limited. In this research with the chronic MPD, we first conducted a series of behavioral tests and then investigated the impact of endurance exercise on the identified Parkinsonian behavioral deficits. Results We report here that the severe chronic MPD mice showed significant deficits in their gait pattern consistency and in learning the cued version of the Morris water maze. Their performances on the challenging beam and walking grid were considerably attenuated suggesting the lack of balance and motor coordination. Furthermore, their spontaneous and amphetamine-stimulated locomotor activities in the open field were significantly suppressed. The behavioral deficits in the chronic MPD lasted for at least 8 weeks after MPTP/probenecid treatment. When the chronic MPD mice were exercise-trained on a motorized treadmill 1 week before, 5 weeks during, and 8–12 weeks after MPTP/probenecid treatment, the behavioral deficits in gait pattern, spontaneous ambulatory movement, and balance performance were reversed; whereas neuronal loss and impairment in cognitive skill, motor coordination, and amphetamine-stimulated locomotor activity were not altered when compared to the sedentary chronic MPD animals. Conclusion This study indicates that in spite of the drastic loss of dopaminergic neurons and depletion of dopamine in the severe chronic MPD, endurance exercise training effectively reverses the Parkinson's like behavioral deficits related to regular movement, balance and gait performance. PMID:19154608

Restorative effect of endurance exercise on behavioral deficits in the chronic mouse model of Parkinson's disease with severe neurodegeneration.

PubMed

Pothakos, Konstantinos; Kurz, Max J; Lau, Yuen-Sum

2009-01-20

Animal models of Parkinson's disease have been widely used for investigating the mechanisms of neurodegenerative process and for discovering alternative strategies for treating the disease. Following 10 injections with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 25 mg/kg) and probenecid (250 mg/kg) over 5 weeks in mice, we have established and characterized a chronic mouse model of Parkinson's disease (MPD), which displays severe long-term neurological and pathological defects resembling that of the human Parkinson's disease in the advanced stage. The behavioral manifestations in this chronic mouse model of Parkinson's syndrome remain uninvestigated. The health benefit of exercise in aging and in neurodegenerative disorders including the Parkinson's disease has been implicated; however, clinical and laboratory studies in this area are limited. In this research with the chronic MPD, we first conducted a series of behavioral tests and then investigated the impact of endurance exercise on the identified Parkinsonian behavioral deficits. We report here that the severe chronic MPD mice showed significant deficits in their gait pattern consistency and in learning the cued version of the Morris water maze. Their performances on the challenging beam and walking grid were considerably attenuated suggesting the lack of balance and motor coordination. Furthermore, their spontaneous and amphetamine-stimulated locomotor activities in the open field were significantly suppressed. The behavioral deficits in the chronic MPD lasted for at least 8 weeks after MPTP/probenecid treatment. When the chronic MPD mice were exercise-trained on a motorized treadmill 1 week before, 5 weeks during, and 8-12 weeks after MPTP/probenecid treatment, the behavioral deficits in gait pattern, spontaneous ambulatory movement, and balance performance were reversed; whereas neuronal loss and impairment in cognitive skill, motor coordination, and amphetamine-stimulated locomotor activity were not altered when compared to the sedentary chronic MPD animals. This study indicates that in spite of the drastic loss of dopaminergic neurons and depletion of dopamine in the severe chronic MPD, endurance exercise training effectively reverses the Parkinson's like behavioral deficits related to regular movement, balance and gait performance.

The ugly side of amphetamines: short- and long-term toxicity of 3,4-methylenedioxymethamphetamine (MDMA, ‘Ecstasy’), methamphetamine and d-amphetamine

PubMed Central

Steinkellner, Thomas; Freissmuth, Michael; Sitte, Harald H.; Montgomery, Therese

2015-01-01

Amphetamine (‘Speed’), methamphetamine (‘Ice’) and its congener 3,4-methylenedioxymethamphetamine (MDMA; ‘Ecstasy’) are illicit drugs abused worldwide for their euphoric and stimulant effects. Despite compelling evidence for chronic MDMA neurotoxicity in animal models, the physiological consequences of such toxicity in humans remain unclear. In addition, distinct differences in the metabolism and pharmacokinetics of MDMA between species and different strains of animals prevent the rationalisation of realistic human dose paradigms in animal studies. Here, we attempt to review amphetamine toxicity and in particular MDMA toxicity in the pathogenesis of exemplary human pathologies, independently of confounding environmental factors such as poly-drug use and drug purity. PMID:21194370

Literature Review: Update on Amphetamine Neurotoxicity and Its Relevance to the Treatment of ADHD

ERIC Educational Resources Information Center

Advokat, Claire

2007-01-01

Objective: A review of amphetamine treatment for attention-deficit/hyperactivity disorder (ADHD) was conducted, to obtain information on the long-term neurological consequences of this therapy. Method: Several databases were accessed for research articles on the effects of amphetamine in the brain of laboratory animals and ADHD diagnosed…

Characteristics of primary amphetamine users in Sweden: a criminal justice population examined with the Addiction Severity Index.

PubMed

Hakansson, A; Schlyter, F; Berglund, M

2009-01-01

Characteristics of primary amphetamine, heroin and cocaine users were compared in a criminal justice population. 7,085 clients with suspected or reported substance use were studied using the Addiction Severity Index. Variables separating amphetamine, heroin and cocaine users were analyzed in stepwise logistic regression. There were considerably more primary amphetamine users (n = 1,396) than heroin (n = 392) and cocaine (n = 119) users. Amphetamine users were older, a more rural population, and less likely to be non-Nordic immigrants. Compared with heroin, amphetamine use was associated with older age, Nordic origin, nonurban residence, memory/concentration problems, parental alcohol problems, and less history of other opioid use, overdose and detoxification. Compared with cocaine, amphetamine use was associated with older age, Nordic origin, nonurban residence, injecting, tobacco and institution treatment. Overlap of drug use between groups was relatively uncommon. This pattern of amphetamine use, common among Swedish criminals, has relatively distinct boundaries from heroin and cocaine use, commonly involves injecting, and differs from other countries. Psychiatric problems and alcohol heredity were common, and evidence-based treatment for amphetamine users is needed. The connection between amphetamine use and criminal behavior is insufficiently understood and should be further addressed. Copyright 2008 S. Karger AG, Basel.

Effects of 21-day d-amphetamine and risperidone treatment on cocaine vs food choice and extended-access cocaine intake in male rhesus monkeys.

PubMed

Hutsell, Blake A; Negus, S Stevens; Banks, Matthew L

2016-11-01

Clinical trial data suggest amphetamine treatment is most efficacious in moderate to high frequency cocaine users. However, preclinical studies have examined amphetamine treatment effects under relatively limited cocaine access conditions with low to moderate cocaine intakes. This study determined d-amphetamine treatment effects on cocaine self-administration in rhesus monkeys under cocaine access conditions allowing for high daily cocaine intake. For comparison and as a negative control, treatment effects with the antipsychotic risperidone were also examined. Continuous 21-day treatments with ramping doses of d-amphetamine (days 1-7: 0.032mg/kg/h; days 8-21: 0.1mg/kg/h, i.v.) or risperidone (days 1-7: 0.001mg/kg/h; days 8-14: 0.0032mg/kg/h; days 15-21: 0.0056mg/kg/h, i.v.) were administered to rhesus monkeys (n=4) with daily access to two types of cocaine self-administration sessions: (1) a 2-h 'choice' session with concurrent availability of 1-g food pellets and intravenous cocaine injections (0-0.1mg/kg per injection) and (2) a 20-h 'extended-access' session with 0.1mg/kg per injection cocaine availability. Total daily cocaine intake increased >6-fold during extended cocaine access. d-Amphetamine significantly decreased total cocaine intake, but not cocaine vs food choice. In contrast, risperidone did not significantly alter either total cocaine intake or cocaine vs. food choice. These results confirm and extend previous results supporting treatment effectiveness for monoamine releasers, but not dopamine antagonists, to reduce cocaine self-administration. Moreover, these results suggest amphetamine treatment efficacy to decrease preclinical cocaine vs. food choice may depend upon cocaine access conditions. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Effects of 21-day d-amphetamine and risperidone treatment on cocaine vs food choice and extended-access cocaine intake in male rhesus monkeys

PubMed Central

Hutsell, Blake A.; Negus, S. Stevens; Banks, Matthew L.

2016-01-01

Background Clinical trial data suggest amphetamine treatment is most efficacious in moderate to high frequency cocaine users. However, preclinical studies have examined amphetamine treatment effects under relatively limited cocaine access conditions with low to moderate cocaine intakes. This study determined d-amphetamine treatment effects on cocaine self-administration in rhesus monkeys under cocaine access conditions allowing for high daily cocaine intake. For comparison and as a negative control, treatment effects with the antipsychotic risperidone were also examined. Methods Continuous 21-day treatments with ramping doses of d-amphetamine (days 1–7: 0.032 mg/kg/h; days 8–21: 0.1 mg/kg/h, i.v.) or risperidone (days 1–7: 0.001 mg/kg/h; days 8–14: 0.0032 mg/kg/h; days 15–21: 0.0056 mg/kg/h, i.v.) were administered to rhesus monkeys (n = 4) with daily access to two types of cocaine self-administration sessions: (1) a 2-h ‘choice’ session with concurrent availability of 1-g food pellets and intravenous cocaine injections (0–0.1 mg/kg per injection) and (2) a 20-h ‘extended-access’ session with 0.1 mg/kg per injection cocaine availability. Results Total daily cocaine intake increased >6-fold during extended cocaine access. d-Amphetamine significantly decreased total cocaine intake, but not cocaine vs food choice. In contrast, risperidone did not significantly alter either total cocaine intake or cocaine vs. food choice. Conclusions These results confirm and extend previous results supporting treatment effectiveness for monoamine releasers, but not dopamine antagonists, to reduce cocaine self-administration. Moreover, these results suggest amphetamine treatment efficacy to decrease preclinical cocaine vs. food choice may depend upon cocaine access conditions. PMID:27615401

Interactions between radiation and amphetamine in taste-aversion learning and the role of the area postrema in amphetamine-induced conditioned taste aversions

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

Rabin, B.M.; Hunt, W.A.; Lee, J.

1987-01-01

Three experiments were run to assess the role of the area postrema in taste-aversion learning resulting from combined treatment with subthreshold unconditioned stimuli and in the acquisition of an amphetamine-induced taste aversion. In the first experiment, it was shown that combined treatment with subthreshold radiation (15 rad) and subthreshold amphetamine (0.5 mg/kg, IP) resulted in the acquisition of a taste aversion. The second experiment showed that lesions of the area postrema blocked taste aversion learning produced by two subthreshold doses of amphetamine. In the third experiment, which looked at the dose-response curve for amphetamine-induced taste aversion learning to intact ratsmore » and rats with area postrema lesions, it was shown that both groups of rats acquired taste aversions following injection of amphetamine, although the rats with lesions showed a less-severe aversion than the intact rats. The results are interpreted as indicating that amphetamine-induced taste-aversion learning may involve area post-remamediated mechanisms, particularly at the lower doses, but an intact area postrema is not a necessary condition of the acquisition of an amphetamine-induced taste aversion.« less

Interactions between radiation and amphetamine in taste aversion learning and the role of the area postrema in amphetamine-induced conditioned taste aversions

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

Rabin, B.M.; Hunt, W.A.; Lee, J.

1987-08-01

Three experiments were run to assess the role of the area postrema in taste aversion learning resulting from combined treatment with subthreshold unconditioned stimuli and in the acquisition of an amphetamine-induced taste aversion. In the first experiment, it was shown that combined treatment with subthreshold radiation (15 rad) and subthreshold amphetamine (0.5 mg/kg, IP) resulted in the acquisition of a taste aversion. The second experiment showed that lesions of the area postrema blocked taste aversion learning produced by two subthreshold doses of amphetamine. In the third experiment, which looked at the dose-response curve for amphetamine-induced taste aversion learning in intactmore » rats and rats with area postrema lesions, it was shown that both groups of rats acquired taste aversions following injection of amphetamine, although the rats with lesions showed a less severe aversion than the intact rats. The results are interpreted as indicating that amphetamine-induced taste aversion learning may involve area postrema-mediated mechanisms, particularly at the lower doses, but that an intact area postrema is not a necessary condition for the acquisition of an amphetamine-induced taste aversion.« less

Psychological treatments for stimulant misuse, comparing and contrasting those for amphetamine dependence and those for cocaine dependence.

PubMed

Vocci, Frank J; Montoya, Iván D

2009-05-01

The aim is to compare and contrast psychological treatments for amphetamine and cocaine dependence. Stimulant dependence, in the form of cocaine or amphetamine/methamphetamine dependence, is prevalent worldwide, and their ratio may vary across different countries and regions of countries. The treatment of stimulant disorders has greatly advanced in recent years, and scientific evaluation of behavioral therapies, using randomized clinical trials designs and a stage-wise approach, have demonstrated the safety and efficacy of interventions. Psychological interventions such as cognitive behavioral therapy and contingency management for cocaine and methamphetamines use disorders are well tolerated and moderately effective in achieving drug abstinence. There is evidence that contingency management interventions can help to improve retention in treatment and, in turn, other treatment outcomes. Although there are important differences in the neuropsychiatric and medical consequences of cocaine and amphetamine use disorders, there is currently no evidence for a differential treatment effect of any psychosocial treatment in the management of these disorders. As there are no Food and Drug Administration-approved medications for the treatment of these disorders, psychological interventions form the basis of their treatment. More research is needed to address the specific psychosocial needs of cocaine and amphetamine-dependent individuals in order to improve their treatment outcomes.

Nicotine Modifies Corticostriatal Plasticity and Amphetamine Rewarding Behaviors in Mice123

PubMed Central

Storey, Granville P.; Heimbigner, Lauren; Walwyn, Wendy M.; Bamford, Nigel S.

2016-01-01

Abstract Corticostriatal signaling participates in sensitized responses to drugs of abuse, where short-term increases in dopamine availability provoke persistent, yet reversible, changes in glutamate release. Prior studies in mice show that amphetamine withdrawal promotes a chronic presynaptic depression in glutamate release, whereas an amphetamine challenge reverses this depression by potentiating corticostriatal activity in direct pathway medium spiny neurons. This synaptic plasticity promotes corticostriatal activity and locomotor sensitization through upstream changes in the activity of tonically active cholinergic interneurons (ChIs). We used a model of operant drug-taking behaviors, in which mice self-administered amphetamine through an in-dwelling catheter. Mice acquired amphetamine self-administration under fixed and increasing schedules of reinforcement. Following a period of abstinence, we determined whether nicotinic acetylcholine receptors modified drug-seeking behavior and associated alterations in ChI firing and corticostriatal activity. Mice responding to conditioned reinforcement showed reduced ChI and corticostriatal activity ex vivo, which paradoxically increased following an amphetamine challenge. Nicotine, in a concentration that increases Ca2+ influx and desensitizes α4β2*-type nicotinic receptors, reduced amphetamine-seeking behaviors following abstinence and amphetamine-induced locomotor sensitization. Nicotine blocked the depression of ChI firing and corticostriatal activity and the potentiating response to an amphetamine challenge. Together, these results demonstrate that nicotine reduces reward-associated behaviors following repeated amphetamine and modifies the changes in ChIs firing and corticostriatal activity. By returning glutamatergic activity in amphetamine self-administering mice to a more stable and normalized state, nicotine limits the depression of striatal activity in withdrawal and the increase in activity following abstinence and a subsequent drug challenge. PMID:26866057

Maintenance on naltrexone+amphetamine decreases cocaine-vs.-food choice in male rhesus monkeys.

PubMed

Moerke, Megan J; Banks, Matthew L; Cheng, Kejun; Rice, Kenner C; Negus, S Stevens

2017-12-01

Cocaine use disorder remains a significant public health issue for which there are no FDA-approved pharmacotherapies. Amphetamine maintenance reduces cocaine use in preclinical and clinical studies, but the mechanism of this effect is unknown. Previous studies indicate a role for endogenous opioid release and subsequent opioid receptor activation in some amphetamine effects; therefore, the current study examined the role of mu-opioid receptor activation in d-amphetamine treatment effects in an assay of cocaine-vs-food choice. Adult male rhesus monkeys with double-lumen intravenous catheters responded for concurrently available food pellets and cocaine injections (0-0.1mg/kg/injection) during daily sessions. Cocaine choice and overall reinforcement rates were evaluated during 7-day treatments with saline or test drugs. During saline treatment, cocaine maintained a dose-dependent increase in cocaine-vs.-food choice. The mu-opioid receptor agonist morphine (0.032-0.32mg/kg/h) dose-dependently increased cocaine choice and decreased rates of reinforcement. A dose of the mu-selective opioid receptor antagonist naltrexone (0.0032mg/kg/h) that completely blocked morphine effects had no effect on cocaine choice when it was administered alone, but it enhanced the effectiveness of a threshold dose of 0.032mg/kg/h amphetamine to decrease cocaine choice without also enhancing nonselective behavioral disruption by this dose of amphetamine. Conversely, the kappa-selective opioid antagonist norbinalorphimine did not enhance amphetamine effects on cocaine choice. These results suggest that amphetamine maintenance produces mu opioid-receptor mediated effects that oppose its anti-cocaine effects. Co-administration of naltrexone may selectively enhance amphetamine potency to decrease cocaine choice without increasing amphetamine potency to produce general behavioral disruption. Copyright © 2017 Elsevier B.V. All rights reserved.

BDNF-Deficient Mice Show Reduced Psychosis-Related Behaviors Following Chronic Methamphetamine.

PubMed

Manning, Elizabeth E; Halberstadt, Adam L; van den Buuse, Maarten

2016-04-01

One of the most devastating consequences of methamphetamine abuse is increased risk of psychosis. Brain-derived neurotrophic factor has been implicated in both psychosis and neuronal responses to methamphetamine. We therefore examined persistent psychosis-like behavioral effects of methamphetamine in brain-derived neurotrophic factor heterozygous mice. Mice were chronically treated with methamphetamine from 6 to 9 weeks of age, and locomotor hyperactivity to an acute D-amphetamine challenge was tested in photocell cages after a 2-week withdrawal period. Methamphetamine-treated wild-type mice, but not brain-derived neurotrophic factor heterozygous mice, showed locomotor sensitization to acute 3mg/kg D-amphetamine. Qualitative analysis of exploration revealed tolerance to D-amphetamine effects on entropy in methamphetamine-treated brain-derived neurotrophic factor heterozygous mice, but not wild-type mice. Chronic methamphetamine exposure induces contrasting profiles of behavioral changes in wild-type and brain-derived neurotrophic factor heterozygous mice, with attenuation of behaviors relevant to psychosis in methamphetamine-treated brain-derived neurotrophic factor heterozygous mice. This suggests that brain-derived neurotrophic factor signalling changes may contribute to development of psychosis in methamphetamine users. © The Author 2015. Published by Oxford University Press on behalf of CINP.

Dextroamphetamine sulfate provided quick relief of severe post-partum depression that was recalcitrant to standard antidepressants and psychotherapy.

PubMed

Check, J H; Jaffe, A

2017-01-01

To determine if dextroamphetamine sulfate could improve symptoms of post-partum depression. A woman with severe post-partum depression that was resistant to standard antidepressant therapy and psychotherapy was treated with dextroamphetamine sulfate extended release capsules 15 mg/day. A quick and complete abrogation of the depression ensued along with improvement of migraine headaches, insomnia, and chronic fatigue. Dextr6amphetamine sulfate should be considered as a treatment modality for post-partum depression.

Withdrawal from repeated treatment with amphetamine reduces novelty-seeking behavior and enhances environmental habituation in mice.

PubMed

Fukushiro, Daniela F; Mári-Kawamoto, Elisa; Aramini, Tatiana C F; Saito, Luis P; Costa, Jacqueline M; Josino, Fabiana S; Frussa-Filho, Roberto

2011-11-01

Anhedonia associated with a dysphoric state is an important feature of amphetamine withdrawal in humans. We aimed to investigate the effects of amphetamine withdrawal on two motivation-related behaviors in mice: novelty seeking and environmental habituation. Because anxiety can interfere with the behavioral outcome of other tasks, amphetamine-withdrawn mice were also evaluated in the elevated plus maze. Swiss male mice (three months old) were treated with 2.0mg/kg amphetamine for 13 days, every other day, in their home cages (a total of seven injections). Twenty-four hours after withdrawal from drug treatment, mice were tested in a free-choice novelty apparatus containing one familiar and one novel compartment or in the elevated plus maze. Novelty-seeking behavior was assessed by comparing the time spent in the novel compartment vs. the familiar compartment, whereas environmental habituation was concomitantly evaluated by the time-response curve of total locomotion (novel+familiar). Novelty seeking was decreased during amphetamine withdrawal, and this result was not associated with changes in the anxiety-like behavior of mice. Additionally, amphetamine withdrawal enhanced environmental habituation. The concomitant decrease in novelty seeking and the increase in environmental habituation seem to be related to amphetamine withdrawal-induced anhedonia. Thus, the model proposed here could be used as a tool for the study of mechanisms and potential treatment of the anhedonic behavioral consequences of psychostimulant withdrawal. Copyright © 2011 Elsevier Inc. All rights reserved.

Profiles of cognitive dysfunction in chronic amphetamine and heroin abusers.

PubMed

Ornstein, T J; Iddon, J L; Baldacchino, A M; Sahakian, B J; London, M; Everitt, B J; Robbins, T W

2000-08-01

Groups of subjects whose primary drug of abuse was amphetamine or heroin were compared, together with age- and IQ-matched control subjects. The study consisted of a neuropsychological test battery which included both conventional tests and also computerised tests of recognition memory, spatial working memory, planning, sequence generation, visual discrimination learning, and attentional set-shifting. Many of these tests have previously been shown to be sensitive to cortical damage (including selective lesions of the temporal or frontal lobes) and to cognitive deficits in dementia, basal ganglia disease, and neuropsychiatric disorder. Qualitative differences, as well as some commonalities, were found in the profile of cognitive impairment between the two groups. The chronic amphetamine abusers were significantly impaired in performance on the extra-dimensional shift task (a core component of the Wisconsin Card Sort Test) whereas in contrast, the heroin abusers were impaired in learning the normally easier intra-dimensional shift component. Both groups were impaired in some of tests of spatial working memory. However, the amphetamine group, unlike the heroin group, were not deficient in an index of strategic performance on this test. The heroin group failed to show significant improvement between two blocks of a sequence generation task after training and additionally exhibited more perseverative behavior on this task. The two groups were profoundly, but equivalently impaired on a test of pattern recognition memory sensitive to temporal lobe dysfunction. These results indicate that chronic drug use may lead to distinct patterns of cognitive impairment that may be associated with dysfunction of different components of cortico-striatal circuitry.

Cardiovascular manifestations of substance abuse: part 2: alcohol, amphetamines, heroin, cannabis, and caffeine.

PubMed

Frishman, William H; Del Vecchio, Alexander; Sanal, Shirin; Ismail, Anjum

2003-01-01

The abuse of alcohol is associated with chronic cardiomyopathy, hypertension, and arrhythmia. Abstinence or using alcohol in moderation can reverse these cardiovascular problems. Alcohol is also distinguished among the substances of abuse by having possible protective effects against coronary artery disease and stroke when used in moderate amounts. Amphetamines (eg, speed, ice, ecstasy) have many of the cardiovascular toxicities seen with cocaine, including acute and chronic cardiovascular diseases. Heroin and other opiates can cause arrhythmias and noncardiac pulmonary edema, and may reduce cardiac output. Cardiovascular problems are less common with cannabis (marijuana) than with opiates, but major cognitive disorders may be seen with its chronic use. It is still controversial whether caffeine can cause hypertension and coronary artery disease, and questions have been raised about its safety in patients with heart failure and arrhythmia.

Breakingtheice: a protocol for a randomised controlled trial of an internet-based intervention addressing amphetamine-type stimulant use.

PubMed

Tait, Robert J; McKetin, Rebecca; Kay-Lambkin, Frances; Bennett, Kylie; Tam, Ada; Bennett, Anthony; Geddes, Jenny; Garrick, Adam; Christensen, Helen; Griffiths, Kathleen M

2012-06-25

The prevalence of amphetamine-type stimulant use is greater than that of opioids and cocaine combined. Currently, there are no approved pharmacotherapy treatments for amphetamine-type stimulant problems, but some face-to-face psychotherapies are of demonstrated effectiveness. However, most treatment services focus on alcohol or opioid disorders, have limited reach and may not appeal to users of amphetamine-type stimulants. Internet interventions have proven to be effective for some substance use problems but none has specifically targeted users of amphetamine-type stimulants. The study will use a randomized controlled trial design to evaluate the effect of an internet intervention for amphetamine-type stimulant problems compared with a waitlist control group. The primary outcome will be assessed as amphetamine-type stimulant use (baseline, 3 and 6 months). Other outcomes measures will include 'readiness to change', quality of life, psychological distress (K-10 score), days out of role, poly-drug use, help-seeking intention and help-seeking behavior. The intervention consists of three modules requiring an estimated total completion time of 90 minutes. The content of the modules was adapted from face-to-face clinical techniques based on cognitive behavior therapy and motivation enhancement. The target sample is 160 men and women aged 18 and over who have used amphetamine-type stimulants in the last 3 months. To our knowledge this will be the first randomized controlled trial of an internet intervention specifically developed for users of amphetamine-type stimulants. If successful, the intervention will offer greater reach than conventional therapies and may engage clients who do not generally seek treatment from existing service providers. Australian and New Zealand Clinical Trials Registry (http://www.anzctr.org.au/) ACTRN12611000947909.

Breakingtheice: A protocol for a randomised controlled trial of an internet-based intervention addressing amphetamine-type stimulant use

PubMed Central

2012-01-01

Background The prevalence of amphetamine-type stimulant use is greater than that of opioids and cocaine combined. Currently, there are no approved pharmacotherapy treatments for amphetamine-type stimulant problems, but some face-to-face psychotherapies are of demonstrated effectiveness. However, most treatment services focus on alcohol or opioid disorders, have limited reach and may not appeal to users of amphetamine-type stimulants. Internet interventions have proven to be effective for some substance use problems but none has specifically targeted users of amphetamine-type stimulants. Design/method The study will use a randomized controlled trial design to evaluate the effect of an internet intervention for amphetamine-type stimulant problems compared with a waitlist control group. The primary outcome will be assessed as amphetamine-type stimulant use (baseline, 3 and 6 months). Other outcomes measures will include ‘readiness to change’, quality of life, psychological distress (K-10 score), days out of role, poly-drug use, help-seeking intention and help-seeking behavior. The intervention consists of three modules requiring an estimated total completion time of 90 minutes. The content of the modules was adapted from face-to-face clinical techniques based on cognitive behavior therapy and motivation enhancement. The target sample is 160 men and women aged 18 and over who have used amphetamine-type stimulants in the last 3 months. Discussion To our knowledge this will be the first randomized controlled trial of an internet intervention specifically developed for users of amphetamine-type stimulants. If successful, the intervention will offer greater reach than conventional therapies and may engage clients who do not generally seek treatment from existing service providers. Trial registration Australian and New Zealand Clinical Trials Registry (www.anzctr.org.au/) ACTRN12611000947909 PMID:22731926

The influence of ionotropic and metabotropic glutamate receptor ligands on anxiety-like effect of amphetamine withdrawal in rats.

PubMed

Koltunowska, D; Gibula-Bruzda, E; Kotlinska, J H

2013-08-01

Chronic amphetamine use results in anxiety-like states after drug cessation. The aim of the study was to determine a role of ionotropic and metabotropic glutamate receptor ligands in amphetamine-evoked withdrawal anxiety in the elevated plus-maze test in rats. In our study memantine (8 and 12 mg/kg), a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist did not reduce amphetamine withdrawal anxiety. Acamprosate (NMDA and metabotropic glutamate 5 receptor (mGluR5) antagonist) at the dose 200 and 400mg/kg showed anxiolytic-like effect, thus increasing the percent of time spent in open arms and a number of open arm entries. mGluR5 selective antagonist, MTEP (3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine hydrochloride) and mGluR2/3 agonist, LY354740 (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid), caused effects similar to acamprosate at doses 1.25-5mg/kg and 2.5-5mg/kg, respectively. None of the glutamate ligands influenced locomotor activity of rats when given to the saline-treated group. Taking into account the positive correlation between amphetamine withdrawal-induced anxiety and relapse to amphetamine taking, our results suggest that modulation of mGluRs may prevent relapse to amphetamine and might pose a new direction in amphetamine abuse therapy. Copyright © 2013 Elsevier Inc. All rights reserved.

Profile of Executive and Memory Function Associated with Amphetamine and Opiate Dependence

PubMed Central

Ersche, Karen D; Clark, Luke; London, Mervyn; Robbins, Trevor W; Sahakian, Barbara J

2007-01-01

Cognitive function was assessed in chronic drug users on neurocognitive measures of executive and memory function. Current amphetamine users were contrasted with current opiate users, and these two groups were compared with former users of these substances (abstinent for at least one year). Four groups of participants were recruited: amphetamine-dependent individuals, opiate-dependent individuals, former users of amphetamines, and/or opiates and healthy non-drug taking controls. Participants were administered the Tower of London (TOL) planning task and the 3D-IDED attentional set-shifting task to assess executive function, and Paired Associates Learning and Delayed Pattern Recognition Memory tasks to assess visual memory function. The three groups of substance users showed significant impairments on TOL planning, Pattern Recognition Memory and Paired Associates Learning. Current amphetamine users displayed a greater degree of impairment than current opiate users. Consistent with previous research showing that healthy men are performing better on visuo-spatial tests than women, our male controls remembered significantly more paired associates than their female counterparts. This relationship was reversed in drug users. While performance of female drug users was normal, male drug users showed significant impairment compared to both their female counterparts and male controls. There was no difference in performance between current and former drug users. Neither years of drug abuse nor years of drug abstinence were associated with performance. Chronic drug users display pronounced neuropsychological impairment in the domains of executive and memory function. Impairment persists after several years of drug abstinence and may reflect neuropathology in frontal and temporal cortices. PMID:16160707

Treatment of ADHD with amphetamine: short-term effects on family interaction.

PubMed

Gustafsson, Peik; Hansson, Kjell; Eidevall, Lena; Thernlund, Gunilla; Svedin, Carl Göran

2008-07-01

This research seeks to study the impact on family function after 3 months of treatment with amphetamine. A total of 43 children, 6 to 11 years of age, with ADHD were treated with amphetamine for 3 months. Family function was studied before and after treatment by parent self-rating and independent observer ratings of videotaped parent-child interactions. The families with a child with ADHD were found to be more dysfunctional than control families. Families with children with severe ADHD behavior showed evidence of more family dysfunction compared to families with children with less severe ADHD behavior. After 3 months of treatment with amphetamine, the children's behavior and the mother's well-being and some aspects of parent-reported and observer-rated family functioning improved. This study gives support to the notion that some aspects of family dysfunction may be related to the child's ADHD behavior.

Wastewater-based epidemiology generated forensic information: Amphetamine synthesis waste and its impact on a small sewage treatment plant.

PubMed

Emke, Erik; Vughs, Dennis; Kolkman, Annemieke; de Voogt, Pim

2018-05-01

Chemical analysis of domestic wastewater can reveal the presence of illicit drugs either consumed by a population or directly discharged into the sewer system. In the search for causes of a recent malfunctioning of a small domestic wastewater treatment plant aberrantly high loads of amphetamine were observed in the influent of the plant. Direct discharges of chemical waste from illegal production sites were suspected to be the cause. Illegal manufacturing of amphetamines creates substantial amounts of chemical waste. Here we show that fly-tipping of chemical waste originating from an amphetamine synthesis in the catchment of a small sewage treatment plant resulted in failure of the treatment process. Target analysis of drugs of abuse and non-target screening using high resolution mass spectrometry provided evidence for the presence of amphetamine produced from the precursor 1-phenylpropan-2-one by the Leuckart process through specific synthesis markers. Furthermore the identity and presence of the pre-precursor 3-oxo-2-phenylbutanamide was confirmed and a route specific marker was proposed. This is the first study that demonstrates that non-target screening of wastewater can identify intermediates, impurities and by products of the synthesis routes used in illegal manufacturing of amphetamine. The profiles of chemicals thus obtained can be used in tracking productions sites within the corresponding sewer catchment. Copyright © 2018 Elsevier B.V. All rights reserved.

Predicting drug court outcome among amphetamine-using participants.

PubMed

Wu, Lora J; Altshuler, Sandra J; Short, Robert A; Roll, John M

2012-06-01

Amphetamine use and abuse carry with it substantial social costs. Although there is a perception that amphetamine users are more difficult to treat than other substance users, drug courts have been used to effectively address drug-related crimes and hold the potential to lessen the impact of amphetamine abuse through efficacious treatment and rehabilitation. The objective of this study was to identify predictors of drug court outcome among amphetamine-using participants. A drug court database was obtained (N = 540) and amphetamine-using participants (n= 341) identified. Multivariate binary regression models run for the amphetamine-using participants identified being employed and being a parent as predictive of successful completion of the program, whereas being sanctioned to jail during the program was inversely related to program completion. Copyright © 2012 Elsevier Inc. All rights reserved.

Jobelyn® pretreatment ameliorates symptoms of psychosis in experimental models.

PubMed

Omogbiya, Itivere Adrian; Umukoro, Solomon; Aderibigbe, Adegbuyi Oladele; Bakre, Adewale Ganiyu

2013-01-01

Psychosis is a chronic neurological disorder and it remains a major medical and social problem in most African countries. Individuals with psychotic illness in this region tend to seek help from traditional medical practitioners, who prescribe herbal remedies as alternative forms of treatment for the disease. Jobelyn® (JB) is a commercial polyherbal formulation that has been acclaimed to show beneficial effects in neurological disorders. However, its usefulness in psychosis has not been scientifically validated. Thus, this study was undertaken to evaluate its effects on animal models predictive of human psychosis. Antipsychotic activity of JB was assessed based on the inhibition of stereotyped behavior induced by amphetamine or apomorphine in mice. Amphetamine-induced hyperactivity and lethality in aggregated mice were additional tests employed to further evaluate the antipsychotic property of JB. The effect of JB on catalepsy was also assessed, using the inclined plane paradigm. JB (5-50 mg/kg, p.o.) significantly (p<0.05) inhibited stereotypy induced by amphetamine (10.0 mg/kg, i.p.) or apomorphine (1 mg/kg, i.p.), which suggests antipsychotic activity. Furthermore, JB (5-50 mg/kg, p.o.) reduced lethality in aggregated mice and inhibited hyperactivity induced by amphetamine, respectively. However, JB (5-50 mg/kg, p.o.) did not cause cataleptic behavior, as it failed to alter the duration of stay of the animals on the inclined plane. Taken together, these findings suggest that JB exhibits antipsychotic-like activity, devoid of the adverse effect of cataleptic behavior, and may offer some beneficial effects in the symptomatic relief of psychotic ailments.

Amphetamine. Report Series 28, No. 1.

ERIC Educational Resources Information Center

National Inst. on Drug Abuse (DHEW/PHS), Rockville, MD. National Clearinghouse for Drug Abuse Information.

This report, prepared by the National Clearinghouse for Drug Abuse Information, presents substantial information on the use and abuse of the drug "family" known as amphetamines. A brief history of the drug is given, along with its basic pharmacology. The current medical uses for amphetamines include: (1) short-term treatment of obesity,…

Role of d-amphetamine and d-methamphetamine as active metabolites of benzphetamine: Evidence from drug discrimination and pharmacokinetic studies in male rhesus monkeys.

PubMed

Banks, Matthew L; Snyder, Rodney W; Fennell, Timothy R; Negus, S Stevens

2017-05-01

Benzphetamine is a Schedule III anorectic agent that is a prodrug for d-amphetamine and d-methamphetamine and may have utility as an "agonist" medication for cocaine use disorder treatment. This study evaluated the pharmacokinetic-pharmacodynamic profile of benzphetamine using a drug discrimination procedure in rhesus monkeys. The potency and time course of cocaine-like discriminative stimulus effects were compared for benzphetamine (10-18mg/kg, intramuscular (IM)) and d-amphetamine (0.032-0.32mg/kg, IM) in monkeys (n=3-4) trained to discriminate IM cocaine (0.32mg/kg) from saline in a two-key food-reinforced discrimination procedure. Parallel pharmacokinetic studies in the same monkeys determined plasma benzphetamine, d-methamphetamine and/or d-amphetamine levels for correlation with behavioral effects. d-Amphetamine produced dose-dependent, time-dependent, and full cocaine-like effects, i.e. ≥90% cocaine-appropriate responding, in all monkeys without altering response rates. The time course of d-amphetamine's cocaine-like discriminative stimulus effects correlated with plasma d-amphetamine levels. Benzphetamine was 180-fold less potent than d-amphetamine and produced full cocaine-like effects in only 2 of 4 monkeys while significantly decreasing response rates. Benzphetamine administration increased plasma d-methamphetamine (peak at 100min) and d-amphetamine (peak at 24h) levels, but the time course of behavioral effects did not correlate with increased levels of benzphetamine, d-methamphetamine or d-amphetamine. These results suggest that benzphetamine yields d-amphetamine and d-methamphetamine as active metabolites in rhesus monkeys, but generation of these metabolites is not sufficient to account for benzphetamine behavioral effects. The incomplete cocaine substitution profile and protracted d-amphetamine plasma levels suggest that benzphetamine may still warrant further evaluation as a candidate pharmacotherapy for cocaine use disorder treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

Enantioselective degradation of amphetamine-like environmental micropollutants (amphetamine, methamphetamine, MDMA and MDA) in urban water.

PubMed

Evans, Sian E; Bagnall, John; Kasprzyk-Hordern, Barbara

2016-08-01

This paper aims to understand enantioselective transformation of amphetamine, methamphetamine, MDMA (3,4-methylenedioxy-methamphetamine) and MDA (3,4-methylenedioxyamphetamine) during wastewater treatment and in receiving waters. In order to undertake a comprehensive evaluation of the processes occurring, stereoselective transformation of amphetamine-like compounds was studied, for the first time, in controlled laboratory experiments: receiving water and activated sludge simulating microcosm systems. The results demonstrated that stereoselective degradation, via microbial metabolic processes favouring S-(+)-enantiomer, occurred in all studied amphetamine-based compounds in activated sludge simulating microcosms. R-(-)-enantiomers were not degraded (or their degradation was limited) which proves their more recalcitrant nature. Out of all four amphetamine-like compounds studied, amphetamine was the most susceptible to biodegradation. It was followed by MDMA and methamphetamine. Photochemical processes facilitated degradation of MDMA and methamphetamine but they were not, as expected, stereoselective. Preferential biodegradation of S-(+)-methamphetamine led to the formation of S-(+)-amphetamine. Racemic MDMA was stereoselectively biodegraded by activated sludge which led to its enrichment with R-(-)-enantiomer and formation of S-(+)-MDA. Interestingly, there was only mild stereoselectivity observed during MDMA degradation in rivers. This might be due to different microbial communities utilised during activated sludge treatment and those present in the environment. Kinetic studies confirmed the recalcitrant nature of MDMA. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Examination of methylphenidate-mediated behavior regulation by glycogen synthase kinase-3 in mice.

PubMed

Mines, Marjelo A; Beurel, Eleonore; Jope, Richard S

2013-01-05

Abnormalities in dopaminergic activity have been implicated in psychiatric diseases, such as attention deficit hyperactivity disorder (ADHD), and are treated with therapeutic stimulants, commonly methylphenidate or amphetamine. Amphetamine administration increases glycogen synthase kinase-3 (GSK3) activation, which is necessary for certain acute behavioral responses to amphetamine, including increased locomotor activity and impaired sensorimotor gating. Here, we tested if modulating GSK3 by administration of the GSK3 inhibitor lithium or expression of constitutively active GSK3 altered behavioral responses to methylphenidate administered to mice acutely or daily for 8 days. Methylphenidate or amphetamine was administered to mice intraperitoneally for 1 or 8 days. Open-field activity and pre-pulse inhibition (PPI) were measured. In contrast to lithium's blockade of acute amphetamine-induced locomotor hyperactivity, lithium treatment did not significantly reduce methylphenidate-induced locomotor hyperactivity in wild-type mice after acute or 8 days of repeated methylphenidate administration. Lithium treatment significantly increased the impairment in PPI caused by methylphenidate, but significantly reduced the amphetamine-induced PPI deficit. In GSK3 knockin mice, expression of constitutively active GSK3β, but not GSK3α, significantly increased locomotor hyperactivity after acute methylphenidate treatment, and significantly impaired PPI, preventing further methylphenidate-induced impairment of PPI that was evident in wild-type mice and GSK3α knockin mice. Lithium does not counteract locomotor activity and PPI responses to methylphenidate as it does these responses to amphetamine, indicating that different mechanisms mediate these behavioral responses to methylphenidate and amphetamine. Only active GSK3β, not GSK3α, modulates behavioral responses to MPH, indicating selectivity in the actions of GSK3 isoforms. Copyright © 2012 Elsevier B.V. All rights reserved.

Circulating adrenal hormones are not necessary for the development of sensitization to the psychomotor activating effects of amphetamine.

PubMed

Badiani, A; Morano, M I; Akil, H; Robinson, T E

1995-02-27

We reported previously that when amphetamine is given in NOVEL test cages both its acute psychomotor activating effects (rotational behaviour and locomotor activity) and the degree of sensitization are greater than when amphetamine is given in HOME cages that are physically identical to the NOVEL test cages. Since exposure to the NOVEL environment increases plasma corticosterone levels (Experiment 1) it is possible that the enhancement in the effects of amphetamine in the NOVEL condition is mediated by corticosterone. If this hypothesis is correct adrenalectomy (ADX) should abolish the difference between the HOME and NOVEL groups. This was tested in three independent experiments, in which the response (rotational behavior in Experiments 2 and 3; locomotor activity and rearing behavior in Experiment 4) to repeated injections of amphetamine was assessed in rats that underwent adrenalectomy (ADX) or a sham operation (SHAM). ADX animals received either no corticosterone replacement or one of two corticosterone replacement treatments. Adrenalectomy, with or without corticosterone replacement treatment, had no significant effect on the development of amphetamine sensitization, either in the HOME or the NOVEL environment. By contrast, the effects of adrenalectomy on the acute response to amphetamine varied depending on the behavioral measure and possibly on the dose of amphetamine (2.0 mg/kg, 3.0 mg/kg and 1.5 mg/kg IP, in Experiments 2, 3 and 4, respectively). We conclude that: (i) a stress-induced secretion of adrenal hormones is not responsible for the enhancement in sensitization to amphetamine seen in animals tested in a NOVEL environment; (ii) circulating adrenal hormones are not necessary for development of sensitization to the psychomotor activating effects of amphetamine.

Antidepressants differentially affect striatal amphetamine-stimulated dopamine and serotonin release in rats with high and low novelty-oriented behaviour.

PubMed

O'Leary, Aet; Kõiv, Kadri; Raudkivi, Karita; Harro, Jaanus

2016-11-01

In the studies of depression pathogenesis and antidepressant action, the monoaminergic hypothesis of depression has mainly focused on the serotonergic and noradrenergic mechanisms. However, dopaminergic neurotransmission is also linked to both depressive symptomatology as well as antidepressant effects. We have previously shown that persistent inter-individual differences in the rat behavioural activity in novel environments is associated with differences in the striatal extracellular levels of dopamine and serotonin, depressive-like behaviour and the expression of several depression-related genes. The aim of the current study was to investigate the relative potency of the tricyclic antidepressant imipramine, the selective serotonin re-uptake inhibitor fluoxetine, and the selective noradrenaline re-uptake inhibitor reboxetine (all drugs administered in the dose of 10mg/kg, i.p.) to enhance amphetamine-stimulated dopamine and serotonin release in the striatum using in vivo microdialysis in awake, freely-moving rats, categorized into high explorers (HE) and low explorers (LE) based on their spontaneous novelty-oriented behaviour. The basal extracellular dopamine and serotonin concentration in the striatum did not differ between the LE- and HE-rats. None of the antidepressants alone were able to modify baseline striatal dopamine levels, but the amphetamine-stimulated dopamine release was significantly higher in the HE-rats after acute and chronic imipramine (but not fluoxetine or reboxetine). Acute imipramine and fluoxetine, but not reboxetine, increased both the basal and amphetamine-stimulated levels of serotonin in the striatum. Again, the HE-rats had higher amphetamine-stimulated serotonin release after fluoxetine administration. These findings suggest that rats with depressive-like phenotype are less sensitive to the neurochemical effects of antidepressants in the striatum. These results may have relevance in understanding the neurobiological bases for inter-individual differences in antidepressant treatment response in humans and development of novel medicines. Copyright © 2016 Elsevier Ltd. All rights reserved.

Inhibition by ketamine and amphetamine analogs of the neurogenic nitrergic vasodilations in porcine basilar arteries

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

Chen, Mei-Fang

The abuse of ketamine and amphetamine analogs is associated with incidence of hypertension and strokes involving activation of sympathetic activities. Large cerebral arteries at the base of the brain from several species receive dense sympathetic innervation which upon activation causes parasympathetic-nitrergic vasodilation with increased regional blood flow via axo-axonal interaction mechanism, serving as a protective mechanism to meet O{sub 2} demand in an acutely stressful situation. The present study was designed to examine effects of ketamine and amphetamine analogs on axo-axonal interaction-mediated neurogenic nitrergic vasodilation in porcine basilar arteries using techniques of blood-vessel myography, patch clamp and two-electrode voltage clamp,more » and calcium imaging. In U46619-contracted basilar arterial rings, nicotine (100 μM) and electrical depolarization of nitrergic nerves by transmural nerve stimulation (TNS, 8 Hz) elicited neurogenic nitrergic vasodilations. Ketamine and amphetamine analogs concentration-dependently inhibited nicotine-induced parasympathetic-nitrergic vasodilation without affecting that induced by TNS, nitroprusside or isoproterenol. Ketamine and amphetamine analogs also concentration-dependently blocked nicotine-induced inward currents in Xenopus oocytes expressing α3β2-nicotinic acetylcholine receptors (nAChRs), and nicotine-induced inward currents as well as calcium influxes in rat superior cervical ganglion neurons. The potency in inhibiting both inward-currents and calcium influxes is ketamine > methamphetamine > hydroxyamphetamine. These results indicate that ketamine and amphetamine analogs, by blocking nAChRs located on cerebral perivascular sympathetic nerves, reduce nicotine-induced, axo-axonal interaction mechanism-mediated neurogenic dilation of the basilar arteries. Chronic abuse of these drugs, therefore, may interfere with normal sympathetic-parasympathetic interaction mechanism resulting in diminished neurogenic vasodilation and, possibly, normal blood flow in the brainstem. - Highlights: • Ketamine/amphetamines inhibit nicotine-induced cerebral neurogenic vasdilation. • Ketamine/amphetamines block cerebral perivascular sympathetic nAChR-mediated current. • The inhibitory potency is ketamine > D-amphetamine > methamphetamine > OH-amphetamine.« less

Role of d-amphetamine and d-methamphetamine as active metabolites of benzphetamine: evidence from drug discrimination and pharmacokinetic studies in male rhesus monkeys

PubMed Central

Banks, Matthew L.; Snyder, Rodney W.; Fennell, Timothy R.; Negus, S. Stevens

2017-01-01

Benzphetamine is a Schedule III anorectic agent that is a prodrug for d-amphetamine and d-methamphetamine and may have utility as an “agonist” medication for cocaine use disorder treatment. This study evaluated the pharmacokinetic-pharmacodynamic profile of benzphetamine using a drug discrimination procedure in rhesus monkeys. The potency and time course of cocaine-like discriminative stimulus effects were compared for benzphetamine (10–18 mg/kg, intramuscular (IM)) and d-amphetamine (0.032–0.32 mg/kg, IM) in monkeys (n=3–4) trained to discriminate IM cocaine (0.32 mg/kg) from saline in a two-key food-reinforced discrimination procedure. Parallel pharmacokinetic studies in the same monkeys determined plasma benzphetamine, d-methamphetamine and/or d-amphetamine levels for correlation with behavioral effects. d-Amphetamine produced dose-dependent, time-dependent, and full cocaine-like effects, i.e. ≥ 90% cocaine-appropriate responding,in all monkeys without altering response rates. The time course of d-amphetamine’s cocaine-like discriminative stimulus effects correlated with plasma d-amphetamine levels. Benzphetamine was 180-fold less potent than d-amphetamine and produced full cocaine-like effects in only 2 of 4 monkeys while significantly decreasing response rates. Benzphetamine administration increased plasma d-methamphetamine (peak at 100 min) and d-amphetamine (peak at 24 h) levels, but the time course of behavioral effects did not correlate with increased levels of benzphetamine, d-methamphetamine or d-amphetamine. These results suggest that benzphetamine yields d-amphetamine and d-methamphetamine as active metabolites in rhesus monkeys, but generation of these metabolites is not sufficient to account for benzphetamine behavioral effects. The incomplete cocaine substitution profile and protracted d-amphetamine plasma levels suggest that benzphetamine may still warrant further evaluation as a candidate pharmacotherapy for cocaine use disorder treatment. PMID:28373066

A rapid enhancement of locomotor sensitization to amphetamine by estradiol in female rats.

PubMed

Zovkic, Iva B; McCormick, Cheryl M

2017-11-14

Estradiol moderates the effects of drugs of abuse in both humans and rodents. Estradiol's enhancement of behavioral effects resulting from high (>2.5mg/kg) doses of amphetamine is established in rats; there is less evidence for the role of estradiol in locomotor effects elicited by lower doses, which are less aversive, increase incentive motivation, involve different neural mechanisms than higher doses, and often more readily reveal group differences than do higher doses. Further, the extent to which estradiol is required for the induction versus the expression of sensitization is unknown. To establish a protocol, we replicated the effects of estradiol on locomotor sensitization to amphetamine reported in a previous study that involved a high locomotor-activating dose (1.5mg/kg) of amphetamine, but with a lower dose. Ovariectomized female rats received 5μg of estradiol benzoate (EB) or OIL 30min before each of 5 treatments of 1.0mg/kg amphetamine or saline; all received a 0.5mg/kg challenge dose three days later. Compared with results for OIL, EB enhanced the locomotor-activating effects of repeated 1.0mg/kg amphetamine across treatment days. In contrast, on challenge day, there was no difference between EB-saline and EB-amphetamine to the lower dose (i.e., no sensitization). Experiments 2 and 3 involved a shorter induction (2days) and a lengthier withdrawal (9days) before the challenge test for the expression of sensitization to better differentiate the induction phase from the expression phase. In Expt2, EB-, and not OIL-, treated rats showed sensitization to 0.5mg/kg amphetamine; neither group showed sensitization to 1.5mg/kg amphetamine (ceiling effect?). In Expt3, rats were treated with EB either in both the induction and expression phases, in one of the phases only, or in neither phase. There was an effect of hormone treatment on challenge day and not on induction day; rats given EB on Challenge day showed sensitization to 0.5mg/kg amphetamine; OIL rats did not. The results suggest rapid effects of estradiol on amphetamine sensitization consistent with rapid effects of estradiol reported for other behaviours. Copyright © 2017. Published by Elsevier Inc.

Lisdexamfetamine: chemistry, pharmacodynamics, pharmacokinetics, and clinical efficacy, safety, and tolerability in the treatment of binge eating disorder.

PubMed

Ward, Kristen; Citrome, Leslie

2018-02-01

The indications for lisdexamfetamine (LDX), a central nervous system stimulant, were recently expanded to include treatment of moderate to severe binge eating disorder (BED). Areas covered: This review aims to describe the chemistry and pharmacology of LDX, as well as the clinical trials investigating the efficacy and safety of this medication for the management of BED. Expert opinion: LDX is the first medication with United States Food and Drug Administration approval for the treatment of BED. It is an inactive prodrug of d-amphetamine that extends the half-life of d-amphetamine to allow for once daily dosing. D-amphetamine acts primarily to increase the concentrations of synaptic dopamine and norepinephrine. Metabolism of LDX to d-amphetamine occurs when peptidases in red blood cells cleave the covalent bond between d-amphetamine and l-lysine. D-amphetamine is then further metabolized by CYP2D6. Excretion is primarily through renal mechanisms. In clinical trials, LDX demonstrated statistical and clinical superiority over placebo in reducing binge eating days per week at doses of 50 and 70 mg daily. Commonly reported side effects of LDX include dry mouth, insomnia, weight loss, and headache, and its use should be avoided in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart arrhythmia or coronary artery disease. As with all CNS stimulants, risk of abuse needs to be assessed prior to prescribing.

Disruption of social approach by MK-801, amphetamine, and fluoxetine in adolescent C57BL/6J mice.

PubMed

Moy, Sheryl S; Nonneman, Randal J; Shafer, Geoffrey O; Nikolova, Viktoriya D; Riddick, Natallia V; Agster, Kara L; Baker, Lorinda K; Knapp, Darin J

2013-01-01

Autism is a severe neurodevelopmental disorder, diagnosed on the basis of core behavioral symptoms. Although the mechanistic basis for the disorder is not yet known, genetic analyses have suggested a role for abnormal excitatory/inhibitory signaling systems in brain, including dysregulation of glutamatergic neurotransmission. In mice, the constitutive knockdown of NMDA receptors leads to social deficits, repetitive behavior, and self-injurious responses that reflect aspects of the autism clinical profile. However, social phenotypes differ with age: mice with reduced NMDA-receptor function exhibit hypersociability in adolescence, but markedly deficient sociability in adulthood. The present studies determined whether acute disruption of NMDA neurotransmission leads to exaggerated social approach, similar to that observed with constitutive disruption, in adolescent C57BL/6J mice. The effects of MK-801, an NMDA receptor antagonist, were compared with amphetamine, a dopamine agonist, and fluoxetine, a selective serotonin reuptake inhibitor, on performance in a three-chamber choice task. Results showed that acute treatment with MK-801 led to social approach deficits at doses without effects on entry numbers. Amphetamine also decreased social preference, but increased number of entries at every dose. Fluoxetine (10 mg/kg) had selective effects on social novelty preference. Withdrawal from a chronic ethanol regimen decreased activity, but did not attenuate sociability. Low doses of MK-801 and amphetamine were also evaluated in a marble-burying assay for repetitive behavior. MK-801, at a dose that did not disrupt sociability or alter entries, led to a profound reduction in marble-burying. Overall, these findings demonstrate that moderate alteration of NMDA, dopamine, or serotonin function can attenuate social preference in wild type mice. Copyright © 2012 Elsevier Inc. All rights reserved.

Disruption of social approach by MK-801, amphetamine, and fluoxetine in adolescent C57BL/6J mice

PubMed Central

Moy, Sheryl S.; Nonneman, Randal J.; Shafer, Geoffrey O.; Nikolova, Viktoriya D.; Riddick, Natallia V.; Agster, Kara L.; Baker, Lorinda K.; Knapp, Darin J.

2012-01-01

Autism is a severe neurodevelopmental disorder, diagnosed on the basis of core behavioral symptoms. Although the mechanistic basis for the disorder is not yet known, genetic analyses have suggested a role for abnormal excitatory/inhibitory signaling systems in brain, including dysregulation of glutamatergic neurotransmission. In mice, the constitutive knockdown of NMDA receptors leads to social deficits, repetitive behavior, and self-injurious responses that reflect aspects of the autism clinical profile. However, social phenotypes differ with age: mice with reduced NMDA-receptor function exhibit hypersociability in adolescence, but markedly deficient sociability in adulthood. The present studies determined whether acute disruption of NMDA neurotransmission leads to exaggerated social approach, similar to that observed with constitutive disruption, in adolescent C57BL/6J mice. The effects of MK-801, an NMDA receptor antagonist, were compared with amphetamine, a dopamine agonist, and fluoxetine, a selective serotonin reuptake inhibitor, on performance in a three-chamber choice task. Results showed that acute treatment with MK-801 led to social approach deficits at doses without effects on entry numbers. Amphetamine also decreased social preference, but increased number of entries at every dose. Fluoxetine (10 mg/kg) had selective effects on social novelty preference. Withdrawal from a chronic ethanol regimen decreased activity, but did not attenuate sociability. Low doses of MK-801 and amphetamine were also evaluated in a marble-burying assay for repetitive behavior. MK-801, at a dose that did not disrupt sociability or alter entries, led to a profound reduction in marble-burying. Overall, these findings demonstrate that moderate alteration of NMDA, dopamine, or serotonin function can attenuate social preference in wild type mice. PMID:22898204

PRESYNAPTIC DOPAMINE MODULATION BY STIMULANT SELF ADMINISTRATION

PubMed Central

España, Rodrigo A.; Jones, Sara R.

2013-01-01

The mesolimbic dopamine system is an essential participant in the initiation and modulation of various forms of goal-directed behavior, including drug reinforcement and addiction processes. Dopamine neurotransmission is increased by acute administration of all drugs of abuse, including the stimulants cocaine and amphetamine. Chronic exposure to these drugs via voluntary self-administration provides a model of stimulant abuse that is useful in evaluating potential behavioral and neurochemical adaptations that occur during addiction. This review describes commonly used methodologies to measure dopamine and baseline parameters of presynaptic dopamine regulation, including exocytotic release and reuptake through the dopamine transporter in the nucleus accumbens core, as well as dramatic adaptations in dopamine neurotransmission and drug sensitivity that occur with acute non-contingent and chronic, contingent self-administration of cocaine and amphetamine. PMID:23277050

Weight loss - unintentional

MedlinePlus

... thyroid medicines Drug abuse such as amphetamines and cocaine Stress or anxiety Chronic digestive system problems that ... health care provider may suggest changes in your diet and an exercise program depending on the cause ...

Estimation of neuronal numbers in rat hippocampus following neonatal amphetamine exposure: a stereology study.

PubMed

Smith, Andrew M; Pappalardo, Dana; Chen, Wei-Jung A

2008-01-01

In this study, the effects of amphetamine exposure during a portion of the brain growth spurt on the total number of hippocampal pyramidal cells (CA1/CA3 subregions) and the granule cells (dentate gyrus) were examined in both neonatal and adult rats. Intragastric intubation was used to administer 5, 15 or 25 mg/kg/day of amphetamine to Sprague-Dawley rat pups from PDs 4-9. Unbiased stereology was used to estimate the total number of cells present within each hippocampal subregion at both PD 9 and PD 68. The results indicated that neonatal amphetamine exposure did not alter the cell number, the reference volume or the density in any of the hippocampal subregions assessed, regardless of age. However, amphetamine significantly altered the rate of neuronal incorporation in both the hippocampal CA3 subregion and the dentate gyrus, and this effect appeared to be dose-related with the most robust effect observed in the highest amphetamine dose. While these findings did not demonstrate significant injurious effects of neonatal amphetamine treatment on the number of hippocampal neurons, these data suggest that amphetamine may interfere with proper hippocampal development. Future studies employing more sensitive measurements or exposing amphetamine during an alternate period of development may provide more information regarding amphetamine-mediated developmental neurotoxicity.

Differential effects of scopolamine and amphetamine on microcomputer-based performance tests

NASA Technical Reports Server (NTRS)

Kennedy, Robert S.; Odenheimer, Robert C.; Baltzley, Dennis R.; Dunlap, William P.; Wood, Charles D.

1990-01-01

The effects of four weekly treatments with scopolamine (1.0 mg) and d-amphetamine (10 mg), separately or in combination, on human performance were investigated in 16 subjects undergoing nine performance tests from a menu of microcomputer-based tests administered after the treatment. It was d-amphetamine treatment that enhanced the results of motor and perceptual speed tests, while scopolamine had no effect on these tests. Two of the five cognitive tests showed reductions with scopolamine. The effects of scopolamine in this and other studies are considered in terms of a model which implies that the magnitude of the performance deficit depends on the performance type and the dosage level of the drug.

Amphetamine reward in food restricted mice lacking the melanin-concentrating hormone receptor-1.

PubMed

Geuzaine, Annabelle; Tyhon, Amélie; Grisar, Thierry; Brabant, Christian; Lakaye, Bernard; Tirelli, Ezio

2014-04-01

Chronic food restriction (FR) and maintenance of low body weight have long been known to increase the rewarding and motor-activating effects of addictive drugs. However, the neurobiological mechanisms through which FR potentiates drug reward remain largely unknown. Melanin-concentrating hormone (MCH) signaling could be one of these mechanisms since this peptide is involved in energy homeostasis and modulates mesolimbic dopaminergic transmission. The purpose of the present study was to test this hypothesis by investigating the impact of FR on amphetamine reward in wild-type (WT) and knockout mice lacking the melanin-concentrating hormone receptor-1 (MCHR1-KO). The rewarding effects of amphetamine (0.75-2.25 mg/kg, i.p.) were measured with the conditioned place preference (CPP) technique. The food of the mice was restricted to maintain their body weight at 80-85% of their free-feeding (FF) weight throughout the entire CPP experiment. Locomotor activity of the animals was recorded during the conditioning sessions. Our results show that locomotion of all the food-restricted mice treated with saline or amphetamine increased over the sessions whatever the genotype. On the place preference test, the amplitude of CPP induced by 0.75 mg/kg amphetamine was higher in food restricted WT mice than in free-fed WT mice and food restricted MCHR1-KO mice. However, FR did not affect amphetamine reward in MCHR1-KO mice. The present results indicate that MCH signaling could be involved in the ability of FR to increase amphetamine-induced CPP. Copyright © 2014 Elsevier B.V. All rights reserved.

Methylphenidate and Amphetamine Do Not Induce Cytogenetic Damage in Lymphocytes of Children with ADHD

ERIC Educational Resources Information Center

Witt, Kristine L.; Shelby, Michael D.; Itchon-Ramos, Nilda; Faircloth, Melissa; Kissling, Grace E.; Chrisman, Allan K.; Ravi, Hima; Murli, Hemalatha; Mattison, Donald R.; Kollins, Scott H.

2008-01-01

The inducement of chromosomal damage in lymphocytes among children with attention deficit hyperactivity disorder receiving treatment with methylphenidate- or amphetamine-based drugs is investigated. Findings did not reveal significant increases in cytogenetic damage related to the treatment. The risk for cytogenetic damage posed by such products…

Involvement of Glutamate NMDA Receptors in the Acute, Long-Term, and Conditioned Effects of Amphetamine on Rat 50kHz Ultrasonic Vocalizations

PubMed Central

Costa, Giulia; Morelli, Micaela

2015-01-01

Background: Rats emit 50kHz ultrasonic vocalizations (USVs) in response to either natural or pharmacological pleasurable stimuli, and these USVs have emerged as a new behavioral measure for investigating the motivational properties of drugs. Earlier studies have indicated that activation of the dopaminergic system is critically involved in 50kHz USV emissions. However, evidence also exists that non-dopaminergic neurotransmitters participate in this behavioral response. Methods: To ascertain whether glutamate transmission plays a role in 50kHz USV emissions stimulated by amphetamine, rats received five amphetamine (1–2mg/kg, i.p.) administrations on alternate days in a test cage, either alone or combined with the glutamate N-methyl-D-aspartate receptor antagonist MK-801 (0.1–0.5mg/kg, i.p.). Seven days after treatment discontinuation, rats were re-exposed to the test cage to assess drug conditioning, and afterwards received a drug challenge. USVs and locomotor activity were evaluated, along with immunofluorescence for Zif-268 in various brain regions and spontaneous alternation in a Y maze. Results: Amphetamine-treated rats displayed higher 50kHz USV emissions and locomotor activity than vehicle-treated rats, and emitted conditioned vocalizations on test cage re-exposure. Rats co-administered amphetamine and MK-801 displayed lower and dose-dependent 50kHz USV emissions, but not lower locomotor activity, during repeated treatment and challenge, and scarce conditioned vocalization compared with amphetamine-treated rats. These effects were associated with lower levels of Zif-268 after amphetamine challenge and spontaneous alternation deficits. Conclusions: These results indicate that glutamate transmission participates in the acute, long-term, and conditioned effects of amphetamine on 50kHz USVs, possibly by influencing amphetamine-induced long-term neuronal changes and/or amphetamine-associated memories. PMID:25991653

Effects of 7-day continuous d-amphetamine, methylphenidate, and cocaine treatment on choice between methamphetamine and food in male rhesus monkeys*

PubMed Central

Schwienteck, Kathryn L.; Banks, Matthew L.

2015-01-01

Background Methamphetamine addiction is a significant public health problem for which no Food and Drug Administration-approved pharmacotherapies exist. Preclinical drug vs. food choice procedures have been predictive of clinical medication efficacy in the treatment of opioid and cocaine addiction. Whether preclinical choice procedures are predictive of candidate medication effects for other abused drugs, such as methamphetamine, remains unclear. The present study aim was to determine continuous 7-day treatment effects with the monoamine releaser d-amphetamine and the monoamine uptake inhibitor methylphenidate on methamphetamine vs. food choice.In addition, 7-day cocaine treatment effects were also examined. Methods Behavior was maintained under a concurrent schedule of food delivery (1-g pellets, fixed-ratio 100 schedule) and methamphetamine injections (0-0.32 mg/kg/injection, fixed-ratio 10 schedule) in male rhesus monkeys (n=4). Methamphetamine choice dose-effect functions were determined daily before and during 7-day periods of continuous intravenous treatment with d-amphetamine (0.01-0.1 mg/kg/h), methylphenidate (0.032-0.32 mg/kg/h), or cocaine (0.1-0.32 mg/kg/h). Results During saline treatment, increasing methamphetamine doses resulted in a corresponding increase in methamphetamine vs. food choice. Continuous 7-day treatments with d-amphetamine, methylphenidate or cocaine did not significantly attenuate methamphetamine vs. food choice up to doses that decreased rates of operant responding. However, 0.1 mg/kg/h d-amphetamine did eliminate methamphetamine choice in two monkeys. Conclusions The present subchronic treatment resultssupport the utility of preclinical methamphetamine choice to evaluate candidate medications for methamphetamine addiction. Furthermore, these results confirm and extend previous results demonstrating differential pharmacological mechanisms between cocaine choice and methamphetamine choice. PMID:26361713

Effects of 7-day continuous D-amphetamine, methylphenidate, and cocaine treatment on choice between methamphetamine and food in male rhesus monkeys.

PubMed

Schwienteck, Kathryn L; Banks, Matthew L

2015-10-01

Methamphetamine addiction is a significant public health problem for which no Food and Drug Administration-approved pharmacotherapies exist. Preclinical drug vs. food choice procedures have been predictive of clinical medication efficacy in the treatment of opioid and cocaine addiction. Whether preclinical choice procedures are predictive of candidate medication effects for other abused drugs, such as methamphetamine, remains unclear. The present study aim was to determine continuous 7-day treatment effects with the monoamine releaser d-amphetamine and the monoamine uptake inhibitor methylphenidate on methamphetamine vs. food choice. In addition, 7-day cocaine treatment effects were also examined. Behavior was maintained under a concurrent schedule of food delivery (1-g pellets, fixed-ratio 100 schedule) and methamphetamine injections (0-0.32mg/kg/injection, fixed-ratio 10 schedule) in male rhesus monkeys (n=4). Methamphetamine choice dose-effect functions were determined daily before and during 7-day periods of continuous intravenous treatment with d-amphetamine (0.01-0.1mg/kg/h), methylphenidate (0.032-0.32mg/kg/h), or cocaine (0.1-0.32mg/kg/h). During saline treatment, increasing methamphetamine doses resulted in a corresponding increase in methamphetamine vs. food choice. Continuous 7-day treatments with d-amphetamine, methylphenidate or cocaine did not significantly attenuate methamphetamine vs. food choice up to doses that decreased rates of operant responding. However, 0.1mg/kg/h d-amphetamine did eliminate methamphetamine choice in two monkeys. The present subchronic treatment results support the utility of preclinical methamphetamine choice to evaluate candidate medications for methamphetamine addiction. Furthermore, these results confirm and extend previous results demonstrating differential pharmacological mechanisms between cocaine choice and methamphetamine choice. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Methamphetamine Cured my Cocaine Addiction

PubMed Central

Haile, Colin N.; De La Garza, Richard; Newton, Thomas F.

2011-01-01

Cocaine dependence is an enduring problem and years of research and drug development has yet to produce an efficacious pharmacotherapy. Recent clinical research suggests that chronic treatment with amphetamine-like medications produces tolerance to cocaine’s reinforcing effects and may offer a viable pharmacotherapy. Three methamphetamine-dependent participants that had been in our clinical laboratory experiments and previously addicted to cocaine are reviewed. Data obtained from initial screen and informal conversation suggested that all participants considered methamphetamine to have helped them stop using cocaine and eliminate cocaine craving. Methamphetamine also significantly decreased their alcohol consumption but did not alter cannabis or nicotine use. PMID:23066512

Differential development of tolerance to the functional and behavioral effects of repeated baclofen treatment in rats

PubMed Central

Beveridge, T.J.R.; Smith, H.R.; Porrino, L.J.

2013-01-01

Baclofen, a gamma-aminobutyric acid (GABA)B receptor agonist, has been used clinically to treat muscle spasticity, rigidity and pain. More recently, interest in the use of baclofen as an addiction medicine has grown, with promising preclinical cocaine and amphetamine data and demonstrated clinical benefit from alcohol and nicotine studies. Few preclinical investigations, however, have utilized chronic dosing of baclofen, which is important given that tolerance can occur to many of its effects. Thus the question of whether chronic treatment of baclofen maintains the efficacy of acute doses is imperative. The neural substrates that underlie the effects of baclofen, particularly those after chronic treatment, are also not known. In the present study, therefore, rats were treated with either a) vehicle, b) acute baclofen (5 mg/kg) or c) chronic baclofen (5 mg/kg, t.i.d. for 5 days). The effects of acute and chronic baclofen administration, compared to vehicle, were assessed using locomotor activity and changes in brain glucose metabolism (a measure of functional brain activity). Acute baclofen significantly reduced locomotor activity (horizontal and total distance traveled), while chronic baclofen failed to affect locomotor activity. Acute baclofen resulted in significantly lower rates of local cerebral glucose utilization throughout many areas of the brain, including the prefrontal cortex, caudate putamen, septum and hippocampus. The majority of these functional effects, with the exception of the caudate putamen and septum, were absent in animals chronically treated with baclofen. Despite the tolerance to the locomotor and functional effects of baclofen following repeated treatment, these persistent effects on functional activity in the caudate putamen and septum may provide insights into the way in which baclofen alters the reinforcing effects of abused substances such as cocaine, alcohol, and methamphetamine both in humans and animal models. PMID:23500188

The effect of amphetamine on regional cerebral blood flow during cognitive activation in schizophrenia

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

Daniel, D.G.; Weinberger, D.R.; Jones, D.W.

1991-07-01

To explore the role of monoamines on cerebral function during specific prefrontal cognitive activation, we conducted a double-blind placebo-controlled crossover study of the effects of 0.25 mg/kg oral dextroamphetamine on regional cerebral blood flow (rCBF) as determined by 133Xe dynamic single-photon emission-computed tomography (SPECT) during performance of the Wisconsin Card Sorting Test (WCST) and a sensorimotor control task. Ten patients with chronic schizophrenia who had been stabilized for at least 6 weeks on 0.4 mg/kg haloperidol participated. Amphetamine produced a modest, nonsignificant, task-independent, global reduction in rCBF. However, the effect of amphetamine on task-dependent activation of rCBF (i.e., WCST minusmore » control task) was striking. Whereas on placebo no significant activation of rCBF was seen during the WCST compared with the control task, on amphetamine significant activation of the left dorsolateral prefrontal cortex (DLPFC) occurred (p = 0.0006). Both the mean number of correct responses and the mean conceptual level increased (p less than 0.05) with amphetamine relative to placebo. In addition, with amphetamine, but not with placebo, a significant correlation (p = -0.71; p less than 0.05) emerged between activation of DLPFC rCBF and performance of the WCST task. These findings are consistent with animal models in which mesocortical catecholaminergic activity modulates and enhances the signal-to-noise ratio of evoked cortical activity.« less

Effects of Pubertal Cannabinoid Administration on Attentional Set-Shifting and Dopaminergic Hyper-Responsivity in a Developmental Disruption Model of Schizophrenia

PubMed Central

Guimarães, Francisco S.; Grace, Anthony A.

2015-01-01

Background: Adolescent exposure to cannabinoids in vulnerable individuals is proposed to be a risk factor for psychiatric conditions later in life, particularly schizophrenia. Evidence from studies in animals has indicated that a combination of repeated pubertal cannabinoid administration with either neonatal prefrontocortical lesion, isolation rearing, or chronic NMDA receptor antagonism administration induces enhanced schizophrenia-like behavioral disruptions. The effects of adolescent exposure to CB1 receptor agonists, however, have not been tested in a developmental disruption model of schizophrenia. Methods: This was tested in the methylazoxymethanol (MAM) model, in which repeated treatment with the synthetic cannabinoid agonist WIN 55,212-2 (WIN; 1.2mg/kg) was extended over 25 days throughout puberty (postnatal days 40–65) in control and MAM rats. The rats received 20 injections, which were delivered irregularly to mimic the human condition. Adult rats were tested for attentional set-shifting task and locomotor response to amphetamine, which was compared with in vivo recording from ventral tegmental area (VTA) dopamine (DA) neurons. Results: MAM-treated rats showed impairment in the attentional set-shifting task, augmented locomotor response to amphetamine administration, and an increased number of spontaneously active DA neurons in the VTA. Interestingly, pubertal WIN treatment in normal animals induced similar changes at adulthood as those observed in MAM-treated rats, supporting the notion that adolescence exposure to cannabinoids may represent a risk factor for developing schizophrenia-like signs at adulthood. However, contrary to expectations, pubertal WIN administration did not exacerbate the behavioral and electrophysiological changes in MAM-treated rats beyond that observed in WIN-treated saline rats (Sal). Indeed, WIN treatment actually attenuated the locomotor response to amphetamine in MAM rats without impacting DA neuron activity states. Conclusions: Taken together, the present results indicate that the impact of cannabinoids during puberty/adolescence on schizophrenia models is more complex than may be predicted. PMID:25522381

Decrease of lymphoproliferative response by amphetamine is mediated by dopamine from the nucleus accumbens: influence on splenic met-enkephalin levels.

PubMed

Assis, María Amparo; Valdomero, Analía; García-Keller, Constanza; Sotomayor, Claudia; Cancela, Liliana Marina

2011-05-01

Despite the mesocorticolimbic dopaminergic pathway being one of the main substrates underlying stimulating and reinforcing effects induced by psychostimulant drugs, there is little information regarding its role in their effects at the immune level. We have previously demonstrated that acute exposure to amphetamine (5 mg/kg, i.p.) induced an inhibitory effect on the splenic T-cell proliferative response, along with an increase in the methionine(met)-enkephalin content at limbic and immune levels, 4 days after drug administration. In this study, we investigated if a possible dopamine mechanism underlies these amphetamine-induced effects by administering D1 and D2 dopaminergic antagonists or a dopaminergic terminal neurotoxin before the drug. Pre-treatment with either SCH-23390 (0.1 mg/kg, i.p.) or raclopride (0.1 mg/kg, i.p.), a D1 or D2 dopaminergic receptor antagonist, respectively, abrogated the effects of amphetamine on the lymphoproliferative response and on met-enkephalin levels of the spleen. The amphetamine-induced increase in limbic met-enkephalin content was suppressed by SCH-23390 but not by raclopride pre-treatment. Finally, an intra-accumbens 6-hydroxy-dopamine injection administered 2 weeks previously prevented amphetamine-induced effects on the lymphoproliferative response and on met-enkephalin levels in the prefrontal cortex and spleen. These findings strongly suggest that D1 and D2 dopaminergic receptors are involved in amphetamine-induced effects at immune level as regards the lymphoproliferative response and the changes in spleen met-enkephalin content, whereas limbic met-enkephalin levels were modulated only by the D1 dopaminergic receptors. In addition, this study showed that a mesolimbic component modulated amphetamine-induced effects on the immune response, as previously shown at a behavioral level. Copyright © 2011 Elsevier Inc. All rights reserved.

Tph2 gene deletion enhances amphetamine-induced hypermotility: effect of 5-HT restoration and role of striatal noradrenaline release.

PubMed

Carli, Mirjana; Kostoula, Chrysaugi; Sacchetti, Giuseppina; Mainolfi, Pierangela; Anastasia, Alessia; Villani, Claudia; Invernizzi, Roberto William

2015-11-01

Variants of tryptophan hydroxylase-2 (Tph2), the gene encoding enzyme responsible for the synthesis of brain serotonin (5-HT), have been associated with neuropsychiatric disorders, substance abuse and addiction. This study assessed the effect of Tph2 gene deletion on motor behavior and found that motor activity induced by 2.5 and 5 mg/kg amphetamine was enhanced in Tph2(-/-) mice. Using the in vivo microdialysis technique we found that the ability of amphetamine to stimulate noradrenaline (NA) release in the striatum was reduced by about 50% in Tph2(-/-) mice while the release of dopamine (DA) was not affected. Tph2 deletion did not affect the release of NA and DA in the prefrontal cortex. The role of endogenous 5-HT in enhancing the effect of amphetamine was confirmed showing that treatment with the 5-HT precursor 5-hydroxytryptophan (10 mg/kg) restored tissue and extracellular levels of brain 5-HT and the effects of amphetamine on striatal NA release and motor activity in Tph2(-/-) mice. Treatment with the NA precursor dihydroxyphenylserine (400 mg/kg) was sufficient to restore the effect of amphetamine on striatal NA release and motor activity in Tph2(-/-) mice. These findings indicate that amphetamine-induced hyperactivity is attenuated by endogenous 5-HT through the inhibition of striatal NA release. Tph2(-/-) mice may be a useful preclinical model to assess the role of 5-HT-dependent mechanisms in the action of psychostimulants. Acute sensitivity to the motor effects of amphetamine has been associated to increased risk of psychostimulant abuse. Here, we show that deletion of Tph2, the gene responsible for brain 5-HT synthesis, enhances the motor effect of amphetamine in mice through the inhibition of striatal NA release. This suggests that Tph2(-/-) mice is a useful preclinical model to assess the role of 5-HT-dependent mechanisms in psychostimulants action. Tph2, tryptophan hydroxylase-2. © 2015 International Society for Neurochemistry.

Annual Research Report, 1 July 1969 - 30 June 1970.

DTIC Science & Technology

1970-06-30

of irradiated rats to tolerate pentobarbital was measured after treatment with amphetamine and/or reserpine. Male Sprague-Dawley rats were given 250...Reserpine treated (24 h after 1000 rads) 10 91.1 + 5.9 Reserpine and Amphetamine treated (24 h after 1000 rads) 11 84.7 + 2.9 * p ɘ. 05 ( treatment group...tolerance to sodium pentobarbital was observed. Four days of reserpine treatment prior to irradiation also abolished the radiation-induced increase in

OPRM1 gene variants modulate amphetamine-induced euphoria in humans

PubMed Central

Dlugos, Andrea M.; Hamidovic, Ajna; Hodgkinson, Colin; Pei-Hong, Shen; Goldman, David; Palmer, Abraham A.; de Wit, Harriet

2012-01-01

The μ-opioid receptor is involved in the rewarding effects of not only opioids like morphine but also psychostimulants like amphetamine. This study aimed to investigate associations between subjective response to amphetamine and genetic polymorphisms and haplotypes in the μ-opioid receptor including the exonic variant rs1799971 (Asp40Asn). 162 Caucasian volunteers participated in three sessions receiving either placebo or d-amphetamine (10 and 20 mg). Associations between levels of self-reported Euphoria, Energy and Stimulation (ARCI-49) after d-amphetamine ingestion and polymorphisms in OPRM1 were investigated. The intronic SNPs rs510769 and rs2281617 were associated with significantly higher ratings of Euphoria, Energy and Stimulation after 10 mg amphetamine. Feelings of Euphoria, Energy and Stimulation were also found to be associated with a 2-SNP haplotype formed with rs1799971 and rs510769 and a 3-SNP haplotype formed with rs1918760, rs2281617 and rs1998220. These results support the hypothesis that genetic variability in the μ-opioid receptor gene influences the subjective effects of amphetamine and may suggest new strategies for prevention and treatment of psychostimulant abuse. PMID:21029375

NTP-CERHR monograph on the potential human reproductive and developmental effects of amphetamines.

PubMed

2005-07-01

The National Toxicology Program (NTP) Center for the Evaluation of Risks to Human Reproduction (CERHR) conducted an evaluation of the potential for amphetamines to cause adverse effects on reproduction and development in humans. Amphetamines evaluated were D- and D,L-amphetamine and methamphetamine. Amphetamine is approved by the U.S. Food and Drug Administration for the treatment of attention deficit hyperactivity disorder (ADHD) in persons over 3 years of age and narcolepsy; methamphetamine is approved for the treatment of ADHD in persons 6 years of age and older and for short-term treatment of obesity. Amphetamines were selected for evaluation because of 1) widespread usage in children, 2) availability of developmental studies in children and experimental animals, and 3) public concern about the effect of this stimulant on child development. The results of this evaluation on amphetamines are published in an NTP-CERHR monograph which includes: 1) the NTP Brief, 2) the Expert Panel Report on the Reproductive and Developmental Toxicity of Methylphenidate, and 3) public comments received on the Expert Panel Report. As stated in the NTP Brief, the NTP reached the following conclusions regarding the possible effects of exposure to methylphenidate on human development and reproduction. First, there is some concern for developmental effects, specifically for potential neurobehavioral alterations, from prenatal amphetamine exposure in humans both in therapeutic and non-therapeutic settings. After prenatal exposure to therapeutic doses of amphetamine, rat pups demonstrated neurobehavioral alterations. Data from human and animal studies were judged insufficient for an evaluation of the effect of amphetamine exposure on growth and other related developmental effects. Second, there is concern for methamphetamine-induced adverse developmental effects, specifically on growth and neurobehavioral development, in therapeutic and non-therapeutic settings. This conclusion is based on evidence from studies in experimental animals that prenatal and postnatal exposures to methamphetamine produce neurobehavioral alterations, small litter size, and low birth weight. Results from studies in humans suggest that methamphetamine may cause low birth weight and shortened gestation, but study confounders such as possible multiple drug usage prevent a definite conclusion. NTP-CERHR monographs are transmitted to federal and state agencies, interested parties, and the public and are available in electronic PDF format on the CERHR web site (http://cerhr.niehs.nih.gov) and in printed text or CD-ROM from the CERHR (National Institute of Environmental Health Sciences, P.O. Box 12233, MD EC-32, Research Triangle Park, NC; fax: 919-316-4511).

Amphetamine regulation of acetylcholine and gamma-aminobutyric acid in nucleus accumbens.

PubMed

Lindefors, N; Hurd, Y L; O'Connor, W T; Brené, S; Persson, H; Ungerstedt, U

1992-01-01

In situ hybridization histochemistry and in vivo microdialysis were combined to study the effect of amphetamine on the expression of choline acetyltransferase and glutamate decarboxylase67 mRNA and in vivo release of acetylcholine and GABA in rat medial nucleus accumbens. Differential effects on acetylcholine and GABA neurons by a single challenge injection of amphetamine (1.5 mg/kg, s.c.) were apparent in saline-pretreated and amphetamine-pretreated (same dose, twice daily for the previous seven days) rats. Extracellular acetylcholine levels were increased up to 50% over a prolonged period following both single and repeated amphetamine. In contrast, extracellular concentrations of GABA were gradually decreased to half the control values, but only in rats receiving repeated amphetamine. Although the increase of acetylcholine release was not associated with any change in choline acetyltransferase mRNA levels, the number of neurons expressing high levels of glutamate decarboxylase67 mRNA was decreased (28%) following repeated injections. Thus we suggest that amphetamine decreases extracellular GABA levels by a slow mechanism, associated with the decreased expression of glutamate decarboxylase67 mRNA in a subpopulation of densely labeled neurons in the medial nucleus accumbens. The delayed response by GABA to amphetamine may reflect supersensitivity in the activity of postsynaptic gamma-aminobutyric acid-containing neurons in nucleus accumbens as a consequence of the repeated amphetamine treatment.

Mechanisms of antimotion sickness drugs

NASA Technical Reports Server (NTRS)

Wood, C. D.; Manno, J. E.; Wood, M. J.; Manno, B. R.; Redetzki, H. M.

1987-01-01

Eight subjects, male and female, were rotated using the step method to progressively increase the speed of rotation (+2 rpm) after every 40 head movements to a maximum of 35 rpm. The end point for motion sickness was the Graybiel Malaise III total of symptoms short of frank nausea. The drug treatments were placebo, scopolamine 0.6 mg and 1 mg, scopolamine 0.6 mg/d-amphetamine 10 mg, scopolamine 1 mg/d-amphetamine 10 mg, and amphetamine 10 mg. Scopolamine increased tolerated head movements over placebo level by + 81; scopolamine 1 mg + 183; d-amphetamine by + 118; scopolamine 0.6/d-amphetamine by + 165; and scopolamine 1 mg/d-amphetamine 10 mg by + 201. The drugs effective in preventing motion sickness are considered to be divided into those with central acetylcholine blocking activity and those which enhance norepinephrine activity. A combination of both of these actions produces the most effective antimotion sickness medications. It is concluded that the balance between the acetylcholine and norepinephrine activity in the CNS appears to be responsible for motion sickness.

Cardiac Safety of Methylphenidate Versus Amphetamine Salts in the Treatment of ADHD

PubMed Central

Winterstein, Almut Gertrud; Gerhard, Tobias; Shuster, Jonathan; Saidi, Arwa

2013-01-01

OBJECTIVES Safety concerns about central nervous system stimulants for the treatment of attention-deficit/hyperactivity disorder (ADHD) include adverse cardiac effects. This study aimed to compare the risk for cardiac events in users of methylphenidate and amphetamine salts. METHODS A retrospective cohort design using claims data from the Florida Medicaid fee-for-service program representing a total of 2 131 953 children and adolescents was used. The analysis included all beneficiaries who were between 3 and 20 years of age, enrolled between July 1994 and June 2004, had at least 1 physician diagnosis of ADHD and were newly started on methylphenidate or amphetamine salts. Each month of follow-up was classified according to stimulant use into current use or former use. We defined cardiac events as first emergency department (ED) visit for cardiac disease or symptoms. Risk between current users of methylphenidate versus amphetamine salts and former users of drugs in these categories was compared by using a time-dependent Cox proportional hazard model that adjusted for differences in gender; race; age; year of the index date; disability; congenital anomalies; history of circulatory disease; history of hospital admission; and use of antidepressants, antipsychotics, and bronchodilators. RESULTS A total of 456 youth visited the ED for cardiac reasons during 52 783 years of follow-up. After adjustment for differences in covariates, the risk for cardiac ED visits was similar among current users of methylphenidate or amphetamines. Periods of former use had a similar risk between youth with an exposure history to methylphenidate or amphetamine. CONCLUSION Exposure to methylphenidate and amphetamines salts showed similar risk for cardiac ED visits. Additional population-based studies that address manifestation of serious heart disease, especially after long-term use, dosage comparisons, and interactions with preexisting cardiac risk factors are needed to inform psychiatric treatment decisions. PMID:19564272

Cardiovascular Complications of Acute Amphetamine Abuse

PubMed Central

Bazmi, Elham; Mousavi, Farinaz; Giahchin, Leila; Mokhtari, Tahmineh; Behnoush, Behnam

2017-01-01

Objectives This study aimed to evaluate cardiovascular complications among patients who abuse amphetamines. Methods This cross-sectional study took place between April 2014 and April 2015 among 3,870 patients referred to the Toxicology Emergency Department of Baharlou Hospital, Tehran University of Medical Sciences, Tehran, Iran. Those with clinical signs of drug abuse and positive urine screening tests were included in the study, while cases of chronic abuse were excluded. Cardiac complications were evaluated via electrocardiography (ECG) and transthoracic echocardiography. Results A total of 230 patients (5.9%) had a history of acute amphetamine abuse and positive urine tests. Of these, 32 patients (13.9%) were <20 years old and 196 (85.2%) were male. In total, 119 (51.7%) used amphetamine and methamphetamine compounds while 111 (48.3%) used amphetamines with morphine or benzodiazepines. The most common ECG finding was sinus tachycardia (43.0%), followed by sinus tachycardia plus a prolonged QT interval (34.3%). Mean creatine kinase-MB and troponin I levels were 35.9 ± 4.3 U/mL and 0.6 ± 0.2 ng/mL, respectively. A total of 60 patients (26.1%) were admitted to the Intensive Care Unit. The majority (83.3%) of these patients had normal echocardiography results. The mean aortic root diameter (ARD) was 27.2 ± 2.8 mm. Abnormalities related to the ARD were found in 10 patients (16.7%), three of whom subsequently died. Conclusion According to these findings, cardiac complications were common among Iranian patients who abuse amphetamines, although the majority of patients had normal echocardiography and ECG findings. PMID:28417026

Chronic metals ingestion by prairie voles produces sex-specific deficits in social behavior: an animal model of autism.

PubMed

Curtis, J Thomas; Hood, Amber N; Chen, Yue; Cobb, George P; Wallace, David R

2010-11-12

We examined the effects of chronic metals ingestion on social behavior in the normally highly social prairie vole to test the hypothesis that metals may interact with central dopamine systems to produce the social withdrawal characteristic of autism. Relative to water-treated controls, 10 weeks of chronic ingestion of either Hg(++) or Cd(++) via drinking water significantly reduced social contact by male voles when they were given a choice between isolation or contact with an unfamiliar same-sex conspecific. The effects of metals ingestion were specific to males: no effects of metals exposure were seen in females. Metals ingestion did not alter behavior of males allowed to choose between isolation or their familiar cage-mates, rather than strangers. We also examined the possibility that metals ingestion affects central dopamine functioning by testing the voles' locomotor responses to peripheral administration of amphetamine. As with the social behavior, we found a sex-specific effect of metals on amphetamine responses. Males that consumed Hg(++) did not increase their locomotor activity in response to amphetamine, whereas similarly treated females and males that ingested only water significantly increased their locomotor activities. Thus, an ecologically relevant stimulus, metals ingestion, produced two of the hallmark characteristics of autism - social avoidance and a male-oriented bias. These results suggest that metals exposure may contribute to the development of autism, possibly by interacting with central dopamine function, and support the use of prairie voles as a model organism in which to study autism. (c) 2010 Elsevier B.V. All rights reserved.

Pleiotrophin overexpression regulates amphetamine-induced reward and striatal dopaminergic denervation without changing the expression of dopamine D1 and D2 receptors: Implications for neuroinflammation.

PubMed

Vicente-Rodríguez, Marta; Rojo Gonzalez, Loreto; Gramage, Esther; Fernández-Calle, Rosalía; Chen, Ying; Pérez-García, Carmen; Ferrer-Alcón, Marcel; Uribarri, María; Bailey, Alexis; Herradón, Gonzalo

2016-11-01

It was previously shown that mice with genetic deletion of the neurotrophic factor pleiotrophin (PTN-/-) show enhanced amphetamine neurotoxicity and impair extinction of amphetamine conditioned place preference (CPP), suggesting a modulatory role of PTN in amphetamine neurotoxicity and reward. We have now studied the effects of amphetamine (10mg/kg, 4 times, every 2h) in the striatum of mice with transgenic PTN overexpression (PTN-Tg) in the brain and in wild type (WT) mice. Amphetamine caused an enhanced loss of striatal dopaminergic terminals, together with a highly significant aggravation of amphetamine-induced increase in the number of GFAP-positive astrocytes, in the striatum of PTN-Tg mice compared to WT mice. Given the known contribution of D1 and D2 dopamine receptors to the neurotoxic effects of amphetamine, we also performed quantitative receptor autoradiography of both receptors in the brains of PTN-Tg and WT mice. D1 and D2 receptors binding in the striatum and other regions of interest was not altered by genotype or treatment. Finally, we found that amphetamine CPP was significantly reduced in PTN-Tg mice. The data demonstrate that PTN overexpression in the brain blocks the conditioning effects of amphetamine and enhances the characteristic striatal dopaminergic denervation caused by this drug. These results indicate for the first time deleterious effects of PTN in vivo by mechanisms that are probably independent of changes in the expression of D1 and D2 dopamine receptors. The data also suggest that PTN-induced neuroinflammation could be involved in the enhanced neurotoxic effects of amphetamine in the striatum of PTN-Tg mice. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

Comparison of Caffeine and d-amphetamine in Cocaine-Dependent Subjects: Differential Outcomes on Subjective and Cardiovascular Effects, Reward Learning, and Salivary Paraxanthine.

PubMed

Lane, Scott D; Green, Charles E; Schmitz, Joy M; Rathnayaka, Nuvan; Fang, Wendy B; Ferré, Sergi; Moeller, F Gerard

2014-01-01

Due to indirect modulation of dopamine transmission, adenosine receptor antagonists may be useful in either treating cocaine use or improving disrupted cognitive-behavioral functions associated with chronic cocaine use. To compare and contrast the stimulant effects of adenosine antagonism to direct dopamine stimulation, we administered 150 mg and 300 mg caffeine, 20 mg amphetamine, and placebo to cocaine-dependent vs. healthy control subjects, matched on moderate caffeine use. Data were obtained on measures of cardiovascular effects, subjective drug effects (ARCI, VAS, DEQ), and a probabilistic reward-learning task sensitive to dopamine modulation. Levels of salivary caffeine and the primary caffeine metabolite paraxanthine were obtained on placebo and caffeine dosing days. Cardiovascular results revealed main effects of dose for diastolic blood pressure and heart rate; follow up tests showed that controls were most sensitive to 300 mg caffeine and 20 mg amphetamine; cocaine-dependent subjects were sensitive only to 300 mg caffeine. Subjective effects results revealed dose × time and dose × group interactions on the ARCI A, ARCI LSD, and VAS 'elated' scales; follow up tests did not show systematic differences between groups with regard to caffeine or d-amphetamine. Large between-group differences in salivary paraxanthine (but not salivary caffeine) levels were obtained under both caffeine doses. The cocaine-dependent group expressed significantly higher paraxanthine levels than controls under 150 mg and 3-4 fold greater levels under 300 mg at 90 min and 150 min post caffeine dose. However, these differences also covaried with cigarette smoking status (not balanced between groups), and nicotine smoking is known to alter caffeine/paraxanthine metabolism via cytochrome P450 enzymes. These preliminary data raise the possibility that adenosine antagonists may affect cocaine-dependent and non-dependent subjects differently. In conjunction with previous preclinical and human studies, the data suggest that adenosine modulating drugs may have value in the treatment of stimulant use disorders.

Amphetamine-metabolites of deprenyl involved in protection against neurotoxicity induced by MPTP and 2'-methyl-MPTP.

PubMed

Sziráki, I; Kardos, V; Patthy, M; Pátfalusi, M; Gaál, J; Solti, M; Kollár, E; Singer, J

1994-01-01

The ability of 1-deprenyl to protect against the parkinsonian effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been attributed to the inhibition of conversion of MPTP to MPP+ (1-methyl-4-phenylpyridinium) catalyzed by MAO-B. We report here that deprenyl-treatment in mice has an additional neuroprotective element associated with the rapid metabolization of 1-deprenyl to 1-methamphetamine and 1-amphetamine. 1-Methamphetamine and 1-amphetamine inhibit MPP(+)-uptake into striatal synaptosomes prepared from rats. Post-treatment by 1-deprenyl, 1-methamphetamine, 1-amphetamine (at times when MPTP is no longer present in the striatum of mice) protects against neurotoxicity in C57BL mice by blocking the uptake of MPP+ into dopaminergic neurons, and even against the neurotoxicity induced by 2'CH3-MPTP, which is partly bioactivated by MAO-A. These findings may have clinical implications since deprenyl has recently been found to delay the progression of Parkinson's disease.

Amphetamine modulation of long-term potentiation in the prefrontal cortex: dose dependency, monoaminergic contributions, and paradoxical rescue in hyperdopaminergic mutant.

PubMed

Xu, Tai-Xiang; Ma, Qi; Spealman, Roger D; Yao, Wei-Dong

2010-12-01

Amphetamine can improve cognition in healthy subjects and patients with schizophrenia, attention-deficit hyperactivity disorder, and other neuropsychiatric diseases; higher doses, however, can impair cognitive function, especially those mediated by the prefrontal cortex. We investigated how amphetamine affects prefrontal cortex long-term potentiation (LTP), a cellular correlate of learning and memory, in normal and hyperdopaminergic mice lacking the dopamine transporter. Acute amphetamine treatment in wild-type mice produced a biphasic dose-response modulation of LTP, with a low dose enhancing LTP and a high dose impairing it. Amphetamine-induced LTP enhancement was prevented by pharmacological blockade of D(1) - (but not D(2)-) class dopamine receptors, by blockade of β-adrenergic receptors, or by inhibition of cAMP-PKA signaling. In contrast, amphetamine-induced LTP impairment was prevented by inhibition of post-synaptic protein phosphatase-1, a downstream target of PKA signaling, or by blockade of either D(1) - or D(2)-class dopamine, but not noradrenergic, receptors. Thus, amphetamine biphasically modulates LTP via cAMP-PKA signaling orchestrated mainly through dopamine receptors. Unexpectedly, amphetamine restored the loss of LTP in dopamine transporter-knockout mice primarily by activation of the noradrenergic system. Our results mirror the biphasic effectiveness of amphetamine in humans and provide new mechanistic insights into its effects on cognition under normal and hyperdopaminergic conditions. © 2010 The Authors. Journal of Neurochemistry © 2010 International Society for Neurochemistry.

Uncertainty exposure causes behavioural sensitization and increases risky decision-making in male rats: toward modelling gambling disorder.

PubMed

Zeeb, Fiona D; Li, Zhaoxia; Fisher, Daniel C; Zack, Martin H; Fletcher, Paul J

2017-11-01

An animal model of gambling disorder, previously known as pathological gambling, could advance our understanding of the disorder and help with treatment development. We hypothesized that repeated exposure to uncertainty during gambling induces behavioural and dopamine (DA) sensitization - similar to chronic exposure to drugs of abuse. Uncertainty exposure (UE) may also increase risky decision-making in an animal model of gambling disorder. Male Sprague Dawley rats received 56 UE sessions, during which animals responded for saccharin according to an unpredictable, variable ratio schedule of reinforcement (VR group). Control animals responded on a predictable, fixed ratio schedule (FR group). Rats yoked to receive unpredictable reward were also included (Y group). Animals were then tested on the Rat Gambling Task (rGT), an analogue of the Iowa Gambling Task, to measure decision-making. Compared with the FR group, the VR and Y groups experienced a greater locomotor response following administration of amphetamine. On the rGT, the FR and Y groups preferred the advantageous options over the risky, disadvantageous options throughout testing (40 sessions). However, rats in the VR group did not have a significant preference for the advantageous options during sessions 20-40. Amphetamine had a small, but significant, effect on decision-making only in the VR group. After rGT testing, only the VR group showed greater hyperactivity following administration of amphetamine compared with the FR group. Reward uncertainty was the only gambling feature modelled. Actively responding for uncertain reward likely sensitized the DA system and impaired the ability to make optimal decisions, modelling some aspects of gambling disorder.

Amphetamine treatment affects the extra-hypothalamic vasopressinergic system in a sex- and nucleus-dependent manner.

PubMed

Ahumada, C; Bahamondes, C; Cerda, C A; Silva, R A; Cruz, G; Moya, P R; Sotomayor-Zárate, R; Renard, G M

2017-04-01

The lateral septum (LS), a brain structure implicated in addictive behaviours, regulates the activation of dopaminergic neurones in the ventral tegmental area. Vasopressinergic projections from the extended amygdala to the LS, which are sexually dimorphic, could be responsible for the vulnerability to addiction in a sex-dependent manner. The present study aimed to investigate the modulatory effects of amphetamine (AMPH) on the expression of vasopressin (AVP) in the vasopressinergic extra-hypothalamic system in sensitised male and female rats. Adult male and female Sprague-Dawley rats underwent an AMPH-locomotor sensitisation protocol. Acute AMPH increased AVP mRNA expression in the medial amygdala (MeA), whereas AMPH-induced sensitisation increased AVP mRNA expression in the bed nucleus of the stria terminalis (BNST) only in females. Interestingly, the increase in AVP expression in BNST was higher in oestrus females compared to dioestrus females and acute AMPH resulted in a decrease in AVP levels in the LS, only in males. Thus, there are complex and region-specific interactions between AMPH and the extra-hypothalamic vasopressinergic system in the brain, underlying possible alterations in different behaviours caused by acute and chronic AMPH exposure. © 2017 British Society for Neuroendocrinology.

Separate and combined impact of acute naltrexone and alprazolam on subjective and physiological effects of oral d-amphetamine in stimulant users

PubMed Central

Marks, Katherine R.; Lile, Joshua A.; Stoops, William W.

2014-01-01

Rationale Opioid antagonists (e.g., naltrexone) and positive modulators of γ-aminobutyric-acidA (GABAA) receptors (e.g., alprazolam) modestly attenuate the abuse-related effects of stimulants like amphetamine. The use of higher doses to achieve greater efficacy is precluded by side effects. Combining naltrexone and alprazolam might safely maximize efficacy while avoiding the untoward effects of the constituent compounds. Objectives The present pilot study tested the hypothesis that acute pretreatment with the combination of naltrexone and alprazolam would not produce clinically problematic physiological effects or negative subjective effects and would reduce the positive subjective effects of d-amphetamine to a greater extent than the constituent drugs alone. Methods Eight nontreatment-seeking, stimulant-using individuals completed an outpatient experiment in which oral d-amphetamine (0, 15, and 30 mg) was administered following acute pretreatment with naltrexone (0 and 50 mg) and alprazolam (0 and 0.5 mg). Subjective effects, psychomotor task performance, and physiological measures were collected. Results Oral d-amphetamine produced prototypical physiological and stimulant-like positive subjective effects (e.g., VAS ratings of Active/Alert/Energetic, Good Effect, and High). Pretreatment with naltrexone, alprazolam, and their combination did not produce clinically problematic acute physiological effects or negative subjective effects. Naltrexone and alprazolam each significantly attenuated some of the subjective effects of d-amphetamine. The combination attenuated a greater number of subjective effects than the constituent drugs alone. Conclusions The present results support the continued evaluation of an opioid receptor antagonist combined with a GABAA-positive modulator using more clinically relevant experimental conditions like examining the effect of chronic dosing with these drugs on methamphetamine self-administration. PMID:24464531

Separate and combined impact of acute naltrexone and alprazolam on subjective and physiological effects of oral d-amphetamine in stimulant users.

PubMed

Marks, Katherine R; Lile, Joshua A; Stoops, William W; Rush, Craig R

2014-07-01

Opioid antagonists (e.g., naltrexone) and positive modulators of γ-aminobutyric-acidA (GABAA) receptors (e.g., alprazolam) modestly attenuate the abuse-related effects of stimulants like amphetamine. The use of higher doses to achieve greater efficacy is precluded by side effects. Combining naltrexone and alprazolam might safely maximize efficacy while avoiding the untoward effects of the constituent compounds. The present pilot study tested the hypothesis that acute pretreatment with the combination of naltrexone and alprazolam would not produce clinically problematic physiological effects or negative subjective effects and would reduce the positive subjective effects of d-amphetamine to a greater extent than the constituent drugs alone. Eight nontreatment-seeking, stimulant-using individuals completed an outpatient experiment in which oral d-amphetamine (0, 15, and 30 mg) was administered following acute pretreatment with naltrexone (0 and 50 mg) and alprazolam (0 and 0.5 mg). Subjective effects, psychomotor task performance, and physiological measures were collected. Oral d-amphetamine produced prototypical physiological and stimulant-like positive subjective effects (e.g., VAS ratings of Active/Alert/Energetic, Good Effect, and High). Pretreatment with naltrexone, alprazolam, and their combination did not produce clinically problematic acute physiological effects or negative subjective effects. Naltrexone and alprazolam each significantly attenuated some of the subjective effects of d-amphetamine. The combination attenuated a greater number of subjective effects than the constituent drugs alone. The present results support the continued evaluation of an opioid receptor antagonist combined with a GABAA-positive modulator using more clinically relevant experimental conditions like examining the effect of chronic dosing with these drugs on methamphetamine self-administration.

Non-Dependent Stimulant Users of Cocaine and Prescription Amphetamines Show Verbal Learning and Memory Deficits

PubMed Central

Reske, Martina; Eidt, Carolyn A.; Delis, Dean C.; Paulus, Martin P.

2010-01-01

Background Stimulants are used increasingly to enhance social (cocaine) or cognitive performance (stimulants normally prescribed, prescription stimulants, e.g. methylphenidate, amphetamines). Chronic use, on the other hand, has been associated with significant verbal memory and learning deficits. This study sought to determine whether subtle learning and memory problems characterize individuals who exhibit occasional but not chronic use of stimulants. Methods 154 young (age 18–25) occasional, non-dependent stimulant users and 48 stimulant naïve comparison subjects performed the California Verbal Learning test (CVLT-II). Lifetime uses of stimulants and co-use of marijuana were considered in correlation and median split analyses. Results Compared to stimulant naïve subjects, occasional stimulant users showed significant performance deficits, most pronounced in the verbal recall and recognition domains. Lifetime uses of stimulants and marijuana did not affect CVLT-II performance. The type of stimulant used, however, was of major relevance: users of cocaine only were less impaired, while cumulative use of prescription stimulants was associated with impaired verbal learning and memory capacities. Conclusions These results support the hypothesis of subtle and possibly pre-existing neurocognitive deficiencies in occasional users of stimulants, which may be related to the motivation of using these drugs. More importantly, despite beneficial short-term effects, cumulative use, particularly of prescription amphetamines and methylphenidate, intensifies these deficits. PMID:20605137

Nondependent stimulant users of cocaine and prescription amphetamines show verbal learning and memory deficits.

PubMed

Reske, Martina; Eidt, Carolyn A; Delis, Dean C; Paulus, Martin P

2010-10-15

Stimulants are used increasingly to enhance social (cocaine) or cognitive performance (stimulants normally prescribed, prescription stimulants [e.g., methylphenidate, amphetamines]). Chronic use, by contrast, has been associated with significant verbal memory and learning deficits. This study sought to determine whether subtle learning and memory problems characterize individuals who exhibit occasional but not chronic use of stimulants. One hundred fifty-four young (age 18-25), occasional, nondependent stimulant users and 48 stimulant-naive comparison subjects performed the California Verbal Learning Test II. Lifetime uses of stimulants and co-use of marijuana were considered in correlation and median split analyses. Compared with stimulant-naive subjects, occasional stimulant users showed significant performance deficits, most pronounced in the verbal recall and recognition domains. Lifetime uses of stimulants and marijuana did not affect California Verbal Learning Test II performance. The type of stimulant used, however, was of major relevance: users of cocaine only were less impaired, whereas cumulative use of prescription stimulants was associated with impaired verbal learning and memory capacities. These results support the hypothesis of subtle and possibly pre-existing neurocognitive deficiencies in occasional users of stimulants, which might be related to the motivation for using these drugs. More importantly, despite beneficial short-term effects, cumulative use, particularly of prescription amphetamines and methylphenidate, intensifies these deficits. Copyright © 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Amphetamine sensitization alters reward processing in the human striatum and amygdala.

PubMed

O'Daly, Owen G; Joyce, Daniel; Tracy, Derek K; Azim, Adnan; Stephan, Klaas E; Murray, Robin M; Shergill, Sukhwinder S

2014-01-01

Dysregulation of mesolimbic dopamine transmission is implicated in a number of psychiatric illnesses characterised by disruption of reward processing and goal-directed behaviour, including schizophrenia, drug addiction and impulse control disorders associated with chronic use of dopamine agonists. Amphetamine sensitization (AS) has been proposed to model the development of this aberrant dopamine signalling and the subsequent dysregulation of incentive motivational processes. However, in humans the effects of AS on the dopamine-sensitive neural circuitry associated with reward processing remains unclear. Here we describe the effects of acute amphetamine administration, following a sensitising dosage regime, on blood oxygen level dependent (BOLD) signal in dopaminoceptive brain regions during a rewarded gambling task performed by healthy volunteers. Using a randomised, double-blind, parallel-groups design, we found clear evidence for sensitization to the subjective effects of the drug, while rewarded reaction times were unchanged. Repeated amphetamine exposure was associated with reduced dorsal striatal BOLD signal during decision making, but enhanced ventromedial caudate activity during reward anticipation. The amygdala BOLD response to reward outcomes was blunted following repeated amphetamine exposure. Positive correlations between subjective sensitization and changes in anticipation- and outcome-related BOLD signal were seen for the caudate nucleus and amygdala, respectively. These data show for the first time in humans that AS changes the functional impact of acute stimulant exposure on the processing of reward-related information within dopaminoceptive regions. Our findings accord with pathophysiological models which implicate aberrant dopaminergic modulation of striatal and amygdala activity in psychosis and drug-related compulsive disorders.

Neurotoxicity of amphetamine derivatives is mediated by caspase pathway activation in rat cerebellar granule cells.

PubMed

Jiménez, Andrés; Jordà, Elvira G; Verdaguer, Ester; Pubill, David; Sureda, Francesc X; Canudas, Anna M; Escubedo, Elena; Camarasa, Jordi; Camins, Antoni; Pallàs, Mercè

2004-04-15

The neurotoxic action of the abuse drugs methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA) on cerebellar granule neurones (CGNs) culture was examined. Treatment for 48 h with METH or MDMA (1-5 mM) induced a higher decrease in viability than 24 h treatment. z.VAD.fmk (100 microM) but not MK-801 nor NBQX recovered control viability values. In both cases, cell death was characterised as apoptotic rather than necrotic by morphology cell observation. Apoptosis measured by flow cytometry indicated an increase in the hypodiploid population after 48 h treatment with METH and MDMA. Apoptosis was reverted by the presence of z.VAD.fmk (100 microM) but not by 10 microM MK-801 or NBQX. Similar results were obtained by analysing nuclear chromatine condensation. These results ruled out excitotoxic participation in amphetamine derivative-induced neurotoxicity in CGNs. Participation of radical oxygen species (ROS) was evaluated using alpha-tocopherol (1-15 microM) and cytometric studies. The co-treatment with 4 mM METH or MDMA for 48 h partially reverted neurotoxic action and apoptotic features, indicating ROS implication in CGNs death by amphetamine derivatives. Alteration of mitochondrial function induced cytochrome C (Cyt C) release after 48-h treatment with METH and MDMA (4 mM). There was also indication of caspase-3-like activation, measured by immunoanalysis and biochemically. Finally, neurodegenerative action caused by amphetamine derivatives may be prevented by using caspase inhibitors.

Addictive illegal drugs: structural neuroimaging.

PubMed

Geibprasert, S; Gallucci, M; Krings, T

2010-05-01

Illegal addictive drugs can lead to functional or structural impairment of the central nervous system. This review provides an overview of the structural imaging findings on CT, MR imaging, and conventional angiography related to chronic and acute abuse of the most commonly abused illegal drugs, including cannabis, organic solvents, and amphetamines and opioids and their respective derivatives. Pathomechanisms include excitotoxicity, which may lead to an acute or subacute leukoencephalopathy, and vascular complications, including vasoconstriction, vasculitis, or hypertension, which may lead to intracranial hemorrhage or ischemia. Because clinical findings alone are often nonspecific, and afflicted patients are unlikely to admit to the substance abuse, the neuroradiologist may play an important role in establishing the diagnosis and, thereby, initiating treatment.

Improvement of attention with amphetamine in low- and high-performing rats.

PubMed

Turner, Karly M; Burne, Thomas H J

2016-09-01

Attentional deficits occur in a range of neuropsychiatric disorders, such as schizophrenia and attention deficit hyperactivity disorder. Psychostimulants are one of the main treatments for attentional deficits, yet there are limited reports of procognitive effects of amphetamine in preclinical studies. Therefore, task development may be needed to improve predictive validity when measuring attention in rodents. This study aimed to use a modified signal detection task (SDT) to determine if and at what doses amphetamine could improve attention in rats. Sprague-Dawley rats were trained on the SDT prior to amphetamine challenge (0.1, 0.25, 0.75 and 1.25 mg/kg). This dose range was predicted to enhance and disrupt cognition with the effect differing between individuals depending on baseline performance. Acute low dose amphetamine (0.1 and 0.25 mg/kg) improved accuracy, while the highest dose (1.25 mg/kg) significantly disrupted performance. The effects differed for low- and high-performing groups across these doses. The effect of amphetamine on accuracy was found to significantly correlate with baseline performance in rats. This study demonstrates that improvement in attentional performance with systemic amphetamine is dependent on baseline accuracy in rats. Indicative of the inverted U-shaped relationship between dopamine and cognition, there was a baseline-dependent shift in performance with increasing doses of amphetamine. The SDT may be a useful tool for investigating individual differences in attention and response to psychostimulants in rodents.

Simulated Driving Changes in Young Adults with ADHD Receiving Mixed Amphetamine Salts Extended Release and Atomoxetine

ERIC Educational Resources Information Center

Kay, Gary G.; Michaels, M. Alex; Pakull, Barton

2009-01-01

Background: Psychostimulant treatment may improve simulated driving performance in young adults with attention-deficit/hyperactivity disorder (ADHD). Method: This was a randomized, double-blind, placebo-controlled, crossover study of simulated driving performance with mixed amphetamine salts--extended release (MAS XR) 50 mg/day (Cohort 1) and…

Case Reports of Aripiprazole Causing False-Positive Urine Amphetamine Drug Screens in Children.

PubMed

Kaplan, Justin; Shah, Pooja; Faley, Brian; Siegel, Mark E

2015-12-01

Urine drug screens (UDSs) are used to identify the presence of certain medications. One limitation of UDSs is the potential for false-positive results caused by cross-reactivity with other substances. Amphetamines have an extensive list of cross-reacting medications. The literature contains reports of false-positive amphetamine UDSs with multiple antidepressants and antipsychotics. We present 2 cases of presumed false-positive UDSs for amphetamines after ingestion of aripiprazole. Case 1 was a 16-month-old girl who accidently ingested 15 to 45 mg of aripiprazole. She was lethargic and ataxic at home with 1 episode of vomiting containing no identifiable tablets. She remained sluggish with periods of irritability and was admitted for observation. UDS on 2 consecutive days came back positive for amphetamines. Case 2 was of a 20-month-old girl who was brought into the hospital after accidental ingestion of an unknown quantity of her father's medications which included aripiprazole. UDS on the first day of admission came back positive only for amphetamines. Confirmatory testing with gas chromatography-mass spectrometry (GC-MS) on the blood and urine samples were also performed for both patients on presentation to detect amphetamines and were subsequently negative. Both patients returned to baseline and were discharged from the hospital. To our knowledge, these cases represent the first reports of false-positive amphetamine urine drug tests with aripiprazole. In both cases, aripiprazole was the drug with the highest likelihood of causing the positive amphetamine screen. The implications of these false-positives include the possibility of unnecessary treatment and monitoring of patients. Copyright © 2015 by the American Academy of Pediatrics.

Monoamine Transporter Inhibitors and Substrates as Treatments for Stimulant Abuse

PubMed Central

Howell, Leonard L.; Negus, S. Stevens

2015-01-01

The acute and chronic effects of abused psychostimulants on monoamine transporters and associated neurobiology have encouraged development of candidate medications that target these transporters. Monoamine transporters in general, and dopamine transporters in particular, are critical molecular targets that mediate abuse-related effects of psychostimulants such as cocaine and amphetamine. Moreover, chronic administration of psychostimulants can cause enduring changes in neurobiology reflected in dysregulation of monoamine neurochemistry and behavior. The current review will evaluate evidence for the efficacy of monoamine transporter inhibitors and substrates to reduce abuse-related effects of stimulants in preclinical assays of stimulant self-administration, drug discrimination and reinstatement. In considering deployment of monoamine transport inhibitors and substrates as agonist-type medications to treat stimulant abuse, the safety and abuse liability of the medications are an obvious concern, and this will also be addressed. Future directions in drug discovery should identify novel medications that retain efficacy to decrease stimulant use but possess lower abuse liability, and evaluate the degree to which efficacious medications can attenuate or reverse neurobiological effects of chronic stimulant use. PMID:24484977

Olanzapine and haloperidol for the treatment of acute symptoms of mental disorders induced by amphetamine-type stimulants: A randomized controlled trial.

PubMed

Xue, Xiaobin; Song, Yun; Yu, Xiaojie; Fan, Qiang; Tang, Jiyou; Chen, Xu

2018-02-01

This study aimed to compare olanzapine and haloperidol efficacies in the treatment of acute psychiatric symptoms due to amphetamine-type stimulants (ATSs). The Zelen II design method was used; 124 patients with acute mental disorders due to amphetamine were randomly divided into olanzapine group (n = 63) and haloperidol group (n = 61). Then, a 4-week open-label medical therapy was performed. Clinical Global Impression Scale Item 2 was employed to evaluate the onset time; meanwhile, Brief Psychiatric Rating Scale (BPRS) was used at baseline and at posttreatment weeks 1, 2, and 4. Moreover, adverse reactions during the treatment were recorded. Onset time in the olanzapine group was significantly earlier than in the haloperidol group; BPRS scores in the olanzapine group were significantly lower than haloperidol group values at 1 and 2 weeks of treatment. The overall effective rates had no statistically significant difference. Short-term olanzapine and haloperidol treatments had equivalent efficacies in the treatment of acute symptoms of mental disorders due to ATSs; however, olanzapine administration resulted in relatively earlier disease onset, with less adverse reactions.

AN ANIMAL MODEL OF SCHIZOPHRENIA BASED ON CHRONIC LSD ADMINISTRATION: OLD IDEA, NEW RESULTS

PubMed Central

Marona-Lewicka, Danuta; Nichols, Charles D.; Nichols, David E.

2011-01-01

Many people who take LSD experience a second temporal phase of LSD intoxication that is qualitatively different, and was described by Daniel Freedman as “clearly a paranoid state.” We have previously shown that the discriminative stimulus effects of LSD in rats also occur in two temporal phases, with initial effects mediated by activation of 5-HT2A receptors (LSD30), and the later temporal phase mediated by dopamine D2-like receptors (LSD90). Surprisingly, we have now found that non-competitive NMDA antagonists produced full substitution in LSD90 rats, but only in older animals, whereas in LSD30, or in younger animals, these drugs did not mimic LSD. Chronic administration of low doses of LSD (>3 months, 0.16 mg/kg every other day) induces a behavioral state characterized by hyperactivity and hyperirritability, increased locomotor activity, anhedonia, and impairment in social interaction that persists at the same magnitude for at least three months after cessation of LSD treatment. These behaviors, which closely resemble those associated with psychosis in humans, are not induced by withdrawal from LSD; rather, they are the result of neuroadaptive changes occurring in the brain during the chronic administration of LSD. These persistent behaviors are transiently reversed by haloperidol and olanzapine, but are insensitive to MDL-100907. Gene expression analysis data show that chronic LSD treatment produced significant changes in multiple neurotransmitter system-related genes, including those for serotonin and dopamine. Thus, we propose that chronic treatment of rats with low doses of LSD can serve as a new animal model of psychosis that may mimic the development and progression of schizophrenia, as well as model the established disease better than current acute drug administration models utilizing amphetamine or NMDA antagonists such as PCP. PMID:21352832

Anticonvulsant medications attenuate amphetamine-induced deficits in behavioral inhibition but not decision making under risk on a rat gambling task.

PubMed

Tremblay, Melanie; Winstanley, Catharine A

2016-11-01

Impulsivity is a major component of mania in bipolar disorder (BD), and patients also show impairments in decision-making involving risk on the Iowa Gambling Task (IGT). Similar deficits are observed in some patients with temporal lobe epilepsy (TLE), and incidence of problem gambling is higher in both these populations. Anticonvulsant drugs are widely used in the treatment of epilepsy, but also as mood stabilizers and prophylaxis for the management of BD. Unfortunately, little is still known about the precise mechanisms of action underlying their efficacy, and the specific behavioral aspect targeted by these drugs. This project explored the effect of the three anticonvulsant drugs currently also used as mood stabilizers- carbamazepine, valproate and lamotrigine on aspects of decision-making using a rat analogue of the IGT, the rat Gambling Task (rGT). In this task, rats choose between four distinct, probabilistic reinforcement schedules. Sugar pellet profits are maximized by adopting a conservative strategy, avoiding tempting high-risk, high-reward options. Effects of the anticonvulsant agents were assessed on baseline performance and also in conjunction with amphetamine administration, in order to approximate a "mania-like" state. Carbamazepine appeared to slow processing speed, decreasing premature responses and increasing choice latency, whereas valproate and lamotrigine had no effect. When administered prior to amphetamine, lamotrigine was the only drug that failed to attenuate the pro-impulsive effect of the psychostimulant. Further studies looking at chronic administration of anticonvulsants may help us understand the impact of this medication class on decision-making and impulsivity in healthy rats and disease models. Copyright © 2016 Elsevier B.V. All rights reserved.

A systematic review of risk factors for methamphetamine-associated psychosis.

PubMed

Arunogiri, Shalini; Foulds, James A; McKetin, Rebecca; Lubman, Dan I

2018-06-01

Chronic methamphetamine use is commonly associated with the development of psychotic symptoms. The predictors and correlates of methamphetamine-associated psychosis are poorly understood. We sought to systematically review factors associated with psychotic symptoms in adults using illicit amphetamine or methamphetamine. A systematic literature search was performed on MEDLINE (OVID), PsycINFO and EMBASE databases from inception to 8 December 2016. The search strategy combined three concept areas: methamphetamine or amphetamine, psychosis and risk factors. Included studies needed to compare adults using illicit methamphetamine or amphetamine, using a validated measure of psychosis, on a range of risk factors. Of 402 identified articles, we removed 45 duplicates, 320 articles based on abstract/title and 17 ineligible full-text articles, leaving 20 included studies that were conducted in 13 populations. Two co-authors independently extracted the following data from each study: country, setting and design; participant demographic and clinical details; sample size; measure/s used and measures of association between psychosis outcomes and risk factors. Individual study quality was assessed using a modified Newcastle-Ottawa Scale, and strength of evidence was assessed using GRADE criteria. Frequency of methamphetamine use and severity of methamphetamine dependence were consistently found to be associated with psychosis, and sociodemographic factors were not. There was inconsistent evidence available for all other risk factors. Individual study quality was low-moderate for the majority of studies. Heterogeneity in study outcomes precluded quantitative synthesis of outcomes across studies. The most consistent correlates of psychotic symptoms were increased frequency of methamphetamine use and dependence on methamphetamine. The findings of this review highlight the need for targeted assessment and treatment of methamphetamine use in individuals presenting with psychosis.

Improving General Intelligence with a Nutrient-Based Pharmacological Intervention

ERIC Educational Resources Information Center

Stough, Con; Camfield, David; Kure, Christina; Tarasuik, Joanne; Downey, Luke; Lloyd, Jenny; Zangara, Andrea; Scholey, Andrew; Reynolds, Josh

2011-01-01

Cognitive enhancing substances such as amphetamine and modafinil have become popular in recent years to improve acute cognitive performance particularly in environments in which enhanced cognition or intelligence is required. Nutraceutical nootropics, which are natural substances that have the ability to bring about acute or chronic changes in…

A single administration of methamphetamine to mice early in the light period decreases running wheel activity observed during the dark period

PubMed Central

Kitanaka, Nobue; Kitanaka, Junichi; Hall, F. Scott; Uhl, George R.; Watabe, Kaname; Kubo, Hitoshi; Takahashi, Hitoshi; Tatsuta, Tomohiro; Morita, Yoshio; Takemura, Motohiko

2014-01-01

Repeated intermittent administration of amphetamines acutely increases appetitive and consummatory aspects of motivated behaviors as well as general activity and exploratory behavior, including voluntary running wheel activity. Subsequently, if the drug is withdrawn, the frequency of these behaviors decrease, which is thought to be indicative of dysphoric symptoms associated with amphetamine withdrawal. Such decreases may be observed after chronic treatment or even after single drug administrations. In the present study, the effect of acute methamphetamine (METH) on running wheel activity, horizontal locomotion, appetitive behavior (food access), and consummatory behavior (food and water intake) was investigated in mice. A multi-configuration behavior apparatus designed to monitor the five behaviors was developed, where combined measures were recorded simultaneously. In the first experiment, naïve male ICR mice showed gradually increasing running wheel activity over three consecutive days after exposure to a running wheel, while mice without a running wheel showed gradually decreasing horizontal locomotion, consistent with running wheel activity being a positively motivated form of natural motor activity. In experiment 2, increased horizontal locomotion and food access, and decreased food intake, were observed for the initial 3 h after acute METH challenge. Subsequently, during the dark phase period decreased running wheel activity and horizontal locomotion were observed. The reductions in running wheel activity and horizontal locomotion may be indicative of reduced dopaminergic function, although it remains to be seen if these changes may be more pronounced after more prolonged METH treatments. PMID:22079320

Adolescent d-Amphetamine Treatment in a Rodent Model of ADHD: Pro-Cognitive Effects in Adolescence without an Impact on Cocaine Cue Reactivity in Adulthood

PubMed Central

Jordan, Chloe J.; Taylor, Danielle M.; Dwoskin, Linda P.; Kantak, Kathleen M.

2015-01-01

Attention-deficit/hyperactivity disorder (ADHD) is comorbid with cocaine abuse. Whereas initiating ADHD medication in childhood does not alter later cocaine abuse risk, initiating medication during adolescence may increase risk. Preclinical work in the Spontaneously Hypertensive Rat (SHR) model of ADHD found that adolescent methylphenidate increased cocaine self-administration in adulthood, suggesting a need to identify alternatively efficacious medications for teens with ADHD. We examined effects of adolescent d-amphetamine treatment on strategy set shifting performance during adolescence and on cocaine self-administration and reinstatement of cocaine-seeking behavior (cue reactivity) during adulthood in male SHR, Wistar-Kyoto (inbred control), and Wistar (outbred control) rats. During the set shift phase, adolescent SHR needed more trials and had a longer latency to reach criterion, made more regressive errors and trial omissions, and exhibited slower and more variable lever press reaction times. d-Amphetamine improved performance only in SHR by increasing choice accuracy and decreasing errors and latency to criterion. In adulthood, SHR self-administered more cocaine, made more cocaine-seeking responses, and took longer to extinguish lever responding than control strains. Adolescent d-amphetamine did not alter cocaine self-administration in adult rats of any strain, but reduced cocaine seeking during the first of seven reinstatement test sessions in adult SHR. These findings highlight utility of SHR in modeling cognitive dysfunction and comorbid cocaine abuse in ADHD. Unlike methylphenidate, d-amphetamine improved several aspects of flexible learning in adolescent SHR and did not increase cocaine intake or cue reactivity in adult SHR. Thus, adolescent d-amphetamine was superior to methylphenidate in this ADHD model. PMID:26467602

A randomized crossover study to assess the pharmacokinetics of a novel amphetamine extended-release orally disintegrating tablet in healthy adults.

PubMed

Stark, Jeffrey G; Engelking, Dorothy; McMahen, Russ; Sikes, Carolyn

2016-09-01

In this pharmacokinetic (PK) study in healthy adults, we sought to: (1) compare the PK properties of a novel amphetamine extended-release orally disintegrating tablet formulation (Adzenys XR-ODT™ [AMP XR-ODT]) to a reference extended-release mixed amphetamine salts (MAS ER) formulation and (2) assess the effect of food on AMP XR-ODT. Forty-two adults were enrolled in a single-dose, open-label, 3-period, 3-treatment, randomized crossover study and received an 18.8-mg dose of AMP XR-ODT (fasted or fed) or equivalent dose (30 mg) of MAS ER (fasted). Plasma samples were analyzed for d-and l-amphetamine. Maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), elimination half-life (T1/2), area under the concentration-time curve from time zero to last quantifiable concentration (AUClast), from time zero to infinity (AUCinf), relevant partial AUCs, and weight-normalized clearance (CL/F/kg) were assessed. The PK parameters were compared across treatments using an ANOVA. Safety was also assessed. A total of 39 adults completed this study. The geometric mean ratios (90% confidence interval [CI]) for AMP XR-ODT/MAS ER Cmax, AUC5-last, AUClast, and AUCinf were within 80%-125% for both d-and l-amphetamine. The 90% CIs for AUC0-5 were slightly below the 80%-125% range. When AMP XR-ODT was administered with food, there was a slight decrease in the d-and l-amphetamine Cmax and approximately a 2-hour delay in Tmax. The most common adverse events reported (>5% of participants) were dry mouth, palpitations, nausea, dizziness, headache, anxiety, and nasal congestion. AMP XR-ODT displayed a PK profile similar to MAS ER, and no clinically relevant food effect was observed.

Amphetamine-induced dopamine release and neurocognitive function in treatment-naive adults with ADHD.

PubMed

Cherkasova, Mariya V; Faridi, Nazlie; Casey, Kevin F; O'Driscoll, Gillian A; Hechtman, Lily; Joober, Ridha; Baker, Glen B; Palmer, Jennifer; Dagher, Alain; Leyton, Marco; Benkelfat, Chawki

2014-05-01

Converging evidence from clinical, preclinical, neuroimaging, and genetic research implicates dopamine neurotransmission in the pathophysiology of attention deficit hyperactivity disorder (ADHD). The in vivo neuroreceptor imaging evidence also suggests alterations in the dopamine system in ADHD; however, the nature and behavioral significance of those have not yet been established. Here, we investigated striatal dopaminergic function in ADHD using [(11)C]raclopride PET with a d-amphetamine challenge. We also examined the relationship of striatal dopamine responses to ADHD symptoms and neurocognitive function. A total of 15 treatment-free, noncomorbid adult males with ADHD (age: 29.87 ± 8.65) and 18 healthy male controls (age: 25.44 ± 6.77) underwent two PET scans: one following a lactose placebo and the other following d-amphetamine (0.3 mg/kg, p.o.), administered double blind and in random order counterbalanced across groups. In a separate session without a drug, participants performed a battery of neurocognitive tests. Relative to the healthy controls, the ADHD patients, as a group, showed greater d-amphetamine-induced decreases in striatal [(11)C]raclopride binding and performed more poorly on measures of response inhibition. Across groups, a greater magnitude of d-amphetamine-induced change in [(11)C]raclopride binding potential was associated with poorer performance on measures of response inhibition and ADHD symptoms. Our findings suggest an augmented striatal dopaminergic response in treatment-naive ADHD. Though in contrast to results of a previous study, this finding appears consistent with a model proposing exaggerated phasic dopamine release in ADHD. A susceptibility to increased phasic dopamine responsivity may contribute to such characteristics of ADHD as poor inhibition and impulsivity.

Attenuation of acute d-amphetamine-induced disruption of conflict resolution by clozapine, but not α-flupenthixol in rats.

PubMed

Reichelt, Amy C; Good, Mark A; Killcross, Simon

2013-11-01

Previous research demonstrates that disruption of forebrain dopamine systems impairs the use of high-order information to guide goal-directed performance, and that this deficit may be related to impaired use of task-setting cues in patients with schizophrenia. Such deficits can be interrogated through conflict resolution, which has been demonstrated to be sensitive to prefrontal integrity in rodents. We sought to examine the effects of acute systemic d-amphetamine administration on the contextual control of response conflict in rats, and whether deficits were reversed through pre-treatment with clozapine or the D₁/D₂ antagonist α-flupenthixol. Acute d-amphetamine (1.5 mg/kg) disrupted the utilisation of contextual cues; therefore rats were impaired during presentation of stimulus compounds that require conflict resolution. Evidence suggested that this effect was attenuated through pre-treatment with the atypical antipsychotic clozapine (5.0 mg/kg), but not the typical antipsychotic α-flupenthixol (0.25 mg/kg), at doses previously shown to attenuate d-amphetamine-induced cognitive deficits. These studies therefore demonstrate a potentially viable model of disrupted executive function such as that seen in schizophrenia.

Methylphenidate for attention deficit hyperactivity disorder and drug relapse in criminal offenders with substance dependence: a 24-week randomized placebo-controlled trial

PubMed Central

Konstenius, Maija; Jayaram-Lindström, Nitya; Guterstam, Joar; Beck, Olof; Philips, Björn; Franck, Johan

2014-01-01

Aim To test the efficacy and safety of osmotic release oral system (OROS) methylphenidate (MPH) in doses up to 180 mg/day to treat attention deficit hyperactivity disorder (ADHD) and prevent any drug relapse in individuals with a co-diagnosis of ADHD and amphetamine dependence. Design Randomized placebo-controlled 24-week double-blind trial with parallel groups design. Setting Participants were recruited from medium security prisons in Sweden. The medication started within 2 weeks before release from prison and continued in out-patient care with twice-weekly visits, including once-weekly cognitive behavioural therapy. Participants Fifty-four men with a mean age of 42 years, currently incarcerated, meeting DSM-IV criteria for ADHD and amphetamine dependence. Measurements Change in self-reported ADHD symptoms, relapse to any drug use (amphetamine and other drugs) measured by urine toxicology, retention to treatment, craving and time to relapse. Findings The MPH-treated group reduced their ADHD symptoms during the trial (P = 0.011) and had a significantly higher proportion of drug-negative urines compared with the placebo group (P = 0.047), including more amphetamine-negative urines (P = 0.019) and better retention to treatment (P = 0.032). Conclusions Methylphenidate treatment reduces attention deficit hyperactivity disorder symptoms and the risk for relapse to substance use in criminal offenders with attention deficit hyperactivity disorder and substance dependence. PMID:24118269

Impact of psychostimulants and atomoxetine on the expression of 8-hydroxyguanine glycosylase 1 in human cells.

PubMed

Schmidt, Andreas Johannes; Clement, Hans-Willi; Gebhardt, Stefan; Hemmeter, Ulrich Michael; Schulz, Eberhard; Krieg, Jürgen-Christian; Kircher, Tilo; Heiser, Philip

2010-06-01

Oxidative DNA damage as one sign of reactive oxygen species induced oxidative stress is an important factor in the pathogenesis of various psychiatric disorders. Altered levels of DNA base damage products as well as the expression of the main repair enzyme 8-hydroxyguanine glycosylase 1 have been described. The aim of the present study was to examine the effects of drugs (amphetamine, methylphenidate and atomoxetine) used in the treatment of attention deficit-hyperactivity disorder on the expression of this enzyme via reverse transcriptase-polymerase chain reaction in human neuroblastoma SH-SY5Y and human monocytic U-937 cells at concentrations of 50, 500 and 5,000 ng/ml. We observed decreased expression of this enzyme for all applied substances. In U-937 cells, the significance level was reached after treatment with 5,000 ng/ml amphetamine as well as after treatment with 50, 500 and 5,000 ng/ml atomoxetine. Incubation of SH-SY5Y cells with 50 and 5,000 ng/ml amphetamine and 5,000 ng/ml methylphenidate led to significant decreases of 8-hydroxyguanine glycosylase 1. As a positive correlation between the expression of 8-hydroxyguanine glycosylase 1 and the level of oxidative DNA damage products has been described, we accordingly consider these substances (amphetamine, methylphenidate and atomoxetine) to possibly play a protective role in this process.

The MAM rodent model of schizophrenia

PubMed Central

Lodge, Daniel J.

2013-01-01

Rodent models of human disease are essential to obtain a better understanding of disease pathology, the mechanism of action underlying conventional treatments, as well as for the generation of novel therapeutic approaches. There are a number of rodent models of schizophrenia based on either genetic manipulations, acute or sub-chronic drug administration, or developmental disturbances. The prenatal methylazoxymethanol acetate (MAM) rodent model is a developmental disruption model gaining increased attention because it displays a number of histological, neurophysiological and behavioral deficits analogous to those observed in schizophrenia patients. This unit describes the procedures required to safely induce the MAM phenotype in rats. In addition, we describe a simple behavioral procedure, amphetamine-induced hyper-locomotion, which can be utilized to verify the MAM phenotype. PMID:23559309

Free radicals are present in human serum of Catha edulis Forsk (Khat) abusers.

PubMed

Al-Akwa, Ahmed A; Shaher, Monira; Al-Akwa, Sameeha; Aleryani, Samir L

2009-09-25

Khat (Catha edulis Forsk) is a naturally occurring drug with an amphetamine-like structure and action. It has been postulated that amphetamine induces free radical formation. On this basis, we have hypothesized that Khat may promote synthesis of reactive oxygen and nitrogen species in the same way that amphetamine promotes free radical production. Forty male subjects were enrolled in two groups: those with a chronic Khat chewing habit (n=20), and those without a chewing habit (controls; n=20). Both groups were matched with regard to age. Total antioxidant capacity and cholinesterase (AChE) activity were assayed. This study showed that Khat consumption inhibited serum free radical scavenging enzymes, resulting in significant elevations in free radical loads (p=0.01; n=20). We also showed that serum acetyl cholinesterase (AChE) was significantly inhibited in the Khat chewing group (p=0.002; n=20). These results show for the first time that Khat may contribute to high levels of free radicals. In addition, the presence of pesticides in Khat leaves is implicated in the inhibition of AChE activity.

Distribution of methylone in four postmortem cases.

PubMed

Cawrse, Brian M; Levine, Barry; Jufer, Rebecca A; Fowler, David R; Vorce, Shawn P; Dickson, Amber J; Holler, Justin M

2012-07-01

Drugs derived from amphetamine, methamphetamine and their methylenedioxy- analogues, although being sold as plant food or bath salts, are being used as legal alternatives to scheduled amphetamine stimulants. These products often contain methylone, mephedrone and methylenedioxypyrovalerone (MDPV)--three amphetamine derivatives shown to have strong pharmacological effects. Four postmortem cases were analyzed for methylone, mephedrone and MDPV, with drug levels quantitated in multiple biological matrices. All four cases had detectable levels of methylone, with heart blood concentrations of 0.740, 0.118, 0.060 and 1.12 mg/L. Analysis of several tissue samples shows that methylone does not sequester in a particular tissue type after death. The average liver-to-blood ratio was 2.68. Two cases also had MDPV present, but insufficient data were collected to formulate a hypothesis on postmortem sequestration or redistribution. Two different extraction methods, as well as analysis of derivatized and underivatized methylone, show that the drug is suitable for analysis in either method. The cases are believed to show one instance of chronic methylone use, with a urine concentration of 38 mg/L.

Khat Use and Neurobehavioral Functions: Suggestions for Future Studies

PubMed Central

Hoffman, Richard; al’Absi, Mustafa

2010-01-01

Although there is a rich body of research available regarding the effect of acute and chronic khat dosing in animal models, research on the behavioral and cognitive effects of khat in human subjects is not extensive and several of the available studies have been done only in the context of observational and single-case studies. In light of the absence of a substantial literature on the neurobehavioral deficits associated with khat use and to provide a context that could be used to identify themes for future research we review previous research that has focused on other stimulant drugs. This review highlights multiple areas of neurocognitive deficit that have been identified in previous studies of individuals who have been chronic users of stimulants, such as amphetamines and methamphetamines. The review highlights a substantial body of evidence demonstrating a wide range of learning and memory impairments including deficits that persist during abstinence from active drug use. This review does not imply a similar khat effect, but due to some similarities pharmacologically between the active components of khat (cathinone and cathine) and amphetamines, future studies examining these same domains of cognitive functioning in chronic khat users and abstinent khat users appears to be warranted, if possible using some of the same or similar laboratory measures. PMID:20553832

Genetic Variation of the Ghrelin Signalling System in Individuals with Amphetamine Dependence

PubMed Central

Jayaram-Lindström, Nitya; Nilsson, Staffan; Toren, Kjell; Rosengren, Annika; Engel, Jörgen A.; Franck, Johan

2013-01-01

The development of amphetamine dependence largely depends on the effects of amphetamine in the brain reward systems. Ghrelin, an orexigenic peptide, activates the reward systems and is required for reward induced by alcohol, nicotine, cocaine and amphetamine in mice. Human genetic studies have shown that polymorphisms in the pre-proghrelin (GHRL) as well as GHS-R1A (GHSR) genes are associated with high alcohol consumption, increased weight and smoking in males. Since the heritability factor underlying drug dependence is shared between different drugs of abuse, we here examine the association between single nucleotide polymorphisms (SNPs) and haplotypes in the GHRL and GHSR, and amphetamine dependence. GHRL and GHSR SNPs were genotyped in Swedish amphetamine dependent individuals (n = 104) and controls from the general population (n = 310). A case-control analysis was performed and SNPs and haplotypes were additionally tested for association against Addiction Severity Interview (ASI) composite score of drug use. The minor G-allele of the GHSR SNP rs2948694, was more common among amphetamine dependent individuals when compared to controls (pc = 0.02). A significant association between the GHRL SNP rs4684677 and ASI composite score of drug use was also reported (pc = 0.03). The haplotype analysis did not add to the information given by the individual polymorphisms. Although genetic variability of the ghrelin signalling system is not a diagnostic marker for amphetamine dependence and problem severity of drug use, the present results strengthen the notion that ghrelin and its receptor may be involved in the development of addictive behaviours and may thus serve as suitable targets for new treatments of such disorders. PMID:23579732

Genetic variation of the ghrelin signalling system in individuals with amphetamine dependence.

PubMed

Suchankova, Petra; Jerlhag, Elisabet; Jayaram-Lindström, Nitya; Nilsson, Staffan; Toren, Kjell; Rosengren, Annika; Engel, Jörgen A; Franck, Johan

2013-01-01

The development of amphetamine dependence largely depends on the effects of amphetamine in the brain reward systems. Ghrelin, an orexigenic peptide, activates the reward systems and is required for reward induced by alcohol, nicotine, cocaine and amphetamine in mice. Human genetic studies have shown that polymorphisms in the pre-proghrelin (GHRL) as well as GHS-R1A (GHSR) genes are associated with high alcohol consumption, increased weight and smoking in males. Since the heritability factor underlying drug dependence is shared between different drugs of abuse, we here examine the association between single nucleotide polymorphisms (SNPs) and haplotypes in the GHRL and GHSR, and amphetamine dependence. GHRL and GHSR SNPs were genotyped in Swedish amphetamine dependent individuals (n = 104) and controls from the general population (n = 310). A case-control analysis was performed and SNPs and haplotypes were additionally tested for association against Addiction Severity Interview (ASI) composite score of drug use. The minor G-allele of the GHSR SNP rs2948694, was more common among amphetamine dependent individuals when compared to controls (pc  = 0.02). A significant association between the GHRL SNP rs4684677 and ASI composite score of drug use was also reported (pc  = 0.03). The haplotype analysis did not add to the information given by the individual polymorphisms. Although genetic variability of the ghrelin signalling system is not a diagnostic marker for amphetamine dependence and problem severity of drug use, the present results strengthen the notion that ghrelin and its receptor may be involved in the development of addictive behaviours and may thus serve as suitable targets for new treatments of such disorders.

Effects of adolescent exposure to methylmercury and d-amphetamine on reversal learning and an extradimensional shift in male mice

PubMed Central

Boomhower, Steven R.; Newland, M. Christopher

2016-01-01

Adolescence is associated with the continued maturation of dopamine neurotransmission and is implicated in the etiology of many psychiatric illnesses. Adolescent exposure to neurotoxicants that distort dopamine neurotransmission, such as methylmercury (MeHg), may modify the effects of chronic d-amphetamine (d-AMP) administration on reversal learning and attentional-set shifting. Male C57Bl/6n mice were randomly assigned to two MeHg-exposure groups (0 ppm and 3 ppm) and two d-AMP-exposure groups (saline and 1 mg/kg/day), producing four treatment groups (n = 10–12/group): Control, MeHg, d-AMP, and MeHg + d-AMP. MeHg exposure (via drinking water) spanned postnatal day 21–59 (the murine adolescent period), and once daily i.p. injections of d-AMP or saline spanned postnatal day 28–42. As adults, mice were trained on a spatial-discrimination-reversal (SDR) task in which the spatial location of a lever press predicted reinforcement. Following two SDRs, a visual-discrimination task (extradimensional shift) was instated in which the presence of a stimulus light above a lever predicted reinforcement. Responding was modeled using a logistic function, which estimated the rate (slope) of a behavioral transition and trials required to complete half a transition (half-max). MeHg, d-AMP, and MeHg + d-AMP exposure increased estimates of half-max on the second reversal. MeHg exposure increased half-max and decreased the slope term following the extradimensional shift, but these effects did not occur following MeHg + d-AMP exposure. MeHg + d-AMP exposure produced more perseverative errors and omissions following a reversal. Adolescent exposure to MeHg can modify the behavioral effects of chronic d-AMP administration. PMID:28287789

Effects of adolescent exposure to methylmercury and d-amphetamine on reversal learning and an extradimensional shift in male mice.

PubMed

Boomhower, Steven R; Newland, M Christopher

2017-04-01

Adolescence is associated with the continued maturation of dopamine neurotransmission and is implicated in the etiology of many psychiatric illnesses. Adolescent exposure to neurotoxicants that distort dopamine neurotransmission, such as methylmercury (MeHg), may modify the effects of chronic d -amphetamine ( d -AMP) administration on reversal learning and attentional-set shifting. Male C57Bl/6n mice were randomly assigned to two MeHg-exposure groups (0 ppm and 3 ppm) and two d -AMP-exposure groups (saline and 1 mg/kg/day), producing four treatment groups (n = 10-12/group): control, MeHg , d -AMP, and MeHg + d -AMP. MeHg exposure (via drinking water) spanned postnatal days 21-59 (the murine adolescent period), and once daily intraperitoneal injections of d -AMP or saline spanned postnatal days 28-42. As adults, mice were trained on a spatial-discrimination-reversal (SDR) task in which the spatial location of a lever press predicted reinforcement. Following 2 SDRs, a visual-discrimination task (extradimensional shift) was instated in which the presence of a stimulus light above a lever predicted reinforcement. Responding was modeled using a logistic function, which estimated the rate (slope) of a behavioral transition and trials required to complete half a transition (half-max). MeHg, d -AMP, and MeHg + d -AMP exposure increased estimates of half-max on the second reversal. MeHg exposure increased half-max and decreased the slope term following the extradimensional shift, but these effects did not occur following MeHg + d -AMP exposure. MeHg + d -AMP exposure produced more perseverative errors and omissions following a reversal. Adolescent exposure to MeHg can modify the behavioral effects of chronic d -AMP administration. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Effects of chronic prenatal MK-801 treatment on object recognition, cognitive flexibility, and drug-induced locomotor activity in juvenile and adult rat offspring.

PubMed

Gallant, S; Welch, L; Martone, P; Shalev, U

2017-06-15

Patients with schizophrenia display impaired cognitive functioning and increased sensitivity to psychomimetic drugs. The neurodevelopmental hypothesis of schizophrenia posits that disruption of the developing brain predisposes neural networks to lasting structural and functional abnormalities resulting in the emergence of such symptoms in adulthood. Given the critical role of the glutamatergic system in early brain development, we investigated whether chronic prenatal exposure to the glutamate NMDA receptor antagonist, MK-801, induces schizophrenia-like behavioural and neurochemical changes in juvenile and adult rats. Pregnant Long-Evans rats were administered saline or MK-801 (0.1mg/kg; s.c.) at gestation day 7-19. Object recognition memory and cognitive flexibility were assessed in the male offspring using a novel object preference task and a maze-based set-shifting procedure, respectively. Locomotor-activating effects of acute amphetamine and MK-801 were also assessed. Adult, but not juvenile, prenatally MK-801-treated rats failed to show novel object preference after a 90min delay, suggesting that object recognition memory may have been impaired. In addition, the set-shifting task revealed impaired acquisition of a new rule in adult prenatally MK-801-treated rats compared to controls. This deficit appeared to be driven by regression to the previously learned behaviour. There were no significant differences in drug-induced locomotor activity in juvenile offspring or in adult offspring following acute amphetamine challenges. Unexpectedly, MK-801-induced locomotor activity in adult prenatally MK-801-treated rats was lower compared to controls. Glutamate transmission dysfunction during early development may modify behavioural parameters in adulthood, though these parameters do not appear to model deficits observed in schizophrenia. Copyright © 2017 Elsevier B.V. All rights reserved.

Plasticity and Functions of the Orbital Frontal Cortex

ERIC Educational Resources Information Center

Kolb, Bryan; Pellis, Sergio; Robinson, Terry E.

2004-01-01

We compare the effects of psychoactive drugs such as morphine and amphetamine on the synaptic organization of neurons in the orbital frontal (OFC) and medial frontal (mPFC) regions in the rat. Both regions are altered chronically by exposure to intermittent doses of either drug but the effects are area-dependent. For example, whereas morphine…

The Impact of Illicit Use of Amphetamine on Male Sexual Functions.

PubMed

Chou, Nan-Hua; Huang, Yung-Jui; Jiann, Bang-Ping

2015-08-01

Data concerning the impact of amphetamine on male sexual functions are limited, although amphetamine has been used as an aphrodisiac. This cross-sectional study was to assess the impact of illicit use of amphetamine on male sexual functions. Male illicit drug users in a Drug Abstention and Treatment Center were recruited to complete a self-administered questionnaire, and data were compared with age-matched controls. The International Index of Erectile Function (IIEF) and global assessment questions were used to assess sexual functions. Of 1,159 amphetamine mono-illicit drug users, the mean age was 31.9 ± 7.5 (18-57) years, and mean duration of drug use was 30.7 ± 52.2 (median 9, range 0.1-252) months. Half of them reported that drug use had no impact on their sexual functions. The other half reported drug impacts as reduced erectile rigidity and sexual life satisfaction, enhanced orgasmic intensity, and prolonged ejaculation latency time more often than the opposite effects, while they reported enhanced or reduced effect equally on sexual desire. Dosing frequency of amphetamine was associated with its impact on sexual functions, but duration of its use had little association with that. Compared with 211 age-matched controls, the amphetamine mono-illicit drug users had lower IIEF scores in the domains of erectile function, orgasmic function, and overall satisfaction, but there are no significant differences in intercourse satisfaction and sexual desire scores. The prevalence of erectile dysfunction (ED) was significantly higher in the drug users than in the controls (29.3% vs. 11.9%). The odds ratio of ED for amphetamine use was 2.1 (95% confidence interval 1.2-3.6) after adjustment for other risk factors. The impact of illicit use of amphetamine on male sexual functions varied among users, and their ED prevalence was higher than the controls. © 2015 International Society for Sexual Medicine.

Cognitive Enhancers for Facilitating Drug Cue Extinction: Insights from Animal Models

PubMed Central

Nic Dhonnchadha, Bríd Áine; Kantak, Kathleen M.

2011-01-01

Given the success of cue exposure (extinction) therapy combined with a cognitive enhancer for reducing anxiety, it is anticipated that this approach will prove more efficacious than exposure therapy alone in preventing relapse in individuals with substance use disorders. Several factors may undermine the efficacy of exposure therapy for substance use disorders, but we suspect that neurocognitive impairments associated with chronic drug use are an important contributing factor. Numerous insights on these issues are gained from research using animal models of addiction. In this review, the relationship between brain sites whose learning, memory and executive functions are impaired by chronic drug use and brain sites that are important for effective drug cue extinction learning is explored first. This is followed by an overview of animal research showing improved treatment outcome for drug addiction (e.g. alcohol, amphetamine, cocaine, heroin) when explicit extinction training is conducted in combination with acute dosing of a cognitive-enhancing drug. The mechanism by which cognitive enhancers are thought to exert their benefits is by facilitating consolidation of drug cue extinction memory after activation of glutamatergic receptors. Based on the encouraging work in animals, factors that may be important for the treatment of drug addiction are considered. PMID:21295059

Interactions between estradiol and haloperidol on perseveration and reversal learning in amphetamine-sensitized female rats.

PubMed

Almey, Anne; Arena, Lauren; Oliel, Joshua; Shams, Waqqas M; Hafez, Nada; Mancinelli, Cynthia; Henning, Lukas; Tsanev, Aleks; Brake, Wayne G

2017-03-01

There are sex differences associated with schizophrenia, as women exhibit later onset of the disorder, less severe symptomatology, and better response to antipsychotic medications. Estrogens are thought to play a role in these sex differences; estrogens facilitate the effects of antipsychotic medications to reduce the positive symptoms of schizophrenia, but it remains unclear whether estrogens protect against the cognitive symptoms of this disorder. Amphetamine sensitization is used to model some symptoms of schizophrenia in rats, including cognitive deficits like excessive perseveration and slower reversal learning. In this experiment female rats were administered a sensitizing regimen of amphetamine to mimic these cognitive symptoms. They were ovariectomized and administered either low or high estradiol replacement as well as chronic administration of the antipsychotic haloperidol, and were assessed in tests of perseveration and reversal learning. Results of these experiments demonstrated that, in amphetamine-sensitized rats, estradiol alone does not affect perseveration or reversal learning. However, low estradiol facilitates a 0.25mg/day dose of haloperidol to reduce perseveration and improve reversal learning. Combined high estradiol and 0.25mg/day haloperidol has no effect on perseveration or reversal learning, but high estradiol facilitates the effects of 0.13mg/day haloperidol to reduce perseveration and improve reversal learning. Thus, in amphetamine-sensitized female rats, 0.25mg/day haloperidol only improved perseveration and reversal learning when estradiol was low, while 0.13mg/day haloperidol only improved these cognitive processes when estradiol was high. These findings suggest that estradiol facilitates the effects of haloperidol to improve perseveration and reversal learning in a dose-dependent manner. Copyright © 2017 Elsevier Inc. All rights reserved.

Modafinil evokes striatal [(3)H]dopamine release and alters the subjective properties of stimulants.

PubMed

Dopheide, Marsha M; Morgan, Russell E; Rodvelt, Kelli R; Schachtman, Todd R; Miller, Dennis K

2007-07-30

Modafinil is a mild psychostimulant used for the treatment of sleep and arousal-related disorders, and has been considered a pharmacotherapy for cocaine and amphetamine dependence; however, modafinil's mechanism of action is largely unclear. The present study investigated modafinil using drug discrimination and slice superfusion techniques. Rats were trained to discriminate cocaine (1.6 or 5 mg/kg) or amphetamine (0.3 mg/kg) from saline injection for food reinforcement. Modafinil (64-128 mg/kg) substituted partially for both cocaine doses and amphetamine. Pretreatment with a lower modafinil dose (32 mg/kg) augmented the discriminative stimulus properties of cocaine (1.6 mg/kg dose group) and amphetamine. In neurochemical experiments, modafinil (100-300 microM) evoked [(3)H]overflow from rat striatal slices preloaded with [(3)H]dopamine in a concentration-dependent manner; however, modafinil was less potent and efficacious than amphetamine and nicotine. The dopamine transporter inhibitor nomifensine (10 microM) blocked modafinil-evoked [(3)H]overflow, and concentrations of modafinil (<100 microM) that did not have intrinsic activity attenuated amphetamine (1 and 3 microM)-evoked [(3)H]overflow. Modafinil-evoked [(3)H]overflow was not altered by the nicotinic acetylcholine receptor antagonist mecamylamine, and modafinil did not alter nicotine-evoked [(3)H]overflow, indicating that nicotinic acetylcholine receptors likely are not important for modafinil's mechanism of action. The present results indicate that modafinil evokes dopamine release from striatal neurons and is a psychostimulant that is pharmacologically similar to, but much less potent and efficacious than, amphetamine.

Cannabidiol effects in the prepulse inhibition disruption induced by amphetamine.

PubMed

Pedrazzi, J F C; Issy, A C; Gomes, F V; Guimarães, F S; Del-Bel, E A

2015-08-01

The information processing appears to be deficient in schizophrenia. Prepulse inhibition (PPI), which measures the inhibition of a motor response by a weak sensory event, is considered particularly useful to understand the biology of information processing in schizophrenia patients. Drugs that facilitate dopaminergic neurotransmission such as amphetamine induce PPI disruption in human and rodents. Clinical and neurobiological findings suggest that the endocannabinoid system and cannabinoids may be implicated in the pathophysiology and treatment of schizophrenia. Cannabidiol (CBD), a non-psychotomimetic constituent of the Cannabis sativa plant, has also been reported to have potential as an antipsychotic. Our aim was to investigate if CBD pretreatment was able to prevent PPI disruption induced by amphetamine. Since one possible mechanism of CBD action is the facilitation of endocannabinoid-mediated neurotransmission through anandamide, we tested the effects of an anandamide hydrolysis inhibitor (URB597) in the amphetamine-induced PPI disruption. Male Swiss mice were treated with CBD systemic or intra-accumbens, or URB597 (systemic) prior to amphetamine and were exposed to PPI test. Amphetamine (10 mg/kg) disrupted PPI while CBD (15-60 mg/kg) or URB597 (0.1-1 mg/kg) administered alone had no effect. Pretreatment with CBD attenuated the amphetamine-disruptive effects on PPI test after systemic or intra-accumbens administration. Similar effects were also found with the inhibitor of anandamide hydrolysis. These results corroborate findings indicating that CBD induces antipsychotic-like effects. In addition, they pointed to the nucleus accumbens as a possible site of these effects. The increase of anandamide availability may be enrolled in the CBD effects.

Does zinc moderate essential fatty acid and amphetamine treatment of attention-deficit/hyperactivity disorder?

PubMed

Arnold, L E; Pinkham, S M; Votolato, N

2000-01-01

Zinc is an important co-factor for metabolism relevant to neurotransmitters, fatty acids, prostaglandins, and melatonin, and indirectly affects dopamine metabolism, believed intimately involved in attention-deficit/hyperactivity disorder (ADHD). To explore the relationship of zinc nutrition to essential fatty acid supplement and stimulant effects in treatment of ADHD, we re-analyzed data from an 18-subject double-blind, placebo-controlled crossover treatment comparison of d-amphetamine and Efamol (evening primrose oil, rich in gamma-linolenic acid). Subjects were categorized as zinc-adequate (n = 5), borderline zinc (n = 5), and zinc-deficient (n = 8) by hair, red cell, and urine zinc levels; for each category, placebo-active difference means were calculated on teachers' ratings. Placebo-controlled d-amphetamine response appeared linear with zinc nutrition, but the relationship of Efamol response to zinc appeared U-shaped; Efamol benefit was evident only with borderline zinc. Placebo-controlled effect size (Cohen's d) for both treatments ranged up to 1.5 for borderline zinc and dropped to 0.3-0.7 with mild zinc deficiency. If upheld by prospective research, this post-hoc exploration suggests that zinc nutrition may be important for treatment of ADHD even by pharmacotherapy, and if Efamol benefits ADHD, it likely does so by improving or compensating for borderline zinc nutrition.

Pharmacotherapy of amphetamine-type stimulant dependence: an update.

PubMed

Brensilver, Matthew; Heinzerling, Keith G; Shoptaw, Steven

2013-09-01

Methamphetamine- or amphetamine-type stimulants are the second most frequently used illicit drug worldwide, second only to cannabis. Behavioural treatments are efficacious, but their impact is limited underscoring the need for other treatment options, notably, pharmacotherapy. A review of randomised controlled trials of pharmacotherapies for methamphetamine- or amphetamine-type stimulants was performed using PubMed and Google Scholar databases. Evidence for efficacy of medications is reported. Clinical trials have yielded no broadly effective pharmacotherapy. Promising signals have been observed for methylphenidate, naltrexone, bupropion and mirtazapine in subgroups of patients in reducing stimulant use (e.g. patients with less severe dependence at baseline and men who have sex with men), though none has produced an unambiguous, replicable signal of efficacy. Problems in Phase II trials, including high dropout rates, missing data and a lack of agreement on outcomes, complicate efforts to find a broadly effective pharmacotherapy for amphetamine-type stimulant disorders. Efforts to address these problems include calls for better validation of pharmacological target exposure, receptor binding and functional modulation. As well, there is a need for agreement in using findings from preclinical and early phases of the medication development process for selecting better pharmacotherapy candidates. After over 20 years of efforts worldwide to develop a broadly effective medication for dependence on methamphetamine- or amphetamine-type stimulants, no candidate has emerged. This highlights the need for new compounds, consistent and stringent research methods, better integration between preclinical and clinical stages of medication development, and improved collaboration between government, industry and researchers. © 2013 Australasian Professional Society on Alcohol and other Drugs.

Effects of amphetamine and/or L-dopa and physiotherapy after stroke - a blinded randomized study.

PubMed

Sonde, L; Lökk, J

2007-01-01

Major therapeutic advances in the rehabilitation of subacute stroke are lacking. A promising approach is treatment with facilitating drugs like amphetamine or levodopa in combination with physiotherapy. In a randomized, double-blind, placebo-controlled clinical trail, the effect of 10 sessions with either 20 mg of D-amphetamine, 100 mg of L-dopa or 10 mg of D-amphetamine + 50 mg of L-dopa combined with physiotherapy during a 2-week period was investigated in 25 patients admitted to a stroke rehabilitation unit. Motor function (Fugl-Meyer score) and activities of daily living (Barthel's index) were assessed. All patients improved significantly over the intervention period. Drug-treated patients did not show any additional increase in motor function or ADL. It is feasible and safe to perform larger clinical trials with this type of four-arm design. However, the lack of significant effects could be because of type, dosage, and time of drugs as well as the physical intervention strategy.

Methamphetamine protects against MPTP neurotoxicity in C57BL mice.

PubMed

Sziráki, I; Kardos, V; Patthy, M; Pátfalusi, M; Budai, G

1994-01-14

Methamphetamine (5 mg/kg) administered 30 min prior to each injection with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (3 x 30 mg/kg, at 24 h intervals) prevents the reduction of striatal levels of dopamine and its metabolites in C57BL mice. Methamphetamine and amphetamine inhibit the uptake of 1-methyl-4-phenylpyridinium (MPP+) by striatal synaptosomes of rats. A 30-min post-treatment with methamphetamine or amphetamine also prevents the MPTP-induced dopamine depletion, suggesting that their protective effect is related to the blockade of MPP+ uptake into dopaminergic neurons. Since amphetamine and methamphetamine are themselves neurotoxins at higher doses, this work demonstrated the protection against the actions of one neurotoxin by the administration of another.

An insight into the hepatocellular death induced by amphetamines, individually and in combination: the involvement of necrosis and apoptosis.

PubMed

Dias da Silva, Diana; Carmo, Helena; Lynch, Adam; Silva, Elisabete

2013-12-01

The liver is a vulnerable target for amphetamine toxicity, but the mechanisms involved in the drug's hepatotoxicity remain poorly understood. The purpose of the current research was to characterize the mode of death elicited by four amphetamines and to evaluate whether their combination triggered similar mechanisms in immortalized human HepG2 cells. The obtained data revealed a time- and temperature-dependent mortality of HepG2 cells exposed to 3,4-methylenedioxymethamphetamine (MDMA, ecstasy; 1.3 mM), methamphetamine (3 mM), 4-methylthioamphetamine (0.5 mM) and D-amphetamine (1.7 mM), alone or combined (1.6 mM mixture). At physiological temperature (37 °C), 24-h exposures caused HepG2 death preferentially by apoptosis, while a rise to 40.5 °C favoured necrosis. ATP levels remained unaltered when the drugs where tested at normothermia, but incubation at 40.5 °C provoked marked ATP depletion for all treatments. Further investigations on the apoptotic mechanisms triggered by the drugs (alone or combined) showed a decline in BCL-2 and BCL- XL mRNA levels, with concurrent upregulation of BAX, BIM, PUMA and BID genes. Elevation of Bax, cleaved Bid, Puma, Bak and Bim protein levels was also seen. To the best of our knowledge, Puma, Bim and Bak have never been linked with the toxicity induced by amphetamines. Time-dependent caspase-3/-7 activation, but not mitochondrial membrane potential (∆ψm) disruption, also mediated amphetamine-induced apoptosis. The cell dismantling was confirmed by poly(ADP-ribose)polymerase proteolysis. Overall, for all evaluated parameters, no relevant differences were detected between individual amphetamines and the mixture (all tested at equieffective cytotoxic concentrations), suggesting that the mode of action of the amphetamines in combination does not deviate from the mode of action of the drugs individually, when eliciting HepG2 cell death.

Protective effects of amphetamine on gastric ulcerations induced by indomethacin in rats

PubMed Central

Sandor, Vlaicu; Cuparencu, Barbu; Dumitrascu, Dan L; Birt, Mircea A; Krausz, Tibor L

2006-01-01

AIM: To study the effects of amphetamine, an indirect-acting adrenomimetic compound on the indomethacin-induced gastric ulcerations in rats. METHODS: Male Wistar-Bratislava rats were randomly divided into four groups: Group 1 (control), received an ulcerogenic dose of indomethacin (50 μmol/kg) and Groups 2, 3 and 4, treated with amphetamine (10, 25 and 50 μmol/kg). The drug was administered simultaneously with indomethacin and once again 4 h later. The animals were sacrificed 8 h after indomethacin treatment. The stomachs were opened and the incidence, the number of lesions and their severity were evaluated. The results were expressed as percentage and as mean ± standard error (mean ± SE). RESULTS: The incidence of ulceration in the control group was 100%. Amphetamine, at doses of 10, 25 and 50 μmol/kg, lowered the incidence to 88.89%, 77.78% and 37.5% respectively. The protection ratio was positive: 24.14%, 55.17% and 80.6% respectively. The total number of ulcerations/rat was 12.44 ± 3.69 in the control group. It decreased to 7.33 ± 1.89, 5.33 ± 2.38 and 2.25 ± 1.97 under the effects of the above-mentioned doses of amphetamine. CONCLUSION: Amphetamine affords a significant dose-dependent protection against the indomethacin-induced gastric ulcerations in rats. It is suggested that the adrenergic system is involved in the gastric mucosa protection. PMID:17131481

Disruptive Effect of Amphetamines on Pavlovian to Instrumental Transfer

PubMed Central

Hall, Darien A.; Gulley, Joshua M.

2010-01-01

Reward seeking behavior can be powerfully modulated by exposure to a conditioned stimulus (CS) that was previously associated with that reward. This can be demonstrated in a Pavlovian-to-instrumental transfer (PIT) task where presentation of a CS (e.g., tone and light) previously paired with a rewarding unconditioned stimulus (US; e.g., food) leads to increases in a behavioral response, such as a lever press, that was also paired with the same US. The transfer effect can be enhanced in rats by exposing them repeatedly to amphetamine after they have undergone Pavlovian conditioning and instrumental training. However, it is not clear if amphetamine injections given immediately after Pavlovian conditioning, which are predicted to enhance memory consolidation for the CS-US association, would also enhance the transfer effect. We tested this hypothesis by giving male, Sprague-Dawley rats i.p. injections of saline or drug (0.5, 1.0, or 3.0 mg/kg amphetamine or methamphetamine) immediately following Pavlovian conditioning sessions. We found that amphetamine, but not methamphetamine, enhanced Pavlovian approach behavior. During a subsequent PIT test done under extinction conditions, we found that rats given either drug, particularly at the highest dose, exhibited deficits in PIT relative to saline-treated controls. These results suggest that treatment with amphetamines after Pavlovian conditioning sessions, when memory consolidation of the CS-US association is hypothesized to occur, inhibits the ability of the CS to subsequently elicit reward-seeking behavior. PMID:20817041

Sensitization to caffeine and cross-sensitization to amphetamine: influence of individual response to caffeine.

PubMed

Simola, Nicola; Cauli, Omar; Morelli, Micaela

2006-09-15

The present study evaluated the ability of a subchronic intermittent administration of caffeine to induce a sensitized motor response and correlated the individual susceptibility of rats to acute caffeine to the development of sensitization. Moreover, individual susceptibility to caffeine and development of motor behaviour sensitization were correlated to the behavioural response obtained after a challenge with amphetamine. To this end, rats were subdivided in "low" and "high" responders according to their individual susceptibility to acute caffeine established on the basis of the motor activity observed after the first caffeine administration. "Low" and "high" responder rats were then repeatedly and intermittently treated with caffeine (15 mg/kg, i.p.), or vehicle, every other day for fourteen days. Three days after treatment discontinuation, behavioural activation induced by acute amphetamine (0.5 mg/kg, s.c.) was measured in vehicle- and caffeine-pretreated rats. Subchronic caffeine resulted in motor sensitization of a variable degree among rats and no difference were observed between "low" and "high" responders. Moreover, caffeine pretreatment potentiated the behavioural effects of amphetamine according to the degree of caffeine sensitization but not to individual susceptibility to acute caffeine. These results demonstrate that individual susceptibility to acute caffeine does not influence the modifications in caffeine motor effects produced by its subchronic administration and does not affect the enhancement of acute behavioural effects of amphetamine in caffeine-pretreated rats, rather sensitization to subchronic caffeine administration critically influences the behavioural effects of amphetamine.

An animal model of schizophrenia based on chronic LSD administration: old idea, new results.

PubMed

Marona-Lewicka, Danuta; Nichols, Charles D; Nichols, David E

2011-09-01

Many people who take LSD experience a second temporal phase of LSD intoxication that is qualitatively different, and was described by Daniel Freedman as "clearly a paranoid state." We have previously shown that the discriminative stimulus effects of LSD in rats also occur in two temporal phases, with initial effects mediated by activation of 5-HT(2A) receptors (LSD30), and the later temporal phase mediated by dopamine D2-like receptors (LSD90). Surprisingly, we have now found that non-competitive NMDA antagonists produced full substitution in LSD90 rats, but only in older animals, whereas in LSD30, or in younger animals, these drugs did not mimic LSD. Chronic administration of low doses of LSD (>3 months, 0.16 mg/kg every other day) induces a behavioral state characterized by hyperactivity and hyperirritability, increased locomotor activity, anhedonia, and impairment in social interaction that persists at the same magnitude for at least three months after cessation of LSD treatment. These behaviors, which closely resemble those associated with psychosis in humans, are not induced by withdrawal from LSD; rather, they are the result of neuroadaptive changes occurring in the brain during the chronic administration of LSD. These persistent behaviors are transiently reversed by haloperidol and olanzapine, but are insensitive to MDL-100907. Gene expression analysis data show that chronic LSD treatment produced significant changes in multiple neurotransmitter system-related genes, including those for serotonin and dopamine. Thus, we propose that chronic treatment of rats with low doses of LSD can serve as a new animal model of psychosis that may mimic the development and progression of schizophrenia, as well as model the established disease better than current acute drug administration models utilizing amphetamine or NMDA antagonists such as PCP. Copyright © 2011 Elsevier Ltd. All rights reserved.

Dopamine release in chronic cannabis users: a [11C]raclopride Positron Emission Tomography study

PubMed Central

Urban, Nina B.L.; Slifstein, Mark; Thompson, Judy L.; Xu, Xiaoyan; Girgis, Ragy R.; Raheja, Sonia; Haney, Margaret; Abi-Dargham, Anissa

2012-01-01

Introduction Low striatal dopamine 2/3 receptor (D2/3) availability and low ventrostriatal (VST) dopamine (DA) release have been observed in alcoholism, cocaine and heroin dependence. Less is known about the dopaminergic system in cannabis dependence. We assessed D2/3 availability and DA release in abstinent cannabis users compared to controls and explored relationships to parameters of cannabis use history, using [11C]raclopride Positron Emission Tomography (PET) and an amphetamine challenge paradigm. Methods 16 recently abstinent, medically and psychiatrically healthy cannabis-using participants (CD, 27.3 ± 6.1 years, 1 female, 15 males) and 16 matched controls (HC, 28.1 ± 6.7 years, 2 females, 14 males) completed two PET scans, before and after injection of i.v. d-amphetamine (0.3 mg/kg). Percent change in [11C]raclopride binding after amphetamine (ΔBPND) in subregions of the striatum was compared between groups. Correlations with clinical parameters were examined. Results Cannabis dependent participants had an average consumption of 517± 465 estimated puffs per month, indicating overall mild to moderate cannabis dependence. Neither baseline BPND nor ΔBPND differed from controls in any ROI, including VST. In CD, earlier age of onset of use correlated with lower [ΔBPND] in the associative striatum (AST) when controlling for current age. Conclusions Unlike other addictions, cannabis dependence of mild to moderate severity is not associated with striatal DA alterations. However, earlier use, or longer duration of use, is related to lower DA release in the AST. These observations suggest a more harmful effect of use during adolescence; more research is needed to distinguish effects of chronicity versus onset. PMID:22290115

Dopamine release in chronic cannabis users: a [11c]raclopride positron emission tomography study.

PubMed

Urban, Nina B L; Slifstein, Mark; Thompson, Judy L; Xu, Xiaoyan; Girgis, Ragy R; Raheja, Sonia; Haney, Margaret; Abi-Dargham, Anissa

2012-04-15

Low striatal dopamine 2/3 receptor (D(2/3)) availability and low ventrostriatal dopamine (DA) release have been observed in alcoholism and cocaine and heroin dependence. Less is known about the dopaminergic system in cannabis dependence. We assessed D(2/3) availability and DA release in abstinent cannabis users compared with control subjects and explored relationships to cannabis use history using [(11)C]raclopride positron emission tomography and an amphetamine challenge paradigm. Sixteen recently abstinent, psychiatrically healthy cannabis-using participants (27.3 ± 6.1 years, 1 woman, 15 men) and 16 matched control subjects (28.1 ± 6.7 years, 2 women, 14 men) completed two positron emission tomography scans, before and after injection of intravenous d-amphetamine (.3 mg/kg). Percent change in [(11)C]raclopride binding after amphetamine (change in nondisplaceable binding potential, ΔBP(ND)) in subregions of the striatum was compared between groups. Correlations with clinical parameters were examined. Cannabis users had an average consumption of 517 ± 465 estimated puffs per month, indicating mild to moderate cannabis dependence. Neither baseline BP(ND) nor ΔBP(ND) differed from control subjects in any region of interest, including ventral striatum. In cannabis-dependent subjects, earlier age of onset of use correlated with lower [ΔBP(ND)] in the associative striatum when controlling for current age. Unlike other addictions, cannabis dependence of mild to moderate severity is not associated with striatal DA alterations. However, earlier or longer duration of use is related to lower DA release in the associative striatum. These observations suggest a more harmful effect of use during adolescence; more research is needed to distinguish effects of chronicity versus onset. Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

[Psychophysiological regin for rehabilition of chronic polydrug users in the Center of the Le Patriarche. 446 cases (author's transl)].

PubMed

Laffont, F; Engelmajer, L; Vourc'h, G; Nahas, G

1980-01-01

From 1974 to 1979, the rehabilitation centers of the association "Le Patriarche" located in the country side of southern France, have received 446 chronic polydrugs users who has consumed at one time or an other cannabis (marihuana, hashish) (87 p. cent), LSD (66 p. cent) and other hallucinogens (35 p. cent), psychodepressants (55 p. cent), psychostimulants (amphetamines, 85 p. cent; cocaïne, 50 p. cent) and opium and its derivatives (brown sugar, 47 p. cent; opiates, 67 p. cent; heroin, 50 p. cent). The dominant addictive drug was heroin and opiates, 52 p. cent, psychodepressants (barbitutiques and benzodiazepines, 33 p. cent, psychostimulants, 15 p. cent. Males were twice as numerous as female. Average age was 21 (range 14-38). Mean duration of drug abuse was 7 years. All these drug abusers display at entrance withdrawal symptoms. These were treated successfully by a drug free, psycho-physiological regimen comprising: 1. An elimination of all psychoactive drugs, including coffee, and alcohol. Tobacco was permitted. 2. Physical therapy (bath, exercise, massage) and forced fluid diuresis. 3. A supportive psychotherapy dispensed by rehabilitated addicts who had undergone successfully a similar regimen. This non-pharmacological method of treating withdrawal symptoms associated with opium, barbiturate and amphetamine addiction, was successful, and was not associated with any major clinical symptoms threatening the vital signs. Mean duration of detoxification was 5 days for opiates, 6 days for amphetamines and 10 days for barbiturates. 78 p. cent of these subjects remained in the centers from 3 months to 2 years, partaking in physical occupational and physiological rehabilitation paograms which allowed then to adopt a drug free life style and prepared them for social reinsertion.

Does random urine drug testing reduce illicit drug use in chronic pain patients receiving opioids?

PubMed

Manchikanti, Laxmaiah; Manchukonda, Rajeev; Pampati, Vidyasagar; Damron, Kim S; Brandon, Doris E; Cash, Kim A; McManus, Carla D

2006-04-01

Prescription drug abuse and illicit drug use are common in chronic pain patients. Adherence monitoring with screening tests, and urine drug testing, periodic monitoring with prescription monitoring programs, has become a common practice in recent years. Random drug testing for appropriate use of opioids and use of illicit drugs is often used in pain management practices. Thus, it is expected that random urine drug testing will deter use of illicit drugs, and also improve compliance. To study the prevalence of illicit drug use in patients receiving opioids for chronic pain management and to compare the results of illicit drug use with the results from a previous study. A prospective, consecutive study. Interventional pain management practice setting in the United States. A total of 500 consecutive patients on opioids, considered to be receiving stable doses of opioids supplemental to their interventional techniques, were studied by random drug testing. Testing was performed by rapid drug screen. Results were considered positive if one or more of the monitored illicit drugs including cocaine, marijuana (THC), methamphetamine or amphetamines were present. Illicit drug use was evident in 80 patients, or 16%, with marijuana in 11%, cocaine in 5%, and methamphetamine and/or amphetamines in 2%. When compared with previous data, the overall illicit drug use was significantly less. Illicit drug use in elderly patients was absent. The prevalence of illicit drug abuse in patients with chronic pain receiving opioids continues to be a common occurence. This study showed significant reductions in overall illicit drug use with adherence monitoring combined with random urine drug testing.

The Combination of Scopolamine and Psychostimulants for the Prevention of Severe Motion Sickness.

PubMed

Zhang, Li-Li; Liu, Hong-Qi; Yu, Xu-Hong; Zhang, Ying; Tian, Jia-Sheng; Song, Xu-Rui; Han, Bing; Liu, Ai-Jun

2016-08-01

Severe motion sickness is a huge obstacle for people conducting precise aviation, marine or emergency service tasks. The combination of scopolamine and d-amphetamine is most effective in preventing severe motion sickness. However, this combination is not included in any present pharmacopoeia due to the abuse liability of d-amphetamine. We wanted to find a combination to replace it for the treatment of severe motion sickness. We compared the efficacy of scopolamine, diphenhydramine, and granisetron (representing three classes of drugs) with different doses, and found that scopolamine was the most effective one. We also found scopolamine inhibited central nervous system at therapeutic doses and caused anxiety. Then, we combined it with different doses of psychostimulants (d-amphetamine, modafinil, caffeine) to find the best combination for motion sickness. The efficacy of scopolamine with modafinil (1 + 10 mg/kg) was equivalent to that of scopolamine with d-amphetamine (1 + 1 mg/kg); This combination also excited central nervous system and abolished the anxiety caused by scopolamine. The optimal dose ratio of scopolamine and modafinil is 1:10. This combination is beneficial for motion sickness and can abolish the side effects of scopolamine. So, it might be a good replacement of scopolamine and d-amphetamine for severe motion sickness. © 2016 John Wiley & Sons Ltd.

Mortality among individuals with cannabis, cocaine, amphetamine, MDMA, and opioid use disorders: a nationwide follow-up study of Danish substance users in treatment.

PubMed

Arendt, Mikkel; Munk-Jørgensen, Povl; Sher, Leo; Jensen, Signe O W

2011-04-01

This is a register-based cohort study of 20,581 individuals in treatment for illicit substance use disorders in Denmark between 1996 and 2006. All in all, 1441 deaths were recorded during 111,445 person-years of follow-up. Standardized mortality ratios (SMRs) associated with different primary substance types were calculated and Cox-regression analyses were performed in order to establish hazard ratios (HR) associated with injection drug use and psychiatric comorbidity. SMRs for primary users of specific substances were: cannabis: 4.9 (95% confidence interval (CI): 4.2-5.8), cocaine: 6.4 (CI: 3.9-10.0), amphetamine: 6.0 (CI: 4.2-8.3), heroin: 9.1 (CI: 8.5-9.8), and other opioids 7.7 (CI: 6.6-8.9). For MDMA ('ecstasy') the crude mortality rate was 1.7/1000 person-years (CI: 0.4-7.0) and the SMR was not significantly elevated. Injection drug use was associated with significantly increased hazard ratios in users of opioids and cocaine/amphetamine. Overall, psychiatric comorbidity was not associated with increased mortality (HR: 1.1 [CI: 0.9-1.2], p=.28), but an association was found specifically among cocaine/amphetamine users (HR: 3.6 [CI: 2.1-6.4], p<.001). Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Effects of serotonin (5-HT)1B receptor ligands on amphetamine-seeking behavior in rats.

PubMed

Miszkiel, Joanna; Przegaliński, Edmund

2013-01-01

Numerous studies have indicated that serotonin (5-HT)1B receptor ligands affect the behavioral effects of psychostimulants (cocaine, amphetamine), including the reinforcing activities of these drugs. To substantiate a role for those receptors in incentive motivation for amphetamine, we used the extinction/reinstatement model to examine the effects of the 5-HT1B receptor ligands on the reinstatement of extinguished amphetamine-seeking behavior. Rats trained to self-administer amphetamine (0.06 mg/kg/infusion) subsequently underwent the extinction procedure. These rats were then tested for the amphetamine-primed or amphetamine-associated cue-induced reinstatement of extinguished amphetamine-seeking behavior. The 5-HT1B receptor antagonist SB 216641 (5-7.5 mg/kg) attenuated the amphetamine (1.5 mg/kg)- and the amphetamine-associated cue combined with the threshold dose of amphetamine (0.5 mg/kg)-induced reinstatement of amphetamine-seeking behavior. The 5-HT1B receptor agonist CP 94253 (1.25-5 mg/kg) also inhibited the amphetamine-seeking behavior induced by amphetamine (1.5 mg/kg) but not by the cue combined with the threshold dose of amphetamine. The inhibitory effect of CP94253 on amphetamine-seeking behavior remained unaffected by the 5-HT1B receptor antagonist. Our results indicate that tonic activation of 5-HT1B receptors is involved in amphetamine- and cue-induced reinstatement of amphetamine-seeking behavior and that the inhibitory effects of 5-HT1B receptor antagonists on these phenomena are directly related to the motivational aspects of amphetamine abuse. The inhibitory effect of CP 94253 on amphetamine-seeking behavior seems to be unrelated to 5-HT1B receptor activation and may result from a general reduction of motivation.

Cognitive enhancers for facilitating drug cue extinction: insights from animal models.

PubMed

Nic Dhonnchadha, Bríd Áine; Kantak, Kathleen M

2011-08-01

Given the success of cue exposure (extinction) therapy combined with a cognitive enhancer for reducing anxiety, it is anticipated that this approach will prove more efficacious than exposure therapy alone in preventing relapse in individuals with substance use disorders. Several factors may undermine the efficacy of exposure therapy for substance use disorders, but we suspect that neurocognitive impairments associated with chronic drug use are an important contributing factor. Numerous insights on these issues are gained from research using animal models of addiction. In this review, the relationship between brain sites whose learning, memory and executive functions are impaired by chronic drug use and brain sites that are important for effective drug cue extinction learning is explored first. This is followed by an overview of animal research showing improved treatment outcome for drug addiction (e.g. alcohol, amphetamine, cocaine, heroin) when explicit extinction training is conducted in combination with acute dosing of a cognitive-enhancing drug. The mechanism by which cognitive enhancers are thought to exert their benefits is by facilitating consolidation of drug cue extinction memory after activation of glutamatergic receptors. Based on the encouraging work in animals, factors that may be important for the treatment of drug addiction are considered. Copyright © 2011. Published by Elsevier Inc.

New chlorinated amphetamine-type-stimulants disinfection-by-products formed during drinking water treatment.

PubMed

Huerta-Fontela, Maria; Pineda, Oriol; Ventura, Francesc; Galceran, Maria Teresa

2012-06-15

Previous studies have demonstrated high removal rates of amphetamine-type-stimulants (ATSs) through conventional drinking water treatments; however the behaviour of these compounds through disinfection steps and their transformation into disinfection-by-products (DBPs) is still unknown. In this work, for the first time, the reactivity of some ATSs such as amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyethylamphetamine (MDEA) with chlorine has been investigated under simulated and real drinking water treatment conditions in order to evaluate their ability to give rise to transformation products. Two new DBPs from these illicit drugs have been found. A common chlorinated-by-product (3-chlorobenzo)-1,3-dioxole, was identified for both MDA and MDEA while for MDMA, 3-chlorocatechol was found. The presence of these DBPs in water samples collected through drinking water treatment was studied in order to evaluate their formation under real conditions. Both compounds were generated through treatment from raw river water samples containing ATSs at concentration levels ranging from 1 to 15 ng/L for MDA and from 2.3 to 78 ng/L for MDMA. One of them, (3-chlorobenzo)-1,3-dioxole, found after the first chlorination step, was eliminated after ozone and GAC treatment while the MDMA DBP mainly generated after the postchlorination step, showed to be recalcitrant and it was found in final treated waters at concentrations ranging from 0.5 to 5.8 ng/L. Copyright © 2012 Elsevier Ltd. All rights reserved.

Substance use - amphetamines

MedlinePlus

Substance abuse - amphetamines; Drug abuse - amphetamines; Drug use - amphetamines ... Amphetamine: goey, louee, speed, uppers, whiz Dextroamphetamine (ADHD medicine used illegally): dexies, kiddie-speed, pep pills, uppers; ...

Methamphetamine, d-amphetamine and p-chloroamphetamine induced neurotoxicity differentially effect impulsive responding on the stop-signal task in rats

PubMed Central

Furlong, Teri M.; Leavitt, Lee S.; Keefe, Kristen A.; Son, Jong-Hyun

2016-01-01

Abused amphetamines, such as d-amphetamine (AMPH) and methamphetamine (METH), are highly addictive and destructive to health and productive lifestyles. The abuse of these drugs is associated with impulsive behavior, which is likely to contribute to addiction. The amphetamines also differentially damage dopamine (DA) and serotonin (5-HT) systems, which regulate impulsive behavior; therefore, exposure to these drugs may differentially alter impulsive behavior to effect the progression of addiction. We examined the impact of neurotoxicity induced by three amphetamines on impulsive action using a stop-signal task in rats. Animals were rewarded with a food pellet after lever pressing (i.e. a go trial), unless an auditory cue was presented and withholding lever press gained reward (i.e. a stop trial). Animals were trained on the task and then exposed to a neurotoxic regimen of either AMPH, p-chloroamphetamine (PCA), or METH. These regimens preferentially reduced DA transporter levels in striatum, 5-HT transporter levels in prefrontal cortex, or both, respectively. Assessment of performance on the stop-signal task beginning one week after the treatment revealed that AMPH produced a deficit in go-trial performance, whereas PCA did not alter performance on either trial type. In contrast, METH produced a deficit in stop-trial performance (i.e. impulsive action) but not go-trial performance. These findings suggest that the different neurotoxic consequences of substituted amphetamines are associated with different effects on inhibitory control over behavior. Thus, the course of addiction and maladaptive behavior resulting from exposure to these substances is likely to differ. PMID:26846719

Reduced efficacy of fluoxetine following MDMA ("Ecstasy")-induced serotonin loss in rats.

PubMed

Durkin, Sarah; Prendergast, Alison; Harkin, Andrew

2008-12-12

Long-term serotonin (5-HT) neuronal loss is currently a major cause of concern associated with recreational use of the substituted amphetamine 3,4 methylenedioxymethamphetamine (MDMA; "Ecstasy"). Such loss may be problematic considering that psychiatric disorders such as depression and anxiety and responses to first line treatments for these disorders are associated with 5-HT. In this study the effects of prior exposure to MDMA on behavioural and central neurochemical changes induced by the serotonin (5-HT) re-uptake inhibitor and antidepressant fluoxetine were examined in rats. Animals were administered MDMA (10 mg/kg. i.p.) four times daily for two consecutive days. One week later the animals were subjected to treatment with fluoxetine (10 mg/kg, i.p.). Fluoxetine treatment groups received either acute (saline injections for 20 days followed by 3 fluoxetine treatments over 24 h) or chronic (once daily fluoxetine for 21 days) drug administration. Prior exposure to MDMA resulted in an attenuation of fluoxetine-induced swimming behaviour in the modified forced swimming test (FST); a behavioural test of antidepressant action. In parallel MDMA treatment resulted in significant regional depletions of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) accompanied by a reduction in cortical [3H] paroxetine binding to nerve terminal 5-HT transporters. MDMA-induced 5-HT loss was enhanced in animals following chronic fluoxetine administration. Elimination of fluoxetine and its metabolite norfluoxetine from the brain abolished this interaction between MDMA and fluoxetine treatment. Fluoxetine administration reduced both 5-HIAA and the 5-HIAA:5-HT metabolism ratio, which was attenuated in animals pre-treated with MDMA. Overall the results show that MDMA induces long-term 5-HT loss in the rodent brain and consequently diminishes behaviour and reductions in 5-HT metabolism induced by the antidepressant fluoxetine. These results have potential clinical relevance, suggesting that 5-HT re-uptake inhibitors such as fluoxetine may be less effective at treating depression in chronic abusers of MDMA.

Effects of Phendimetrazine Treatment on Cocaine vs Food Choice and Extended-Access Cocaine Consumption in Rhesus Monkeys

PubMed Central

Banks, Matthew L; Blough, Bruce E; Fennell, Timothy R; Snyder, Rodney W; Negus, S Stevens

2013-01-01

There is currently no Food and Drug Administration-approved pharmacotherapy for cocaine addiction. Monoamine releasers such as d-amphetamine constitute one class of candidate medications, but clinical use and acceptance are hindered by their own high-abuse liability. Phendimetrazine (PDM) is a schedule III anorectic agent that functions as both a low-potency monoamine-uptake inhibitor and as a prodrug for the monoamine-releaser phenmetrazine (PM), and it may serve as a clinically available, effective, and safer alternative to d-amphetamine. This study determined efficacy of chronic PDM to reduce cocaine self-administration by rhesus monkeys (N=4) using a novel procedure that featured both daily assessments of cocaine vs food choice (to assess medication efficacy to reallocate behavior away from cocaine choice and toward choice of an alternative reinforcer) and 20 h/day cocaine access (to allow high-cocaine intake). Continuous 21-day treatment with ramping PDM doses (days 1–7: 0.32 mg/kg/h; days 8–21: 1.0 mg/kg/h) reduced cocaine choices, increased food choices, and nearly eliminated extended-access cocaine self-administration without affecting body weight. There was a trend for plasma PDM and PM levels to correlate with efficacy to decrease cocaine choice such that the monkey with the highest plasma PDM and PM levels also demonstrated the greatest reductions in cocaine choice. These results support further consideration of PDM as a candidate anti-cocaine addiction pharmacotherapy. Moreover, PDM may represent a novel pharmacotherapeutic approach for cocaine addiction because it may simultaneously function as both a monoamine-uptake inhibitor (via the parent drug PDM) and as a monoamine releaser (via the active metabolite PM). PMID:23893022

Effects of phendimetrazine treatment on cocaine vs food choice and extended-access cocaine consumption in rhesus monkeys.

PubMed

Banks, Matthew L; Blough, Bruce E; Fennell, Timothy R; Snyder, Rodney W; Negus, S Stevens

2013-12-01

There is currently no Food and Drug Administration-approved pharmacotherapy for cocaine addiction. Monoamine releasers such as d-amphetamine constitute one class of candidate medications, but clinical use and acceptance are hindered by their own high-abuse liability. Phendimetrazine (PDM) is a schedule III anorectic agent that functions as both a low-potency monoamine-uptake inhibitor and as a prodrug for the monoamine-releaser phenmetrazine (PM), and it may serve as a clinically available, effective, and safer alternative to d-amphetamine. This study determined efficacy of chronic PDM to reduce cocaine self-administration by rhesus monkeys (N=4) using a novel procedure that featured both daily assessments of cocaine vs food choice (to assess medication efficacy to reallocate behavior away from cocaine choice and toward choice of an alternative reinforcer) and 20 h/day cocaine access (to allow high-cocaine intake). Continuous 21-day treatment with ramping PDM doses (days 1-7: 0.32 mg/kg/h; days 8-21: 1.0 mg/kg/h) reduced cocaine choices, increased food choices, and nearly eliminated extended-access cocaine self-administration without affecting body weight. There was a trend for plasma PDM and PM levels to correlate with efficacy to decrease cocaine choice such that the monkey with the highest plasma PDM and PM levels also demonstrated the greatest reductions in cocaine choice. These results support further consideration of PDM as a candidate anti-cocaine addiction pharmacotherapy. Moreover, PDM may represent a novel pharmacotherapeutic approach for cocaine addiction because it may simultaneously function as both a monoamine-uptake inhibitor (via the parent drug PDM) and as a monoamine releaser (via the active metabolite PM).

[Parkinson's disease of Adolf Hitler and its influence in the development of World War Second].

PubMed

Guerrero, A L

2003-03-01

Adolf Hitler very probably suffered from Parkinson's disease. The first symptoms of it began to appear in 1937/1938. It is likely that its appearance, and the fear that it caused regarding his survival, lead Hitler to advance his initial projects of military expansion of the great Germany beginning in 1943. Thus, the Second World War broke out in 1939, perhaps quite before the time in which Germany would be prepared. Chronic treatment carried out with opiates, cocaine, amphetamines, and strychnine may very well be related with a very abnormal judgement of the problems and absence of trust in the advice of his team. With this, he would make military decisions that would end up being ill-fated for his interests and which, after 1942, would lead to a change in the course of the war.

Relationships between sleep and addiction: the role of drug-environment conditioning.

PubMed

Berro, Laís F; Frussa-Filho, Roberto; Tufik, Sergio; Andersen, Monica L

2014-03-01

Addiction to cocaine and other amphetamine-like psychostimulants is a chronic relapsing disorder characterized by loss of control over drug taking. Sleep disturbance is common among patients in recovery from drug abuse and can precipitate relapse. It has been widely demonstrated that sleep deprivation and psychostimulants share similar neurobiological effects regarding the dopaminergic system. In addition, the persistence of a drug-environment conditioning induced by repeated psychostimulant treatment, which is deeply related to the dopaminergic neurotransmission, is thought to play a key role in the addictive cycle. In this scenario, we hypothesized that sleep deprivation is a potential detrimental factor to the extinction process of previously established drug-environment conditioning. Therefore, sleep deprivation would extend the pairing between the cocaine reinforcing effects and the environmental cues, thereby leading drug abusers to relapse. Copyright © 2014 Elsevier Ltd. All rights reserved.

3,4-Methylenedioxy analogues of amphetamine: defining the risks to humans.

PubMed

Hegadoren, K M; Baker, G B; Bourin, M

1999-03-01

The 3,4-methylenedioxy analogues of amphetamine [MDMA ("Ecstasy", "Adam"), MDA ("Love") and MDE ("Eve")] are recreational drugs that produce feelings of euphoria and energy and a desire to socialize, which go far to explain their current popularity as "rave drugs". In addition to these positive effects, the drugs are relatively inexpensive to purchase and have the reputation of being safe compared to other recreational drugs. Yet there is mounting evidence that these drugs do not deserve this reputation of being safe. This review examines the relevant human and animal literature to delineate the possible risks MDMA, MDA and MDE engender with oral consumption in humans. Following a summary of the behavioral and cognitive effects of MDMA, MDA and MDE, risks will be discussed in terms of toxicity, psychopathology, neurotoxicity, abuse potential and the potential for drug-drug interactions associated with acute and chronic use.

'Fingerprints' of central stimulatory drug effects by means of quantitative radioelectroencephalography in the rat (tele-stereo-EEG).

PubMed

Dimpfel, W; Spüler, M; Nickel, B; Tibes, U

1986-01-01

The new electrophysiological model earlier described as stereo-EEG is extended now to allow recording from the freely moving rat by means of a telemetric device. Chronic implantation of 4 electrodes into the brain allows simultaneous transmission of field potentials from frontal cortex, hippocampus, striatum and reticular formation. Frequency analysis of these potentials results in a drug-specific 'fingerprint' which cannot only be used to compare different chemicals with each other but also to detect onset and time dependence of drug actions. Application of the model to the question if fenetylline has its own intrinsic mode of action or merely develops its stimulatory effect after metabolic separation into its molecular moieties amphetamine and theophylline (prodrug hypothesis) revealed that fenetylline indeed displays its own stimulatory effect to the same extent and at a similar time course as amphetamine and theophylline. The 'fingerprint' as obtained by the analysis of the action of fenetylline in the rat resembles closely that obtained after the application of theophylline with respect to decreased alpha activity, but resembles amphetamine with respect to beta 1 activity. Thus the applied method allows studying structure function relationships as the action of fenetylline seems to reflect both its molecular moieties.

Predictors of time to relapse in amphetamine-type substance users in the matrix treatment program in Iran: a Cox proportional hazard model application.

PubMed

Moeeni, Maryam; Razaghi, Emran M; Ponnet, Koen; Torabi, Fatemeh; Shafiee, Seyed Ali; Pashaei, Tahereh

2016-07-26

The aim of this study was to determine which predictors influence the risk of relapse among a cohort of amphetamine-type substance (ATS) users in Iran. A Cox proportional hazards model was conducted to determine factors associated with the relapse time in the Matrix treatment program provided by the Iranian National Center of Addiction Studies (INCAS) between March 2010 and October 2011. Participating in more treatment sessions was associated with a lower probability of relapse. On the other hand, patients with less family support, longer dependence on ATS, and those with an experience of casual sex and a history of criminal offenses were more likely to relapse. This study broadens our understanding of factors influencing the risk of relapse in ATS use among an Iranian sample. The findings can guide practitioners during the treatment program.

Prescriptions, Nonmedical Use, and Emergency Department Visits Involving Prescription Stimulants

PubMed Central

Chen, Lian-Yu; Crum, Rosa M.; Strain, Eric C.; CalebAlexander, G.; Kaufmann, Christopher; Mojtabai, Ramin

2018-01-01

Objective Little is known regarding the temporal trends in prescription, nonmedical use and emergency department (ED) visits involving prescription stimulants in the United States. We aimed to examine the three national trends involving dextroamphetamine-amphetamin (Adderall) and methylphenidate in adults and adolescents. Method Three national surveys conducted between 2006-2011 were used: National Disease and Therapeutic Index (NDTI), a survey of office-based practices, National Survey on Drug Use and Health (NSDUH), a population survey of substance use, and Drug Abuse Warning Network (DAWN), a survey of ED visits. Ordinary least square regression was used to examine temporal changes over time and the associations between these three trends. Results In adolescents, treatment visits involving dextroamphetamine-amphetamine and methylphenidate decreased over time; nonmedical dextroamphetamine-amphetamine use remained stable while nonmedical methylphenidate use declined by 54.4% in 6 years. ED visits involving either medication remained stable. In adults, treatment visits involving dextroamphetamine-amphetamine remained unchanged while nonmedical use went up by 67% and ED visits went up by 156%. These three trends involving methylphenidate remained unchanged. The major source for both medications was a friend or relative across age groups; two-thirds of these friends/relatives had obtained the medication from a physician. Conclusions Trends of prescriptions for stimulants do not correspond to trends in reports of nonmedical use and ED visits. Increased nonmedical stimulant use may not be simply attributed to increased prescribing trends. Future studies should focus on deeper understanding of the proportion, risk factors and motivations for drug diversions. PMID:26890573

High prevalence of previous arrests for illicit drug use and/or impaired driving among drivers killed in motor vehicle crashes in Sweden with amphetamine in blood at autopsy.

PubMed

Jones, Alan Wayne; Holmgren, Anita; Ahlner, Johan

2015-08-01

Amphetamine, and to a lesser extent the secondary amine methamphetamine, are major recreational drugs of abuse in Sweden. These central stimulant amines are identified in blood from roughly 50% of people arrested for driving under the influence of drugs (DUID). However, much less information is available about the presence of amphetamine in blood of drivers killed in road-traffic crashes. This retrospective 10-year study (2001-2010) used a forensic toxicology database (TOXBASE) to retrieve information about road-traffic crashes when the driver had amphetamine and/or methamphetamine in autopsy blood. Forensic toxicology results were available from over 95% of all drivers killed on Swedish roads during this 10-year period. Amphetamine was present in the blood of 106 drivers (3.9%) either alone or together with other psychoactive substances (e.g. alcohol, cannabis, diazepam, alprazolam, etc.). The vast majority of fatalities were male (95%) with a mean age (±standard deviation) of 37±11.4 years (range 16-67 years). The mean (median) and highest concentrations of amphetamine in femoral blood were 1.36 mg/L (1.0mg/L) and 6.74 mg/L, respectively. Many of the victims (75%) had been arrested previously for use of illicit drugs or DUID. The median number of previous arrests was 4 (range 0-83) and amphetamine or methamphetamine were among the drugs identified in blood samples from 89% of cases (0-100%). The high prevalence of repeat DUID offending and/or use of illicit drugs among the drivers killed in road-traffic crashes suggests that an early intervention and treatment for stimulant abuse might have been more beneficial than conventional punishments for such drug-related crimes. Copyright © 2015 Elsevier B.V. All rights reserved.

Single Prazosin Infusion in Prelimbic Cortex Fosters Extinction of Amphetamine-Induced Conditioned Place Preference.

PubMed

Latagliata, Emanuele C; Lo Iacono, Luisa; Chiacchierini, Giulia; Sancandi, Marco; Rava, Alessandro; Oliva, Valeria; Puglisi-Allegra, Stefano

2017-01-01

Exposure to drug-associated cues to induce extinction is a useful strategy to contrast cue-induced drug seeking. Norepinephrine (NE) transmission in medial prefrontal cortex has a role in the acquisition and extinction of conditioned place preference induced by amphetamine. We have reported recently that NE in prelimbic cortex delays extinction of amphetamine-induced conditioned place preference (CPP). A potential involvement of α1-adrenergic receptors in the extinction of appetitive conditioned response has been also suggested, although their role in prelimbic cortex has not been yet fully investigated. Here, we investigated the effects of the α1-adrenergic receptor antagonist prazosin infusion in the prelimbic cortex of C57BL/6J mice on expression and extinction of amphetamine-induced CPP. Acute prelimbic prazosin did not affect expression of amphetamine-induced CPP on the day of infusion, while in subsequent days it produced a clear-cut advance of extinction of preference for the compartment previously paired with amphetamine (Conditioned stimulus, CS). Moreover, prazosin-treated mice that had extinguished CS preference showed increased mRNA expression of brain-derived neurotrophic factor ( BDNF ) and post-synaptic density 95 ( PSD-95 ) in the nucleus accumbens shell or core, respectively, thus suggesting that prelimbic α1-adrenergic receptor blockade triggers neural adaptations in subcortical areas that could contribute to the extinction of cue-induced drug-seeking behavior. These results show that the pharmacological blockade of α1-adrenergic receptors in prelimbic cortex by a single infusion is able to induce extinction of amphetamine-induced CPP long before control (vehicle) animals, an effect depending on contingent exposure to retrieval, since if infused far from or after reactivation it did not affect preference. Moreover, they suggest strongly that the behavioral effects depend on post-treatment neuroplasticity changes in corticolimbic network, triggered by a possible "priming" effect of prazosin, and point to a potential therapeutic power of the antagonist for maladaptive memories.

Associations of substance use patterns with attempted suicide among persons who inject drugs: can distinct use patterns play a role?

PubMed

Artenie, Andreea Adelina; Bruneau, Julie; Zang, Geng; Lespérance, François; Renaud, Johanne; Tremblay, Joël; Jutras-Aswad, Didier

2015-02-01

While the elevated risk of suicide attempt among persons who inject drugs (PWID) is well documented, whether use of different substances is associated with varying degrees of risk remains unclear. We sought to examine the associations between substance use patterns and attempted suicide in a prospective cohort of PWID in Montreal, Canada. Between 2004 and 2011, participants completed an interviewer-administered questionnaire eliciting information on socio-demographics, substance use patterns, related behaviors, and mental health markers. Generalized estimating equations were used to model the relationship between self-reported use of six common substances (cocaine, amphetamine, opioids, sedative-hypnotics, cannabis and alcohol), associated patterns of use (chronic, occasional and none), and a recent (past six-month) suicide attempt. At baseline, of 1240 participants (median age: 39.1, 83.7% male), 71 (5.7%) reported a recent suicide attempt. Among 5621 observations collected during follow-up, 221 attempts were reported by 143 (11.5%) participants. In multivariate analyses adjusting for socio-demographics and psychosocial stressors, among primary drugs of abuse, chronic [adjusted odds ratio (AOR): 1.97] and occasional (AOR: 1.92) cocaine use, and chronic amphetamine use (AOR: 1.96) were independently associated with attempted suicide. Among co-used substances, chronic sedative-hypnotic use was independently associated with an attempt (AOR: 2.29). No statistically significant association was found for the remaining substances. Among PWID at high risk of attempted suicide, stimulant users appear to constitute a particularly vulnerable sub-group. While the mechanisms underlying these associations remain to be elucidated, findings suggest that stimulant-using PWID should constitute a prime focus of suicide prevention efforts. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Differential housing and novelty response: Protection and risk from locomotor sensitization

PubMed Central

Garcia, Erik J.; Haddon, Tara N.; Saucier, Donald A.; Cain, Mary E.

2017-01-01

High novelty seeking increases the risk for drug experimentation and locomotor sensitization. Locomotor sensitization to psychostimulants is thought to reflect neurological adaptations that promote the transition to compulsive drug taking. Rats reared in enrichment (EC) show less locomotor sensitization when compared to rats reared in isolation (IC) or standard conditions (SC). The current research study was designed to test if novelty response contributed locomotor sensitization and more importantly, if the different housing environments could change the novelty response to protect against the development of locomotor sensitization in both adolescence and adulthood. Experiment 1: rats were tested for their response to novelty using the inescapable novelty test (IEN) and pseudorandomly assigned to enriched (EC), isolated (IC), or standard (SC) housing conditions for 30 days. After housing, they were tested with IEN. Rats were then administered amphetamine (0.5 mg/kg) or saline and locomotor activity was measured followed by a sensitization test 14 days later. Experiment 2: rats were tested in the IEN test early adulthood and given five administrations of amphetamine (0.3 mg/kg) or saline and then either stayed in or switched housing environments for 30 days. Rats were then re-tested in the IEN test in late adulthood and administered five more injections of their respective treatments and tested for locomotor sensitization. Results indicate that IC and SC increased the response to novelty. EC housing decreased locomotor response to amphetamine and saline, and SC housing increased the locomotor response to amphetamine. Mediation results indicated that the late adult novelty response fully mediates the locomotor response to amphetamine and saline, while the early adulthood novelty response did not. Conclusions Differential housing changes novelty and amphetamine locomotor response. Novelty response is altered into adulthood and provides evidence that enrichment can be used to reduce drug vulnerability. PMID:28108176

Changes of cytosolic calcium and contractility of young rat vas deferens by acute treatment with amphetamine, fluoxetine or sibutramine.

PubMed

Jurkiewicz, Neide Hyppolito; da Silva Júnior, Edilson Dantas; de Souza, Bruno Palmieri; Ferreira Verde, Luciana; Drawanz Pereira, Janaina; Mendes Sobrinho, Cairo; Soubhi Smaili, Soraya; Caricati-Neto, Afonso; Miranda-Ferreira, Regiane; Jurkiewicz, Aron

2012-09-15

Previous studies conducted in our laboratory indicated that administration of amphetamine, fluoxetine or sibutramine affects the sympathetic nervous system of the rat vas deferens. Therefore, our goal was to verify the role of calcium in vasa deferentia from young rats pretreated with a single dose of these drugs. Young 40-day-old male Wistar rats were pretreated with amphetamine 3 mg/kg, fluoxetine 10 mg/kg or sibutramine 6 mg/kg for 4 h before the experiments. CaCl(2) (10 mM) was used to induce contraction through time-effect curves in calcium-free solution to measure phasic and tonic components. We also evaluated the calcium-induced fluorescence of vas deferens cut into thin slices. In rats pretreated with amphetamine, we found an increase of the tonic contraction component which was reduced by verapamil. The phasic and tonic responses were increased in the group treated with fluoxetine, but only the tonic response was more sensitive to the antagonism by verapamil. The group treated with sibutramine showed an increase of phasic response whereas the tonic component was decreased. In this group an increase of the affinity for verapamil antagonism was found. In the calcium fluorescence study it was observed that the group treated with amphetamine, fluoxetine or sibutramine showed higher basal Ca(2+) fluorescence after stimulus with KCl (70 mM), noradrenaline (10(-4)M) or acetylcholine (10(-4)M). In all pretreated groups the calcium fluorescence was diminished by nifedipine 10(-7)M. Therefore, the pretreatment with amphetamine, fluoxetine or sibutramine seems to affect the calcium contractility and homeostasis in young rat vas deferens. Copyright © 2012 Elsevier B.V. All rights reserved.

Catecholaminergic responses to stressful motion stimuli, scopolamine plus amphetamine, and dexamethasone

NASA Technical Reports Server (NTRS)

Kohl, R. L.; Chelen, W. E.

1992-01-01

Peripheral levels of epinephrine (EPI) and neoepinephrine (NE) generally rise following stressful motion stimuli. Effective anti-motion sickness drugs, scopolamine plus, d-amphetamine (S/D) and dexamthasone (DEX) modulate release of EPI and NE. This modulation may be of etiological relevance. Methods: Severe nausea was induced by exposure to coriolis simulation using a rotating chair. Chronic administration of S/D (0.4 and 5 mg/da) DEX (3 mg/day) and placebo preceded coriolis simulation. EPI and NE were measured immediately before and after simulation. A double-blind crossover design was used. Results: Nausea-induced elevations of EPI (2.5 fold, p less than .01) and NE were not diminished upon repeated exposure and adaptation to the stressor. Subjects with more pronounced elevations of EPI following simulation displayed higher resistance to stressful motion (p less .05). Alteration of peripheral catechlomaine levels following drug suggested that motion sickness was not mediated by peripheral catechlolamine receptor simulation. EPI and NE levels were 2.8 and 3.6-fold higher (p less than .03 and .01) after nausea without DEX treatment. DEX loading halved pre-stress levels of EPI and NE (p less than .05). Conclusions: Marked differences were noted in individual responses to drug and systematic responses of EPI and NE. It is possible that the responses of EPI to motion sickness may predict resistance to stressful motion and represent a peripheral manifestation of some as yet unknown central event of etiologic relevance.

The effect of methamphetamine on an animal model of erectile function

PubMed Central

Tar, Moses T.; Martinez, Luis R.; Nosanchuk, Joshua D.; Davies, Kelvin P.

2014-01-01

In the U.S. methamphetamine is considered a first-line treatment for attention-deficit hyperactivity disorder. It is also a common drug of abuse. Reports in patients and abusers suggest its use results in impotence. The efficacy of phosphodiesterase-5 inhibitors (PDE5i) to restore erectile function in these patient groups also has not been determined. In these studies we determined if the rat is a suitable animal model for the physiological effects of methamphetamine on erectile function, and if a PDE5i (tadalafil) has an effect on erectile function following methamphetamine treatment. In acute phase studies, erectile function was measured in male Sprague-Dawley rats, before and after administration of 10 mg/kg methamphetamine i.p. Chronically treated animals received escalating doses of methamphetamine (2.5 mg/kg (1st week), 5 mg/kg (2nd week), and 10 mg/kg (3rd week)) i.p. daily for three weeks and erectile function compared to untreated controls. The effect of co-administration of tadalafil was also investigated in rats acutely and chronically treated with methamphetamine. Erectile function was determined by measuring the intracorporal pressure/blood pressure ratio (ICP/BP) following cavernous nerve stimulation. In both acute and chronic phase studies we observed a significant increase in the rates of spontaneous erections after methamphetamine administration. In addition, following stimulation of the cavernous nerve at 4 and 6mA, there was a significant decrease in the ICP/BP ratio (approximately 50%), indicative of impaired erectile function. Tadalafil treatment reversed this effect. In chronically treated animals the ICP/BP ratio following 4 and 6mA stimulation decreased by approximately 50% compared to untreated animals and erectile dysfunction was also reversed by tadalafil. Overall our data suggests that the rat is a suitable animal model to study the physiological effect of methamphetamine on erectile function. Our work also provides a rationale for treating patients that report erectile dysfunction associated with therapeutics containing methamphetamine or amphetamine with PDE5i. PMID:24706617

Metabolism, distribution and elimination of lisdexamfetamine dimesylate: open-label, single-centre, phase I study in healthy adult volunteers.

PubMed

Krishnan, Suma M; Pennick, Michael; Stark, Jeffrey G

2008-01-01

Attention-deficit/hyperactivity disorder (ADHD) in children often persists into adulthood and is potentially associated with significant social and occupational impairments. It is important to understand the effects of pharmacological treatments of ADHD in adults. This study aimed to assess the absorption, metabolism and elimination of lisdexamfetamine dimesylate in normal, healthy adult subjects following a single oral dose. A secondary objective was to assess the safety and tolerability of treatment. In an open-label, single-centre study, six healthy adult volunteers aged 22-52 years received a single oral 70 mg dose of (14)C-radiolabelled lisdexamfetamine dimesylate in solution following a 10-hour fast. Blood samples drawn pre-dose and at time points up to 120 hours post-dose were used for plasma pharmacokinetic analysis of the active d-amphetamine and the intact parent compound lisdexamfetamine dimesylate. Recovery of radioactivity was determined by liquid scintillation counting of blood samples (whole blood and plasma), urine samples and faecal samples collected pre-dose and at designated time points up to 120 hours post-dose. Urine samples were also analysed for the presence of amphetamine-derived metabolites. Safety was assessed by adverse event reporting, changes in physical findings, vital sign measurements, ECG measurements, and clinical laboratory test results. For intact lisdexamfetamine dimesylate, the median time to reach maximum plasma drug concentration (t(max)) was 1.00 hour, and the mean maximum plasma drug concentration (C(max)) was 58.2 +/- 28.1 ng/mL. Intact lisdexamfetamine dimesylate exhibited modest systemic exposure (area under the drug concentration-time curve from time 0 to infinity [AUC(infinity)] 67.04 +/- 18.94 ng . h/mL), and rapid elimination (mean apparent terminal elimination half-life [t((1/2)beta)] 0.47 hours). For d-amphetamine, the median t(max) was 3.00 hours, and the mean C(max) was 80.3 +/- 11.8 ng/mL. The AUC(infinity) of d-amphetamine was 1342 +/- 216.9 ng . h/mL, and elimination occurred as a first-order process. The t((1/2)beta) of d-amphetamine was 10.39 hours. Peaks consistent with amphetamine and hippuric acid were identified in urine samples by high-performance liquid chromatography radioactive profiling. Relative to dose administered, 41.5% was recovered in urine as d-amphetamine, 24.8% as hippuric acid and 2.2% as intact lisdexamfetamine dimesylate. Less than 0.3% of the administered dose was recovered in the faeces. During the 0- to 48-hour urine samples, no unexpected adverse events or clinically significant laboratory, ECG or physical examination findings related to the study medication were observed. Following a single 70 mg oral dose, lisdexamfetamine dimesylate was quickly absorbed, extensively metabolized to d-amphetamine and its derivatives, and rapidly eliminated. Systemic exposure to d-amphetamine was approximately 20-fold higher than systemic exposure to intact lisdexamfetamine dimesylate in healthy adults. Lisdexamfetamine dimesylate, administered as a single 70 mg dose, was generally well tolerated in this study.

Involvement of NO/NMDA-R pathway in the behavioral despair induced by amphetamine withdrawal.

PubMed

Haj-Mirzaian, Arvin; Amiri, Shayan; Amini-Khoei, Hossein; Haj-Mirzaian, Arya; Hashemiaghdam, Arsalan; Ramezanzadeh, Kiana; Ghesmati, Maria; Afshari, Khashayar; Dehpour, Ahmad Reza

2018-05-01

Abrupt discontinuation of chronic amphetamine consumption leads to withdrawal symptoms including depression, anhedonia, dysphoria, fatigue, and anxiety. These irritating symptoms may result in continuing to take the drug or can lead to suicidal behavior. Past studies have shown the involvement of various biologic systems in depression induced following amphetamine withdrawal (AW). However, there is no evidence about the relation between nitric oxide (NO) with NMDA receptors on depression following AW. In this study, we examined the involvement of the NO/NMDA pathways on depressive-like behaviors after 24 h withdrawal following 5 continuous days of amphetamine administration in male NMRI mice. Behavioral tasks used for depression assessment included the forced swimming test (FST), the Splash test and the open field test (OFT). In order to evaluate the role of NO/NMDA pathways animals treated with MK-801 (NMDA-R antagonist), Aminoguanidine (AG), a selective iNOS inhibitor, Nω-Nitro-l-arginine (L-NNA), a non-selective NOS inhibitor and 7-Nitro indazole (7-NI), a selective nNOS inhibitor. We also measured the level of nitrite in the hippocampus. Our data showed that AW induced the depressive-like effect in the FST and the Splash test. We showed that administration of AG, L-NNA, and MK-801 mitigated AW induced depression, however, 7-NI was failed to decrease depressive-like behaviors. Also, the antidepressant-like effect of co-injection of sub-effective doses of MK-801 with AG suggested that inducible nitric oxide synthase (iNOS) is associated with NMDA-R in AW induced depression. In conclusion, both NO and NMDA-R pathways are involved and related to each other in depression induced following AW. Copyright © 2018. Published by Elsevier Inc.

Midkine and Pleiotrophin in the Treatment of Neurodegenerative Diseases and Drug Addiction.

PubMed

Alguacil, Luis F; Herradón, Gonzalo

2015-01-01

Pleiotrophin (PTN) and Midkine (MK) are neurotrophines with documented protective actions in experimental models of neurodegenerative diseases and beneficial effects on toxicity and addictive behaviours related to drug abuse. Concerning the latter, both PTN and MK prevent the neurotoxic effects of amphetamine on nigrostriatal pathways and endogenous PTN also limits amphetamine reward. Moreover, endogenous PTN overexpression in the prefontral cortex abolishes alcohol- induced conditioned place preference. This review summarizes the existing patents for using PTN and MK in the treatment and diagnosis of neuropsychiatric disorders with a focus on neurotoxicity, neurodegeneration and substance use disorders. We have also reviewed the mechanism of action of PTN and MK and summarized existing patents on downstream modulators in their signaling pathways for the same indications.

Inclusion dynamics in PC12 is comparable between amphetamines and MPTP.

PubMed

Gesi, Marco; Lazzeri, Gloria; Ferrucci, Michela; Pellegrini, Antonio; Lenzi, Paola; Ruggieri, Stefano; Fornai, Francesco; Paparelli, Antonio

2006-08-01

In previous studies it was demonstrated that amphetamine derivatives and 1-methyl article-4-phenylpyridinium produce neuronal cell bodies. In the present work, we compared the fine ultrastructure of the intracellular inclusions induced by these different neurotoxic treatments. In particular, we compared the dynamical changes occurring when a mild toxic stimulus acts for different time intervals. For this purpose, we exposed catecholamine-synthesizing PC12 cells to different amphetamine derivatives (methamphetamine and 3,4-methylenedioxymethamphetamine), or 1-methyl-4-phenylpyridinium ion, which represents the active metabolite of the neurotoxin 1-methyl-4-phenyl-1,3,4,6-tetrahydropyridine. Despite inclusions that are elicited by different mechanisms depending on the specific neurotoxin, their ultrastructural features are similar and there is a high parallelism in their temporal evolution. This suggests that formation of inclusions is a multi-step process that might be elicited by different stimuli and, once triggered, leads to the same final effect.

Dexamethasone mimicks the antimotion sickness effects of amphetamine and scopolamine

NASA Astrophysics Data System (ADS)

Kohl, Randall Lee

Based on preliminary suggestions that individual differences in susceptibility to stressful motion might be related to physiological differences in responses of the hypothalamic-pituitary-adrenal axis, we tested the efficacy of dexamethasone and metyrapone in subjects exposed to cross-coupled accelerative semicircular canal stimulation on a rotating chair. Subjects given 0.5 mg of dexamethasone every 6 h for 48 h could endure 80% more stressful motion ( P = 0.03) in a within-subjects design study, whereas, no improvement followed treatment with 750 mg of metryapone every 4 h for 24 h. The efficacy of dexamethasone might be explained in terms of its neurochemical actions on several neurotransmitter systems which are also modulated by such classical antimotion sickness drugs as amphetamine and scopolamine. Because dexamethasone induces adaptive changes within the central nervous system it may prove superior to scopolamine and amphetamine which possess significant side effects, are short acting, and rapidly tolerated.

Dexamethasone mimicks the antimotion sickness effects of amphetamine and scopolamine

NASA Technical Reports Server (NTRS)

Kohl, Randall Lee

1986-01-01

Based on preliminary suggestions that individual differences in susceptibility to stressful motion might be related to physiological differences in responses of the hypothalamic-pituitary-adrenal axis, the efficacy of dexamethasone and metyrapone is tested in subjects exposed to cross-coupled accelerative semicircular canal stimulation on a rotating chair. Subjects given 0.5 mg of dexamethasone every 6 h for 48 h could endure 80 percent more stressful motion (P = 0.03) in a within-subjects design study, whereas, no improvement followed treatment with 750 mg of metryapone every 4 h for 24 h. The efficacy of dexamethasone might be explained in terms of its neurochemical actions on several neurotransmitter systems which are also modulated by such classical antimotion sickness drugs as amphetamine and scopolamine. Because dexamethasone induces adaptive changes within the central nervous system it may prove superior to scopolamine and amphetamine which possess significant side effects, are short acting, and rapidly tolerated.

The behavioral effects of chronic sugar and/or caffeine consumption in adult and adolescent rats.

PubMed

Franklin, Jane L; Wearne, Travis A; Homewood, Judi; Cornish, Jennifer L

2017-08-01

Caffeine is a psychostimulant frequently consumed by adults and children, often in combination with high levels of sugar. Chronic pretreatment with either substance can amplify both amphetamine and cocaine-induced hyperactivity in rodents. The present study sought to elucidate whether age at the time of exposure to sugar and/or caffeine alters sensitivity to an acute illicit psychostimulant (methamphetamine, [METH]) challenge in adulthood. Adult and adolescent (Postnatal Day 35 on first day of treatment) male Sprague-Dawley rats were treated for 26 days with water, caffeine (0.6 g/L), 10% sucrose or their combination. Locomotor behavior was measured on the first and last day of treatment. Following 9-days treatment free, animals were challenged with saline (1 ml/kg, i.p.) or METH (1 mg/kg, i.p.) and locomotor activity was measured. During the treatment period, adolescent rats maintained a higher caffeine (mg/kg) dose than their adult counterparts. Adding sugar to caffeine increased adolescent consumption and the highest caffeine dose consumed was measured in these animals. Drinking sugar-sweetened caffeinated water or combination did not produce cross-sensitization to METH administration in either age group. Nevertheless, the finding that regular exposure through adolescence to caffeinated sugar-sweetened beverages could increase consumption of caffeine and sugar later in life is important, as there is a large body of evidence that has linked excess consumption of sugar-sweetened beverages to a broad range of other negative physical and mental health outcomes. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Addiction-Related Gene Regulation: Risks of Exposure to Cognitive Enhancers vs. Other Psychostimulants

PubMed Central

Steiner, Heinz; Van Waes, Vincent

2012-01-01

The psychostimulants methylphenidate (Ritalin, Concerta), amphetamine (Adderall), and modafinil (Provigil) are widely used in the treatment of medical conditions such as attention-deficit hyperactivity disorder and narcolepsy and, increasingly, as “cognitive enhancers” by healthy people. The long-term neuronal effects of these drugs, however, are poorly understood. A substantial amount of research over the past 2 decades has investigated the effects of psychostimulants such as cocaine and amphetamines on gene regulation in the brain because these molecular changes are considered critical for psychostimulant addiction. This work has determined in some detail the neurochemical and cellular mechanisms that mediate psychostimulant-induced gene regulation and has also identified the neuronal systems altered by these drugs. Among the most affected brain systems are corticostriatal circuits, which are part of cortico-basal ganglia-cortical loops that mediate motivated behavior. The neurotransmitters critical for such gene regulation are dopamine in interaction with glutamate, while other neurotransmitters (e.g., serotonin) play modulatory roles. This review presents (1) an overview of the main findings on cocaine- and amphetamine-induced gene regulation in corticostriatal circuits in an effort to provide a cellular framework for (2) an assessment of the molecular changes produced by methylphenidate, medical amphetamine (Adderall), and modafinil. The findings lead to the conclusion that protracted exposure to these cognitive enhancers can induce gene regulation effects in corticostriatal circuits that are qualitatively similar to those of cocaine and other amphetamines. These neuronal changes may contribute to the addiction liability of the psychostimulant cognitive enhancers. PMID:23085425

Priapism associated with the use of stimulant medications and atomoxetine for attention-deficit/hyperactivity disorder in children.

PubMed

Eiland, Lea S; Bell, Edward A; Erramouspe, John

2014-10-01

To review the association of priapism with stimulant medications and atomoxetine commonly used in the treatment of attention-deficit/hyperactivity disorder (ADHD). A comprehensive literature search was conducted through PubMed (1966-May 15, 2014) using the search terms priapism, methylphenidate, amphetamine, atomoxetine, attention-deficit disorder with hyperactivity, and pediatrics. Google Scholar, Scopus, and the Food and Drug Administration (FDA) Web site were also searched. References from identified literature were also reviewed. All identified literature focused on ADHD treatment. Literature regarding priapism caused by methylphenidate, amphetamines, and atomoxetine were included. Stimulant medications and atomoxetine have been linked to the occurrence of priapism in children. Specifically, methylphenidate has been implicated in a recent FDA safety announcement warning as a result of 15 case reports (mean age = 12.5 years), and thus, the drug label and medication guides have been updated to reflect this concern. Prolonged erections and priapism occurred with immediate- and long-acting products, dose increases, and drug withdrawal periods. Priapism has also occurred in 4 patients taking amphetamines and one 11-year-old patient taking atomoxetine for ADHD. Priapism has been associated with stimulants, amphetamines, and atomoxetine use for ADHD in children. Providers and health care practitioners should educate male patients prescribed these ADHD medications as well as caregivers regarding the signs, symptoms, and complications with priapism. Discontinuation and evaluation of the medication is warranted if this adverse drug reaction occurs. Depending on the priapism subtype, other products may be initiated or medications not associated with priapism may be utilized. © The Author(s) 2014.

Relationship between discriminative stimulus effects and plasma methamphetamine and amphetamine levels of intramuscular methamphetamine in male rhesus monkeys.

PubMed

Banks, Matthew L; Smith, Douglas A; Kisor, David F; Poklis, Justin L

2016-02-01

Methamphetamine is a globally abused drug that is metabolized to amphetamine, which also produces abuse-related behavioral effects. However, the contributing role of methamphetamine metabolism to amphetamine in methamphetamine's abuse-related subjective effects is unknown. This preclinical study was designed to determine 1) the relationship between plasma methamphetamine levels and methamphetamine discriminative stimulus effects and 2) the contribution of the methamphetamine metabolite amphetamine in the discriminative stimulus effects of methamphetamine in rhesus monkeys. Adult male rhesus monkeys (n=3) were trained to discriminate 0.18mg/kg intramuscular (+)-methamphetamine from saline in a two-key food-reinforced discrimination procedure. Time course of saline, (+)-methamphetamine (0.032-0.32mg/kg), and (+)-amphetamine (0.032-0.32mg/kg) discriminative stimulus effects were determined. Parallel pharmacokinetic studies were conducted in the same monkeys to determine plasma methamphetamine and amphetamine levels after methamphetamine administration and amphetamine levels after amphetamine administration for correlation with behavior in the discrimination procedure. Both methamphetamine and amphetamine produced full, ≥90%, methamphetamine-like discriminative stimulus effects. Amphetamine displayed a slightly, but significantly, longer duration of action than methamphetamine in the discrimination procedure. Both methamphetamine and amphetamine behavioral effects were related to methamphetamine and amphetamine plasma levels by a clockwise hysteresis loop indicating acute tolerance had developed to the discriminative stimulus effects. Furthermore, amphetamine levels after methamphetamine administration were absent when methamphetamine stimulus effects were greatest and peaked when methamphetamine discriminative stimulus effects returned to saline-like levels. Overall, these results demonstrate the methamphetamine metabolite amphetamine does not contribute to methamphetamine's abuse-related subjective effects. Copyright © 2015 Elsevier Inc. All rights reserved.

Acute d-amphetamine pretreatment does not alter stimulant self-administration in humans.

PubMed

Stoops, William W; Vansickel, Andrea R; Lile, Joshua A; Rush, Craig R

2007-05-01

Recent clinical research indicates that d-amphetamine is effective in treating cocaine and methamphetamine dependence. There is concern, however, with the use of d-amphetamine as a pharmacotherapy because acute administration of d-amphetamine decreases inhibition in cocaine-using individuals and may increase drug-taking behavior. The purpose of the present experiment was to determine whether acute d-amphetamine pretreatment would alter the reinforcing, subject-rated, and cardiovascular effects of d-amphetamine. To this end, 7 human volunteers first sampled doses of oral d-amphetamine (0, 8, and 16 mg). These doses engender moderate drug taking and were selected to avoid a ceiling or floor effect. Volunteers were then allowed to self-administer these sampled doses using a modified progressive-ratio procedure in two sessions in which they received pretreatment with either 0 or 15 mg oral d-amphetamine 2 h prior to completing the modified progressive-ratio procedure. d-Amphetamine produced prototypical stimulant-like effects (e.g., increased ratings of stimulated, elevated blood pressure) and maintained responding on the modified progressive-ratio schedule. Pretreatment with 15 mg oral d-amphetamine also produced prototypical stimulant-like effects, but failed to alter break points for d-amphetamine on the modified progressive-ratio procedure relative to placebo pretreatment. These results indicate that acute d-amphetamine pretreatment does not increase stimulant self-administration.

Efficacy and Safety of Amphetamine Extended-Release Oral Suspension in Children with Attention-Deficit/Hyperactivity Disorder.

PubMed

Childress, Ann C; Wigal, Sharon B; Brams, Matthew N; Turnbow, John M; Pincus, Yulia; Belden, Heidi W; Berry, Sally A

2018-06-01

To determine the efficacy and safety of amphetamine extended-release oral suspension (AMPH EROS) in the treatment of attention-deficit/hyperactivity disorder (ADHD) in a dose-optimized, randomized, double-blind, parallel-group study. Boys and girls aged 6 to 12 years diagnosed with ADHD were enrolled. During a 5-week, open-label, dose-optimization phase, patients began treatment with 2.5 or 5 mg/day of AMPH EROS; doses were titrated until an optimal dose (maximum 20 mg/day) was reached. During the double-blind phase, patients were randomized to receive treatment with either their optimized dose (10-20 mg/day) of AMPH EROS or placebo for 1 week. Efficacy was assessed in a laboratory classroom setting on the final day of double-blind treatment using the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Rating Scale and Permanent Product Measure of Performance (PERMP) test. Safety was assessed measuring adverse events (AEs) and vital signs. The study was completed by 99 patients. The primary efficacy endpoint (change from predose SKAMP-Combined score at 4 hours postdose) and secondary endpoints (change from predose SKAMP-Combined scores at 1, 2, 6, 8, 10, 12, and 13 hours postdose) were statistically significantly improved with AMPH EROS treatment versus placebo at all time points. Onset of treatment effect was present by 1 hour postdosing, the first time point measured, and duration of efficacy lasted 13 hours postdosing. PERMP data mirrored the SKAMP-Combined score data. AEs (>5%) reported during dose optimization were decreased appetite, insomnia, affect lability, upper abdominal pain, mood swings, and headache. AMPH EROS was effective in reducing symptoms of ADHD and had a rapid onset and extended duration of effect. Reported AEs were consistent with those of other extended-release amphetamine products.

Combined Dextroamphetamine and Transcranial Direct Current Stimulation in Poststroke Aphasia.

PubMed

Keser, Zafer; Dehgan, Michelle Weber; Shadravan, Shaparak; Yozbatiran, Nuray; Maher, Lynn M; Francisco, Gerard E

2017-10-01

There is a growing need for various effective adjunctive treatment options for speech recovery after stroke. A pharmacological agent combined with noninvasive brain stimulation has not been previously reported for poststroke aphasia recovery. In this "proof of concept" study, we aimed to test the safety of a combined intervention consisting of dextroamphetamine, transcranial direct current stimulation, and speech and language therapy in subjects with nonfluent aphasia. Ten subjects with chronic nonfluent aphasia underwent two experiments where they received dextroamphetamine or placebo along with transcranial direct current stimulation and speech and language therapy on two separate days. The Western Aphasia Battery-Revised was used to monitor changes in speech performance. No serious adverse events were observed. There was no significant increase in blood pressure with amphetamine or deterioration in speech and language performance. Western Aphasia Battery-Revised aphasia quotient and language quotient showed a statistically significant increase in the active experiment. Comparison of proportional changes of aphasia quotient and language quotient in active experiment with those in placebo experiment showed significant difference. We showed that the triple combination therapy is safe and implementable and seems to induce positive changes in speech and language performance in the patients with chronic nonfluent aphasia due to stroke.

Chronic Treatment with Mood-Stabilizers Attenuates Abnormal Hyperlocomotion of GluA1-Subunit Deficient Mice

PubMed Central

Maksimovic, Milica; Vekovischeva, Olga Y.; Aitta-aho, Teemu; Korpi, Esa R.

2014-01-01

Abnormal excitatory glutamate neurotransmission and plasticity have been implicated in schizophrenia and affective disorders. Gria1−/− mice lacking GluA1 subunit (encoded by Gria1 gene) of AMPA-type glutamate receptor show robust novelty-induced hyperactivity, social deficits and heightened approach features, suggesting that they could be used to test for anti-manic activity of drugs. Here, we tested the efficacy of chronic treatment with established anti-manic drugs on behavioural properties of the Gria1−/− mice. The mice received standard mood stabilizers (lithium and valproate) and novel ones (topiramate and lamotrigine, used more as anticonvulsants) as supplements in rodent chow for at least 4 weeks. All drugs attenuated novelty-induced locomotor hyperactivity of the Gria1−/− mice, especially by promoting the habituation, while none of them attenuated 2-mg/kg amphetamine-induced hyperactivity as compared to control diet. Treatment with lithium and valproate reversed the elevated exploratory activity of Gria1−/− mice. Valproate treatment also reduced struggling behaviour in tail suspension test and restored reciprocally-initiated social contacts of Gria1−/− mice to the level shown by the wild-type Gria1+/+ mice. Gria1−/− mice consumed slightly more sucrose during intermittent sucrose exposure than the wild-types, but ran similar distances on running wheels. These behaviours were not consistently affected by lithium and valproate in the Gria1−/− mice. The efficacy of various anti-manic drug treatments on novelty-induced hyperactivity suggests that the Gria1−/− mouse line can be utilized in screening for new therapeutics. PMID:24932798

Effects of environmental enrichment on extinction and reinstatement of amphetamine self-administration and sucrose-maintained responding.

PubMed

Stairs, Dustin J; Klein, Emily D; Bardo, Michael T

2006-11-01

The current experiments aimed to determine whether differential rearing alters extinction and/or reinstatement of amphetamine self-administration or sucrose-maintained responding. Male Sprague-Dawley rats were raised in either an enriched condition or an isolated condition. Rats were then trained to lever press on a continuous reinforcement schedule across either 15 daily amphetamine self-administration sessions or 15 sucrose-reinforced sessions, followed by 10 sessions of extinction. After the extinction sessions, priming doses of amphetamine (0, 0.25 or 1.0 mg/kg) were administered 15 min before the session, or sucrose (one or 10 pellets) was delivered non-contingently at the beginning of the session. Enriched condition rats showed greater extinction for amphetamine and sucrose-maintained responding than isolated condition rats. When primed with amphetamine, isolated condition rats reinstated responding following 0.25 mg/kg of amphetamine, whereas enriched condition rats only reinstated responding after 1.0 mg/kg of amphetamine. Isolated condition rats failed to reinstate responding following sucrose delivery, while enriched condition rats reinstated responding following the delivery of 10 sucrose pellets. These results indicate that environmental enrichment enhanced the extinction of both amphetamine and sucrose-maintained responding. Environmental enrichment also raised the reinstatement threshold specific to the amphetamine prime, suggesting a reduction in the incentive motivational effect of amphetamine.

[Persistent amphetamine consumption by truck drivers in São Paulo State, Brazil, despite the ban on production, prescription, and use].

PubMed

Oliveira, Lúcio Garcia de; Endo, Ligia Goes; Sinagawa, Daniele Mayumi; Yonamine, Maurício; Munoz, Daniel Romero; Leyton, Vilma

2013-09-01

Amphetamine use by truck drivers for occupational purposes is widely known. The production and consumption of amphetamines was banned by the Brazilian National Health Surveillance Agency (ANVISA) in October 2011. This study analyzes persistent amphetamine use by truck drivers since the ban was implemented. A convenience sample of 427 truck drivers was taken along highways in São Paulo State in 2012. Participants were asked to answer a structured questionnaire and provide a urine sample to screen for recent amphetamine consumption through toxicological analysis. Among the interviewed drivers, 7% had used some illicit drug recently and 2.7% had used amphetamines. Amphetamines are still consumed by truck drivers despite the risks and the recent ban. The authorities should thus monitor the possession and use of amphetamines by drivers in order to effectively enforce the ban.

Sexual-incentive motivation and paced sexual behavior in female rats after treatment with drugs modifying dopaminergic neurotransmission.

PubMed

Ellingsen, Ellinor; Agmo, Anders

2004-03-01

The effects of the dopamine receptor agonist apomorphine, the dopamine releaser amphetamine, and the dopamine receptor antagonist cis(Z)-flupenthixol on sexual-incentive motivation and on paced-mating behavior were studied in female rats. Apomorphine, in the doses of 0.125 and 0.5 mg/kg, showed a tendency to reduce incentive motivation. Ambulatory activity was inhibited, evidenced both by diminished distance moved and reduced velocity of movement. Amphetamine (0.25 and 1 mg/kg) and flupenthixol (0.25 and 0.5 mg/kg) failed to modify incentive motivation while stimulating and reducing ambulatory activity, respectively. In the mating test, apomorphine enhanced the latency to enter the male's half and reduced the number of proceptive behaviors. However, these effects were associated with the appearance of stereotyped sniffing. Amphetamine increased the propensity to escape from the male after a mount without having other effects. Flupenthixol augmented the duration of the lordosis posture. Neither amphetamine nor flupenthixol affected sniffing. These data show that facilitated dopaminergic neurotransmission stimulates neither paced female sexual behavior nor sexual-incentive motivation. Dopamine receptor blockade has slight consequences. It is concluded that dopamine is not a transmitter of major importance for unconditioned female sexual motivation and behavior.

Differential housing and novelty response: Protection and risk from locomotor sensitization.

PubMed

Garcia, Erik J; Haddon, Tara N; Saucier, Donald A; Cain, Mary E

2017-03-01

High novelty seeking increases the risk for drug experimentation and locomotor sensitization. Locomotor sensitization to psychostimulants is thought to reflect neurological adaptations that promote the transition to compulsive drug taking. Rats reared in enrichment (EC) show less locomotor sensitization when compared to rats reared in isolation (IC) or standard conditions (SC). The current research study was designed to test if novelty response contributed locomotor sensitization and more importantly, if the different housing environments could change the novelty response to protect against the development of locomotor sensitization in both adolescence and adulthood. Experiment 1: rats were tested for their response to novelty using the inescapable novelty test (IEN) and pseudorandomly assigned to enriched (EC), isolated (IC), or standard (SC) housing conditions for 30days. After housing, they were tested with IEN. Rats were then administered amphetamine (0.5mg/kg) or saline and locomotor activity was measured followed by a sensitization test 14days later. Experiment 2: rats were tested in the IEN test early adulthood and given five administrations of amphetamine (0.3mg/kg) or saline and then either stayed in or switched housing environments for 30days. Rats were then re-tested in the IEN test in late adulthood and administered five more injections of their respective treatments and tested for locomotor sensitization. Results indicate that IC and SC increased the response to novelty. EC housing decreased locomotor response to amphetamine and saline, and SC housing increased the locomotor response to amphetamine. Mediation results indicated that the late adult novelty response fully mediates the locomotor response to amphetamine and saline, while the early adulthood novelty response did not. Differential housing changes novelty and amphetamine locomotor response. Novelty response is altered into adulthood and provides evidence that enrichment can be used to reduce drug vulnerability. Copyright © 2017 Elsevier Inc. All rights reserved.

Effects of aberrant gamma frequency oscillations on prepulse inhibition.

PubMed

Jones, Nigel C; Anderson, Paul; Rind, Gil; Sullivan, Caley; van den Buuse, Maarten; O'Brien, Terence J

2014-10-01

Emerging literature implicates abnormalities in gamma frequency oscillations in the pathophysiology of schizophrenia, with hypofunction of N-methyl-D-aspartate (NMDA) receptors implicated as a key factor. Prepulse inhibition (PPI) is a behavioural measure of sensorimotor gating, which is disrupted in schizophrenia. We studied relationships between ongoing and sensory-evoked gamma oscillations and PPI using pharmacological interventions designed to increase gamma oscillations (ketamine, MK-801); reduce gamma oscillations (LY379268); or disrupt PPI (amphetamine). We predicted that elevating ongoing gamma power would lead to increased 'neural noise' in cortical circuits, dampened sensory-evoked gamma responses and disrupted behaviour. Wistar rats were implanted with EEG recording electrodes. They received ketamine (5 mg/kg), MK-801 (0.16 mg/kg), amphetamine (0.5 mg/kg), LY379268 (3 mg/kg) or vehicle and underwent PPI sessions with concurrent EEG recording. Ketamine and MK-801 increased the power of ongoing gamma oscillations and caused time-matched disruptions of PPI, while amphetamine marginally affected ongoing gamma power. In contrast, LY379268 reduced ongoing gamma power, but had no effect on PPI. The sensory gamma response evoked by the prepulse was reduced following treatment with all psychotomimetics, associating with disruptions in PPI. This was most noticeable following treatment with NMDA receptor antagonists. We found that ketamine and MK-801 increase ongoing gamma power and reduce evoked gamma power, both of which are related to disruptions in sensorimotor gating. This appears to be due to antagonism of NMDA receptors, since amphetamine and LY379268 differentially impacted these outcomes and possess different neuropharmacological substrates. Aberrant gamma frequency oscillations caused by NMDA receptor hypofunction may mediate the sensory processing deficits observed in schizophrenia.

Amphetamine-induced psychosis - a separate diagnostic entity or primary psychosis triggered in the vulnerable?

PubMed Central

2012-01-01

Use of amphetamine and methamphetamine is widespread in the general population and common among patients with psychiatric disorders. Amphetamines may induce symptoms of psychosis very similar to those of acute schizophrenia spectrum psychosis. This has been an argument for using amphetamine-induced psychosis as a model for primary psychotic disorders. To distinguish the two types of psychosis on the basis of acute symptoms is difficult. However, acute psychosis induced by amphetamines seems to have a faster recovery and appears to resolve more completely compared to schizophrenic psychosis. The increased vulnerability for acute amphetamine induced psychosis seen among those with schizophrenia, schizotypal personality and, to a certain degree other psychiatric disorders, is also shared by non-psychiatric individuals who previously have experienced amphetamine-induced psychosis. Schizophrenia spectrum disorder and amphetamine-induced psychosis are further linked together by the finding of several susceptibility genes common to both conditions. These genes probably lower the threshold for becoming psychotic and increase the risk for a poorer clinical course of the disease. The complex relationship between amphetamine use and psychosis has received much attention but is still not adequately explored. Our paper reviews the literature in this field and proposes a stress-vulnerability model for understanding the relationship between amphetamine use and psychosis. PMID:23216941

A Comparative Study of the Attitudes of College Students and Drug Treatment Center Residents Toward Drugs, Other Drug Users and Themselves.

ERIC Educational Resources Information Center

Page, Richard C.; Mitchell, Sam

1986-01-01

Assessed the attitudes of college students and drug treatment center residents with histories of using marijuana and amphetamines. The drug treatment center residents tended to devalue themselves, drugs, and peers in the drug culture to a greater extent than the students. (Author/BL)

Development and validation of a magnetic solid-phase extraction with high-performance liquid chromatography method for the simultaneous determination of amphetamine and methadone in urine.

PubMed

Taghvimi, Arezou; Hamishehkar, Hamed; Ebrahimi, Mahmoud

2016-06-01

The simultaneous determination of amphetamine and methadone was carried out by magnetic graphene oxide nanoparticles, a magnetic solid-phase extraction adsorbent, as a new sample treatment technique. The main factors (the amounts of sample volume, amount of adsorbent, type and amount of extraction organic solvent, time of extraction and desorption, pH, the ionic strength of extraction medium, and agitation rate) influencing the extraction efficiency were investigated and optimized. Under the optimized conditions, good linearity was observed in the range of 100-1500 ng/mL for amphetamine and 100-1000 ng/mL for methadone. The method was evaluated for determination of AM and methadone in positive urine samples, satisfactory results were obtained, therefore magnetic solid-phase extraction can be applied as a novel method for the determination of drugs of abuse in forensic laboratories. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

On the treatment of the alcoholic organic brain syndrome with an alpha-adrenergic agonist modafinil: double-blind, placebo-controlled clinical, psychometric and neurophysiological studies.

PubMed

Saletu, B; Saletu, M; Grünberger, J; Frey, R; Zatschek, I; Mader, R

1990-01-01

1. In a double-blind study forty abstinent hospitalized male patients with an alcoholic organic brain syndrome (OBS) were treated for 6 weeks with either 200 mg modafinil or placebo. 2. Modafinil (CRL 40476) is a putative central alpha-1 adrenergic agonist. It's pharmacological profile is quite different from that of amphetamine, which can be seen by the lack of peripheral sympathomimetic effects. The vigilance promoting effect of modafinil has been shown previously in pharmaco-EEG and psychometric studies as well as in clinical studies involving treatment of daytime sleepiness in idiopathic hypersomniacs and narcoleptics. 3. The present clinical investigations demonstrated that the spontaneous restitution of the alcoholic OBS was significantly augmented and accelerated by modafinil. 4. Psychometric tests did not show significant intergroup differences. Modafinil- and placebo-treated patients improved continously over the 6-week period. 5. Psychophysiological and autonomous nervous system parameters were affected neither by placebo nor by modafinil. 6. Neurophysiological investigations by means of quantitative pharmaco-EEG showed partly inconsistent findings. However, superimposed dosages of modafinil (on the top of 6 weeks chronic administration) induced a decrease of slow activity and an increase of alpha activity suggesting an improvement of vigilance after the daily drug intake. 7. Considering the beneficial effects of modafinil in abstinent chronic alcoholic patients, it may be said that activation and improvement of adaptive behaviour by an alpha-adrenergic agonist could be regarded as a therapeutic principle in the treatment of the OBS, eventually due to noradrenergic deficits.

Amphetamine derivative related deaths.

PubMed

Lora-Tamayo, C; Tena, T; Rodríguez, A

1997-02-28

Amphetamine its methylendioxy (methylendioxyamphetamine methylenedioxymethylamphetamine, methylenedioxyethylamphetamine) and methoxy derivatives (p-methoxyamphetamine and p-methoxymethylamphetamine) are widely abused in Spanish society. We present here the results of a systematic study of all cases of deaths brought to the attention of the Madrid department of the Instituto Nacional de Toxicologia from 1993 to 1995 in which some of these drugs have been found in the cadaveric blood. The cases were divided into three categories: amphetamine and derivatives, amphetamines and alcohol, amphetamines and other drugs. Data on age, sex, clinical symptoms, morphological findings, circumstances of death, when known, and concentration of amphetamine derivatives, alcohol and other drugs in blood are given for each group. The information provided here may prove to be useful for the forensic interpretation of deaths which are directly or indirectly related to abuse of amphetamine derivatives.

Methamphetamine/Dextroamphetamine and Pregnancy

MedlinePlus

... d-amphetamine is a prescription medication used for attention deficit hyperactivity disorder (ADHD) and narcolepsy (extreme daytime sleepiness). ... of dexamphetamine into breast milk during treatment for attention deficit hyperactivity disorder. Br J Clin Pharmacol. 63(3): ...

Update on therapy for narcolepsy.

PubMed

Thorpy, Michael J

2015-05-01

Narcolepsy is a severe, incurable, neurological disorder that is treated by pharmacological management of its symptoms. The main symptoms are excessive daytime sleepiness (EDS) and cataplexy, although addition symptoms that may require treatment include sleep paralysis, hypnagogic hallucinations, and disturbed nocturnal sleep. Sodium oxybate and modafinil/armodafinil are the first-line treatments for EDS, and sodium oxybate for cataplexy. Sodium oxybate treats all the symptoms of narcolepsy, whereas modafinil is effective for EDS only. Alternative medications for EDS include methylphenidate or amphetamines such as dextroamphetamine, lisdexamfetamine, methamphetamine, or combination amphetamine salts. Non-FDA approved medications for cataplexy include norepinephrine reuptake inhibitors such as venlafaxine or atomoxetine. Combination therapy can be more effective for sleepiness such as sodium oxybate and modafinil/armodafinil. Medication for narcolepsy is generally well tolerated and usually required life-long although does not eliminate all symptoms of narcolepsy.

Methylphenidate modulates dorsal raphe neuronal activity: Behavioral and neuronal recordings from adolescent rats.

PubMed

Kharas, Natasha; Whitt, Holly; Reyes-Vasquez, Cruz; Dafny, Nachum

2017-01-01

Methylphenidate (MPD) is a widely prescribed psychostimulants used for the treatment of attention deficit hyperactive disorder (ADHD). Unlike the psychostimulants cocaine and amphetamine, MPD does not exhibit direct actions on the serotonin transporter, however there is evidence suggesting that the therapeutic effects of MPD may be mediated in part by alterations in serotonin transmission. This study aimed to investigate the role of the dorsal raphe (DR) nucleus, one of the major sources of serotonergic innervation in the mammalian brain, in the response to MPD exposure. Freely behaving adolescent rats previously implanted bilaterally with permanent electrodes were used. An open field assay and a wireless neuronal recording system were used to concomitantly record behavioral and DR electrophysiological activity following acute and chronic MPD exposure. Four groups were used: one control (saline) and three experimental groups treated with 0.6, 2.5, and 10.0mg/kg MPD respectively. Animals received daily MPD or saline injections on experimental days 1-6, followed by 3 washout days and MPD rechallenge dose on experimental day (ED)10. The same chronic dose of MPD resulted in either behavioral sensitization or tolerance, and we found that neuronal activity recorded from the DR neuronal units of rats expressing behavioral sensitization to chronic MPD exposure responded significantly differently to MPD rechallenge on ED10 compared to the DR unit activity recorded from animals that expressed behavioral tolerance. This correlation between behavioral response and DR neuronal activity following chronic MPD exposure provides evidence that the DR is involved in the acute effects as well as the chronic effects of MPD in adolescent rats. Copyright © 2016 Elsevier Inc. All rights reserved.

Destruction of amphetamine in aqueous solution using gamma irradiation

NASA Astrophysics Data System (ADS)

Alkhuraiji, Turki S.; Ajlouni, Abdul-Wali

2017-10-01

Amphetamine-type stimulants are among the most prevalent and widespread commonly abused drugs. Amphetamine and its derivatives were detected in aquatic environment. This study aimed to demonstrate experimentally the ability of γ-irradiation combined with persulfate anions (S2O82-) to degrade and mineralize the amphetamine in aqueous solution. An initial amphetamine concentration of 125 μM in distilled water was completely degraded by a γ-ray dose of 2.8 kGy. Generation of the sulfate radical (SO4•-) from the fast reaction of added S2O82- with hydrated electrons (eaq-; keaq-/S2O82- = 1.1×1010 M-1 s-1) improved the efficiency of amphetamine degradation and mineralization. A γ-ray dose of 0.667 and 0.350 kGy in the absence and presence of S2O82- anions degraded 90% of the amphetamine, respectively. For γ-ray/free O2 and γ-ray/S2O82- systems, 11.5 and 7 kGy was required for 50% amphetamine mineralization, respectively. Addition of HCO3- anions lowered the amphetamine degradation yield, whereas N2 gas, SO42-, and Cl- anions had a negligible effect.

A rapid novel derivatization of amphetamine and methamphetamine using 2,2,2-trichloroethyl chloroformate for gas chromatography electron ionization and chemical ionization mass spectrometric analysis.

PubMed

Dasgupta, A; Spies, J

1998-05-01

Amphetamine and methamphetamine are commonly abused central nervous system stimulants. We describe a rapid new derivatization of amphetamine and methamphetamine using 2,2,2-trichloroethyl chloroformate for gas chromatography-mass spectrometric analysis. Amphetamine and methamphetamine, along with N-propyl amphetamine (internal standard), were extracted from urine using 1-chlorobutane. The derivatization with 2,2,2-trichloroethyl chloroformate can be achieved at room temperature in 10 minutes. The electron ionization mass spectrum of amphetamine 2,2,2-trichloroethyl carbamate showed two weak molecular ions at m/z 309 and 311, but showed diagnostic strong peaks at m/z 218, 220, and 222. In contrast, chemical ionization of the mass spectrum of amphetamine 2,2,2-trichloroethyl carbamate showed strong (M + 1) ions at m/z 310 and 312 and other strong diagnostic peaks at m/z 274 and 276. The major advantages of this derivative are the presence of a diagnostic cluster of peaks due to the isotopic effect of three chlorine atoms (isotopes 35 and 37) in the derivatized molecule and the relative ease of its preparation. We also observed strong molecular ions for derivatized methamphetamine in the chemical ionization mass spectrum, but the molecular ions were very weak in the electron ionization mass spectrum. We used the scan mode of mass spectrometry in all analyses. When using a urine standard containing 1,000 ng/mL of amphetamine (a 7.4-micromol/L concentration) and methamphetamine (a 6.7-micromol/L concentration), the within-run precisions were 4.8% for amphetamine and 3.6% for methamphetamine. The corresponding between-run precisions were 5.3% for amphetamine and 6.7% for methamphetamine. The assay was linear for amphetamine and methamphetamine concentrations of 250 to 5,000 ng/mL (amphetamine, 1.9-37.0 micromol/L; methamphetamine, 1.7-33.6 micromol/L). The detection limit was 100 ng/mL (amphetamine, 0.74 micromol/L; methamphetamine, 0.67 micromol/L) using the scan mode of electron ionization mass spectrometry. We observed good a correlation between the concentrations of amphetamine and methamphetamine in five urine specimens positive for amphetamines using the more conventional pentafluoropropionyl derivative and our new derivative using 2,2,2-trichloroethyl chloroformate.

Differential effects of acute amphetamine and phencyclidine treatment and withdrawal from repeated amphetamine or phencyclidine treatment on social interaction and social memory in rats.

PubMed

Li, Ming; He, Wei; Munro, Rebecca

2012-06-01

Although animal models based on amphetamine (AMPH) or phencyclidine (PCP) treatment have been used extensively to study the neurobiological and behavioral characteristics of schizophrenia, there are conflicting reports regarding their validity in modeling the negative symptoms and cognitive deficits of schizophrenia. The present study examined how acute AMPH or PCP treatment (Experiment 1) and withdrawal from repeated AMPH treatment (Experiment 2) or PCP treatment (Experiment 3) affects social behavior and social recognition memory in male Sprague-Dawley rats. Each subject was tested on two consecutive days. On the first day, the rats were tested four times (5 min/each) at 10-min intervals with the same partner rat (termed "AAAA" day). One day later, the rats were tested with the previous partner in the first three sessions and with a new partner rat in the final session (termed "AAAB" day). The results show that acute AMPH treatment (1.5 mg/kg, sc) significantly reduced the time spent on social interaction, but did not affect social recognition on the first day. Acute AMPH only disrupted social recognition on the second day of drug testing. In contrast, acute PCP treatment (2.0 mg/kg, sc) had no effect on time spent on social interaction, but did significantly disrupt social recognition on both days. Withdrawal from repeated AMPH (3.0 mg/kg/day for 7 days, ip) or PCP (5.0 mg/kg/twice daily for 7 days, ip) treatment did not affect social interaction or social recognition, indicating a lack of long-term detrimental effect of repeated AMPH or PCP treatment. These results suggest that acute AMPH treatment at a low dose (1.5 mg/kg) may be useful in modeling social withdrawal symptoms of schizophrenia, whereas acute PCP treatment at a similar dose range (2.0 mg/kg) may be useful in modeling the social cognitive deficit of schizophrenia. © 2012 The Institute of Psychology, Chinese Academy of Sciences and Blackwell Publishing Asia Pty Ltd.

A perforated duodenal ulcer presenting as inferior lead ST elevation following amphetamine use.

PubMed

Jones, H G; Hopkins, L; Clayton, A; McKain, E

2012-05-01

Typical symptoms of duodenal ulcers include epigastric pain, nausea, vomiting, chest pain and shortness of breath. Here we present the case of a 39-year-old man who had a sudden onset of chest and epigastric pain following the use of recreational amphetamines. There were ST changes in the inferior leads of his electrocardiogram, indicating the possibility of a myocardial infarction. Following double contrast computed tomography of the abdomen and an urgent laparotomy, a diagnosis of a perforated duodenal ulcer was made. We discuss the aetiologies, presentation, investigation and treatment of the disorder, and make recommendations on the management.

Tripling of Methamphetamine/Amphetamine Use among Homeless and Marginally Housed Persons, 1996–2003

PubMed Central

Colfax, Grant; Moss, Andrew R.; Bangsberg, David R.; Hahn, Judith A.

2007-01-01

Methamphetamine/amphetamine (MA)-related morbidity and mortality has been increasing in the United States. MA use is associated with high-risk sexual behavior and syringe-sharing practices. Homeless and marginalized housed persons (H/M) have high rates of substance use and mental health disorders. Little is known about trends of MA use among the H/M. The objective of this study was to quantify increases in MA use among H/M in San Francisco and to determine which demographic and behavioral subgroups have experienced the greatest increases in MA use. We conducted serial cross-sectional population-based studies in three waves: 1996–1997, 1999–2000, and 2003 and studied 2,348 H/M recruited at shelters and lunch lines. The main outcome was self-reported current (30-day) MA use. We found a tripling of current MA use among H/M persons from 1996 to 2003, with a sevenfold increase in smoked MA use. MA use doubled to tripled in most demographic and behavioral subgroups, whereas it quadrupled in those under age 35, and there was a fivefold increase among HIV-infected persons. The increase in MA use among H/M places a vulnerable population at additional increased risk for HIV infection and MA-use related morbidity and mortality. Among HIV-infected H/M, the increase in MA use has important public health implications for the development and secondary transmission of drug-resistant HIV caused by synergistic neurocognitive decline, poor adherence to HIV medications, and increased sexual risk behavior. Clinicians caring for H/M persons should inquire about MA use, refer interested MA users to MA dependence treatment programs and provide targeted HIV sexual risk reduction counseling. For HIV-infected H/M MA users, clinicians should closely monitor adherence to HIV or other chronic medications, to avoid unnecessary morbidity and mortality. Further research is needed to elucidate the most effective prevention and treatment for MA use and dependence among the H/M. PMID:18163214

The effects of amphetamine exposure on outcome-selective Pavlovian-instrumental transfer in rats

PubMed Central

Shiflett, Michael W.

2012-01-01

Rationale Repeated exposure to psychostimulants alters behavioral responses to reward-related cues; however, the motivational underpinnings of this effect have not been fully characterized. Objectives The following study was designed to examine how amphetamine sensitization affects performance in rats on a series of Pavlovian and operant tasks that distinguish between general-incentive and outcome-selective forms of conditioned responses. Methods Adult male rats underwent Pavlovian and instrumental training for food pellet rewards. Following training, rats were sensitized to d-amphetamine (2 mg/kg for 7 days). Rats were subsequently tested on an outcome-selective Pavlovian-instrumental transfer (PIT) task, an outcome-reinstatement task, and an outcome devaluation task. Additionally, in a separate experiment PIT was assessed in amphetamine-sensitized and control rats using a Pavlovian backward-conditioned stimulus. Results Repeated amphetamine exposure sensitized locomotor activity to acute amphetamine challenge. Amphetamine altered responses to CS presentations by increasing conditioned approach. During tests of PIT amphetamine-treated rats showed no outcome-selectivity in their responding, responding to a CS whether or not it shared a common outcome with the instrumental response. No effect of amphetamine sensitization was observed on tests of outcome-selective reinstatement by outcome delivery, or action selection based on outcome value. Amphetamine-sensitized rats showed impaired outcome-selective PIT to a backward CS but were unaltered in conditioned approach. Conclusions Amphetamine sensitization prevents outcome-selective responding during PIT, which is dissociable from amphetamine’s effects on conditioned approach. These data suggest fundamental alterations in how stimuli motivate action in addiction. PMID:22562522

History of childhood adversity is positively associated with ventral striatal dopamine responses to amphetamine.

PubMed

Oswald, Lynn M; Wand, Gary S; Kuwabara, Hiroto; Wong, Dean F; Zhu, Shijun; Brasic, James R

2014-06-01

Childhood exposure to severe or chronic trauma is an important risk factor for the later development of adult mental health problems, such as substance abuse. Even in nonclinical samples of healthy adults, persons with a history of significant childhood adversity seem to experience greater psychological distress than those without this history. Evidence from rodent studies suggests that early life stress may impair dopamine function in ways that increase risks for drug abuse. However, the degree to which these findings translate to other species remains unclear. This study was conducted to examine associations between childhood adversity and dopamine and subjective responses to amphetamine in humans. Following intake assessment, 28 healthy male and female adults, aged 18-29 years, underwent two consecutive 90-min positron emission tomography studies with high specific activity [(11)C]raclopride. The first scan was preceded by intravenous saline; the second by amphetamine (AMPH 0.3 mg/kg). Consistent with prior literature, findings showed positive associations between childhood trauma and current levels of perceived stress. Moreover, greater number of traumatic events and higher levels of perceived stress were each associated with higher ventral striatal dopamine responses to AMPH. Findings of mediation analyses further showed that a portion of the relationship between childhood trauma and dopamine release may be mediated by perceived stress. Overall, results are consistent with preclinical findings suggesting that early trauma may lead to enhanced sensitivity to psychostimulants and that this mechanism may underlie increased vulnerability for drug abuse.

Chronic caffeine produces sexually dimorphic effects on amphetamine-induced behavior, anxiety and depressive-like behavior in adolescent rats.

PubMed

Turgeon, Sarah M; Townsend, Shannon E; Dixon, Rushell S; Hickman, Emma T; Lee, Sabrina M

2016-04-01

Caffeine consumption has been increasing rapidly in adolescents; however, most research on the behavioral effects of caffeine has been conducted in adults. Two experiments were conducted in which adolescent male and female rats were treated with a moderate dose of caffeine (0.25 g/l) in their drinking water beginning on P26-28. In the first experiment, animals were maintained on caffeinated drinking water or normal tap water for 14 days and were then tested for behavioral and striatal c-Fos response to amphetamine (1.5 mg/kg). In the second experiment, rats were maintained on caffeinated drinking water or normal tap water beginning on P28 and were tested for novel object recognition, anxiety in the light/dark test (L/D) and elevated plus maze (EPM), and depressive like behavior in the forced swim test (FST) beginning on the 14th day of caffeine exposure. Caffeine decreased amphetamine-induced rearing in males, but had no effect in females; however, this behavioral effect was not accompanied by changes in striatal c-Fos, which was increased by amphetamine but not altered by caffeine. No effects of caffeine were observed on novel object recognition or elevated plus maze behavior. However, in the L/D test, there was a sex by caffeine interaction on time spent in the light driven by a caffeine-induced increase in light time in the males but not the females. On the pretest day of the FST, sex by caffeine interactions were observed for swimming and struggling; caffeine decreased struggling behavior and increased swimming behavior in males and caffeine-treated females demonstrated significantly more struggling and significantly less swimming than caffeine-treated males. A similar pattern was observed on the test day in which caffeine decreased immobility overall and increased swimming. These data reveal sex dependent effects of caffeine on behavior in adolescent rats. Copyright © 2016 Elsevier Inc. All rights reserved.

Enhanced appetitive conditioning following repeated pretreatment with d-amphetamine.

PubMed

Harmer, C J; Phillips, G D

1998-07-01

The behavioural response to psychomotor stimulants is augmented with repeated exposure to these drugs. Enhanced stimulated dopamine overflow within the nucleus accumbens and amygdala has been found to accompany this behavioural sensitization. In the present experiment, rats received 2 mg/kg d-amphetamine or 1 ml/kg physiological saline once per day for 5 days. Five days later, a behavioural assay confirmed that prior repeated d-amphetamine treatment markedly enhanced the locomotor activating effects of a d-amphetamine (0.5 mg/kg, i.p.) challenge. Training on a Pavlovian conditioning task began six days subsequently. In Stage 1, a stimulus (light or tone, S-) was presented negatively correlated with a sucrose reward. In Stage 2, presentation of the alternative counterbalanced stimulus (light or tone, S+) was paired with the availability of a 10% sucrose solution. There were no differences between the two groups in their response to the the S- stimulus. However, sensitized animals showed a selective enhancement in the acquisition of conditioned responding to S+, relative to vehicle-injected controls. No differences in behaviour were recorded during the prestimulus periods, nor during presentations of sucrose. Levels of activity within the operant chamber extraneous to alcove approach were also similar in both groups of animals. The conditioned instrumental efficacy of S+, relative to S- was assessed in Stage 3, in which stimulus availability was made contingent on a novel lever-pressing response. Both groups showed a similar preference for the S+ over the S- stimulus. Hence, rats sensitized by prior repeated d-amphetamine showed enhanced appetitive Pavlovian conditioning, without subsequent effect on conditioned reward efficacy. These data are discussed in light of possible changes in mesoamygdaloid dopamine functioning.

Differential sensitivity of Pak5, Pak6, and Pak5/Pak6 double-knockout mice to the stimulant effects of amphetamine and exercise-induced alterations in body weight.

PubMed

Furnari, Melody A; Jobes, Michelle L; Nekrasova, Tanya; Minden, Audrey; Wagner, George C

2014-04-01

PAK5 and PAK6 are protein kinases highly expressed in the brain. Previously, we observed that Pak6 knockout mice gained significantly more weight during development than Pak5 knockout mice as well as wild-type controls and double-knockout mice lacking both Pak5 and Pak6. In this study, we assessed the effects of exercise on food intake and weight gain of these mice as well as their sensitivity to the stimulant effects of amphetamine. Mice of each genotype were placed in cages with free access to run wheel exercise or in cages without run wheels for a total of 74 days. Food and fluid intake as well as body weight of each mouse were measured on a weekly basis. Finally, mice were given a high dose of amphetamine and activity levels were observed immediately thereafter for 90 minutes. Brains and testes of mice were assayed for protein levels of the estrogen alpha and progesterone receptors. While run wheel mice consumed significantly more food, they weighed less than non-run wheel mice. In addition, although Pak6 knockout mice consumed the same amount of food as wild-type mice, they were significantly heavier regardless of run wheel condition. Pak5 knockout mice were found to be more active than other genotypes after amphetamine treatment. Finally, protein levels of the progesterone and estrogen alpha receptors were altered in brain and testes of the Pak6 knockout mice. Collectively, these data suggest that PAK6 play a role in weight gain unrelated to exercise and caloric intake and that Pak5 knockout mice are more sensitive to the stimulant effects of amphetamine.

Does prenatal methamphetamine exposure affect the drug-seeking behavior of adult male rats?

PubMed

Slamberová, Romana; Schutová, Barbora; Hrubá, Lenka; Pometlová, Marie

2011-10-10

Methamphetamine (MA) is one of the most frequently used illicit drugs worldwide and also one of the most common drugs abused by pregnant women. Repeated administration of psychostimulants induces behavioral sensitization in response to treatment of the same or related drugs in rodents. The effect of prenatal MA exposure on sensitivity to drugs in adulthood is not yet fully determined. Because our most recent studies demonstrated that prenatal MA (5mg/kg) exposure makes adult rats more sensitive to acute injection of the same drug, we were interested whether the increased sensitivity corresponds with the increased drug-seeking behavior. The aim of the present study was to examine the effect of prenatal MA exposure on drug-seeking behavior of adult male rats tested in the conditioned place preference (CPP). The following psychostimulant drugs were used as a challenge in adulthood: MA (5mg/kg), amphetamine (5mg/kg) and cocaine (10mg/kg). All psychostimulant drugs induced increased drug-seeking behavior in adult male rats. However, while MA and amphetamine-induced increase in drug-seeking behavior did not differ based on the prenatal drug exposure, prenatally MA-exposed rats displayed tolerance effect to cocaine in adulthood. In addition, prenatally MA-exposed rats had decreased weight gain after administration of MA or amphetamine, while the weight of prenatally MA-exposed rats stayed unchanged after cocaine administration. Defecation was increased by all the drugs (MA, amphetamine and cocaine), while only amphetamine increased the tail temperature. In conclusion, our results did not confirm our hypothesis that prenatal MA exposure increases drug-seeking behavior in adulthood in the CPP test. Copyright © 2011 Elsevier B.V. All rights reserved.

The modulation effects of d-amphetamine and procaine on the spontaneously generated action potentials in the central neuron of snail, Achatina fulica Ferussac.

PubMed

Lin, Chia-Hsien; Tsai, Ming-Cheng

2005-05-01

The modulation effects of d-amphetamine and procaine on the spontaneously generated action potentials were studied on the RP1 central neuron of giant African snails (Achatina fulica Ferussac). Extra-cellular application of d-amphetamine or procaine reversibly elicited bursts of potential (BoP). Prazosin, propranolol, atropine or d-tubocurarine did not alter the BoP elicited by either d-amphetamine or procaine. KT-5720 or H89 (protein kinase A inhibitors) blocked d-amphetamine-elicited BoP, whereas they did not block the procaine-elicited BoP. U73122, neomycin (phospholipase C inhibitors) blocked the procaine-elicited BoP, whereas they did not block the d-amphetamine-elicited BoP in the same neuron. These results suggest that BoP elicited by d-amphetamine or procaine were associated with protein kinase A and phospholipase C activity in the neuron.

Narcolepsy Treated with Racemic Amphetamine during Pregnancy and Breastfeeding.

PubMed

Öhman, Inger; Wikner, Birgitta Norstedt; Beck, Olof; Sarman, Ihsan

2015-08-01

This case report describes a woman with narcolepsy treated with racemic amphetamine (rac-amphetamine) during pregnancy and breastfeeding with follow-up on the infant's development up to 10 months of age. The pregnancy outcome and the pharmacokinetics of rac-amphetamine were studied during breastfeeding. The pregnancy and the delivery were uneventful. Concentrations of rac-amphetamine were determined in the plasma of the mother and infant, and in the breast milk with a liquid chromatography-mass spectrometry method. Samples were obtained at 2, 5, and 9 weeks postpartum. The transfer of rac-amphetamine to the breast milk was extensive (mean milk/maternal plasma concentration ratio approximately 3). The breastfed infant had a low plasma concentration of rac-amphetamine (about 9% of the maternal plasma level) and the calculated relative infant dose was low (2%). No adverse effects were observed in the breastfed infant. The infant's somatic and psychomotor development up to 10 months of age was normal. Further studies of amphetamine prescribed for medical reasons during pregnancy and lactation are needed. © The Author(s) 2015.

Microglial activation is a pharmacologically specific marker for the neurotoxic amphetamines.

PubMed

Thomas, David M; Dowgiert, Jennifer; Geddes, Timothy J; Francescutti-Verbeem, Dina; Liu, Xiuli; Kuhn, Donald M

2004-09-09

Neurotoxic amphetamines cause damage to monoamine nerve terminals of the striatum by unknown mechanisms. Microglial activation contributes to the neuronal damage that accompanies injury, disease, and inflammation, but a role for these cells in amphetamine-induced neurotoxicity has received little attention. We show presently that D-methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA), D-amphetamine, and p-chloroamphetamine, each of which has been linked to dopamine (DA) or serotonin nerve terminal damage, result in microglial activation in the striatum. The non-neurotoxic amphetamines l-methamphetamine, fenfluramine, and DOI do not have this effect. All drugs that cause microglial activation also increase expression of glial fibrillary acidic protein (GFAP). At a minimum, microglial activation serves as a pharmacologically specific marker for striatal nerve terminal damage resulting only from those amphetamines that exert neurotoxicity. Because microglia are known to produce many of the reactive species (e.g., nitric oxide, superoxide, cytokines) that mediate the neurotoxicity of the amphetamine-class of drugs, their activation could represent an early and essential event in the neurotoxic cascade associated with high-dose amphetamine intoxication.

Impairment related to blood amphetamine and/or methamphetamine concentrations in suspected drugged drivers.

PubMed

Gustavsen, Ingebjørg; Mørland, Jørg; Bramness, Jørgen G

2006-05-01

Experimental studies have investigated effects of low oral doses of amphetamine and methamphetamine on psychomotor functions, while less work has been done on effects of high doses taken by abusers in real-life settings. There are indications that intake of high doses may impair traffic related skills, and that abuse of amphetamines may cause hypersomnolence at the end-of-binge. The present study aimed at investigating the concentration-effect relationship between blood amphetamines concentrations and impairment in a population of real-life users. Eight hundred and seventy-eight cases with amphetamine or methamphetamine as the only drugs present in the blood samples were selected from the impaired driver registry at The Norwegian Institute of Public Health. In each case the police physician had concluded on whether the driver was impaired or not. 27% of the drivers were judged as not impaired, while 73% were judged as impaired. There was a positive relationship between blood amphetamines concentrations and impairment. The relationship reached a ceiling at blood amphetamines concentrations of 0.27-0.53 mg/l. Younger drivers were more often judged impaired than older drivers at similar concentrations. Despite the performance enhancing qualities of amphetamines demonstrated in some low dose laboratory experiments; this study revealed a positive relationship between blood amphetamines concentration and traffic related impairment.

Functional neuroimaging of amphetamine-induced striatal neurotoxicity in the pleiotrophin knockout mouse model.

PubMed

Soto-Montenegro, María Luisa; Vicente-Rodríguez, Marta; Pérez-García, Carmen; Gramage, Esther; Desco, Manuel; Herradón, Gonzalo

2015-03-30

Amphetamine-induced neurotoxic effects have traditionally been studied using immunohistochemistry and other post-mortem techniques, which have proven invaluable for the definition of amphetamine-induced dopaminergic damage in the nigrostriatal pathway. However, these approaches are limited in that they require large numbers of animals and do not provide the temporal data that can be collected in longitudinal studies using functional neuroimaging techniques. Unfortunately, functional imaging studies in rodent models of drug-induced neurotoxicity are lacking. The aim of this study was to evaluate in vivo the changes in brain glucose metabolism caused by amphetamine in the pleiotrophin knockout mouse (PTN-/-), a genetic model with increased vulnerability to amphetamine-induced neurotoxic effects. We showed that administration of amphetamine causes a significantly greater loss of striatal tyrosine hydroxylase content in PTN-/- mice than in wild-type (WT) mice. In addition, [(18)F]-FDG-PET shows that amphetamine produces a significant decrease in glucose metabolism in the striatum and prefrontal cortex in the PTN-/- mice, compared to WT mice. These findings suggest that [(18)F]-FDG uptake measured by PET is useful for detecting amphetamine-induced changes in glucose metabolism in vivo in specific brain areas, including the striatum, a key feature of amphetamine-induced neurotoxicity. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Amphetamine as a social drug: Effects of d-amphetamine on social processing and behavior

PubMed Central

Wardle, Margaret C.; Garner, Matthew J.; Munafò, Marcus R.; de Wit, Harriet

2012-01-01

Rationale Drug users often report using drugs to enhance social situations, and empirical studies support the idea that drugs increase both social behavior and the value of social interactions. One way drugs may affect social behavior is by altering social processing, for example by decreasing perceptions of negative emotion in others. Objectives We examined effects of d-amphetamine on processing of emotional facial expressions, and on the social behavior of talking. We predicted amphetamine would enhance attention, identification and responsivity to positive expressions, and that this in turn would predict increased talkativeness. Methods Over three sessions, 36 healthy normal adults received placebo, 10mg, and 20mg d-amphetamine under counterbalanced double-blind conditions. At each session we measured processing of happy, fearful, sad and angry expressions using an attentional visual probe task, a dynamic emotion identification task, and measures of facial muscle activity. We also measured talking. Results Amphetamine decreased the threshold for identifying all emotions, increased negative facial responses to sad expressions, and increased talkativeness. Contrary to our hypotheses, amphetamine did not alter attention to, identification of or facial responses to positive emotions specifically. Interestingly, the drug decreased the threshold to identify all emotions, and this effect was uniquely related to increased talkativeness, even after controlling for overall sensitivity to amphetamine. Conclusions The results suggest that amphetamine may encourage sociability by increasing sensitivity to subtle emotional expressions. These findings suggest novel social mechanisms that may contribute to the rewarding effects of amphetamine. PMID:22526538

Predictors of young adults' amphetamine use and disorders: a prospective study.

PubMed

Hayatbakhsh, Mohammad R; Najman, Jake M; Bor, William; Williams, Gail M

2009-05-01

Understanding the risk factors that predict amphetamine use and development of amphetamine abuse or dependence (disorder) may help guide preventive interventions. This study aimed to investigate the correlates and predictors of young adults' amphetamine use and use disorders. Prospective cohort, population-based study which started in Brisbane, South East Queensland (Australia) in 1981. The study participants were a cohort of 2042 young adults, followed up from birth to young adulthood. At the 21-year follow-up, amphetamine use was assessed via a self-report questionnaire, and amphetamine use disorder (AUD) was assessed using the Composite International Diagnostic Interview (CIDI-Auto). Potential predictors (15 risk factors) were assessed between baseline (antenatal visit) and the 21-year follow-up. These included participant's gender, mother's age and education, maternal marital status and quality of marital relationship, maternal tobacco and alcohol consumption, mother-child communication, child mental health and problem behaviours, child smoking and alcohol consumption and child school performance. Young adult amphetamine users were more likely to have concurrent symptoms of mental illness and problem behaviours and to use or abuse cigarettes, cannabis, or other illicit drugs. In multivariate analyses, young adults' amphetamine use and disorder were disproportionately more common among males and those who have prospectively reported aggression/delinquency or smoking at 14 years, or who have experienced childhood sexual abuse. Our findings suggest that problem behaviours, smoking and childhood sexual abuse are predictors of initiation to use of amphetamines and development of amphetamine abuse and dependence.

Extended Detection of Amphetamine and Methamphetamine in Oral Fluid.

PubMed

Andås, Hilde T; Enger, Asle; Øiestad, Åse Marit L; Vindenes, Vigdis; Christophersen, Asbjørg S; Huestis, Marilyn A; Øiestad, Elisabeth L

2016-02-01

Amphetamine and methamphetamine are popular drugs of abuse worldwide and are important components of drug monitoring programs. Windows of detection for amphetamine and methamphetamine in oral fluid after high doses have not been investigated. Repeated high-dose ingestions are likely to cause positive samples for extended periods. Common routes of administration of amphetamine/methamphetamine in Norway are oral intake or injection. The aim of this study was to investigate windows of detection for amphetamine and methamphetamine in oral fluid from drug addicts under sustained abstinence during detoxification. Twenty-five patients admitted to a closed detoxification unit were included in this study. Oral fluid samples were collected daily in the morning and evening, and urine every morning for 10 days. A blood sample was drawn during the first 5 days after admission if the patient consented. Oral fluid results were compared with urine results to determine whether a new ingestion occurred. Oral fluid was collected with the Intercept oral fluid collection device. In-house cutoff concentrations for amphetamine and methamphetamine were 6.8 and 7.5 mcg/L, respectively, in oral fluid, and 135 and 149 mcg/L, respectively, in urine. Amphetamines were detected in 11 oral fluid, 5 urine, and 2 blood specimens from 25 patients. Patients self-reported amphetamines intake of up to 0.5-2 g daily. Windows of detection for amphetamine and methamphetamine in oral fluid were up to 8 days, longer than in urine at the applied cutoff values. These data confirm that oral fluid is a viable alternative to urine for monitoring amphetamine abuse, and that these substances might be detected in oral fluid for at least 1 week after ingestion of high doses. Such long detection times were, as far as we are aware, never reported previously for oral fluid amphetamines.

Amphetamine concentrations in human urine following single-dose administration of the calcium antagonist prenylamine-studies using fluorescence polarization immunoassay (FPIA) and GC-MS.

PubMed

Kraemer, Thomas; Roditis, Susanne K; Peters, Frank T; Maurer, Hans H

2003-03-01

Prenylamine (R,S-N-(3,3-diphenylpropyl-methyl-2-phenethylamine), a World Health Organization class V calcium antagonist, is known to be metabolized to amphetamine. In this study, amphetamine concentrations after a single-dose administration of prenylamine were determined to check if they reached values that could be of analytical and/or pharmacological importance in clinical and forensic toxicology. Enantiomeric composition of amphetamine was also studied. Five volunteers received a single 120-mg oral dose of prenylamine. Urine samples were analyzed using the Abbott TDx immunoassay Amphetamine/Methamphetamine II and using our routine systematic toxicological analysis (STA) gas chromatography-mass spectrometry (GC-MS) procedure. For quantitation purposes, GC-MS was used in the selected-ion monitoring (SIM) mode (ions m/z 118, 122, 240, 244) after solid-phase extraction (Isolute Confirm HCX) and derivatization (heptafluorobutyric anhydride). Amphetamine-d5 was used as internal standard (IS). Chiral separation of the heptafluorobutyrated amphetamine enantiomers was achieved using an Astec Chiraldex G-PN column. The TDx results showed a great variability for the different volunteers. A urine sample of one volunteer showed results as high as 3200 ng/mL, whereas the urine samples of another volunteer never gave results greater than the TDx detection limit (100 ng/mL). Using the STA procedure, the presence of amphetamine could be confirmed in all urine samples with TDx results greater than the cutoff value (300 ng/mL). Using the GC-MS SIM method, amphetamine concentrations up to 1280 ng/mL were determined. Chiral analysis revealed that both enantiomers of amphetamine were present in the samples with a surplus of the S(+)-enantiomer in the early phase of excretion. Forensic implications are discussed.

Amphetamine withdrawal differentially affects hippocampal and peripheral corticosterone levels in response to stress.

PubMed

Bray, Brenna; Scholl, Jamie L; Tu, Wenyu; Watt, Michael J; Renner, Kenneth J; Forster, Gina L

2016-08-01

Amphetamine withdrawal is associated with heightened anxiety-like behavior, which is directly driven by blunted stress-induced glucocorticoid receptor-dependent serotonin release in the ventral hippocampus. This suggests that glucocorticoid availability in the ventral hippocampus during stress may be reduced during amphetamine withdrawal. Therefore, we tested whether amphetamine withdrawal alters either peripheral or hippocampal corticosterone stress responses. Adult male rats received amphetamine (2.5mg/kg, ip) or saline for 14 days followed by 2 weeks of withdrawal. Contrary to our prediction, microdialysis samples from freely-moving rats revealed that restraint stress-induced corticosterone levels in the ventral hippocampus are enhanced by amphetamine withdrawal relative to controls. In separate groups of rats, plasma corticosterone levels increased immediately after 20min of restraint and decreased to below stress-naïve levels after 1h, indicating negative feedback regulation of corticosterone following stress. However, plasma corticosterone responses were similar in amphetamine-withdrawn and control rats. Neither amphetamine nor stress exposure significantly altered protein expression or enzyme activity of the steroidogenic enzymes 11β-hydroxysteroid dehydrogenase (11β-HSD1) or hexose-6-phosphate dehydrogenase (H6PD) in the ventral hippocampus. Our findings demonstrate for the first time that amphetamine withdrawal potentiates stress-induced corticosterone in the ventral hippocampus, which may contribute to increased behavioral stress sensitivity previously observed during amphetamine withdrawal. However, this is not mediated by either changes in plasma corticosterone or hippocampal steroidogenic enzymes. Establishing enhanced ventral hippocampal corticosterone as a direct cause of greater stress sensitivity may identify the glucocorticoid system as a novel target for treating behavioral symptoms of amphetamine withdrawal. Copyright © 2016 Elsevier B.V. All rights reserved.

Amphetamine enhances endurance by increasing heat dissipation.

PubMed

Morozova, Ekaterina; Yoo, Yeonjoo; Behrouzvaziri, Abolhassan; Zaretskaia, Maria; Rusyniak, Daniel; Zaretsky, Dmitry; Molkov, Yaroslav

2016-09-01

Athletes use amphetamines to improve their performance through largely unknown mechanisms. Considering that body temperature is one of the major determinants of exhaustion during exercise, we investigated the influence of amphetamine on the thermoregulation. To explore this, we measured core body temperature and oxygen consumption of control and amphetamine-trea ted rats running on a treadmill with an incrementally increasing load (both speed and incline). Experimental results showed that rats treated with amphetamine (2 mg/kg) were able to run significantly longer than control rats. Due to a progressively increasing workload, which was matched by oxygen consumption, the control group exhibited a steady increase in the body temperature. The administration of amphetamine slowed down the temperature rise (thus decreasing core body temperature) in the beginning of the run without affecting oxygen consumption. In contrast, a lower dose of amphetamine (1 mg/kg) had no effect on measured parameters. Using a mathematical model describing temperature dynamics in two compartments (the core and the muscles), we were able to infer what physiological parameters were affected by amphetamine. Modeling revealed that amphetamine administration increases heat dissipation in the core. Furthermore, the model predicted that the muscle temperature at the end of the run in the amphetamine-treated group was significantly higher than in the control group. Therefore, we conclude that amphetamine may mask or delay fatigue by slowing down exercise-induced core body temperature growth by increasing heat dissipation. However, this affects the integrity of thermoregulatory system and may result in potentially dangerous overheating of the muscles. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Amphetamine Self-Administration and Dopamine Function: Assessment of Gene x Environment Interactions in Lewis and Fischer 344 Rats

PubMed Central

Meyer, Andrew C.; Bardo, Michael T.

2015-01-01

Rationale Previous research suggests both genetic and environmental influences on substance abuse vulnerability. Objectives The current work sought to investigate the interaction of genes and environment on the acquisition of amphetamine self-administration, as well as amphetamine-stimulated dopamine (DA) release in nucleus accumbens shell using in vivo microdialysis. Methods Inbred Lewis (LEW) and Fischer (F344) rat strains were raised in either an enriched condition (EC), social condition (SC), or isolated condition (IC). Acquisition of amphetamine self-administration (0.1 mg/kg/infusion) was determined across an incrementing daily fixed ratio (FR) schedule. In a separate cohort of rats, extracellular DA and the metabolite dihydroxyphenylacetic acid (DOPAC) were measured in the nucleus accumbens shell following an acute amphetamine injection (1 mg/kg). Results “Addiction-prone” LEW had greater acquisition of amphetamine self-administration on a FR1 schedule compared to “addiction-resistant” F344 when raised in the SC environment. These genetic differences were negated in both the EC and IC environments, with enrichment buffering against self-administration and isolation enhancing self-administration in both strains. On a FR5 schedule, the isolation-induced increase in amphetamine self-administration was greater in F344 than LEW. While no group differences were obtained in extracellular DA, gene x environment differences were obtained in extracellular levels of the metabolite DOPAC. In IC rats only, LEW showed an attenuation in the amphetamine-induced decrease in DOPAC compared to F344. IC LEW rats also had an attenuated DOPAC response to amphetamine compared to EC LEW. Conclusions The current results demonstrate gene x environment interactions in amphetamine self-administration and amphetamine-induced changes in extracellular DOPAC in NAc shell. However, the behavioral and neurochemical differences were not related directly, indicating that mechanisms independent of DA metabolism in NAc shell likely mediate the gene x environment effects in amphetamine self-administration. PMID:25566972

Previous Exposure to Δ9-Tetrahydrocannibinol Enhances Locomotor Responding to but Not Self-Administration of AmphetamineS⃞

PubMed Central

Cortright, James J.; Lorrain, Daniel S.; Beeler, Jeff A.; Tang, Wei-Jen

2011-01-01

Previous exposure to amphetamine leads to enhanced locomotor and nucleus accumbens (NAcc) dopamine (DA) responding to the drug as well as enhanced amphetamine self-administration. Here, we investigated the effects of exposure to Δ9-tetrahydrocannibinol (Δ9-THC) on behavioral and biochemical responding to amphetamine. Rats in different groups received five exposure injections of vehicle or one of five doses of Δ9-THC (0.4, 0.75, 1.5, 3.0, and 6.0 mg/kg i.p.) and were tested 2 days and 2 weeks later. Exposure to all but the lowest and highest doses of Δ9-THC enhanced the locomotor response to amphetamine (0.75 mg/kg i.p.), but all failed to enhance NAcc DA overflow in response to the drug. Moreover, exposure to 3.0 mg/kg i.p. Δ9-THC increased forskolin-evoked adenylyl cyclase activity in the NAcc and rats' locomotor response to the direct DA receptor agonist apomorphine (1.0 mg/kg s.c.), suggesting that Δ9-THC sensitized locomotor responding to amphetamine by up-regulating postsynaptic DA receptor signaling in the NAcc. Finally, amphetamine self-administration (200 μg/kg/infusion i.v.) was enhanced in amphetamine (5 × 1.5 mg/kg i.p.)-exposed rats, but not in rats exposed to Δ9-THC (5 × 3.0 mg/kg i.p.). Previous exposure to this dose of Δ9-THC modestly increased apomorphine SA (0.5 mg/kg/infusion i.v.). Thus, unlike amphetamine exposure, exposure to Δ9-THC does not enhance the subsequent NAcc DA response to amphetamine or promote amphetamine self-administration. Although Δ9-THC leads to alterations in postsynaptic DA receptor signaling in the NAcc and these can affect the generation of locomotion, these neuroadaptations do not seem to be linked to the expression of enhanced amphetamine self-administration. PMID:21389094

Amphetamine self-administration and dopamine function: assessment of gene × environment interactions in Lewis and Fischer 344 rats.

PubMed

Meyer, Andrew C; Bardo, Michael T

2015-07-01

Previous research suggests both genetic and environmental influences on substance abuse vulnerability. The current work sought to investigate the interaction of genes and environment on the acquisition of amphetamine self-administration as well as amphetamine-stimulated dopamine (DA) release in nucleus accumbens shell using in vivo microdialysis. Inbred Lewis (LEW) and Fischer (F344) rat strains were raised in either an enriched condition (EC), social condition (SC), or isolated condition (IC). Acquisition of amphetamine self-administration (0.1 mg/kg/infusion) was determined across an incrementing daily fixed ratio (FR) schedule. In a separate cohort of rats, extracellular DA and the metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were measured in the nucleus accumbens shell following an acute amphetamine injection (1 mg/kg). "Addiction-prone" LEW rats had greater acquisition of amphetamine self-administration on a FR1 schedule compared to "addiction-resistant" F344 rats when raised in the SC environment. These genetic differences were negated in both the EC and IC environments, with enrichment buffering against self-administration and isolation enhancing self-administration in both strains. On a FR5 schedule, the isolation-induced increase in amphetamine self-administration was greater in F344 than LEW rats. While no group differences were obtained in extracellular DA, gene × environment differences were obtained in extracellular levels of the metabolite DOPAC. In IC rats only, LEW rats showed attenuation in the amphetamine-induced decrease in DOPAC compared to F344 rats. IC LEW rats also had an attenuated DOPAC response to amphetamine compared to EC LEW rats. The current results demonstrate gene × environment interactions in amphetamine self-administration and amphetamine-induced changes in extracellular DOPAC in nucleus accumbens (NAc) shell. However, the behavioral and neurochemical differences were not related directly, indicating that mechanisms independent of DA metabolism in NAc shell likely mediate the gene × environment effects in amphetamine self-administration.

Brain Angiotensin II AT1 receptors are involved in the acute and long-term amphetamine-induced neurocognitive alterations.

PubMed

Marchese, Natalia Andrea; Artur de laVillarmois, Emilce; Basmadjian, Osvaldo Martin; Perez, Mariela Fernanda; Baiardi, Gustavo; Bregonzio, Claudia

2016-03-01

Angiotensin II, by activation of its brain AT1-receptors, plays an active role as neuromodulator in dopaminergic transmission. These receptors participate in the development of amphetamine-induced behavioral and dopamine release sensitization. Dopamine is involved in cognitive processes and provides connectivity between brain areas related to these processes. Amphetamine by its mimetic activity over dopamine neurotransmission elicits differential responses after acute administration or after re-exposure following long-term withdrawal periods in different cognitive processes. The purpose of this study is to evaluate the AT1-receptor involvement in the acute and long-term amphetamine-induced alterations in long-term memory and in cellular-related events. Male Wistar rats (250-300 g) were used in this study. Acute effects: Amphetamine (0.5/2.5 mg/kg i.p.) was administered after post-training in the inhibitory avoidance (IA) response. The AT1-receptor blocker Losartan was administered i.c.v. before a single dose of amphetamine (0.5 mg/kg i.p.). Long-term effects: The AT1-receptors blocker Candesartan (3 mg/kg p.o.) was administered for 5 days followed by 5 consecutive days of amphetamine (2.5 mg/kg/day, i.p.). The neuroadaptive changes were evidenced after 1 week of withdrawal by an amphetamine challenge (0.5 mg/kg i.p.). The IA response, the neuronal activation pattern, and the hippocampal synaptic transmission were evaluated. The impairing effect in the IA response of post-training acute amphetamine was partially prevented by Losartan. The long-term changes induced by repeated amphetamine (resistance to acute amphetamine interference in the IA response, neurochemical altered response, and increased hippocampal synaptic transmission) were prevented by AT1-receptors blockade. AT1-receptors are involved in the acute alterations and in the neuroadaptations induced by repeated amphetamine associated with neurocognitive processes.

The effect of methamphetamine on an animal model of erectile function.

PubMed

Tar, M T; Martinez, L R; Nosanchuk, J D; Davies, K P

2014-07-01

In the US methamphetamine is considered a first-line treatment for attention-deficit hyperactivity disorder. It is also a common drug of abuse. Reports in patients and abusers suggest its use results in impotence. The efficacy of phosphodiesterase-5 inhibitors (PDE5i) to restore erectile function in these patient groups also has not been determined. In these studies, we determined if the rat is a suitable animal model for the physiological effects of methamphetamine on erectile function, and if a PDE5i (tadalafil) has an effect on erectile function following methamphetamine treatment. In acute phase studies, erectile function was measured in male Sprague-Dawley rats, before and after administration of 10 mg/kg methamphetamine i.p. Chronically treated animals received escalating doses of methamphetamine [2.5 mg/kg (1st week), 5 mg/kg (2nd week), and 10 mg/kg (3rd week)] i.p. daily for 3 weeks and erectile function compared with untreated controls. The effect of co-administration of tadalafil was also investigated in rats acutely and chronically treated with methamphetamine. Erectile function was determined by measuring the intracorporal pressure/blood pressure ratio (ICP/BP) following cavernous nerve stimulation. In both acute and chronic phase studies, we observed a significant increase in the rates of spontaneous erections after methamphetamine administration. In addition, following stimulation of the cavernous nerve at 4 and 6 mA, there was a significant decrease in the ICP/BP ratio (approximately 50%), indicative of impaired erectile function. Tadalafil treatment reversed this effect. In chronically treated animals, the ICP/BP ratio following 4 and 6 mA stimulation decreased by approximately 50% compared with untreated animals and erectile dysfunction (ED) was also reversed by tadalafil. Overall, our data suggest that the rat is a suitable animal model to study the physiological effect of methamphetamine on erectile function. Our work also provides a rationale for treating patients that report ED associated with therapeutics-containing methamphetamine or amphetamine with PDE5i. © 2014 American Society of Andrology and European Academy of Andrology.

Abuse of Medications Employed for the Treatment of ADHD: Results From a Large-Scale Community Survey

PubMed Central

Bright, George M.

2008-01-01

Objective The objective is to assess abuse of prescription and illicit stimulants among individuals being treated for attention-deficit/hyperactivity disorder (ADHD). Methods A survey was distributed to patients enrolled in an ADHD treatment center. It included questions designed to gain information about demographics; ADHD treatment history; illicit drug use; and misuse of prescribed stimulant medications, including type of stimulant medication most frequently misused or abused, and how the stimulant was prepared and administered. Results A total of 545 subjects (89.2% with ADHD) were included in the survey. Results indicated that 14.3% of respondents abused prescription stimulants. Of these, 79.8% abused short-acting agents; 17.2% abused long-acting stimulants; 2.0% abused both short- and long-acting agents; and 1.0% abused other agents. The specific medications abused most often were mixed amphetamine salts (Adderall; 40.0%), mixed amphetamine salts extended release (Adderall XR; 14.2%), and methylphenidate (Ritalin; 15.0%), and the most common manner of stimulant abuse was crushing pills and snorting (75.0%). Survey results also showed that 39.1% of respondents used nonprescription stimulants, most often cocaine (62.2%), methamphetamine (4.8%), and both cocaine and amphetamine (31.1%). Choice of illicit drug was based on rapidity of high onset (43.5%), ease of acquisition (40.7%), ease of use (10.2%), and cost (5.5%). Conclusions The risks for abuse of prescription and illicit stimulants are elevated among individuals being treated in an ADHD clinic. Prescription agents used most often are those with pharmacologic and pharmacokinetic characteristics that provide a rapid high. This suggests that long-acting stimulant preparations that have been developed for the treatment of ADHD may have lower abuse potential than short-acting formulations. PMID:18596945

Amphetamines and cannabinoids testing in hair: Evaluation of results from a two-year period.

PubMed

Burgueño, María José; Alonso, Amaya; Sánchez, Sergio

2016-08-01

This paper presents an overview of a set of amphetamines and cannabinoids tests performed on head hair samples from the Medico-Legal sector at the Madrid Department of the Spanish National Institute of Toxicology and Forensic Sciences during the years 2013 and 2014. The hair samples were tested for five stimulant phenylalkylamine derivatives -amphetamine (AP), methamphetamine (MA), 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxy-amphetamine (MDA), and 3,4-methylenedioxy-N-ethylamphetamine (MDEA)- and/or two cannabinoids-Δ(9)-tetrahydrocannabinol (THC) and cannabinol (CBN)- by gas chromatography equipped with mass spectrometry detection in selected-ion monitoring mode, applying a method accredited to ISO/IEC 17025 standards. The test results were interpreted according to the confirmation cut-offs proposed by the Society of Hair Testing (SoHT) to identify chronic drug use. The ratios of positive results were studied in relation to gender, age, hair colour, dyeing and length of the tested samples to assess the independence from these variables or the association with them. Low, medium and high ranges of concentration were also estimated for each drug. 21.94% of the 2954 hair samples tested for phenylalkylamine derivatives were positive for one or more substances. 16.38% of the samples were positive for AP, 12.09% for MDMA and only 0.44% for MA. 6.60% of the tested samples were positive for AP/MDMA combination. A total of 3178 samples were tested for cannabinoids, resulting in 53.40% positive for THC and CBN. Simultaneous tests for phenylalkylamine derivatives and cannabinoids were performed in 2931 of the samples; 14.94% of them were positive for THC, CBN, and one or more amphetamines. According to the results from the statistical analysis, the use of THC and MDMA vary with age and gender among the Medico-Legal sector in an extended area of Spain, while the use of AP appears to be independent of these variables. On the other hand, the results of THC in hair could be influenced by the length of the tested segment; therefore, a consensus regarding the hair length between 3.0 and 5.5cm for THC testing should be reached. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Brain pattern of histone H3 phosphorylation after acute amphetamine administration: its relationship to brain c-fos induction is strongly dependent on the particular brain area.

PubMed

Rotllant, David; Armario, Antonio

2012-02-01

Recent evidence strongly suggests a critical role of chromatin remodelling in the acute and chronic effects of addictive drugs. We reasoned that Immunohistochemical detection of certain histone modifications may be a more specific tool than induction of immediate early genes (i.e. c-fos) to detect brain areas and neurons that are critical for the action of addictive drugs. Thus, in the present work we studied in adult male rats the effects of a high dose of amphetamine on brain pattern of histone H3 phosphorylation in serine 10 (pH3S(10)) and c-fos expression. We firstly observed that amphetamine-induced an increase in the number of pH3S(10) positive neurons in a restricted number of brain areas, with maximum levels at 30 min after the drug administration that declined at 90 min in most areas. In a second experiment we studied colocalization of pH3S(10) immunoreactivity (pH3S(10)-IR) and c-fos expression. Amphetamine increased c-fos expression in medial prefrontal cortex (mPFC), dorsal striatum, nucleus accumbens (Acb), major Island of Calleja (ICjM), central amygdala (CeA), bed nucleus of stria terminalis lateral dorsal (BSTld) and paraventricular nucleus of the hypothalamus (PVN). Whereas no evidence for increase in pH3S(10) positive neurons was found in the mPFC and the PVN, in the striatum and the Acb basically all pH3S(10) positive neurons showed colocalization with c-fos. In ICjM, CeA and BSTld a notable degree of colocalization was found, but an important number of neurons expressing c-fos were negative for pH3S(10). The present results give support to the hypothesis that amphetamine-induced pH3S(10)-IR showed a more restricted pattern than brain c-fos induction, being this difference strongly dependent on the particular brain area studied. It is likely that those nuclei and neurons showing pH3S(10)-IR are more specifically associated to important effects of the drug, including neural plasticity. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'. Copyright © 2011 Elsevier Ltd. All rights reserved.

Alternative pharmacological strategies for adult ADHD treatment: a systematic review.

PubMed

Buoli, Massimiliano; Serati, Marta; Cahn, Wiepke

2016-01-01

Adult Attention Deficit Hyperactivity Disorder (ADHD) is a prevalent psychiatric condition associated with high disability and frequent comorbidity. Current standard pharmacotherapy (methylphenidate and atomoxetine) improves ADHD symptoms in the short-term, but poor data were published about long-term treatment. In addition a number of patients present partial or no response to methylphenidate and atomoxetine. Research into the main database sources has been conducted to obtain an overview of alternative pharmacological approaches in adult ADHD patients. Among alternative compounds, amphetamines (mixed amphetamine salts and lisdexamfetamine) have the most robust evidence of efficacy, but they may be associated with serious side effects (e.g. psychotic symptoms or hypertension). Antidepressants, particularly those acting as noradrenaline or dopamine enhancers, have evidence of efficacy, but they should be avoided in patients with comorbid bipolar disorder. Finally metadoxine and lithium may be particularly suitable in case of comorbid alcohol misuse or bipolar disorder.

Methylphenidate as a treatment for stuttering: a case report.

PubMed

Devroey, D; Beerens, G; Van De Vijver, E

2012-10-01

A randomized placebo controlled trial with methylphenidate (MPH) was set up to identify the effects of MPH on cognition in healthy young adults (ea. without attention deficit hyperactivity disorder, ADHD). Subjects repeatedly performed tests of the immediate and delayed memory and vigilance tasks after administration of placebo or 20 mg MPH. We report the case of an 18 year old man who participated in the study. He suffered from stuttering since childhood. During the study phase he reported a remarkable relief of the stuttering after the intake of 20 mg MPH. For D-amphetamine the beneficial effect on stuttering has been demonstrated but it was never implemented in clinical practice because of important adverse events. MPH, an amphetamine analogue, doesn't present these side effects. For this reason, MPH seems to merit further investigation in a randomized-controlled trial as a possible agent in the treatment of stuttering.Methylphenidate, Stuttering.

49 CFR 40.137 - On what basis does the MRO verify test results involving marijuana, cocaine, amphetamines, or PCP?

Code of Federal Regulations, 2012 CFR

2012-10-01

... involving marijuana, cocaine, amphetamines, or PCP? 40.137 Section 40.137 Transportation Office of the... results involving marijuana, cocaine, amphetamines, or PCP? (a) As the MRO, you must verify a confirmed positive test result for marijuana, cocaine, amphetamines, and/or PCP unless the employee presents a...

49 CFR 40.137 - On what basis does the MRO verify test results involving marijuana, cocaine, amphetamines, or PCP?

Code of Federal Regulations, 2010 CFR

2010-10-01

... involving marijuana, cocaine, amphetamines, or PCP? 40.137 Section 40.137 Transportation Office of the... results involving marijuana, cocaine, amphetamines, or PCP? (a) As the MRO, you must verify a confirmed positive test result for marijuana, cocaine, amphetamines, and/or PCP unless the employee presents a...

49 CFR 40.137 - On what basis does the MRO verify test results involving marijuana, cocaine, amphetamines, or PCP?

Code of Federal Regulations, 2011 CFR

2011-10-01

... involving marijuana, cocaine, amphetamines, or PCP? 40.137 Section 40.137 Transportation Office of the... results involving marijuana, cocaine, amphetamines, or PCP? (a) As the MRO, you must verify a confirmed positive test result for marijuana, cocaine, amphetamines, and/or PCP unless the employee presents a...

49 CFR 40.137 - On what basis does the MRO verify test results involving marijuana, cocaine, amphetamines, or PCP?

Code of Federal Regulations, 2013 CFR

2013-10-01

... involving marijuana, cocaine, amphetamines, or PCP? 40.137 Section 40.137 Transportation Office of the... results involving marijuana, cocaine, amphetamines, or PCP? (a) As the MRO, you must verify a confirmed positive test result for marijuana, cocaine, amphetamines, and/or PCP unless the employee presents a...

49 CFR 40.137 - On what basis does the MRO verify test results involving marijuana, cocaine, amphetamines, or PCP?

Code of Federal Regulations, 2014 CFR

2014-10-01

... involving marijuana, cocaine, amphetamines, or PCP? 40.137 Section 40.137 Transportation Office of the... results involving marijuana, cocaine, amphetamines, or PCP? (a) As the MRO, you must verify a confirmed positive test result for marijuana, cocaine, amphetamines, and/or PCP unless the employee presents a...

[Driving under the influence of amphetamine and metamphetamine].

PubMed

Lia, Kjersti; Spigset, Olav; Slørdal, Lars

2009-01-15

The CNS stimulatory agents amphetamine and methamphetamine are often detected in blood samples from apprehended subjects driving under the influence of drugs. Relevant literature was identified through searches in PubMed and Google Scholar. The current state of knowledge regarding effects of amphetamines on traffic behaviour is reviewed and discussed. Limited epidemiological data and a small number of experimental studies using low doses of amphetamines are available. Low amphetamine doses have been associated with enhanced performance in studies of sleep-deprived subjects. Theoretical considerations and empirical observations suggest that higher doses may impede performance, but not in accordance with usual concentration/effect relationships. There is a conspicuous lack of data on how to handle cases of driving under the influence of amphetamines.

Current pharmacotherapy of attention deficit hyperactivity disorder.

PubMed

Reddy, D S

2013-10-01

Attention deficit hyperactivity disorder (ADHD) is a neurobehavioral developmental disorder in children and adults characterized by a persistent pattern of impulsiveness, inattention and hyperactivity. It affects about 3-10% of children and 2-5% of adolescents and adults and occurs about four times more commonly in boys than girls. The cause of ADHD is unknown, but it has strong genetic and environment components. The first-line treatment options for ADHD include behavioral therapy, pharmacotherapy with stimulants or both. Methylphenidate and amphetamine salts are the stimulant drugs of choice for ADHD treatment. Amphetamines act by increasing presynaptic release of dopamine and other biogenic amines in the brain. Methylphenidate inhibits the reuptake of dopamine and norepinephrine and therefore its pharmacology is identical to that of amphetamines. Lisdex-amfetamine is a prodrug of dextroamphetamine with low feasibility for abuse. Atomoxetine, a selective norepinephrine reuptake inhibitor, is an alternative, non-stimulant drug for ADHD but it is less efficacious than stimulants. Stimulants are generally safe but are associated with adverse effects including headache, insomnia, anorexia and weight loss. There is increased awareness about serious cardiovascular and psychiatric adverse events with ADHD drugs including concern for growth suppression in children. Stimulants have a high potential for abuse and dependence, and should be handled safely to prevent misuse and abuse. Copyright 2013 Prous Science, S.A.U. or its licensors. All rights reserved.

Repeated aripiprazole treatment causes dopamine D2 receptor up-regulation and dopamine supersensitivity in young rats

PubMed Central

Varela, Fausto A.; Der-Ghazarian, Taleen; Lee, Ryan J.; Charntikov, Sergios; Crawford, Cynthia A.; McDougall, Sanders A.

2017-01-01

Aripiprazole is a second-generation antipsychotic that is increasingly being prescribed to children and adolescents. Despite this trend, little preclinical research has been done on the neural and behavioral actions of aripiprazole during early development. In the present study, young male and female Sprague-Dawley rats were pretreated with vehicle, haloperidol (1 mg/kg), or aripiprazole (10 mg/kg) once daily on postnatal days (PD) 10–20. After one, four, or eight days (i.e., on PD 21, PD 24, or PD 28), amphetamine-induced locomotor activity and stereotypy, as well as dorsal striatal D2 receptor levels, were measured in separate groups of rats. Pretreating young rats with aripiprazole or haloperidol increased D2 binding sites in the dorsal striatum. Consistent with these results, dopamine supersensitivity was apparent when aripiprazole- and haloperidol-pretreated rats were given a test day injection of amphetamine (2 or 4 mg/kg). Increased D2 receptor levels and altered behavioral responding persisted for at least eight days after conclusion of the pretreatment regimen. Contrary to what has been reported in adults, repeated aripiprazole treatment caused D2 receptor up-regulation and persistent alterations of amphetamine-induced behavior in young rats. These findings are consistent with human clinical studies showing that children and adolescents are more prone than adults to aripiprazole-induced side-effects, including extrapyramidal symptoms. PMID:24045880

Amphetamine abuse in Sweden: subject demographics, changes in blood concentrations over time, and the types of coingested substances.

PubMed

Jones, Alan Wayne; Holmgren, Anita

2013-04-01

Amphetamine is a major drug of abuse in Sweden and in the other Nordic countries. The demographics of amphetamine abusers in Sweden and the concentrations of this stimulant in blood are reported for 10 years of forensic blood samples (2001-2010). Using a forensic toxicology database (TOXBASE), we studied 1183 amphetamine-related deaths, 20,452 users of illicit drugs, and 47,366 people arrested for driving under the influence of drugs (DUID). Most amphetamine abusers were male (82%-87%), and their average age was 33 to 39 years with males being 2 to 3 years older than females (P < 0.001). Mean (median) concentrations of amphetamine in blood were 1.25 (0.40) mg/L in autopsy cases, 0.61 (0.40) mg/L in users of illicit drugs, and 0.76 (0.58) mg/L in DUID suspects. Median concentration in DUID suspects was significantly higher than in the other forensic materials (P < 0.001). Women also had higher median concentrations of amphetamine in blood than male abusers of this central stimulant (P < 0.001). The major coingested drugs were benzodiazepines (41%), cannabis (26%), opiates (21%), and alcohol (18%) in autopsy cases. Polydrug use was less common in DUID suspects and users of illicit drugs, although benzodiazepines (13%), tetrahydrocannabinol (12%), and opiates (5%) were often identified along with amphetamine. Because median concentration of amphetamine was higher in living subjects (DUID suspects) compared with amphetamine-related deaths, this points toward toxicity of coingested drugs or adverse drug-drug interaction as being responsible for death.

Intracellular Methamphetamine Prevents the Dopamine-induced Enhancement of Neuronal Firing*

PubMed Central

Saha, Kaustuv; Sambo, Danielle; Richardson, Ben D.; Lin, Landon M.; Butler, Brittany; Villarroel, Laura; Khoshbouei, Habibeh

2014-01-01

The dysregulation of the dopaminergic system is implicated in multiple neurological and neuropsychiatric disorders such as Parkinson disease and drug addiction. The primary target of psychostimulants such as amphetamine and methamphetamine is the dopamine transporter (DAT), the major regulator of extracellular dopamine levels in the brain. However, the behavioral and neurophysiological correlates of methamphetamine and amphetamine administration are unique from one another, thereby suggesting these two compounds impact dopaminergic neurotransmission differentially. We further examined the unique mechanisms by which amphetamine and methamphetamine regulate DAT function and dopamine neurotransmission; in the present study we examined the impact of extracellular and intracellular amphetamine and methamphetamine on the spontaneous firing of cultured midbrain dopaminergic neurons and isolated DAT-mediated current. In dopaminergic neurons the spontaneous firing rate was enhanced by extracellular application of amphetamine > dopamine > methamphetamine and was DAT-dependent. Amphetamine > methamphetamine similarly enhanced DAT-mediated inward current, which was sensitive to isosmotic substitution of Na+ or Cl− ion. Although isosmotic substitution of extracellular Na+ ions blocked amphetamine and methamphetamine-induced DAT-mediated inward current similarly, the removal of extracellular Cl− ions preferentially blocked amphetamine-induced inward current. The intracellular application of methamphetamine, but not amphetamine, prevented the dopamine-induced increase in the spontaneous firing of dopaminergic neurons and the corresponding DAT-mediated inward current. The results reveal a new mechanism for methamphetamine-induced dysregulation of dopaminergic neurons. PMID:24962577

Discriminative stimulus effects of caffeine and benzphetamine in amphetamine-trained volunteers.

PubMed

Chait, L D; Johanson, C E

1988-01-01

The discriminative stimulus (DS) and subjective effects of caffeine (100 and 300 mg, PO) and benzphetamine (12.5 and 50 mg, PO) were studied in 18 normal human volunteers trained to discriminate between d-amphetamine (10 mg) and placebo. d-Amphetamine increased ratings of drug liking and activity level and produced a profile of subjective effects characteristic of amphetamine and related psychomotor stimulants. The DS effects of d-amphetamine generalized only partially to caffeine and benzphetamine; mean percent d-amphetamine-appropriate responding was 42 and 58 after 100 and 300 mg caffeine, respectively, and 17 and 56 after 12.5 and 50 mg benzphetamine, respectively. Neither dose of caffeine affected ratings of drug liking or activity level, but 300 mg caffeine did produce a profile of subjective effects that partially overlapped with that produced by d-amphetamine. Benzphetamine 50 mg, but not 12.5 mg, increased ratings of drug liking and activity level and produced a profile of subjective effects qualitatively similar to, but weaker than, that produced by d-amphetamine. For both caffeine and benzphetamine, a close relationship was observed between their subjective effects and their ability to substitute for the DS effects of d-amphetamine. These results correspond well with findings obtained from similar studies conducted with laboratory animals, providing further support for the reliability and validity of human drug discrimination paradigms.

Class identity assignment for amphetamines using neural networks and GC-FTIR data

NASA Astrophysics Data System (ADS)

Gosav, S.; Praisler, M.; Van Bocxlaer, J.; De Leenheer, A. P.; Massart, D. L.

2006-08-01

An exploratory analysis was performed in order to evaluate the feasibility of building of neural network (NN) systems automating the identification of amphetamines necessary in the investigation of drugs of abuse for epidemiological, clinical and forensic purposes. A first neural network system was built to distinguish between amphetamines and nonamphetamines. A second, more refined system, aimed to the recognition of amphetamines according to their toxicological activity (stimulant amphetamines, hallucinogenic amphetamines, nonamphetamines). Both systems proved that discrimination between amphetamines and nonamphetamines, as well as between stimulants, hallucinogens and nonamphetamines is possible (83.44% and 85.71% correct classification rate, respectively). The spectroscopic interpretation of the 40 most important input variables (GC-FTIR absorption intensities) shows that the modeling power of an input variable seems to be correlated with the stability and not with the intensity of the spectral interaction. Thus, discarding variables only because they correspond to spectral windows with weak absorptions does not seem be not advisable.

Fenetylline: new results on pharmacology, metabolism and kinetics.

PubMed

Nickel, B; Niebch, G; Peter, G; von Schlichtegroll, A; Tibes, U

1986-06-01

In the fenetylline molecule, theophylline is covalently linked with amphetamine via an alkyl chain. The inclusion of amphetamine and results from early metabolic studies have led to speculation that fenetylline may be merely a prodrug for amphetamine and/or theophylline. Although previous studies are not consistent with this hypothesis, additional studies were conducted to comparatively evaluate the profiles of activity exhibited by fenetylline and its two postulated primary metabolites, (+/-)-amphetamine and theophylline. Investigations were also initiated using newly developed high pressure liquid chromatography (HPLC) techniques to further characterize the metabolic pattern that fenetylline undergoes and to examine the relationship between plasma pharmacokinetics and the pharmacodynamic actions of the drug. Fenetylline inhibits activity associated with amphetamine in certain test systems, an effect similar to that previously observed with fenfluramine. Only small amounts of the amphetamine theoretically available in the fenetylline molecule are released. Pharmacodynamic activity associated with fenetylline administration is more closely tied to plasma levels of the parent compound than to any (+/-)-amphetamine produced.

Spontaneous pneumomediastinum: A rare complication of methamphetamine use.

PubMed

Albanese, Jessica; Gross, Cole; Azab, Mohamed; Mahalean, Sinziana; Makar, Ranjit

2017-01-01

To present an unusual case of spontaneous pneumomediastinum subsequent to recreational amphetamine use. A young African American adult male was admitted to internal medicine service for treatment of rhabdomyolysis secondary to methamphetamine use. On admission, he was complaining of chest pain in addition to nausea and generalized muscle aches. By his second hospital day, chest pain had resolved yet physical exam demonstrated crepitation of the anterior chest and left axilla. Portable chest x-ray revealed subcutaneous emphysema in addition to pneumomediastinum. Spontaneous pneumomediastinum is a rare complication of amphetamine use that is often associated with subcutaneous emphysema and can be diagnosed with chest x-ray. Management is conservative, with observation, pain control, and supplemental oxygen as needed.

Effects of cysteamine on dopamine-mediated behaviors: evidence for dopamine-somatostatin interactions in the striatum

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

Martin-Iverson, M.T.; Radke, J.M.; Vincent, S.R.

1986-06-01

The effects of prior treatment with cysteamine, a drug which appears to deplete selectively the neuropeptide somatostatin, on apomorphine-induced stereotypy and amphetamine-induced locomotor activity and conditioned place preferences were investigated. Twelve hours following systemic cysteamine injections apomorphine-induced stereotypy was attenuated and striatal somatostatin levels were reduced by half. Systemic cysteamine also decreased the motor stimulant effects of amphetamine, without influencing the rewarding properties as determined by the conditioned place preference procedure. Direct injections of cysteamine into the nucleus accumbens also decreased the locomotor response to amphetamine, and produced a local reduction in somatostatin levels in the accumbens. Cysteamine did notmore » appear to alter monoamine turnover in the striatum after either systemic or intra-accumbens injections. These results suggest that somatostatin in the nucleus accumbens and caudate-putamen modulates the motor, but not the reinforcing properties of dopaminergic drugs, possibly via an action postsynaptic to dopamine-releasing terminals. Furthermore, it is evident from these results that cysteamine is an important tool with which to study the central actions of somatostatin.« less

Ghrelin receptor antagonism attenuates cocaine- and amphetamine-induced locomotor stimulation, accumbal dopamine release, and conditioned place preference.

PubMed

Jerlhag, Elisabet; Egecioglu, Emil; Dickson, Suzanne L; Engel, Jörgen A

2010-09-01

Recently we demonstrated that genetic or pharmacological suppression of the central ghrelin signaling system, involving the growth hormone secretagogue receptor 1A (GHS-R1A), lead to a reduced reward profile from alcohol. As the target circuits for ghrelin in the brain include a mesolimbic reward pathway that is intimately associated with reward-seeking behaviour, we sought to determine whether the central ghrelin signaling system is required for reward from drugs of abuse other than alcohol, namely cocaine or amphetamine. We found that amphetamine-as well as cocaine-induced locomotor stimulation and accumbal dopamine release were reduced in mice treated with a GHS-R1A antagonist. Moreover, the ability of these drugs to condition a place preference was also attenuated by the GHS-R1A antagonist. Thus GHS-R1A appears to be required not only for alcohol-induced reward, but also for reward induced by psychostimulant drugs. Our data suggest that the central ghrelin signaling system constitutes a novel potential target for treatment of addictive behaviours such as drug dependence.

Skills Training for Drug Abusers: Generalization, Maintenance, and Effects on Drug Use.

ERIC Educational Resources Information Center

Hawkins, J. David; And Others

1989-01-01

Analyzed follow-up data for drug abuse treatment study of residential drug treatment program clients (N=89) enrolled in control group or behavior skills training group. Found training group had higher skills than control group 12 months after training. Found, with exceptions of marijuana and amphetamine use, that skill training did not affect…

The pharmacology and toxicology of “ecstasy” (MDMA) and related drugs

PubMed Central

Kalant, Harold

2001-01-01

Abtract "Ecstasy" (MDMA) and related drugs are amphetamine derivatives that also have some of the pharmacological properties of mescaline. They have become popular with participants in "raves," because they enhance energy, endurance, sociability and sexual arousal. This vogue among teenagers and young adults, together with the widespread belief that "ecstasy" is a safe drug, has led to a thriving illicit traffic in it. But these drugs also have serious toxic effects, both acute and chronic, that resemble those previously seen with other amphetamines and are caused by an excess of the same sympathomimetic actions for which the drugs are valued by the users. Neurotoxicity to the serotonergic system in the brain can also cause permanent physical and psychiatric problems. A detailed review of the literature has revealed over 87 "ecstasy"-related fatalities, caused by hyperpyrexia, rhabdomyolysis, intravascular coagulopathy, hepatic necrosis, cardiac arrhythmias, cerebrovascular accidents, and drug-related accidents or suicide. The toxic or even fatal dose range overlaps the range of recreational dosage. The available evidence does not yet permit an accurate assessment of the size of the problem presented by the use of these drugs. PMID:11599334

Association study of GABA system genes polymorphisms with amphetamine-induced psychotic disorder in a Han Chinese population.

PubMed

Zhang, Kai; Zhao, Yan; Wang, Qingzhong; Jiang, Haifeng; Du, Jiang; Yu, Shunying; Zhao, Min

2016-05-27

GABA system genes have been implicated in neurotrophy and neurogenesis, which play pivotal roles in an individual's variation in vulnerability to amphetamine addiction or amphetamine-induced psychosis (AIP). We hypothesized that common genetic variants in the GABA system genes may be associated with amphetamine-induced psychotic disorder. In our study, thirty-six single nucleotide polymorphisms (SNPs) within the GABA system genes were genotyped in 400 amphetamine-induced psychotic disorder patients and 400 amphetamine use disorders patients (AUP) (not including those categorized as psychosis) in the Han Chinese population. In this study, 51.88% of the Han Chinese amphetamine-type substance use disorder patients met the criteria of amphetamine-induced psychotic disorder, and 79.5% amphetamine-induced psychotic disorder patients had auditory hallucinations, while 46.5% had delusions of reference. The allele frequency of rs1129647 showed nominal association with AIP in the Han Chinese population (P=0.03). Compared with AUP group patients, T allele frequency of AIP group patients was significantly increased. The adjustment for age and gender factors in the AIP and AUP patients was executed using unconditional logistic regression under five inheritance models. The genotype frequency of rs1129647 showed nominal association with AIP in the log-additive model (P=0.04). The genotype frequency of rs2290733 showed nominal association with AIP in the recessive model (P=0.04). Compared with female AIP patients, male patients were more likely to have the CC genotype of rs17545383 (P=0.04). Moreover, we determined that more male patients carried the T allele of rs2290733 in the AIP group (P=0.004). Unfortunately, the significant differences did not survive Benjamini-Hochberg false discovery rate correction (adjusted P>0.05). No association between the SNPs of the GABA system genes and amphetamine-induced psychotic disorder risk was identified. No haplotype of the GABA system genes affected amphetamine-induced psychotic disorder risk. This report describes the first association study between the GABA system genes and amphetamine-induced psychotic disorder in the Han Chinese population. Our data may provide a reference for future research. Copyright © 2016. Published by Elsevier Ireland Ltd.

Treatment of the alcoholic organic brain syndrome: double-blind, placebo-controlled clinical, psychometric and electroencephalographic mapping studies with modafinil.

PubMed

Saletu, B; Saletu, M; Grünberger, J; Frey, R; Anderer, P; Mader, R

1993-01-01

In a double-blind study 40 abstinent hospitalized male patients with an alcoholic organic brain syndrome (OBS; ICD 9: 291.2) were treated for 6 weeks with either placebo or 200 mg modafinil b.i.d. Modafinil (CRL 40476) is a vigilance-promoting, putative central alpha 1-adrenergic agonist with a pharmacological profile quite different from that of amphetamine. Clinical investigations demonstrated that the spontaneous remission of the alcoholic OBS was augmented and accelerated by modafinil, which was found significant as compared with placebo by confirmatory statistics in the target variable, the Clinical Global Impression scale. The drug was well tolerated. Psychometric tests revealed significant improvement of the noopsyche after modafinil as compared with placebo, while the thymopsyche and psychophysiological measurements were not affected. Electroencephalographic mapping showed significant differences between the central effects of modafinil and placebo indicating an improvement of vigilance under modafinil. Typical vigilance-promoting properties were seen after acute drug administration, were less evident before the morning dose after chronic treatment but re-occurred after super-imposed daily drug administration. Thus, our clinical, psychometric and neurophysiological investigations in alcoholic OBS patients demonstrated a therapeutic effect of modafinil in the early phase of abstinence.

Association between travel length and drug use among Brazilian truck drivers.

PubMed

Sinagawa, Daniele Mayumi; De Carvalho, Heráclito Barbosa; Andreuccetti, Gabriel; Do Prado, Natanael Vitoriano; De Oliveira, Keziah Cristina Barbosa Gruber; Yonamine, Mauricio; Muñoz, Daniel Romero; Gjerde, Hallvard; Leyton, Vilma

2015-01-01

To investigate whether the use of the stimulants amphetamines and cocaine by truck drivers in Brazil was related to travel length. Truck drivers were randomly stopped by the Federal Highway Police on interstate roads in Sao Paulo State during morning hours from 2008 to 2011 and invited to participate in the project "Comandos de Saúde nas Rodovias" (Health Commands on the Roads). Participants were asked about the use of drugs, travel distance, and age, and gender was recorded. Samples of urine were collected and analyzed for amphetamine, benzoylecgonine (a metabolite of cocaine), and carboxytetrahydrocannabinol (THC-COOH; a metabolite of cannabis) by immunological screening and quantification by gas chromatography-mass spectroscopy. Current use of amphetamine, cocaine, and cannabis was reported by 5.7%, 0.7%, and 0.3% of the truck drivers, respectively. Amphetamine, benzoylecgonine, and THC-COOH were found in urine samples from 5.4%, 2.6,% and in 1.0% of the drivers, respectively. There was a significant association between the positive cases for amphetamine and reported travel length; 9.9% of urine samples from drivers who reported travel length of more than 270 km were positive for amphetamine, and 10.9% of those drivers reported current use of amphetamines. In most cases, appetite suppressants containing amphetamines had been used, but the purpose was most often to stay awake and alert while driving. Truck drivers with travel length of more than 270 km had significantly higher odds ratio (OR) for having a urine sample that was positive for amphetamine when adjusted for age as confounding factor (OR = 9.41, 95% confidence interval [CI], 3.97-22.26). No significant association was found between the use of cocaine or cannabis and travel length. Truck drivers who reported driving more than 270 km had significantly higher frequencies of urine samples positive for amphetamine and reported significantly more frequent current use of amphetamines than those who reported shorter driving distances.

Antipsychotic treatment leading to dopamine supersensitivity persistently alters nucleus accumbens function.

PubMed

El Hage, Cynthia; Bédard, Anne-Marie; Samaha, Anne-Noël

2015-12-01

Chronic exposure to some antipsychotic medications can induce supersensitivity to dopamine receptor stimulation. This is linked to a worsening of clinical outcome and to antipsychotic treatment failure. Here we investigated the role of striatal subregions [nucleus accumbens (NAc) and caudate-putamen (CPu)] in the expression of antipsychotic-induced dopamine supersensitivity. We treated rats with haloperidol (HAL) or olanzapine (OLZ), using regimens that achieve clinically relevant kinetics of striatal D2 receptor occupancy. Under these conditions, HAL produces dopamine supersensitivity whereas OLZ does not. We then assessed behaviors evoked by the dopamine agonist amphetamine (AMPH). We either injected AMPH into the striatum or inhibited striatal function with microinjections of GABA receptor agonists prior to injecting AMPH systemically. HAL-treated rats were dopamine supersensitive, as indicated by sensitization to systemic AMPH-induced potentiation of both locomotor activity and operant responding for a conditioned reward (CR). Intra-CPu injections of AMPH had no effect on these behaviors, in any group. Intra-NAc injections of AMPH enhanced operant responding for CR in OLZ-treated and control rats, but not in HAL-treated rats. In HAL-treated rats, inhibition of the NAc also failed to disrupt systemic AMPH-induced potentiation of operant responding for CR. Furthermore, while intra-NAc AMPH enhanced locomotion in both HAL-treated and control animals, inhibition of the NAc disrupted systemic AMPH-induced locomotion only in control rats. Thus, antipsychotic-induced dopamine supersensitivity persistently disrupts NAc function, such that some behaviors that normally depend upon NAc dopamine no longer do so. This has implications for understanding dysfunctions in dopamine-mediated behaviors in patients undergoing chronic antipsychotic treatment. Copyright © 2015 Elsevier Ltd. All rights reserved.

Cocaine abuse and its treatment.

PubMed

Resnick, R B; Resnick, E B

1984-12-01

Increasing numbers of individuals with a diagnosis of cocaine abuse (DSM-III, 305.6) are seeking medical and psychiatric care. The majority of users inhale the drug in powdered form, as cocaine is rapidly absorbed by mucous membranes. The patterns of use resemble those for the use of alcohol and marijuana: recreational, intensified, circumstantial, and compulsive. When cocaine is taken intravenously or by freebasing, individuals are much more vulnerable to developing a compulsive pattern of use that could lead to an organic delusional syndrome. Cocaine causes systemic effects that are similar to those of amphetamine, but they have a much shorter duration of action. Blood pressure, heart rate, feelings of "pleasantness" and "stimulation" are increased, and hunger is decreased. Acute tolerance may develop over hours of continuous use, but it disappears after a short period of abstinence (overnight). In psychomotor testing, performance that is impaired by fatigue is restored to baseline levels. Users like cocaine because they feel more alert, energetic, sociable, and sensual. However, these positive feelings are commonly followed by anxiety, depression, irritability, fatigue, and craving more cocaine. Chronic intoxication is always associated with adverse psychosocial sequelae. Treatment initially must be directed toward the patient's stopping all use of cocaine, employing strategies such as contingency contracts, urinalysis, family intervention, the assignment of financial control to others, or hospitalization. Several psychopharmacologic agents are helpful as an adjunct to a comprehensive treatment plan. Overdoses of cocaine are treated by diazepam and propranolol. Antidepressant medications, both TCAs and MAOIs, often help relieve the symptoms of depression that emerge when chronic use of cocaine is discontinued. Classical and operant conditioning contribute to craving for the drug and opportunities to extinguish these factors are valuable in preventing relapse. Compulsive users often have an Axis II diagnosis of borderline or narcissistic personality disorder, which require long-term psychodynamic psychotherapy.

Who are the new amphetamine users? A 10-year prospective study of young Australians.

PubMed

Degenhardt, Louisa; Coffey, Carolyn; Carlin, John B; Moran, Paul; Patton, George C

2007-08-01

Despite good evidence of increased availability and use of amphetamines world-wide, relatively little is known about the epidemiology of young adult amphetamine use; relationships with social functioning, other drug use and mental health at this age; nor of the adolescent predictors of such use. We examined these issues using a representative cohort of young people followed-up in Victoria, Australia. A stratified, random sample of 1943 adolescents was recruited from secondary schools across Victoria at age 14-15 years. This cohort was interviewed on eight occasions until the age of 24-25 years (78% follow-up at that age). Cross-sectional and predictive associations were assessed using logistic regression. At age 24 years, 12% of the sample had used amphetamines in the past year, with 1-2% using at least weekly. Young adult amphetamine use was predicted strongly by adolescent drug use and was associated robustly with other drug use and dependence in young adulthood. Associations were stronger for more frequent users. Among young adults who had not been using amphetamines at age 20 years, the strongest predictor of use at age 24 years was the use of other drugs, particularly cannabis, at 20 years. Psychological distress did not predict independently an increased likelihood of amphetamine use in this cohort. Young people in Australia using amphetamine at age 24 years are highly likely to be significant polydrug users. The risks for both initiation of young adult amphetamine use, and maintenance of such use, pertain to the heavy use of other drugs. Interventions for heavy amphetamine users at this age are likely to require attention to multiple drug problems.

Enhancement of a visual reinforcer by D-amphetamine and nicotine in adult rats: relation to habituation and food restriction.

PubMed

Wright, Jennifer M; Ren, Suelynn; Constantin, Annie; Clarke, Paul B S

2018-03-01

Nicotine and D-amphetamine can strengthen reinforcing effects of unconditioned visual stimuli. We investigated whether these reinforcement-enhancing effects reflect a slowing of stimulus habituation and depend on food restriction. Adult male rats pressed an active lever to illuminate a cue light during daily 60-min sessions. Depending on the experiment, rats were challenged with fixed or varying doses of D-amphetamine (0.25-2 mg/kg IP) and nicotine (0.025-0.2 mg/kg SC) or with the tobacco constituent norharman (0.03-10 μg/kg IV). Experiment 1 tested for possible reinforcement-enhancing effects of D-amphetamine and norharman. Experiment 2 investigated whether nicotine and amphetamine inhibited the spontaneous within-session decline in lever pressing. Experiment 3 assessed the effects of food restriction. Amphetamine (0.25-1 mg/kg) and nicotine (0.1 mg/kg) increased active lever pressing specifically (two- to threefold increase). The highest doses of nicotine and amphetamine also affected inactive lever responding (increase and decrease, respectively). With the visual reinforcer omitted, responding was largely extinguished. Neither drug appeared to slow habituation, as assessed by the within-session decline in lever pressing, and reinforcement-enhancing effects still occurred if the drugs were given after this decline had occurred. Food restriction enhanced the reinforcement-enhancing effect of amphetamine but not that of nicotine. Responding remained goal-directed after several weeks of testing. Low doses of D-amphetamine and nicotine produced reinforcement enhancement even in free-feeding subjects, independent of the spontaneous within-session decline in responding. Reinforcement enhancement by amphetamine, but not nicotine, was enhanced by concurrent subchronic food restriction.

Cocaine-like discriminative stimulus effects of amphetamine, cathinone, methamphetamine, and their 3,4-methylenedioxy analogs in male rhesus monkeys.

PubMed

Smith, Douglas A; Blough, Bruce E; Banks, Matthew L

2017-01-01

Synthetic cathinones have emerged as the newest class of abused monoamine transporter substrates. Structurally, these compounds are all beta-ketone amphetamine (cathinone) analogs. Whether synthetic cathinone analogs produce differential behavioral effects from their amphetamine analog counterparts has not been systematically examined. Preclinical drug discrimination procedures have been useful for determining the structure activity relationships (SARs) of abused drugs; however, direct comparisons between amphetamine and cathinone analogs are lacking and, in particular, in non-human primate models. The study aim was to determine the potency and time course of (±)-amphetamine, (±)-cathinone, and (±)-methamphetamine and their 3,4-methylenedioxy analogs (±)-MDA, (±)-MDC, and (±)-MDMA, respectively, to produce cocaine-like discriminative stimulus effects. If cathinone analogs have similar behavioral pharmacological properties to their amphetamine counterparts, then we would predict similar potencies and efficacies to produce cocaine-like discriminative stimulus effects. Male rhesus monkeys (n = 4) were trained to discriminate intramuscular cocaine (0.32 mg/kg) from saline in a two-key food-reinforced discrimination procedure. Racemic amphetamine, cathinone, and methamphetamine produced dose-dependent and full substitution, ≥90 % cocaine-appropriate responding, in all monkeys. Addition of 3,4-methylenedioxy moiety attenuated both the potency and efficacy of amphetamine (MDA), cathinone (MDC), and methamphetamine (MDMA) to produce full cocaine-like effects. Moreover, the cocaine-like effects of amphetamine and cathinone were attenuated to a greater extent than those of methamphetamine or previously published methcathinone (Smith et al. 2016). The presence of an N-methyl group blunted both the potency and the efficacy shift of the 3,4-methylenedioxy addition for both amphetamine and cathinone analogs.

Prenatal exposure to amphetamines. Risks and adverse outcomes in pregnancy.

PubMed

Plessinger, M A

1998-03-01

Based on findings in humans and the confirmation of prenatal exposures in animals, amphetamines and methamphetamines increase the risk of an adverse outcome when abused during pregnancy. Clefting, cardiac anomalies, and fetal growth reduction deficits that have been seen in infants exposed to amphetamines during pregnancy have all been reproduced in animal studies involving prenatal exposures to amphetamines. The differential effects of amphetamines between genetic strains of mice and between species demonstrate that pharmacokinetics and the genetic disposition of the mother and developing embryo can have an enormous influence on enhancing or reducing these potential risks. The effects of prenatal exposure to amphetamines in producing altered behavior in humans appear less compelling when one considers other confounding variables of human environment, genetics, and polydrug abuse. In view of the animal data concerning altered behavior and learning tasks in comparison with learning deficits observed in humans, the influence of the confounding variables in humans may serve to increase the sensitivity of the developing embryo/fetus to prenatal exposure to amphetamines. These factors and others may predispose the developing conceptus to the damaging effects of amphetamines by actually lowering the threshold of susceptibility at the sites where damage occurs. Knowledge of the effects of prenatal exposure of the fetus and the mother to designer amphetamines is lacking. Based on the few studies in which designer drugs have been examined in animal models, more questions are raised than answered. Possible reasons why no malformations or significant fetal effects were found in the study by St. Omer include the genetic strain of rat used, the conservative exposure profile, or the fact that the placenta metabolized MDMA before reaching the embryo. These questions underscore the need for further investigations concerning the prenatal exposure effects of designer compounds and the effects of amphetamine and methamphetamine in general.

The association between spending on methamphetamine/amphetamine and cannabis for personal use and earnings from acquisitive crime among police detainees in New Zealand.

PubMed

Wilkins, Chris; Sweetsur, Paul

2011-04-01

Few studies have examined the statistical association between methamphetamine/amphetamine use and acquisitive crime. Both methamphetamine/amphetamine and cannabis use have been implicated by New Zealand Police as factors in acquisitive offending among active criminal populations. The aim of our study was to examine the statistical association between spending on methamphetamine/amphetamine and cannabis and earnings from acquisitive crime among police detainees in New Zealand. Four police stations in different regions. A sample of 2125 police detainees were interviewed about their drug use and acquisitive crime. Statistical models were developed to predict involvement in acquisitive crime using spending on methamphetamine/amphetamine and cannabis for personal use, and to examine associations between the level of spending on methamphetamine/amphetamine and cannabis for personal use and level of dollar earnings from acquisitive crime. Self-reported spending on drug use and self-reported earnings from acquisitive crime in the past 30 days. Spending on cannabis and methamphetamine/amphetamine could predict involvement in acquisitive crime. Level of spending on methamphetamine/amphetamine and cannabis was associated positively with the level of earnings from property crime. Level of spending on methamphetamine/amphetamine was also associated positively with level of earnings from drug dealing. There was a largely negative association between level of spending on cannabis and level of earnings from drug dealing. High spending on methamphetamine/amphetamine is associated statistically with higher earnings from acquisitive crime among police detainees. Further research into this association, and in particular the causal nature of the association, is required to obtain clear policy recommendations. © 2010 The Authors, Addiction © 2010 Society for the Study of Addiction.

Cocaine-like discriminative stimulus effects of amphetamine, cathinone, methamphetamine, and their 3,4-methylenedioxy analogs in male rhesus monkeys

PubMed Central

Smith, Douglas A.; Blough, Bruce. E.; Banks, Matthew L.

2016-01-01

Rationale Synthetic cathinones have emerged as the newest class of abused monoamine transporter substrates. Structurally, these compounds are all beta-ketone amphetamine (cathinone) analogs. Whether synthetic cathinone analogs produce differential behavioral effects from their amphetamine analog counterparts has not been systematically examined. Preclinical drug discrimination procedures have been useful for determining the structure activity relationships (SAR) of abused drugs; however, direct comparisons between amphetamine and cathinone analogs are lacking and, in particular, in nonhuman primate models. Objectives The study aim was to determine the potency and time course of (±)-amphetamine, (±)-cathinone, (±)-methamphetamine, and their 3,4-methylenedioxy analogs (±)-MDA, (±)-MDC, and (±)-MDMA, respectively to produce cocaine-like discriminative stimulus effects. If cathinone analogs have similar behavioral pharmacological properties to their amphetamine counterparts, then we would predict similar potencies and efficacies to produce cocaine-like discriminative stimulus effects. Methods Male rhesus monkeys (n=4) were trained to discriminate intramuscular cocaine (0.32 mg/kg) from saline in a two-key food-reinforced discrimination procedure. Results Racemic amphetamine, cathinone, and methamphetamine produced dose-dependent and full, ≥90% cocaine-appropriate responding, in all monkeys. Addition of 3,4-methylenedioxy moiety attenuated both the potency and efficacy of amphetamine (MDA), cathinone (MDC), and methamphetamine (MDMA) to produce full cocaine-like effects. Moreover, the cocaine-like effects of amphetamine and cathinone were attenuated to a greater extent than methamphetamine or previously published methcathinone (Smith et al. 2016). Conclusion The presence of an N-methyl group blunted both the potency and efficacy shift of the 3,4-methylenedioxy addition for both amphetamine and cathinone analogs. PMID:27709249

Effect of low doses of delta9-tetrahydrocannabinol and cannabidiol on the extinction of cocaine-induced and amphetamine-induced conditioned place preference learning in rats.

PubMed

Parker, Linda A; Burton, Page; Sorge, Robert E; Yakiwchuk, Christine; Mechoulam, Raphael

2004-09-01

Using the place-preference conditioning paradigm, we evaluated the potential of the two most prominent cannabinoids found in marijuana, the psychoactive component delta9-tetrahydrocannabinol (delta9-THC) and the nonpsychoactive component cannabidiol (CBD), to potentiate extinction of a cocaine-induced and an amphetamine-induced conditioned place preference in rats. To determine the effects of pretreatment with delta9-THC or CBD on extinction, a cocaine-induced and amphetamine-induced place preference was first established. Rats were then given an extinction trial, during which they were confined to the treatment-paired floor for 15 min. Thirty minutes prior to the extinction trial, they were injected with a low dose of delta9-THC (0.5 mg/kg), CBD (5 mg/kg) or vehicle. The potential of the CB1 receptor antagonist, SR141716, to reverse the effects of delta9-THC or CBD was also evaluated. To determine the hedonic effects of CBD, one distinctive floor was paired with CBD (5 mg/kg) and another with saline. Finally, to determine the effect of delta9-THC.or CBD on the establishment and/or the expression of a place preference during four cycles of conditioning trials, rats were injected with delta9-THC (0.25-1 mg/kg), CBD (5 mg/kg) or vehicle 25 min prior to receiving an injection of amphetamine followed by placement on the treatment floor; on alternate days, they received injections of vehicle followed by saline and placement on the nontreatment floor. The rats then received two test trials; on one trial they were pretreated with the cannabinoid and on the other trial with vehicle. delta9-THC and CBD potentiated the extinction of both cocaine-induced and amphetamine-induced conditioned place preference learning, and this effect was not reversed by SR141716. The cannabinoids did not affect learning or retrieval, and CBD was not hedonic on its own. These results are the first to show that both delta9-THC, which acts on both CB 1 and CB2 receptors, and CBD, which does not bind to CB1 or CB2 receptors, potentiate the extinction of conditioned incentive learning.

Amphetamine Elicits Opposing Actions on Readily Releasable and Reserve Pools for Dopamine

PubMed Central

Covey, Dan P.; Juliano, Steven A.; Garris, Paul A.

2013-01-01

Amphetamine, a highly addictive drug with therapeutic efficacy, exerts paradoxical effects on the fundamental communication modes employed by dopamine neurons in modulating behavior. While amphetamine elevates tonic dopamine signaling by depleting vesicular stores and driving non-exocytotic release through reverse transport, this psychostimulant also activates phasic dopamine signaling by up-regulating vesicular dopamine release. We hypothesized that these seemingly incongruent effects arise from amphetamine depleting the reserve pool and enhancing the readily releasable pool. This novel hypothesis was tested using in vivo voltammetry and stimulus trains of varying duration to access different vesicular stores. We show that amphetamine actions are stimulus dependent in the dorsal striatum. Specifically, amphetamine up-regulated vesicular dopamine release elicited by a short-duration train, which interrogates the readily releasable pool, but depleted release elicited by a long-duration train, which interrogates the reserve pool. These opposing actions of vesicular dopamine release were associated with concurrent increases in tonic and phasic dopamine responses. A link between vesicular depletion and tonic signaling was supported by results obtained for amphetamine in the ventral striatum and cocaine in both striatal sub-regions, which demonstrated augmented vesicular release and phasic signals only. We submit that amphetamine differentially targeting dopamine stores reconciles the paradoxical activation of tonic and phasic dopamine signaling. Overall, these results further highlight the unique and region-distinct cellular mechanisms of amphetamine and may have important implications for its addictive and therapeutic properties. PMID:23671560

Cortical cholinergic deficiency enhances amphetamine-induced dopamine release in the accumbens but not striatum.

PubMed

Mattsson, Anna; Olson, Lars; Svensson, Torgny H; Schilström, Björn

2007-11-01

Cholinergic dysfunction has been implicated as a putative contributing factor in the pathogenesis of schizophrenia. Recently, we showed that cholinergic denervation of the neocortex in adult rats leads to a marked increase in the behavioral response to amphetamine. The main objective of this study was to investigate if the enhanced locomotor response to amphetamine seen after cortical cholinergic denervation was paralleled by an increased amphetamine-induced release of dopamine in the nucleus accumbens and/or striatum. The corticopetal cholinergic projections were lesioned by intraparenchymal infusion of 192 IgG-saporin into the nucleus basalis magnocellularis of adult rats. Amphetamine-induced dopamine release in the nucleus accumbens or striatum was monitored by in vivo microdialysis 2 to 3 weeks after lesioning. We found that cholinergic denervation of the rat neocortex leads to a significantly increased amphetamine-induced dopamine release in the nucleus accumbens. Interestingly, the cholinergic lesion did not affect amphetamine-induced release of dopamine in the striatum. The enhanced amphetamine-induced dopamine release in the nucleus accumbens in the cholinergically denervated rats could be reversed by administration of the muscarinic agonist oxotremorine, but not nicotine, prior to the amphetamine challenge, suggesting that loss of muscarinic receptor stimulation is likely to have caused the observed effect. The results suggest that abnormal responsiveness of dopamine neurons can be secondary to cortical cholinergic deficiency. This, in turn, might be of relevance for the pathophysiology of schizophrenia and provides a possible link between cholinergic disturbances and alteration of dopamine transmission.

Effects of 14-day treatment with the schedule III anorectic phendimetrazine on choice between cocaine and food in rhesus monkeys.

PubMed

Banks, Matthew L; Blough, Bruce E; Negus, S Stevens

2013-08-01

The clinical utility of monoamine releasers such as phenmetrazine or d-amphetamine as candidate agonist medications for cocaine dependence is hindered by their high abuse liability. Phendimetrazine is a clinically available schedule III anorectic that functions as a prodrug for phenmetrazine and thus may have lower abuse liability. This study determined the effects of continuous 14-day treatment with phendimetrazine on cocaine vs. food choice in rhesus monkeys (N=4). Responding was maintained under a concurrent schedule of food delivery (1-g pellets, fixed-ratio 100 schedule) and cocaine injections (0-0.1mg/kg/injection, fixed-ratio 10 schedule). Cocaine choice dose-effect curves were determined daily before and during 14-day periods of continuous intravenous treatment with saline or (+)-phendimetrazine (0.32-1.0mg/kg/h). Effects of 14-day treatment with (+)-phenmetrazine (0.1-0.32 mg/kg/h; N=5) and d-amphetamine (0.032-0.1mg/kg/h; N=6) were also examined for comparison. During saline treatment, food was primarily chosen during availability of low cocaine doses (0, 0.0032, and 0.01 mg/kg/injection), and cocaine was primarily chosen during availability of higher cocaine doses (0.032 and 0.1mg/kg/injection). Phendimetrazine initially decreased overall responding without significantly altering cocaine choice. Over the course of 14 days, tolerance developed to rate decreasing effects, and phendimetrazine dose-dependently decreased cocaine choice (significant at 0.032 mg/kg/injection cocaine). Phenmetrazine and d-amphetamine produced qualitatively similar effects. These results demonstrate that phendimetrazine can produce significant, though modest, reductions in cocaine choice in rhesus monkeys. Phendimetrazine may be especially suitable as a candidate medication for human studies because of its schedule III clinical availability. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Similar discriminative-stimulus effects of D-amphetamine in women and men.

PubMed

Vansickel, Andrea R; Lile, Joshua A; Stoops, William W; Rush, Craig R

2007-01-01

The results of controlled non-human animal and human laboratory studies are mixed regarding whether women and men respond differently to stimulant drugs. In order to assess potential gender differences in the effects of D-amphetamine, we conducted a retrospective analysis of six studies conducted in our laboratory that used identical procedures and measures. Thirteen women and fourteen men learned to discriminate 15 mg oral D-amphetamine. After acquiring the discrimination (i.e., >or=80% correct responding on 4 consecutive sessions), the effects of a range of doses of D-amphetamine (0, 2.5, 5, 10, and 15 mg) alone and in combination with other drugs, were assessed. Only data from sessions in which D-amphetamine was administered alone were included in this analysis. D-amphetamine functioned as a discriminative stimulus and dose-dependently increased drug-appropriate responding. Women and men did not differ in their ability to discriminate D-amphetamine. Women and men differed on participant-ratings of high (womenmen) and sluggish (women

Effect of food on early drug exposure from extended-release stimulants: results from the Concerta, Adderall XR Food Evaluation (CAFE) Study.

PubMed

Auiler, J F; Liu, K; Lynch, J M; Gelotte, C K

2002-01-01

Stimulant therapy is the mainstay of treatment for children, adolescents and adults with attention-deficit/hyperactivity disorder (ADHD). Once-daily, extended-release oral formulations offer long acting control of symptoms by modifying drug delivery and absorption. In particular, consistency in early drug exposure is important for symptom control during school or work hours. Because these once-daily formulations are usually taken in the morning, the timing of the doses with breakfast is important. This study compared the effect of a high-fat breakfast on early drug exposure from a morning dose of two extended-release stimulant formulations: the osmotic-controlled OROS tablet of methylphenidate HCI (CONCERTA) and the capsule containing extended-release beads of mixed amphetamine salts (ADDERALL XR). The study had a single-dose, open-label, randomised, four-treatment, crossover design in which healthy subjects received either 36 mg CONCERTA or 20 mg ADDERALL XR in the morning after an overnight fast or a high-fat breakfast. Serial blood samples were collected over 28h to determine plasma concentrations of methylphenidate and amphetamine. The food effect on early drug exposure and the pharmacokinetic profiles up to 8 h after dosing of the two extended-release stimulants were directly compared using partial area (AUC(p4h), AUC(p6h) and AUC(p8h)) fed/fasted ratios. Amphetamine concentrations were markedly lower when the subjects had eaten breakfast, resulting in lower early drug exposures (p < 0.0001). By contrast, methylphenidate concentrations over the same 8 h were unaffected by breakfast, providing consistent levels of early drug exposure. Therefore, as a child's or adult's eating pattern varies, methylphenidate exposure over the first 8 h would be expected to have less day-to-day variation compared with amphetamine exposure. The osmotic-controlled OROS tablet provides a reliable and consistent delivery of methylphenidate HCI, independent of food, for patients with ADHD.

A Randomized Controlled Trial Investigating the Effects of a Special Extract of Bacopa monnieri (CDRI 08) on Hyperactivity and Inattention in Male Children and Adolescents: BACHI Study Protocol (ANZCTRN12612000827831)

PubMed Central

Kean, James D.; Kaufman, Jordy; Lomas, Justine; Goh, Antionette; White, David; Simpson, David; Scholey, Andrew; Singh, Hemant; Sarris, Jerome; Zangara, Andrea; Stough, Con

2015-01-01

Clinical diagnoses of Attention Deficit Hyperactivity Disorder (ADHD) and the use of prescription medications for its treatment have increased in recent years. Current treatments may involve the administration of amphetamine-type substances, a treatment path many parents are apprehensive to take. Therefore, alternative pharmacological treatments are required. Few nutritional or pharmacological alternatives that reduce ADHD associated symptoms (hyperactivity and inattention) have been subjected to rigorous clinical trials. Bacopa monnieri is a perennial creeping herb. CDRI 08 is a special extract of Bacopa monnieri which has been subjected to hundreds of scientific studies and has been shown in human randomized controlled trials (RCTs) to improve memory, attention, and mood. It is hypothesised that chronic administration of CDRI 08 will improve attention, concentration and behaviour in children with high levels of hyperactivity and/or inattention. This paper reports the protocol for the first 16-week, randomized, placebo-controlled, double-blind, parallel groups trial examining the efficacy and safety of CDRI 08 in male children aged 6–14 years with high levels of inattention and hyperactivity. The primary outcome variable will be the level of hyperactivity and inattention measured by the Conners’ Parent Rating Scale (CPRS). Secondary outcome variables include cognition, mood, sleep, and EEG. Trial registration: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12612000827831. PMID:26633481

A Randomized Controlled Trial Investigating the Effects of a Special Extract of Bacopa monnieri (CDRI 08) on Hyperactivity and Inattention in Male Children and Adolescents: BACHI Study Protocol (ANZCTRN12612000827831).

PubMed

Kean, James D; Kaufman, Jordy; Lomas, Justine; Goh, Antionette; White, David; Simpson, David; Scholey, Andrew; Singh, Hemant; Sarris, Jerome; Zangara, Andrea; Stough, Con

2015-12-02

Clinical diagnoses of Attention Deficit Hyperactivity Disorder (ADHD) and the use of prescription medications for its treatment have increased in recent years. Current treatments may involve the administration of amphetamine-type substances, a treatment path many parents are apprehensive to take. Therefore, alternative pharmacological treatments are required. Few nutritional or pharmacological alternatives that reduce ADHD associated symptoms (hyperactivity and inattention) have been subjected to rigorous clinical trials. Bacopa monnieri is a perennial creeping herb. CDRI 08 is a special extract of Bacopa monnieri which has been subjected to hundreds of scientific studies and has been shown in human randomized controlled trials (RCTs) to improve memory, attention, and mood. It is hypothesised that chronic administration of CDRI 08 will improve attention, concentration and behaviour in children with high levels of hyperactivity and/or inattention. This paper reports the protocol for the first 16-week, randomized, placebo-controlled, double-blind, parallel groups trial examining the efficacy and safety of CDRI 08 in male children aged 6-14 years with high levels of inattention and hyperactivity. The primary outcome variable will be the level of hyperactivity and inattention measured by the Conners' Parent Rating Scale (CPRS). Secondary outcome variables include cognition, mood, sleep, and EEG. Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12612000827831.

Blue-yellow colour vision impairment and cognitive deficits in occasional and dependent stimulant users.

PubMed

Hulka, Lea M; Wagner, Michael; Preller, Katrin H; Jenni, Daniela; Quednow, Boris B

2013-04-01

Specific blue-yellow colour vision impairment has been reported in dependent cocaine users and it was postulated that drug-induced changes in retinal dopamine neurotransmission are responsible. However, it is unclear whether these changes are confined to chronic cocaine users, whether they are specific for dopaminergic stimulants such as cocaine and amphetamine and whether they are related to cognitive functions such as working memory, encoding and consolidation. In 47 occasional and 29 dependent cocaine users, 23 MDMA (commonly known as 'ecstasy') users and 47 stimulant-naive controls, colour vision discrimination was measured with the Lanthony Desaturated Panel D-15 Test and memory performance with the Auditory Verbal Learning Test. Both occasional and dependent cocaine users showed higher colour confusion indices than controls. Users of the serotonergic stimulant MDMA (26%), occasional (30%) and dependent cocaine users (34%) exhibited more frequent blue-yellow colour vision disorders compared to controls (9%). Inferior performance of MDMA users was caused by a subgroup with high amphetamine co-use (55%), while MDMA use alone was not associated with decreased blue-yellow discrimination (0%). Cognitive performance was worse in cocaine users with colour vision disorder compared to users and controls with intact colour vision and both colour vision impairment and cognitive deficits were related to cocaine use. Occasional cocaine and amphetamine use might induce blue-yellow colour vision impairment, whereas the serotonergic stimulant MDMA does not impair colour vision. The association between colour vision impairment and cognitive deficits in cocaine users may reflect that retinal and cerebral dopamine alterations are linked to a certain degree.

Clinical Characteristics and Outcomes of Patients with Amphetamine-Associated Cardiomyopathy in South Auckland, New Zealand.

PubMed

Kueh, Shaw-Hua Anthony; Gabriel, Ruvin S; Lund, Mayanna; Sutton, Tim; Bradley, Joshua; Kerr, Andrew J; Looi, Jen-Li

2016-11-01

Amphetamine-associated cardiomyopathy (AAC) is becoming an increasingly recognised entity. The characteristics and outcomes of these patients are poorly understood. Thirty patients admitted with heart failure and echocardiographic evidence of cardiomyopathy between 2005 and 2014 and who had a documented history of amphetamine abuse that was considered an important factor in the causation of their cardiomyopathy were retrospectively identified. Mean age at presentation was 40±10 years with a male predominance (n=25, 83%). The majority were of indigenous Maori ethnicity. At presentation, four patients were in cardiogenic shock. Five patients required intensive care unit (ICU) admission for inotropic support and mechanical ventilation. Fifteen had severe left ventricular (LV) dilation (mean LV end-diastolic dimension 6.8±1.0cm) and all patients had severe LV dysfunction (mean LV ejection fraction 22±8%). Despite optimal heart failure therapy, LV size remained significantly dilated with minimal improvement in LV function. During median follow-up of 18 months, five patients died from end-stage heart failure and 17 had at least one readmission with decompensated heart failure. Amphetamine-associated cardiomyopathy was seen predominantly in young indigenous Maori men. They presented with severe cardiomyopathy, often requiring ICU admission. Severe LV dilation and significant LV dysfunction persisted despite treatment and mortality was high. Copyright © 2016 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.

Effect of amphetamine on human macronutrient intake.

PubMed

Foltin, R W; Kelly, T H; Fischman, M W

1995-11-01

Six male subjects participated in a 15-day residential study examining the effects of amphetamine on macronutrient intake. During the first 11 days, carbohydrate intake was manipulated by providing lunch meals high (155 g) or low (25 g) in carbohydrate. Subjects received oral d-amphetamine (5, 10 mg/70 kg, BID) or placebo. Total daily caloric intake was similar under both lunch conditions (approximately 3400/Kcal), but carbohydrate contributed more energy under the high-carbohydrate condition. Both doses of amphetamine decreased total caloric intake to approximately 2600 Kcal, by decreasing the number of eating bouts, without affecting macronutrient selection. During the last four days subjects received a higher daily dose of amphetamine (30 mg/70 kg in four doses) or placebo, and were allowed to self-select lunch. Although 30 mg amphetamine decreased intake of all macronutrients, the relative contribution of carbohydrate to total caloric intake was increased from 54% to 62%, while the contribution of fat was decreased from 32% to 26% and the contribution of protein was decreased from 14% to 12%. Thus, at a high dose, amphetamine altered the relative contribution of specific macronutrients to total caloric intake.

Extended-Release Mixed Amphetamine Salts vs Placebo for Comorbid Adult Attention-Deficit/Hyperactivity Disorder and Cocaine Use Disorder

PubMed Central

Levin, Frances R.; Mariani, John J.; Specker, Sheila; Mooney, Marc; Mahony, Amy; Brooks, Daniel J.; Babb, David; Bai, Yun; Eberly, Lynn E.; Nunes, Edward V.; Grabowski, John

2015-01-01

IMPORTANCE Adult attention-deficit/hyperactivity disorder (ADHD) is prevalent but often unrecognized, in part because it tends to co-occur with other disorders such as substance use disorders. Cocaine use disorder is one such disorder with high co-occurrence of ADHD. OBJECTIVE To examine whether treatment of co-occurring ADHD and cocaine use disorder with extended-release mixed amphetamine salts is effective at both improving ADHD symptoms and reducing cocaine use. DESIGN, SETTING, AND PARTICIPANTS Thirteen-week, randomized, double-blind, 3-arm, placebo-controlled trial of participants meeting DSM-IV-TR criteria for both ADHD and cocaine use disorder conducted between December 1, 2007, and April 15, 2013, at 2 academic health center substance abuse treatment research sites. One hundred twenty-six adults diagnosed as having comorbid ADHD and cocaine use disorder were randomized to extended-release mixed amphetamine salts or placebo. Analysis was by intent-to-treat population. INTERVENTIONS Participants received extended-release mixed amphetamine salts (60 or 80 mg) or placebo daily for 13 weeks and participated in weekly individual cognitive behavioral therapy. MAIN OUTCOMES AND MEASURES For ADHD, percentage of participants achieving at least a 30% reduction in ADHD symptom severity, measured by the Adult ADHD Investigator Symptom Rating Scale; for cocaine use, cocaine-negative weeks (by self-report of no cocaine use and weekly benzoylecgonine urine screens) during maintenance medication (weeks 2–13) and percentage of participants achieving abstinence for the last 3 weeks. RESULTS More patients achieved at least a 30% reduction in ADHD symptom severity in the medication groups (60 mg: 30 of 40 participants [75.0%]; odds ratio [OR] = 5.23; 95% CI, 1.98–13.85; P < .001; and 80 mg: 25 of 43 participants [58.1%]; OR = 2.27; 95% CI, 0.94–5.49; P = .07) compared with placebo (17 of 43 participants [39.5%]). The odds of a cocaine-negative week were higher in the 80-mg group (OR = 5.46; 95% CI, 2.25–13.27; P < .001) and 60-mg group (OR = 2.92; 95% CI, 1.15–7.42; P = .02) compared with placebo. Rates of continuous abstinence in the last 3 weeks were greater for the medication groups than the placebo group: 30.2% for the 80-mg group (OR = 11.87; 95% CI, 2.25–62.62; P = .004) and 17.5% for the 60-mg group (OR = 5.85; 95% CI, 1.04–33.04; P = .04) vs 7.0% for placebo. CONCLUSIONS AND RELEVANCE Extended-release mixed amphetamine salts in robust doses along with cognitive behavioral therapy are effective for treatment of co-occurring ADHD and cocaine use disorder, both improving ADHD symptoms and reducing cocaine use. The data suggest the importance of screening and treatment of ADHD in adults presenting with cocaine use disorder. PMID:25887096

Metabolic Precursors to Amphetamine and Methamphetamine.

PubMed

Cody, J D

1993-12-01

Analysis and interpretation of amphetamine results is a challenging process made difficult by a number of factors. One of the complications comes from determination of the origin of amphetamine or methamphetamine in a sample. Given the relatively rare occasions that either of these two drugs are prescribed, legal prescription of one of these drugs is seldom a reason for positive findings. A number of other precursor compounds are metabolized by the body to amphetamine or methamphetamine, many of which could be used for legitimate reasons. Fourteen different metabolic precursors of amphetamine or methamphetamine are included in this review. They are amphetaminil, benzphetamine, clobenzorex, deprenyl, dimethylamphetamine, ethylamphetamine, famprofazone, fencamine, fenethylline, fenproporex, furfenorex, mefenorex, mesocarb, and prenylamine. Medical use, metabolism, analysis, and interpretation are described to afford sufficient information to evaluate the possible involvement of these drugs in positive amphetamine or methamphetamine results. Copyright © 1993 Central Police University.

Amphetamine increases activity but not exploration in humans and mice

PubMed Central

Minassian, Arpi; Young, Jared W.; Cope, Zackary A.; Henry, Brook L.; Geyer, Mark A.; Perry, William

2015-01-01

Rationale Cross-species quantification of physiological behavior enables a better understanding of the biological systems underlying neuropsychiatric diseases such as Bipolar Disorder (BD). Cardinal symptoms of manic BD include increased motor activity and goal-directed behavior, thought to be related to increased catecholamine activity, potentially selective to dopamine homeostatic dysregulation. Objectives The objective of this study was to test whether acute administration of amphetamine, a norepinephrine/dopamine transporter inhibitor and dopamine releaser, would replicate the profile of activity and exploration observed in both humans with manic BD and mouse models of mania. Methods Healthy volunteers with no psychiatric history were randomized to a one-time dose of placebo (n=25), 10 mg d-amphetamine (n=18), or 20 mg amphetamine (n=23). 80 mice were administered one of 4 doses of d-amphetamine or vehicle. Humans and mice were tested in the Behavioral Pattern Monitor (BPM), which quantifies motor activity, exploratory behavior, and spatial patterns of behavior. Results In humans, the 20-mg dose of amphetamine increased motor activity as measured by acceleration without marked effects on exploration or spatial patterns of activity. In mice, amphetamine increased activity, decreased specific exploration, and caused straighter, one-dimensional movements in a dose-dependent manner. Conclusions Consistent with mice, amphetamine increased motoric activity in humans without increasing exploration. Given that BD patients exhibit heightened exploration, these data further emphasize the limitation of amphetamine-induced hyperactivity as a suitable model for BD. Further, these studies highlight the utility of cross-species physiological paradigms in validating biological mechanisms of psychiatric diseases. PMID:26449721

Amphetamine-induced sensitization and reward uncertainty similarly enhance incentive salience for conditioned cues.

PubMed

Robinson, Mike J F; Anselme, Patrick; Suchomel, Kristen; Berridge, Kent C

2015-08-01

Amphetamine and stress can sensitize mesolimbic dopamine-related systems. In Pavlovian autoshaping, repeated exposure to uncertainty of reward prediction can enhance motivated sign-tracking or attraction to a discrete reward-predicting cue (lever-conditioned stimulus; CS+), as well as produce cross-sensitization to amphetamine. However, it remains unknown how amphetamine sensitization or repeated restraint stress interact with uncertainty in controlling CS+ incentive salience attribution reflected in sign-tracking. Here rats were tested in 3 successive phases. First, different groups underwent either induction of amphetamine sensitization or repeated restraint stress, or else were not sensitized or stressed as control groups (either saline injections only, or no stress or injection at all). All next received Pavlovian autoshaping training under either certainty conditions (100% CS-UCS association) or uncertainty conditions (50% CS-UCS association and uncertain reward magnitude). During training, rats were assessed for sign-tracking to the CS+ lever versus goal-tracking to the sucrose dish. Finally, all groups were tested for psychomotor sensitization of locomotion revealed by an amphetamine challenge. Our results confirm that reward uncertainty enhanced sign-tracking attraction toward the predictive CS+ lever, at the expense of goal-tracking. We also reported that amphetamine sensitization promoted sign-tracking even in rats trained under CS-UCS certainty conditions, raising them to sign-tracking levels equivalent to the uncertainty group. Combining amphetamine sensitization and uncertainty conditions did not add together to elevate sign-tracking further above the relatively high levels induced by either manipulation alone. In contrast, repeated restraint stress enhanced subsequent amphetamine-elicited locomotion, but did not enhance CS+ attraction. (c) 2015 APA, all rights reserved).

Amphetamine-induced sensitization and reward uncertainty similarly enhance incentive salience for conditioned cues

PubMed Central

Robinson, Mike J.F.; Anselme, Patrick; Suchomel, Kristen; Berridge, Kent C.

2015-01-01

Amphetamine and stress can sensitize mesolimbic dopamine-related systems. In Pavlovian autoshaping, repeated exposure to uncertainty of reward prediction can enhance motivated sign-tracking or attraction to a discrete reward-predicting cue (lever CS+), as well as produce cross-sensitization to amphetamine. However, it remains unknown how amphetamine-sensitization or repeated restraint stress interact with uncertainty in controlling CS+ incentive salience attribution reflected in sign-tracking. Here rats were tested in three successive phases. First, different groups underwent either induction of amphetamine sensitization or repeated restraint stress, or else were not sensitized or stressed as control groups (either saline injections only, or no stress or injection at all). All next received Pavlovian autoshaping training under either certainty conditions (100% CS-UCS association) or uncertainty conditions (50% CS-UCS association and uncertain reward magnitude). During training, rats were assessed for sign-tracking to the lever CS+ versus goal-tracking to the sucrose dish. Finally, all groups were tested for psychomotor sensitization of locomotion revealed by an amphetamine challenge. Our results confirm that reward uncertainty enhanced sign-tracking attraction toward the predictive CS+ lever, at the expense of goal-tracking. We also report that amphetamine sensitization promoted sign-tracking even in rats trained under CS-UCS certainty conditions, raising them to sign-tracking levels equivalent to the uncertainty group. Combining amphetamine sensitization and uncertainty conditions together did not add together to elevate sign-tracking further above the relatively high levels induced by either manipulation alone. In contrast, repeated restraint stress enhanced subsequent amphetamine-elicited locomotion, but did not enhance CS+ attraction. PMID:26076340

The Role of Hypothalamic Insulin and Dopamine in the Anorectic Effect of Cocaine and d-amphetamine

DTIC Science & Technology

1992-08-21

15: Figure 16: Figure 17: Figure 18: LIST OF FIGURES Chemical structure of cocaine Chemical structure of amphetamine Cocaine groups! Average...prevent hypotension (Hoffman, 1987). The chemical structure of amphetamine is shown in figure 2. General Aspects: The term amphetamine applies to a group...cormnunication, 1991). 26 Germany in the 1930’s, with c hemical structures resembling those of epinephrine and NE. Their effects are similar to those of

Long-term changes in amphetamine-induced reinforcement and aversion in rats following exposure to 56Fe particle

NASA Astrophysics Data System (ADS)

Rabin, B. M.; Joseph, J. A.; Shukitt-Hale, B.

Exposing rats to heavy particles produces alterations in the functioning of dopaminergic neurons and in the behaviors that depend upon the integrity of the dopaminergic system. Two of these dopamine-dependent behaviors include amphetamine-induced reinforcement, measure using the conditioned place preference procedure, and amphetamine-induced reinforcement, measured using the conditioned place preference procedure, and amphetamine-induced aversion, measured using the conditioned taste aversion. Previous research has shown that exposing rats to 1.0 Gy of 1GeV/n 56Fe particles produced a disruption of an amphetamine-induced taste aversion 3 days following exposure, but produced an apparent enhancement of the aversion 112 days following exposure. The present experiments were designed to provide a further evaluation of these results by examining taste aversion learning 154 days following exposure to 1.0Gy 56Fe particles and to establish the convergent validity of the taste aversion results by looking at the effects of exposure on the establishment of an amphetamine-induced conditioned place preference 3, 7, and 16 weeks following irradiation. The taste aversion results failed to confirm the apparent enhancement of the amphetamine-induced CTA observed in the prior experiment. However, exposure to 56Fe particles prevented the acquisition of amphetamine-induced place preference at all three-time intervals. The results are interpreted as indicating that exposure to heavy particles can produce long-term changes in behavioral functioning.

The effects of amphetamine sensitization on conditioned inhibition during a Pavlovian-instrumental transfer task in rats.

PubMed

Shiflett, Michael W; Riccie, Meaghan; DiMatteo, RoseMarie

2013-11-01

Psychostimulant sensitization heightens behavioral and motivational responses to reward-associated stimuli; however, its effects on stimuli associated with reward absence are less understood. We examined whether amphetamine sensitization alters performance during Pavlovian-instrumental transfer (PIT) to conditioned excitors and inhibitors. We further sought to characterize the effects of amphetamine sensitization on learning versus performance by exposing rats to amphetamine prior to Pavlovian training or between training and test. Adult male Long-Evans rats were given conditioned inhibition (A+/AX-) and Pavlovian (B+) training, followed by variable-interval instrumental conditioning. Rats were sensitized to D-amphetamine (2 mg/kg daily injections for 7 days) or served as non-exposed controls. Rats were given a PIT test, in which they were presented with stimulus B alone or in compound with the conditioned inhibitor (BX). During the PIT test, control rats significantly reduced instrumental responding on BX trials (to approximately 50 % of responding to B). Amphetamine sensitization prior to Pavlovian conditioning increased lever pressing on BX trials and reduced lever pressing on B trials compared to controls. Amphetamine sensitization between training and test increased lever pressing on B and BX trials compared to controls. No effects of sensitization were observed on conditioned food cup approach. Amphetamine sensitization increases instrumental responding during PIT to a conditioned inhibitor by enhancing the excitation of conditioned stimuli and reducing the inhibition of conditioned inhibitors.

Near-infrared oxymeter biosensor prototype for non-invasive in vivo analysis of rat brain oxygenation: effects of drugs of abuse

NASA Astrophysics Data System (ADS)

Crespi, F.; Donini, M.; Bandera, A.; Congestri, F.; Formenti, F.; Sonntag, V.; Heidbreder, C.; Rovati, L.

2006-07-01

The feasibility of non-invasive analysis of brain activities was studied in the attempt to overcome the major limitation of actual in vivo methodologies, i.e. invasiveness. Optic fibre probes were used as the optical head of a novel, highly sensitive near-infrared continuous wave spectroscopy (CW-NIR) instrument. This prototype was designed for non-invasive analysis of the two main forms of haemoglobin: oxy-haemoglobin (HbO2) and deoxy-haemoglobin (Hb), chromophores present in biological tissues. It was tested in peripheral tissue (human gastrocnemius muscle) and then reset to perform the measurement on rat brain. In animal studies, the optical head was firmly placed using stereotaxic apparatus upon the sagittal line of the head of anaesthetized adult rats, without any surgery. Then pharmacological treatments with saline (300 µl s.c.) amphetamine (2 mg kg-1) or nicotine (0.4 mg kg-1) were performed. Within 10-20 min amphetamine substantially increased HbO2 and reduced Hb control levels. Nicotine produced a rapid initial increase followed by a decrease in HbO2. In contrast to amphetamine, nicotine treatment also reduced Hb and blood volume. These results support the capacity of our CW-NIR prototype to measure non-invasively HbO2 and Hb levels in the rat brain, that are markers of the degree of tissue oxygenation, thus providing an index of blood levels and therefore of brain metabolism.

CRISIS UNDER THE RADAR: ILLICIT AMPHETAMINE USE IS REACHING EPIDEMIC PROPORTIONS AND CONTRIBUTING TO RESOURCE OVER-UTILIZATION AT A LEVEL 1 TRAUMA CENTER.

PubMed

Gemma, Vincent A; Chapple, Kristina A; Goslar, Pamela W; Israr, Sharjeel; Petersen, Scott R; Weinberg, Jordan A

2018-05-21

Trauma centers reported illicit amphetamine use in approximately 10% of trauma admissions in the previous decade. From experience at a trauma center located in a southwestern metropolis, our perception is that illicit amphetamine use is on the rise, and that these patients utilize in-hospital resources beyond what would be expected for their injuries. The purpose of this study was to document the incidence of illicit amphetamine use among our trauma patients and to evaluate its impact on resource utilization. We conducted a retrospective cohort study using 7 consecutive years of data (starting July 2010) from our institution's trauma registry. Toxicology screenings were used to categorize patients into one of three groups: illicit amphetamine, other drugs, or drug free. Adjusted linear and logistic regression models were used to predict hospital cost, length of stay, ICU admission and ventilation between drug groups. Models were conducted with combined injury severity (ISS) and then repeated for ISS <9, ISS 9-15 and ISS 16 and above. 8,589 patients were categorized into the following three toxicology groups: 1255 (14.6%) illicit amphetamine, 2214 (25.8%) other drugs, and 5120 (59.6%) drug free. Illicit amphetamine use increased threefold over the course of the study (from 7.85% to 25.0% of annual trauma admissions). Adjusted linear models demonstrated that illicit amphetamine among patients with ISS<9 was associated with 4.6% increase in hospital cost (P=.019) and 7.4% increase in LOS (P=.043). Logistic models revealed significantly increased odds of ventilation across all ISS groups and increased odds of ICU admission when all ISS groups were combined (P=.001) and within the ISS<9 group (P=.002). Hospital resource utilization of amphetamine patients with minor injuries is significant. Trauma centers with similar epidemic growth in proportion of amphetamine patients face a potentially significant resource strain relative to other centers. Prognostic and Epidemiological LEVEL OF EVIDENCE: III.

Sleep deprivation precipitates the development of amphetamine-induced conditioned place preference in rats.

PubMed

Berro, Laís F; Tufik, Sergio B; Frussa-Filho, Roberto; Andersen, Monica L; Tufik, Sergio

2018-04-03

Sleep deprivation (SD) and amphetamine use are commonly associated conditions. SD shares similar neurobiological effects with psychostimulants, playing an important role in drug addiction, especially through conditioning manipulations. The aim of the present study was to investigate the effects of SD on the development of amphetamine-induced conditioned place preference (CPP) in a protocol with a reduced number of conditioning sessions. Male adult Wistar rats were submitted to 4 conditioning sessions (2 sessions/day) in the CPP apparatus, half with saline (non-drug-paired compartment) and half with 2 mg/kg amphetamine (drug-paired compartment) after control (home-cage maintained) or SD (6 h gentle handling method) conditions. Control animals did not express a preference for the amphetamine-paired compartment, showing that 2 conditioning sessions with the drug were not sufficient to establish CPP. On the other hand, animals submitted to SD during the conditioning sessions expressed a preference for the amphetamine-paired compartment, which was maintained across the entire test session. SD precipitated the development of CPP to amphetamine, showing that lack of sleep can contribute to the establishment of a conditioning between the drug effect and environmental cues. Copyright © 2018 Elsevier B.V. All rights reserved.

An update on the pharmacotherapy of attention-deficit/hyperactivity disorder in adults

PubMed Central

Wilens, Timothy E; Morrison, Nicholas R; Prince, Jefferson

2011-01-01

Adults with attention-deficit/hyperactivity disorder (ADHD) are more frequently presenting for diagnosis and treatment. Medication is considered to be appropriate among available treatments for ADHD; however, the evidence supporting the use of pharmacotherapeutics for adults with ADHD remains less established. In this article, the effectiveness and dosing parameters of the various agents investigated for adult ADHD are reviewed. In adults with ADHD, short-term improvements in symptomatology have been documented through the use of stimulants and antidepressants. Studies suggest that methylphenidate and amphetamine maintained an immediate onset of action, whereas the ADHD response to the nonstimulants appeared to be delayed. At a group level, there appears to be some, albeit not entirely consistent, dose-dependent responses to amphetamine and methylphenidate. Generally speaking, variability in diagnostic criteria, dosing parameters and response rates between the various studies was considerable, and most studies were of a relatively short duration. The aggregate literature shows that the stimulants and catecholaminergic nonstimulants investigated had a clinically significant beneficial effect on treating ADHD in adults. PMID:21955201

Using Interactive Web-Based Screening, Brief Intervention and Referral to Treatment in an Urban, Safety-Net HIV Clinic

PubMed Central

Rose, Carol Dawson; Cuca, Yvette P.; Kamitani, Emiko; Eng, Shannon; Zepf, Roland; Draughon, Jessica; Lum, Paula

2015-01-01

Substance use among PLHIV is high, and screening, brief intervention, and referral to treatment (SBIRT) is an evidence-based approach to addressing the issue. We examined the acceptability of a technology-based SBIRT program in an urban HIV clinic. An SBIRT intervention was programmed into the clinic’s electronic personal health record. We examined: demographic, health, HIV, and substance use characteristics of participants who completed the web-based intervention compared to those who did not. Fewer than half of the 96 participants assigned to the web-based SBIRT completed it (n=39; 41%). Severity of tobacco and amphetamine use differed significantly between participants who did and did not complete the intervention (p=.03, .04 respectively). Participants with higher severity of tobacco and amphetamines were significantly more likely to utilize the web-based SBIRT. It is important for technology-based approaches to behavioral interventions in clinic take into consideration feasibility, client knowledge, and comfort using technology. PMID:25963770

Amphetamine self-administration in light and moderate drinkers.

PubMed

Stanley, Matthew D; Poole, Mégan M; Stoops, William W; Rush, Craig R

2011-03-01

Light and moderate drinkers respond differently to the effects of abused drugs, including stimulants such as amphetamine. The purpose of this study was to determine whether light and moderate drinkers differ in their sensitivity to the reinforcing and subjective effects of d-amphetamine. We hypothesized that moderate drinkers (i.e., participants that reported consuming at least seven alcohol-containing beverages per week) would be more sensitive to the reinforcing and positive subject-rated effects of d-amphetamine than light drinkers. Data from four studies that employed similar d-amphetamine self-administration procedures and subject-rated drug-effect measures were included in the analysis. Light (n = 17) and moderate (n = 16) drinkers sampled placebo, low (8 to 10 mg), and high (16 to 20 mg) doses of oral d-amphetamine administered in eight capsules. Following sampling sessions, participants worked for a maximum of eight capsules, each containing 12.5% of the previously sampled dose, on a modified progressive-ratio schedule of reinforcement. Both active doses of d-amphetamine functioned as a reinforcer in the moderate drinkers, while only the high dose did so in the light drinkers. The moderate drinkers worked for significantly more capsules that contained the high dose of d-amphetamine than did the light drinkers. d-Amphetamine produced prototypical stimulant-like subjective effects (e.g., dose-dependent increases in ratings of Good Effects; Like Drug and Willing to Take Again). Moderate drinkers reported significantly greater subjective effects than the light drinkers. These results are consistent with those from previous laboratory experiments and suggest that moderate alcohol consumption may increase vulnerability to the abuse-related effects of stimulants. Copyright © 2010 by the Research Society on Alcoholism.

Cross-Reactivity of Chloroquine and Hydroxychloroquine With DRI Amphetamine Immunoassay.

PubMed

Gomila, Isabel; Quesada, Loreto; López-Corominas, Victoria; Fernández, Julia; Servera, Miguel Á; Sahuquillo, Laura; Dastis, Macarena; Torrents, Albert; Barceló, Bernardino

2017-04-01

Chloroquine and hydroxychloroquine are medical drugs used to treat the chemoprophylaxis of malaria and a second-line anti-inflammatory drug. We performed a study of cross-reactivity of chloroquine and hydroxychloroquine in the DRI Amphetamine Assay inspired by a case report of a self-ingestion of chloroquine after a family dispute, that involved the following: (1) an in vitro study with control samples of healthy subjects, (2) an in vivo study with samples of patients with rheumatoid arthritis, and (3) an evaluation of the cross-reactivity of chloroquine and hydroxychloroquine in 3 additional immunoassays. In the case report, the Amphetamine DRI assay resulted positive both at 1000 ng/mL cutoff (1507 and 1137 ng/mL) and at 500 ng/mL cutoff (1178 and 642 ng/mL). Chloroquine urine levels were 103,900 and 100,900 ng/mL at 5 and 9 hours after ingestion. The results with control samples showed a positive cross-reactivity of chloroquine in the DRI Amphetamine Assay (approximately 0.74% and 0.89% at cutoff of 1000 and 500 ng/mL, respectively). Hydroxychloroquine did not cross-react with the DRI Amphetamine Assay up to 1,000,000 ng/mL. In patients treated with chloroquine or hydroxychloroquine, DRI Amphetamine did not produce false-positive results. The comparative assay study showed a positive cross-reactivity of chloroquine in the Emit II Plus Amphetamines Assay with control samples. Chloroquine can cause false-positive results in the DRI Amphetamine Assay when it is present at high concentrations. Hydroxychloroquine did not produce false-positive results neither in the DRI Amphetamine Assay nor in the others immunoassays evaluated.

Contextual conditioning enhances the psychostimulant and incentive properties of d-amphetamine in humans

PubMed Central

Childs, Emma; de Wit, Harriet

2014-01-01

Learned associations between drugs and the places they are used are critical to the development of drug addiction. Contextual conditioning has long been studied in animals as an indirect measure of drug reward, but little is known about the process in humans. Here, we investigated de novo contextual conditioning with d-amphetamine in healthy humans (n = 34). Volunteers underwent four conditioning sessions conducted in two testing rooms with double-blind, alternating d-amphetamine (20 mg) and placebo administration. Before conditioning procedures began, they rated the two rooms to examine pre-existing preferences. One group (Paired, n = 19) always received d-amphetamine in their least preferred room and placebo in the other during conditioning sessions. Another group (Unpaired, n = 15) received d-amphetamine and placebo in both rooms. Subjective drug effects were monitored at repeated times. At a separate re-exposure test, preference ratings for the drug-associated room were increased among the Paired group only, and more subjects in the Paired than the Unpaired group switched their preference to their initially least preferred room. Also, ratings of d-amphetamine drug liking independently predicted room liking at test among the Paired group only. Further, Paired group subjects reported greater stimulation and drug craving after d-amphetamine on the second administration, relative to the first. This study supports preliminary findings that humans, like animals, develop a preference for a place associated with d-amphetamine that is related to its subjective effects. These findings also suggest that experiencing d-amphetamine in a consistent environment produces context-dependent changes in its subjective effects, including an enhanced rewarding efficacy and abuse potential. PMID:22129527

Adolescent social defeat increases adult amphetamine conditioned place preference and alters D2 dopamine receptor expression

PubMed Central

Burke, Andrew R.; Watt, Michael J.; Forster, Gina L.

2011-01-01

Components of the brain’s dopaminergic system, such as dopamine receptors, undergo final maturation in adolescence. Exposure to social stress during human adolescence contributes to substance abuse behaviors. We utilized a rat model of adolescent social stress to investigate the neural mechanisms underlying this correlation. Rats exposed to repeated social defeat in adolescence (P35–P39) exhibited increased conditioned place preference (CPP) for amphetamine (1 mg/kg) in adulthood (P70). In contrast, rats experiencing foot-shock during the same developmental period exhibited amphetamine CPP levels similar to non-stressed controls. Our previous experiments suggested adolescent defeat alters dopamine activity in the mesocorticolimbic system. Furthermore, dopamine receptors have been implicated in the expression of amphetamine CPP. Therefore, we hypothesized that alteration to dopamine receptor expression in the mesocorticolimbic system may be associated with to heightened amphetamine CPP of adult rats exposed to adolescence defeat. We measured D1 and D2 dopamine receptor protein content in the medial prefrontal cortex, nucleus accumbens (NAc) and dorsal striatum following either adolescent social defeat or foot-shock stress and then adult amphetamine CPP. In controls, amphetamine CPP training reduced D2 receptor protein content in the NAc core. However, this down-regulation of NAc core D2 receptors was blocked by exposure to social defeat but not foot-shock stress in adolescence. These results suggest social defeat stress in adolescence alters the manner in which later amphetamine exposure down-regulates D2 receptors. Furthermore, persistent alterations to adult D2 receptor expression and amphetamine responses may depend on the type of stress experienced in adolescence. PMID:21933700

MK-801 and amphetamine result in dissociable profiles of cognitive impairment in a rodent paired associates learning task with relevance for schizophrenia.

PubMed

Talpos, John; Aerts, Nancy; Waddell, Jason; Steckler, Thomas

2015-11-01

Paired associates learning (PAL) has been suggested to be predictive of functional outcomes in first episode psychosis and of conversion from mild cognitive impairment to Alzheimer's disease. An automated touch screen-based rodent PAL (rPAL) task has been developed and is sensitive to manipulations of the dopaminergic and glutamatergic system. Accordingly, rPAL when used with pharmacological models of schizophrenia, like NMDA receptor blockade with MK-801 or dopaminergic stimulation with amphetamine, may have utility as a translational model of cognitive impairment in schizophrenia. The purpose of this study was to determine if amphetamine- and MK-801-induced impairment represent distinct models of cognitive impairment by testing their sensitivity to common antipsychotics and determine the relative contributions of D1 versus D2 receptors on performance of PAL. Rats were trained in rPAL and were then treated with MK-801, amphetamine, risperidone, haloperidol, quinpirole, SK-82958, or SCH-23390 alone and in combination. While both amphetamine and MK-801 caused clear impairments in accuracy, MK-801 induced a profound "perseverative" type behavior that was more pronounced when compared to amphetamine. Moreover, amphetamine-induced impairments, but not the effects of MK-801, could be reversed by antipsychotics as well as the D1 receptor antagonist SCH-23390, suggesting a role for both the D1 and D2 receptor in the amphetamine impairment model. These data suggest that amphetamine and MK-801 represent dissociable models of impairment in PAL, dependent on different underlying neurobiology. The ability to distinguish dopaminergic versus glutamatergic effects on performance in rPAL makes it a unique and useful tool in the modeling of cognitive impairments in schizophrenia.

Amphetamines and pH-shift agents for brain imaging

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

Biersack, H.J.; Winkler, C.

1986-01-01

This book gives a review of the results of experimental and clinical research on both I-amphetamine derivatives and pH-shift agents. Virtually all relevant working groups from the USA and Europe have contributed to this volume. The pharmacology of amphetamine and the corresponding receptor theories are described in detail, whereas other chapters deal with the labeling as well as the metabolic process of this drug. In addition to this, new amphetamine derivatives are presented together with other essential products which play a significant role in scintigraphy of the brain function. Finally, there are two chapters on instrumentation problems followed by eightmore » contributions on the clinical results of amphetamine scintigraphy in cerebral vascular diseases, epilepsy, migraine and brain tumors.« less

Age at initiation of amphetamine use and age at onset of psychosis: the Australian Survey of High Impact Psychosis.

PubMed

Power, Brian D; Stefanis, Nikos C; Dragovic, Milan; Jablensky, Assen; Castle, David; Morgan, Vera

2014-01-01

Individuals with a psychotic disorder who had a premorbid history of amphetamine use (n=382) were analyzed in groups according to age of initiation to amphetamine (AIA) and mean number of years of duration of premorbid exposure to amphetamine (DPEA) was calculated. Univariate General Linear Models were used to test for group differences in age at onset of psychotic illness (AOI) and DPEA. Although a temporal direct relationship between AIA and AOI was detected (mean duration 5.3 years), our findings suggested this association was spurious and better explained by a later initiation to amphetamine than to cannabis (by 2-3 years). Copyright © 2013 Elsevier B.V. All rights reserved.

Surveillance of Diversion and Nonmedical Use of Extended-Release Prescription Amphetamine and Oral Methylphenidate in the United States

PubMed Central

Sembower, Mark A.; Ertischek, Michelle D.; Buchholtz, Chloe; Dasgupta, Nabarun; Schnoll, Sidney H.

2013-01-01

This article examines rates of nonmedical use and diversion of extended-release amphetamine and extended-release oral methylphenidate in the United States. Prescription dispensing data were sourced from retail pharmacies. Nonmedical use data were collected from the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS) System Drug Diversion Program and Poison Center Program. Drug diversion trends nearly overlapped for extended-release amphetamine and extended-release oral methylphenidate. Calls to poison centers were generally similar; however, calls regarding extended-release amphetamine trended slightly lower than those for extended-release oral methylphenidate. Data suggest similar diversion and poison center call rates for extended-release amphetamine and extended-release oral methylphenidate. PMID:23480245

Sex differences in methamphetamine pharmacokinetics in adult rats and its transfer to pups through the placental membrane and breast milk.

PubMed

Rambousek, Lukas; Kacer, Petr; Syslova, Kamila; Bumba, Jakub; Bubenikova-Valesova, Vera; Slamberova, Romana

2014-06-01

Methamphetamine (METH) abuse is a growing health problem worldwide, and METH use during pregnancy not only endangers the mother's health but also the developing fetus. To provide better insight into these risks, we performed the following experiments. First, we investigated how sex influences the pharmacokinetics of METH and amphetamine (AMP) in male and female rats. Subsequently, we simulated chronic exposure of prenatal infants to METH abuse by investigating brain and plasma levels of METH and AMP in dams and pups. Finally, we modeled chronic exposure of infants to METH via breast milk and investigated sex differences in pups with regard to drug levels and possible sensitization effect of chronic prenatal METH co-treatment. We observed significantly higher levels of METH and AMP in the plasma and brain of female rats compared to males. Additionally, brain concentrations of METH and AMP in pups exposed to METH prenatally were equivalent to 62.13% and 37.78% relative to dam, respectively. Plasma concentrations of AMP where equivalent to 100% of the concentration in dams, while METH was equivalent to only 36.98%. Finally, we did not observe a significant effect relative to sex with regard to METH/AMP levels or sensitization effects linked to prenatal METH exposure. We demonstrated that female rats display higher levels of METH and AMP, thus indicating a greater risk of addiction and toxicity. Furthermore, our data show that pups are exposed to both METH and AMP following dam exposure. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Glucostatic regulation of (+)-(/sup 3/H)amphetamine binding in the hypothalamus: correlation with Na/sup +/, K/sup +/-ATPase activity

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

Angel, I.; Hauger, R.L.; Luu, M.D.

1985-09-01

Preincubation of rat hypothalamic slices in glucose-free Krebs-Ringer buffer (37/sup 0/C) resulted in a time-dependent decrease in specific (+)-(/sup 3/H)amphetamine binding in the crude synaptosomal fraction prepared from these slices. The addition of D-glucose resulted in a dose- and time-dependent stimulation of (+)-(/sup 3/H)amphetamine binding, whereas incubations with L-glucose, 2-deoxy-D-glucose, or 3-O-methyl-D-glucose failed to increase the number of (+)-(/sup 3/H)amphetamine binding sites. Ouabain potently inhibited the glucose-induced stimulation of (+)-(/sup 3/H)amphetamine binding, suggesting the involvement of Na/sup +/, K/sup +/-ATPase. Preincubation of hypothalamic slices with glucose also resulted in an increase in Na/sup +/,K/sup +/-ATPase activity and the number ofmore » specific high-affinity binding sites for (/sup 3/H)ouabain, and a good correlation was observed between the glucose-stimulated increase in (+)-(/sup 3/H)amphetamine and (/sup 3/H)ouabain binding. These data suggest that the (+)-(/sup 3/H)amphetamine binding site in hypothalamus, previously linked to the anorectic actions of various phenylethylamines, is regulated both in vitro and in vivo by physiological concentrations of glucose. Glucose and amphetamine appear to interact at common sites in the hypothalamus to stimulate Na/sup +/,K/sup +/-ATPase activity, and the latter may be involved in the glucostatic regulation of appetite.« less

Long-term changes in amphetamine-induced reinforcement and aversion in rats following exposure to 56Fe particle

NASA Technical Reports Server (NTRS)

Rabin, B. M.; Joseph, J. A.; Shukitt-Hale, B.

2003-01-01

Exposing rats to heavy particles produces alterations in the functioning of dopaminergic neurons and in the behaviors that depend upon the integrity of the dopaminergic system. Two of these dopamine-dependent behaviors include amphetamine-induced reinforcement, measure using the conditioned place preference procedure, and amphetamine-induced reinforcement, measured using the conditioned place preference procedure, and amphetamine-induced aversion, measured using the conditioned taste aversion. Previous research has shown that exposing rats to 1.0 Gy of 1GeV/n 56Fe particles produced a disruption of an amphetamine-induced taste aversion 3 days following exposure, but produced an apparent enhancement of the aversion 112 days following exposure. The present experiments were designed to provide a further evaluation of these results by examining taste aversion learning 154 days following exposure to 1.0 Gy 56Fe particles and to establish the convergent validity of the taste aversion results by looking at the effects of exposure on the establishment of an amphetamine-induced conditioned place preference 3, 7, and 16 weeks following irradiation. The taste aversion results failed to confirm the apparent enhancement of the amphetamine-induced CTA observed in the prior experiment. However, exposure to 56Fe particles prevented the acquisition of amphetamine-induced place preference at all three-time intervals. The results are interpreted as indicating that exposure to heavy particles can produce long-term changes in behavioral functioning. c2002 COSPAR. Published by Elsevier Science Ltd. All rights reserved.

The effects of amphetamine sensitization on conditioned inhibition during a Pavlovian-instrumental transfer task in rats

PubMed Central

Shiflett, Michael W.; Riccie, Meaghan; DiMatteo, RoseMarie

2013-01-01

Rationale Psychostimulant sensitization heightens behavioral and motivational responses to reward-associated stimuli; however, its effects on stimuli associated with reward absence are less understood. Objectives We examined whether amphetamine sensitization alters performance during Pavlovian-instrumental transfer (PIT) to conditioned excitors and inhibitors. We further sought to characterize the effects of amphetamine sensitization on learning versus performance by exposing rats to amphetamine prior to Pavlovian training or between training and test. Methods Adult male Long Evans rats were given conditioned inhibition (A+/AX−) and Pavlovian (B+) training, followed by variable-interval instrumental conditioning. Rats were sensitized to d-amphetamine (2 mg/kg daily injections for seven days), or served as non-exposed controls. Rats were given a PIT test, in which they were presented with stimulus B alone or in compound with the conditioned inhibitor (BX). Results During the PIT test, control rats significantly reduced instrumental responding on BX trials (to approximately 50% of responding to B). Amphetamine sensitization prior to Pavlovian conditioning increased lever-pressing on BX trials and reduced lever-pressing on B trials compared to controls. Amphetamine sensitization between training and test increased lever-pressing on B and BX trials compared to controls. No effects of sensitization were observed on conditioned food-cup approach. Conclusions Amphetamine sensitization increases instrumental responding during PIT to a conditioned inhibitor, by enhancing excitation of conditioned stimuli and reducing inhibition of conditioned inhibitors. PMID:23715640

Specific impact of stimulant, alcohol and cannabis use disorders on first-episode psychosis: 2-year functional and symptomatic outcomes.

PubMed

Ouellet-Plamondon, C; Abdel-Baki, A; Salvat, É; Potvin, S

2017-10-01

Many studies have concluded that cannabis use disorder (CUD) negatively influences outcomes in first-episode psychosis (FEP). However, few have taken into account the impact of concurrent misuse of other substances. This 2-year, prospective, longitudinal study of FEP patients, aged between 18 and 30 years, admitted to early intervention programs in Montreal, Quebec, Canada, examined the specific influence of different substance use disorders (SUD) (alcohol, cannabis, cocaine, amphetamines) on service utilization, symptomatic and functional outcomes in FEP. Drugs and alcohol were associated with lower functioning, but drugs had a greater negative impact on most measures at 2-year follow-up. Half of CUD patients and more than 65% of cocaine or amphetamine abusers presented polysubstance use disorder (poly-SUD). The only group that deteriorated from years 1 to 2 (symptoms and functioning) were patients with persistent CUD alone. Outcome was worse in CUD than in the no-SUD group at 2 years. Cocaine, amphetamines and poly-SUD were associated with worse symptomatic and functional outcomes from the 1st year of treatment, persisting over time with higher service utilization (hospitalization). The negative impact attributed to CUD in previous studies could be partly attributed to methodological flaws, like including polysubstance abusers among cannabis misusers. However, our investigation confirmed the negative effect of CUD on outcome. Attention should be paid to persistent cannabis misusers, since their condition seems to worsen over time, and to cocaine and amphetamine misusers, in view of their poorer outcome early during follow-up and high service utilization.

Norepinephrine in prelimbic cortex delays extinction of amphetamine-induced conditioned place preference.

PubMed

Latagliata, Emanuele Claudio; Saccoccio, Pamela; Milia, Chiara; Puglisi-Allegra, Stefano

2016-03-01

Drug-associated cues exposure to induce extinction is a useful strategy to contrast cue-induced drug seeking. Treatments aimed at reducing motivational properties of cues are considered highly promising since they could decrease their ability to induce drug-conditioned behaviors. Norepinephrine (NE) in the medial prefrontal cortex (mPFC) is critical for attribution of motivational salience to highly salient stimuli, suggesting a major role in prelimbic (PL) mpFC to modulate the motivational properties of drug-related cues, invigorating them, and consequently, delaying extinction. To investigate if NE in PL fosters the maintenance of drug-seeking behavior, we assessed its role on amphetamine-induced conditioned place preference (CPP). Moreover, to affirm the specificity of NE in PL, we also assessed the role of NE in the infralimbic (IL) mPFC. The effects of selective NE depletion in the PL or in the IL of C57BL/6J mice were assessed on the expression of amphetamine-induced CPP before and after extinction procedure. NE-depleted mice in PL extinguished preference for Amph-paired chamber long before sham animals. By contrast, IL-depleted animals maintained place preference for more than 4 weeks after the procedure of extinction, having at that moment interrupted the test. Inactivation of NE in PL cortex blunts amphetamine-induced CPP, thus fostering extinction and showing to be critical for the maintenance of conditioned Amph-seeking behavior. Opposite effects of NE depletion in IL, seemingly in agreement with literature on extinction, are discussed in terms of balance of activity between PL and IL in extinction.

21 CFR 862.3100 - Amphetamine test system.

Code of Federal Regulations, 2012 CFR

2012-04-01

... measure amphetamine, a central nervous system stimulating drug, in plasma and urine. Measurements obtained... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Amphetamine test system. 862.3100 Section 862.3100...) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862...

21 CFR 862.3100 - Amphetamine test system.

Code of Federal Regulations, 2013 CFR

2013-04-01

... measure amphetamine, a central nervous system stimulating drug, in plasma and urine. Measurements obtained... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Amphetamine test system. 862.3100 Section 862.3100...) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862...

21 CFR 862.3100 - Amphetamine test system.

Code of Federal Regulations, 2011 CFR

2011-04-01

... measure amphetamine, a central nervous system stimulating drug, in plasma and urine. Measurements obtained... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Amphetamine test system. 862.3100 Section 862.3100...) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862...

21 CFR 862.3100 - Amphetamine test system.

Code of Federal Regulations, 2014 CFR

2014-04-01

... measure amphetamine, a central nervous system stimulating drug, in plasma and urine. Measurements obtained... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Amphetamine test system. 862.3100 Section 862.3100...) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862...

21 CFR 862.3100 - Amphetamine test system.

Code of Federal Regulations, 2010 CFR

2010-04-01

... measure amphetamine, a central nervous system stimulating drug, in plasma and urine. Measurements obtained... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Amphetamine test system. 862.3100 Section 862.3100...) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862...

Drug treatment of poststroke aphasia.

PubMed

Bakheit, A M O

2004-03-01

Impairment of language function (aphasia) is one of the most common neurological symptoms after stroke. Approximately one in every three patients who have an acute stroke will suffer from aphasia. The estimated incidence and prevalence of stroke in Western Europe is 140 and 800 per 100,000 of the population. Aphasia often results in significant disability and handicap. It is a major obstacle for patients to live independently in the community. When recovery from aphasia occurs, it is usually incomplete and patients are rarely able to return to full employment and other social activities. Currently, the main treatment for aphasia is conventional speech and language therapy. However, the effectiveness of this intervention has not been conclusively demonstrated and empirical observations suggest that spontaneous biological recovery may explain most of the improvement in language function that occurs in aphasics. The generally poor prognosis of the severe forms of poststroke language impairment (Broca, Wernicke and global aphasia), coupled with the limited effectiveness of conventional speech and language therapy has stimulated the search for other treatments that may be used in conjunction with speech and language therapy, including the use of various drugs. Dopamine agonists, piracetam (Nootropil), amphetamines, and more recently donepezil (Aricept), have been used in the treatment of aphasia in both the acute and chronic phase. The justification for the use of drugs in the treatment of aphasia is based on two types of evidence. Some drugs, such as dextroamphetamine (Dexedrine), improve attention span and enhance learning and memory. Learning is an essential mechanism for the acquisition of new motor and cognitive skills, and hence, for recovery from aphasia. Second, laboratory and clinical data suggest that drug treatment may partially restore the metabolic function in the ischemic zone that surrounds the brain lesion and also has a neuroprotective effect following acute brain damage. An example of this is the nootropic agent piracetam. Extensive animal studies have demonstrated the beneficial effects of this and other drugs on neural plasticity, but data on humans are still sparse. This review provides a critical analysis of the current evidence of the effectiveness of these drugs in the treatment of acute and chronic aphasia.

21 CFR 250.101 - Amphetamine and methamphetamine inhalers regarded as prescription drugs.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 4 2013-04-01 2013-04-01 false Amphetamine and methamphetamine inhalers regarded... DRUGS New Drug or Prescription Status of Specific Drugs § 250.101 Amphetamine and methamphetamine inhalers regarded as prescription drugs. (a) Recurring reports of abuse and misuse of methamphetamine (also...

21 CFR 250.101 - Amphetamine and methamphetamine inhalers regarded as prescription drugs.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 4 2012-04-01 2012-04-01 false Amphetamine and methamphetamine inhalers regarded... DRUGS New Drug or Prescription Status of Specific Drugs § 250.101 Amphetamine and methamphetamine inhalers regarded as prescription drugs. (a) Recurring reports of abuse and misuse of methamphetamine (also...

21 CFR 250.101 - Amphetamine and methamphetamine inhalers regarded as prescription drugs.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 4 2011-04-01 2011-04-01 false Amphetamine and methamphetamine inhalers regarded... DRUGS New Drug or Prescription Status of Specific Drugs § 250.101 Amphetamine and methamphetamine inhalers regarded as prescription drugs. (a) Recurring reports of abuse and misuse of methamphetamine (also...

21 CFR 250.101 - Amphetamine and methamphetamine inhalers regarded as prescription drugs.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 4 2014-04-01 2014-04-01 false Amphetamine and methamphetamine inhalers regarded... DRUGS New Drug or Prescription Status of Specific Drugs § 250.101 Amphetamine and methamphetamine inhalers regarded as prescription drugs. (a) Recurring reports of abuse and misuse of methamphetamine (also...

21 CFR 250.101 - Amphetamine and methamphetamine inhalers regarded as prescription drugs.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 4 2010-04-01 2010-04-01 false Amphetamine and methamphetamine inhalers regarded... DRUGS New Drug or Prescription Status of Specific Drugs § 250.101 Amphetamine and methamphetamine inhalers regarded as prescription drugs. (a) Recurring reports of abuse and misuse of methamphetamine (also...

Amphetamine-induced place preference in humans

PubMed Central

Childs, Emma L.; de Wit, Harriet

2009-01-01

Background The conditioned place preference procedure is a widely used animal model of rewarding drug effects that, to date, has not been tested in humans. In this study, we sought to demonstrate that humans, like non-humans, would exhibit a preference for a place previously associated with amphetamine. Further, we investigated the relationship between conditioned place preference and the mood-altering effects of the drug. Methods Thirty-one healthy individuals participated in a five-session procedure during which they experienced the effects of d-amphetamine (20mg) or placebo on two occasions in two distinctive environments (sessions 1 to 4). One group of subjects (paired group, N=19) received amphetamine consistently in one room and placebo in another room, while a second group (unpaired group, N=12) received amphetamine and placebo without regard to the rooms. During the sessions, participants completed questionnaires to rate their mood. On the fifth session, they rated their preference for the two rooms. Results Individuals in the paired group rated their liking of the amphetamine-paired room significantly higher than the placebo-associated room, while there was no difference between ratings of the two rooms for individuals in the unpaired group. In the paired group, drug liking ratings during the conditioning sessions positively predicted preference for the drug-associated room, whereas reports of amphetamine-induced anxiety and dysphoria negatively predicted room liking scores. Conclusions This study demonstrates that humans, like non-humans, prefer a place associated with amphetamine administration. These findings support the idea that subjective responses to a drug contribute to its ability to establish place conditioning. PMID:19111278

Does COMT genotype influence the effects of d-amphetamine on executive functioning?

PubMed Central

Wardle, Margaret C.; Hart, Amy B.; Palmer, Abraham A.; de Wit, Harriet

2012-01-01

In a widely cited study, Mattay et al. (2003) reported that amphetamine (0.25 mg/kg oral, or 17mg for a 68kg individual) impaired behavioral and brain indices of executive functioning, measured using the Wisconsin Card Sorting Task (WCST) and N-Back working memory task, in 6 individuals homozygous for the met allele of the val158met polymorphism in the catechol-O-methyltransferase (COMT) gene, whereas it improved executive functioning in 10 individuals homozygous for the more active val allele. We attempted to replicate their behavioral findings in a larger sample, using similar executive functioning tasks and a broader range of amphetamine doses. Over four sessions, n = 200 healthy normal adults received oral placebo, d-amphetamine 5mg, 10mg, and 20mg (average of 0.07, 0.15 and 0.29 mg/kg), under counterbalanced double-blind conditions, and completed WCST and N-back tests of executive functioning. Amphetamine had typical effects on blood pressure and processing speed but did not affect executive functioning. COMT genotype (val158met) was not related to executive functioning under placebo or amphetamine conditions, even when we compared only the homozygous val/val and met/met genotypes at the highest dose of amphetamine (20 mg). Thus, we were not able to replicate the behavioral interaction between COMT and amphetamine seen in Mattay et al. (Mattay et al., 2003). We discuss possible differences between the studies and the implications of our findings for the use of COMT genotyping to predict clinical responses to dopaminergic drugs, and the use of intermediate phenotypes in genetic research. PMID:23231539

Post-training amphetamine administration enhances memory consolidation in appetitive Pavlovian conditioning: Implications for drug addiction.

PubMed

Simon, Nicholas W; Setlow, Barry

2006-11-01

It has been suggested that some of the addictive potential of psychostimulant drugs of abuse such as amphetamine may result from their ability to enhance memory for drug-related experiences through actions on memory consolidation. This experiment examined whether amphetamine can specifically enhance consolidation of memory for a Pavlovian association between a neutral conditioned stimulus (CS-a light) and a rewarding unconditioned stimulus (US-food), as Pavlovian conditioning of this sort plays a major role in drug addiction. Male Long-Evans rats were given six training sessions consisting of 8 CS presentations followed by delivery of the food into a recessed food cup. After the 1st, 3rd, and 5th session, rats received subcutaneous injections of amphetamine (1.0 or 2.0 mg/kg) or saline vehicle immediately following training. Conditioned responding was assessed using the percentage of time rats spent in the food cup during the CS relative to a pre-CS baseline period. Both amphetamine-treated groups showed significantly more selective conditioned responding than saline controls. In a control experiment, there were no differences among groups given saline, 1.0 or 2.0 mg/kg amphetamine 2 h post-training, suggesting that immediate post-training amphetamine enhanced performance specifically through actions on memory consolidation rather than through non-mnemonic processes. This procedure modeled Pavlovian learning involved in drug addiction, in which the emotional valence of a drug reward is transferred to neutral drug-predictive stimuli such as drug paraphernalia. These data suggest that amphetamine may contribute to its addictive potential through actions specifically on memory consolidation.

Preventing growth in amphetamine use: long-term effects of the Midwestern Prevention Project (MPP) from early adolescence to early adulthood.

PubMed

Riggs, Nathaniel R; Chou, Chih-Ping; Pentz, Mary Ann

2009-10-01

The aim of the current study was to examine the long-term effect of an early adolescent substance abuse prevention program on trajectories and initiation of amphetamine use into early adulthood. Eight middle schools were assigned randomly to a program or control condition. The randomized controlled trial followed participants through 15 waves of data, from ages 11-28 years. This longitudinal study design includes four separate periods of development from early adolescence to early adulthood. The intervention took place in middle schools. A total of 1002 adolescents from one large mid-western US city were the participants in the study. The intervention was a multi-component community-based program delivered in early adolescence with a primary emphasis on tobacco, alcohol and marijuana use. At each wave of data collection participants completed a self-report survey that included questions about life-time amphetamine use. Compared to a control group, participants in the Midwestern Prevention Project (MPP) intervention condition had reduced growth (slope) in amphetamine use in emerging adulthood, a lower amphetamine use intercept at the commencement of the early adulthood and delayed amphetamine use initiation. The pattern of results suggests that the program worked first to prevent amphetamine use, and then to maintain the preventive effect into adulthood. Study findings suggest that early adolescent substance use prevention programs that focus initially on the 'gateway' drugs have utility for long-term prevention of amphetamine use. © 2009 The Authors. Journal compilation © 2009 Society for the Study of Addiction.

CHARACTERIZING THE PSYCHOLOGICAL STATE PRODUCED BY LSD.

ERIC Educational Resources Information Center

KATZ, MARTIN M.; AND OTHERS

THE DEVELOPMENT AND COMPONENTS OF LYSERGIC ACID DIETHYLAMIDE (LSD) PRODUCED PSYCHOLOGICAL STATES ARE INVESTIGATED. THE SUBJECTS WERE PAID VOLUNTEERS FROM THE PATUXENT INSTITUTION, A TREATMENT CENTER FOR EMOTIONALLY UNSTABLE CRIMINAL OFFENDERS. IN ONE STUDY, GROUPS OF 23 SUBJECTS RECEIVED LSD, AN AMPHETAMINE, OR A PLACEBO. IN THE SECOND STUDY, 11…

Illegal or legitimate use? Precursor compounds to amphetamine and methamphetamine.

PubMed

Musshoff, F

2000-02-01

The interpretation of methamphetamine and amphetamine positive test results in biological samples is a challenge to clinical and forensic toxicology for several reasons. The effects of pH and dilution of urine samples and the knowledge about legitimate and illicit sources have to be taken into account. Besides a potentially legal prescription of amphetamines, many substances metabolize to methamphetamine or amphetamine in the body: amphetaminil, benzphetamine, clobenzorex, deprenyl, dimethylamphetamine, ethylamphetamine, famprofazone, fencamine, fenethylline, fenproporex, furfenorex, mefenorex, mesocarb, and prenylamine. Especially the knowledge of potential origins of methamphetamine and amphetamine turns out to be very important to prevent a misinterpretation of the surrounding circumstances and to prove illegal drug abuse. In this review, potential precursor compounds are described, including their medical use and major clinical effects and their metabolic profiles, as well as some clues which help to identify the sources.

The neuropharmacology of ADHD drugs in vivo: insights on efficacy and safety.

PubMed

Heal, D J; Cheetham, S C; Smith, S L

2009-12-01

Results from in vivo techniques, especially intracerebral microdialysis in freely-moving rats, have provided insights into potential mechanisms responsible for the efficacy and safety of catecholaminergic drugs for ADHD treatment. The drugs reviewed come from distinct pharmacological classes: psychostimulant releasing agents, eg d-amphetamine; psychostimulant reuptake inhibitors, eg dl-threo-methylphenidate (dl-MPH), and non-stimulant reuptake inhibitors, eg atomoxetine. Psychostimulants, which currently deliver the best efficacy in treating ADHD, exhibit the following characteristics on extraneuronal catecholamine concentrations in rodent brain in vivo: 1) They enhance the efflux and function of both noradrenaline and dopamine in the central nervous system. 2) The increase of dopamine efflux that they produce is not limited to cortical regions. 3) They have a rapid onset of action with no ceiling on drug effect. d-Amphetamine has a mechanism independent of neuronal firing rate, displacing intraneuronal stores of catecholamines, delaying their reuptake and inhibiting catabolism by monoamine oxidase. dl-MPH has an enigmatic, extraneuronal action that is neuronal firing rate-dependent and reuptake transporter-mediated, yet paradoxically, almost as powerful as that of d-amphetamine. In safety terms, these powerful catecholaminergic effects also make the psychostimulants liable for abuse. Since efficacy and safety derive from the same pharmacological mechanisms, it has not yet been possible to separate these two components. However, the development of once-daily psychostimulant formulations and a prodrug, lisdexamfetamine, has improved patient compliance and markedly reduced scope for their diversion/abuse. This review will discuss the in vivo pharmacological profiles of approved catecholaminergic drugs for treatment of ADHD and implications for their clinical efficacy and abuse liability.

Pregabalin abuse among opiate addicted patients.

PubMed

Grosshans, Martin; Lemenager, Tagrid; Vollmert, Christian; Kaemmerer, Nina; Schreiner, Rupert; Mutschler, Jochen; Wagner, Xenija; Kiefer, Falk; Hermann, Derik

2013-12-01

Pregabalin is a novel GABA-analogue approved for the treatment of partial onset seizures, neuropathic pain, and general anxiety disorder. Pregabalin has been classified as a Schedule V drug with a low risk of inflicting abuse or addiction. However, some publications have indicated that pregabalin may have a potential for abuse among patients with past or current opiate addiction. Thus, we hypothesized that pregabalin might be abused by patients who were undergoing an opiate replacement therapy and never had an indication for taking pregabalin on medical grounds. Urine specimens from 124 patients with opiate dependency syndrome and from 111 patients with other addiction disorders (alcohol, benzodiazepines, cannabis, amphetamines) were screened for pregabalin by means of a mass spectrometer analysis. We found 12.1 % of all urine specimens from patients with opiate addiction to be positive for pregabalin. None of the patients concerned had a medical indication for using pregabalin. In the control group, 2.7 % of the patients were tested positively for pregabalin, due to their taking it regularly for chronic pain or general anxiety. Our data suggest that pregabalin is liable to be abused among individuals with opiate dependency syndrome Thus, vigilance and caution are called for when patients with a past or current opiate dependency are exposed to treatment with pregabalin.

Effect of methylphenidate and/or levodopa coupled with physiotherapy on functional and motor recovery after stroke--a randomized, double-blind, placebo-controlled trial.

PubMed

Lokk, J; Salman Roghani, R; Delbari, A

2011-04-01

Amphetamine-like drugs are reported to enhance motor recovery and activities of daily living (ADL) in stroke rehabilitation, but results from trials with humans are inconclusive. This study is aimed at investigating whether levodopa (LD) and/or methylphenidate (MPH) in combination with physiotherapy could improve functional motor recovery and ADL in patients with stroke. A randomized, double-blind, placebo-controlled trial with ischemic stroke patients randomly allocated to one of four treatment groups of either MPH, LD or MPH+LD or placebo combined with physiotherapy was performed. Motor function, ADL, and stroke severity were assessed by Fugl-Meyer (FM), Barthel index (BI), and National Institute of Health Stroke Scale (NIHSS) at baseline, 15, 90, and 180 days respectively. All participants showed recovery of motor function and ADL during treatment and at 6-month follow-up. There were slightly but significant differences in BI and NIHSS compared to placebo at the 6-month follow-up. Ischemic chronic stroke patients having MPH and/or LD in combination with physiotherapy showed a slight ADL and stroke severity improvement over time. Future studies should address the issue of the optimal therapeutic window and dosage of medications to identify those patients who would benefit most. © 2010 John Wiley & Sons A/S.

One day of motor training with amphetamine impairs motor recovery following spinal cord injury.

PubMed

Wong, Jamie K; Steward, Oswald

2012-02-01

It has previously been reported that a single dose of amphetamine paired with training on a beam walking task can enhance locomotor recovery following brain injury (Feeney et al., 1982). Here, we investigated whether this same drug/training regimen could enhance functional recovery following either thoracic (T9) or cervical (C5) spinal cord injury. Different groups of female Sprague-Dawley rats were trained on a beam walking task, and in a straight alley for assessment of hindlimb locomotor recovery using the BBB locomotor scale. For rats that received C5 hemisections, forelimb grip strength was assessed using a grip strength meter. Three separate experiments assessed the consequences of training rats on the beam walking task 24 h following a thoracic lateral hemisection with administration of either amphetamine or saline. Beginning 1 h following drug administration, rats either received additional testing/retraining on the beam hourly for 6 h, or they were returned to their home cages without further testing/retraining. Rats with thoracic spinal cord injuries that received amphetamine in conjunction with testing/retraining on the beam at 1 day post injury (DPI) exhibited significantly impaired recovery on the beam walking task and BBB. Rats with cervical spinal cord injuries that received training with amphetamine also exhibited significant impairments in beam walking and locomotion, as well as impairments in gripping and reaching abilities. Even when administered at 14 DPI, the drug/training regimen significantly impaired reaching ability in cervical spinal cord injured rats. Impairments were not seen in rats that received amphetamine without training. Histological analyses revealed that rats that received training with amphetamine had significantly larger lesions than saline controls. These data indicate that an amphetamine/training regimen that improves recovery after cortical injury has the opposite effect of impairing recovery following spinal cord injury because early training with amphetamine increases lesion severity. Copyright © 2011 Elsevier Inc. All rights reserved.

The stigmatisation of 'ice' and under-reporting of meth/amphetamine use in general population surveys: A case study from Australia.

PubMed

Chalmers, Jenny; Lancaster, Kari; Hughes, Caitlin

2016-10-01

Stigmatisation of illicit drug use is known to discourage people from reporting their use of illicit drugs. In the context of Australia's two recent "ice-epidemics" this study examines whether rapid increases in community concern about meth/amphetamine concurrent with increased stigmatising media reporting about meth/amphetamine "epidemics" are associated with increased under-reporting of its use in population surveys. We examined the relationship between general population trends in self-reported lifetime use of and attitudes towards meth/amphetamine between 2001 and 2013, contextualised against related stimulants and heroin, using five waves of Australia's National Drug Strategy Household Survey (NDSHS), alongside trends in print media reporting on meth/amphetamine from 2001 to 2014. Analysis of NDSHS data showed significant increases in community concern about meth/amphetamine between 2004 and 2007, and 2010 and 2013 in all birth cohorts and age groups. In both periods self-reported lifetime use of meth/amphetamine fell in many birth cohorts. The falls were only statistically significant in the first period, for birth cohorts from 1961-1963 to 1973-1975. Falls in lifetime use within a cohort from one period to the next are incongruous and we did not observe them in the other drugs considered. Equally, increases in concern were specific to meth/amphetamine. We counted substantial and rapid increase in the number of newspaper reports about meth/amphetamine in both periods, particularly reports including the term 'epidemic'. Rapid increases in the quantum of media reporting stigmatising a drug (through its construction as an 'epidemic') accompanying increased general public concerns about the drug may increase the tendency to under-report lifetime use. This may make it difficult to rely upon household surveys to observe trends in patterns of use and suggests that policy makers, media and others in the AOD sector should avoid stigmatisation of drugs, particularly during periods of heightened concern. Copyright © 2016 Elsevier B.V. All rights reserved.

Recoverable hearing loss with amphetamines and other drugs.

PubMed

Iqbal, Nayyer

2004-06-01

Prolonged and sustained consumption of alcohol, heroin and volatiles had been reported to impair hearing. Amphetamine related hearing loss is clinically different from the hearing loss seen with other agents. It seems that illicit drug use could result in two clinically different types of hearing losses. In May and June of 2001, 183 men aged 18 and above who met DSM-IV criteria for substance dependence were studied in a hospital in Saudia Arabia. The purpose of the study was to ascertain the prevalence of amphetamine-related recoverable hearing loss, establish whether similar hearing loss also occurred with other drugs of abuse and determine if drug-related psychosis was more prevalent in those amphetamine users who developed this type of hearing loss. Recoverable type of hearing loss was not just seen in amphetamine users but also occurred with cannabis, heroin, alcohol, dextromethorphan and glue use. Drug-induced psychosis was three and a half times more common in those amphetamine users who developed a hearing loss. Major depression and suicidality was also more common in these individuals. This association of major depression and subsequent development of hearing loss was also found in those using other type of drugs. It was concluded that a history of major depression was a good predictor of later development of both drug-induced psychosis and hearing loss in amphetamine users, and hypoperfusion was proposed as the possible explanation.

Brain abnormalities detected on magnetic resonance imaging of amphetamine users presenting to an emergency department: a pilot study.

PubMed

Fatovich, Daniel M; McCoubrie, David L; Song, Swithin J; Rosen, David M; Lawn, Nick D; Daly, Frank F

2010-09-06

To determine the prevalence of occult brain abnormalities in magnetic resonance imaging of active amphetamine users. Prospective convenience study in a tertiary hospital emergency department (ED). Patients presenting to the ED for an amphetamine-related reason were eligible for inclusion. We collected demographic data, drug use data, and performed a mini-mental state examination (MMSE). The proportion of patients with an abnormality on their MRI scan. Of 38 patients enrolled, 30 had MRI scans. Nineteen were male and their mean age was 26.7 +/- 5.4 years (range 19-41 years). The mean age of first amphetamine use was 18 years (range 13-26 years). Sixteen patients used crystal methamphetamine (mean amount 2.5 g/week), nine used amphetamine ("speed") (mean amount 2.9 g/week), and 23 used ecstasy (mean amount 2.3 tablets/week). Marijuana was smoked by 26 (mean amount 5.9 g/week), and 28 drank alcohol (mean amount 207 g/week). The median MMSE score was 27/30 (interquartile range, 26-29). Abnormalities on brain MRI scans were identified in six patients, most commonly an unidentified bright object (n = 4). In this pilot study of brain MRI of young people attending the ED with an amphetamine-related presentation, one in five had an occult brain lesion. While the significance of this is uncertain, it is congruent with evidence that amphetamines cause brain injury.

Caffeine induces differential cross tolerance to the amphetamine-like discriminative stimulus effects of dopaminergic agonists.

PubMed

Jain, Raka; Holtzman, Stephen G

2005-05-15

The purpose of this study was to determine if caffeine induces cross tolerance to the amphetamine-like discriminative stimulus effects of dopaminergic drugs that act through distinct mechanisms (e.g., release, uptake inhibition, direct activation of dopamine D(1)- or D(2)-family receptors). Rats were trained to discriminate 1.0 mg/kg d-amphetamine from saline in a two-choice discrete-trial procedure. Stimulus-generalization curves were generated by cumulative dosing for d-amphetamine (0.1-1.0 mg/kg), methylphenidate (0.3-5.6 mg/kg), SKF 81297 (0.3-3.0 mg/kg), and R-(-)-propylnorapomorphine (NPA; 0.001-1.78 mg/kg), as well as for caffeine (3.0-56 mg/kg); curves were re-determined after twice daily injections of caffeine (30 mg/kg) for 3.5 days. The rats generalized dose dependently to the four dopaminergic drugs, but only to a limited extent to caffeine. Twice daily injections of caffeine induced significant cross tolerance (i.e., increased ED(50)) to the amphetamine-like discriminative effects of methylphenidate and SKF 81297, attenuated non-significantly the effects of NPA, and did not alter the effects of amphetamine. Thus, caffeine produces differential cross tolerance to the amphetamine-like discriminative effects of dopaminergic drugs, a phenomenon in which the dopamine D(1) receptor appears to have an important role.

Evolution of the treatment of attention-deficit/hyperactivity disorder in children: a review.

PubMed

Findling, Robert L

2008-05-01

Efficacious and well-tolerated medications are available for the treatment of attention-deficit/hyperactivity disorder (ADHD). Stimulants such as methylphenidate (MPH) and amphetamines are the most widely used medications approved by the US Food and Drug Administration for the treatment of ADHDin children. This article reviews the literature on the development and use of medications for the treatment of ADHD in children. A search of MEDLINE was conducted toidentify relevant studies and critical reviews on the treatment of ADHD in children. The main criteria for inclusion of a study were that it have a controlled design, enroll >100 subjects if a clinical trial and >20 subjects if a classroom study, assess symptoms with the most widely used scales and tests,and be published from 2000 to 2008.A few older pivotal studies were also included. Many studies have reported the long-term efficacy and tolerability of immediate-release formulations of MPH. The disadvantages of such formulations include the need for multiple daily dosing and a potential for abuse. Various extended-release formulations of MPH have been found effective in controlled studies enrolling large numbers of children with ADHD. The efficacy and tolerability of dexmethylphenidate, the active D-isomer of MPH, in an extended-release formulation have also been reported. An extended-release formulation of mixed amphetamine salts (MMAS-XR) that is dosed once daily has been found to be efficacious and well tolerated. The non-stimulant atomoxetine has been reported to be well tolerated and efficacious, although it may not be as effective as stimulants; this formulation is, however, less likely than stimulants to be associated with abuse and diversion. A recently approved prodrug stimulant, lisdexamfetamine dimesylate (LDX), was developed to provide a long duration of effect that is consistent throughout the day, with a reduced potential for abuse. In a placebo-controlled study in children with ADHD, less intersubject variability in T(max), C(max), and AUC from time zero to the last quantifiable concentration was seen in the 8 subjects who received LDX (percent coefficient of variation, 15.3, 20.3, and 21.6, respectively) compared with the 9 subjects who received MAS-XR (52.8, 44.0, and 42.8).In 2 clinical trials, significantly greater improvements in teacher and parent ratings of ADHD symptoms were seen with LDX compared with placebo (P<0.001).A study of the abuse potential of LDX evaluated subjective responses to the effects of oral LDX and immediate-release d-amphetamine in adults with a history of stimulant abuse. LDX was associated with a significantly lower abuse-related liking effect than d-aamphetamine (P = 0.039). Currently available treatments for ADHD in children are efficacious and well tolerated, but many of them are limited by the requirement for multiple daily dosing and abuse potential. LDX, a long-acting prodrug of d-amphetamine, has been reported to be effective and appears to overcome some of these limitations.

Maintaining class, producing gender: enhancement discourses about amphetamine in entertainment media.

PubMed

McKenna, Stacey A

2011-11-01

Since the 1930s, amphetamine has been used for a variety of socially and medically condoned purposes including personal and performance enhancement. In the contemporary U.S., although amphetamine and its derivatives share a history, similar chemical composition, and physiological and psychiatric effects, they are typically treated and researched as two distinct groups: illegally produced methamphetamine and prescription amphetamine. This study is an examination of the social meanings of these categories and their users as represented in popular media. To complement existing research on drug discourses in popular news media, this study analysed entertainment media: ten novels, three seasons of Breaking Bad, six television episodes, and eight movies. Media were coded inductively and deductively using tenets of critical discourse analysis and rhetorical criticism. The author identified discourses about user subject positions and ideologies pertaining to enhancement-related motivations for use. Two important themes emerged from this analysis that construct amphetamine use and users in ways that reflect, legitimize and reproduce class and gender ideologies. First, discourses illustrate that distinct meanings of methamphetamine versus prescription amphetamine are linked to expectations about the respective socioeconomic class and social status of their users. Second, the discourses reflect gendered values and ideals about productivity and sexuality. In reality, American cultural and political-economic contexts may encourage the use of amphetamine to meet a variety of social expectations and economic needs. However, many policy and prevention efforts surrounding amphetamine use disproportionately target methamphetamine users and women. Because policy and prevention efforts can be influenced as much by social values as by data, it is important to examine the many arenas in which social values are produced and disseminated. Copyright © 2011 Elsevier B.V. All rights reserved.

Abuse of Amphetamines and Structural Abnormalities in Brain

PubMed Central

Berman, Steven; O’Neill, Joseph; Fears, Scott; Bartzokis, George; London, Edythe D.

2009-01-01

We review evidence that structural brain abnormalities are associated with abuse of amphetamines. A brief history of amphetamine use/abuse, and evidence for toxicity is followed by a summary of findings from structural magnetic resonance imaging (MRI) studies of human subjects who had abused amphetamines and children who were exposed to amphetamines in utero. Evidence comes from studies that used a variety of techniques that include manual tracing, pattern matching, voxel-based, tensor-based, or cortical thickness mapping, quantification of white matter signal hyperintensities, and diffusion tensor imaging. Ten studies compared controls to individuals who were exposed to methamphetamine. Three studies assessed individuals exposed to 3-4-methylenedioxymethamphetamine (MDMA). Brain structural abnormalities were consistently reported in amphetamine abusers, as compared to control subjects. These included lower cortical gray matter volume and higher striatal volume than control subjects. These differences might reflect brain features that could predispose to substance dependence. High striatal volumes might also reflect compensation for toxicity in the dopamine-rich basal ganglia. Prenatal exposure was associated with striatal volume that was below control values, suggesting that such compensation might not occur in utero. Several forms of white matter abnormality are also common, and may involve gliosis. Many of the limitations and inconsistencies in the literature relate to techniques and cross-sectional designs, which cannot infer causality. Potential confounding influences include effects of pre-existing risk/protective factors, development, gender, severity of amphetamine abuse, abuse of other drugs, abstinence, and differences in lifestyle. Longitudinal designs in which multimodal datasets are acquired and are subjected to multivariate analyses would enhance our ability to provide general conclusions regarding the associations between amphetamine abuse and brain structure. PMID:18991959

Dissociation in effects of lesions of the nucleus accumbens core and shell on appetitive pavlovian approach behavior and the potentiation of conditioned reinforcement and locomotor activity by D-amphetamine.

PubMed

Parkinson, J A; Olmstead, M C; Burns, L H; Robbins, T W; Everitt, B J

1999-03-15

Dopamine release within the nucleus accumbens (NAcc) has been associated with both the rewarding and locomotor-stimulant effects of abused drugs. The functions of the NAcc core and shell were investigated in mediating amphetamine-potentiated conditioned reinforcement and locomotion. Rats were initially trained to associate a neutral stimulus (Pavlovian CS) with food reinforcement (US). After excitotoxic lesions that selectively destroyed either the NAcc core or shell, animals underwent additional CS-US training sessions and then were tested for the acquisition of a new instrumental response that produced the CS acting as a conditioned reinforcer (CR). Animals were infused intra-NAcc with D-amphetamine (0, 1, 3, 10, or 20 microg) before each session. Shell lesions affected neither Pavlovian nor instrumental conditioning but completely abolished the potentiative effect of intra-NAcc amphetamine on responding with CR. Core-lesioned animals were impaired during the Pavlovian retraining sessions but showed no deficit in the acquisition of responding with CR. However, the selectivity in stimulant-induced potentiation of the CR lever was reduced, as intra-NAcc amphetamine infusions dose-dependently increased responding on both the CR lever and a nonreinforced (control) lever. Shell lesions produced hypoactivity and attenuated amphetamine-induced activity. In contrast, core lesions resulted in hyperactivity and enhanced the locomotor-stimulating effect of amphetamine. These results indicate a functional dissociation of subregions of the NAcc; the shell is a critical site for stimulant effects underlying the enhancement of responding with CR and locomotion after intra-NAcc injections of amphetamine, whereas the core is implicated in mechanisms underlying the expression of CS-US associations.

The N Terminus of Monoamine Transporters Is a Lever Required for the Action of Amphetamines*

PubMed Central

Sucic, Sonja; Dallinger, Stefan; Zdrazil, Barbara; Weissensteiner, René; Jørgensen, Trine N.; Holy, Marion; Kudlacek, Oliver; Seidel, Stefan; Cha, Joo Hwan; Gether, Ulrik; Newman, Amy H.; Ecker, Gerhard F.; Freissmuth, Michael; Sitte, Harald H.

2010-01-01

The serotonin transporter (SERT) terminates neurotransmission by removing serotonin from the synaptic cleft. In addition, it is the site of action of antidepressants (which block the transporter) and of amphetamines (which induce substrate efflux). We explored the functional importance of the N terminus in mediating the action of amphetamines by focusing initially on the highly conserved threonine residue at position 81, a candidate site for phosphorylation by protein kinase C. Molecular dynamics simulations of the wild type SERT, compared with its mutations SERTT81A and SERTT81D, suggested structural changes in the inner vestibule indicative of an opening of the inner vestibule. Predictions from this model (e.g. the preferential accumulation of SERTT81A in the inward conformation, its reduced turnover number, and a larger distance between its N and C termini) were verified. Most importantly, SERTT81A (and the homologous mutations in noradrenaline and dopamine) failed to support amphetamine-induced efflux, and this was not remedied by aspartate at this position. Amphetamine-induced currents through SERTT81A were comparable with those through the wild type transporter. Both abundant Na+ entry and accumulation of SERTT81A in the inward facing conformation ought to favor amphetamine-induced efflux. Thus, we surmised that the N terminus must play a direct role in driving the transporter into a state that supports amphetamine-induced efflux. This hypothesis was verified by truncating the first 64 amino acids and by tethering the N terminus to an additional transmembrane helix. Either modification abolished amphetamine-induced efflux. We therefore conclude that the N terminus of monoamine transporters acts as a lever that sustains reverse transport. PMID:20118234

Identification of specific markers for amphetamine synthesised from the pre-precursor APAAN following the Leuckart route and retrospective search for APAAN markers in profiling databases from Germany and the Netherlands.

PubMed

Hauser, Frank M; Rößler, Thorsten; Hulshof, Janneke W; Weigel, Diana; Zimmermann, Ralf; Pütz, Michael

2018-04-01

α-Phenylacetoacetonitrile (APAAN) is one of the most important pre-precursors for amphetamine production in recent years. This assumption is based on seizure data but there is little analytical data available showing how much amphetamine really originated from APAAN. In this study, several syntheses of amphetamine following the Leuckart route were performed starting from different organic compounds including APAAN. The organic phases were analysed using gas chromatography-mass spectrometry (GC-MS) to search for signals caused by possible APAAN markers. Three compounds were discovered, isolated, and based on the performed syntheses it was found that they are highly specific for the use of APAAN. Using mass spectra, high resolution MS and nuclear magnetic resonance (NMR) data the compounds were characterised and identified as 2-phenyl-2-butenenitrile, 3-amino-2-phenyl-2-butenenitrile, and 4-amino-6-methyl-5-phenylpyrimidine. To investigate their significance, they were searched in data from seized amphetamine samples to determine to what extent they were present in illicitly produced amphetamine. Data of more than 580 cases from amphetamine profiling databases in Germany and the Netherlands were used for this purpose. These databases allowed analysis of the yearly occurrence of the markers going back to 2009. The markers revealed a trend that was in agreement with seizure reports and reflected an increasing use of APAAN from 2010 on. This paper presents experimental proof that APAAN is indeed the most important pre-precursor of amphetamine in recent years. It also illustrates how important it is to look for new ways to identify current trends in drug production since such trends can change within a few years. Copyright © 2017 John Wiley & Sons, Ltd.

Protection against amphetamine-induced neurotoxicity toward striatal dopamine neurons in rodents by LY274614, an excitatory amino acid antagonist.

PubMed

Fuller, R W; Hemrick-Luecke, S K; Ornstein, P L

1992-10-01

LY274614, 3SR,4aRS,6SR,8aRS-6-[phosphonomethyl]decahydr oisoquinoline-3- carboxylic acid, has been described as a potent antagonist of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. Here its ability to antagonize the prolonged depletion of dopamine in the striatum by amphetamine in iprindole-treated rats is reported. A single 18.4 mg/kg (i.p.) dose of (+/-)-amphetamine hemisulfate, given to rats pretreated with iprindole, resulted in persistent depletion of dopamine in the striatum 1 week later. This prolonged depletion of dopamine in the striatum was antagonized by dizocilpine (MK-801, a non-competitive antagonist of NMDA receptors) or by LY274614 (a competitive antagonist of NMDA receptors). The protective effect of LY274614 was dose-dependent, being maximum at 10-40 mgkg (i.p.). A 10 mg/kg dose of LY274614 was effective in antagonizing the depletion of dopamine in the striatum, when given as long as 8 hr prior to amphetamine but not when given 24 hr prior to amphetamine. Depletion of dopamine in the striatum was also antagonized when LY274614 was given after the injection of amphetamine; LY274614 protected when given up to 4 hr after but not when given 8 or 24 hr after amphetamine. The prolonged depletion of dopamine in the striatum in mice, given multiple injections of methamphetamine, was also antagonized dose-dependently and completely by LY274614. The data strengthen the evidence that the neurotoxic effect of amphetamine and related compounds toward nigrostriatal dopamine neurons involves NMDA receptors and that LY274614 is an NMDA receptor antagonist with long-lasting in vivo effects in rats.

PKC phosphorylates residues in the N-terminal of the DA transporter to regulate amphetamine-induced DA efflux.

PubMed

Wang, Qiang; Bubula, Nancy; Brown, Jason; Wang, Yunliang; Kondev, Veronika; Vezina, Paul

2016-05-27

The DA transporter (DAT), a phosphoprotein, controls extracellular dopamine (DA) levels in the central nervous system through transport or reverse transport (efflux). Multiple lines of evidence support the claim that PKC significantly contributes to amphetamine-induced DA efflux. Other signaling pathways, involving CaMKII and ERK, have also been shown to regulate DAT mediated efflux. Here we assessed the contribution of putative PKC residues (S4, S7, S13) in the N-terminal of the DAT to amphetamine-induced DA efflux by transfecting DATs containing different serine to alanine (S-A) point mutations into DA pre-loaded HEK-293 cells and incubating these cells in amphetamine (2μM). The effects of a S-A mutation at the non-PKC residue S12 and a threonine to alanine (T-A) mutation at the ERK T53 residue were also assessed for comparison. WT-DATs were used as controls. In an initial experiment, we confirmed that inhibiting PKC with Go6976 (130nM) significantly reduced amphetamine-induced DA efflux. In subsequent experiments, cells transfected with the S4A, S12A, S13A, T53A and S4,7,13A mutants showed a reduction in amphetamine-induced DA efflux similar to that observed with Go6976. Interestingly, cells transfected with the S7A mutant, identified by some as a PKC-PKA residue, showed unperturbed WT-DAT levels of amphetamine-induced DA efflux. These results indicate that phosphorylation by PKC of select residues in the DAT N-terminal can regulate amphetamine-induced efflux. PKC can act either independently or in concert with other kinases such as ERK to produce this effect. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Toxicokinetics of amphetamines: metabolism and toxicokinetic data of designer drugs, amphetamine, methamphetamine, and their N-alkyl derivatives.

PubMed

Kraemer, Thomas; Maurer, Hans H

2002-04-01

This paper reviews the toxicokinetics of amphetamines. The designer drugs MDA (methylenedioxy-amphetamine, R,S-1-(3;,4;-methylenedioxyphenyl)2-propanamine), MDMA (R,S-methylenedioxymethamphetamine), and MDE (R,S-methylenedioxyethylamphetamine), as well as BDB (benzodioxolylbutanamine; R,S-1-(1;,3;-benzodioxol-5;-yl)-2-butanamine or R,S-1-(3;,4;-methylenedioxyphenyl)-2-butanamine) and MBDB (R,S-N-methyl-benzodioxolylbutanamine), were taken into consideration, as were the following N-alkylated amphetamine derivatives: amphetaminil, benzphetamine, clobenzorex, dimethylamphetamine, ethylamphetamine, famprofazone, fencamine, fenethylline, fenproporex, furfenorex, mefenorex, mesocarb, methamphetamine, prenylamine, and selegiline. English-language publications from 1995 to 2000 were reviewed. Papers describing identification of metabolites or cytochrome P450 isoenzyme-dependent metabolism and papers containing pharmacokinetic/toxicokinetic data were considered and summarized. The implications of toxicokinetics for toxicologic assessment or for interpretation in forensic cases are discussed.

Object recognition impairment in Fmr1 knockout mice is reversed by amphetamine: involvement of dopamine in the medial prefrontal cortex.

PubMed

Ventura, R; Pascucci, T; Catania, M V; Musumeci, S A; Puglisi-Allegra, S

2004-09-01

Fragile X syndrome is an X-linked form of mental retardation including, among others, symptoms such as stereotypic behaviour, hyperactivity, hyperarousal, and cognitive deficits. We hypothesized that hyperactivity and/or compromised attentional, cognitive functions may lead to impaired performance in cognitive tasks in Fmr1 knockout mice, the most widely used animal model of fragile X syndrome, and suggested that psychostimulant treatment may improve performance by acting on one or both components. Since hyperactivity and cognitive functions have been suggested to depend on striatal and prefrontal cortex dopaminergic dysfunction, we assessed whether amphetamine produced beneficial, positive effects by acting on dopaminergic corticostriatal systems. Our results show that Fmr1 knockout mice are not able to discriminate between a familiar object and a novel one in the object recognition test, thus showing a clear-cut cognitive impairment that, to date, has been difficult to demonstrate in other cognitive tasks. Amphetamine improved performance of Fmr1 knockout mice, leading to enhanced ability to discriminate novel versus familiar objects, without significantly affecting locomotor activity. In agreement with behavioural data, amphetamine produced a greater increase in dopamine release in the prefrontal cortex of Fmr1 knockout compared with the wild-type mice, while a weak striatal dopaminergic response was observed in Fmr1 knockout mice. Our data support the view that the psychostimulant ameliorates performance in Fmr1 knockout mice by improving merely cognitive functions through its action on prefrontal cortical dopamine, irrespective of its action on motor hyperactivity. These results indicate that prefrontal cortical dopamine plays a major role in cognitive impairments characterizing Fmr1 knockout mice, thus pointing to an important aetiological factor in the fragile X syndrome.

Scopolamine and amphetamine produce similar decision-making deficits on a rat gambling task via independent pathways.

PubMed

Silveira, Mason M; Malcolm, Emma; Shoaib, Mohammed; Winstanley, Catharine A

2015-03-15

Disorders characterized by disturbed cholinergic signaling, such as schizophrenia, exhibit impaired performance on measures of real-world cost/benefit decision-making. Whether the cholinergic system contributes to the choice deficits observed is currently unknown. We therefore determined the effects of broad-acting agonists and antagonists at the nicotinic and muscarinic receptor on decision making, as measured by the rodent gambling task (rGT). Given the anatomical and functional connectivity of the cholinergic and dopaminergic systems, we also sought to modulate amphetamine's previously reported effect on rGT performance via the cholinergic system. Male rats were trained on the rGT, during which animals chose from four different options. The optimal strategy on the rGT is to favor options associated with smaller immediate rewards and less punishment/loss. Impulsive action was also measured by recording the number of premature responses made. Performance on the rGT was assessed following acute treatment with the muscarinic receptor agonist oxotremorine, the muscarinic receptor antagonist scopolamine, nicotine, and the nicotinic receptor antagonist mecamylamine. Similar to the effect produced by amphetamine, muscarinic receptor antagonism with scopolamine (0.1mg/kg) impaired decision making, albeit to a lesser degree. Prior muscarinic agonism with oxotremorine was unable to attenuate amphetamine's effects on rGT performance. Oxotremorine, nicotine, and mecamylamine did not affect the choice profile. We therefore conclude that modulation of the muscarinic, but not nicotinic, receptor system can affect decision making under conditions of risk and uncertainty. Such findings contribute to a broader understanding of the cognitive deficits observed in disorders in which cholinergic signaling is compromised. Copyright © 2014 Elsevier B.V. All rights reserved.

Increased anxiety and impaired memory in rats 3 months after administration of 3,4-methylenedioxymethamphetamine ("ecstasy").

PubMed

Morley, K C; Gallate, J E; Hunt, G E; Mallet, P E; McGregor, I S

2001-12-14

Male Wistar rats were administered either (a) a high dose regime of 3,4-methylenedioxymethamphetamine (MDMA) (4 x 5 mg/kg, i.p. over 4 h on each of 2 consecutive days), (b) a moderate dose regime of MDMA (1 x 5 mg/kg on each of 2 consecutive days), (c) D-amphetamine (4 x 1 mg/kg over 4 h on each of 2 days), or (d) vehicle injections. The high MDMA dose regime and the amphetamine treatment both produced acute hyperactivity and hyperthermia. Twelve weeks later, all rats were tested in the drug-free state on a battery of anxiety tests (elevated plus maze, emergence and social interaction tests). A further 2 weeks later they were tested on a novel object recognition memory task. Rats previously given the neurotoxic dose of MDMA showed greater anxiety-like behaviour on all three anxiety tests relative to both controls and D-amphetamine-treated rats. Rats given the moderate MDMA dose regime also showed increased anxiety-like behaviour on all three tests, although to a lesser extent than rats in the high dose group. In the object recognition task, rats given the high MDMA dose regime showed impaired memory relative to all other groups when tested at a 15-min delay but not at a 60-min delay. Rats previously exposed to amphetamine did not differ from saline controls in the anxiety or memory tests. These data suggest that moderate to heavy MDMA exposure over 48 h may lead to increased anxiety and memory impairment 3 months later, possibly through a neurotoxic effect on brain serotonin systems.

[Addiction to cocaine and other stimulants].

PubMed

Lacoste, Jérôme; Delavenne-Garcia, Héloïse; Charles-Nicolas, Aimé; Duarte Garcia, Frederico; Jehel, Louis

2012-12-01

Due to many available forms (powder, pasta base, freebase and crack…) and because of multiple routes of administration (intranasal, intravenous, or smoked), cocaine has become in 30 years one of the most consumed illegal drugs worldwide, after cannabis. While the frequency of consumption decreases in North America, it continues to rise in Europe, and in some countries in South America, including Brazil, despite a growing knowledge of its specific effects, physical complications and psychiatric consequences. Elsewhere (notably in Asia and Indian Ocean), amphetamine and other stimulants (including methamphetamine), whose properties and patterns of use are very similar to those of cocaine, tend to replace it. Another amphetamine derivative, MDMA or ecstasy, is also consumed by many young people of less than 25 years, in Europe and North America, in a festive setting, with specific consequences and special procedures of care. Although there is currently no consensus for a specific medication, the most appropriate therapeutic approach seems to involve a psychosocial treatment associated with an anticraving medication, which will reduce compulsive desire to consume, in order to facilitate the psychotherapeutic and social care. However, pharmacological research remains very active, and many options are explored (GABAergic or dopaminergic agonists, amphetamine derivatives with long half-life, vaccine…), whether to treat addiction to cocaine or to methamphetamine. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Modafinil: the unique properties of a new stimulant.

PubMed

Lyons, T J; French, J

1991-05-01

Modafinil, a novel stimulant which has several remarkable features that distinguish it from other stimulants, has been developed by Lafon, a French pharmaceutical company. Unlike the amphetamines, for example, modafinil is reported to have minimal peripheral side effects at therapeutic doses. It also appears to have a low abuse potential, does not interfere with normal sleep, and does not seem to produce tolerance. It improves vigilance especially in sleep-deprived subjects. It has been used clinically for up to 3 years in the treatment of narcolepsy and idiopathic hypersomnia. It could be an ideal replacement for amphetamine in short-term operations in which fatigue might threaten the successful completion of a mission. We recommend that military laboratories experienced in studying sustained performance include modafinil or perhaps a more selective alpha 1 receptor agonist in their investigations.

Dietary triglycerides as signaling molecules that influence reward and motivation

PubMed Central

Berland, Chloé; Cansell, Céline; Hnasko, Thomas S.; Magnan, Christophe; Luquet, Serge

2017-01-01

The reinforcing and motivational aspects of food are tied to the release of the dopamine in the mesolimbic system (ML). Free fatty acids from triglyceride (TG)-rich particles are released upon action of TG-lipases found at high levels in peripheral oxidative tissue (muscle, heart), but also in the ML. This suggests that local TG-hydrolysis in the ML might regulate food seeking and reward. Indeed, evidence now suggests that dietary TG directly target the ML to regulate amphetamine-induced locomotion and reward seeking behavior. Though the cellular mechanisms of TG action are unresolved, TG act in part through ML lipoprotein lipase, upstream of dopamine 2 receptor (D2R), and show desensitization in conditions of chronically elevated plasma TG as occur in obesity. TG sensing in the ML therefore represents a new mechanism by which chronic consumption of dietary fat might lead to adaptations in the ML and dysregulated feeding behaviors. PMID:28191490

[Epileptic insults, cerebral infarction and rhabdomyolysis as complications of amphetamine use].

PubMed

Roebroek, R M; Korten, J J

1996-01-27

In a 16-year-old boy with acute generalised epileptic convulsions, cerebral infarction and rhabdomyolysis were diagnosed. The urine was positive for amphetamine. Until that moment the patient had denied using drugs. He recovered and was discharged after nine days. Recreational use of ecstasy (methylenedioxymethamphetamine) and other amphetamine derivatives is gaining popularity worldwide. This drug abuse is rarely reported spontaneously.

HIV Risk Behavior among Amphetamine Injectors at U.S. Syringe Exchange Programs

ERIC Educational Resources Information Center

Braine, Naomi; Des Jarlais, Don C.; Goldblatt, Cullen; Zadoretzky, Cathy; Turner, Charles

2005-01-01

The goal of this study was to compare HIV risk behaviors of amphetamine and non-amphetamine injectors at syringe exchange programs (SEP) in the United States and to identify factors associated with injection risk. This analysis is based on data from a random cross-section of participants at 13 SEPs in different parts of the country. All interviews…

[Urine levels of fenethylline and amphetamine after administration of Captagon].

PubMed

Iffland, R

1982-01-01

The limit for detecting fenethylline and its metabolite amphetamine in GLC with N-FID is in the range of nanograms. The elimination of these substances in urine was measured after giving different quantities of Captagon to six volunteers. The concentrations of fenethylline and amphetamine in urine allow to estimate with some limitations time and amount of consuming Captagon for forensic purposes.

Dopaminergic Actions of D-Amphetamine on Schedule-Induced Polydipsia in Rats

ERIC Educational Resources Information Center

Pellon, Ricardo; Ruiz, Ana; Rodriguez, Cilia; Flores, Pilar

2007-01-01

Schedule-induced polydipsia in rats was developed by means of a fixed-time 60-s schedule of food presentation. The acute administration of d-amphetamine sulfate (0.1-3.0 mg/kg) produced a dose-dependent decrease in the rate of licking. D-Amphetamine shifted to the left the temporal distribution of adjunctive drinking within interfood intervals.…

[Hallucinogens, amphetamines and entactogens].

PubMed

Vollenweider, F X; Vollenweider-Scherpenhuyzen, M F

2003-06-01

MDMA ("Ecstasy") and its analogues such as MDE and MDA are amphetamine derivatives reported to produce an altered state with emotional overtones. Since more than ten years, ecstasy is after cannabis the most frequently used recreational drug by young adults, particularly in the so-called techno-scene. However, according to a recent survey there is an increasing trend for a revival of classic amphetamine and hallucinogen abuse, possibly due to the concern about the potential neurotoxicity and somatic risks associated with ecstasy use. Of the hallucinogens consumed, psilocybin containing mushroom ("magic mushrooms"), but also LSD are at the forefront. The present contribution summarizes the psychological and somatic effects of hallucinogens, amphetamines, and entactogens.

Sensitive and selective determination of methylenedioxylated amphetamines by high-performance liquid chromatography with fluorimetric detection.

PubMed

Sadeghipour, F; Veuthey, J L

1997-11-07

A rapid, sensitive and selective liquid chromatographic method with fluorimetric detection was developed for the separation and quantification of four methylenedioxylated amphetamines without interference of other drugs of abuse and common substances found in illicit tablets. The method was validated by examining linearity, precision and accuracy as well as detection and quantification limits. Methylenedioxylated amphetamines were quantified in eight tablets from illicit drug seizures and results were quantitatively compared to HPLC-UV analyses. To demonstrate the better sensitivity of the fluorimetric detection, methylenedioxylated amphetamines were analyzed in serum after a liquid-liquid extraction procedure and results were also compared to HPLC-UV analyses.

The effect of antimotion sickness drugs on habituation to motion

NASA Technical Reports Server (NTRS)

Wood, C. D.; Manno, J. E.; Manno, B. R.; Odenheimer, R. C.; Bairnsfather, L. E.

1986-01-01

The mechanism which allows for increased exposure to motion and accelerates habituation is investigated. The responses of 12 male and female subjects between 18-30 years rotated once a day for 5 days on the Contraves Goerz rotating chair after receiving placebo, 10 mg d-amphetamine, 0.6 mg scopolamine with 5 mg d-amphetamine, and 1.0 mg scopolamine are studied. It is observed that with placebo the subjects performed 48 more head movements than untreated subjects, 118 more movements with d-amphetamine, 176 more with 0.6 mg scopolamine with d-amphetamine, and 186 more with 1.0 scopolamine. The data reveal that exposure to rotation increases tolerance from 88 head movements on day 2 to 159 on day 4 at 17.4 rpm and with placebo; 96 to 186 at 19.9 rpm with 10 mg d-amphetamine; 111 to 273 at 20.2 rpm with scopolamine with d-amphetamine, and 141 to 279 at 22.4 rpm with 1.0 mg scopolamine. It is noted that a combination of cholinergic blocking and norepinephrine activation action is most effective in preventing the development of motion sickness and habituation is due to the greater exposure to vestibular simulation permitted by the drugs.

Tracing methamphetamine and amphetamine sources in wastewater and receiving waters via concentration and enantiomeric profiling.

PubMed

Xu, Zeqiong; Du, Peng; Li, Kaiyang; Gao, Tingting; Wang, Zhenglu; Fu, Xiaofang; Li, Xiqing

2017-12-01

Wastewater analysis is a promising approach to monitor illicit drug abuse of a community. However, drug use estimation via wastewater analysis may be biased by sources other than abuse. This is especially true for methamphetamine and amphetamine as their presence in wastewater may come from many sources, such as direct disposal or excretion following administration of prescription drugs. Here we traced methamphetamine and amphetamine sources via concentration and enantiomeric profiling of the two compounds from black market to receiving waters. Methamphetamine in wastewater was found to predominantly arise from abuse, proving the feasibility of using wastewater analysis for estimating its consumption in China. Amphetamine abuse was previously considered negligible in East and Southeast Asia. However, we found that amphetamine was abused considerably (up to 90.7mg/1000inh/day) in a significant number (>20%) of major cities in China. Combined concentration and enantiomeric profiling also revealed direct disposal into receiving waters of methamphetamine manufactured by different processes. These findings have important implications for monitoring of and law enforcement against methamphetamine/amphetamine abuse and related crimes in China and abroad. Copyright © 2017. Published by Elsevier B.V.

The pharmacology of amphetamine and methylphenidate: Relevance to the neurobiology of attention-deficit/hyperactivity disorder and other psychiatric comorbidities.

PubMed

Faraone, Stephen V

2018-04-01

Psychostimulants, including amphetamines and methylphenidate, are first-line pharmacotherapies for individuals with attention-deficit/hyperactivity disorder (ADHD). This review aims to educate physicians regarding differences in pharmacology and mechanisms of action between amphetamine and methylphenidate, thus enhancing physician understanding of psychostimulants and their use in managing individuals with ADHD who may have comorbid psychiatric conditions. A systematic literature review of PubMed was conducted in April 2017, focusing on cellular- and brain system-level effects of amphetamine and methylphenidate. The primary pharmacologic effect of both amphetamine and methylphenidate is to increase central dopamine and norepinephrine activity, which impacts executive and attentional function. Amphetamine actions include dopamine and norepinephrine transporter inhibition, vesicular monoamine transporter 2 (VMAT-2) inhibition, and monoamine oxidase activity inhibition. Methylphenidate actions include dopamine and norepinephrine transporter inhibition, agonist activity at the serotonin type 1A receptor, and redistribution of the VMAT-2. There is also evidence for interactions with glutamate and opioid systems. Clinical implications of these actions in individuals with ADHD with comorbid depression, anxiety, substance use disorder, and sleep disturbances are discussed. Copyright © 2018 The Author. Published by Elsevier Ltd.. All rights reserved.

Retention of sequential drug discriminations under fixed-interval schedules for long time periods without training.

PubMed

Li, Mi; McMillan, Donald E

2003-08-22

The experiments showed that sequential drug discriminations can be learned and retained under a fixed-interval (FI) schedule for more than 18 months without additional training under a complex three-choice procedure. Pigeons were trained to discriminate among 5 mg/kg pentobarbital, 2 mg/kg D-amphetamine, and saline. After responding stabilized, dose-response curves were determined for other drugs. Subsequently, pentobarbital was replaced with 5 mg/kg morphine as a training drug, and D-amphetamine was replaced with 30 mg/kg caffeine. After the pigeons learned these new discriminations, dose-response curves were redetermined. Initially, chlordiazepoxide substituted for pentobarbital, cocaine substituted for D-amphetamine, and nicotine partially substituted for D-amphetamine. Morphine, Delta9-tetrahydrocannabinol, and caffeine did not substitute for either drug. After retraining with morphine and caffeine, responding occurred on the pentobarbital/morphine key after pentobarbital, chlordiazepoxide and morphine and on the D-amphetamine/caffeine key after D-amphetamine, cocaine and caffeine. After nicotine and Delta9-tetrahyrdocannabinol, responding occurred on the saline key. These data show that drug discriminations learned under fixed-interval schedules are retained for long time periods, even when discrimination training with other drugs occurs during the retention period.

Development of Computer-Supported Assessment and Treatment Consultation for Emotional Crises (CATCEC) for a Submarine Environment.

DTIC Science & Technology

1986-03-01

SCHIZOPHRENIC DISORDER Amphetamine Delusional Disorder PARANOID DISORDER Cannabis Delusional Disorder Hallucinogen Delusional Disorder BRIEF REACTIVE...Intoxication Borderline Personality Disorder Cocaine Intoxication Histrionic Personality Disorder Caffeine Intoxication Narcissistic Personality Disorder... Cannabis Intoxication Dependent Personality Disorder ON, Inhalant Intoxication Schizoid Personality Disorder Minor Tranquilizer Intoxication Compulsive

Individual vulnerabilities relative for potential pathological conditions.

PubMed

Moal, Michel Le

2016-08-15

It is not a usual venture to review experiments conducted decades ago in the context of interests of that time and replace them in a long-term historical perspective. These investigations were the product of a long-standing interest for individual differences in vulnerabilities relative to coping with stressful situations and for potential pathological conditions such as drug abuse. The rationale was, and still is, to decipher the psychobiological characteristics of these complex traits. STRESS- AND PHARMACOLOGICALLY-INDUCED BEHAVIORAL SENSITIZATION INCREASES VULNERABILITY TO ACQUISITION OF AMPHETAMINE SELF-ADMINISTRATION: Individual vulnerability to drug addiction may be an important factor in the prognosis of pathological behavior in man. However, experimental investigations have largely neglected the psychobiological substrate of predisposition to addiction. In this study, we use a self-administration (SA) acquisition paradigm showing that previous repeated exposure to a stressful experience (tail-pinch) or to amphetamine increases the locomotor response to this drug (behavioral sensitization) and enhances vulnerability to amphetamine SA. These results show that vulnerability to developing amphetamine SA may be influenced by stressful experiences, and that previous contact with the drug may also enhance a predisposition to amphetamine-taking behavior. As tail-pinch and amphetamine sensitization affect both the dopamine (DA) neural system and the propensity to self-administer amphetamine (a behavior also modulated by DA activity), stress may influence SA via an action on the DA system. © 1990. This article is part of a Special Issue entitled SI:50th Anniversary Issue. Copyright © 2016 Elsevier B.V. All rights reserved.

Amphetamine increases schedule-induced drinking reduced by negative punishment procedures.

PubMed

Pérez-Padilla, Angeles; Pellón, Ricardo

2003-05-01

d-Amphetamine has been reported to increase schedule-induced drinking punished by lick-dependent signalled delays in food delivery. This might reflect a drug-behaviour interaction dependent on the type of punisher, because no such effect has been found when drinking was reduced by lick-contingent electric shocks. However, the anti-punishment effect of amphetamine could be mediated by other behavioural processes, such as a loss of discriminative control or an increase in the value of delayed reinforcers. To test the effects of d-amphetamine on the acquisition and maintenance of schedule-induced drinking reduced by unsignalled delays in food delivery. Rats received 10-s unsignalled delays initiated by each lick after polydipsia was induced by a fixed-time 30-s food reinforcement schedule or from the outset of the experiment. Yoked-control rats received these same delays but independently of their own behaviour. d-Amphetamine (0.1-3.0 mg/kg) was then tested IP. d-Amphetamine dose-dependently increased and then decreased punished schedule-induced drinking. The drug led to dose-dependent reductions when the delays were not contingent or when they were applied from the outset of training. These results support the contention that d-amphetamine has an increasing effect on schedule-induced drinking that has been previously reduced by a negative punishment procedure. This effect cannot be attributed to other potentially involved processes, and therefore support the idea that drug effects on punished behaviour depend on punishment being delays in food or shock deliveries.

Individual behavioural predictors of amphetamine-induced emission of 50 kHz vocalization in rats.

PubMed

Mulvihill, Kevin G; Brudzynski, Stefan M

2018-05-11

Measurement of ultrasonic vocalizations (USVs) produced by adult rats represents a highly useful index of emotional arousal. The associations found between 50 kHz USV production and a variety of behavioural and pharmacological protocols increasingly suggests they serve as a marker of positive motivational states. This study used a powerful within-subjects design to investigate the relationships among individual differences in approach to a sweet-food reward, predisposition to emit 50 kHz USVs spontaneously, and 50 kHz USVs emission following acute systemic administration of amphetamine. Both approach motivation and predisposition to call were found to not correlate with each other but did predict 50 kHz USV response to acute amphetamine. These two behavioural phenotypes appear to represent dissociable predictors of acute amphetamine-induced emission of 50 kHz USVs in a non-sensitization paradigm. In contrast to that, a measure of sucrose preference was not found to predict 50 kHz USV emission following amphetamine. Acute amphetamine was also found to increase average sound frequency of emitted USVs and selectively increase the proportion of Trill subtype 50 kHz USVs. Together, these data demonstrate that acute amphetamine-induced 50 kHz USVs in the adult rat represent more than just a univariate motivational state and may represent the product of dissociable subsystems of emotional behavior. Copyright © 2018. Published by Elsevier B.V.

Bilateral six-hydroxydopamine administration to PFC prevents the expression of behavioral sensitization to methylphenidate.

PubMed

Wanchoo, S J; Lee, M J; Swann, A C; Dafny, N

2010-02-02

Psychostimulants like amphetamine and methylphenidate (MPD) are used to treat attention deficit hyperactivity disorder (ADHD), which is marked by developmentally inappropriate inattention, hyperactivity, and impulsivity. Neuropsychological analyses indicate that ADHD patients are impaired on tasks of behavioral inhibition, reward reversal, and working memory, which are functions of the prefrontal cortex (PFC) and are modulated by the mesocortical dopamine (DA) system. Non-specific electrical lesioning of PFC eliminated the expression of behavioral sensitization elicited by chronic MPD administration. Behavioral sensitization is the progressive augmentation of locomotor activity as a result of repetitive (chronic) exposure to the drug. It is believed that the sensitization to chronic drug treatment is caused due to an increase in DA in the mesocorticolimbic DA system, which includes the PFC. Therefore, this study investigated the role of PFC DA in mediating the behavioral sensitization to repeated administration of MPD in adult male Sprague-Dawley rats. On experimental day (ED) 1, the behavior was recorded post-saline injection. On ED 2, the rats were divided into three groups--control, sham and bilateral 6-OHDA treated group; and the sham and 6-OHDA treated groups underwent respective surgeries. After 5 days of rest following surgery, the post-surgery baseline was recorded on ED 8 following a saline injection. All three groups received 2.5 mg/kg MPD for 6 days (from ED 9 to ED 14), followed by a 3-day washout period (ED 15 to ED 18). On ED 19, a rechallenge injection of 2.5 mg/kg MPD was given and locomotor activity was recorded. It was found that the 6-OHDA lesion group failed to exhibit behavioral sensitization to MPD. The involvement of the dopaminergic afferents of PFC in behavioral sensitization to MPD is discussed. (c) 2009 Elsevier B.V. All rights reserved.

Amphetamine manipulates monoamine oxidase-A level and behavior using theranostic aptamers of transcription factors AP-1/NF-kB.

PubMed

Liu, Christina H; Ren, Jiaqian; Liu, Philip K

2016-02-03

Monoamine oxidase (MAO) enzymes play a critical role in controlling the catabolism of monoamine neurotransmitters and biogenic trace amines and behavior in humans. However, the mechanisms that regulate MAO are unclear. Several transcription factor proteins are proposed to modulate the transcription of MAO gene, but evidence supporting these hypotheses is controversial. We aimed to investigate the mechanism of gene transcription regulator proteins on amphetamine-induced behavior. We applied aptamers containing a DNA binding sequence, as well as a random sequence (without target) to study the modulation of amphetamine-induced MAO levels and hyperactivity in living mice. We pretreated in adult male C57black6 mice (Taconic Farm, Germantown, NY) (n ≥ 3 litters at a time), 2 to 3 months of age (23 ± 2 gm body weight) with double-stranded (ds) DNA aptamers with sequence specific to activator protein-1 (5ECdsAP1), nuclear factor-kappa beta (5ECdsNF-kB), special protein-1 (5ECdsSP-1) or cyclicAMP responsive element binding (5ECdsCreB) protein binding regions, 5ECdsRan [a random sequence without target], single-stranded AP-1 (5ECssAP-1) (8 nmol DNA per kg) or saline (5 μl, intracerebroventricular [icv] injection) control before amphetamine administration (4 mg/kg, i.p.). We then measured and analyzed locomotor activities and the level of MAO-A and MAO-B activity. In the pathological condition of amphetamine exposure, we showed here that pretreatment with 5ECdsAP1 and 5ECdsNF-kB reversed the decrease of MAO-A activity (p < 0.05, t test), but not activity of the B isomer (MAO-B), in the ventral tegmental area (VTA) and substantia nigra (SN) of C57black6 mice. The change in MAO-A level coincided with a reversed amphetamine-induced restless behavior of mice. Pretreatments with saline, 5ECdsCreB, 5ECdsSP-1, 5ECdsRan or 5ECssAP-1 had no effect. Our data lead us to conclude that elevation of AP-1 or NF-kB indirectly decreases MAO-A protein levels which, in turn, diminishes MAO-A ability in the VTA of the mesolimbic dopaminergic pathway that has been implicated in cells under stress especially in the SN and VTA. This study has implications for design for the treatment of drug exposure and perhaps Parkinson's dementia.

Treatment of toxicity from amphetamines, related derivatives, and analogues: a systematic clinical review.

PubMed

Richards, John R; Albertson, Timothy E; Derlet, Robert W; Lange, Richard A; Olson, Kent R; Horowitz, B Zane

2015-05-01

Overdose of amphetamine, related derivatives, and analogues (ARDA) continues to be a serious worldwide health problem. Patients frequently present to the hospital and require treatment for agitation, psychosis, and hyperadrenegic symptoms leading to pathologic sequelae and mortality. To review the pharmacologic treatment of agitation, psychosis, and the hyperadrenergic state resulting from ARDA toxicity. MEDLINE, PsycINFO, and the Cochrane Library were searched from inception to September 2014. Articles on pharmacologic treatment of ARDA-induced agitation, psychosis, and hyperadrenergic symptoms were selected. Evidence was graded using Oxford CEBM. Treatment recommendations were compared to current ACCF/AHA guidelines. The search resulted in 6082 articles with 81 eligible treatment involving 835 human subjects. There were 6 high-quality studies supporting the use of antipsychotics and benzodiazepines for control of agitation and psychosis. There were several case reports detailing the successful use of dexmedetomidine for this indication. There were 9 high-quality studies reporting the overall safety and efficacy of β-blockers for control of hypertension and tachycardia associated with ARDA. There were 3 high-quality studies of calcium channel blockers. There were 2 level I studies of α-blockers and a small number of case reports for nitric oxide-mediated vasodilators. High-quality evidence for pharmacologic treatment of overdose from ARDA is limited but can help guide management of acute agitation, psychosis, tachycardia, and hypertension. The use of butyrophenone and later-generation antipsychotics, benzodiazepines, and β-blockers is recommended based on existing evidence. Future randomized prospective trials are needed to evaluate new agents and further define treatment of these patients. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Effect of desipramine and citalopram treatment on forced swimming test-induced changes in cocaine- and amphetamine-regulated transcript (CART) immunoreactivity in mice.

PubMed

Chung, Sung; Kim, Hee Jeong; Kim, Hyun Ju; Choi, Sun Hye; Kim, Jin Wook; Kim, Jeong Min; Shin, Kyung Ho

2014-05-01

Recent study demonstrates antidepressant-like effect of cocaine- and amphetamine-regulated transcript (CART) in the forced swimming test (FST), but less is known about whether antidepressant treatments alter levels of CART immunoreactivity (CART-IR) in the FST. To explore this possibility, we assessed the treatment effects of desipramine and citalopram, which inhibit the reuptake of norepinephrine and serotonin into the presynaptic terminals, respectively, on changes in levels of CART-IR before and after the test swim in mouse brain. Levels of CART-IR in the nucleus accumbens shell (AcbSh), dorsal bed nucleus of the stria terminalis (dBNST), and hypothalamic paraventricular nucleus (PVN) were significantly increased before the test swim by desipramine and citalopram treatments. This increase in CART-IR in the AcbSh, dBNST, and PVN before the test swim remained elevated by desipramine treatment after the test swim, but this increase in these brain areas returned to near control levels after test swim by citalopram treatment. Citalopram, but not desipramine, treatment increased levels of CART-IR in the central nucleus of the amygdala (CeA) and the locus ceruleus (LC) before the test swim, and this increase was returned to control levels after the test swim in the CeA, but not in the LC. These results suggest common and distinct regulation of CART by desipramine and citalopram treatments in the FST and raise the possibility that CART in the AcbSh, dBNST, and CeA may be involved in antidepressant-like effect in the FST.

The inhibition of amine oxidase and the central stimulating action of the stereoisomeric amphetamines and 1-phenylethylamines

PubMed Central

Grana, E.; Lilla, L.

1959-01-01

The stereoisomers of amphetamine and 1-phenylethylamine have been studied in the rat both as central stimulants and as inhibitors of amine oxidase from brain, liver, and kidney. There was no correlation between these two effects; thus it is unlikely that the central stimulating action of amphetamine is due to inhibition of amine oxidase. PMID:13828860

Effects of Amphetamine-CNS Depressant Combinations and of Other CNS Stimulants in Four-Choice Drug Discriminations

ERIC Educational Resources Information Center

Li, Mi; Wessinger, William D.; McMillan, D. E.

2005-01-01

Three pigeons were trained to discriminate among 5 mg/kg pentobarbital, 2 mg/kg amphetamine, a combination of these two drugs at these doses, and saline using a four-choice procedure (amphetamine--pentobarbital group). Three other pigeons were trained to discriminate among 5 mg/kg morphine, 2 mg/kg methamphetamine, a combination of these two drugs…

High Fat Diet Augments Amphetamine Sensitization in Mice: Role of Feeding Pattern, Obesity, and Dopamine Terminal Changes

PubMed Central

Fordahl, Steve C.; Locke, Jason L.; Jones, Sara R.

2016-01-01

High fat (HF) diet-induced obesity has been shown to augment behavioral responses to psychostimulants that target the dopamine system. The purpose of this study was to characterize dopamine terminal changes induced by a HF diet that correspond with enhanced locomotor sensitization to amphetamine. C57BL/6J mice had limited (2hr 3d/week) or extended (24h 7d/week) access to a HF diet or standard chow for six weeks. Mice were then repeatedly exposed to amphetamine (AMPH), and their locomotor responses to an amphetamine challenge were measured. Fast scan cyclic voltammetry was used to identify changes in dopamine terminal function after AMPH exposure. Exposure to a HF diet reduced dopamine uptake and increased locomotor responses to acute, high-dose AMPH administration compared to chow fed mice. Microdialysis showed elevated extracellular dopamine in the nucleus accumbens (NAc) coincided with enhanced locomotion after acute AMPH in HF-fed mice. All mice exhibited locomotor sensitization to amphetamine, but both extended and limited access to a HF diet augmented this response. Neither HF-fed group showed the robust amphetamine sensitization-induced increases in dopamine release, reuptake, and amphetamine potency observed in chow fed animals. However, the potency of amphetamine as an uptake inhibitor was significantly elevated after sensitization in mice with extended (but not limited) access to HF. Conversely, after amphetamine sensitization, mice with limited (but not extended) access to HF displayed reduced autoreceptor sensitivity to the D2/D3 agonist quinpirole. Additionally, we observed reduced membrane dopamine transporter (DAT) levels after HF, and a shift in DAT localization to the cytosol was detected with limited access to HF. This study showed that different patterns of HF exposure produced distinct dopamine terminal adaptations to repeated AMPH, which differed from chow fed mice, and enhanced sensitization to AMPH. Locomotor sensitization in chow fed mice coincided with elevated DAT function and increased AMPH potency; however, the enhanced behavioral response to AMPH after HF exposure was unique in that it coincided with reduced DAT function and diet pattern-specific adaptations. PMID:27267686

Barriers to accessing methamphetamine treatment: A systematic review and meta-analysis.

PubMed

Cumming, Craig; Troeung, Lakkhina; Young, Jesse T; Kelty, Erin; Preen, David B

2016-11-01

Methamphetamine use is associated with a range of poor health, social and justice outcomes. In many parts of the world increased methamphetamine use has been identified as a major public health concern. Methamphetamine treatment programmes have been effective in reducing and ceasing use, however a range of barriers have prevented these programmes being widely adopted by methamphetamine users. This review examines the barriers to accessing meth/amphetamine treatment identified in the literature. Databases were systematically searched using relevant terms for peer-reviewed articles describing original research exploring the barriers to accessing treatment for meth/amphetamine use. Reviews and grey literature were excluded. Eleven studies conducted in 5 countries were included in data synthesis; this involved a systematic review of all 11 studies, and meta-analysis of the prevalence of barriers reported in 6 studies that published sufficient quantitative data. Psychosocial/internal barriers to accessing methamphetamine treatment were most prevalent across studies (10/11 studies). Meta-analysis confirmed the four most commonly endorsed barriers to treatment access across studies all psychosocial barriers were embarrassment or stigma (60%, 95% CI: 54-67%); belief that treatment was unnecessary (59%, 95% CI:54-65%); preferring to withdraw alone without assistance (55%, 95% CI:45-65); and privacy concerns (51%, 95% CI:44-59%). The primary barriers to accessing methamphetamine treatment are psychosocial/internal. Services and treatment models that address these barriers are urgently required. There is a growing need for methamphetamine-appropriate treatment services. Further research evaluating treatment engagement and effectiveness for methamphetamine and polysubstance use, including the development of effective pharmacotherapies is warranted. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Acute heroin intoxication in a baby chronically exposed to cocaine and heroin: a case report

PubMed Central

2011-01-01

Introduction Acute intoxication with drugs of abuse in children is often only the tip of the iceberg, actually hiding chronic exposure. Analysis using non-conventional matrices such as hair can provide long-term information about exposure to recreational drugs. Case presentation We report the case of a one-month-old Caucasian boy admitted to our pediatric emergency unit with respiratory distress and neurological abnormalities. A routine urine test was positive for opiates, suggesting an acute opiate ingestion. No other drugs of misuse, such as cocaine, cannabis, amphetamines or derivatives, were detected in the baby's urine. Subsequently, hair samples from the baby and the parents were collected to evaluate the possibility of chronic exposure to drug misuse by segmental analysis. Opiates and cocaine metabolites were detected in hair samples from the baby boy and his parents. Conclusions In light of these and previous results, we recommend hair analysis in babies and children from risky environments to detect exposure to heroin and other drug misuse, which could provide the basis for specific social and health interventions. PMID:21729296

America’s First Amphetamine Epidemic 1929–1971

PubMed Central

Rasmussen, Nicolas

2008-01-01

Using historical research that draws on new primary sources, I review the causes and course of the first, mainly iatrogenic amphetamine epidemic in the United States from the 1940s through the 1960s. Retrospective epidemiology indicates that the absolute prevalence of both nonmedical stimulant use and stimulant dependence or abuse have reached nearly the same levels today as at the epidemic’s peak around 1969. Further parallels between epidemics past and present, including evidence that consumption of prescribed amphetamines has also reached the same absolute levels today as at the original epidemic’s peak, suggest that stricter limits on pharmaceutical stimulants must be considered in any efforts to reduce amphetamine abuse today. PMID:18445805

Essential Oils from the Medicinal Herbs Upregulate Dopamine Transporter in Rat Pheochromocytoma Cells.

PubMed

Choi, Min Sun; Choi, Bang-sub; Kim, Sang Heon; Pak, Sok Cheon; Jang, Chul Ho; Chin, Young-Won; Kim, Young-Mi; Kim, Dong-il; Jeon, Songhee; Koo, Byung-Soo

2015-10-01

The dopamine transporter (DAT) protein, a component of the dopamine system, undergoes adaptive neurobiological changes from drug abuse. Prevention of relapse and reduction of withdrawal symptoms are still the major limitations in the current pharmacological treatments of drug addiction. The present study aimed to investigate the effects of essential oils extracted from Elsholtzia ciliata, Shinchim, Angelicae gigantis Radix, and Eugenia caryophyllata, well-known traditional Korean medicines for addiction, on the modulation of dopamine system in amphetamine-treated cells and to explore the possible mechanism underlying its therapeutic effect. The potential cytotoxic effect of essential oils was evaluated in PC12 rat pheochromocytoma cells using cell viability assays. Quantification of DAT, p-CREB, p-MAPK, and p-Akt was done by immunoblotting. DAT was significantly reduced in cells treated with 50 μM of amphetamine in a time-dependent manner. No significant toxicity of essential oils from Elsholtzia ciliata and Shinchim was observed at doses of 10, 25, and 50 μg/mL. However, essential oils from A. gigantis Radix at a dose of 100 μg/mL and E. caryophyllata at doses of 50 and 100 μg/mL showed cytotoxicity. Treatment with GBR 12909, a highly selective DAT inhibitor, significantly increased DAT expression compared with that of amphetamine only by enhancing phosphorylation of mitogen-activated protein kinases (MAPK) and Akt. In addition, essential oils effectively induced hyperphosphorylation of cyclic-AMP response element-binding protein (CREB), MAPK, and Akt, which resulted in DAT upregulation. Our study implies that the essential oils may rehabilitate brain dopamine function through increased DAT availability in abstinent former drug users.

Contrasting effects of increased and decreased dopamine transmission on latent inhibition in ovariectomized rats and their modulation by 17beta-estradiol: an animal model of menopausal psychosis?

PubMed

Arad, Michal; Weiner, Ina

2010-06-01

Women with schizophrenia have later onset and better response to antipsychotic drugs (APDs) than men during reproductive years, but the menopausal period is associated with increased symptom severity and reduced treatment response. Estrogen replacement therapy has been suggested as beneficial but clinical data are inconsistent. Latent inhibition (LI), the capacity to ignore irrelevant stimuli, is a measure of selective attention that is disrupted in acute schizophrenia patients and in rats and humans treated with the psychosis-inducing drug amphetamine and can be reversed by typical and atypical APDs. Here we used amphetamine (1 mg/kg)-induced disrupted LI in ovariectomized rats to model low levels of estrogen along with hyperfunction of the dopaminergic system that may be occurring in menopausal psychosis, and tested the efficacy of APDs and estrogen in reversing disrupted LI. 17beta-Estradiol (50, 150 microg/kg), clozapine (atypical APD; 5, 10 mg/kg), and haloperidol (typical APD; 0.1, 0.3 mg/kg) effectively reversed amphetamine-induced LI disruption in sham rats, but were much less effective in ovariectomized rats; 17beta-estradiol and clozapine were effective only at high doses (150 microg/kg and 10 mg/kg, respectively), whereas haloperidol failed at both doses. Haloperidol and clozapine regained efficacy if coadministered with 17beta-estradiol (50 microg/kg, an ineffective dose). Reduced sensitivity to dopamine (DA) blockade coupled with spared/potentiated sensitivity to DA stimulation after ovariectomy may provide a novel model recapitulating the combination of increased vulnerability to psychosis with reduced response to APD treatment in female patients during menopause. In addition, our data show that 17beta-estradiol exerts antipsychotic activity.

SLI381 (Adderall XR), a two-component, extended-release formulation of mixed amphetamine salts: bioavailability of three test formulations and comparison of fasted, fed, and sprinkled administration.

PubMed

Tulloch, Simon J; Zhang, Yuxin; McLean, Angus; Wolf, Kathleen N

2002-11-01

To assess the bioavailability of three test formulations of a single dose of extended-release Adderall 20-mg capsules compared with two doses of immediate-release Adderall 10-mg tablets, and to assess the bioequivalence of a single 30-mg dose of the chosen extended-release Adderall formulation (designated as SLI381) administered in applesauce (sprinkled) and the same dose administered as an intact capsule with or without food. Randomized, open-label, crossover study. Clinical research unit. Forty-one healthy adults. Study A had four treatment sequences: three test formulations (A, B, and C) of a single dose of extended-release Adderall 20 mg, and two 10-mg doses of Adderall given 4 hours apart. Study B had three treatment sequences: a single dose of SLI381 30 mg as an intact capsule after overnight fast, an intact capsule after a high-fat breakfast, and the contents of a capsule sprinkled in 1 tablespoon of applesauce. The 20-mg test formulation A had comparable pharmacokinetic profiles and bioequivalence in rate and extent of drug absorption to Adderall 10 mg twice/day for both d- and l-amphetamine. Formulations B and C had statistically significant differences from the reference drug in some pharmacokinetic parameters. A 30-mg dose of SLI381 showed no significant differences in rate and extent of absorption of d- and l-amphetamine for fasted or sprinkled conditions compared with the high-fat meal condition. SLI381 20 mg/day is bioequivalent to Adderall 10 mg twice/day. SLI381 30 mg administered in applesauce is bioequivalent in terms of both rate and extent of absorption to the same dose administered as an intact capsule in both fasted and fed states.

Cross-reactivity of amphetamine analogues with Roche Abuscreen radioimmunoassay reagents

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

Cody, J.T.

1990-01-01

Cross-reactivity of amphetamine analogues with the Abuscreen amphetamine radioimmunoassay reagents was determined for both the standard and high specificity antibody systems. Compounds tested included 2-methoxyamphetamine, 4-hydroxymethamphetamine, 2,5-dimethoxyamphetamine (DMA), 4-bromo-2,5-dimethoxyamphetamine (DOB), 4-bromo-2,5-dimethoxy-beta-phenethylamine (BDMPEA), 3,4,5-trimethoxyamphetamine (TMA), 3,4-methylenedioxyamphetamine (MDA), N,N-dimethyl-3,4-methylenedioxyamphetamine and N-hydroxy-3,4-methylenedioxyamphetamine (N-OH MDA), 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyethylamphetamine (MDEA), 2,5-dimethoxy-4-ethylamphetamine, 2,5-dimethoxy-4-methylamphetamine (DOM), and 3,4,5-trimethoxyphenethylamine (mescaline). Blank negative reference material was spiked with 1,000 to 100,000 ng/mL of the amphetamine analogue and used as sample in the assays. MDA was the only analogue that showed cross reactivity equal to or greater than that of amphetamine. None of the other analogue compounds demonstrated a positive resultmore » at even the highest concentration; however several showed depressed counts at various concentration levels.« less

Pharmacokinetic and pharmacodynamic analysis of d-amphetamine in an attention task in rodents.

PubMed

Slezak, Jonathan M; Mueller, Melanie; Ricaurte, George A; Katz, Jonathan L

2018-06-02

Amphetamine is a common therapeutic agent for alleviating the core symptoms associated with attention-deficit hyperactivity disorder (ADHD) in children and adults. The current study used a translational model of attention, the five-choice serial reaction time (5-CSRT) procedure with rats, to examine the time-course effects of d-amphetamine. Effects of different dosages of d-amphetamine were related to drug-plasma concentrations, fashioned after comprehensive pharmacokinetic/pharmacodynamic assessments that have been employed in clinical investigations. We sought to determine whether acute drug-plasma concentrations that enhance performance in the 5-CSRT procedure are similar to those found to be therapeutic in patients diagnosed with ADHD. Results from the pharmacokinetic/pharmacodynamic assessment indicate that d-amphetamine plasma concentrations associated with improved performance on the 5-CSRT procedure overlap with those that have been reported to be therapeutic in clinical trials. The current findings suggest that the 5-CSRT procedure may be a useful preclinical model for predicting the utility of novel ADHD therapeutics and their effective concentrations.

Cocaine- and amphetamine-regulated transcript facilitates the neurite outgrowth in cortical neurons after oxygen and glucose deprivation through PTN-dependent pathway.

PubMed

Wang, Y; Qiu, B; Liu, J; Zhu, Wei-Guo; Zhu, S

2014-09-26

Cocaine- and amphetamine-regulated transcript (CART) is a neuropeptide that plays neuroprotective roles in cerebral ischemia and reperfusion (I/R) injury in animal models or oxygen and glucose deprivation (OGD) in cultured neurons. Recent data suggest that intranasal CART treatment facilitates neuroregeneration in stroke brain. However, little is known about the effects of post-treatment with CART during the neuronal recovery after OGD and reoxygenation in cultured primary cortical neurons. The present study was to investigate the role of CART treated after OGD injury in neurons. Primary mouse cortical neurons were subjected to OGD and then treated with CART. Our data show that post-treatment with CART reduced the neuronal apoptosis caused by OGD injury. In addition, CART repaired OGD-impaired cortical neurons by increasing the expression of growth-associated protein 43 (GAP43), which promotes neurite outgrowth. This effect depends on pleiotrophin (PTN) as siRNA-mediated PTN knockdown totally abolished the increase in CART-stimulated GAP43 protein levels. In summary, our findings demonstrate that CART repairs the neuronal injury after OGD by facilitating neurite outgrowth through PTN-dependent pathway. The role for CART in neurite outgrowth makes it a new potential therapeutic agent for the treatment of neurodegenerative diseases. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

Detection of Delta9-tetrahydrocannabinol and amphetamine-type stimulants in oral fluid using the Rapid Stat point-of-collection drug-testing device.

PubMed

Röhrich, J; Zörntlein, S; Becker, J; Urban, R

2010-04-01

The Rapid Stat assay, a point-of-collection drug-testing device for detection of amphetamines, cannabinoids, cocaine, opiates, methadone, and benzodiazepines in oral fluid, was evaluated for cannabis and amphetamine-type stimulants. The Rapid Stat tests (n = 134) were applied by police officers in routine traffic checks. Oral fluid and blood samples were analyzed using gas chromatography-mass spectrometry (GC-MS) for Delta(9)-tetrahydrocannabinol, amphetamine, methamphetamine, methylenedioxymethamphetamine, methylenedioxyethylamphetamine, and methylenedioxyamphetamine. The comparison of GC-MS analysis of oral fluid with the Rapid Stat results for cannabis showed a sensitivity of 85%, a specificity of 87%, and a total confirmation rate of 87%. When compared with serum, the sensitivity of the cannabis assay decreased to 71%, the specificity to 60%, and the total confirmation rate to 66%. These findings were possibly caused by an incorrect reading of the THC test results. Comparison of the Rapid Stat amphetamine assay with GC-MS in oral fluid showed a sensitivity of 94%, a specificity of 97%, and a total confirmation rate of 97%. Compared with serum, a sensitivity of 100%, a specificity of 90%, and a total confirmation rate of 92% was found. The amphetamine assay must, therefore, be regarded as satisfactory.

Pathology of deaths associated with "ecstasy" and "eve" misuse.

PubMed

Milroy, C M; Clark, J C; Forrest, A R

1996-02-01

To study the postmortem pathology associated with ring substituted amphetamine (amphetamine derivatives) misuse. The postmortem findings in deaths associated with the ring substituted amphetamines 3,4-methylenedioxymethyl-amphetamine (MDMA, ecstasy) and 3,4-methylenedioxyethylamphetamine (MDEA, eve) were studied in seven young white men aged between 20 and 25 years. Striking changes were identified in the liver, which varied from foci of individual cell necrosis to centrilobular necrosis. In one case there was massive hepatic necrosis. Changes consistent with catecholamine induced myocardial damage were seen in five cases. In the brain perivascular haemorrhagic and hypoxic changes were identified in four cases. Overall, the changes in four cases were the same as those reported in heart stroke, although only two cases had a documented history of hyperthermia. Of these four cases, all had changes in their liver, three had changes in their brains, and three in their heart. Of the other three cases, one man died of fulminant liver failure, one of water intoxication and one probably from a cardiac arrhythmia associated with myocardial fibrosis. These data suggest that there is more than one mechanism of damage in ring substituted amphetamine misuse, injury being caused by hyperthermia in some cases, but with ring substituted amphetamines also possibly having a toxic effect on the liver and other organs in the absence of hyperthermia.

The amphetamine sensitization model of schizophrenia symptoms and its effect on schedule-induced polydipsia in the rat.

PubMed

Hawken, Emily R; Beninger, Richard J

2014-05-01

Amphetamine enhances dopamine (DA) transmission and induces psychotic states or exacerbates psychosis in at-risk individuals. Amphetamine sensitization of the DA system has been proposed as a rodent model of schizophrenia-like symptoms. In humans, excessive nonphysiologic drinking or primary polydipsia is significantly associated with a diagnosis of schizophrenia. In rodents, nonphysiologic drinking can be induced by intermittent presentation of food in the presence of a drinking spout to a hungry animal; this phenomenon is termed, "schedule-induced polydipsia" (SIP). This study aims to determine the effects of amphetamine sensitization on SIP. We injected rats with amphetamine (1.5 mg/kg) daily for 5 days. Following 4 weeks of withdrawal, animals were food restricted and exposed to the SIP protocol (noncontingent fixed-time 1-min food schedule) for daily 2-h sessions for 24 days. Results showed that previously amphetamine-injected animals drank more in the SIP protocol and drank more than controls when the intermittent food presentation schedule was removed. These findings suggest that hyperdopaminergia associated with schizophrenia may contribute to the development of polydipsia in this population. Whether animals that develop SIP have DA dysfunction or aberrant activity of other circuits that modulate DA activity has yet to be clearly defined.

Catecholaminergic consolidation of motor cortical neuroplasticity in humans.

PubMed

Nitsche, Michael A; Grundey, Jessica; Liebetanz, David; Lang, Nicolas; Tergau, Frithjof; Paulus, Walter

2004-11-01

Amphetamine, a catecholaminergic re-uptake-blocker, is able to improve neuroplastic mechanisms in humans. However, so far not much is known about the underlying physiological mechanisms. Here, we study the impact of amphetamine on NMDA receptor-dependent long-lasting excitability modifications in the human motor cortex elicited by weak transcranial direct current stimulation (tDCS). Amphetamine significantly enhanced and prolonged increases in anodal, tDCS-induced, long-lasting excitability. Under amphetamine premedication, anodal tDCS resulted in an enhancement of excitability which lasted until the morning after tDCS, compared to approximately 1 h in the placebo condition. Prolongation of the excitability enhancement was most pronounced for long-term effects; the duration of short-term excitability enhancement was only slightly increased. Since the additional application of the NMDA receptor antagonist dextromethorphane blocked any enhancement of tDCS-driven excitability under amphetamine, we conclude that amphetamine consolidates the tDCS-induced neuroplastic effects, but does not initiate them. The fact that propanolol, a beta-adrenergic antagonist, diminished the duration of the tDCS-generated after-effects suggests that adrenergic receptors play a certain role in the consolidation of NMDA receptor-dependent motor cortical excitability modifications in humans. This result may enable researchers to optimize neuroplastic processes in the human brain on the rational basis of purpose-designed pharmacological interventions.

Transcriptomic configuration of mouse brain induced by adolescent exposure to 3,4-methylenedioxymethamphetamine

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

Eun, Jung Woo; Kwack, Seung Jun; Noh, Ji Heon

The amphetamine derivative ({+-})-3,4-methylenedioxymethamphetamine (MDMA or ecstasy) is a synthetic amphetamine analogue used recreationally to obtain an enhanced affiliative emotional response. MDMA is a potent monoaminergic neurotoxin with the potential to damage brain serotonin and/or dopamine neurons. As the majority of MDMA users are young adults, the risk that users may expose the fetus to MDMA is a concern. However, the majority of studies on MDMA have investigated the effects on adult animals. Here, we investigated whether long-term exposure to MDMA, especially in adolescence, could induce comprehensive transcriptional changes in mouse brain. Transcriptomic analysis of mouse brain regions demonstrated significantmore » gene expression changes in the cerebral cortex. Supervised analysis identified 1028 genes that were chronically dysregulated by long-term exposure to MDMA in adolescent mice. Functional categories most represented by this MDMA characteristic signature are intracellular molecular signaling pathways of neurotoxicity, such as, the MAPK signaling pathway, the Wnt signaling pathway, neuroactive ligand-receptor interaction, long-term potentiation, and the long-term depression signaling pathway. Although these resultant large-scale molecular changes remain to be studied associated with functional brain damage caused by MDMA, our observations delineate the possible neurotoxic effects of MDMA on brain function, and have therapeutic implications concerning neuro-pathological conditions associated with MDMA abuse.« less

Comparative peptidomics analysis of neural adaptations in rats repeatedly exposed to amphetamine.

PubMed

Romanova, Elena V; Lee, Ji Eun; Kelleher, Neil L; Sweedler, Jonathan V; Gulley, Joshua M

2012-10-01

Repeated exposure to amphetamine (AMPH) induces long-lasting behavioral changes, referred to as sensitization, that are accompanied by various neuroadaptations in the brain. To investigate the chemical changes that occur during behavioral sensitization, we applied a comparative proteomics approach to screen for neuropeptide changes in a rodent model of AMPH-induced sensitization. By measuring peptide profiles with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and comparing signal intensities using principal component analysis and variance statistics, subsets of peptides are found with significant differences in the dorsal striatum, nucleus accumbens, and medial prefrontal cortex of AMPH-sensitized male Sprague-Dawley rats. These biomarker peptides, identified in follow-up analyses using liquid chromatography and tandem mass spectrometry, suggest that behavioral sensitization to AMPH is associated with complex chemical adaptations that regulate energy/metabolism, neurotransmission, apoptosis, neuroprotection, and neuritogenesis, as well as cytoskeleton integrity and neuronal morphology. Our data contribute to a growing number of reports showing that in addition to the mesolimbic dopamine system, which is the best known signaling pathway involved with reinforcing the effect of psychostimulants, concomitant chemical changes in other pathways and in neuronal organization may play a part in the overall effect of chronic AMPH exposure on behavior. © 2012 The Authors Journal of Neurochemistry © 2012 International Society for Neurochemistry.

Amphetamines promote mitochondrial dysfunction and DNA damage in pulmonary hypertension

PubMed Central

Chen, Pin-I; Cao, Aiqin; Miyagawa, Kazuya; Tojais, Nancy F.; Hennigs, Jan K.; Li, Caiyun G.; Sweeney, Nathaly M.; Inglis, Audrey S.; Wang, Lingli; Li, Dan; Ye, Matthew; Feldman, Brian J.

2017-01-01

Amphetamine (AMPH) or methamphetamine (METH) abuse can cause oxidative damage and is a risk factor for diseases including pulmonary arterial hypertension (PAH). Pulmonary artery endothelial cells (PAECs) from AMPH-associated-PAH patients show DNA damage as judged by γH2AX foci and DNA comet tails. We therefore hypothesized that AMPH induces DNA damage and vascular pathology by interfering with normal adaptation to an environmental perturbation causing oxidative stress. Consistent with this, we found that AMPH alone does not cause DNA damage in normoxic PAECs, but greatly amplifies DNA damage in hypoxic PAECs. The mechanism involves AMPH activation of protein phosphatase 2A, which potentiates inhibition of Akt. This increases sirtuin 1, causing deacetylation and degradation of HIF1α, thereby impairing its transcriptional activity, resulting in a reduction in pyruvate dehydrogenase kinase 1 and impaired cytochrome c oxidase 4 isoform switch. Mitochondrial oxidative phosphorylation is inappropriately enhanced and, as a result of impaired electron transport and mitochondrial ROS increase, caspase-3 is activated and DNA damage is induced. In mice given binge doses of METH followed by hypoxia, HIF1α is suppressed and pulmonary artery DNA damage foci are associated with worse pulmonary vascular remodeling. Thus, chronic AMPH/METH can induce DNA damage associated with vascular disease by subverting the adaptive responses to oxidative stress. PMID:28138562

Effects of amphetamine on reactivity to emotional stimuli

PubMed Central

Wardle, Margaret C.; de Wit, Harriet

2011-01-01

Rationale Most studies of the reinforcing effects of stimulants have focused on the drugs’ capacity to induce positive mood (i.e., euphoria). However, recent findings suggest drugs may also alter emotional reactivity to external stimuli, and that this may occur independently of direct effects on mood. Objectives We aimed to examine effects of d-amphetamine, a prototypic stimulant, on self-reported and psychophysiological reactivity to emotional stimuli as well as overall subjective mood. We predicted that amphetamine would enhance reactivity to pleasant stimuli, particularly, stimuli with social content and that these effects would be independent of the drug’s direct effects on mood. Methods Over three sessions, 36 healthy normal adults received placebo, d-amphetamine 10 and 20 mg under counterbalanced double-blind conditions. At each session, emotional reactivity to standardized positive, neutral, and negative pictures with and without social content was measured in self-reports and facial muscles sensitive to emotional state. Drug effects on cardiovascular variables and subjective mood were also measured. Results Amphetamine produced euphoria, feelings of drug effect, and increased blood pressure. Most notably, amphetamine enhanced self-reported positive reactions to all pictures and psychophysiological reactions to positive pictures. These effects were not significantly related to drug-induced mood changes. Contrary to our hypothesis, effects of amphetamine on emotional reactivity were not moderated by social content. Conclusions This study demonstrates a previously unexamined and potentially reinforcing effect of stimulant drugs in humans, distinct from more typically measured euphorigenic effects, and suggests new areas of research in stimulant abuse risk and adaptations occurring during drug dependence. PMID:21947316

The predictors and consequences of adolescent amphetamine use: findings from the Victoria Adolescent Health Cohort Study.

PubMed

Degenhardt, Louisa; Coffey, Carolyn; Moran, Paul; Carlin, John B; Patton, George C

2007-07-01

Previous work has highlighted the adverse consequences of early-onset cannabis use. However, little is known about the predictors and effects of early-onset amphetamine use. We set out to examine these issues using a representative cohort of young people followed-up over 11 years in Victoria, Australia. A stratified, random sample of 1943 adolescents was recruited from secondary schools across Victoria at age 14-15 years. This cohort was interviewed on eight occasions until the age of 24-25 years (78% follow-up at that age). Cross-sectional associations were assessed using logistic regression with allowance for repeated measures. Both proportional hazards models and logistic regression models were used to assess prospective associations. Approximately 7% of the sample had used amphetamines by the age of 17 years. Amphetamine use by this age was associated with poorer mental health and other drug use. The incidence of amphetamine use during the teenage years was predicted by heavier drug use and by mental health problems. By young adulthood (age 24-25 years), adolescent amphetamine users were more likely to meet criteria for dependence upon a range of drugs, to have greater psychological morbidity and to have some limitations in educational attainment. Most of these associations were not sustained after adjustment for early-onset cannabis use. Young people in Australia who begin amphetamine use by age 17 years are at increased risk for a range of mental health, substance use and psychosocial problems in young adulthood. However, these problems are largely accounted for by their even earlier-onset cannabis use.

Sweet taste liking is associated with subjective response to amphetamine in women but not men.

PubMed

Weafer, Jessica; Lyon, Nicholas; Hedeker, Donald; de Wit, Harriet

2017-11-01

Preference for sweet taste rewards has been linked to the propensity for drug use in both animals and humans. Here, we tested the association between sweet taste liking and sensitivity to amphetamine reward in healthy adults. We hypothesized that sweet likers would report greater euphoria and stimulation following D-amphetamine (20 mg) compared to sweet dislikers. Men (n = 36) and women (n = 34) completed a sweet taste test in which they rated their liking of various concentrations of sucrose and filtered water (0.05, 0.10, 0.21, 0.42, and 0.83 M). Participants who preferred the highest concentration were classified as "sweet likers." All others were classified as "sweet dislikers." They then completed four sessions in which they received D-amphetamine (20 mg) and placebo in alternating order, providing self-report measures of euphoria and stimulation on the Addiction Research Center Inventory (ARCI) at regular intervals. We conducted linear mixed effects models to examine relationships between sweet liking and drug-induced euphoria and stimulation. Sweet likers reported significantly greater amphetamine-induced euphoria than did sweet dislikers among women. By contrast, sweet liking was not associated with amphetamine response in men. No associations with stimulation were observed. The association between sweet preference and amphetamine response in women is consistent with animal studies linking sweet taste preference and drug reward and also fits with observations that individuals who use drugs show a preference for sweet tastes. Whether the sex difference is related to circulating hormones, or other variables, remains to be determined.

A Single Amphetamine Infusion Reverses Deficits in Dopamine Nerve-Terminal Function Caused by a History of Cocaine Self-Administration.

PubMed

Ferris, Mark J; Calipari, Erin S; Rose, Jamie H; Siciliano, Cody A; Sun, Haiguo; Chen, Rong; Jones, Sara R

2015-07-01

There are ∼ 1.6 million people who meet the criteria for cocaine addiction in the United States, and there are currently no FDA-approved pharmacotherapies. Amphetamine-based dopamine-releasing drugs have shown efficacy in reducing the motivation to self-administer cocaine and reducing intake in animals and humans. It is hypothesized that amphetamine acts as a replacement therapy for cocaine through elevation of extracellular dopamine levels. Using voltammetry in brain slices, we tested the ability of a single amphetamine infusion in vivo to modulate dopamine release, uptake kinetics, and cocaine potency in cocaine-naive animals and after a history of cocaine self-administration (1.5 mg/kg/infusion, fixed-ratio 1, 40 injections/day × 5 days). Dopamine kinetics were measured 1 and 24 h after amphetamine infusion (0.56 mg/kg, i.v.). Following cocaine self-administration, dopamine release, maximal rate of uptake (Vmax), and membrane-associated dopamine transporter (DAT) levels were reduced, and the DAT was less sensitive to cocaine. A single amphetamine infusion reduced Vmax and membrane DAT levels in cocaine-naive animals, but fully restored all aspects of dopamine terminal function in cocaine self-administering animals. Here, for the first time, we demonstrate pharmacologically induced, immediate rescue of deficits in dopamine nerve-terminal function in animals with a history of high-dose cocaine self-administration. This observation supports the notion that the DAT expression and function can be modulated on a rapid timescale and also suggests that the pharmacotherapeutic actions of amphetamine for cocaine addiction go beyond that of replacement therapy.

Prenatal and early postnatal dietary sodium restriction sensitizes the adult rat to amphetamines.

PubMed

McBride, Shawna M; Culver, Bruce; Flynn, Francis W

2006-10-01

Acute sodium deficiency sensitizes adult rats to psychomotor effects of amphetamine. This study determined whether prenatal and early life manipulation of dietary sodium sensitized adult offspring to psychomotor effects of amphetamine (1 or 3 mg/kg ip) in two strains of rats. Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) dams were fed chow containing low NaCl (0.12%; LN), normal NaCl (1%; NN), or high NaCl (4%; HN) throughout breeding, gestation, and lactation. Male offspring were maintained on the test diet for an additional 3 wk postweaning and then fed standard chow thereafter until testing began. Overall, blood pressure (BP), total fluid intake, salt preference, and adrenal gland weight were greater in SHR than in WKY. WKY LN offspring had greater water intake and adrenal gland weight than did WKY NN and HN offspring, whereas WKY HN offspring had increased BP, salt intake, and salt preference compared with other WKY offspring. SHR HN offspring also had increased BP compared with other SHR offspring; all other measures were similar for SHR offspring. The low-dose amphetamine increased locomotor and stereotypical behavior compared with baseline and saline injection in both WKY and SHR offspring. Dietary sodium history affected the rats' psychomotor response to the higher dose of amphetamine. Injections of 3 mg/kg amphetamine in both strains produced significantly more behavioral activity in the LN offspring than in NN and HN offspring. These results show that early life experience with low-sodium diets produce long-term changes in adult rats' behavioral responses to amphetamine.

Psychostimulants and forced swim stress interaction: how activation of the hypothalamic-pituitary-adrenal axis and stress-induced hyperglycemia are affected.

PubMed

Gagliano, Humberto; Ortega-Sanchez, Juan Antonio; Nadal, Roser; Armario, Antonio

2017-10-01

We recently reported that simultaneous exposure to amphetamine and various stressors resulted in reduced hypothalamic-pituitary-adrenal (HPA) and glycemic responses to the stressors. Since this is a new and relevant phenomenon, we wanted to further explore this interaction. This study aims (i) to characterize the effect of various doses of amphetamine on the physiological response to a predominantly emotional stressor (forced swim) when the drug was given immediately before stress; (ii) to study if an interaction appears when the drug was given 30 min or 7 days before swim; and (iii) to know whether cocaine causes similar effects when given just before stress. Adult male rats were used and plasma levels of ACTH, corticosterone, and glucose were the outcomes. Amphetamine caused a dose-dependent activation of the HPA axis, but all doses reduced HPA and glycemic responses to swim when given just before the stressor. Importantly, during the post-swim period, the stressor potently inhibited the ACTH response to amphetamine, demonstrating mutual inhibition between the two stimuli. The highest dose of amphetamine also reduced the response to swim when given 30 min before stress, whereas it caused HPA sensitization when given 7 days before. Cocaine also reduced stress-induced HPA activation when given just before swim. The present results demonstrate a negative synergy between psychostimulants (amphetamine and cocaine) and stress regarding HPA and glucose responses when rats were exposed simultaneously to both stimuli. The inhibitory effect of amphetamine is also observed when given shortly before stress, but not some days before.

Responses of the extrapyramidal and limbic substance P systems to ibogaine and cocaine treatments.

PubMed

Alburges, M E; Ramos, B P; Bush, L; Hanson, G R

2000-02-25

Ibogaine is an indolamine found in the West Africa shrub, Tabernanthe iboga, and has been proposed for the treatment of addiction to central nervous system (CNS) stimulants such as cocaine and amphetamine. The mechanism of ibogaine action and its suitability as a treatment for drug addiction still remains unclear. Since previous studies demonstrated differential effects of stimulants of abuse (amphetamines) on neuropeptide systems such as substance P, we examined the impact of ibogaine and cocaine on extrapyramidal (striatum and substantia nigra) and limbic (nucleus accumbens and frontal cortex) substance P-like immunoreactivity. Ibogaine and cocaine treatments altered substance P systems by increasing striatal and nigral substance P-like immunoreactivity concentration 12 h after the last drug treatment. However, substance P-like immunoreactivity content was not significantly increased in nucleus accumbens after treatment with either drug. The ibogaine- and cocaine-induced increases in substance P-like immunoreactivity in striatum and substantia nigra were blocked by coadministration of selective dopamine D(1) receptor antagonist (SCH 23390; R(+)-7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine hydrochloride) or dopamine D(2) receptor antagonist (eticlopride; S(-)-3-Chloro-5-ethyl-N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-hydroxy-2- methoxy-benzamide hydrochloride). Most of the responses by substance P systems to ibogaine administration resembled those caused by cocaine, except in cortical tissue where multiple administration of cocaine, but not ibogaine increased substance P-like immunoreactivity. These data suggest that substance P systems may contribute to the effects of ibogaine and cocaine treatment.

Psychotic disorders among inpatients with abuse of cannabis, amphetamine and opiates. Do dopaminergic stimulants facilitate psychiatric illness?

PubMed

Dalmau, A; Bergman, B; Brismar, B

1999-11-01

We have studied the occurrence of dual diagnoses (psychoses as well as abuse of either amphetamine, cannabis or opiates) during a 15-year period, among patients treated at Huddinge Hospital, Stockholm, Sweden. The purpose of the study is to evaluate if the different drugs were coupled to different rates of psychiatric co-morbidity. During the period in question, 461, 425 and 371 different patients respectively had been admitted at least once due to dependency on amphetamine, cannabis and opiates. Approximately 30% of the patients with a pure abuse of amphetamine or cannabis and less than 6% of the opiate abusers had been diagnosed at least once with any of the psychoses studied. Comparing the frequency of psychoses among mixed and pure abusers of illegal drugs, with and without a concomitant abuse of alcohol, we found that the co-morbidity rate for mixed opiate abusers increased significantly from 7.2 to 20.2% when alcohol abuse was also present. For abusers of amphetamine and cannabis (both pure and mixed), no differences in co-morbidity rates were seen when an abuse of alcohol was added to that of the drugs. It is difficult to find an explanation for the significant difference between the co-morbidity of pure abuse of amphetamine or cannabis on the one hand and opiates on the other. In conclusion, our findings show that the distribution of psychotic illness is high among abusers of amphetamine and cannabis, in contrast to the generally lower co-morbidity among abusers of opiates. Although these findings are consistent with earlier studies that have shown a propensity for developing psychoses among abusers of amphetamine and cannabis, one should bear in mind that this study is based on inpatients, and is not necessarily representative for all abusers of the drugs in question.

Evidence for Fibroblast Growth Factor-2 as a Mediator of Amphetamine-Enhanced Motor Improvement following Stroke

PubMed Central

Wolf, William A.; Martin, Jody L.; Kartje, Gwendolyn L.; Farrer, Robert G.

2014-01-01

Previously we have shown that addition of amphetamine to physical therapy results in enhanced motor improvement following stroke in rats, which was associated with the formation of new motor pathways from cortical projection neurons of the contralesional cortex. It is unclear what mechanisms are involved, but amphetamine is known to induce the neuronal release of catecholamines as well as upregulate fibroblast growth factor-2 (FGF-2) expression in the brain. Since FGF-2 has been widely documented to stimulate neurite outgrowth, the present studies were undertaken to provide evidence for FGF-2 as a neurobiological mechanism underlying amphetamine-induced neuroplasticity. In the present study rats that received amphetamine plus physical therapy following permanent middle cerebral artery occlusion exhibited significantly greater motor improvement over animals receiving physical therapy alone. Amphetamine plus physical therapy also significantly increased the number of FGF-2 expressing pyramidal neurons of the contralesional cortex at 2 weeks post-stroke and resulted in significant axonal outgrowth from these neurons at 8 weeks post-stroke. Since amphetamine is a known releaser of norepinephrine, in vitro analyses focused on whether noradrenergic stimulation could lead to neurite outgrowth in a manner requiring FGF-2 activity. Primary cortical neurons did not respond to direct stimulation by norepinephrine or amphetamine with increased neurite outgrowth. However, conditioned media from astrocytes exposed to norepinephrine or isoproterenol (a beta adrenergic agonist) significantly increased neurite outgrowth when applied to neuronal cultures. Adrenergic agonists also upregulated FGF-2 expression in astrocytes. Pharmacological analysis indicated that beta receptors and alpha1, but not alpha2, receptors were involved in both effects. Antibody neutralization studies demonstrated that FGF-2 was a critical contributor to neurite outgrowth induced by astrocyte-conditioned media. Taken together the present results suggest that noradrenergic activation, when combined with physical therapy, can improve motor recovery following ischemic damage by stimulating the formation of new neural pathways in an FGF-2-dependent manner. PMID:25229819

Use of amphetamine-type stimulants in the Islamic Republic of Iran, 2004-2015: a review.

PubMed

Shadloo, Behrang; Amin-Esmaeili, Masoumeh; Haft-Baradaran, Minoo; Noroozi, Alireza; Ghorban-Jahromi, Reza; Rahimi-Movaghar, Afarin

2017-05-01

Amphetamine-type stimulants (ATS) are the second most commonly used illicit drugs in the world, after cannabis. The production of ATS has increased worldwide, including in the Middle East. This review aims to assess ATS use in the Islamic Republic of Iran. PubMed, Scientific Information Database (a national database) and Iranian Center for Addiction Studies were searched. The review included studies on the general population, university and high school students, other specific populations, and drug users. The result show that self-reported methamphetamine and ecstasy use in 2016 was < 1% in the general population and university and high-school students, but the prevalence was higher in certain groups. There has also been an increase in the proportion of ATS users among clients of drug treatment centres. The findings highlight the need for high quality epidemiological studies and closer monitoring of stimulant use in different populations.

New challenges and opportunities in managing substance abuse in Malaysia.

PubMed

Mazlan, Mahmud; Schottenfeld, Richard S; Chawarski, Marek C

2006-09-01

Until recently, Malaysia has lagged behind in the treatment of drug addiction and related disorders, despite experiencing severe drug problems. By the end of 2004, 234,000 heroin users or heroin-dependent individuals had been registered in the official government registry, but other estimates exceed 500,000 for heroin abusers in the country. Amphetamine-type stimulant abuse is also increasing and of considerable public and government concern. Among the population of drug users, HIV and other infectious diseases rates are very high. In the Western Pacific regions, Malaysia has the second highest HIV prevalence (after Vietnam) among adult populations (0.62%) and the highest proportion of HIV cases resulting from injection drug use (76.3%). Drug use and related disorders exert a heavy burden on the country's health care and legal systems. Historically, drug abusers were rehabilitated involuntarily in correctional, rather than health-care, facilities. This primarily criminal treatment approach had limited effectiveness which led to widespread public dissatisfaction and the recent introduction of medical treatments for addiction. Naltrexone was introduced in 1999; buprenorphine was introduced in 2001 and methadone in 2003. Agonist maintenance programmes were embraced rapidly by the medical community in Malaysia. Currently, over 30,000 opiate-dependent patients are treated with agonist maintenance treatments by more than 500 medical practitioners in Malaysia. Despite these recent advances, treatments for amphetamine-type stimulant abuse or dependence are underdeveloped, and diversion of agonist medications is an emerging concern.

Application of drug testing using exhaled breath for compliance monitoring of drug addicts in treatment.

PubMed

Carlsson, Sten; Olsson, Robert; Lindkvist, Irene; Beck, Olof

2015-04-01

Exhaled breath has recently been identified as a possible matrix for drug testing. This study explored the potential of this new method for compliance monitoring of patients being treated for dependence disorders. Outpatients in treatment programs were recruited for this study. Urine was collected as part of clinical routine and a breath sample was collected in parallel together with a questionnaire about their views of the testing procedure. Urine was analyzed for amphetamines, benzodiazepines, cannabis, cocaine, buprenorphine, methadone and opiates using CEDIA immunochemical screening and mass spectrometry confirmation. The exhaled breath was collected using the SensAbues device and analyzed by mass spectrometry for amphetamine, methamphetamine, diazepam, oxazepam, tetrahydrocannabinol, cocaine, benzoylecgonine, buprenorphine, methadone, morphine, codeine and 6-acetylmorphine. A total of 122 cases with parallel urine and breath samples were collected; 34 of these were negative both in urine and breath. Out of 88 cases with positive urine samples 51 (58%) were also positive in breath. Among the patients on methadone treatment, all were positive for methadone in urine and 83% were positive in breath. Among patients in treatment with buprenorphine, 92% were positive in urine and among those 80% were also positive in breath. The questionnaire response documented that in general, patients accepted drug testing well and that the breath sampling procedure was preferred. Compliance testing for the intake of prescribed and unprescribed drugs among patients in treatment for dependence disorders using the exhaled breath sampling technique is a viable method and deserves future attention.

Amphetamines

MedlinePlus

... site Sitio para adolescentes Body Mind Sexual Health Food & Fitness Diseases & ... español Anfetaminas What It Is: Amphetamines are very addictive stimulants. They speed up functions in the brain and ...

Monoamine oxidase-B inhibition in the treatment of Parkinson's disease.

PubMed

Fernandez, Hubert H; Chen, Jack J

2007-12-01

Inhibitors of monoamine oxidase (MAO) with selectivity and specificity for MAO type B prolong the activity of both endogenously and exogenously derived dopamine, making them an option either as monotherapy in early Parkinson's disease or as adjunctive therapy in patients treated with levodopa who are experiencing motor complications. In addition to symptomatic benefits, experimental data suggest that MAO-B inhibitors may be neuroprotective through MAO-B inhibition and other mechanisms that have yet to be clearly defined. The two available MAO-B inhibitors approved for use in the United States, rasagiline and selegiline, each provide symptomatic relief as monotherapy and as adjunctive therapy, and have shown potential disease-modifying effects in experimental models and clinical studies. Selegiline in a conventional tablet formulation is less bioavailable than rasagiline, resulting in limited potency. It also has amphetamine metabolites that may produce adverse effects and interfere with any putative disease-modifying effects. The oral disintegrating tablet formulation of selegiline allows pregastric absorption, minimizing first-pass metabolism, thereby increasing selegiline bioavailability and reducing the concentration of amphetamine metabolites. Rasagiline, more potent than selegiline, exhibits disease-modifying effects in experimental models and lacks amphetamine metabolites. Both the symptomatic and potential disease-modifying effects of rasagiline are under investigation. A third agent with MAO-B inhibition properties, safinamide, is in phase III development. Although not yet approved, safinamide may offer the added advantage of combined MAO-B and dopamine reuptake inhibition.

Effects of methylphenidate during emotional processing in amphetamine users: preliminary findings.

PubMed

Bottelier, M A; Schouw, M L J; de Ruiter, M B; Ruhe, H G; Lindauer, R J L; Reneman, L

2015-12-01

D-amphetamine (dAMPH) and methylphenidate (MPH) are stimulants used in the treatment of Attention Deficit Hyperactivity Disorder (ADHD). Preclinical studies have shown that in healthy animals, dAMPH induces dopamine (DA) dysfunction, as evidenced for instance by loss of DA levels and its transporters. It has also been suggested that DA plays an important role in emotional processing, and that altered DA-ergic intervention may modulate amygdala function. To explore the role of the DA system in emotional processing we examined emotional processing using functional magnetic resonance imaging (fMRI) in eight male recreational users of dAMPH and eight male healthy controls. We compared brain activation between both groups during an emotional face-processing task with and without an oral MPH challenge. All subjects were abstinent for at least 2 weeks during the baseline scan. The second scan was performed on the same day 1½ hours after receiving an oral dose of 35 mg MPH. A significant Valence*Group interaction (p = .037) indicated amygdala hyperreactivity to fearful facial expressions in dAMPH users that was robust against adjustment for age (p = .015). Furthermore, duration of amphetamine use in years was positively correlated with amygdala reactivity in dAMPH users (r = .76; p = .029). These exploratory findings are in line with previous findings suggesting that DA plays a role in emotional processing.

Free-Operant Avoidance Behavior by Rats after Reinforcer Revaluation Using Opioid Agonists and d-Amphetamine

PubMed Central

Urcelay, Gonzalo; Mar, Adam; Dickinson, Anthony; Robbins, Trevor

2014-01-01

The associative processes that support free-operant instrumental avoidance behavior are still unknown. We used a revaluation procedure to determine whether the performance of an avoidance response is sensitive to the current value of the aversive, negative reinforcer. Rats were trained on an unsignaled, free-operant lever press avoidance paradigm in which each response avoided or escaped shock and produced a 5 s feedback stimulus. The revaluation procedure consisted of noncontingent presentations of the shock in the absence of the lever either paired or unpaired with systemic morphine and in a different cohort with systemic d-amphetamine. Rats were then tested drug free during an extinction test. In both the d-amphetamine and morphine groups, pairing of the drug and shock decreased subsequent avoidance responding during the extinction test, suggesting that avoidance behavior was sensitive to the current incentive value of the aversive negative reinforcer. Experiment 2 used central infusions of D-Ala2, NMe-Phe4, Gly-ol5]-enkephalin (DAMGO), a mu-opioid receptor agonist, in the periacqueductal gray and nucleus accumbens shell to revalue the shock. Infusions of DAMGO in both regions replicated the effects seen with systemic morphine. These results are the first to demonstrate the impact of revaluation of an aversive reinforcer on avoidance behavior using pharmacological agents, thereby providing potential therapeutic targets for the treatment of avoidance behavior symptomatic of anxiety disorders. PMID:24790199

Treatment of addiction and addiction-related behavior

DOEpatents

Dewey, Stephen L.; Brodie, Jonathan D.; Ashby, Jr., Charles R.

2004-12-07

The present invention provides a highly efficient method for treating substance addiction and for changing addiction-related behavior of a mammal suffering from substance addiction. The method includes administering to a mammal an effective amount of gamma vinylGABA or a pharmaceutically acceptable salt thereof. The present invention also provides a method of treatment of cocaine, morphine, heroin, nicotine, amphetamine, methamphetamine, or ethanol addiction by treating a mammal with an effective amount of gamma vinylGABA or a pharmaceutically acceptable salt thereof.

Methamphetamine and Amphetamine Isomer Concentrations in Human Urine Following Controlled Vicks VapoInhaler Administration

PubMed Central

Smith, Michael L.; Nichols, Daniel C.; Underwood, Paula; Fuller, Zachary; Moser, Matthew A.; Flegel, Ron; Gorelick, David A.; Newmeyer, Matthew N.; Concheiro, Marta; Huestis, Marilyn A.

2014-01-01

Legitimate use of legal intranasal decongestants containing l-methamphetamine may complicate interpretation of urine drug tests positive for amphetamines. Our study hypotheses were that commonly used immunoassays would produce no false-positive results and a recently developed enantiomer-specific gas chromatography–mass spectrometry (GC–MS) procedure would find no d-amphetamine or d-methamphetamine in urine following controlled Vicks VapoInhaler administration at manufacturer's recommended doses. To evaluate these hypotheses, 22 healthy adults were each administered one dose (two inhalations in each nostril) of a Vicks VapoInhaler every 2 h for 10 h on Day 1 (six doses), followed by a single dose on Day 2. Every urine specimen was collected as an individual void for 32 h after the first dose and assayed for d- and l-amphetamines specific isomers with a GC–MS method with >99% purity of R-(−)-α-methoxy-α-(trifluoromethyl)phenylacetyl derivatives and 10 µg/L lower limits of quantification. No d-methamphetamine or d-amphetamine was detected in any urine specimen by GC–MS. The median l-methamphetamine maximum concentration was 62.8 µg/L (range: 11.0–1,440). Only two subjects had detectable l-amphetamine, with maximum concentrations coinciding with l-methamphetamine peak levels, and always ≤4% of the parent's maximum. Three commercial immunoassays for amphetamines EMIT® II Plus, KIMS® II and DRI® had sensitivities, specificities and efficiencies of 100, 97.8, 97.8; 100, 99.6, 99.6 and 100, 100, 100%, respectively. The immunoassays had high efficiencies, but our first hypothesis was not affirmed. The EMIT® II Plus assay produced 2.2% false-positive results, requiring an enantiomer-specific confirmation. PMID:25217541

Adults with a history of illicit amphetamine use exhibit abnormal substantia nigra morphology and parkinsonism.

PubMed

Todd, Gabrielle; Pearson-Dennett, Verity; Wilcox, Robert A; Chau, Minh T; Thoirs, Kerry; Thewlis, Dominic; Vogel, Adam P; White, Jason M

2016-04-01

The sonographic appearance of the substantia nigra is abnormally bright and enlarged (hyperechogenic) in young adults with a history of illicit stimulant use. The abnormality is a risk factor for Parkinson's disease. The aim of the current study was to identify the type of illicit stimulant drug associated with substantia nigra hyperechogenicity and to determine if individuals with a history of illicit stimulant use exhibit clinical signs of parkinsonism. We hypothesised that use of amphetamines (primarily methamphetamine) is associated with substantia nigra hyperechogenicity and clinical signs of parkinsonism. The area of echogenic signal in the substantia nigra was measured in abstinent human amphetamine users (n = 27; 33 ± 8 years) and in three control groups comprising a) 'ecstasy' users (n = 19; 23 ± 3 years), b) cannabis users (n = 30; 26 ± 8 years), and c) non-drug users (n = 37; 25 ± 7 years). A subset of subjects (n = 55) also underwent a neurological examination comprising the third and fifth part of the Unified Parkinson's Disease Rating Scale. Area of substantia nigra echogenicity was significantly larger in the amphetamine group (0.276 ± 0.080 cm(2)) than in the control groups (0.200 ± 0.075, 0.190 ± 0.049, 0.191 ± 0.055 cm(2), respectively; P < 0.002). The score on the clinical rating scale was also significantly higher in the amphetamine group (8.4 ± 8.1) than in pooled controls (3.3 ± 2.8; P = 0.002). Illicit use of amphetamines is associated with abnormal substantia nigra morphology and subtle clinical signs of parkinsonism. The results support epidemiological findings linking use of amphetamines, particularly methamphetamine, with increased risk of developing Parkinson's disease later in life. Copyright © 2016 Elsevier Ltd. All rights reserved.

Cannabinoid CB1 Receptor Activation Mediates the Opposing Effects of Amphetamine on Impulsive Action and Impulsive Choice

PubMed Central

Wiskerke, Joost; Stoop, Nicky; Schetters, Dustin; Schoffelmeer, Anton N. M.; Pattij, Tommy

2011-01-01

It is well known that acute challenges with psychostimulants such as amphetamine affect impulsive behavior. We here studied the pharmacology underlying the effects of amphetamine in two rat models of impulsivity, the 5-choice serial reaction time task (5-CSRTT) and the delayed reward task (DRT), providing measures of inhibitory control, an aspect of impulsive action, and impulsive choice, respectively. We focused on the role of cannabinoid CB1 receptor activation in amphetamine-induced impulsivity as there is evidence that acute challenges with psychostimulants activate the endogenous cannabinoid system, and CB1 receptor activity modulates impulsivity in both rodents and humans. Results showed that pretreatment with either the CB1 receptor antagonist/inverse agonist SR141716A or the neutral CB1 receptor antagonist O-2050 dose-dependently improved baseline inhibitory control in the 5-CSRTT. Moreover, both compounds similarly attenuated amphetamine-induced inhibitory control deficits, suggesting that CB1 receptor activation by endogenously released cannabinoids mediates this aspect of impulsive action. Direct CB1 receptor activation by Δ9-Tetrahydrocannabinol (Δ9-THC) did, however, not affect inhibitory control. Although neither SR141716A nor O-2050 affected baseline impulsive choice in the DRT, both ligands completely prevented amphetamine-induced reductions in impulsive decision making, indicating that CB1 receptor activity may decrease this form of impulsivity. Indeed, acute Δ9-THC was found to reduce impulsive choice in a CB1 receptor-dependent way. Together, these results indicate an important, though complex role for cannabinoid CB1 receptor activity in the regulation of impulsive action and impulsive choice as well as the opposite effects amphetamine has on both forms of impulsive behavior. PMID:22016780

Sulfur compounds in therapy: Radiation-protective agents, amphetamines, and mucopolysaccharide sulfation

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

Foye, W.O.

1992-09-01

Sulfur-containing compounds have been used in the search for whole-body radiation-protective compounds, in the design of amphetamine derivatives that retain appetite-suppressive effects but lack most behavioral effects characteristic of amphetamines, and in the search for the cause of kidney stone formation in recurrently stoneforming patients. Organic synthetic procedures were used to prepare radiation-protective compounds having a variety of sulfur-containing functional groups, and to prepare amphetamine derivatives having electron-attracting sulfur functions. In the case of the kidney stone causation research, isolation of urinary mucopolysaccharides (MPS) from recurrently stoneforming patients was carried out and the extent of sulfation of the MPS wasmore » determined by electrophoresis. Whole-body radiation-protective agents with a high degree of protection against lethal doses of gamma-radiation in mice were found in a series of quinolinium and pyridinium bis(methylthio) and methylthio amino derivatives. Mechanism studies showed that the copper complexes of these agents mimicked the beneficial action of superoxide dismutase. Electron-attracting sulfur-containing functions on amphetamine nitrogen, as well as 4'-amino nitrogen provided amphetamine derivatives with good appetite-suppressant effects and few or no adverse behavioral effects. Higher than normal levels of sulfation of the urinary MPS of stone formers suggested a cause for recurrent kidney stone formation. A sulfation inhibitor was found to prevent recurrence of stone formation and inhibit growth of existing stones. The inclusion of various sulfur-containing functions in organic molecules yielded compounds having whole-body radiation protection from lethal doses of gamma-radiation in animals. The presence of electron-attracting sulfur functions in amphetamine gave derivatives that retained appetite-suppressant effects and eliminated most adverse behavioral effects.« less

Amphetamine Dependence and Co-Morbid Alcohol Abuse: Associations to Brain Cortical Thickness

PubMed Central

2010-01-01

Background Long-term amphetamine and methamphetamine dependence has been linked to cerebral blood perfusion, metabolic, and white matter abnormalities. Several studies have linked methamphetamine abuse to cortical grey matter reduction, though with divergent findings. Few publications investigate unmethylated amphetamine's potential effects on cortical grey matter. This work investigated if amphetamine dependent patients showed reduced cortical grey matter thickness. Subjects were 40 amphetamine dependent subjects and 40 healthy controls. While all subjects were recruited to be free of alcohol dependence, structured clinical interviews revealed significant patterns of alcohol use in the patients. Structural magnetic resonance brain images were obtained from the subjects using a 1.5 Tesla GE Signa machine. Brain cortical thickness was measured with submillimeter precision at multiple finely spaced cortical locations using semi-automated post-processing (FreeSurfer). Contrast analysis of a general linear model was used to test for differences between the two groups at each cortical location. In addition to contrasting patients with controls, a number of analyses sought to identify possible confounding effects from alcohol. Results No significant cortical thickness differences were observed between the full patient group and controls, nor between non-drinking patients and controls. Patients with a history of co-morbid heavy alcohol use (n = 29) showed reductions in the superior-frontal right hemisphere and pre-central left hemisphere when compared to healthy controls (n = 40). Conclusions Amphetamine usage was associated with reduced cortical thickness only in patients co-morbid for heavy alcohol use. Since cortical thickness is but one measure of brain structure and does not capture brain function, further studies of brain structure and function in amphetamine dependence are warranted. PMID:20487539

A Single Amphetamine Infusion Reverses Deficits in Dopamine Nerve-Terminal Function Caused by a History of Cocaine Self-Administration

PubMed Central

Ferris, Mark J; Calipari, Erin S; Rose, Jamie H; Siciliano, Cody A; Sun, Haiguo; Chen, Rong; Jones, Sara R

2015-01-01

There are ∼1.6 million people who meet the criteria for cocaine addiction in the United States, and there are currently no FDA-approved pharmacotherapies. Amphetamine-based dopamine-releasing drugs have shown efficacy in reducing the motivation to self-administer cocaine and reducing intake in animals and humans. It is hypothesized that amphetamine acts as a replacement therapy for cocaine through elevation of extracellular dopamine levels. Using voltammetry in brain slices, we tested the ability of a single amphetamine infusion in vivo to modulate dopamine release, uptake kinetics, and cocaine potency in cocaine-naive animals and after a history of cocaine self-administration (1.5 mg/kg/infusion, fixed-ratio 1, 40 injections/day × 5 days). Dopamine kinetics were measured 1 and 24 h after amphetamine infusion (0.56 mg/kg, i.v.). Following cocaine self-administration, dopamine release, maximal rate of uptake (Vmax), and membrane-associated dopamine transporter (DAT) levels were reduced, and the DAT was less sensitive to cocaine. A single amphetamine infusion reduced Vmax and membrane DAT levels in cocaine-naive animals, but fully restored all aspects of dopamine terminal function in cocaine self-administering animals. Here, for the first time, we demonstrate pharmacologically induced, immediate rescue of deficits in dopamine nerve-terminal function in animals with a history of high-dose cocaine self-administration. This observation supports the notion that the DAT expression and function can be modulated on a rapid timescale and also suggests that the pharmacotherapeutic actions of amphetamine for cocaine addiction go beyond that of replacement therapy. PMID:25689882

Mortality and causes of death among people who inject amphetamine: A long-term follow-up cohort study from a needle exchange program in Sweden.

PubMed

Åhman, Ada; Jerkeman, Anna; Blomé, Marianne Alanko; Björkman, Per; Håkansson, Anders

2018-07-01

Abuse of amphetamines is a worldwide problem with around 34 million users, and amphetamine is commonly used by people who inject drugs (PWID). Despite this, there is relatively little research on mortality and cause of death among people who use amphetamines primarily. The present study aimed to examine mortality and causes of death among people who inject amphetamine, and compare these results to the general population. This retrospective cohort study was based on data from The Malmö Needle Exchange Program in Sweden (MNEP) and on data from The Swedish National Cause of Death Register. Participants in the MNEP, between 1987 and 2011, with registered national identity number and amphetamine as their primary drug of injection use, were included in the study. Standardized mortality ratios (SMR) was calculated for overall mortality and categories of causes of death. 2019 individuals were included (mean follow-up-time 13.7 years [range 0.02-24.2 years], a total of 27,698 person-years). Of the 448 deceased, 428 had a registered cause of death. The most common causes of death were external causes (n = 162, 38%), followed by diseases of the circulatory system (n = 67, 16%). SMR were significantly elevated (8.3, 95% CI [7.5-9.1]) for the entire study population, and for every category of causes of death respectively. People injecting amphetamine as a primary drug were found to have significantly elevated mortality compared with the general population, with high rates of both external and somatic causes of death. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Occupational conditions and the risk of the use of amphetamines by truck drivers.

PubMed

de Oliveira, Lúcio Garcia; de Souza, Letícia Maria de Araújo; Barroso, Lúcia Pereira; Gouvêa, Marcela Júlio César; de Almeida, Carlos Vinícius Dias; Muñoz, Daniel Romero; Leyton, Vilma

2015-01-01

OBJECTIVE To test whether the occupational conditions of professional truck drivers are associated with amphetamine use after demographic characteristics and ones regarding mental health and drug use are controlled for.METHODS Cross-sectional study, with a non-probabilistic sample of 684 male truck drivers, which was collected in three highways in Sao Paulo between years 2012 and 2013. Demographic and occupational information was collected, as well as data on drug use and mental health (sleep quality, emotional stress, and psychiatric disorders). A logistic regression model was developed to identify factors associated with amphetamine use. Odds ratio (OR; 95%CI) was defined as the measure for association. The significance level was established as p < 0.05.RESULTS The studied sample was found to have an average age of 36.7 (SD = 7.8) years, as well as low education (8.6 [SD = 2.3] years); 29.0% of drivers reported having used amphetamines within the twelve months prior to their interviews. After demographic and occupational variables had been controlled for, the factors which indicated amphetamine use among truck drivers were the following: being younger than 38 years (OR = 3.69), having spent less than nine years at school (OR = 1.76), being autonomous (OR = 1.65), working night shifts or irregular schedules (OR = 2.05), working over 12 hours daily (OR = 2.14), and drinking alcohol (OR = 1.74).CONCLUSIONS Occupational aspects are closely related to amphetamine use among truck drivers, which reinforces the importance of closely following the application of law (Resting Act ("Lei do Descanso"); Law 12,619/2012) which regulates the workload and hours of those professionals. Our results show the need for increased strictness on the trade and prescription of amphetamines in Brazil.

A previous history of repeated amphetamine exposure modifies brain angiotensin II AT1 receptor functionality.

PubMed

Casarsa, B S; Marinzalda, M Á; Marchese, N A; Paz, M C; Vivas, L; Baiardi, G; Bregonzio, C

2015-10-29

Previous results from our laboratory showed that angiotensin II AT1 receptors (AT1-R) are involved in the neuroadaptative changes induced by amphetamine. The aim of the present work was to study functional and neurochemical responses to angiotensin II (ANG II) mediated by AT1-R activation in animals previously exposed to amphetamine. For this purpose male Wistar rats (250-320 g) were treated with amphetamine (2.5mg/kg/day intraperitoneal) or saline for 5 days and implanted with intracerebroventricular (i.c.v.) cannulae. Seven days after the last amphetamine administration the animals received ANG II (400 pmol) i.c.v. One group was tested in a free choice paradigm for sodium (2% NaCl) and water intake and sacrificed for Fos immunoreactivity (Fos-IR) determinations. In a second group of rats, urine and plasma samples were collected for electrolytes and plasma renin activity determination and then they were sacrificed for Fos-IR determination in Oxytocinergic neurons (Fos-OT-IR). Repeated amphetamine exposure (a) prevented the increase in sodium intake and Fos-IR cells in caudate-putamen and accumbens nucleus induced by ANG II i.c.v. (b) potentiated urinary sodium excretion and Fos-OT-IR in hypothalamus and (c) increased the inhibitory response in plasma renin activity, in response to ANG II i.c.v. Our results indicate a possible functional desensitisation of AT1-R in response to ANG II, induced by repeated amphetamine exposure. This functional AT1-R desensitisation allows to unmask the effects of ANG II i.c.v. mediated by oxytocin. We conclude that the long lasting changes in brain AT1-R functionality should be considered among the psychostimulant-induced neuroadaptations. Published by Elsevier Ltd.

Increased risk of Parkinson's disease in individuals hospitalized with conditions related to the use of methamphetamine or other amphetamine-type drugs.

PubMed

Callaghan, Russell C; Cunningham, James K; Sykes, Jenna; Kish, Stephen J

2012-01-01

Since methamphetamine and other amphetamine-type stimulants (meth/amphetamine) can damage dopaminergic neurons, researchers have long speculated that these drugs may predispose users to develop Parkinson's disease (PD), a dopamine deficiency neurological disorder. We employed a retrospective population-based cohort study using all linked statewide California inpatient hospital episodes and death records from January 1, 1990 through December 31, 2005. Patients at least 30 years of age were followed for up to 16 years. Competing risks analysis was used to determine whether the meth/amphetamine cohort had elevated risk of developing PD (ICD-9 332.0; ICD-10 G20) in comparison to a matched population-proxy appendicitis group and a matched cocaine drug control group. Individuals admitted to hospital with meth/amphetamine-related conditions (n=40,472; ICD-9 codes 304.4, 305.7, 969.7, E854.2) were matched on age, race, sex, date of index admission, and patterns of hospital admission with patients with appendicitis conditions (n=207,831; ICD-9 codes 540-542) and also individuals with cocaine-use disorders (n=35,335; ICD-9 codes 304.2, 305.6, 968.5). The meth/amphetamine cohort showed increased risk of PD compared to both that of the matched appendicitis group [hazard ratio (HR)=1.76, 95% CI: 1.12-2.75, p=0.017] and the matched cocaine group [HR=2.44, 95% CI: 1.32-4.41, p=0.004]. The cocaine group did not show elevated hazard of PD compared to the matched appendicitis group [HR=1.04, 95% CI: 0.56-1.93, p=0.80]. These data provide evidence that meth/amphetamine users have above-normal risk for developing PD. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Mephedrone, compared with MDMA (ecstasy) and amphetamine, rapidly increases both dopamine and 5-HT levels in nucleus accumbens of awake rats

PubMed Central

Kehr, J; Ichinose, F; Yoshitake, S; Goiny, M; Sievertsson, T; Nyberg, F; Yoshitake, T

2011-01-01

BACKGROUND AND PURPOSE The designer drug 1-(4-methylphenyl)-2-methylaminopropan-1-one (4-methylmethcathinone, mephedrone) is reported to possess psychostimulant, entactogenic and hallucinogenic effects. The purpose of this study was to examine the effects of acute administration of mephedrone on extracellular levels of dopamine (DA) and 5-HT in the nucleus accumbens of awake rats and compare these effects with those induced by 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) and amphetamine. EXPERIMENTAL APPROACH Microdialysis sampling was performed while simultaneously recording locomotor activity in rats and the monoamines were determined by HPLC with electrochemical detection. KEY RESULTS Mephedrone (3 mg·kg−1 s.c.) and (+)-amphetamine (1 mg·kg−1 s.c.) caused rapid increases in extracellular DA levels of 496% and 412%, respectively, whereas MDMA (3 mg·kg−1 s.c.) showed only a moderate effect (235%). The corresponding 5-HT levels increased to 941% (mephedrone) and 911% (MDMA), but only to 165% following amphetamine. The calculated t1/2 values for elimination rate of mephedrone, MDMA and amphetamine-induced increases in extracellular DA levels were 25, 303 and 51 min, the corresponding t1/2 values for 5-HT were 26, 48 and 84 min, respectively. Locomotor activity was increased most by amphetamine, whereas both mephedrone and MDMA showed about three times lower and shorter-lasting effects. CONCLUSIONS AND IMPLICATIONS The neurochemical and functional properties of mephedrone resemble those of MDMA, but it also shows an amphetamine-like effect in that it evokes a rapid release and elimination of DA in the brain reward system, a feature that may contribute to its potent re-inforcing properties. PMID:21615721

Occupational conditions and the risk of the use of amphetamines by truck drivers

PubMed Central

de Oliveira, Lúcio Garcia; de Souza, Letícia Maria de Araújo; Barroso, Lúcia Pereira; Gouvêa, Marcela Júlio César; de Almeida, Carlos Vinícius Dias; Muñoz, Daniel Romero; Leyton, Vilma

2015-01-01

OBJECTIVE To test whether the occupational conditions of professional truck drivers are associated with amphetamine use after demographic characteristics and ones regarding mental health and drug use are controlled for. METHODS Cross-sectional study, with a non-probabilistic sample of 684 male truck drivers, which was collected in three highways in Sao Paulo between years 2012 and 2013. Demographic and occupational information was collected, as well as data on drug use and mental health (sleep quality, emotional stress, and psychiatric disorders). A logistic regression model was developed to identify factors associated with amphetamine use. Odds ratio (OR; 95%CI) was defined as the measure for association. The significance level was established as p < 0.05. RESULTS The studied sample was found to have an average age of 36.7 (SD = 7.8) years, as well as low education (8.6 [SD = 2.3] years); 29.0% of drivers reported having used amphetamines within the twelve months prior to their interviews. After demographic and occupational variables had been controlled for, the factors which indicated amphetamine use among truck drivers were the following: being younger than 38 years (OR = 3.69), having spent less than nine years at school (OR = 1.76), being autonomous (OR = 1.65), working night shifts or irregular schedules (OR = 2.05), working over 12 hours daily (OR = 2.14), and drinking alcohol (OR = 1.74). CONCLUSIONS Occupational aspects are closely related to amphetamine use among truck drivers, which reinforces the importance of closely following the application of law (Resting Act (“Lei do Descanso”); Law 12,619/2012) which regulates the workload and hours of those professionals. Our results show the need for increased strictness on the trade and prescription of amphetamines in Brazil. PMID:26398875

Amphetamine-type stimulant use and the risk of injury or death as a result of a road-traffic accident: A systematic review of observational studies.

PubMed

Hayley, Amie C; Downey, Luke A; Shiferaw, Brook; Stough, Con

2016-06-01

Amphetamine-type substances are frequently detected among drivers injured or killed due to road-trauma. However, the role of this substance in crash causation remains equivocal. We performed a systematic review to evaluate existing evidence regarding the association between amphetamine use and the risk of injury or death due to road traffic accidents. A bibliographical search of PubMed, SafetyLit, Scopus, and Science Direct literature databases from 01 January 1980 until May 2015 was performed. The quality of included studies was assessed using the Newcastle-Ottowa Scale (NOS) (cut-off of ≥7 indicated high quality). Inter-rater reliability between three independent reviewers for the NOS was calculated using Cohens kappa (κ) statistic, and best-evidence synthesis was performed. A total of 182 articles were found. Nine studies met eligibility criteria for inclusion for review, and seven studies were included for best-evidence synthesis. Best-evidence synthesis demonstrated a conflicting level of evidence for associations between the use of-amphetamine-type substances and the risk of sustaining an injury, and a moderate level of evidence between amphetamine use and the risk of death due to road trauma. This is the first review to synthesise evidence regarding the association between amphetamine-type substance use and the risk of injury or death due to a road traffic accident. More conclusive evidence of death due to road trauma among amphetamine users may reflect significant and global deficits in functioning associated with effective vehicular control under the influence of this substance. Additional high quality, sufficiently powered studies are required to elucidate the magnitude of these associations. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

Simultaneous ultra-high-pressure liquid chromatography-tandem mass spectrometry determination of amphetamine and amphetamine-like stimulants, cocaine and its metabolites, and a cannabis metabolite in surface water and urban wastewater.

PubMed

Bijlsma, Lubertus; Sancho, Juan V; Pitarch, Elena; Ibáñez, Maria; Hernández, Félix

2009-04-10

An ultra-high-pressure liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method has been developed for the simultaneous quantification and confirmation of 11 basic/acidic illicit drugs and relevant metabolites in surface and urban wastewater at ng/L levels. The sample pre-treatment consisted of a solid-phase extraction using Oasis MCX cartridges. Analyte deuterated compounds were used as surrogate internal standards (except for norbenzoylecgonine and norcocaine) to compensate for possible errors resulting from matrix effects and those associated to the sample preparation procedure. After SPE enrichment, the selected drugs were separated within 6min under UHPLC optimized conditions. To efficiently combine UHPLC with MS/MS, a fast-acquisition triple quadrupole mass analyzer (TQD from Waters) in positive-ion mode (ESI+) was used. The excellent selectivity and sensitivity of the TQD analyzer in selected reaction monitoring mode allowed quantification and reliable identification at the LOQ levels. Satisfactory recoveries (70-120%) and precision (RSD<20%) were obtained for most compounds in different types of water samples, spiked at two concentration levels [limit of quantification (LOQ) and 10LOQ]. Thus, surface water was spiked at 30 ng/L and 300 ng/L (amphetamine and amphetamine-like stimulants), 10 ng/L and 100 ng/L (cocaine and its metabolites), 300 ng/L and 3000 ng/L (tetrahydrocannabinol-COOH). Recovery experiments in effluent and influent wastewater were performed at spiking levels of three and fifteen times higher than the levels spiked in surface water, respectively. The validated method was applied to urban wastewater samples (influent and effluent). The acquisition of three selected reaction monitoring transitions per analyte allowed positive findings to be confirmed by accomplishment of ion ratios between the quantification transition and two additional specific confirmation transitions. In general, drug consumption increased in the weekends and during an important musical event. The highest concentration levels were 27.5 microg/L and 10.5 microg/L, which corresponded to 3,4-methylenedioxymethamphetamine (MDMA, or ecstasy) and to benzoylecgonine (a cocaine metabolite), respectively. The wastewater treatment plants showed good removal efficiency (>99%) for low levels of illicit drugs in water, but some difficulties were observed when high drug levels were present in wastewaters.

A novel pentadecapeptide, BPC 157, blocks the stereotypy produced acutely by amphetamine and the development of haloperidol-induced supersensitivity to amphetamine.

PubMed

Jelovac, N; Sikirić, P; Rucman, R; Petek, M; Perović, D; Konjevoda, P; Marović, A; Seiwerth, S; Grabarević, Z; Sumajstorcić, J; Dodig, G; Perić, J

1998-04-01

A novel gastric pentadecapeptide, BPC 157, has been shown to attenuate different lesions (i.e., gastrointestinal tract, liver, pancreas, somatosensory neurons). This suggests an interaction with the dopamine system. When used alone, BPC 157 does not affect gross behavior or induce stereotypy. We first investigated the effect of pentadecapeptide BPC 157 on stereotypy and acoustic startle response in rats, given as either a prophylactic (10 micrograms/kg i.p.) or therapeutic (10 ng/kg i.p.) regimen, with the dopamine indirect agonist amphetamine (10 mg/kg i.p.). There was a marked attenuation of stereotypic behavior and acoustic startle response. When the medication was given at the time of maximum amphetamine-induced excitability, there was a reversal of this behavior. A further focus was on the effect of this pentadecapeptide on increased climbing behavior in mice pretreated with the dopamine antagonist haloperidol (5.0 mg/kg i.p.), and subsequently treated with amphetamine (20 mg/kg i.p. challenge 1, 2, 4, and 10 days after haloperidol pretreatment). This protocol is usually used for the study of behavioral supersensitivity to the amphetamine stimulating effect. An almost complete reversal was noted when pentadecapeptide was coadministered with haloperidol. Together, these data provide compelling evidence for the interaction of pentadecapeptide BPC 157 with the dopamine system.

Amphetamine effects on dopamine levels and behavior following cannabinoid exposure during adolescence.

PubMed

Ellgren, Maria; Hurd, Yasmin L; Franck, Johan

2004-08-23

The cannabis gateway hypothesis purports that early exposure to cannabis is a risk factor for subsequent use of other addictive drugs, e.g., psychostimulants. Neurobiological sensitization, consistent with a gateway hypothesis, was currently studied in regard to amphetamine response. Rats were exposed to the cannabinoid receptor agonist WIN 55,212-2 [(R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone] 1.25 mg/kg, intraperitoneally; i.p. for 5 days during early adolescence. Amphetamine (0.5 mg/kg, i.p.) or WIN 55,212-2 (1.25 mg/kg, i.p.) was administered in late adolescence and in vivo dopamine levels were simultaneously measured in the nucleus accumbens. Locomotor and stereotyped behaviors were also monitored in rats pretreated with WIN 55,212-2 (0.625, 1.25 or 2.5 mg/kg) or Delta-9-tetrahydrocannabinol (0.75, 1.5 or 3.0 mg/kg, i.p.) for 5 days during early adolescence and challenged with amphetamine (0.5 or 2.0 mg/kg) in late adolescence or as adults. Pretreatment with WIN 55,212-2 or Delta-9-tetrahydrocannabinol during early adolescence did not alter the dopaminergic or behavioral responses to amphetamine in adolescence or adulthood. In conclusion, these findings do not support the cannabis gateway hypothesis in regard to subsequent amphetamine exposure.

Matrix effect and cross-reactivity of select amphetamine-type substances, designer analogues, and putrefactive amines using the Bio-Quant direct ELISA presumptive assays for amphetamine and methamphetamine.

PubMed

Apollonio, Luigino G; Whittall, Ian R; Pianca, Dennis J; Kyd, Jennelle M; Maher, William A

2007-05-01

The aim of this study was to evaluate the Bio-Quant Direct ELISA assays for amphetamine and methamphetamine in the routine presumptive screening of biological fluids. Standard concentration curves of the target analytes were assayed to assess sensitivity, and known concentrations of common amphetamine-type substances (ephedrine, pseudoephedrine, phentermine), designer analogues (MDA, MDMA, MDEA, MBDB, PMA, 4-MTA, 2CB), and putrefactive amines (phenylethylamine, putrescine, tryptamine, tyramine) were analyzed to determine cross-reactivity. Results of the standard curve studies show the capacity of both Direct ELISA kits to confidently detect down to 3 ng/mL interday (PBS matrix; CVs 6.3-15.5%). Cross-reactivity relative to that of 50 ng/mL preparations of the target compounds demonstrated that the Direct ELISA kit for amphetamine also detected MDA (282%), PMA (265%), 4-MTA (280%), and phentermine (61%), and the Direct ELISA for methamphetamine also assayed positive for MDMA (73%), MDEA (18%), pseudoephedrine (19%), MBDB (8%), and ephedrine (9%). Matrix studies demonstrated that both ELISA kits could be applied to screening of blood, urine, and saliva to a concentration of 6 ng/mL or lower. In conclusion, the Bio-Quant Direct ELISA kits for amphetamine and methamphetamine are fast and accurate and have demonstrated themselves to be useful tools in routine toxicological testing.

Analysis of amphetamine and methamphetamine in municipal wastewater influent and effluent using weak cation-exchange SPE and LC-MS/MS.

PubMed

Boles, Tammy H; Wells, Martha J M

2016-12-01

Amphetamine and methamphetamine are emerging contaminants-those for which no regulations currently require monitoring or public reporting of their presence in our water supply. In this research, a protocol for weak cation-exchange (WCX) SPE coupled with LC-MS/MS was developed for determination of emerging contaminants amphetamine and methamphetamine in a complex wastewater matrix. Gradient LC parameters were adjusted to yield baseline separation of methamphetamine from other contaminants. Methamphetamine-D5 was used as the internal standard (IS) to compensate for sample loss during SPE and for signal loss during MS (matrix effects). Recoveries were 102.1 ± 7.9% and 99.4 ± 4.0% for amphetamine and methamphetamine, respectively, using WCX sorbent. Notably, methamphetamine was determined to be present in wastewater influent at each sampling date tested. Amphetamine was present in wastewater influent on two of four sampling dates. Amphetamine concentrations ranged from undetectable to 86.4 ng/L in influent, but it was undetectable in wastewater effluent. Methamphetamine was detected in influent at concentrations ranging from 27.0-60.3 ng/L. Methamphetamine concentration was reduced but incompletely removed at this facility. Although absent in one post-UV effluent sample, concentrations of methamphetamine ranged from 10.8-14.8 ng/L. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Hyphenated GC-FTIR and GC-MS techniques applied in the analysis of bioactive compounds

NASA Astrophysics Data System (ADS)

Gosav, Steluta; Paduraru, Nicoleta; Praisler, Mirela

2014-08-01

The drugs of abuse, which affect human nature and cause numerous crimes, have become a serious problem throughout the world. There are hundreds of amphetamine analogues on the black market. They consist of various alterations of the basic amphetamine molecular structure, which are yet not yet included in the lists of forbidden compounds although they retain or slightly modify the hallucinogenic effects of their parent compound. It is their important variety that makes their identification quite a challenge. A number of analytical procedures for the identification of amphetamines and their analogues have recently been reported. We are presenting the profile of the main hallucinogenic amphetamines obtained with the hyphenated techniques that are recommended for the identification of illicit amphetamines, i. e. gas chromatography combined with mass spectrometry (GC-MS) and gas chromatography coupled with Fourier transform infrared spectrometry (GC-FTIR). The infrared spectra of the analyzed hallucinogenic amphetamines present some absorption bands (1490 cm-1, 1440 cm-1, 1245 cm-1, 1050 cm-1 and 940 cm-1) that are very stable as position and shape, while their intensity depends of the side-chain substitution. The specific ionic fragment of the studied hallucinogenic compounds is the 3,4-methylenedioxybenzyl cation (m/e = 135) which has a small relative abundance (lesser than 20%). The complementarity of the above mentioned techniques for the identification of hallucinogenic compounds is discussed.

Pathology of deaths associated with "ecstasy" and "eve" misuse.

PubMed Central

Milroy, C M; Clark, J C; Forrest, A R

1996-01-01

AIMS: To study the postmortem pathology associated with ring substituted amphetamine (amphetamine derivatives) misuse. METHODS: The postmortem findings in deaths associated with the ring substituted amphetamines 3,4-methylenedioxymethyl-amphetamine (MDMA, ecstasy) and 3,4-methylenedioxyethylamphetamine (MDEA, eve) were studied in seven young white men aged between 20 and 25 years. RESULTS: Striking changes were identified in the liver, which varied from foci of individual cell necrosis to centrilobular necrosis. In one case there was massive hepatic necrosis. Changes consistent with catecholamine induced myocardial damage were seen in five cases. In the brain perivascular haemorrhagic and hypoxic changes were identified in four cases. Overall, the changes in four cases were the same as those reported in heart stroke, although only two cases had a documented history of hyperthermia. Of these four cases, all had changes in their liver, three had changes in their brains, and three in their heart. Of the other three cases, one man died of fulminant liver failure, one of water intoxication and one probably from a cardiac arrhythmia associated with myocardial fibrosis. CONCLUSIONS: These data suggest that there is more than one mechanism of damage in ring substituted amphetamine misuse, injury being caused by hyperthermia in some cases, but with ring substituted amphetamines also possibly having a toxic effect on the liver and other organs in the absence of hyperthermia. Images PMID:8655682

Practice Parameters for the Treatment of Narcolepsy and other Hypersomnias of Central Origin An American Academy of Sleep Medicine Report

PubMed Central

Morgenthaler, Timothy I.; Kapur, Vishesh K.; Brown, Terry; Swick, Todd J.; Alessi, Cathy; Aurora, R. Nisha; Boehlecke, Brian; Chesson, Andrew L.; Friedman, Leah; Maganti, Rama; Owens, Judith; Pancer, Jeffrey; Zak, Rochelle

2007-01-01

These practice parameters pertain to the treatment of hypersomnias of central origin. They serve as both an update of previous practice parameters for the therapy of narcolepsy and as the first practice parameters to address treatment of other hypersomnias of central origin. They are based on evidence analyzed in the accompanying review paper. The specific disorders addressed by these parameters are narcolepsy (with cataplexy, without cataplexy, due to medical condition and unspecified), idiopathic hypersomnia (with long sleep time and without long sleep time), recurrent hypersomnia and hypersomnia due to medical condition. Successful treatment of hypersomnia of central origin requires an accurate diagnosis, individual tailoring of therapy to produce the fullest possible return of normal function, and regular follow-up to monitor response to treatment. Modafinil, sodium oxybate, amphetamine, methamphetamine, dextroamphetamine, methylphenidate, and selegiline are effective treatments for excessive sleepiness associated with narcolepsy, while tricyclic antidepressants and fluoxetine are effective treatments for cataplexy, sleep paralysis, and hypnagogic hallucinations; but the quality of published clinical evidence supporting them varies. Scheduled naps can be beneficial to combat sleepiness in narcolepsy patients. Based on available evidence, modafinil is an effective therapy for sleepiness due to idiopathic hypersomnia, Parkinson's disease, myotonic dystrophy, and multiple sclerosis. Based on evidence and/or long history of use in the therapy of narcolepsy committee consensus was that modafinil, amphetamine, methamphetamine, dextroamphetamine, and methylphenidate are reasonable options for the therapy of hypersomnias of central origin. Citation: Morgenthaler TI; Kapur VK; Brown T; Swick TJ; Alessi C; Aurora RN; Boehlecke B; Chesson AL; Friedman L; Maganti R; Owens J; Pancer J; Zak R; Standards of Practice Committee of the AASM. Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin. SLEEP 2007;30(12):1705-1711. PMID:18246980

4 CFR 25.8 - Alcoholic beverages and narcotics.

Code of Federal Regulations, 2014 CFR

2014-01-01

... alcoholic beverages, narcotic drugs, hallucinogens, marijuana, barbiturates, or amphetamines is prohibited..., marijuana, barbiturate, or amphetamine. This prohibition shall not apply in cases where the drug is being...

4 CFR 25.8 - Alcoholic beverages and narcotics.

Code of Federal Regulations, 2011 CFR

2011-01-01

... alcoholic beverages, narcotic drugs, hallucinogens, marijuana, barbiturates, or amphetamines is prohibited..., marijuana, barbiturate, or amphetamine. This prohibition shall not apply in cases where the drug is being...

4 CFR 25.8 - Alcoholic beverages and narcotics.

Code of Federal Regulations, 2012 CFR

2012-01-01

... alcoholic beverages, narcotic drugs, hallucinogens, marijuana, barbiturates, or amphetamines is prohibited..., marijuana, barbiturate, or amphetamine. This prohibition shall not apply in cases where the drug is being...

4 CFR 25.8 - Alcoholic beverages and narcotics.

Code of Federal Regulations, 2010 CFR

2010-01-01

... alcoholic beverages, narcotic drugs, hallucinogens, marijuana, barbiturates, or amphetamines is prohibited..., marijuana, barbiturate, or amphetamine. This prohibition shall not apply in cases where the drug is being...

4 CFR 25.8 - Alcoholic beverages and narcotics.

Code of Federal Regulations, 2013 CFR

2013-01-01

... alcoholic beverages, narcotic drugs, hallucinogens, marijuana, barbiturates, or amphetamines is prohibited..., marijuana, barbiturate, or amphetamine. This prohibition shall not apply in cases where the drug is being...

A new screening method for amphetamine and methamphetamine using dansyl chloride derivatization and cartridge fluorescence.

PubMed

Yamada, H; Ikeda-Wada, S; Oguri, K

1998-07-01

A new screening method for amphetamines was developed. It consists of derivatization with dansyl chloride, extraction of the derivative using a Sep-Pak C18 or a Bond Elut C18, solid phase extraction columns, and visualization of the fluorescence of the cartridge. A control test using drug-free urine showed no fluorescence. Amphetamine, methamphetamine and the methylenedioxy derivatives exhibited strong fluorescence, while related compounds, such as N-ethylamphetamine and fenetylline, were negative or weakly positive. The disadvantage of the present method is that it is a multi-step procedure and 20-30 min is required for screening. However, since it has a different specificity from the widely used immunochemical technique, it is suggested to be a useful screen for amphetamines.

Hazards associated with the recreational drug 'ecstasy'.

PubMed

O'Connor, B

The amphetamine analogue 'ecstasy' is a popular 'designer' drug and is perceived by its users to be relatively harmless. However, it has been associated with several fatalities through a disorder of thermoregulation, and severe reactions have been reported across many disciplines. This article emphasises the hazardous nature of the drug and highlights the urgency and nature of treatment in the acutely toxic state.

Synthetic Cathinone and Cannabinoid Designer Drugs Pose a Major Risk for Public Health

PubMed Central

Weinstein, Aviv M.; Rosca, Paola; Fattore, Liana; London, Edythe D.

2017-01-01

As part of an increasing worldwide use of designer drugs, recent use of compounds containing cathinones and synthetic cannabinoids is especially prevalent. Here, we reviewed current literature on the prevalence, epidemiology, bio-behavioral effects, and detection of these compounds. Gender differences and clinical effects will also be examined. Chronic use of synthetic cathinone compounds can have major effects on the central nervous system and can induce acute psychosis, hypomania, paranoid ideation, and delusions, similar to the effects of other better-known amphetamine-type stimulants. Synthetic cannabinoid products have effects that are somewhat similar to those of natural cannabis but more potent and long-lasting than THC. Some of these compounds are potent and dangerous, having been linked to psychosis, mania, and suicidal ideation. Novel compounds are developed rapidly and new screening techniques are needed to detect them as well as a rigorous regulation and legislation reinforcement to prevent their distribution and use. Given the rapid increase in the use of synthetic cathinones and cannabinoid designer drugs, their potential for dependence and abuse, and harmful medical and psychiatric effects, there is a need for research and education in the areas of prevention and treatment. PMID:28878698

32 CFR 228.9 - Prohibition on narcotics and illegal substances.

Code of Federal Regulations, 2014 CFR

2014-07-01

... narcotic drug, hallucinogen, marijuana, barbiturate or amphetamine is prohibited. Operation of a motor..., hallucinogens, marijuana, barbiturates or amphetamines is also prohibited. These prohibitions shall not apply in...

32 CFR 228.9 - Prohibition on narcotics and illegal substances.

Code of Federal Regulations, 2011 CFR

2011-07-01

... narcotic drug, hallucinogen, marijuana, barbiturate or amphetamine is prohibited. Operation of a motor..., hallucinogens, marijuana, barbiturates or amphetamines is also prohibited. These prohibitions shall not apply in...

32 CFR 228.9 - Prohibition on narcotics and illegal substances.

Code of Federal Regulations, 2013 CFR

2013-07-01

... narcotic drug, hallucinogen, marijuana, barbiturate or amphetamine is prohibited. Operation of a motor..., hallucinogens, marijuana, barbiturates or amphetamines is also prohibited. These prohibitions shall not apply in...

32 CFR 228.9 - Prohibition on narcotics and illegal substances.

Code of Federal Regulations, 2012 CFR

2012-07-01

... narcotic drug, hallucinogen, marijuana, barbiturate or amphetamine is prohibited. Operation of a motor..., hallucinogens, marijuana, barbiturates or amphetamines is also prohibited. These prohibitions shall not apply in...

32 CFR 228.9 - Prohibition on narcotics and illegal substances.

Code of Federal Regulations, 2010 CFR

2010-07-01

... narcotic drug, hallucinogen, marijuana, barbiturate or amphetamine is prohibited. Operation of a motor..., hallucinogens, marijuana, barbiturates or amphetamines is also prohibited. These prohibitions shall not apply in...

Anti-motion-sickness therapy. [amphetamine preparation effects in human acceleration tolerance

NASA Technical Reports Server (NTRS)

Wood, C. D.

1973-01-01

Neither alterations in environmental temperature nor moderate intake of alcohol was found to alter susceptibility to motion sickness in subjects exposed to rotation in the Pensacola slow rotation room. Scopolamine with d-amphetamine was found to be the most effective preparation for the prevention of motion sickness under the experimental conditions of the studies reported here. Promethazine in combination with d-amphetamine was in the same range of effectiveness. Drug actions suggest that acetylcholine and norepinephrine may be involved in motion sickness.

Amphetamine sensitization in mice is sufficient to produce both manic- and depressive-related behaviors as well as changes in the functional connectivity of corticolimbic structures.

PubMed

Pathak, G; Ibrahim, B A; McCarthy, S A; Baker, K; Kelly, M P

2015-08-01

It has been suggested that amphetamine abuse and withdrawal mimics the diverse nature of bipolar disorder symptomatology in humans. Here, we determined if a single paradigm of amphetamine sensitization would be sufficient to produce both manic- and depressive-related behaviors in mice. CD-1 mice were subcutaneously dosed for 5 days with 1.8 mg/kg d-amphetamine or vehicle. On days 6-31 of withdrawal, amphetamine-sensitized (AS) mice were compared to vehicle-treated (VT) mice on a range of behavioral and biochemical endpoints. AS mice demonstrated reliable mania- and depression-related behaviors from day 7 to day 28 of withdrawal. Relative to VT mice, AS mice exhibited long-lasting mania-like hyperactivity following either an acute 30-min restraint stress or a low-dose 1 mg/kg d-amphetamine challenge, which was attenuated by the mood-stabilizers lithium and quetiapine. In absence of any challenge, AS mice showed anhedonia-like decreases in sucrose preference and depression-like impairments in the off-line consolidation of motor memory, as reflected by the lack of spontaneous improvement across days of training on the rotarod. AS mice also demonstrated a functional impairment in nest building, an ethologically-relevant activity of daily living. Western blot analyses revealed a significant increase in methylation of histone 3 at lysine 9 (H3K9), but not lysine 4 (H3K4), in hippocampus of AS mice relative to VT mice. In situ hybridization for the immediate-early gene activity-regulated cytoskeleton-associated protein (Arc) further revealed heightened activation of corticolimbic structures, decreased functional connectivity between frontal cortex and striatum, and increased functional connectivity between the amygdala and hippocampus of AS mice. The effects of amphetamine sensitization were blunted in C57BL/6J mice relative to CD-1 mice. These results show that a single amphetamine sensitization protocol is sufficient to produce behavioral, functional, and biochemical phenotypes in mice that are relevant to bipolar disorder. Copyright © 2015 Elsevier Ltd. All rights reserved.

Effects of Acute Oral Naltrexone on the Subjective and Physiological Effects of Oral D-Amphetamine and Smoked Cocaine in Cocaine Abusers

PubMed Central

Comer, Sandra D; Mogali, Shanthi; Saccone, Phillip A; Askalsky, Paula; Martinez, Diana; Walker, Ellen A; Jones, Jermaine D; Vosburg, Suzanne K; Cooper, Ziva D; Roux, Perrine; Sullivan, Maria A; Manubay, Jeanne M; Rubin, Eric; Pines, Abigail; Berkower, Emily L; Haney, Margaret; Foltin, Richard W

2013-01-01

Despite the prevalent worldwide abuse of stimulants, such as amphetamines and cocaine, no medications are currently approved for treating this serious public health problem. Both preclinical and clinical studies suggest that the opioid antagonist naltrexone (NTX) is effective in reducing the abuse liability of amphetamine, raising the question of whether similar positive findings would be obtained for cocaine. The purpose of this study was to evaluate the ability of oral NTX to alter the cardiovascular and subjective effects of D-amphetamine (D-AMPH) and cocaine (COC). Non-treatment-seeking COC users (N=12) completed this 3-week inpatient, randomized, crossover study. Participants received 0, 12.5, or 50 mg oral NTX 60 min before active or placebo stimulant administration during 10 separate laboratory sessions. Oral AMPH (0, 10, and 20 mg; or all placebo) was administered in ascending order within a laboratory session using a 60-min interdose interval. Smoked COC (0, 12.5, 25, and 50 mg; or all placebo) was administered in ascending order within a laboratory session using a 14-min interdose interval. Active COC and AMPH produced dose-related increases in cardiovascular function that were of comparable magnitude. In contrast, COC, but not AMPH, produced dose-related increases in several subjective measures of positive drug effect (eg, high, liking, and willingness to pay for the drug). NTX did not alter the cardiovascular effects of AMPH or COC. NTX also did not alter positive subjective ratings after COC administration, but it did significantly reduce ratings of craving for COC and tobacco during COC sessions. These results show that (1) oral AMPH produces minimal abuse-related subjective responses in COC smokers, and (2) NTX reduces craving for COC and tobacco during COC sessions. Future studies should continue to evaluate NTX as a potential anti-craving medication for COC dependence. PMID:23736314

Positive modulation of α5 GABAA receptors in preadolescence prevents reduced locomotor response to amphetamine in adult female but not male rats prenatally exposed to lipopolysaccharide.

PubMed

Batinić, Bojan; Santrač, Anja; Jančić, Ivan; Li, Guanguan; Vidojević, Aleksandra; Marković, Bojan; Cook, James M; Savić, Miroslav M

2017-10-01

We previously demonstrated that lipopolysaccharide (LPS) administered intraperitoneally (i.p.) to pregnant Wistar rat dams, at embryonic days 15 and 16 (E15/16), induced a decrease of baseline locomotor activity and diminished reactivity to amphetamine in adult female offspring. In the present study we aimed to assess the duration of LPS-induced maternal immune activation (MIA) and investigate possible changes in levels of main neurotransmitters in fetal brain during MIA. We hypothesized that the observed behavioral changes may be linked with MIA-induced disturbance of prenatal GABAergic system development, especially with α5 GABA A receptors (α5GABA A Rs), expression of which takes place between E14 and E17. Thereafter, we set to investigate if later potentiation of α5GABA A Rs in offspring's preadolescence (from postnatal day 22-28) could prevent the deficit in locomotor reactivity to amphetamine observed in adulthood, at postnatal day P60. The elevation of IL-6 in amniotic fluid 6h after LPS treatment (100μg/kg, i.p.) at E15 was concurrent with a significant increase of GABA and decrease of glutamate concentration in fetal brain. Moreover, repeated administration of MP-III-022, a selective positive allosteric modulator of α5GABA A Rs, at a dose (2mg/kg daily, i.p.) derived from a separate pharmacokinetic study, prevented the LPS-induced decrease in locomotor reactivity to amphetamine (0.5mg/kg, i.p.) in adult females. These results were not mirrored in the parallel set of experiments with male offspring from LPS-treated rats. The results suggest that pharmacological potentiation of α5GABA A Rs activity in preadolescence may ameliorate at least some of adverse consequences of exposure to MIA in utero. Copyright © 2017 ISDN. Published by Elsevier Ltd. All rights reserved.

Pre-treatment Drug Use Characteristics and Experiences among Patients in a Voluntary Substance Abuse Treatment Center in Malaysia: A Mixed Methods Approach

PubMed Central

Krishnan, Archana; Brown, Shan-Estelle; Ghani, Mansur; Khan, Farrah; Kamarulzaman, Adeeba; Altice, Frederick L.

2017-01-01

Background Drug use in Malaysia remains a significant public health and social problem despite implementation of harsh punitive drug policies such as forcibly placing suspected drug users into compulsory drug detention centers (CDDCs). Following criticism over human right violations in CDDCs, Malaysia has begun to transition towards voluntary drug treatment centers known as Cure & Care (C&C) Centers. To best serve the needs of regional C&Cs, data on drug use are essential among patients accessing treatment. Using a mixed methods approach, we examined pre-treatment drug use characteristics and experiences with addiction treatment among C&C patients in Kelantan – a religiously conservative state in Northeast Malaysia with high prevalence of drug use but where limited data are available on drug use patterns. Methods A mixed methods study utilizing surveys (N=96) and semi-structured interviews (N=20) was conducted among a convenience sample of inpatients and outpatients at the Pengkalan Chepa C&C Center in Kelantan. Results Survey results showed 89.6% of participants met screening criteria for moderate to severe addiction severity. Nearly 90% reported lifetime illicit amphetamine (syabu, meth, ice, and pil kuda) use followed by alcohol (60.4%) and opioids (52.1%). Qualitative results pointed to the powerful influence of peer networks in drug initiation and relapse, and the positive effect of the C&C on drug rehabilitation. Conclusions The drug use profile of the Kelantan C&C enrollees shows extensive pre-treatment amphetamine use, polysubstance use, and injection drug use including high-risk behaviors such as sharing needles, syringes and containers. Evidence points to the need for integration of social support-oriented practices and behavioral interventions into the rehabilitation of drug users in this region. PMID:26914230

Attention Deficit Hyperactivity Disorder, Aggression, and Illicit Stimulant Use: Is This Self-Medication?

PubMed

Odell, Annie P; Reynolds, Grace L; Fisher, Dennis G; Huckabay, Loucine M; Pedersen, William C; Xandre, Pamela; Miočević, Milica

2017-05-01

This study compares adults with and without attention deficit hyperactivity disorder (ADHD) on measures of direct and displaced aggression and illicit drug use. Three hundred ninety-six adults were administered the Wender Utah Rating Scale, the Risk Behavior Assessment, the Aggression Questionnaire (AQ), and the Displaced Aggression Questionnaire (DAQ). Those with ADHD were higher on all scales of the AQ and DAQ, were younger at first use of amphetamines, and were more likely to have ever used crack and amphetamines. A Structural Equation Model found a significant interaction in that for those with medium and high levels of verbal aggression, ADHD predicts crack and amphetamine. Follow-up logistic regression models suggest that blacks self-medicate with crack and whites and Hispanics self-medicate with amphetamine when they have ADHD and verbal aggression.

Amphetamine-induced incentive sensitization of sign-tracking behavior in adolescent and adult female rats

PubMed Central

Doremus-Fitzwater, Tamara L.; Spear, Linda P.

2010-01-01

Age-specific behavioral and neural characteristics may predispose adolescents to initiate and escalate use of alcohol and drugs. Adolescents may avidly seek novel experiences, including drugs of abuse, because of enhanced incentive motivation for drugs and natural rewards, perhaps especially when that incentive motivation is sensitized by prior drug exposure. Using a Pavlovian conditioned approach (PCA) procedure, sign-tracking (ST) and goal-tracking (GT) behavior was examined in amphetamine-sensitized and control adolescent and adult female Sprague-Dawley rats, with expression of elevated ST behavior used to index enhanced incentive motivation for reward-associated cues. Rats were first exposed to a sensitizing regimen of amphetamine injections (3.0 mg/kg/ml d-amphetamine per day) or given saline (0.9% w/v) once daily for 4 days. Expression of ST and GT was then examined over 8 days of PCA training consisting of 25 pairings of an 8-sec presentation of an illuminated lever immediately followed by response-independent delivery of a banana-flavored food pellet. Results showed that adults clearly displayed more ST behavior than adolescents, reflected via both more contacts with, and shorter latencies to approach, the lever. Prior amphetamine sensitization increased ST (but not GT) behaviors regardless of age. Thus, when indexed via ST, incentive motivation was found to be greater in adults than adolescents, with a prior history of amphetamine exposure generally sensitizing incentive motivation for cues predicting a food reward regardless of age. PMID:21534648

Altered visual perception in long-term ecstasy (MDMA) users.

PubMed

White, Claire; Brown, John; Edwards, Mark

2013-09-01

The present study investigated the long-term consequences of ecstasy use on visual processes thought to reflect serotonergic functions in the occipital lobe. Evidence indicates that the main psychoactive ingredient in ecstasy (methylendioxymethamphetamine) causes long-term changes to the serotonin system in human users. Previous research has found that amphetamine-abstinent ecstasy users have disrupted visual processing in the occipital lobe which relies on serotonin, with researchers concluding that ecstasy broadens orientation tuning bandwidths. However, other processes may have accounted for these results. The aim of the present research was to determine if amphetamine-abstinent ecstasy users have changes in occipital lobe functioning, as revealed by two studies: a masking study that directly measured the width of orientation tuning bandwidths and a contour integration task that measured the strength of long-range connections in the visual cortex of drug users compared to controls. Participants were compared on the width of orientation tuning bandwidths (26 controls, 12 ecstasy users, 10 ecstasy + amphetamine users) and the strength of long-range connections (38 controls, 15 ecstasy user, 12 ecstasy + amphetamine users) in the occipital lobe. Amphetamine-abstinent ecstasy users had significantly broader orientation tuning bandwidths than controls and significantly lower contour detection thresholds (CDTs), indicating worse performance on the task, than both controls and ecstasy + amphetamine users. These results extend on previous research, which is consistent with the proposal that ecstasy may damage the serotonin system, resulting in behavioral changes on tests of visual perception processes which are thought to reflect serotonergic functions in the occipital lobe.

Memory-related hippocampal functioning in ecstasy and amphetamine users: a prospective fMRI study.

PubMed

Becker, Benjamin; Wagner, Daniel; Koester, Philip; Bender, Katja; Kabbasch, Christoph; Gouzoulis-Mayfrank, Euphrosyne; Daumann, Jörg

2013-02-01

Recreational use of ecstasy (3,4-methylenedioxymethamphetamine [MDMA]) has been associated with memory impairments. Functional neuroimaging studies with cross-sectional designs reported altered memory-related hippocampal functioning in ecstasy-polydrug users. However, differences might be pre-existing or related to the concomitant use of amphetamine. To prospectively investigate the specific effects of ecstasy on memory-related hippocampal functioning. We used an associative memory task and functional magnetic resonance imaging (fMRI) in 40 ecstasy and/or amphetamine users at baseline (t1) and after 12 months (t2). At t1, all subjects had very limited amphetamine and/or ecstasy experience (less than 5 units lifetime dose). Based on the reported drug use at t2, subjects with continued ecstasy and/or amphetamine use (n = 17) were compared to subjects who stopped use after t1 (n = 12). Analysis of repeated measures revealed that encoding-related activity in the left parahippocampal gyrus changed differentially between the groups. Activity in this region increased in abstinent subjects from t1 to t2, however, decreased in subjects with continued use. Decreases within the left parahippocampal gyrus were associated with the use of ecstasy, but not amphetamine, during the follow-up period. However, there were no significant differences in memory performance. The current findings suggest specific effects of ecstasy use on memory-related hippocampal functioning. However, alternative explanations such as (sub-)acute cannabis effects are conceivable.

Influence of N-alkylation on organ distribution of radioiodinated amphetamines

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

Machulla, H.J.; Schmidt, U.; Mehdorn, H.M.

1985-05-01

In spite of numerous animal data and the widespread clinical application of p-(I-123)-N-isopropyl-amphetamine, questions remain open about the role of N-alkylation. Therefore, amphetamine (AP), N-methyl- (MeAP), and N-isopropyl-amphetamine (IsAP) were radioiodinated in the para position and the organ distribution was determined in male mice (Freiburg tribe) 10 weeks of age. In the lungs, all derivatives showed principally the same kinetics. In brain, the maximum uptake was reached after 30 min with 12%/g for AP and MeAP, and 10.5%/g for IsAP. In liver, the radioactivity similarly increased during the first 15 min to approx. 12%/g; afterwards, AP clearly decreased but MeAPmore » remained almost constant up to 120 min and, even more, IsAP increased to a maximum of 18%/g at 30 min. The same brain uptake kinetics for all 3 substances exclude the importance of lipophilicity increased by the N-alkylation. Furthermore, the differences in the liver kinetics of AP and both MeAP and IsAP indicate the importance of liver metabolism on the alkylated amphetamines. The results support the hypothesis that the first important metabolite of the N-alkylated derivatives is the amphetamine which accumulates in the brain as do MeAP and IsAP. On the basis of these findings, AP was applied clinically showing the same efficient brain uptake and distribution in SPECT as IsAP.« less

Khat use and appetite: an overview and comparison of amphetamine, khat and cathinone.

PubMed

Lemieux, Andrine M; Li, Bingshuo; al'Absi, Mustafa

2015-02-03

To understand the role of khat (Catha edulis) use on the aberrations in appetite and weight which are common comorbidities for khat and other amphetamine users. We provide a comprehensive overview and conceptual summary of the historical cultural use of khat as a natural stimulant and describe the similarities and differences between cathinone (the main psychoactive constituent of khat) and amphetamine highlighting the limited literature on the neurophysiology of appetite and subsequent weight effects of khat. Animal and some human studies indicate that khat produces appetite suppression, although little is known about mechanisms of this effect. Both direct and indirect effects of khat stem from multiple factors including behavioral, chemical and neurophysiological effects on appetite and metabolism. Classic and newly identified appetite hormones have not been explored sufficiently in the study of appetite and khat use. Unique methodological challenges and opportunities are encountered when examining effects of khat and cathinone including khat-specific medical comorbidities, unique route of administration, differential patterns of behavioral effects relative to amphetamines and the nascent state of our understanding of the neurobiology of this drug. A considerable amount of work remains in the study of the appetite effects of khat chewing and outline a program of research that could inform our understanding of this natural amphetamine׳s appetite effects and help prepare health care workers for the unique health effects of this drug. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Neural activation to monetary reward is associated with amphetamine reward sensitivity.

PubMed

Crane, Natania A; Gorka, Stephanie M; Weafer, Jessica; Langenecker, Scott A; de Wit, Harriet; Phan, K Luan

2018-03-14

One known risk factor for drug use and abuse is sensitivity to rewarding effects of drugs. It is not known whether this risk factor extends to sensitivity to non-drug rewards. In this study with healthy young adults, we examined the association between sensitivity to the subjective rewarding effects of amphetamine and a neural indicator of anticipation of monetary reward. We hypothesized that greater euphorigenic response to amphetamine would be associated with greater neural activation to anticipation of monetary reward (Win > Loss). Healthy participants (N = 61) completed four laboratory sessions in which they received d-amphetamine (20 mg) and placebo in alternating order, providing self-report measures of euphoria and stimulation at regular intervals. At a separate visit 1-3 weeks later, participants completed the guessing reward task (GRT) during fMRI in a drug-free state. Participants reporting greater euphoria after amphetamine also exhibited greater neural activation during monetary reward anticipation in mesolimbic reward regions, including the bilateral caudate and putamen. This is the first study to show a relationship between neural correlates of monetary reward and sensitivity to the subjective rewarding effects of amphetamine in humans. These findings support growing evidence that sensitivity to reward in general is a risk factor for drug use and abuse, and suggest that sensitivity of drug-induced euphoria may reflect a general sensitivity to rewards. This may be an index of vulnerability for drug use or abuse.

Accelerated habit formation following amphetamine exposure is reversed by D1, but enhanced by D2, receptor antagonists

PubMed Central

Nelson, Andrew J. D.; Killcross, Simon

2013-01-01

Repeated exposure to the psychostimulant amphetamine has been shown to disrupt goal-directed instrumental actions and promote the early and abnormal development of goal-insensitive habitual responding (Nelson and Killcross, 2006). To investigate the neuropharmacological specificity of this effect as well as restore goal-directed responding in animals with pre-training amphetamine exposure, animals were treated with the non-selective dopamine antagonist α-flupenthixol, the selective D1 antagonist SCH 23390 or the selective D2 antagonist eticlopride, prior to instrumental training (three sessions). Subsequently, the reinforcer was paired with LiCL-induced gastric-malaise and animals were given a test of goal-sensitivity both in extinction and reacquisition. The effect of these dopaminergic antagonists on the sensitivity of lever press performance to outcome devaluation was assessed in animals with pre-training exposure to amphetamine (Experiments 1A–C) or in non-sensitized animals (Experiment 2). Both α-flupenthixol and SCH23390 reversed accelerated habit formation following amphetamine sensitization. However, eticlopride appeared to enhance this effect and render instrumental performance compulsive as these animals were unable to inhibit responding both in extinction and reacquisition, even though a consumption test confirmed they had acquired an aversion to the reinforcer. These findings demonstrate that amphetamine induced-disruption of goal-directed behavior is mediated by activity at distinct dopamine receptor subtypes and may represent a putative model of the neurochemical processes involved in the loss of voluntary control over behavior. PMID:23720609

Changes in patterns of injecting drug use in Hungary: a shift to synthetic cathinones.

PubMed

Péterfi, Anna; Tarján, Anna; Horváth, Gergely Csaba; Csesztregi, Tamás; Nyírády, Adrienn

2014-01-01

The spread of synthetic cathinone injecting is a new phenomenon observed in recent years in Hungary. Until 2010, when the first anecdotal reports on cathinone injecting appeared, injecting was associated with the use of heroin and amphetamine. In this paper we review available evidence of the changes in the drug market and a concurrent shift in patterns of injecting drug use that have been taking place in Hungary since 2010. Remarkable changes have been observed in police seizures data since 2010. While new psychoactive substances have appeared, the availability of heroin has dropped significantly. A qualitative study in 2011 revealed that these market changes correlate with changes in patterns of injecting drug use: decreasing heroin use and the appearance of mephedrone injecting were reported by treatment and needle and syringe programme (NSP) personnel. These changes are detectable in other routine epidemiological data collection systems in the following years as well (i.e. treatment, drug-related deaths, NSP clientele). Heroin-related treatment demand dropped, as did heroin-related mortality. Parallel to this, a growing number of clients appeared in treatment and in NSPs who were primarily injecting cathinones. The shift to cathinones can be observed in amphetamine and heroin injectors as well. Monitoring changes in patterns of injecting drug use are especially important because of the vulnerability of this drug-user population and the consequences of this high-risk route of drug administration. The realignment observed in Hungary is to be further investigated with regard to its determinants, changes in risk behaviour, and in treatment needs. Copyright © 2014 John Wiley & Sons, Ltd.

Molecularly imprinted polymer-sol-gel tablet toward micro-solid phase extraction: II. Determination of amphetamine in human urine samples by liquid chromatography-tandem mass spectrometry.

PubMed

El-Beqqali, Aziza; Andersson, Lars I; Jeppsson, Amin Dadoun; Abdel-Rehim, Mohamed

2017-09-15

Amphetamine selective molecularly imprinted sol-gel polymer tablets, MIP-tablets, for solid-phase microextraction of biofluid samples were prepared. An acetonitrile solution of deuterated amphetamine template and silane precursor, 3-(propylmethacrylate) trimethoxysilane, was soaked into the pores of polyethylene tablet substrates and polymerized by an acid-catalysed sol-gel process. Application of the resultant MIP-tablets to extract amphetamine from human urine samples followed by LC-MS/MS analysis was investigated. The extraction protocol was optimised with respect to pH of sample, addition of sodium chloride, extraction time, desorption solvent and desorption time. The final analysis method determined amphetamine in human urine with a limit of detection (LOD) of 1.0ng/mL and a lower limit of quantification (LLOQ) of 5ng/mL. Validation demonstrated accuracy of the method was 91.0-104.0% and inter-assay precision was 4.8-8.5% (RSD). Extraction recovery was 80%. The MIP-tablets could be re-used and the same tablet could be employed for more than twenty extractions. Copyright © 2017 Elsevier B.V. All rights reserved.

Effect of di-amphetamine injected into N. Accumbens on ethanol self-administration in the rat

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

Samson, H.H.; Tolliver, G.A.; Haraguchi, M.

1991-03-11

Adult, male Long-Evans rats were initiated to lever press with 10% (v/v) ethanol reinforcement using the sucrose-fading technique. Following initiation and the development of stable ethanol self-administration behavior, bilateral cannula guides directed at the N.Accumbens were surgically implanted. Following recovery, the animals received microinjections once a week of either saline, 4, 10 or 20 ug/brain of dl-amphetamine sulfate dissolved in saline. Injections were 10 minutes prior to the daily 30min ethanol self-administration session.; At all doses tested, amphetamine had no significant effect upon the number of responses or ethanol. Reinforcements received during the session. However, a clear alteration in themore » pattern of responding was found at the 10 and 20 ug dose, with some animals showing effects at 4 ug. This alteration in response pattern with no effect upon total responding is different from prior work using systemic amphetamine injections, where both pattern and number of responses were affected. The data suggest that some but not all of the systemic effects could be related to amphetamine's actions on the N. Accumbens.« less

[Identification of Methamphetamine Abuse and Selegiline Use： Chiral Analysis of Methamphetamine and Amphetamine in Urine].

PubMed

Xiang, P; Bu, J; Qiao, Z; Zhuo, X Y; Wu, H J; Shen, M

2017-12-01

To study the content variation of selegiline and its metabolites in urine, and based on actual cases, to explore the feasibility for the identification of methamphetamine abuse and selegiline use by chiral analysis. The urine samples were tested by chiral separation and LC-MS/MS method using CHIROBIOTIC™ V2 chiral liquid chromatography column. The chiral analysis of methamphetamine and amphetamine were performed on the urine samples from volunteers of selegiline use and drug addicts whom suspected taking selegiline. After 5 mg oral administration, the positive test time of selegiline in urine was less than 7 h. The mass concentrations of R（-）-methamphetamine and R（-）-amphetamine in urine peaked at 7 h which were 0.86 μg/mL and 0.18 μg/mL and couldn't be detected after 80 h and 168 h, respectively. The sources of methamphetamine and amphetamine in the urine from the drug addicts whom suspected taking selegiline were analysed successfully by present method. The chiral analysis of methamphetamine and amphetamine, and the determination of selegiline's metabolites can be used to distinguish methamphetamine abuse from selegiline use. Copyright© by the Editorial Department of Journal of Forensic Medicine

Effects of cat exposure and cat odors on subsequent amphetamine-induced stereotypy.

PubMed

Williams, J L; Barber, R G

1990-06-01

The effect of exposure to a cat, as a predatory stressor, was examined in male and female rats during subsequent tests of amphetamine-induced stereotypy in which cat odors were present or absent. Rats in Group C/O were given a 15-min exposure session to a male cat while they were protected in a wire cage. They were then given an IP injection of d-amphetamine (1 mg/kg) and tested 30 min later for stereotypy in the presence of cat odors (soiled cat litter). Rats in Group NC/O were given a no-cat-exposure control session, and amphetamine tested with cat odors. Groups C/NO and NC/NO were both tested without cat odors (fresh litter), with the former group having been previously exposed to a cat. During the 90-min test sessions, female rats showed significantly more stereotypy than males. More importantly, the male subjects in group C/O exhibited significantly more stereotypy than the males in the other groups, and group NC/NO males showed the least amount of stereotypy. These findings clearly indicate that amphetamine reactivity is influenced by prior exposure to a predator, the presence of predatory odors during testing, and the subject's sex.

Neurotoxicity of drugs of abuse - the case of methylenedioxy amphetamines (MDMA, ecstasy ), and amphetamines

PubMed Central

Gouzoulis-Mayfrank, Euphrosyne; Daumann, Joerg

2009-01-01

Ecstasy (MDMA, 3,4-methylendioxymethamphetamine) and the stimulants methamphetamine (METH, speed) and amphetamine are popular drugs among young people, particularly in the dance scene. When given in high doses both MDMA and the stimulant amphetamines are clearly neurotoxic in laboratory animals. MDMA causes selective and persistent lesions of central serotonergic nerve terminals, whereas amphetamines damage both the serotonergic and dopaminergic systems. In recent years, the question of ecstasy-induced neurotoxicity and possible functional sequelae has been addressed in several studies in drug users. Despite large methodological problems, the bulk of evidence suggests residual alterations of serotonergic transmission in MDMA users, although at least partial recovery may occur after long-term abstinence. However, functional sequelae may persist even after longer periods of abstinence. To date, the most consistent findings associate subtle cognitive impairments with ecstasy use, particularly with memory. In contrast, studies on possible long-term neurotoxic effects of stimulant use have been relatively scarce. Preliminary evidence suggests that alterations of the dopaminergic system may persist even after years of abstinence from METH, and may be associated with deficits in motor and cognitive performance. In this paper, we will review the literature focusing on human studies. PMID:19877498

ANN expert system screening for illicit amphetamines using molecular descriptors

NASA Astrophysics Data System (ADS)

Gosav, S.; Praisler, M.; Dorohoi, D. O.

2007-05-01

The goal of this study was to develop and an artificial neural network (ANN) based on computed descriptors, which would be able to classify the molecular structures of potential illicit amphetamines and to derive their biological activity according to the similarity of their molecular structure with amphetamines of known toxicity. The system is necessary for testing new molecular structures for epidemiological, clinical, and forensic purposes. It was built using a database formed by 146 compounds representing drugs of abuse (mainly central stimulants, hallucinogens, sympathomimetic amines, narcotics and other potent analgesics), precursors, or derivatized counterparts. Their molecular structures were characterized by computing three types of descriptors: 38 constitutional descriptors (CDs), 69 topological descriptors (TDs) and 160 3D-MoRSE descriptors (3DDs). An ANN system was built for each category of variables. All three networks (CD-NN, TD-NN and 3DD-NN) were trained to distinguish between stimulant amphetamines, hallucinogenic amphetamines, and nonamphetamines. A selection of variables was performed when necessary. The efficiency with which each network identifies the class identity of an unknown sample was evaluated by calculating several figures of merit. The results of the comparative analysis are presented.

Individual differences in drug abuse vulnerability: d-amphetamine and sensation-seeking status.

PubMed

Kelly, Thomas H; Robbins, Glenn; Martin, Catherine A; Fillmore, Mark T; Lane, Scott D; Harrington, Nancy G; Rush, Craig R

2006-11-01

While the personality dimensions of novelty seeking and sensation seeking are associated with drug abuse vulnerability, the mechanisms associated with this vulnerability remain obscure. This study examined the behavioral effects of d-amphetamine in healthy volunteers scoring in the upper and lower quartiles based on age- and gender-adjusted population norms on the impulsive Sensation-Seeking Scale (SSS) of the Zuckerman-Kuhlman personality questionnaire (ZKPQ). Participants completed 7-day outpatient studies examining the subjective, performance, and cardiovascular effects of d-amphetamine (0, 7.5, and 15 mg/70 kg, p.o.) under double-blind conditions according to a randomized block design. Performance tasks included behavioral measures of impulsivity, including attention, inhibition, and risk-taking behavior. No differences in baseline performance or d-amphetamine effects on measures of attention, inhibition, and risk-taking behavior were observed. High impulsive sensation seekers reported greater increases on several subjective report measures associated with drug abuse potential, including visual analog scales feel drug, like drug, and high. Healthy adults scoring in the top quartile on the population of the impulsive SSS of the ZKPQ may be vulnerable to the abuse potential of d-amphetamine.

Acute mutism: a useful lesson.

PubMed

Maguire, Melissa; Seidi, Osheik; Baker, Mark; Gupta, Arun; Muwanga, Cyrus

2011-01-01

Broca's aphasia may manifest as mutism in some patients. Mutism may be misinterpreted as part of a depressive illness in patients with a psychiatric history. We report on a patient presenting with acute mutism who had a history of amphetamine and cannabis abuse and was later found to have sustained an infarct of the dorsolateral frontal cortex. Recognition of this mode of presentation will aid early diagnosis and treatment.

The Clinical Pharmacokinetics of Amphetamines Utilized in the Treatment of Attention-Deficit/Hyperactivity Disorder.

PubMed

Markowitz, John S; Patrick, Kennerly S

2017-10-01

Amphetamine (AMP), an indirectly acting psychostimulant approved for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children, adolescents, and adults, is among the most long-standing therapeutic agents in all of clinical psychopharmacology. This review focuses on AMP absorption, metabolism, and elimination brought to bear on comparative pharmacokinetics in its various formulations. A comprehensive search of the published literature was conducted using MEDLINE (PubMed) and Google Scholar databases through April 2017 to retrieve all pertinent in vitro and human studies for review and synthesis. Additionally, Food and Drug Administration (FDA) databases were accessed for otherwise unavailable data when possible. Initially available as racemic (dl)-AMP, this drug was later supplanted by enantiopure (d)-AMPH or enantioenriched (75:25 dl)-AMP formulations; although racemic AMP returned as an approved drug to treat ADHD in 2014. Presently, there are several immediate-release (IR) formulations available, including d-AMP, dl-AMP, and mixed amphetamine salts, which are neither racemic nor the pure d-enantiomer (i.e., a 3:1 mixture of d-AMP and l-AMP). Furthermore, new modified-release AMP formulations, including an oral suspension and an orally disintegrating tablet, are now available. A lysine-bonded prodrug form of d-AMP also serves as a treatment option. Oral AMP is rapidly absorbed, with high absolute bioavailability, followed by extensive metabolism involving multiple enzymes. Some metabolic pathways exhibit stereoselective biotransformations favoring the l-isomer substrate. Drug exposure exhibits dose-proportional pharmacokinetics. Body weight is a fundamental determinant of differences in observed AMP plasma concentrations. IR formulations typically provide a T max from 2 to 3 hours. In replicated studies, children exhibit a shorter plasma T 1/2 (∼7 hours) relative to adults (∼10 to 12 hours). There are few documented pharmacokinetic drug interactions of clinical significance beyond influences of drug-induced alteration of urinary pH. The array of AMP formulations addressed in this review offer flexibility in dosing, drug onset, and offset to assist in individualized pharmacotherapy of ADHD.

Amphetamine-associated ischemic stroke: clinical presentation and proposed pathogenesis.

PubMed

De Silva, Deidre Anne; Wong, Meng Cheong; Lee, Moi Pin; Chen, Christopher Li-Hsian; Chang, Hui Meng

2007-01-01

We report a young lady with acute left middle cerebral artery infarction after acute intake of amphetamine. This is the first case report of amphetamine-induced ischemic stroke with serial angiography and transcranial color-coded Doppler studies. The temporal sequence of stenosis of at least 3 weeks with subsequent complete resolution by 3 months and a "beaded" appearance on angiography support vasculitis or vasospasm as the pathogenesis of ischemic stroke in this patient. The presence of microembolic signals supports acute thrombosis at the site of vasculitis/vasospasm with distal embolism.

Genes and pathways co-associated with the exposure to multiple drugs of abuse, including alcohol, amphetamine/methamphetamine, cocaine, marijuana, morphine, and/or nicotine: a review of proteomics analyses.

PubMed

Wang, Ju; Yuan, Wenji; Li, Ming D

2011-12-01

Drug addiction is a chronic neuronal disease. In recent years, proteomics technology has been widely used to assess the protein expression in the brain tissues of both animals and humans exposed to addictive drugs. Through this approach, a large number of proteins potentially involved in the etiology of drug addictions have been identified, which provide a valuable resource to study protein function, biochemical pathways, and networks related to the molecular mechanisms underlying drug dependence. In this article, we summarize the recent application of proteomics to profiling protein expression patterns in animal or human brain tissues after the administration of alcohol, amphetamine/methamphetamine, cocaine, marijuana, morphine/heroin/butorphanol, or nicotine. From available reports, we compiled a list of 497 proteins associated with exposure to one or more addictive drugs, with 160 being related to exposure to at least two abused drugs. A number of biochemical pathways and biological processes appear to be enriched among these proteins, including synaptic transmission and signaling pathways related to neuronal functions. The data included in this work provide a summary and extension of the proteomics studies on drug addiction. Furthermore, the proteins and biological processes highlighted here may provide valuable insight into the cellular activities and biological processes in neurons in the development of drug addiction.

Chronic variable stress and intravenous methamphetamine self-administration – role of individual differences in behavioral and physiological reactivity to novelty

PubMed Central

Taylor, S.B.; Watterson, L.R.; Kufahl, P.R.; Nemirovsky, N.E.; Tomek, S.E.; Conrad, C.D.; Olive, M.F.

2016-01-01

Stress is a contributing factor to the development and maintenance of addiction in humans. However, few studies have shown that stress potentiates the rewarding and/or reinforcing effects of methamphetamine in rodent models of addiction. The present study assessed the effects of exposure to 14 days of chronic variable stress (CVS), or no stress as a control (CON), on the rewarding and reinforcing effects of methamphetamine in adult rats using the conditioned place preference (Experiment 1) and intravenous self-administration (Experiment 2) paradigms. In Experiment 2, we also assessed individual differences in open field locomotor activity, anxiety-like behavior in the elevated plus maze (EPM), and physiological responses to a novel environment as possible predictors of methamphetamine intake patterns. Exposure to CVS for 14 days did not affect overall measures of methamphetamine conditioned reward or reinforcement. However, analyses of individual differences and direct vs. indirect effects revealed that rats exhibiting high physiological reactivity and locomotor activity in the EPM and open field tests self-administered more methamphetamine and reached higher breakpoints for drug reinforcement than rats exhibiting low reactivity. In addition, CVS exposure significantly increased the proportion of rats that exhibited high reactivity, and high reactivity was significantly correlated with increased levels of methamphetamine intake. These findings suggest that individual differences in physiological and locomotor reactivity to novel environments, as well as their interactions with stress history, predict patterns of drug intake in rodent models of methamphetamine addiction. Such predictors may eventually inform future strategies for implementing individualized treatment strategies for amphetamine use disorders. PMID:27163191

Methamphetamine and amphetamine isomer concentrations in human urine following controlled Vicks VapoInhaler administration.

PubMed

Smith, Michael L; Nichols, Daniel C; Underwood, Paula; Fuller, Zachary; Moser, Matthew A; Flegel, Ron; Gorelick, David A; Newmeyer, Matthew N; Concheiro, Marta; Huestis, Marilyn A

2014-10-01

Legitimate use of legal intranasal decongestants containing l-methamphetamine may complicate interpretation of urine drug tests positive for amphetamines. Our study hypotheses were that commonly used immunoassays would produce no false-positive results and a recently developed enantiomer-specific gas chromatography-mass spectrometry (GC-MS) procedure would find no d-amphetamine or d-methamphetamine in urine following controlled Vicks VapoInhaler administration at manufacturer's recommended doses. To evaluate these hypotheses, 22 healthy adults were each administered one dose (two inhalations in each nostril) of a Vicks VapoInhaler every 2 h for 10 h on Day 1 (six doses), followed by a single dose on Day 2. Every urine specimen was collected as an individual void for 32 h after the first dose and assayed for d- and l-amphetamines specific isomers with a GC-MS method with >99% purity of R-(-)-α-methoxy-α-(trifluoromethyl)phenylacetyl derivatives and 10 µg/L lower limits of quantification. No d-methamphetamine or d-amphetamine was detected in any urine specimen by GC-MS. The median l-methamphetamine maximum concentration was 62.8 µg/L (range: 11.0-1,440). Only two subjects had detectable l-amphetamine, with maximum concentrations coinciding with l-methamphetamine peak levels, and always ≤ 4% of the parent's maximum. Three commercial immunoassays for amphetamines EMIT(®) II Plus, KIMS(®) II and DRI(®) had sensitivities, specificities and efficiencies of 100, 97.8, 97.8; 100, 99.6, 99.6 and 100, 100, 100%, respectively. The immunoassays had high efficiencies, but our first hypothesis was not affirmed. The EMIT(®) II Plus assay produced 2.2% false-positive results, requiring an enantiomer-specific confirmation. Published by Oxford University Press 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Psychostimulant Effect of the Synthetic Cannabinoid JWH-018 and AKB48: Behavioral, Neurochemical, and Dopamine Transporter Scan Imaging Studies in Mice

PubMed Central

Ossato, Andrea; Uccelli, Licia; Bilel, Sabrine; Canazza, Isabella; Di Domenico, Giovanni; Pasquali, Micol; Pupillo, Gaia; De Luca, Maria Antonietta; Boschi, Alessandra; Vincenzi, Fabrizio; Rimondo, Claudia; Beggiato, Sarah; Ferraro, Luca; Varani, Katia; Borea, Pier Andrea; Serpelloni, Giovanni; De-Giorgio, Fabio; Marti, Matteo

2017-01-01

JWH-018 and AKB48 are two synthetic cannabinoids (SCBs) belonging to different structural classes and illegally marketed as incense, herbal preparations, or chemical supply for theirs psychoactive cannabis-like effects. Clinical reports from emergency room reported psychomotor agitation as one of the most frequent effects in people assuming SCBs. This study aimed to investigate the psychostimulant properties of JWH-018 and AKB48 in male CD-1 mice and to compare their behavioral and biochemical effects with those caused by cocaine and amphetamine. In vivo studies showed that JWH-018 and AKB48, as cocaine and amphetamine, facilitated spontaneous locomotion in mice. These effects were prevented by CB1 receptor blockade and dopamine (DA) D1/5 and D2/3 receptors inhibition. SPECT-CT studies on dopamine transporter (DAT) revealed that, as cocaine and amphetamine, JWH-018 and AKB48 decreased the [123I]-FP-CIT binding in the mouse striatum. Conversely, in vitro competition binding studies revealed that, unlike cocaine and amphetamine, JWH-018 and AKB48 did not bind to mouse or human DAT. Moreover, microdialysis studies showed that the systemic administration of JWH-018, AKB48, cocaine, and amphetamine stimulated DA release in the nucleus accumbens (NAc) shell of freely moving mice. Finally, unlike amphetamine and cocaine, JWH-018 and AKB48 did not induce any changes on spontaneous [3H]-DA efflux from murine striatal synaptosomes. The present results suggest that SCBs facilitate striatal DA release possibly with different mechanisms than cocaine and amphetamine. Furthermore, they demonstrate, for the first time, that JWH-018 and AKB48 induce a psychostimulant effect in mice possibly by increasing NAc DA release. These data, according to clinical reports, outline the potential psychostimulant action of SCBs highlighting their possible danger to human health. PMID:28824464

Psychostimulant Effect of the Synthetic Cannabinoid JWH-018 and AKB48: Behavioral, Neurochemical, and Dopamine Transporter Scan Imaging Studies in Mice.

PubMed

Ossato, Andrea; Uccelli, Licia; Bilel, Sabrine; Canazza, Isabella; Di Domenico, Giovanni; Pasquali, Micol; Pupillo, Gaia; De Luca, Maria Antonietta; Boschi, Alessandra; Vincenzi, Fabrizio; Rimondo, Claudia; Beggiato, Sarah; Ferraro, Luca; Varani, Katia; Borea, Pier Andrea; Serpelloni, Giovanni; De-Giorgio, Fabio; Marti, Matteo

2017-01-01

JWH-018 and AKB48 are two synthetic cannabinoids (SCBs) belonging to different structural classes and illegally marketed as incense, herbal preparations, or chemical supply for theirs psychoactive cannabis-like effects. Clinical reports from emergency room reported psychomotor agitation as one of the most frequent effects in people assuming SCBs. This study aimed to investigate the psychostimulant properties of JWH-018 and AKB48 in male CD-1 mice and to compare their behavioral and biochemical effects with those caused by cocaine and amphetamine. In vivo studies showed that JWH-018 and AKB48, as cocaine and amphetamine, facilitated spontaneous locomotion in mice. These effects were prevented by CB 1 receptor blockade and dopamine (DA) D 1/5 and D 2/3 receptors inhibition. SPECT-CT studies on dopamine transporter (DAT) revealed that, as cocaine and amphetamine, JWH-018 and AKB48 decreased the [ 123 I]-FP-CIT binding in the mouse striatum. Conversely, in vitro competition binding studies revealed that, unlike cocaine and amphetamine, JWH-018 and AKB48 did not bind to mouse or human DAT. Moreover, microdialysis studies showed that the systemic administration of JWH-018, AKB48, cocaine, and amphetamine stimulated DA release in the nucleus accumbens (NAc) shell of freely moving mice. Finally, unlike amphetamine and cocaine, JWH-018 and AKB48 did not induce any changes on spontaneous [ 3 H]-DA efflux from murine striatal synaptosomes. The present results suggest that SCBs facilitate striatal DA release possibly with different mechanisms than cocaine and amphetamine. Furthermore, they demonstrate, for the first time, that JWH-018 and AKB48 induce a psychostimulant effect in mice possibly by increasing NAc DA release. These data, according to clinical reports, outline the potential psychostimulant action of SCBs highlighting their possible danger to human health.

Differential effects of psychomotor stimulants on attentional performance in rats: nicotine, amphetamine, caffeine and methylphenidate.

PubMed

Bizarro, L; Patel, S; Murtagh, C; Stolerman, I P

2004-05-01

Nicotine can improve attentional performance in the rat as assessed by a modified five-choice serial reaction time task (5-CSRTT), but it is not known if the effect is shared with other psychomotor stimulants. This study compared the effects of nicotine, amphetamine, caffeine and methylphenidate on performance in the 5-CSRTT and determined whether presenting stimuli at unpredictable times by using variable inter-trial intervals (ITI) influenced the sensitivity of the task to the drugs. One group of male hooded rats was trained to obtain food reinforcers by nose-poking in response to 1 s light stimuli presented randomly in one of five apertures, with fixed ITI; for a second group of rats, ITI varied randomly (n=12 per group). As observed previously, nicotine (tested in doses of 0.05-0.2 mg/kg) produced dose-related improvements in accuracy, reduced omission errors and response latencies, but increased anticipatory responding. Amphetamine (0.1-0.8 mg/kg) and methylphenidate (2.5-10 mg/kg) increased accuracy and reduced response latency, and decreased anticipatory responding. Caffeine (2.5-20 mg/kg) did not improve performance except at a small dose that decreased omission errors only. Training at different levels of stimulus predictability influenced performance in the undrugged state but had little impact on profiles of responses to the drugs. The findings with methylphenidate support the potential value of the 5-CSRTT for testing drugs that may be useful in the treatment of attention deficit hyperactivity disorder.

Negative modulation of α5 GABAA receptors in rats may partially prevent memory impairment induced by MK-801, but not amphetamine- or MK-801-elicited hyperlocomotion

PubMed Central

Stamenić, Tamara Timić; Joksimović, Srdjan; Biawat, Poonam; Stanković, Tamara; Marković, Bojan; Cook, James M; Savić, Miroslav M

2016-01-01

Reportedly, negative modulation of α5 GABAA receptors may improve cognition in normal and pharmacologically-impaired animals, and such modulation has been proposed as an avenue for treatment of cognitive symptoms in schizophrenia. This study assessed the actions of PWZ-029, administered at doses (2, 5 and 10 mg/kg) at which it reached micromolar concentrations in brain tissue with estimated free concentrations adequate for selective modulation of α5 GABAA receptors, in three cognitive tasks in male Wistar rats acutely treated with the noncompetitive N-methyl-D-aspartate – receptor antagonist, MK-801 (0.1 mg/kg), as well in tests of locomotor activity potentiated by MK-801 (0.2 mg/kg) or amphetamine (0.5 mg/kg). In a hormetic-like manner, only 5 mg/kg PWZ-029 reversed MK-801-induced deficits in novel object recognition test (visual recognition memory), whereas in the Morris water maze, the 2 mg/kg dose of PWZ-029 exerted partial beneficial effects on spatial learning impairment. PWZ-029 did not affect recognition memory deficits in social novelty discrimination procedure. Motor hyperactivity induced with MK-801 or amphetamine was not preventable by PWZ-029. Our results show that certain MK-801-induced memory deficits can be ameliorated by negative modulation of α5 GABAA receptors, and point to the need for further elucidation of their translational relevance to cognitive deterioration in schizophrenia. PMID:26105958

Negative modulation of α₅ GABAA receptors in rats may partially prevent memory impairment induced by MK-801, but not amphetamine- or MK-801-elicited hyperlocomotion.

PubMed

Timić Stamenić, Tamara; Joksimović, Srdjan; Biawat, Poonam; Stanković, Tamara; Marković, Bojan; Cook, James M; Savić, Miroslav M

2015-09-01

Reportedly, negative modulation of α5 GABAA receptors may improve cognition in normal and pharmacologically-impaired animals, and such modulation has been proposed as an avenue for treatment of cognitive symptoms in schizophrenia. This study assessed the actions of PWZ-029, administered at doses (2, 5, and 10 mg/kg) at which it reached micromolar concentrations in brain tissue with estimated free concentrations adequate for selective modulation of α5 GABAA receptors, in three cognitive tasks in male Wistar rats acutely treated with the noncompetitive N-methyl-d-aspartate receptor antagonist, MK-801 (0.1 mg/kg), as well in tests of locomotor activity potentiated by MK-801 (0.2 mg/kg) or amphetamine (0.5 mg/kg). In a hormetic-like manner, only 5 mg/kg PWZ-029 reversed MK-801-induced deficits in novel object recognition test (visual recognition memory), whereas in the Morris water maze, the 2 mg/kg dose of PWZ-029 exerted partial beneficial effects on spatial learning impairment. PWZ-029 did not affect recognition memory deficits in social novelty discrimination procedure. Motor hyperactivity induced with MK-801 or amphetamine was not preventable by PWZ-029. Our results show that certain MK-801-induced memory deficits can be ameliorated by negative modulation of α5 GABAA receptors, and point to the need for further elucidation of their translational relevance to cognitive deterioration in schizophrenia. © The Author(s) 2015.

Automated touch screen device for recording complex rodent behaviors

PubMed Central

Mabrouk, O.S.; Dripps, I.J.; Ramani, S.; Chang, C.; Han, J.L.; Rice, KC; Jutkiewicz, E.M.

2016-01-01

Background Monitoring mouse behavior is a critical step in the development of modern pharmacotherapies. New Method Here we describe the application of a novel method that utilizes a touch display computer (tablet) and software to detect, record, and report fine motor behaviors. A consumer-grade tablet device is placed in the bottom of a specially made acrylic cage allowing the animal to walk on the device (MouseTrapp). We describe its application in open field (for general locomotor studies) which measures step lengths and velocity. The device can perform light-dark (anxiety) tests by illuminating half of the screen and keeping the other half darkened. A divider is built into the lid of the device allowing the animal free access to either side. Results Treating mice with amphetamine and the delta opioid peptide receptor agonist SNC80 stimulated locomotor activity on the device. Amphetamine increased step velocity but not step length during its peak effect (40–70 min after treatment), thus indicating detection of subtle amphetamine-induced effects. Animals showed a preference (74% of time spent) for the darkened half compared to the illuminated side. Comparison with Existing Method Animals were videotaped within the chamber to compare quadrant crosses to detected motion on the device. The slope, duration and magnitude of quadrant crosses tightly correlated with overall locomotor activity as detected by Mousetrapp. Conclusions We suggest that modern touch display devices such as MouseTrapp will be an important step toward automation of behavioral analyses for characterizing phenotypes and drug effects. PMID:24952323

Effects of amphetamine, morphine, and CP 55, 940 on Go/No-Go task performance in rhesus monkeys.

PubMed

Koek, Wouter; Gerak, Lisa R; France, Charles P

2015-08-01

In humans, impulsivity measured as false alarms in a Go/No-Go task is reportedly decreased by amphetamine and is not affected by oxycodone and delta(9)-tetrahydrocannabinol. To model these findings in animals, three rhesus monkeys were trained to perform a food-reinforced Go/No-Go task. In this task, amphetamine was found to decrease false alarms (i.e. responding during No-Go trials), but only at doses that also decreased hits (i.e. responding during Go trials). Morphine generally decreased hits but not false alarms. The cannabinoid receptor agonist CP 55, 940 decreased both false alarms and hits, but only at doses that also decreased the number of trials completed. Additional studies in animals and humans are necessary to delineate the conditions under which amphetamine and other psychoactive drugs affect impulsivity in Go/No-Go tasks.

Prevalence of malnutrition and nutritional risk factors in patients undergoing alcohol and drug treatment.

PubMed

Ross, Lynda J; Wilson, Michael; Banks, Merrilyn; Rezannah, Fiona; Daglish, Mark

2012-07-01

Chronic substance abuse is recognized to affect nutritional status and is associated with nutrient deficiencies and malnutrition. This study aimed to identify the prevalence of malnutrition and nutritional risk factors using a spread of measurements in patients undergoing alcohol and drug treatment. Sixty-seven patients (48 male, 19 female) admitted to a public hospital detoxification unit participated: 49 were alcohol dependent (73%) and the remaining were opiate, benzodiazepine, and/or amphetamine dependent. Nutritional status was assessed by the Subjective Global Assessment. An appetite questionnaire (Simplified Nutritional Appetite Questionnaire), a diet-quality questionnaire (Australian Recommended Food Score), and blood biochemistry and hematologic tests were also applied. The prevalence of mild/moderate malnutrition was 24% according to the Subjective Global Assessment. Weight and body mass index were associated with nutritional status (P < 0.05). Appetite and diet quality were poor overall, with 88% of all participants requiring advice and guidance. Blood markers showed that 50% of all subjects were deficient in iron or vitamins (low vitamin A levels in 21%, low iron levels in 18%, low-range potassium in 12%, and low vitamin C levels in 8%). The prevalence of malnutrition in this patient population is likely to underestimate the prevalence of nutritional risk factors and micronutrient undernutrition. Multiple tools assessing nutritional status, appetite, diet quality, and blood test results have different advantages and can further identify the specific needs and appropriateness of nutritional education in patients during treatment for drug and alcohol use. Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.

Crystal methamphetamine, its analogues, and HIV infection: medical and psychiatric aspects of a new epidemic.

PubMed

Urbina, Antonio; Jones, Kristina

2004-03-15

The use of the recreational drug crystal methamphetamine among younger homosexual men is expanding, and with it, unsafe sex behaviors that increase the transmission of human immunodeficiency virus (HIV). This article reviews available literature on the medical and psychiatric morbidities associated with methamphetamine abuse in HIV-infected patients. Medical complications include hypertension, hyperthermia, rhabdoymyolysis, and stroke. One fatal case of ingestion of methamphetamine with HIV medication has been documented. Two fatal cases of ingestion of HIV medication with the amphetamine analogue n-methyl-3,4 methylenedioxymethamphetamine (MDMA, or "ecstasy") have also been reported. Some molecular researchers suggest that dopaminergic systems are vulnerable to the combined neurotoxicity of HIV infection and methamphetamine. Population surveys indicate high rates of HIV infection among methamphetamine abusers and high rates of unprotected anal intercourse during drug intoxication. Intoxication can sometimes produce paranoia, auditory hallucinations, and, occasionally, violent behavior. Amphetamine withdrawal commonly results in symptoms of depression. Methamphetamine is a new challenge related to treatment and prevention of HIV infection.

Effects of amphetamine on striatal dopamine release, open-field activity, and play in Fischer 344 and Sprague-Dawley rats.

PubMed

Siviy, Stephen M; McDowell, Lana S; Eck, Samantha R; Turano, Alexandra; Akopian, Garnik; Walsh, John P

2015-12-01

Previous work from our laboratories has shown that juvenile Fischer 344 (F344) rats are less playful than other strains and also appear to be compromised in dopamine (DA) functioning. To determine whether the dysfunctional play in this strain is associated with deficits in the handling and delivery of vesicular DA, the following experiments assessed the extent to which F344 rats are differentially sensitive to the effects of amphetamine. When exposed to amphetamine, striatal slices obtained from F344 rats showed a small increase in unstimulated DA release when compared with slices from Sprague-Dawley rats; they also showed a more rapid high K+-mediated release of DA. These data provide tentative support for the hypothesis that F344 rats have a higher concentration of cytoplasmic DA than Sprague-Dawley rats. When rats were tested for activity in an open field, F344 rats presented a pattern of results that was consistent with either an enhanced response to amphetamine (3 mg/kg) or a more rapid release of DA (10 mg/kg). Although there was some indication that amphetamine had a dose-dependent differential effect on play in the two strains, play in F344 rats was not enhanced to any degree by amphetamine. Although these results are not consistent with our working hypothesis that F344 rats are less playful because of a deficit in vesicular release of DA, they still suggest that this strain may be a useful model for better understanding the role of DA in social behavior during the juvenile period.

Screening for and validated quantification of amphetamines and of amphetamine- and piperazine-derived designer drugs in human blood plasma by gas chromatography/mass spectrometry.

PubMed

Peters, Frank T; Schaefer, Simone; Staack, Roland F; Kraemer, Thomas; Maurer, Hans H

2003-06-01

The classical stimulants amphetamine, methamphetamine, ethylamphetamine and the amphetamine-derived designer drugs MDA, MDMA ('ecstasy'), MDEA, BDB and MBDB have been widely abused for a relatively long time. In recent years, a number of newer designer drugs have entered the illicit drug market. 4-Methylthioamphetamine (MTA), p-methoxyamphetamine (PMA) and p-methoxymethamphetamine (PMMA) are also derived from amphetamine. Other designer drugs are derived from piperazine, such as benzylpiperazine (BZP), methylenedioxybenzylpiperazine (MDBP), trifluoromethylphenylpiperazine (TFMPP), m-chlorophenylpiperazine (mCPP) and p-methoxyphenylpiperazine (MeOPP). A number of severe or even fatal intoxications involving these newer substances, especially PMA, have been reported. This paper describes a method for screening for and simultaneous quantification of the above-mentioned compounds and the metabolites p-hydroxyamphetamine and p-hydroxymethamphetamine (pholedrine) in human blood plasma. The analytes were analyzed by gas chromatography/mass spectrometry in the selected-ion monitoring mode after mixed-mode solid-phase extraction (HCX) and derivatization with heptafluorobutyric anhydride. The method was fully validated according to international guidelines. It was linear from 5 to 1000 micro g l(-1) for all analytes. Data for accuracy and precision were within required limits with the exception of those for MDBP. The limit of quantification was 5 micro g l(-1) for all analytes. The applicability of the assay was proven by analysis of authentic plasma samples and of a certified reference sample. This procedure should also be suitable for confirmation of immunoassay results positive for amphetamines and/or designer drugs of the ecstasy type. Copyright 2003 John Wiley & Sons, Ltd.

Effects of prior amphetamine exposure on approach strategy in appetitive Pavlovian conditioning in rats.

PubMed

Simon, Nicholas W; Mendez, Ian A; Setlow, Barry

2009-03-01

Pavlovian conditioning with a discrete reward-predictive visual cue can elicit two classes of behaviors: "sign-tracking" (approach toward and contact with the cue) and "goal-tracking" (approach toward the site of reward delivery). Sign-tracking has been proposed to be linked to behavioral disorders involving compulsive reward-seeking, such as addiction. Prior exposure to psychostimulant drugs of abuse can facilitate reward-seeking behaviors through enhancements in incentive salience attribution. Thus, it was predicted that a sensitizing regimen of amphetamine exposure would increase sign-tracking behavior. The purpose of these experiments was to determine how a regimen of exposure to amphetamine affects subsequent sign-tracking behavior. Male Long-Evans rats were given daily injections of d-amphetamine (2.0 mg/kg) or saline for 5 days, then given a 7-day drug-free period followed by testing in a Pavlovian conditioning task. In experiment 1, rats were presented with a visual cue (simultaneous illumination of a light and extension of a lever) located either to the left or right of a centrally located food trough. One cue (CS+) was always followed by food delivery, whereas the other (CS-) was not. In experiment 2, rats were tested in a nondiscriminative (CS+ only) version of the task. In both experiments, amphetamine-exposed rats showed less sign-tracking and more goal-tracking compared to saline controls. Contrary to predictions, prior amphetamine exposure decreased sign-tracking and increased goal-tracking behavior. However, these results do support the hypothesis that psychostimulant exposure and incentive sensitization enhance behavior directed toward reward-proximal cues at the expense of reward-distal cues.

Long-Term Exposure to Oral Methylphenidate or dl-Amphetamine Mixture in Peri-Adolescent Rhesus Monkeys: Effects on Physiology, Behavior, and Dopamine System Development

PubMed Central

Soto, Paul L; Wilcox, Kristin M; Zhou, Yun; Ator, Nancy A; Riddle, Mark A; Wong, Dean F; Weed, Michael R

2012-01-01

The stimulants methylphenidate and amphetamine are used to treat children with attention deficit/hyperactivity disorder over important developmental periods, prompting concerns regarding possible long-term health impact. This study assessed the effects of such a regimen in male, peri-adolescent rhesus monkeys on a variety of cognitive/behavioral, physiological, and in vivo neurochemical imaging parameters. Twice daily (0900 and 1200 hours), for a total of 18 months, juvenile male monkeys (8 per group) consumed either an unadulterated orange-flavored solution, a methylphenidate solution, or a dl-amphetamine mixture. Doses were titrated to reach blood/plasma levels comparable to therapeutic levels in children. [11C]MPH and [11C]raclopride dynamic PET scans were performed to image dopamine transporter and D2-like receptors, respectively. Binding potential (BPND), an index of tracer-specific binding, and amphetamine-induced changes in BPND of [11C]raclopride were estimated by kinetic modeling. There were no consistent differences among groups on the vast majority of measures, including cognitive (psychomotor speed, timing, inhibitory control, cognitive flexibility), general activity, physiological (body weight, head circumference, crown-to-rump length), and neurochemical (ie, developmental changes in dopamine transporter, dopamine D2 receptor density, and amphetamine-stimulated dopamine release were as expected). Cytogenetic studies indicated that neither drug was a clastogen in rhesus monkeys. Thus, methylphenidate and amphetamine at therapeutic blood/plasma levels during peri-adolescence in non-human primates have little effect on physiological or behavioral/cognitive development. PMID:22805599

Long-term exposure to oral methylphenidate or dl-amphetamine mixture in peri-adolescent rhesus monkeys: effects on physiology, behavior, and dopamine system development.

PubMed

Soto, Paul L; Wilcox, Kristin M; Zhou, Yun; Kumar, Anil; Ator, Nancy A; Riddle, Mark A; Wong, Dean F; Weed, Michael R

2012-11-01

The stimulants methylphenidate and amphetamine are used to treat children with attention deficit/hyperactivity disorder over important developmental periods, prompting concerns regarding possible long-term health impact. This study assessed the effects of such a regimen in male, peri-adolescent rhesus monkeys on a variety of cognitive/behavioral, physiological, and in vivo neurochemical imaging parameters. Twice daily (0900 and 1200 hours), for a total of 18 months, juvenile male monkeys (8 per group) consumed either an unadulterated orange-flavored solution, a methylphenidate solution, or a dl-amphetamine mixture. Doses were titrated to reach blood/plasma levels comparable to therapeutic levels in children. [¹¹C]MPH and [¹¹C]raclopride dynamic PET scans were performed to image dopamine transporter and D₂-like receptors, respectively. Binding potential (BP(ND)), an index of tracer-specific binding, and amphetamine-induced changes in BP(ND) of [¹¹C]raclopride were estimated by kinetic modeling. There were no consistent differences among groups on the vast majority of measures, including cognitive (psychomotor speed, timing, inhibitory control, cognitive flexibility), general activity, physiological (body weight, head circumference, crown-to-rump length), and neurochemical (ie, developmental changes in dopamine transporter, dopamine D₂ receptor density, and amphetamine-stimulated dopamine release were as expected). Cytogenetic studies indicated that neither drug was a clastogen in rhesus monkeys. Thus, methylphenidate and amphetamine at therapeutic blood/plasma levels during peri-adolescence in non-human primates have little effect on physiological or behavioral/cognitive development.

Acute recreational drug toxicity

PubMed Central

Liakoni, Evangelia; Yates, Christopher; Dines, Alison M.; Dargan, Paul I.; Heyerdahl, Fridtjof; Hovda, Knut Erik; Wood, David M.; Eyer, Florian; Liechti, Matthias E.

2018-01-01

Abstract The aim of the study was to compare self-reported and analytically confirmed substance use in cases of acute recreational drug toxicity. We performed a retrospective analysis of emergency department presentations of acute recreational drug toxicity over 2 years (October 2013 to September 2015) within the European Drug Emergencies Network Plus project. Among the 10,956 cases of acute recreational drug toxicity during the study period, 831 could be included. Between the self-reported substance use and the toxicological results, the highest agreement was found for heroin (86.1%) and cocaine (74.1%), whereas inhalants, poppers, and magic mushrooms were self-reported but not analytically detected. Cathinones and other new psychoactive substances (NPS) could be detected using additional analytical methods. Among cases with both immunoassay (IA) and confirmation with mass spectrometry (MS), the results were consistent for methadone (100%) and cocaine (95.5%) and less consistent for amphetamines (81.8%). In cases with a positive IA for amphetamines (n = 54), MS confirmed the presence of 3,4-methylenedioxymethamphetamine (MDMA), amphetamine, methamphetamine, and NPS in 37, 20, 10, and 6 cases, respectively, also revealing use of more than 1 substance in some cases. MS yielded positive results in 21 cases with a negative IA for amphetamines, including amphetamine, MDMA, methamphetamine, and NPS, in 14, 7, 2, and 2 cases, respectively. In conclusion, the highest agreement was found between self-reports and analytical findings for heroin and cocaine. The diagnosis of NPS use was mainly based on self-report. The IAs accurately identified methadone and cocaine, and MS had advantages for the detection of NPS and amphetamine derivatives. PMID:29384873

Using cheminformatics to predict cross reactivity of “designer drugs” to their currently available immunoassays

PubMed Central

2014-01-01

Background A challenge for drug of abuse testing is presented by ‘designer drugs’, compounds typically discovered by modifications of existing clinical drug classes such as amphetamines and cannabinoids. Drug of abuse screening immunoassays directed at amphetamine or methamphetamine only detect a small subset of designer amphetamine-like drugs, and those immunoassays designed for tetrahydrocannabinol metabolites generally do not cross-react with synthetic cannabinoids lacking the classic cannabinoid chemical backbone. This suggests complexity in understanding how to detect and identify whether a patient has taken a molecule of one class or another, impacting clinical care. Methods Cross-reactivity data from immunoassays specifically targeting designer amphetamine-like and synthetic cannabinoid drugs was collected from multiple published sources, and virtual chemical libraries for molecular similarity analysis were built. The virtual library for synthetic cannabinoid analysis contained a total of 169 structures, while the virtual library for amphetamine-type stimulants contained 288 compounds. Two-dimensional (2D) similarity for each test compound was compared to the target molecule of the immunoassay undergoing analysis. Results 2D similarity differentiated between cross-reactive and non-cross-reactive compounds for immunoassays targeting mephedrone/methcathinone, 3,4-methylenedioxypyrovalerone, benzylpiperazine, mephentermine, and synthetic cannabinoids. Conclusions In this study, we applied 2D molecular similarity analysis to the designer amphetamine-type stimulants and synthetic cannabinoids. Similarity calculations can be used to more efficiently decide which drugs and metabolites should be tested in cross-reactivity studies, as well as to design experiments and potentially predict antigens that would lead to immunoassays with cross reactivity for a broader array of designer drugs. PMID:24851137

Blunted Endogenous Opioid Release Following an Oral Amphetamine Challenge in Pathological Gamblers

PubMed Central

Mick, Inge; Myers, Jim; Ramos, Anna C; Stokes, Paul R A; Erritzoe, David; Colasanti, Alessandro; Gunn, Roger N; Rabiner, Eugenii A; Searle, Graham E; Waldman, Adam D; Parkin, Mark C; Brailsford, Alan D; Galduróz, José C F; Bowden-Jones, Henrietta; Clark, Luke; Nutt, David J; Lingford-Hughes, Anne R

2016-01-01

Pathological gambling is a psychiatric disorder and the first recognized behavioral addiction, with similarities to substance use disorders but without the confounding effects of drug-related brain changes. Pathophysiology within the opioid receptor system is increasingly recognized in substance dependence, with higher mu-opioid receptor (MOR) availability reported in alcohol, cocaine and opiate addiction. Impulsivity, a risk factor across the addictions, has also been found to be associated with higher MOR availability. The aim of this study was to characterize baseline MOR availability and endogenous opioid release in pathological gamblers (PG) using [11C]carfentanil PET with an oral amphetamine challenge. Fourteen PG and 15 healthy volunteers (HV) underwent two [11C]carfentanil PET scans, before and after an oral administration of 0.5 mg/kg of d-amphetamine. The change in [11C]carfentanil binding between baseline and post-amphetamine scans (ΔBPND) was assessed in 10 regions of interest (ROI). MOR availability did not differ between PG and HV groups. As seen previously, oral amphetamine challenge led to significant reductions in [11C]carfentanil BPND in 8/10 ROI in HV. PG demonstrated significant blunting of opioid release compared with HV. PG also showed blunted amphetamine-induced euphoria and alertness compared with HV. Exploratory analysis revealed that impulsivity positively correlated with caudate baseline BPND in PG only. This study provides the first evidence of blunted endogenous opioid release in PG. Our findings are consistent with growing evidence that dysregulation of endogenous opioids may have an important role in the pathophysiology of addictions. PMID:26552847

Effect of Varient Dosages of Amphetamine Upon Endurance

ERIC Educational Resources Information Center

Williams, Melvin H.; Thompson, John

1973-01-01

This study sought to provide basic information concerning the acute effects of a small, moderate, and large dose of d-amphetamine sulfate upon muscular endurance; a secondary purpose involved the effect upon submaximal and maximal heart rate. (Author/JA)

A scoping review of home-produced heroin and amphetamine-type stimulant substitutes: implications for prevention, treatment, and policy.

PubMed

Hearne, Evelyn; Grund, Jean-Paul Cornelius; Van Hout, Marie Claire; McVeigh, Jim

2016-04-19

Several home-produced substances such as krokodil and boltushka are prevalent in many Eastern European countries. Anecdotal reports of its use have been circulating in Germany and Norway; however, this has not been confirmed. Its use has also been reported by the media in the USA, although only one confirmed report of its use exists. Home-produced drugs are associated with high levels of morbidity and a number of complex health issues such as the spread of blood borne viruses, gangrene, and internal organ damage. The high incidence of HIV rates amongst people who inject home-produced substances is a public health concern. The resulting physical health consequences of injecting these crude substances are very severe in comparison to heroin or amphetamine acquired in black markets. Due to this fact and the increased mortality associated with these substances, professionals in the area of prevention, treatment, and policy development need to be cognisant of the presentation, harms, and the dangers associated with home-produced substances globally. This scoping review aimed to examine existing literature on the subject of home-produced heroin and amphetamine-type stimulant substitutes. The review discussed the many implications such research may have in the areas of policy and practice. Data were gathered through the use of qualitative secondary resources such as journal articles, reports, reviews, case studies, and media reports. The home production of these substances relies on the utilisation of precursor drugs such as less potent stimulants, tranquillizers, analgesics, and sedatives or natural plant ingredients. The Internet underpins the facilitation of this practice as recipes, and diverted pharmaceutical sales are available widely online, and currently, ease of access to the Internet is evident worldwide. This review highlights the necessity of prevention, education, and also harm reduction related to home-produced drugs and also recommends consistent monitoring of online drug fora, online drug marketplaces, and unregulated pharmacies.

Drugs of abuse and their metabolites in the Ebro River basin: occurrence in sewage and surface water, sewage treatment plants removal efficiency, and collective drug usage estimation.

PubMed

Postigo, Cristina; López de Alda, María José; Barceló, Damià

2010-01-01

Drugs of abuse and their metabolites have been recently recognized as environmental emerging organic contaminants. Assessment of their concentration in different environmental compartments is essential to evaluate their potential ecotoxicological effects. It also constitutes an indirect tool to estimate drug abuse by the population at the community level. The present work reports for the first time the occurrence of drugs of abuse and metabolites residues along the Ebro River basin (NE Spain) and also evaluates the contribution of sewage treatment plants (STPs) effluents to the presence of these chemicals in natural surface waters. Concentrations measured in influent sewage waters were used to back calculate drug usage at the community level in the main urban areas of the investigated river basin. The most ubiquitous and abundant compounds in the studied aqueous matrices were cocaine, benzoylecgonine, ephedrine and ecstasy. Lysergic compounds, heroin, its metabolite 6-monoacetyl morphine, and Delta(9)-tetradhydrocannabinol were the substances less frequently detected. Overall, total levels of the studied illicit drugs and metabolites observed in surface water (in the low ng/L range) were one and two orders of magnitude lower than those determined in effluent (in the ng/L range) and influent sewage water (microg/L range), respectively. The investigated STPs showed overall removal efficiencies between 45 and 95%. Some compounds, such as cocaine and amphetamine, were very efficiently eliminated (>90%) whereas others, such as ecstasy, methamphetamine, nor-LSD, and THC-COOH where occasionally not eliminated at all. Drug consumption estimates pointed out cocaine as the most abused drug, followed by cannabis, amphetamine, heroin, ecstasy and methamphetamine, which slightly differs from national official estimates (cannabis, followed by cocaine, ecstasy, amphetamine and heroin). Extrapolation of the consumption data obtained for the studied area to Spain points out a total annual consumption of drugs of abuse of the order of 36 tonnes, which would translate into 1100million Euros in the black market.

Boltushka: A Homemade Amphetamine-Type Stimulant and HIV Risk in Odessa, Ukraine

PubMed Central

Chintalova-Dallas, Repsina; Case, Patricia; Kitsenko, Nataliya; Lazzarini, Zita

2009-01-01

Background Homemade amphetamine-type stimulants (ATSs) have been reported in Russia and Eastern Europe for decades. Recipes differ geographically and over time producing differing active ingredients. Vint and jeff (active ingredients methamphetamine and methcathinone, respectively) are two such homemade ATSs originally produced from over-the-counter cold medications and household chemicals. Methods During a Rapid Policy Assessment and Responses (RPAR) project in Odessa, Ukraine, researchers found use of boltushka, a novel homemade ATS. Fourteen supplemental qualitative interviews were conducted, including ten interviews with boltushka injectors and four interviews with pharmacists. We report patterns of boltushka use among local injection drug users (IDUs) as well as the role of laws, regulations, and current pharmacy practices. Results Legal restrictions on over-the-counter cold medicines in Ukraine led to products containing phenypropanolamine (PPA), which oxidized with KMnO4 (potassium permanganate), produces a weak ATS, cathinone, called boltushka. Boltushka’s ingredients are easily available in pharmacies or on the black market. IDUs reported a mean age at first use of 16 years old (range 12–21). While published data are scant, anecdotal evidence reported here include amphetamine-like effects on energy and appetite, binging patterns of use, and some reports of shaking and other neurological damage consistent with earlier reports from exposure to KMnO4. Users reported sharing syringes and other non-sterile injection practices. No users reported specific treatment or prevention programs for boltushka users. Conclusions Although Ukrainian government regulations have limited access to precursor chemicals, IDUs have continued to make and use boltushka. The actual extent and demographics of boltushka use are unknown. Besides risk of bloodborne disease, the health effects of injected homemade ATSs and their constituent chemicals are poorly documented. Interventions beyond available harm reduction efforts may be required. Education/treatment specific to boltushka users and screening for other physical harms are critical interventions. PMID:18976896

Ethanol induces rotational behavior in 6-hydroxydopamine lesioned mice

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

Silverman, P.B.

1987-03-09

Mice with unilateal striatal lesions created by 6-hydroxydopamine (6HDA) injection were screened for rotational (circling) behavior in response to injection of amphetamine and apomorphine. Those that rotated ipsilaterally in response to amphetamine and contralaterally in response to apomorphine were subsequently challenged with 1 to 3 g/kg (i.p.) ethanol. Surprisingly, ethanol induced dose related contralateral (apomorphine-like) rotation which, despite gross intoxication, was quite marked in most animals. No significant correlation was found between the number of turns made following ethanol and made after apomorphine or amphetamine. 14 references, 2 figures, 1 table.

Exertional heat stroke induced by amphetamine analogues. Does dantrolene have a place?

PubMed

Watson, J D; Ferguson, C; Hinds, C J; Skinner, R; Coakley, J H

1993-12-01

There are increasing numbers of patients admitted to hospital as a result of ingesting amphetamine-like drugs. The most severe cases exhibit hyperthermia, rhabdomyolysis, coagulopathy and renal failure. We describe six such patients with varying severity of intoxication, and have reviewed the recent literature with particular reference to the use of dantrolene. One of our patients died but the others all survived. There is little evidence that dantrolene influenced the outcome in patients reported to date. We believe that a controlled trial should be carried out in amphetamine-related hyperthermia before the use of dantrolene becomes widespread.

Bupropion interference with immunoassays for amphetamines and LSD.

PubMed

Vidal, Christian; Skripuletz, Thomas

2007-06-01

A 50-year-old male patient suddenly had lost consciousness, although he had previously been healthy. On arrival at hospital seizures arose. The authors investigated a urine sample of the patient, and performed toxicological drug screening with immunochemical Cloned Enzyme Donor Immunoassay (CEDIA) assays. Positive findings for amphetamines and LSD could not be confirmed. Using gas chromatography/mass spectrometry (GC/MS), and liquid chromatography/mass spectrometry (LC/MS), the authors identified bupropion, a drug used to aid in smoking cessation, as the interfering compound, which may cause false-positive results for amphetamines and LSD using the CEDIA assays.

Hospital separations for cannabis- and methamphetamine-related psychotic episodes in Australia.

PubMed

Degenhardt, Louisa; Roxburgh, Amanda; McKetin, Rebecca

2007-04-02

To examine trends in hospital separations related to "drug-induced" psychosis for cannabis and methamphetamine, in the context of patterns of cannabis and methamphetamine use in the Australian population. Analysis of prospectively collected data from the National Hospital Morbidity Database on hospital separations primarily attributed to drug-induced psychosis (July 1993 - June 2004), and specifically for cannabis and amphetamines (1999-2004). Calculation of Australian population-adjusted rates of drug-induced psychosis hospital separations using estimated resident population data from the Australian Bureau of Statistics (at 30 June each year) and data on cannabis and methamphetamine use from the 2004 National Drug Strategy Household Survey. Number of hospital separations due to drug-induced psychosis, and standardised (age-specific) rates per million population and per million users. There have been notable increases in hospital separations due to drug-induced psychosis, which appear to have been driven by amphetamine-related rather than cannabis-related episodes. The rate of hospital separations was higher for amphetamine users than for cannabis users in all age groups, and the rate increased among older amphetamine users. The risk of hospitalisation for a drug-induced psychotic episode associated with amphetamine use appears to be greater than that for cannabis use in all age groups.

The enigma of conditioned taste aversion learning: stimulus properties of 2-phenylethylamine derivatives.

PubMed

Greenshaw, A J; Turrkish, S; Davis, B A

2002-01-01

The functional aversive stimulus properties of several IP doses of (+/-)-amphetamine (1.25-10 mg.kg-1), 2-phenylethylamine (PEA, 2.5-10 mg.kg-1, following inhibition of monoamine oxidase with pargyline 50 mg.kg-1) and phenylethanolamine (6.25-50 mg.kg-1) were measured with the conditioned taste aversion (CTA) paradigm. A two-bottle choice procedure was used, water vs. 0.1 % saccharin with one conditioning trial and three retention trials. (+/-)-Amphetamine and phenylethanolamine induced a significant conditioned taste aversion but PEA did not. (+/-)-Amphetamine and PEA increased spontaneous locomotor activity but phenylethanolamine had no effects on this measure. Measurement of whole brain levels of these drugs revealed that the peak brain elevation of PEA occurred at approximately 10 min whereas the peak elevations of (+/-)-amphetamine and phenylethanolamine occurred at approximately 20 min. The present failure of PEA to elicit conditioned taste aversion learning is consistent with previous reports for this compound. The differential functional aversive stimulus effects of these three compounds are surprising since they exhibit similar discriminative stimulus properties and both (+/-)-amphetamine and PEA are self-administered by laboratory animals. The present data suggest that time to maximal brain concentrations following peripheral injection may be a determinant of the aversive stimulus properties of PEA derivatives.

High-anxiety rats are less sensitive to the rewarding affects of amphetamine on 50kHz USV.

PubMed

Lehner, Małgorzata H; Taracha, Ewa; Kaniuga, Ewelina; Wisłowska-Stanek, Aleksandra; Wróbel, Jacek; Sobolewska, Alicja; Turzyńska, Danuta; Skórzewska, Anna; Płaźnik, Adam

2014-12-15

This study assessed behaviour, as measured by 50kHz calls related to positive affect, in rats with different fear conditioned response strengths: low-anxiety rats (LR) and high-anxiety rats (HR), after amphetamine injection in a two-injection protocol (TIPS). The results showed that the first dose of amphetamine evoked similar behavioural effects in frequency-modulated (FM) 50kHz calls in the LR and HR groups. The second injection of amphetamine resulted in stronger FM 50kHz calls in LR compared with HR rats. The biochemical data ('ex vivo' analysis) showed that the LR rats had increased basal levels of dopamine in the amygdala, and increased homovanilic acid (HVA), dopamine's main metabolite, in the amygdala and prefrontal cortex compared with HR rats. The 'in vivo' analysis (microdialysis study) showed that the LR rats had increased HVA concentrations in the basolateral amygdala in response to an aversively conditioned context. Research has suggested that differences in dopaminergic system activity in the amygdala and prefrontal cortex may be one of the biological factors that underlie individual differences in response to fear stimuli, which may also affect the rewarding effects of amphetamine. Copyright © 2014 Elsevier B.V. All rights reserved.

Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor.

PubMed

Bunzow, J R; Sonders, M S; Arttamangkul, S; Harrison, L M; Zhang, G; Quigley, D I; Darland, T; Suchland, K L; Pasumamula, S; Kennedy, J L; Olson, S B; Magenis, R E; Amara, S G; Grandy, D K

2001-12-01

The trace amine para-tyramine is structurally and functionally related to the amphetamines and the biogenic amine neurotransmitters. It is currently thought that the biological activities elicited by trace amines such as p-tyramine and the psychostimulant amphetamines are manifestations of their ability to inhibit the clearance of extracellular transmitter and/or stimulate the efflux of transmitter from intracellular stores. Here we report the discovery and pharmacological characterization of a rat G protein-coupled receptor that stimulates the production of cAMP when exposed to the trace amines p-tyramine, beta-phenethylamine, tryptamine, and octopamine. An extensive pharmacological survey revealed that psychostimulant and hallucinogenic amphetamines, numerous ergoline derivatives, adrenergic ligands, and 3-methylated metabolites of the catecholamine neurotransmitters are also good agonists at the rat trace amine receptor 1 (rTAR1). These results suggest that the trace amines and catecholamine metabolites may serve as the endogenous ligands of a novel intercellular signaling system found widely throughout the vertebrate brain and periphery. Furthermore, the discovery that amphetamines, including 3,4-methylenedioxymethamphetamine (MDMA; "ecstasy"), are potent rTAR1 agonists suggests that the effects of these widely used drugs may be mediated in part by this receptor as well as their previously characterized targets, the neurotransmitter transporter proteins.

Effects of heavy particle irradiation and diet on amphetamine- and lithium chloride-induced taste avoidance learning in rats

NASA Technical Reports Server (NTRS)

Rabin, Bernard M.; Shukitt-Hale, Barbara; Szprengiel, Aleksandra; Joseph, James A.

2002-01-01

Rats were maintained on diets containing either 2% blueberry or strawberry extract or a control diet for 8 weeks prior to being exposed to 1.5 Gy of 56Fe particles in the Alternating Gradient Synchrotron at Brookhaven National Laboratory. Three days following irradiation, the rats were tested for the effects of irradiation on the acquisition of an amphetamine- or lithium chloride-induced (LiCl) conditioned taste avoidance (CTA). The rats maintained on the control diet failed to show the acquisition of a CTA following injection of amphetamine. In contrast, the rats maintained on antioxidant diets (strawberry or blueberry extract) continued to show the development of an amphetamine-induced CTA following exposure to 56Fe particles. Neither irradiation nor diet had an effect on the acquisition of a LiCl-induced CTA. The results are interpreted as indicating that oxidative stress following exposure to 56Fe particles may be responsible for the disruption of the dopamine-mediated amphetamine-induced CTA in rats fed control diets; and that a reduction in oxidative stress produced by the antioxidant diets functions to reinstate the dopamine-mediated CTA. The failure of either irradiation or diet to influence LiCl-induced responding suggests that oxidative stress may not be involved in CTA learning following injection of LiCl.

An Overview of Sleep Deprivation and The Ameliorative Effects of Modafinil

DTIC Science & Technology

2002-11-01

H., and Jouvet, M., Successful treatment of idiopathic hypersomnia and narcolepsy with modafinil. Progress in Neuro-Psychopharmacology and Biological...Laffont, F., Cathala, H.P., and Kohler, F. Effect of modafinil on narcolepsy and idiopathic hypersomnia . in the 5th European Congress of Sleep Research...amphetamine and modafinil on the sleep/wake cycle during experimental hypersomnia induced by sleep deprivation in the cat. Journal of Sleep Research, 2000. 9

Risk factors for criminal recidivism - a prospective follow-up study in prisoners with substance abuse.

PubMed

Håkansson, Anders; Berglund, Mats

2012-08-15

Substance use in general has been shown to predict criminal recidivism. The present study aimed to examine potential predictors of criminal recidivism, including substance-specific substance use patterns, in prisoners with substance use. A cohort of prisoners with substance use problems (N = 4,152) were assessed with the Addiction Severity Index (ASI) in the Swedish criminal justice system. Clients were followed for an average of 2.7 years. Criminal recidivism was defined as any return to the criminal justice system. During follow-up, 69 percent (n = 2,862) returned to the criminal justice system. Recidivism was associated with amphetamine and heroin use, with an additive risk for injectors, and with polysubstance use. Also, recidivism was negatively associated with alcohol, other opioids than heroin/methadone and with hallucinogenic drugs, and positively associated with previous psychiatric in-patient treatment, violent behaviour, and with a shorter index sentence. Associations remained when controlling for type of crime. Even when controlling for type and severity of crime, and for psychiatric problems, risk of criminal relapse was increased by substance use variables, including amphetamine, heroin and polysubstance use, and an additional risk was shown for injection drug users. These findings have implications for the need for substance abuse treatment after release from prison.

Activations of c-fos/c-jun signaling are involved in the modulation of hypothalamic superoxide dismutase (SOD) and neuropeptide Y (NPY) gene expression in amphetamine-mediated appetite suppression

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

Hsieh, Y.-S.; Yang, S.-F.; Chiou, H.-L.

2006-04-15

Amphetamine (AMPH) is known as an anorectic agent. The mechanism underlying the anorectic action of AMPH has been attributed to its inhibitory action on hypothalamic neuropeptide Y (NPY), an appetite stimulant in the brain. This study was aimed to examine the molecular mechanisms behind the anorectic effect of AMPH. Results showed that AMPH treatment decreased food intake, which was correlated with changes of NPY mRNA level, but increased c-fos, c-jun and superoxide dismutase (SOD) mRNA levels in hypothalamus. To determine if c-fos or c-jun was involved in the anorectic response of AMPH, infusions of antisense oligonucleotide into the brain weremore » performed at 1 h before daily AMPH treatment in freely moving rats, and the results showed that c-fos or c-jun knockdown could block this anorectic response and restore NPY mRNA level. Moreover, c-fos or c-jun knockdown could partially block SOD mRNA level that might involve in the modulation of NPY gene expression. It was suggested that c-fos/c-jun signaling might involve in the central regulation of AMPH-mediated feeding suppression via the modulation of NPY gene expression.« less

Behavioral Abnormalities in a Mouse Model of Chronic Toxoplasmosis Are Associated with MAG1 Antibody Levels and Cyst Burden.

PubMed

Xiao, Jianchun; Li, Ye; Prandovszky, Emese; Kannan, Geetha; Viscidi, Raphael P; Pletnikov, Mikhail V; Yolken, Robert H

2016-04-01

There is marked variation in the human response to Toxoplasma gondii infection. Epidemiological studies indicate associations between strain virulence and severity of toxoplasmosis. Animal studies on the pathogenic effect of chronic infection focused on relatively avirulent strains (e.g. type II) because they can easily establish latent infections in mice, defined by the presence of bradyzoite-containing cysts. To provide insight into virulent strain-related severity of human toxoplasmosis, we established a chronic model of the virulent type I strain using outbred mice. We found that type I-exposed mice displayed variable outcomes ranging from aborted to severe infections. According to antibody profiles, we found that most of mice generated antibodies against T. gondii organism but varied greatly in the production of antibodies against matrix antigen MAG1. There was a strong correlation between MAG1 antibody level and brain cyst burden in chronically infected mice (r = 0.82, p = 0.0021). We found that mice with high MAG1 antibody level displayed lower weight, behavioral changes, altered levels of gene expression and immune activation. The most striking change in behavior we discovered was a blunted response to amphetamine-trigged locomotor activity. The extent of most changes was directly correlated with levels of MAG1 antibody. These changes were not found in mice with less cyst burden or mice that were acutely but not chronically infected. Our finding highlights the critical role of cyst burden in a range of disease severity during chronic infection, the predictive value of MAG1 antibody level to brain cyst burden and to changes in behavior or other pathology in chronically infected mice. Our finding may have important implications for understanding the heterogeneous effects of T. gondii infections in human.

Behavioral Abnormalities in a Mouse Model of Chronic Toxoplasmosis Are Associated with MAG1 Antibody Levels and Cyst Burden

PubMed Central

Xiao, Jianchun; Li, Ye; Prandovszky, Emese; Kannan, Geetha; Viscidi, Raphael P.; Pletnikov, Mikhail V.; Yolken, Robert H.

2016-01-01

There is marked variation in the human response to Toxoplasma gondii infection. Epidemiological studies indicate associations between strain virulence and severity of toxoplasmosis. Animal studies on the pathogenic effect of chronic infection focused on relatively avirulent strains (e.g. type II) because they can easily establish latent infections in mice, defined by the presence of bradyzoite-containing cysts. To provide insight into virulent strain-related severity of human toxoplasmosis, we established a chronic model of the virulent type I strain using outbred mice. We found that type I-exposed mice displayed variable outcomes ranging from aborted to severe infections. According to antibody profiles, we found that most of mice generated antibodies against T. gondii organism but varied greatly in the production of antibodies against matrix antigen MAG1. There was a strong correlation between MAG1 antibody level and brain cyst burden in chronically infected mice (r = 0.82, p = 0.0021). We found that mice with high MAG1 antibody level displayed lower weight, behavioral changes, altered levels of gene expression and immune activation. The most striking change in behavior we discovered was a blunted response to amphetamine-trigged locomotor activity. The extent of most changes was directly correlated with levels of MAG1 antibody. These changes were not found in mice with less cyst burden or mice that were acutely but not chronically infected. Our finding highlights the critical role of cyst burden in a range of disease severity during chronic infection, the predictive value of MAG1 antibody level to brain cyst burden and to changes in behavior or other pathology in chronically infected mice. Our finding may have important implications for understanding the heterogeneous effects of T. gondii infections in human. PMID:27124472

The effects of oral d-amphetamine on impulsivity in smoked and intranasal cocaine users.

PubMed

Reed, Stephanie Collins; Evans, Suzette M

2016-06-01

Effective treatments for cocaine use disorders remain elusive. Two factors that may be related to treatment failures are route of cocaine used and impulsivity. Smoked cocaine users are more likely to have poorer treatment outcomes compared to intranasal cocaine users. Further, cocaine users are impulsive and impulsivity is associated with poor treatment outcomes. While stimulants are used to treat Attention Deficit Hyperactivity Disorder (ADHD) and attenuate certain cocaine-related behaviors, few studies have comprehensively examined whether stimulants can reduce behavioral impulsivity in cocaine users, and none examined route of cocaine use as a factor. The effects of immediate release oral d-amphetamine (AMPH) were examined in 34 cocaine users (13 intranasal, 21 smoked). Participants had three separate sessions where they were administered AMPH (0, 10, or 20mg) and completed behavioral measures of impulsivity and risk-taking and subjective measures of abuse liability. Smoked cocaine users were more impulsive on the Delayed Memory Task, the GoStop task and the Delay Discounting Task than intranasal cocaine users. Smoked cocaine users also reported more cocaine craving and negative mood than intranasal cocaine users. AMPH produced minimal increases on measures of abuse liability (e.g., Drug Liking). Smoked cocaine users were more impulsive than intranasal cocaine users on measures of impulsivity that had a delay component. Additionally, although AMPH failed to attenuate impulsive responding, there was minimal evidence of abuse liability in cocaine users. These preliminary findings need to be confirmed in larger samples that control for route and duration of cocaine use. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The Effects of Oral d-Amphetamine on Impulsivity in Smoked and Intranasal Cocaine Users

PubMed Central

Reed, Stephanie Collins; Evans, Suzette M.

2016-01-01

BACKGROUND Effective treatments for cocaine use disorders remain elusive. Two factors that may be related to treatment failures are route of cocaine used and impulsivity. Smoked cocaine users are more likely to have poorer treatment outcomes compared to intranasal cocaine users. Further, cocaine users are impulsive and impulsivity is associated with poor treatment outcomes. While stimulants are used to treat Attention Deficit Hyperactivity Disorder (ADHD) and attenuate certain cocaine-related behaviors, few studies have comprehensively examined whether stimulants can reduce behavioral impulsivity in cocaine users, and none examined route of cocaine use as a factor. METHODS The effects of immediate release oral d-amphetamine (AMPH) were examined in 34 cocaine users (13 intranasal, 21 smoked). Participants had three separate sessions where they were administered AMPH (0, 10, or 20 mg) and completed behavioral measures of impulsivity and risk-taking and subjective measures of abuse liability. RESULTS Smoked cocaine users were more impulsive on the Delayed Memory Task, the GoStop task and the Delay Discounting Task than intranasal cocaine users. Smoked cocaine users also reported more cocaine craving and negative mood than intranasal cocaine users. AMPH produced minimal increases on measures of abuse liability (e.g., Drug Liking). CONCLUSIONS Smoked cocaine users were more impulsive than intranasal cocaine users on measures of impulsivity that had a delay component. Additionally, although AMPH failed to attenuate impulsive responding, there was minimal evidence of abuse liability in cocaine users. These preliminary findings need to be confirmed in larger samples that control for route and duration of cocaine use. PMID:27114203

Monamine oxidase inhibitors: current and emerging agents for Parkinson disease.

PubMed

Fernandez, Hubert H; Chen, Jack J

2007-01-01

Monoamine oxidase type B (MAO-B) is the predominant isoform responsible for the metabolic breakdown of dopamine in the brain. Selective inhibition of brain MAO-B results in elevation of synaptosomal dopamine concentrations. Data have been reported regarding the selective MAO-B inhibitors, rasagiline and selegiline, for the symptomatic treatment of Parkinson disease (PD). Selegiline has demonstrated efficacy as monotherapy in patients with early PD (Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism study), but evidence of selegiline efficacy as adjunctive treatment in levodopa-treated PD patients with motor fluctuations is equivocal. A new formulation of selegiline (Zydis selegiline) has been evaluated in 2 small, placebo-controlled studies as adjunctive therapy to levodopa. The Zydis formulation allows pregastric absorption of selegiline, minimizing first-pass metabolism, and thereby increasing selegiline bioavailability and reducing the concentration of amphetamine metabolites. Rasagiline is a selective, second-generation, irreversible MAO-B inhibitor, with at least 5 times the potency of selegiline in vitro and in animal models. Rasagiline has demonstrated efficacy in 1 large, randomized, double-blind, placebo-controlled trial (TVP-1012 in Early Monotherapy for Parkinson's Disease Outpatients) as initial monotherapy in patients with early PD, and in 2 large, controlled trials (Parkinson's Rasagiline: Efficacy and Safety in the Treatment of "Off," Lasting Effect in Adjunct Therapy With Rasagiline Given Once Daily) as adjunctive treatment in levodopa-treated PD patients with motor fluctuations. Unlike selegiline, rasagiline is an aminoindan derivative with no amphetamine metabolites. A randomized clinical trial is underway to confirm preclinical and preliminary clinical data suggesting rasagiline has disease-modifying effects.