Subcortical grey matter alterations in cocaine dependent individuals with substance-induced psychosis compared to non-psychotic cocaine users.

PubMed

Willi, Taylor S; Lang, Donna J; Honer, William G; Smith, Geoff N; Thornton, Allen E; Panenka, William J; Procyshyn, Ric M; Vila-Rodriguez, Fidel; Su, Wayne; Vertinsky, A Talia; Leonova, Olga; Rauscher, Alexander; MacEwan, G William; Barr, Alasdair M

2016-10-01

After prolonged psychostimulant abuse, transient psychotic symptoms referred to as "substance-induced psychosis" (SIP) can develop - closely resembling symptoms observed in schizophrenia spectrum disorders. The comparability in psychotic presentation between SIP and schizophrenias suggests that similar underlying neural deficits may contribute to the expression of psychosis across these disorders. To date, neuroanatomical characterization of grey matter structural alterations in SIP has been limited to methamphetamine associated psychosis, with no studies controlling for potential neurotoxic effects of the psychostimulant that precipitates psychosis. To investigate grey matter subcortical alterations in SIP, a voxel-based analysis of magnetic resonance images (MRI) was performed between a group of 74 cocaine dependent nonpsychotic individuals and a group of 29 individuals with cocaine-associated psychosis. The cocaine-associated psychosis group had significantly smaller volumes of the thalamus and left hippocampus, controlling for age, total brain volume, current methamphetamine dependence, and current marijuana dependence. No differences were present in bilateral caudate structures. The findings of reduced thalamic and hippocampal volumes agree with previous reports in the schizophrenia literature, suggesting alterations of these structures are not specific to schizophrenia, but may be common to multiple forms of psychosis. Copyright © 2016 Elsevier B.V. All rights reserved.

Parallel changes in serum proteins and diffusion tensor imaging in methamphetamine-associated psychosis.

PubMed

Breen, Michael S; Uhlmann, Anne; Ozcan, Sureyya; Chan, Man; Pinto, Dalila; Bahn, Sabine; Stein, Dan J

2017-03-02

Methamphetamine-associated psychosis (MAP) involves widespread neurocognitive and molecular deficits, however accurate diagnosis remains challenging. Integrating relationships between biological markers, brain imaging and clinical parameters may provide an improved mechanistic understanding of MAP, that could in turn drive the development of better diagnostics and treatment approaches. We applied selected reaction monitoring (SRM)-based proteomics, profiling 43 proteins in serum previously implicated in the etiology of major psychiatric disorders, and integrated these data with diffusion tensor imaging (DTI) and psychometric measurements from patients diagnosed with MAP (N = 12), methamphetamine dependence without psychosis (MA; N = 14) and healthy controls (N = 16). Protein analysis identified changes in APOC2 and APOH, which differed significantly in MAP compared to MA and controls. DTI analysis indicated widespread increases in mean diffusivity and radial diffusivity delineating extensive loss of white matter integrity and axon demyelination in MAP. Upon integration, several co-linear relationships between serum proteins and DTI measures reported in healthy controls were disrupted in MA and MAP groups; these involved areas of the brain critical for memory and social emotional processing. These findings suggest that serum proteomics and DTI are sensitive measures for detecting pathophysiological changes in MAP and describe a potential diagnostic fingerprint of the disorder.

Differences in Clinical Features of Methamphetamine Users with Persistent Psychosis and Patients with Schizophrenia.

PubMed

Wang, Liang-Jen; Lin, Shih-Ku; Chen, Yi-Chih; Huang, Ming-Chyi; Chen, Tzu-Ting; Ree, Shao-Chun; Chen, Chih-Ken

Methamphetamine exerts neurotoxic effects and elicits psychotic symptoms. This study attempted to compare clinical differences between methamphetamine users with persistent psychosis (MAP) and patients with schizophrenia. In addition, we examined the discrimination validity by using symptom clusters to differentiate between MAP and schizophrenia. We enrolled 53 MAP patients and 53 patients with schizophrenia. The psychopathology of participants was assessed using the Chinese version of the Diagnostic Interview for Genetic Studies and the 18-item Brief Psychiatric Rating Scale. Logistic regression was used to examine the predicted probability scores of different symptom combinations on discriminating between MAP and schizophrenia. The receiver operating characteristic (ROC) analyses and area under the curve (AUC) were further applied to examine the discrimination validity of the predicted probability scores on differentiating between MAP and schizophrenia. We found that MAP and schizophrenia demonstrated similar patterns of delusions. Compared to patients with schizophrenia, MAP experienced significantly higher proportions of visual hallucinations and of somatic or tactile hallucinations. However, MAP exhibited significantly lower severity in conceptual disorganization, mannerism/posturing, blunted affect, emotional withdrawal, and motor retardation compared to patients with schizophrenia. The ROC analysis showed that a predicted probability score combining the aforementioned 7 items of symptoms could significantly differentiate between MAP and schizophrenia (AUC = 0.77). Findings in the current study suggest that nuanced differences might exist in the clinical presentation of secondary psychosis (MAP) and primary psychosis (schizophrenia). Combining the symptoms as a whole may help with differential diagnosis for MAP and schizophrenia. © 2016 S. Karger AG, Basel.

Effectiveness of Electroconvulsive Therapy in Persistent Methamphetamine Psychosis: A Pilot Study

PubMed Central

Ziaaddini, Hassan; Roohbakhsh, Toktam; Nakhaee, Nouzar; Ghaffari-Nejad, Alireza

2015-01-01

Background Persistent methamphetamine (METH) psychosis is a psychotic state beyond 1-month after abstinence, for which there is no effective treatment. This study aimed to evaluate the effectiveness of electroconvulsive therapy (ECT) in persistent METH psychosis patients hospitalized at Shahid Beheshti Hospital, Kerman, Iran, from 6 September 2012 until 6 September 2013, who were not remitted after treatment with olanzapine. Methods This research was a pilot study on hospitalized patients. After 4 weeks of treatment with olanzapine, 10 out of 71 studied patients did not show complete remission of psychotic symptoms despite their response to the treatment. The mentioned 10 patients were divided into 2 groups by random digit numbers. 5 patients had continued olanzapine and other 5 received 6 sessions of bilateral ECT every other day in addition to olanzapine. Findings Remission rate of patients in the initial 4 weeks was 78.7%. Reduction in total brief psychiatric rating scale (BPRS) scale at the end of 1-week compared with the next week demonstrated improvement in the symptoms until the end of the study. There was no significant difference in BPRS scores between weeks 4 and 6 in the two groups. Conclusion This research demonstrated that few sessions of ECT in persistent METH psychosis will not lead to remission in all patients. PMID:26322206

Brain site- and transmitter-dependent actions of methamphetamine, morphine and antipsychotics.

PubMed

Mori, Tomohisa; Iwase, Yoshiyuki; Murata, Asami; Iwata, Noriyuki; Suzuki, Tsutomu

2016-06-01

While several methamphetamine- and morphine-induced psychotic states are ordinarily treated by antipsychotics, the therapeutic mechanisms of antipsychotic drugs have yet been elucidated. The present study was designed to investigate the mechanisms how antipsychotic drugs suppress the behavioral changes induced by psychoactive drugs in mice. Low to medium doses of methamphetamine produced hyperlocomotion, whereas high dose of methamphetamine induced hypolocomotion. Hyperlocomotion induced by methamphetamine was potently suppressed by clozapine and 5-HT2 receptor antagonists, but not by the intra-accumbens injection of haloperidol. On the other hand, microinjection of haloperidol into the ventrolateral striatum increased locomotor activity with high dose of methamphetamine. In contrast, morphine-induced hyperlocomotion was suppressed by systemic as well as intra-accumbens injection of haloperidol, whereas relatively resistant to clozapine, compared to its effects in the case of methamphetamine. It has been widely believed that methamphetamine-induced psychosis is an animal model of schizophrenia, which is mediated by activation of accumbal dopamine receptors. Our findings suggest that methamphetamine differentially regulate monoaminergic systems (e.g., dopaminergic vs. 5-HTnergic), and accumbal dopamine receptors are not involved in methamphetamine-induced hyperlocomotion in mice. Thus, our findings may lead to a better understanding of the therapeutic mechanisms that underlie the effects of antipsychotic drugs and behavioral effects of methamphetamine and morphine. Copyright © 2016 Elsevier B.V. All rights reserved.

Pavlovian Discriminative Stimulus Effects of Methamphetamine in Male Japanese quail (Coturnix japonica)

PubMed Central

Bolin, B. Levi; Singleton, Destiny L.; Akins, Chana K.

2014-01-01

Pavlovian drug discrimination (DD) procedures demonstrate that interoceptive drug stimuli may come to control behavior by informing the status of conditional relationships between stimuli and outcomes. This technique may provide insight into processes that contribute to drug-seeking, relapse, and other maladaptive behaviors associated with drug abuse. The purpose of the current research was to establish a model of Pavlovian DD in male Japanese quail. A Pavlovian conditioning procedure was used such that 3.0 mg/kg methamphetamine served as a feature positive stimulus for brief periods of visual access to a female quail and approach behavior was measured. After acquisition training, generalization tests were conducted with cocaine, nicotine, and haloperidol under extinction conditions. SCH 23390 was used to investigate the involvement of the dopamine D1 receptor subtype in the methamphetamine discriminative stimulus. Results showed that cocaine fully substituted for methamphetamine but nicotine only partially substituted for methamphetamine in quail. Haloperidol dose-dependently decreased approach behavior. Pretreatment with SCH 23390 modestly attenuated the methamphetamine discrimination suggesting that the D1 receptor subtype may be involved in the discriminative stimulus effects of methamphetamine. The findings are discussed in relation to drug abuse and associated negative health consequences. PMID:24965811

Cannabinoid Receptors Mediate Methamphetamine Induction of High Frequency Gamma Oscillations in the Nucleus Accumbens

PubMed Central

Morra, Joshua T.; Glick, Stanley D.; Cheer, Joseph F.

2012-01-01

Patients suffering from amphetamine---induced psychosis display repetitive behaviors, partially alleviated by antipsychotics, which are reminiscent of rodent stereotypies. Due to recent evidence implicating endocannabinoid involvement in brain disorders, including psychosis, we studied the effects of endocannabinoid signaling on neuronal oscillations of rats exhibiting methamphetamine stereotypy. Neuronal network oscillations were recorded with multiple single electrode arrays aimed at the nucleus accumbens of freely moving rats. During the experiments, animals were dosed intravenously with the CB1 receptor antagonist rimonabant (0.3 mg/kg) or vehicle followed by an ascending dose regimen of methamphetamine (0.01, 0.1, 1, and 3 mg/kg; cumulative dosing). The effects of drug administration on stereotypy and local gamma oscillations were evaluated. Methamphetamine treatment significantly increased high frequency gamma oscillations (~ 80 Hz). Entrainment of a subpopulation of nucleus accumbens neurons to high frequency gamma was associated with stereotypy encoding in putative fast-spiking interneurons, but not in putative medium spiny neurons. The observed ability of methamphetamine to induce both stereotypy and high frequency gamma power was potently disrupted following CB1 receptor blockade. The present data suggest that CB1 receptor-dependent mechanisms are recruited by methamphetamine to modify striatal interneuron oscillations that accompany changes in psychomotor state, further supporting the link between endocannabinoids and schizophrenia spectrum disorders. PMID:22609048

Lithium protects against methamphetamine-induced neurotoxicity in PC12 cells via Akt/GSK3β/mTOR pathway

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

Wu, Jintao; Zhu, Dexiao; Zhang, Jing

Methamphetamine (MA) is neurotoxic, especially in dopaminergic neurons. Long-lasting exposure to MA causes psychosis and increases the risk of Parkinson's disease. Lithium (Li) is a known mood stabilizer and has neuroprotective effects. Previous studies suggest that MA exposure decreases the phosphorylation of Akt/GSK3β pathway in vivo, whereas Li facilitates the phosphorylation of Akt/GSK3β pathway. Moreover, GSK3β and mTOR are implicated in the locomotor sensitization induced by psychostimulants and mTOR plays a critical role in MA induced toxicity. However, the effect of MA on Akt/GSK3β/mTOR pathway has not been fully investigated in vitro. Here, we found that MA exposure significantly dephosphorylated Akt/GSK3β/mTOR pathwaymore » in PC12 cells. In addition, Li remarkably attenuated the dephosphorylation effect of MA exposure on Akt/GSK3β/mTOR pathway. Furthermore, Li showed obvious protective effects against MA toxicity and LY294002 (Akt inhibitor) suppressed the protective effects of Li. Together, MA exposure dephosphorylates Akt/GSK3β/mTOR pathway in vitro, while lithium protects against MA-induced neurotoxicity via phosphorylation of Akt/GSK3β/mTOR pathway. - Highlights: • Lithium protects against methamphetamine-induced neurotoxicity in vitro. • Methamphetamine exposure dephosphorylates Akt/GSK3β/mTOR pathway. • Lithium attenuates methamphetamine-induced toxicity via phosphorylating Akt/GSK3β/mTOR pathway.« less

Social cognition and aggression in methamphetamine dependence with and without a history of psychosis.

PubMed

Uhlmann, Anne; Ipser, Jonathan C; Wilson, Don; Stein, Dan J

2018-04-01

In substance use and psychotic disorders, socially problematic behaviours, such as high aggression may, in part, be explained by deficits in social cognition skills, like the detection of emotions or intentions in others. The aim of this study was to assess the magnitude of social cognition impairment and its association with aggression in individuals with methamphetamine (MA) dependence, methamphetamine-associated psychosis (MAP), and healthy controls (CTRL). A total of 20 MAP participants, 21 MA-dependent participants without psychosis, and 21 CTRL participants performed a facial morphing emotion recognition task (ERT) across four basic emotions (anger, fear, happiness and sadness) and the reading the mind in the eyes task (RMET), and completed the aggression questionnaire. Both MA-dependent groups showed impairment in social cognition in terms of lower RMET scores relative to CTRL participants (MA; p = .047; MAP: p < .001). Additionally, performance decrements were significantly greater in MAP (p = .040), compared to MA-dependent participants. While deficits in recognising emotional expressions were restricted to anger in the MA group (p = .020), a generalized impairment across all four emotions was observed in MAP (all p ≤ .001). Additionally, both patient groups demonstrated higher levels of aggression than CTRLs, yet no association was found with social cognition. This study supported the notion of deficits in recognising facial emotional expressions and inferring mental states of others in MA dependence, with additional impairments in MAP. Failure to detect an association between social cognitive impairment and aggressive behaviour may implicate independent disturbances of the two phenomena in MA dependence.

Altered social cognition in male BDNF heterozygous mice and following chronic methamphetamine exposure.

PubMed

Manning, Elizabeth E; van den Buuse, Maarten

2016-05-15

Growing clinical evidence suggests that persistent psychosis which occurs in methamphetamine users is closely related to schizophrenia. However, preclinical studies in animal models have focussed on psychosis-related behaviours following methamphetamine, and less work has been done to assess endophenotypes relevant to other deficits observed in schizophrenia. Altered social behaviour is a feature of both the negative symptoms and cognitive deficits in schizophrenia, and significantly impacts patient functioning. We recently found that brain-derived neurotrophic factor (BDNF) heterozygous mice show disrupted sensitization to methamphetamine, supporting other work suggesting an important role of this neurotrophin in the pathophysiology of psychosis and the neuronal response to stimulant drugs. In the current study, we assessed social and cognitive behaviours in methamphetamine-treated BDNF heterozygous mice and wildtype littermate controls. Following chronic methamphetamine exposure male wildtype mice showed a 50% reduction in social novelty preference. Vehicle-treated male BDNF heterozygous mice showed a similar impairment in social novelty preference, with a trend for no further disruption by methamphetamine exposure. Female mice were unaffected in this task, and no groups showed any changes in sociability or short-term spatial memory. These findings suggest that chronic methamphetamine alters behaviour relevant to disruption of social cognition in schizophrenia, supporting other studies which demonstrate a close resemblance between persistent methamphetamine psychosis and schizophrenia. Together these findings suggest that dynamic regulation of BDNF signalling is necessary to mediate the effects of methamphetamine on behaviours relevant to schizophrenia. Copyright © 2016 Elsevier B.V. All rights reserved.

Cannabinoid receptors mediate methamphetamine induction of high frequency gamma oscillations in the nucleus accumbens.

PubMed

Morra, Joshua T; Glick, Stanley D; Cheer, Joseph F

2012-09-01

Patients suffering from amphetamine-induced psychosis display repetitive behaviors, partially alleviated by antipsychotics, which are reminiscent of rodent stereotypies. Due to recent evidence implicating endocannabinoid involvement in brain disorders, including psychosis, we studied the effects of endocannabinoid signaling on neuronal oscillations of rats exhibiting methamphetamine stereotypy. Neuronal network oscillations were recorded with multiple single electrode arrays aimed at the nucleus accumbens of freely-moving rats. During the experiments, animals were dosed intravenously with the CB1 receptor antagonist rimonabant (0.3 mg/kg) or vehicle followed by an ascending dose regimen of methamphetamine (0.01, 0.1, 1, and 3 mg/kg; cumulative dosing). The effects of drug administration on stereotypy and local gamma oscillations were evaluated. Methamphetamine treatment significantly increased high frequency gamma oscillations (∼80 Hz). Entrainment of a subpopulation of nucleus accumbens neurons to high frequency gamma was associated with stereotypy encoding in putative fast-spiking interneurons, but not in putative medium spiny neurons. The observed ability of methamphetamine to induce both stereotypy and high frequency gamma power was potently disrupted following CB1 receptor blockade. The present data suggest that CB1 receptor-dependent mechanisms are recruited by methamphetamine to modify striatal interneuron oscillations that accompany changes in psychomotor state, further supporting the link between endocannabinoids and schizophrenia spectrum disorders. Copyright © 2012 Elsevier Ltd. All rights reserved.

Involvement of PUMA in pericyte migration induced by methamphetamine.

PubMed

Zhang, Yanhong; Zhang, Yuan; Bai, Ying; Chao, Jie; Hu, Gang; Chen, Xufeng; Yao, Honghong

2017-07-01

Mounting evidence indicates that methamphetamine causes blood-brain barrier damage, with emphasis on endothelial cells. The role of pericytes in methamphetamine-induced BBB damage remains unknown. Our study demonstrated that methamphetamine increased the migration of pericytes from the endothelial basement membrane. However, the detailed mechanisms underlying this process remain poorly understood. Thus, we examined the molecular mechanisms involved in methamphetamine-induced pericyte migration. The results showed that exposure of C3H/10T1/2 cells and HBVPs to methamphetamine increased PUMA expression via activation of the sigma-1 receptor, MAPK and Akt/PI3K pathways. Moreover, methamphetamine treatment resulted in the increased migration of C3H/10T1/2 cells and HBVPs. Knockdown of PUMA in pericytes transduced with PUMA siRNA attenuated the methamphetamine-induced increase in cell migration through attenuation of integrin and tyrosine kinase mechanisms, implicating a role of PUMA in the migration of C3H/10T1/2 cells and HBVPs. This study has demonstrated that methamphetamine-mediated pericytes migration involves PUMA up-regulation. Thus, targeted studies of PUMA could provide insights to facilitate the development of a potential therapeutic approach for alleviation of methamphetamine-induced pericyte migration. Copyright © 2017. Published by Elsevier Inc.

Methamphetamine induces the release of endothelin.

PubMed

Seo, Jeong-Woo; Jones, Susan M; Hostetter, Trisha A; Iliff, Jeffrey J; West, G Alexander

2016-02-01

Methamphetamine is a potent psychostimulant drug of abuse that increases release and blocks reuptake of dopamine, producing intense euphoria, factors that may contribute to its widespread abuse. It also produces severe neurotoxicity resulting from oxidative stress, DNA damage, blood-brain barrier disruption, microgliosis, and mitochondrial dysfunction. Intracerebral hemorrhagic and ischemic stroke have been reported after intravenous and oral abuse of methamphetamine. Several studies have shown that methamphetamine causes vasoconstriction of vessels. This study investigates the effect of methamphetamine on endothelin-1 (ET-1) release in mouse brain endothelial cells by ELISA. ET-1 transcription as well as endothelial nitric oxide synthase (eNOS) activation and transcription were measured following methamphetamine treatment. We also examine the effect of methamphetamine on isolated cerebral arteriolar vessels from C57BL/6 mice. Penetrating middle cerebral arterioles were cannulated at both ends with a micropipette system. Methamphetamine was applied extraluminally, and the vascular response was investigated. Methamphetamine treatment of mouse brain endothelial cells resulted in ET-1 release and a transient increase in ET-1 message. The activity and transcription of eNOS were only slightly enhanced after 24 hr of treatment with methamphetamine. In addition, methamphetamine caused significant vasoconstriction of isolated mouse intracerebral arterioles. The vasoconstrictive effect of methamphetamine was attenuated by coapplication of the endothelin receptor antagonist PD145065. These findings suggest that vasoconstriction induced by methamphetamine is mediated through the endothelin receptor and may involve an endothelin-dependent pathway. © 2015 Wiley Periodicals, Inc.

Agmatine attenuates methamphetamine-induced conditioned place preference in rats.

PubMed

Thorn, David A; Winter, Jerrold C; Li, Jun-Xu

2012-04-05

The polyamine agmatine modulates a variety of behavioral effects including the abuse-related effects of opioids and has been proposed as a potential medication candidate for the treatment of opioid abuse. However, little is known of the effects of agmatine on the abuse-related effects of other drugs of abuse. This study examined the effects of agmatine on the rewarding effects of methamphetamine in rats using a conditioned place preference paradigm. Methamphetamine (0.1-1.0mg/kg) dose-dependently increased the time spent in methamphetamine-paired side (place preference). Agmatine, at doses that did not produce place preference or aversion (10-32mg/kg), significantly decreased the development of methamphetamine-induced place preference when agmatine was administered in combination with methamphetamine during place conditioning. Agmatine also significantly decreased the expression of methamphetamine-induced place preference when an acute injection of agmatine was given immediately before test session. These doses of agmatine do not alter the motor activity in rats, suggesting that the observed attenuation of methamphetamine-induced place preference was not due to general behavioral disruption. Together, these data suggests that agmatine attenuates the rewarding effects of methamphetamine and may be able to modulate the abuse liability of methamphetamine. Copyright © 2012 Elsevier B.V. All rights reserved.

Chronic wheel running reduces maladaptive patterns of methamphetamine intake: regulation by attenuation of methamphetamine-induced neuronal nitric oxide synthase.

PubMed

Engelmann, Alexander J; Aparicio, Mark B; Kim, Airee; Sobieraj, Jeffery C; Yuan, Clara J; Grant, Yanabel; Mandyam, Chitra D

2014-03-01

We investigated whether prior exposure to chronic wheel running (WR) alters maladaptive patterns of excessive and escalating methamphetamine intake under extended access conditions, and intravenous methamphetamine self-administration-induced neurotoxicity. Adult rats were given access to WR or no wheel (sedentary) in their home cage for 6 weeks. A set of WR rats were injected with 5-bromo-2'-deoxyuridine (BrdU) to determine WR-induced changes in proliferation (2-h old) and survival (28-day old) of hippocampal progenitors. Another set of WR rats were withdrawn (WRw) or continued (WRc) to have access to running wheels in their home cages during self-administration days. Following self-administration [6 h/day], rats were tested on the progressive ratio (PR) schedule. Following PR, BrdU was injected to determine levels of proliferating progenitors (2-h old). WRc rats self-administered significantly less methamphetamine than sedentary rats during acquisition and escalation sessions, and demonstrated reduced motivation for methamphetamine seeking. Methamphetamine reduced daily running activity of WRc rats compared with that of pre-methamphetamine days. WRw rats self-administered significantly more methamphetamine than sedentary rats during acquisition, an effect that was not observed during escalation and PR sessions. WR-induced beneficial effects on methamphetamine self-administration were not attributable to neuroplasticity effects in the hippocampus and medial prefrontal cortex, but were attributable to WR-induced inhibition of methamphetamine-induced increases in the number of neuronal nitric oxide synthase expressing neurons and apoptosis in the nucleus accumbens shell. Our results demonstrate that WR prevents methamphetamine-induced damage to forebrain neurons to provide a beneficial effect on drug-taking behavior. Importantly, WR-induced neuroprotective effects are transient and continued WR activity is necessary to prevent compulsive methamphetamine intake.

Chronic wheel running reduces maladaptive patterns of methamphetamine intake: regulation by attenuation of methamphetamine-induced neuronal nitric oxide synthase

PubMed Central

Engelmann, Alexander J.; Aparicio, Mark B.; Kim, Airee; Sobieraj, Jeffery C.; Yuan, Clara J.; Grant, Yanabel

2013-01-01

We investigated whether prior exposure to chronic wheel running (WR) alters maladaptive patterns of excessive and escalating methamphetamine intake under extended access conditions, and intravenous methamphetamine self-administration-induced neurotoxicity. Adult rats were given access to WR or no wheel (sedentary) in their home cage for 6 weeks. A set of WR rats were injected with 5-bromo-2′-deoxyuridine (BrdU) to determine WR-induced changes in proliferation (2-h old) and survival (28-day old) of hippocampal progenitors. Another set of WR rats were withdrawn (WRw) or continued (WRc) to have access to running wheels in their home cages during self-administration days. Following self-administration [6 h/day], rats were tested on the progressive ratio (PR) schedule. Following PR, BrdU was injected to determine levels of proliferating progenitors (2-h old). WRc rats self-administered significantly less methamphetamine than sedentary rats during acquisition and escalation sessions, and demonstrated reduced motivation for methamphetamine seeking. Methamphetamine reduced daily running activity of WRc rats compared with that of pre-methamphetamine days. WRw rats self-administered significantly more methamphetamine than sedentary rats during acquisition, an effect that was not observed during escalation and PR sessions. WR-induced beneficial effects on methamphetamine self-administration were not attributable to neuroplasticity effects in the hippocampus and medial prefrontal cortex, but were attributable to WR-induced inhibition of methamphetamine-induced increases in the number of neuronal nitric oxide synthase expressing neurons and apoptosis in the nucleus accumbens shell. Our results demonstrate that WR prevents methamphetamine-induced damage to forebrain neurons to provide a beneficial effect on drug-taking behavior. Importantly, WR-induced neuroprotective effects are transient and continued WR activity is necessary to prevent compulsive methamphetamine intake

Nicotine Administration Attenuates Methamphetamine-Induced Novel Object Recognition Deficits

PubMed Central

Vieira-Brock, Paula L.; McFadden, Lisa M.; Nielsen, Shannon M.; Smith, Misty D.; Hanson, Glen R.

2015-01-01

Background: Previous studies have demonstrated that methamphetamine abuse leads to memory deficits and these are associated with relapse. Furthermore, extensive evidence indicates that nicotine prevents and/or improves memory deficits in different models of cognitive dysfunction and these nicotinic effects might be mediated by hippocampal or cortical nicotinic acetylcholine receptors. The present study investigated whether nicotine attenuates methamphetamine-induced novel object recognition deficits in rats and explored potential underlying mechanisms. Methods: Adolescent or adult male Sprague-Dawley rats received either nicotine water (10–75 μg/mL) or tap water for several weeks. Methamphetamine (4×7.5mg/kg/injection) or saline was administered either before or after chronic nicotine exposure. Novel object recognition was evaluated 6 days after methamphetamine or saline. Serotonin transporter function and density and α4β2 nicotinic acetylcholine receptor density were assessed on the following day. Results: Chronic nicotine intake via drinking water beginning during either adolescence or adulthood attenuated the novel object recognition deficits caused by a high-dose methamphetamine administration. Similarly, nicotine attenuated methamphetamine-induced deficits in novel object recognition when administered after methamphetamine treatment. However, nicotine did not attenuate the serotonergic deficits caused by methamphetamine in adults. Conversely, nicotine attenuated methamphetamine-induced deficits in α4β2 nicotinic acetylcholine receptor density in the hippocampal CA1 region. Furthermore, nicotine increased α4β2 nicotinic acetylcholine receptor density in the hippocampal CA3, dentate gyrus and perirhinal cortex in both saline- and methamphetamine-treated rats. Conclusions: Overall, these findings suggest that nicotine-induced increases in α4β2 nicotinic acetylcholine receptors in the hippocampus and perirhinal cortex might be one mechanism by which

Bee venom suppresses methamphetamine-induced conditioned place preference in mice.

PubMed

Kwon, Young Bae; Li, Jing; Kook, Ji Ae; Kim, Tae Wan; Jeong, Young Chan; Son, Ji Seon; Lee, Hyejung; Kim, Kee Won; Lee, Jang Hern

2010-02-01

Although acupuncture is most commonly used for its analgesic effect, it has also been used to treat various drug addictions including cocaine and morphine in humans. This study was designed to investigate the effect of bee venom injection on methamphetamine-induced addictive behaviors including conditioned place preference and hyperlocomotion in mice. Methamphetamine (1 mg/kg) was subcutaneously treated on days 1, 3 and 5 and the acquisition of addictive behaviors was assessed on day 7. After confirming extinction of addictive behaviors on day 17, addictive behaviors reinstated by priming dose of methamphetamine (0.1 mg/kg) was evaluated on day 18. Bee venom (20 microl of 1 mg/ml in saline) was injected to the acupuncture point ST36 on days 1, 3 and 5. Repeated bee venom injections completely blocked development of methamphetamine-induced acquisition and subsequent reinstatement. Single bee venom acupuncture 30 minutes before acquisition and reinstatement test completely inhibited methamphetamine-induced acquisition and reinstatement. Repeated bee venom acupunctures from day 8 to day 12 after methamphetamine-induced acquisition partially but significantly suppressed reinstatement. These findings suggest that bee venom acupuncture has a preventive and therapeutic effect on methamphetamine-induced addiction.

Mutual enhancement of central neurotoxicity induced by ketamine followed by methamphetamine

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

Ke, J.-J.; Chen, H.-I.; Jen, C.J.

2008-03-01

We hereby report that repeated administration of ketamine (350 mg/kg in total) and methamphetamine (30 mg/kg in total) causes specific glutamatergic and dopaminergic neuron deficits, respectively, in adult mouse brain. Acute ketamine did not affect basal body temperature or the later methamphetamine-induced hyperthermia. However, pretreatment with repeated doses of ketamine aggravated methamphetamine-induced dopaminergic terminal loss as evidenced by a drastic decrease in the levels of dopamine, 3,4-dihydroxyphenylacetic acid, and dopamine transporter density as well as poor gait balance performance. In contrast, methamphetamine-induced serotonergic depletion was not altered by ketamine pretreatment. Likewise, the subsequent treatment with methamphetamine exacerbated the ketamine-induced glutamatergicmore » damage as indicated by reduced levels of the vesicular glutamate transporter in hippocampus and striatum and poor memory performance in the Morris water maze. Finally, since activation of the D1 and AMPA/kainate receptors has been known to be involved in the release of glutamate and dopamine, we examined the effects of co-administration of SCH23390, a D1 antagonist, and CNQX, an AMPA/kainate antagonist. Intraventricular CNQX infusion abolished ketamine's potentiation of methamphetamine-induced dopamine neurotoxicity, while systemic SCH23390 mitigated methamphetamine's potentiation of ketamine-induced glutamatergic toxicity. We conclude that repeated doses of ketamine potentiate methamphetamine-induced dopamine neurotoxicity via AMPA/kainate activation and that conjunctive use of methamphetamine aggravates ketamine-induced glutamatergic neurotoxicity possibly via D1 receptor activation.« less

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

Familial liability for metoprolol-induced psychosis.

PubMed

Rietveld, L; van der Hoek, T; van Beek, M H C T; Schellekens, A F A

2015-01-01

Beta-blockers are commonly used in the treatment of hypertension and cardiac arrhythmias. The incidence of neuropsychiatric side effects is generally low. This case report shows the potential familial liability of a metoprolol-induced psychosis. We report a case of metoprolol-induced psychosis. Potential pharmocogenetic factors mediating this familial metoprolol-induced psychosis are discussed. A middle-aged man developed psychosis after starting metoprolol, which diminished after ceasing the medication. Two of his family members experienced similar symptoms after using metoprolol. All family members were genotyped as CYP2D6*4 allele carriers indicating reduced CYP2D6 enzyme activity. The case presented here suggests a potential familial liability for metoprolol- induced psychosis. Pharmacokinetic mechanisms are hypothesized to mediate this familial liability through genetic variation in the CYP2D6 genotype. A family history of psychotic symptoms after treatment with beta-blockers should be taken into account, when prescribing this beta-blocker. Copyright © 2015 Elsevier Inc. All rights reserved.

Attenuation of methamphetamine-induced nigrostriatal dopaminergic neurotoxicity in mice by lipopolysaccharide pretreatment.

PubMed

Lin, Yin Chiu; Kuo, Yu-Min; Liao, Pao-Chi; Cherng, Chianfang G; Su, Su-Wen; Yu, Lung

2007-04-30

Immunological activation has been proposed to play a role in methamphetamine-induced dopaminergic terminal damage. In this study, we examined the roles of lipopolysaccharide, a pro-inflammatory and inflammatory factor, treatment in modulating the methamphetamine-induced nigrostriatal dopamine neurotoxicity. Lipopolysaccharide pretreatment did not affect the basal body temperature or methamphetamine-elicited hyperthermia three days later. Such systemic lipopolysaccharide treatment mitigated methamphetamine-induced striatal dopamine and 3,4-dihydroxyphenylacetic acid depletions in a dose-dependent manner. As the most potent dose (1 mg/kg) of lipopolysaccharide was administered two weeks, one day before or after the methamphetamine dosing regimen, methamphetamine-induced striatal dopamine and 3,4-dihydroxyphenylacetic acid depletions remained unaltered. Moreover, systemic lipopolysaccharide pretreatment (1 mg/kg) attenuated local methamphetamine infusion-produced dopamine and 3,4-dihydroxyphenylacetic acid depletions in the striatum, indicating that the protective effect of lipopolysaccharide is less likely due to interrupted peripheral distribution or metabolism of methamphetamine. We concluded a critical time window for systemic lipopolysaccharide pretreatment in exerting effective protection against methamphetamine-induced nigrostriatal dopamine neurotoxicity.

Interleukin 1 receptor contributes to methamphetamine- and sleep deprivation-induced hypersomnolence

PubMed Central

Schmidt, Michelle A.; Wisor, Jonathan P.

2014-01-01

Methamphetamine-induced wakefulness is dependent on monoamine transporter blockade. Subsequent to methamphetamine-induced wakefulness, the amount of time spent asleep and the depth of sleep are increased relative to baseline sleep. The mechanisms that drive methamphetamine-induced hypersomnolence are not fully understood. We recently observed that methamphetamine exposure elevates the expression of the sleep-promoting cytokine, interleukin-1 β in CD11b-positive monocytes within the brain. Here, we sought to determine whether activation of the interleukin 1 receptor (IL1R) drives the increase in the depth and amount of sleep that occurs subsequent to methamphetamine-induced wakefulness. IL1R-deficient mice and wild type control mice were subjected to systemic methamphetamine (1 and 2mg/kg) and saline treatments. The wake-promoting effect of methamphetamine was modestly potentiated by IL1R-deficiency. Additionally, the increase in time spent in NREMS subsequent to methamphetamine-induced wakefulness in wild type mice was abolished in IL1R-deficient mice. The increase in time spent asleep after 3 h of behaviorally enforced wakefulness was also abolished in IL1R-deficient mice. Increases in EEG slow wave activity triggered by methamphetamine and sleep deprivation were of equal magnitude in IL1R-deficient and wild type mice. These data demonstrate that IL1R activation contributes to hypersomnolence that occurs after sleep loss, whether that sleep loss is triggered pharmacologically by methamphetamine or through behavioral sleep deprivation. PMID:22387068

Crystalline methamphetamine use and methamphetamine-related harms in Australia.

PubMed

Degenhardt, Louisa; Sara, Grant; McKetin, Rebecca; Roxburgh, Amanda; Dobbins, Timothy; Farrell, Michael; Burns, Lucinda; Hall, Wayne D

2017-03-01

Concerns about crystal methamphetamine use and harm have increased in multiple countries. This paper describes how changes in the availability and use of crystal methamphetamine have impacted on methamphetamine-related harms in Australia. Data on methamphetamine use were obtained from population-level surveys, health service data and surveys of drug use among sentinel groups of ecstasy users and people who inject drugs. Data were obtained on seizures, arrests, clandestine laboratory detections, hospital separations, mental health unit admissions, drug telephone helpline calls and drug treatment episodes. Segmented linear regression models were fitted to identify changes in these series using log-transformed data where appropriate. The availability of crystal methamphetamine has increased as evidenced by increased laboratory detections, domestic seizures and purity of the seized drug. Population surveys do not report an increase in the number of people who used at least once in the past year. However, more users report using crystal methamphetamine rather than lower-purity powder methamphetamine and more regular use. Indicators of methamphetamine-related harms have increased in parallel with this change. Amphetamine-related helpline calls, drug treatment, arrests and hospital admissions for amphetamine disorders and psychosis all peaked in the mid-2000s, declined for several years and have increased steeply since 2010. The increased availability and use of crystal methamphetamine have been associated with increased regular use and harms. Treatment is required for those experiencing problems and the capacity of health services to provide care needs to be enhanced.[Degenhardt L, Sara G, Connor JP, McKetin R, Roxburgh A, Dobbins T, Farrell M, Burns L, Hall WD. Crystalline methamphetamine use and methamphetamine-related harms in Australia. Drug Alcohol Rev 2017;36:160-170]. © 2016 Australasian Professional Society on Alcohol and other Drugs.

Effects of Electroacupuncture on Methamphetamine-Induced Behavioral Changes in Mice

PubMed Central

Lee, Chiang-Wen; Lu, Zi-Yun; Lane, Hsien-Yuan; Tsai, Ming-Horng; Ho, Ing-Kang

2017-01-01

Methamphetamine (METH) is a major drug of abuse worldwide, and no efficient therapeutic strategies for treating METH addiction are currently available. Continuous METH use can cause behavioral upregulation or psychosis. The dopaminergic pathways, particularly the neural circuitry from the ventral tegmental area to the nucleus accumbens (NAc), have a critical role in this behavioral stage. Acupuncture has been used for treating diseases in China for more than 2000 years. According to a World Health Organization report, acupuncture can be used to treat several functional disorders, including substance abuse. In addition, acupuncture is effective against opioids addiction. In this study, we used electroacupuncture (EA) for treating METH-induced behavioral changes and investigated the possible therapeutic mechanism. Results showed that EA at the unilateral Zhubin (KI9)–Taichong (LR3) significantly reduced METH-induced behavioral sensitization and conditioned place preference. In addition, both dopamine and tyrosine hydroxylase (TH) levels decreased but monoamine oxidase A (MAO-A) levels increased in the NAc of the METH-treated mice receiving EA compared with those not receiving EA. EA may be a useful nonpharmacological approach for treating METH-induced behavioral changes, probably because it reduces the METH-induced TH expression and dopamine levels and raises MAO-A expression in the NAc. PMID:28400844

Dopamine D3 receptor antagonist SB-277011A inhibits methamphetamine self-administration and methamphetamine-induced reinstatement of drug-seeking in rats

PubMed Central

Higley, Amanda E.; Kiefer, Stephen W.; Li, Xia; Gaál, József; Xi, Zheng-Xiong; Gardner, Eliot L.

2013-01-01

We have previously reported that selective blockade of brain dopamine D3 receptors by SB-277011A significantly attenuates cocaine self-administration and cocaine-induced reinstatement of drug-seeking behavior. In the present study, we investigated whether SB-277011A similarly inhibits methamphetamine self-administration and methamphetamine-induced reinstatement to drug-seeking behavior. Male Long–Evans rats were allowed to intravenously self-administer methamphetamine (0.05 mg/kg/infusion) under fixed-ratio 2 (FR2) or progressive-ratio (PR) reinforcement conditions, and some rats were tested for methamphetamine-induced reinstatement of drug-seeking behavior after extinction of self-administration. The effects of SB-277011A on each of these methamphetamine-supported behaviors were then tested. Acute intraperitoneal (i.p.) administration of SB-277011A failed to alter methamphetamine self-administration under FR2 reinforcement, but significantly lowered the break-point for methamphetamine self-administration under PR reinforcement. SB-277011A also significantly inhibited methamphetamine-triggered reinstatement of extinguished drug-seeking behavior. Overall, these data show that blockade of dopamine D3 receptors by SB-277011A attenuates the rewarding and incentive motivational effects of methamphetamine in rats, supporting the development of selective dopamine D3 antagonists for the treatment of methamphetamine addiction. PMID:21466803

Effect of 7-nitroindazole on body temperature and methamphetamine-induced dopamine toxicity.

PubMed

Callahan, B T; Ricaurte, G A

1998-08-24

The present study was undertaken to examine the role of temperature on the ability of 7-nitroindazole (7-NI) to prevent methamphetamine-induced dopamine (DA) neurotoxicity. Male Swiss-Webster mice received methamphetamine alone or in combination with 7-NI at either room temperature (20+/-1 degrees C) or at 28+/-1 degrees C. At 20+/-1 degrees C, 7-NI produced hypothermic effects and afforded total protection against methamphetamine-induced DA depletions in the striatum. At 28+/-1 degrees C, 7-NI produced minimal effects on body temperature and failed to prevent methamphetamine-induced DA reductions. These findings indicate that the neuroprotection afforded by 7-NI is likely related to its ability to produce hypothermia because agents that produce hypothermia and/or prevent hyperthermia are known to attenuate methamphetamine-induced neurotoxicity.

Incubation of methamphetamine and palatable food craving after punishment-induced abstinence.

PubMed

Krasnova, Irina N; Marchant, Nathan J; Ladenheim, Bruce; McCoy, Michael T; Panlilio, Leigh V; Bossert, Jennifer M; Shaham, Yavin; Cadet, Jean L

2014-07-01

In a rat model of drug craving and relapse, cue-induced drug seeking progressively increases after withdrawal from methamphetamine and other drugs, a phenomenon termed 'incubation of drug craving'. However, current experimental procedures used to study incubation of drug craving do not incorporate negative consequences of drug use, which is a common factor promoting abstinence in humans. Here, we studied whether incubation of methamphetamine craving is observed after suppression of drug seeking by adverse consequences (punishment). We trained rats to self-administer methamphetamine or palatable food for 9 h per day for 14 days; reward delivery was paired with a tone-light cue. Subsequently, for one group within each reward type, 50% of the lever-presses were punished by mild footshock for 9-10 days, whereas for the other group lever-presses were not punished. Shock intensity was gradually increased over time. Next, we assessed cue-induced reward seeking in 1-h extinction sessions on withdrawal days 2 and 21. Response-contingent punishment suppressed extended-access methamphetamine or food self-administration; surprisingly, food-trained rats showed greater resistance to punishment than methamphetamine-trained rats. During the relapse tests, both punished and unpunished methamphetamine- and food-trained rats showed significantly higher cue-induced reward seeking on withdrawal day 21 than on day 2. These results demonstrate that incubation of both methamphetamine and food craving occur after punishment-induced suppression of methamphetamine or palatable food self-administration. Our procedure can be used to investigate mechanisms of relapse to drug and palatable food seeking under conditions that more closely approximate the human condition.

Cyclooxygenase-2 is an obligatory factor in methamphetamine-induced neurotoxicity.

PubMed

Thomas, David M; Kuhn, Donald M

2005-05-01

Methamphetamine causes persistent damage to dopamine nerve endings of the striatum. The mechanisms underlying its neurotoxicity are not fully understood, but considerable evidence points to oxidative stress as a probable mechanism. A recent microarray analysis of gene expression changes caused by methamphetamine revealed that cyclooxygenase-2 (COX-2) was induced along with its transcription factor CCAAT/enhancer-binding protein (Thomas DM, Francescutti-Verbeem DM, Liu X, and Kuhn DM, 2004). We report presently that methamphetamine increases striatal expression of COX-2 protein. Cyclooxygenase-1 (COX-1) expression was not changed. Mice bearing a null mutation of the gene for COX-2 were resistant to methamphetamine-induced neurotoxicity. COX-1 knockouts, like wild-type mice, showed extensive dopamine nerve terminal damage. Selective inhibitors of COX-1 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethyl pyrazole (SC-560)], COX-2 [N-[2-(cyclohexyloxy)-4-nitrophenyl] methanesulfonamide (NS-398), rofecoxib], or COX-3 (antipyrine) or a nonselective inhibitor of the COX-1/2 isoforms (ketoprofen) did not protect mice from neurotoxicity. Finally, methamphetamine did not change striatal prostaglandin E(2) content. Taken together, these data suggest that COX-2 is an obligatory factor in methamphetamine-induced neurotoxicity. The functional aspect of COX-2 that contributes to drug-induced neurotoxicity does not appear to be its prostaglandin synthetic capacity. Instead, the peroxidase activity associated with COX-2, which can lead to the formation of reactive oxygen species and dopamine quinones, can account for its role.

Oxidative stress contributes to methamphetamine-induced left ventricular dysfunction.

PubMed

Lord, Kevin C; Shenouda, Sylvia K; McIlwain, Elizabeth; Charalampidis, Dimitrios; Lucchesi, Pamela A; Varner, Kurt J

2010-07-01

Our aim was to test the hypothesis that the repeated, binge administration of methamphetamine would produce oxidative stress in the myocardium leading to structural remodeling and impaired left ventricular function. Echocardiography and Millar pressure-volume catheters were used to monitor left ventricular structure and function in rats subjected to four methamphetamine binges (3 mg/kg, iv for 4 days, separated by a 10-day drug-free period). Hearts from treated and control rats were used for histological or proteomic analysis. When compared with saline treatment, four methamphetamine binges produced eccentric left ventricular hypertrophy. The drug also significantly impaired systolic function (decreased fractional shortening, ejection fraction, and adjusted maximal power) and produced significant diastolic dysfunction (increased -dP/dt and tau). Dihydroethedium staining showed that methamphetamine significantly increased (285%) the levels of reactive oxygen species in the left ventricle. Treatment with methamphetamine also resulted in the tyrosine nitration of myofilament (desmin, myosin light chain) and mitochondrial (ATP synthase, NADH dehydrogenase, cytochrome c oxidase, prohibitin) proteins. Treatment with the superoxide dismutase mimetic, tempol in the drinking water prevented methamphetamine-induced left ventricular dilation and systolic dysfunction; however, tempol (2.5 mM) did not prevent the diastolic dysfunction. Tempol significantly reduced, but did not eliminate dihydroethedium staining in the left ventricle, nor did it prevent the tyrosine nitration of mitochondrial and contractile proteins. This study shows that oxidative stress plays a significant role in mediating methamphetamine-induced eccentric left ventricular dilation and systolic dysfunction.

Incubation of Methamphetamine and Palatable Food Craving after Punishment-Induced Abstinence

PubMed Central

Krasnova, Irina N; Marchant, Nathan J; Ladenheim, Bruce; McCoy, Michael T; Panlilio, Leigh V; Bossert, Jennifer M; Shaham, Yavin; Cadet, Jean L

2014-01-01

In a rat model of drug craving and relapse, cue-induced drug seeking progressively increases after withdrawal from methamphetamine and other drugs, a phenomenon termed ‘incubation of drug craving'. However, current experimental procedures used to study incubation of drug craving do not incorporate negative consequences of drug use, which is a common factor promoting abstinence in humans. Here, we studied whether incubation of methamphetamine craving is observed after suppression of drug seeking by adverse consequences (punishment). We trained rats to self-administer methamphetamine or palatable food for 9 h per day for 14 days; reward delivery was paired with a tone-light cue. Subsequently, for one group within each reward type, 50% of the lever-presses were punished by mild footshock for 9–10 days, whereas for the other group lever-presses were not punished. Shock intensity was gradually increased over time. Next, we assessed cue-induced reward seeking in 1-h extinction sessions on withdrawal days 2 and 21. Response-contingent punishment suppressed extended-access methamphetamine or food self-administration; surprisingly, food-trained rats showed greater resistance to punishment than methamphetamine-trained rats. During the relapse tests, both punished and unpunished methamphetamine- and food-trained rats showed significantly higher cue-induced reward seeking on withdrawal day 21 than on day 2. These results demonstrate that incubation of both methamphetamine and food craving occur after punishment-induced suppression of methamphetamine or palatable food self-administration. Our procedure can be used to investigate mechanisms of relapse to drug and palatable food seeking under conditions that more closely approximate the human condition. PMID:24584329

Expression and Activity of Nitric Oxide Synthase Isoforms in Methamphetamine-Induced Striatal Dopamine Toxicity

PubMed Central

Friend, Danielle M.; Son, Jong H.; Keefe, Kristen A.

2013-01-01

Nitric oxide is implicated in methamphetamine (METH)-induced neurotoxicity; however, the source of the nitric oxide has not been identified. Previous work has also revealed that animals with partial dopamine loss induced by a neurotoxic regimen of methamphetamine fail to exhibit further decreases in striatal dopamine when re-exposed to methamphetamine 7–30 days later. The current study examined nitric oxide synthase expression and activity and protein nitration in striata of animals administered saline or neurotoxic regimens of methamphetamine at postnatal days 60 and/or 90, resulting in four treatment groups: Saline:Saline, METH:Saline, Saline:METH, and METH:METH. Acute administration of methamphetamine on postnatal day 90 (Saline:METH and METH:METH) increased nitric oxide production, as evidenced by increased protein nitration. Methamphetamine did not, however, change the expression of endothelial or inducible isoforms of nitric oxide synthase, nor did it change the number of cells positive for neuronal nitric oxide synthase mRNA expression or the amount of neuronal nitric oxide synthase mRNA per cell. However, nitric oxide synthase activity in striatal interneurons was increased in the Saline:METH and METH:METH animals. These data suggest that increased nitric oxide production after a neurotoxic regimen of methamphetamine results from increased nitric oxide synthase activity, rather than an induction of mRNA, and that constitutively expressed neuronal nitric oxide synthase is the most likely source of nitric oxide after methamphetamine administration. Of interest, animals rendered resistant to further methamphetamine-induced dopamine depletions still show equivalent degrees of methamphetamine-induced nitric oxide production, suggesting that nitric oxide production alone in response to methamphetamine is not sufficient to induce acute neurotoxic injury. PMID:23230214

Dexmedetomidine use in the ED for control of methamphetamine-induced agitation.

PubMed

Lam, Rex Pui Kin; Yip, Wai Lam; Wan, Chi Keung; Tsui, Matthew Sik Hon

2017-04-01

Chemical restraint is often required to control agitation induced by methamphetamine. Dexmedetomidine is an α-2 adrenergic receptor agonist with sedative, analgesic, and sympatholytic properties. Its use in the emergency department (ED) to control methamphetamine-induced agitation has not been reported. To report two cases of methamphetamine-induced agitation successfully sedated with dexmedetomidine in the ED. The first case was a 42-year-old man with unstable emotion and violent behaviours after smoking methamphetamine. His agitation did not respond to a large cumulative dose of benzodiazepines (10mg of diazepam and 332mg of midazolam) administered over 48h and sedation was achieved with dexmedetomidine. The second case was a 38-year-old methamphetamine user with unstable emotion and recurrent episodes of agitation despite repeated doses of benzodiazepines, whose agitation was controlled with dexmedetomidine infusion. In both cases, dexmedetomidine apparently reduced the dose of benzodiazepines needed to achieve adequate sedation. Transient falls in blood pressure and slowing of the heart rate were noted, which resolved either spontaneously or after reducing the infusion rate without requiring drug treatment. Dexmedetomidine can be considered as an adjunct for chemical restraint when standard treatment fails to control the agitation induced by methamphetamine, but patient's hemodynamic state should be monitored closely during administration. Its efficacy and safety in the ED warrant further evaluation with prospective controlled trials. Copyright © 2016 Elsevier Inc. All rights reserved.

Methamphetamine-induced dopaminergic toxicity prevented owing to the neuroprotective effects of salicylic acid.

PubMed

Thrash-Williams, Bessy; Karuppagounder, Senthilkumar S; Bhattacharya, Dwipayan; Ahuja, Manuj; Suppiramaniam, Vishnu; Dhanasekaran, Muralikrishnan

2016-06-01

Methamphetamine (Schedule-II drug, U.S. Drug Enforcement Administration) is one of the most abused illicit drug following cocaine, marijuana, and heroin in the USA. There are numerous health impairments and substantial economic burden caused by methamphetamine abuse. Salicylic acid, potent anti-inflammatory drug and a known neuroprotectant has shown to protect against toxicity-induced by other dopaminergic neurotoxins. Hence, in this study we investigated the neuroprotective effects of salicylic acid against methamphetamine-induced toxicity in mice. The current study investigated the effects of sodium salicylate and/or methamphetamine on oxidative stress, monoamine oxidase, mitochondrial complex I & IV activities using spectrophotometric and fluorimetric methods. Behavioral analysis evaluated the effect on movement disorders-induced by methamphetamine. Monoaminergic neurotransmitter levels were evaluated using high pressure liquid chromatography-electrochemical detection. Methamphetamine caused significant generation of reactive oxygen species and decreased complex-I activity leading to dopamine depletion. Striatal dopamine depletion led to significant behavioral changes associated with movement disorders. Sodium salicylate (50 & 100mg/kg) significantly scavenged reactive oxygen species, blocked mitochondrial dysfunction and exhibited neuroprotection against methamphetamine-induced neurotoxicity. In addition, sodium salicylate significantly blocked methamphetamine-induced behavioral changes related to movement abnormalities. One of the leading causative theories in nigral degeneration associated with movement disorders such as Parkinson's disease is exposure to stimulants, drugs of abuse, insecticide and pesticides. These neurotoxic substances can induce dopaminergic neuronal insult by oxidative stress, apoptosis, mitochondrial dysfunction and inflammation. Salicylic acid due to its antioxidant and anti-inflammatory effects could provide neuroprotection against the

Oxidative stress contributes to methamphetamine-induced left ventricular dysfunction

PubMed Central

Lord, Kevin C.; Shenouda, Sylvia K.; McIlwain, Elizabeth; Charalampidis, Dimitrios; Lucchesi, Pamela A.; Varner, Kurt J.

2010-01-01

Aims Our aim was to test the hypothesis that the repeated, binge administration of methamphetamine would produce oxidative stress in the myocardium leading to structural remodeling and impaired left ventricular function. Methods and results Echocardiography and Millar pressure–volume catheters were used to monitor left ventricular structure and function in rats subjected to four methamphetamine binges (3 mg/kg, iv for 4 days, separated by a 10-day drug-free period). Hearts from treated and control rats were used for histological or proteomic analysis. When compared with saline treatment, four methamphetamine binges produced eccentric left ventricular hypertrophy. The drug also significantly impaired systolic function (decreased fractional shortening, ejection fraction, and adjusted maximal power) and produced significant diastolic dysfunction (increased −dP/dt and tau). Dihydroethedium staining showed that methamphetamine significantly increased (285%) the levels of reactive oxygen species in the left ventricle. Treatment with methamphetamine also resulted in the tyrosine nitration of myofilament (desmin, myosin light chain) and mitochondrial (ATP synthase, NADH dehydrogenase, cytochrome c oxidase, prohibitin) proteins. Treatment with the superoxide dismutase mimetic, tempol in the drinking water prevented methamphetamine-induced left ventricular dilation and systolic dysfunction; however, tempol (2.5 mM) did not prevent the diastolic dysfunction. Tempol significantly reduced, but did not eliminate dihydroethedium staining in the left ventricle, nor did it prevent the tyrosine nitration of mitochondrial and contractile proteins. Conclusion This study shows that oxidative stress plays a significant role in mediating methamphetamine-induced eccentric left ventricular dilation and systolic dysfunction. PMID:20139112

Dopamine D3 receptors contribute to methamphetamine-induced alterations in dopaminergic neuronal function: Role of hyperthermia

PubMed Central

Baladi, Michelle G.; Newman, Amy H.; Nielsen, Shannon M.; Hanson, Glen R.; Fleckenstein, Annette E.

2014-01-01

Methamphetamine administration causes long-term deficits to dopaminergic systems that, in humans, are thought to be associated with motor slowing and memory impairment. Methamphetamine interacts with the dopamine transporter (DAT) and increases extracellular concentrations of dopamine that, in turn, binds to a number of dopamine receptor subtypes. Although the relative contribution of each receptor subtype to the effects of methamphetamine is not fully known, non-selective dopamine D2/D3 receptor antagonists can attenuate methamphetamine-induced changes to dopamine systems. The present study extended these findings by testing the role of the dopamine D3 receptor subtype in mediating the long-term dopaminergic, and for comparison serotonergic, deficits caused by methamphetamine. Results indicate that the dopamine D3 receptor selective antagonist, PG01037, attenuated methamphetamine-induced decreases in striatal DAT, but not hippocampal serotonin (5HT) transporter (SERT), function, as assessed 7 days after treatment. However, PG01037 also attenuated methamphetamine-induced hyperthermia. When methamphetamine-induced hyperthermia was maintained by treating rats in a warm ambient environment, PG01037 failed to attenuate the effects of methamphetamine on DAT uptake. Furthermore, PG01037 did not attenuate methamphetamine-induced decreases in dopamine and 5HT content. Taken together, the present study demonstrates that dopamine D3 receptors mediate, in part, the long-term deficits in DAT function caused by methamphetamine, and that this effect likely involves an attenuation of methamphetamine-induced hyperthermia. PMID:24685638

Dopamine D(3) receptors contribute to methamphetamine-induced alterations in dopaminergic neuronal function: role of hyperthermia.

PubMed

Baladi, Michelle G; Newman, Amy H; Nielsen, Shannon M; Hanson, Glen R; Fleckenstein, Annette E

2014-06-05

Methamphetamine administration causes long-term deficits to dopaminergic systems that, in humans, are thought to be associated with motor slowing and memory impairment. Methamphetamine interacts with the dopamine transporter (DAT) and increases extracellular concentrations of dopamine that, in turn, binds to a number of dopamine receptor subtypes. Although the relative contribution of each receptor subtype to the effects of methamphetamine is not fully known, non-selective dopamine D2/D3 receptor antagonists can attenuate methamphetamine-induced changes to dopamine systems. The present study extended these findings by testing the role of the dopamine D3 receptor subtype in mediating the long-term dopaminergic, and for comparison serotonergic, deficits caused by methamphetamine. Results indicate that the dopamine D3 receptor selective antagonist, PG01037, attenuated methamphetamine-induced decreases in striatal DAT, but not hippocampal serotonin (5HT) transporter (SERT), function, as assessed 7 days after treatment. However, PG01037 also attenuated methamphetamine-induced hyperthermia. When methamphetamine-induced hyperthermia was maintained by treating rats in a warm ambient environment, PG01037 failed to attenuate the effects of methamphetamine on DAT uptake. Furthermore, PG01037 did not attenuate methamphetamine-induced decreases in dopamine and 5HT content. Taken together, the present study demonstrates that dopamine D3 receptors mediate, in part, the long-term deficits in DAT function caused by methamphetamine, and that this effect likely involves an attenuation of methamphetamine-induced hyperthermia. Copyright © 2014 Elsevier B.V. All rights reserved.

Levetiracetam-induced acute psychosis in a child

PubMed Central

Zaki, Syed Ahmed; Gupta, Saurabh

2014-01-01

Levetiracetam is well-tolerated and commonly used as a broad spectrum antiepileptic in both partial and generalized seizures. Few cases of levetiracetam-induced psychosis in children are reported in the literature. The present case of levetiracetam-induced acute psychosis highlights the adverse effect of this drug and also emphasizes the need for close monitoring of children on levetiracetam. PMID:24987186

A comparison of psychotic symptoms in subjects with methamphetamine versus cocaine dependence.

PubMed

Alexander, Peter D; Gicas, Kristina M; Willi, Taylor S; Kim, Clara N; Boyeva, Veronika; Procyshyn, Ric M; Smith, Geoff N; Thornton, Allen E; Panenka, William J; Jones, Andrea A; Vila-Rodriguez, Fidel; Lang, Donna J; William MacEwan, G; Honer, William G; Barr, Alasdair M

2017-05-01

The psychostimulant drugs cocaine and methamphetamine are potent indirect dopamine receptor agonists which act through similar but not identical mechanisms. Studies in humans have observed that a large proportion of those who chronically use these drugs experience psychotic symptoms. However, direct comparisons of psychotic symptom severity between cocaine and methamphetamine users are lacking. The goal of the present study was to directly compare severity of psychotic symptoms between cocaine- and methamphetamine-dependent individuals. Additionally, we sought to determine how concurrent cocaine + methamphetamine dependence would influence psychotic symptoms. We recruited 153 polysubstance-using subjects meeting DSM-IV-TR criteria for cocaine dependence, 38 with methamphetamine dependence, and 32 with cocaine + methamphetamine dependence. Psychotic symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS) and analyzed using a five-factor model. All participants were also assessed for physical and mental illnesses as well as recent substance use. Most subjects completed a comprehensive neurocognitive battery. While all three groups exhibited high total PANSS scores, the positive symptom subscale was significantly higher in the methamphetamine-dependent (17.03 ± 6.3) than the cocaine-dependent group (13.51 ± 4.12) and non-significantly higher (p = 0.08) than the cocaine + methamphetamine group (14.44 ± 5.50). Groups also differed on demographic variables, viral infection, and other indices of substance use, which were unlikely to account for the difference in positive symptoms. There were only modest differences between groups in neurocognitive function. Methamphetamine dependence was associated with more severe positive symptoms of psychosis than cocaine dependence. Concurrent cocaine + methamphetamine dependence did not increase psychosis severity.

[Underlying Mechanisms of Methamphetamine-Induced Self-Injurious Behavior and Lethal Effects in Mice].

PubMed

Mori, Tomohisa; Sawaguchi, Toshiko

2018-01-01

Relatively high doses of psychostimulants induce neurotoxicity on the dopaminergic system and self-injurious behavior (SIB) in rodents. However the underlying neuronal mechanisms of SIB remains unclear. Dopamine receptor antagonists, N-methyl-D-aspartic acid (NMDA) receptor antagonists, Nitric Oxide Synthase (NOS) inhibitors and free radical scavengers significantly attenuate methamphetamine-induced SIB. These findings indicate that activation of dopamine as well as NMDA receptors followed by radical formation and oxidative stress, especially when mediated by NOS activation, is associated with methamphetamine-induced SIB. On the other hand, an increase in the incidence of polydrug abuse is a major problem worldwide. Coadministered methamphetamine and morphine induced lethality in more than 80% in mice, accompanied by an increase in the number of poly (ADP-ribose) polymerase (PARP)-immunoreactive cells in the heart, kidney and liver. The lethal effect and the increase in the incidence of rupture or PARP-immunoreactive cells induced by the coadministration of methamphetamine and morphine were significantly attenuated by pretreatment with a phospholipase A2 inhibitor or a radical scavenger, or by cooling of body from 30 to 90 min after drug administration. These results suggest that free radicals play an important role in the increased lethality induced by the coadministration of methamphetamine and morphine. Therefore, free radical scavengers and cooling are beneficial for preventing death that is induced by the coadministration of methamphetamine and morphine. These findings may help us better understand for masochistic behavior, which is a clinical phenomenon on SIB, as well as polydrug-abuse-induced acute toxicity.

Role of Prefrontal Serotonergic and Dopaminergic Systems in Encounter-Induced Hyperactivity in Methamphetamine-Sensitized Mice.

PubMed

Tanaka, Tatsunori; Ago, Yukio; Umehara, Chiaki; Imoto, Emina; Hasebe, Shigeru; Hashimoto, Hitoshi; Takuma, Kazuhiro; Matsuda, Toshio

2017-05-01

Isolation-reared mice show social encounter-induced hyperactivity with activation of prefrontal serotonergic and dopaminergic systems, but it is not known whether this stress response is observed in other pathological conditions. Here we examined whether the social encounter stimulation induces abnormal behavior during withdrawal in chronic methamphetamine-treated mice. To induce methamphetamine-induced behavioral sensitization, male mice were injected with methamphetamine (1 mg/kg) once daily for 7 days. The encounter with an intruder elicited hyperactivity 24 h after the last injection of methamphetamine in methamphetamine-sensitized mice. This response was observed even as long as 2 weeks after withdrawal of methamphetamine. The encounter increased c-Fos expression in the prefrontal cortex, dorsal raphe nucleus and ventral tegmental area in methamphetamine-sensitized mice, while it did not in control mice. Furthermore, the encounter increased extracellular serotonin (5-HT) and dopamine, but not noradrenaline, levels in the prefrontal cortex in methamphetamine-sensitized mice. Local injection of 5,7-dihydroxytryptamine and 6-hydroxydopamine into the prefrontal cortex attenuated encounter-induced hyperactivity in methamphetamine-sensitized mice and it markedly decreased prefrontal 5-HT and dopamine levels, respectively. Pharmacological analysis showed that the encounter-induced hyperactivity is mediated by dopamine D1 receptors and 5-HT2A receptors and attenuated by anxiolytics and antidepressants such as diazepam, osemozotan and selective 5-HT reuptake inhibitors. The effect of paroxetine was blocked by the 5-HT3 receptor antagonist azasetron. The present study shows that psychological stress elicits hyperactivity with activation of prefrontal 5-HT and dopamine systems in methamphetamine-dependent mice and suggests that the abnormal behavior is associated with anxiety and depression. © The Author 2016. Published by Oxford University Press on behalf of CINP.

Primary psychosis with comorbid drug abuse and drug-induced psychosis: Diagnostic and clinical evolution at follow up.

PubMed

Mauri, M C; Di Pace, C; Reggiori, A; Paletta, S; Colasanti, A

2017-10-01

The study reports a follow-up assessment of 48 patients with concomitant drug abuse at the first admission for psychosis. We focused on the diagnostic distinction between primary psychosis with concomitant drug abuse and drug induced psychosis, to observe whether the diagnoses are stable over time and whether the clinical course significantly differs. The study examined 25 primary psychotic disorder with comorbid drug abuse and 23 drug-induced psychotic disorder patients. Diagnostic and psychopathological assessments were made at baseline and at follow-up. Mean follow-up period was 4.96 years. Patients with comorbid Drug Abuse exhibited higher scores in the item Unusual Content of Thought at baseline than drug-induced psychotic disorder patients: 5.48 vs 4.39 while the two patients groups did not differ in any of the BPRS items evaluated at follow-up. The primary psychosis with comorbid drug abuse and the substance induced psychosis groups were similar regarding diagnostic stability, and a diagnosis of schizophrenia at follow-up occurred similarly. There was no evidence that Drug Induced psychotic patients' symptoms tend to improve more after cessation of drug abuse. An earlier age of onset was found in primary psychotic patients, particularly for patients diagnosed as affected by schizophrenia at follow up. These results might reflect the uncertainty of the distinction between Primary and Drug Induced Psychosis and the difficulties in applying the DSM IV-TR criteria for diagnosing comorbid drug use disorders and psychotic disorders. Copyright © 2017 Elsevier B.V. All rights reserved.

MK-801 and dextromethorphan block microglial activation and protect against methamphetamine-induced neurotoxicity.

PubMed

Thomas, David M; Kuhn, Donald M

2005-07-19

Methamphetamine causes long-term toxicity to dopamine nerve endings of the striatum. Evidence is emerging that microglia can contribute to the neuronal damage associated with disease, injury, or inflammation, but their role in methamphetamine-induced neurotoxicity has received relatively little attention. Lipopolysaccharide (LPS) and the neurotoxic HIV Tat protein, which cause dopamine neuronal toxicity after direct infusion into brain, cause activation of cultured mouse microglial cells as evidenced by increased expression of intracellular cyclooxygenase-2 and elevated secretion of tumor necrosis factor-alpha. MK-801, a non-competitive NMDA receptor antagonist that is known to protect against methamphetamine neurotoxicity, prevents microglial activation by LPS and HIV Tat. Dextromethorphan, an antitussive agent with NMDA receptor blocking properties, also prevents microglial activation. In vivo, MK-801 and dextromethorphan reduce methamphetamine-induced activation of microglia in striatum and they protect dopamine nerve endings against drug-induced nerve terminal damage. The present results indicate that the ability of MK-801 and dextromethorphan to protect against methamphetamine neurotoxicity is related to their common property as blockers of microglial activation.

Necroptosis contributes to methamphetamine-induced cytotoxicity in rat cortical neurons.

PubMed

Xiong, Kun; Liao, Huidan; Long, Lingling; Ding, Yanjun; Huang, Jufang; Yan, Jie

2016-09-01

Necroptosis, a programmed necrosis, is involved in various types of neurodegenerative diseases. In this study, we investigated whether necroptosis contributed to neuronal damage in a methamphetamine injury model. Primary cultures of embryonic cortical neurons from Sprague-Dawley rats were subjected to different doses of methamphetamine with/without pre-treatment with a specific necroptosis inhibitor, Necrostatin-1. Necrosis was assessed by determining lactate dehydrogenase release and by Annexin V/propidium iodide double staining, while the neuronal ultra-structure was examined by electron microscopy. Tumor necrosis factor-α protein levels were determined by enzyme-linked immunosorbent assay. At early stages (12h) of post-treatment with methamphetamine, significant necrosis occurred and the viability of neurons decreased in a dose- and time-dependent manner in this model of acute neuronal injury. Pretreatment with Necrostatin-1 led to significant neuronal preservation compared with the methamphetamine-treated groups. Furthermore, tumor necrosis factor-α expression increased in a dose-dependent manner following methamphetamine exposure. Methamphetamine induced necrosis in rat cortical neurons in vitro, both time and dose dependently, and necroptosis may be an important newly identified mode of cortical neuronal death caused by single high-dose methamphetamine administration. Copyright © 2016 Elsevier B.V. All rights reserved.

White matter microstructure and impulsivity in methamphetamine dependence with and without a history of psychosis.

PubMed

Uhlmann, Anne; Fouche, Jean-Paul; Lederer, Katharina; Meintjes, Ernesta M; Wilson, Don; Stein, Dan J

2016-06-01

Methamphetamine (MA) use may lead to white matter injury and to a range of behavioral problems and psychiatric disorders, including psychosis. The present study sought to assess white matter microstructural impairment as well as impulsive behavior in MA dependence and MA-associated psychosis (MAP). Thirty patients with a history of MAP, 39 participants with MA dependence and 40 healthy controls underwent diffusion tensor imaging (DTI). Participants also completed the UPPS-P impulsive behavior questionnaire. We applied tract-based spatial statistics (TBSS) to investigate group differences in mean diffusivity (MD), fractional anisotropy (FA), axial (λ‖ ) and radial diffusivity (λ⊥ ), and their association with impulsivity scores and psychotic symptoms. The MAP group displayed widespread higher MD, λ‖ and λ⊥ levels compared to both controls and the MA group, and lower FA in extensive white matter areas relative to controls. MD levels correlated positively with negative psychotic symptoms in MAP. No significant DTI group differences were found between the MA group and controls. Both clinical groups showed high levels of impulsivity, and this dysfunction was associated with DTI measures in frontal white matter tracts. MAP patients show distinct patterns of impaired white matter integrity of global nature relative to controls and the MA group. Future work to investigate the precise nature and timing of alterations in MAP is needed. The results are further suggestive of frontal white matter pathology playing a role in impulsivity in MA dependence and MAP. Hum Brain Mapp 37:2055-2067, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Methamphetamine-induced alterations in monoamine transport: implications for neurotoxicity, neuroprotection and treatment.

PubMed

Volz, Trent J; Fleckenstein, Annette E; Hanson, Glen R

2007-04-01

To review studies delineating the neurotoxic effects of methamphetamine on monoamine transport in dopaminergic neurons of the striatum and nucleus accumbens. The scope of this review includes the English language dopamine transporter and vesicular monoamine transporter-2 primary literature to April 2006 identified by Pubmed, Science Citation Index and SciFinder Scholar literature searches. Changes in the function of the plasmalemmal dopamine transporter and the vesicular monoamine transporter-2 are key components of methamphetamine-induced persistent dopaminergic deficits. These deficits include persistent reductions in dopamine content, dopamine transporter density and tyrosine hydroxylase activity. The striatum is susceptible to these effects of methamphetamine while the nucleus accumbens is resistant. Differences in dopamine transporter density and activity, extracellular dopamine levels and antioxidant levels in these two brain regions may, in part, account for the resistance of the nucleus accumbens. These findings concerning the nature of methamphetamine-induced changes in plasmalemmal and vesicular dopamine transport have very important implications for drug targets and for understanding the etiology of dopaminergic neurodegenerative processes, such as those associated with methamphetamine addiction and Parkinson's disease.

Role for excitatory amino acids in methamphetamine-induced nigrostriatal dopaminergic toxicity.

PubMed

Sonsalla, P K; Nicklas, W J; Heikkila, R E

1989-01-20

The systemic administration of either methamphetamine or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to experimental animals produces degenerative changes in nigrostriatal dopaminergic neurons or their axon terminals. This study was conducted to determine if excitatory amino acids, which appear to be involved in various neurodegenerative disorders, might also contribute to the dopaminergic neurotoxicity produced in mice by either methamphetamine or MPTP. MK-801, phencyclidine, and ketamine, noncompetitive antagonists of one subtype of excitatory amino acid receptor, the N-methyl-D-aspartate receptor, provided substantial protection against neurotoxicity produced by methamphetamine but not that produced by MPTP. These findings indicate that excitatory amino acids play an important role in the nigrostriatal dopaminergic damage induced by methamphetamine.

N,N-Dimethyltryptamine-Induced Psychosis.

PubMed

Paterson, Neil E; Darby, W Connor; Sandhu, Preetpal S

2015-01-01

N,N-dimethyltryptamine (DMT) is a 5-hydroxytryptamine 2A and 1A receptor agonist that exhibits potent psychoactive properties in humans. Recreational use of this drug has increased precipitously and is likely to result in an increase in patients presenting with substance-induced psychoses. The present case provides an early example of substance-induced psychosis attributable to repeated use of DMT. A 42-year-old white man, with no significant past psychiatric history, was brought to the emergency department by the police and was found to exhibit disinhibited behavior, elevated affect, disorganized thought process, and delusions of reference. Laboratory studies revealed elevated creatinine kinase level indicative of rhabdomyolysis. The patient endorsed recent and repeated use of DMT, as well as long-term Cannabis (marijuana) use. Over the course of the next 3 weeks, the patient was successfully treated with quetiapine for psychosis, divalproex sodium (Depakote) for impulsivity, gabapentin for anxiety, and hydroxyzine for sleep, which resulted in the resolution of his symptoms and development of reasonable insight and judgment. Approximately 6 months after discharge, the patient remained treatment compliant, as well as drug and symptom free. This case report illustrates an important example of substance-induced psychosis that resolved with antipsychotic treatment in a 42-year-old white man with no past psychiatric history likely attributable to the use of DMT. Given the increasing use of this substance, the emergency department, primary care, and inpatient services are likely to see a significant increase in similar cases.

Neurologic Manifestations of Chronic Methamphetamine Abuse

PubMed Central

Rusyniak, Daniel E.

2013-01-01

COMMENTARY ON METHAMPHETAMINE ABUSE FOR PSYCHIATRIC PRACTICE Every decade seems to have its own unique drug problem. The 1970s had hallucinogens, the 1980s had crack cocaine, the 1990s had designer drugs, the 2000s had methamphetamine (Meth), and in the 2010s we are dealing with the scourge of prescription drug abuse. While each of these drug epidemics has distinctive problems and history, the one with perhaps the greatest impact on the practice of Psychiatry is Meth. By increasing the extracellular concentrations of dopamine while slowly damaging the dopaminergic neurotransmission, Meth is a powerfully addictive drug whose chronic use preferentially causes psychiatric complications. Chronic Meth users have deficits in memory and executive functioning as well as higher rates of anxiety, depression, and most notably psychosis. It is because of addiction and chronic psychosis from Meth abuse that the Meth user is most likely to come to the attention of the practicing Psychiatrist/Psychologist. Understanding the chronic neurologic manifestations of Meth abuse will better arm practitioners with the diagnostic and therapeutic tools needed to make the Meth epidemic one of historical interest only. PMID:23688691

ACTIVATION OF MU OPIOID RECEPTORS IN THE STRIATUM DIFFERENTIALLY AUGMENTS METHAMPHETAMINE-INDUCED GENE EXPRESSION AND ENHANCES STEREOTYPIC BEHAVIOR

PubMed Central

Horner, Kristen A.; Hebbard, John C.; Logan, Anna S.; Vanchipurakel, Golda A.; Gilbert, Yamiece E.

2013-01-01

Mu opioid receptors are densely expressed in the patch compartment of striatum and contribute to methamphetamine-induced patch-enhanced gene expression and stereotypy. In order to further elucidate the role of mu opioid receptor activation in these phenomena, we examined whether activation of mu opioid receptors would enhance methamphetamine-induced stereotypy and prodynorphin, c-fos, arc and zif/268 expression in the patch and/or matrix compartments of striatum, as well as the impact of mu opioid receptor activation on the relationship between patch-enhanced gene expression and stereotypy. Male Sprague-Dawley rats were intrastriatally infused with D-Ala(2)-N-Me-Phe(4),Gly(5)-ol]enkephalin (DAMGO; 1 μg/μl), treated with methamphetamine (0.5 mg/kg) and sacrificed at 45 minutes or 2 hours later. DAMGO augmented methamphetamine-induced zif/268 mRNA expression in the patch and matrix compartments, while prodynorphin expression was increased in the dorsolateral patch compartment. DAMGO pretreatment did not affect methamphetamine-induced arc and c-fos expression. DAMGO enhanced methamphetamine-induced stereotypy and resulted in greater patch versus matrix expression of prodynorphin in the dorsolateral striatum, leading to a negative correlation between the two. These findings indicate that mu opioid receptors contribute to methamphetamine-induced stereotypy, but can differentially influence the genomic responses to methamphetamine. These data also suggest that prodynorphin may offset the overstimulation of striatal neurons by methamphetamine. PMID:22150526

Chlorogenic and Caftaric Acids in Liver Toxicity and Oxidative Stress Induced by Methamphetamine

PubMed Central

Koriem, Khaled M. M.; Soliman, Rowan E.

2014-01-01

Methamphetamine intoxication can cause acute hepatic failure. Chlorogenic and caftaric acids are the major dietary polyphenols present in various foods. The aim of this study was to evaluate the protective role of chlorogenic and caftaric acids in liver toxicity and oxidative stress induced by methamphetamine in rats. Thirty-two male albino rats were divided into 4 equal groups. Group 1, which was control group, was injected (i.p) with saline (1 mL/kg) twice a day over seven-day period. Groups 2, 3, and 4 were injected (i.p) with methamphetamine (10 mg/kg) twice a day over seven-day period, where groups 3 and 4 were injected (i.p) with 60 mg/kg chlorogenic acid and 40 mg/kg caftaric acid, respectively, one day before methamphetamine injections. Methamphetamine increased serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, bilirubin, cholesterol, low-density lipoprotein, and triglycerides. Also, malondialdehyde in serum, liver, and brain and plasma and liver nitric oxide levels were increased while methamphetamine induced a significant decrease in serum total protein, albumin, globulin, albumin/globulin ratio, brain serotonin, norepinephrine and dopamine, blood and liver superoxide dismutase, and glutathione peroxidase levels. Chlorogenic and caftaric acids prior to methamphetamine injections restored all the above parameters to normal values. In conclusion, chlorogenic and caftaric acids before methamphetamine injections prevented liver toxicity and oxidative stress where chlorogenic acid was more effective. PMID:25136360

Pharmacological evaluation of SN79, a sigma (σ) receptor ligand, against methamphetamine-induced neurotoxicity in vivo

PubMed Central

Kaushal, Nidhi; Seminerio, Michael J.; Robson, Matthew J.; McCurdy, Christopher R.; Matsumoto, Rae R.

2013-01-01

Methamphetamine is a highly addictive psychostimulant drug of abuse, causing hyperthermia and neurotoxicity at high doses. Currently, there is no clinically proven pharmacotherapy to treat these effects of methamphetamine, necessitating identification of potential novel therapeutic targets. Earlier studies showed that methamphetamine binds to sigma (σ) receptors in the brain at physiologically relevant concentrations, where it acts in part as an agonist. SN79 (6-acetyl-3-(4-(4-(4-florophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one) was synthesized as a putative σ receptor antagonist with nanomolar affinity and selectivity for σ receptors over 57 other binding sites. SN79 pretreatment afforded protection against methamphetamine-induced hyperthermia and striatal dopaminergic and serotonergic neurotoxicity in male, Swiss Webster mice (measured as depletions in striatal dopamine and serotonin levels, and reductions in striatal dopamine and serotonin transporter expression levels). In contrast, di-o-tolylguanidine (DTG), a well established σ receptor agonist, increased the lethal effects of methamphetamine, although it did not further exacerbate methamphetamine-induced hyperthermia. Together, the data implicate σ receptors in the direct modulation of some effects of methamphetamine such as lethality, while having a modulatory role which can mitigate other methamphetamine-induced effects such as hyperthermia and neurotoxicity. PMID:22921523

Pharmacological evaluation of SN79, a sigma (σ) receptor ligand, against methamphetamine-induced neurotoxicity in vivo.

PubMed

Kaushal, Nidhi; Seminerio, Michael J; Robson, Matthew J; McCurdy, Christopher R; Matsumoto, Rae R

2013-08-01

Methamphetamine is a highly addictive psychostimulant drug of abuse, causing hyperthermia and neurotoxicity at high doses. Currently, there is no clinically proven pharmacotherapy to treat these effects of methamphetamine, necessitating identification of potential novel therapeutic targets. Earlier studies showed that methamphetamine binds to sigma (σ) receptors in the brain at physiologically relevant concentrations, where it "acts in part as an agonist." SN79 (6-acetyl-3-(4-(4-(4-florophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one) was synthesized as a putative σ receptor antagonist with nanomolar affinity and selectivity for σ receptors over 57 other binding sites. SN79 pretreatment afforded protection against methamphetamine-induced hyperthermia and striatal dopaminergic and serotonergic neurotoxicity in male, Swiss Webster mice (measured as depletions in striatal dopamine and serotonin levels, and reductions in striatal dopamine and serotonin transporter expression levels). In contrast, di-o-tolylguanidine (DTG), a well established σ receptor agonist, increased the lethal effects of methamphetamine, although it did not further exacerbate methamphetamine-induced hyperthermia. Together, the data implicate σ receptors in the direct modulation of some effects of methamphetamine such as lethality, while having a modulatory role which can mitigate other methamphetamine-induced effects such as hyperthermia and neurotoxicity. Copyright © 2012 Elsevier B.V. and ECNP. All rights reserved.

Tamoxifen protects male mice nigrostriatal dopamine against methamphetamine-induced toxicity.

PubMed

Bourque, Mélanie; Liu, Bin; Dluzen, Dean E; Di Paolo, Thérèse

2007-11-01

The selective estrogen receptor modulator tamoxifen and estradiol were shown to protect nigrostriatal dopamine concentration loss by methamphetamine in female mice whereas male mice were protected only by tamoxifen. The present study examined the protective properties of tamoxifen in male mice on several nigrostriatal dopaminergic markers and body temperature. Intact male mice were administered 12.5 or 50 microg tamoxifen 24 h before methamphetamine treatment. Basal body temperatures of male mice remained unchanged by the tamoxifen treatment. Methamphetamine reduced striatal dopamine and its metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid concentrations, striatal and substantia nigra dopamine and vesicular monoamine transporter specific binding as well substantia nigra dopamine and vesicular monoamine transporter mRNA levels and increased striatal preproenkephalin mRNA levels. These methamphetamine effects were not altered by 12.5 microg tamoxifen except for increased striatal dopamine metabolites and turnover. Tamoxifen at 50 microg reduced the methamphetamine effect on striatal dopamine concentration, dopamine transporter specific binding and prevented the increase in preproenkephalin mRNA levels; in the substantia nigra tamoxifen prevented the decrease of dopamine transporter mRNA levels. The present results show a tamoxifen dose-dependent prevention of loss of various dopaminergic markers against methamphetamine-induced toxicity in male mice. Since this is the only known hormonal protection of male mice against methamphetamine toxicity, these findings provide important new information on specific parameters of nigrostriatal dopaminergic function preserved by tamoxifen.

Age-dependent methamphetamine-induced alterations in vesicular monoamine transporter-2 function: implications for neurotoxicity.

PubMed

Truong, Jannine G; Wilkins, Diana G; Baudys, Jakub; Crouch, Dennis J; Johnson-Davis, Kamisha L; Gibb, James W; Hanson, Glen R; Fleckenstein, Annette E

2005-09-01

Tens of thousands of adolescents and young adults have used illicit methamphetamine. This is of concern since its high-dose administration causes persistent dopaminergic deficits in adult animal models. The effects in adolescents are less studied. In adult rodents, toxic effects of methamphetamine may result partly from aberrant cytosolic dopamine accumulation and subsequent reactive oxygen species formation. The vesicular monoamine transporter-2 (VMAT-2) sequesters cytoplasmic dopamine into synaptic vesicles for storage and perhaps protection against dopamine-associated oxidative consequences. Accordingly, aberrant VMAT-2 function may contribute to the methamphetamine-induced persistent dopaminergic deficits. Hence, this study examined effects of methamphetamine on VMAT-2 in adolescent (postnatal day 40) and young adult (postnatal day 90) rats. Results revealed that high-dose methamphetamine treatment caused greater acute (within 1 h) decreases in vesicular dopamine uptake in postnatal day 90 versus 40 rats, as determined in a nonmembrane-associated subcellular fraction. Greater basal levels of VMAT-2 at postnatal day 90 versus 40 in this purified fraction seemed to contribute to the larger effect. Basal tissue dopamine content was also greater in postnatal day 90 versus 40 rats. In addition, postnatal day 90 rats were more susceptible to methamphetamine-induced persistent dopaminergic deficits as assessed by measuring VMAT-2 activity and dopamine content 7 days after treatment, even if drug doses were adjusted for age-related pharmacokinetic differences. Together, these data demonstrate dynamic changes in VMAT-2 susceptibility to methamphetamine as a function of development. Implications with regard to methamphetamine-induced dopaminergic deficits, as well as dopamine-associated neurodegenerative disorders such as Parkinson's disease, are discussed.

[Minocycline as a therapeutic drug for methamphetamine use disorders].

PubMed

Hashimoto, Kenji

2008-02-01

Use of methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) is an extremely serious and growing problem throughout the world, including Japan. Antipsychotic drugs have been used for psychotic symptoms associated with these abused drugs. However, there are currently no particular pharmacological treatments for the wide range of symptoms associated with these abused drugs. Recently, we reported that the second generation antibiotic drug minocycline can attenuate behavioral abnormalities and neurotoxicity in the brain after administration of methamphetamine or MDMA. In this review, we discuss minocycline as a new potential therapeutic drug for schizophrenia as well as psychosis associated with these abused drugs.

Chronic wheel running-induced reduction of extinction and reinstatement of methamphetamine seeking in methamphetamine dependent rats is associated with reduced number of periaqueductal gray dopamine neurons

PubMed Central

Sobieraj, Jeffery C.; Kim, Airee; Fannon, McKenzie J.; Mandyam, Chitra D.

2015-01-01

Exercise (physical activity) has been proposed as a treatment for drug addiction. In rodents, voluntary wheel running reduces cocaine and nicotine seeking during extinction, and reinstatement of cocaine seeking triggered by drug cues. The purpose of this study was to examine the effects of chronic wheel running during withdrawal and protracted abstinence on extinction and reinstatement of methamphetamine seeking in methamphetamine dependent rats, and to determine a potential neurobiological correlate underlying the effects. Rats were given extended access to methamphetamine (0.05 mg/kg, 6h/day) for 22 sessions. Rats were withdrawn and were given access to running wheels (wheel runners) or no wheels (sedentary) for three weeks after which they experienced extinction and reinstatement of methamphetamine seeking. Extended access to methamphetamine self-administration produced escalation in methamphetamine intake. Methamphetamine experience reduced running output, and conversely, access to wheel running during withdrawal reduced responding during extinction and, context- and cue-induced reinstatement of methamphetamine seeking. Immunohistochemical analysis of brain tissue demonstrated that wheel running during withdrawal did not regulate markers of methamphetamine neurotoxicity (neurogenesis, neuronal nitric oxide synthase, vesicular monoamine transporter-2) and cellular activation (c-Fos) in brain regions involved in relapse to drug seeking. However, reduced methamphetamine seeking was associated with running-induced reduction (and normalization) of the number of tyrosine hydroxylase (TH) immunoreactive neurons in the periaqueductal gray (PAG). The present study provides evidence that dopamine neurons of the PAG region show adaptive biochemical changes during methamphetamine seeking in methamphetamine dependent rats and wheel running abolishes these effects. Given that the PAG dopamine neurons project onto the structures of the extended amygdala, the present findings

Chronic wheel running-induced reduction of extinction and reinstatement of methamphetamine seeking in methamphetamine dependent rats is associated with reduced number of periaqueductal gray dopamine neurons.

PubMed

Sobieraj, Jeffery C; Kim, Airee; Fannon, McKenzie J; Mandyam, Chitra D

2016-01-01

Exercise (physical activity) has been proposed as a treatment for drug addiction. In rodents, voluntary wheel running reduces cocaine and nicotine seeking during extinction, and reinstatement of cocaine seeking triggered by drug-cues. The purpose of this study was to examine the effects of chronic wheel running during withdrawal and protracted abstinence on extinction and reinstatement of methamphetamine seeking in methamphetamine dependent rats, and to determine a potential neurobiological correlate underlying the effects. Rats were given extended access to methamphetamine (0.05 mg/kg, 6 h/day) for 22 sessions. Rats were withdrawn and were given access to running wheels (wheel runners) or no wheels (sedentary) for 3 weeks after which they experienced extinction and reinstatement of methamphetamine seeking. Extended access to methamphetamine self-administration produced escalation in methamphetamine intake. Methamphetamine experience reduced running output, and conversely, access to wheel running during withdrawal reduced responding during extinction and, context- and cue-induced reinstatement of methamphetamine seeking. Immunohistochemical analysis of brain tissue demonstrated that wheel running during withdrawal did not regulate markers of methamphetamine neurotoxicity (neurogenesis, neuronal nitric oxide synthase, vesicular monoamine transporter-2) and cellular activation (c-Fos) in brain regions involved in relapse to drug seeking. However, reduced methamphetamine seeking was associated with running-induced reduction (and normalization) of the number of tyrosine hydroxylase immunoreactive neurons in the periaqueductal gray (PAG). The present study provides evidence that dopamine neurons of the PAG region show adaptive biochemical changes during methamphetamine seeking in methamphetamine dependent rats and wheel running abolishes these effects. Given that the PAG dopamine neurons project onto the structures of the extended amygdala, the present findings also

Limonene inhibits methamphetamine-induced locomotor activity via regulation of 5-HT neuronal function and dopamine release.

PubMed

Yun, Jaesuk

2014-05-15

Methamphetamine is a psychomotor stimulant that produces hyperlocomotion in rodents. Limonene (a cyclic terpene from citrus essential oils) has been reported to induce sedative effects. In this study, we demonstrated that limonene administration significantly inhibited serotonin (5-hydroxytryptamine, 5-HT)-induced head twitch response in mice. In rats, pretreatment with limonene decreased hyperlocomotion induced by methamphetamine injection. In addition, limonene reversed the increase in dopamine levels in the nucleus accumbens of rats given methamphetamine. These results suggest that limonene may inhibit stimulant-induced behavioral changes via regulating dopamine levels and 5-HT receptor function. Copyright © 2013 Elsevier GmbH. All rights reserved.

Rates and Predictors of Conversion to Schizophrenia or Bipolar Disorder Following Substance-Induced Psychosis.

PubMed

Starzer, Marie Stefanie Kejser; Nordentoft, Merete; Hjorthøj, Carsten

2018-04-01

The authors investigated the rates of conversion to schizophrenia and bipolar disorder after a substance-induced psychosis, as well as risk factors for conversion. All patient information was extracted from the Danish Civil Registration System and the Psychiatric Central Research Register. The study population included all persons who received a diagnosis of substance-induced psychosis between 1994 and 2014 (N=6,788); patients were followed until first occurrence of schizophrenia or bipolar disorder or until death, emigration, or August 2014. The Kaplan-Meier method was used to obtain cumulative probabilities for the conversion from a substance-induced psychosis to schizophrenia or bipolar disorder. Cox proportional hazards regression models were used to calculate hazard ratios for all covariates. Overall, 32.2% (95% CI=29.7-34.9) of patients with a substance-induced psychosis converted to either bipolar or schizophrenia-spectrum disorders. The highest conversion rate was found for cannabis-induced psychosis, with 47.4% (95% CI=42.7-52.3) converting to either schizophrenia or bipolar disorder. Young age was associated with a higher risk of converting to schizophrenia. Self-harm after a substance-induced psychosis was significantly linked to a higher risk of converting to both schizophrenia and bipolar disorder. Half the cases of conversion to schizophrenia occurred within 3.1 years after a substance-induced psychosis, and half the cases of conversion to bipolar disorder occurred within 4.4 years. Substance-induced psychosis is strongly associated with the development of severe mental illness, and a long follow-up period is needed to identify the majority of cases.

Melatonin attenuates methamphetamine-induced neuroinflammation through the melatonin receptor in the SH-SY5Y cell line.

PubMed

Wongprayoon, Pawaris; Govitrapong, Piyarat

2015-09-01

Methamphetamine is a well-known psychostimulant drug, the abuse of which is a serious worldwide public health issue. In addition to its addictive effect, methamphetamine exposure has been shown to be associated with neuroinflammation in several brain areas. Several lines of evidence indicate that TNFα plays an important role in the methamphetamine-induced neuroinflammatory processes that result in apoptotic cell death. Many investigators have demonstrated the anti-neuroinflammatory effects of melatonin, but the mechanism by which this occurs still needs to be explored. In this study, we investigated the effect of methamphetamine on TNFα expression and NFκB activation in the neuroblastoma cell line SH-SY5Y. We demonstrated the time-dependent effect of methamphetamine on the induction of TNFα expression as well as IκB degradation and NFκB nuclear translocation. Furthermore, we investigated the effect of melatonin on methamphetamine-induced TNFα overexpression and NFκB activation. The results showed that pretreatment with 100nM melatonin could prevent the TNFα overexpression caused by methamphetamine exposure. This attenuating effect was prevented by pre-incubation with luzindole, an antagonist of the melatonin MT1/MT2 receptors. Furthermore, methamphetamine-induced IκB degradation and NFκB nuclear translocation were also suppressed by pretreatment with melatonin, and pretreatment with luzindole diminished these protective effects. MT2 knockdown by siRNA abrogated the anti-inflammatory effect exerted by melatonin. From these findings, we propose that melatonin exerts its protective effects on methamphetamine-induced neuroinflammation through the membrane receptor, at least in part MT2 subtype, in the SH-SY5Y neuroblastoma cell line. Copyright © 2015 Elsevier Inc. All rights reserved.

A Sex- and Region-Specific Role of Akt1 in the Modulation of Methamphetamine-Induced Hyperlocomotion and Striatal Neuronal Activity: Implications in Schizophrenia and Methamphetamine-Induced Psychosis

PubMed Central

Lai, Wen-Sung

2014-01-01

AKT1 (also known as protein kinase B, α), a serine/threonine kinase of AKT family, has been implicated in both schizophrenia and methamphetamine (Meth) use disorders. AKT1 or its protein also has epistatic effects on the regulation of dopamine-dependent behaviors or drug effects, especially in the striatum. The aim of this study is to investigate the sex-specific role of Akt1 in the regulation of Meth-induced behavioral sensitization and the alterations of striatal neurons using Akt1 −/− mice and wild-type littermates as a model. A series of 4 Experiments were conducted. Meth-induced hyperlocomotion and Meth-related alterations of brain activity were measured. The neural properties of striatal medium spiny neurons (MSNs) were also characterized. Further, 17β-estradiol was applied to examine its protective effect in Meth-sensitized male mice. Our findings indicate that (1) Akt1 −/− males were less sensitive to Meth-induced hyperlocomotion during Meth challenge compared with wild-type controls and Akt1 −/− females, (2) further sex differences were revealed by coinjection of Meth with raclopride but not SCH23390 in Meth-sensitized Akt1 −/− males, (3) Meth-induced alterations of striatal activity were confirmed in Akt1 −/− males using microPET scan with 18F-flurodeoxyglucose, (4) Akt1 deficiency had a significant impact on the electrophysiological and neuromorphological properties of striatal MSNs in male mice, and (5) subchronic injections of 17β-estradiol prevented the reduction of Meth-induced hyperactivity in Meth-sensitized Akt1 −/− male mice. This study highlights a sex- and region-specific effect of Akt1 in the regulation of dopamine-dependent behaviors and implies the importance of AKT1 in the modulation of sex differences in Meth sensitivity and schizophrenia. PMID:23474853

Melatonin in concentrated ethanol and ethanol alone attenuate methamphetamine-induced dopamine depletions in C57BL/6J mice.

PubMed

Yu, L; Cherng, C-F G; Chen, C

2002-12-01

The present study aimed to investigate the protective effects of melatonin, ethanol and temperature changes on methamphetamine-induced neurotoxicity in both sexes of mice. Mice exhibited a similar degree of striatal dopamine depletion when methamphetamine was administered during the light and dark cycles. Moreover, 10 mg/kg, but not 5 mg/kg, of methamphetamine, significantly increased body temperature even though dopamine depletions were observed following both doses. Melatonin (80 mg/kg) dissolved in 30% (v/v) ethanol and 30% ethanol alone exerted a moderate to full protection against methamphetamine-induced dopamine depletions in both sexes of mice, whereas the same dose of melatonin in 3% ethanol exerted no protective effect. Furthermore, ethanol attenuated methamphetamine-induced dopamine depletions in a dose-dependent manner with the exception of high efficacy of ethanol at low doses. Finally, the protective effects of ethanol were not blocked by bicuculline. Together, we conclude that ethanol may protect mice against methamphetamine-induced dopamine depletion probably via non-GABAA receptor activation.

Nicotine and varenicline ameliorate changes in reward-based choice strategy and altered decision-making in methamphetamine-treated rats.

PubMed

Mizoguchi, Hiroyuki; Wang, Tian; Kusaba, Mizuki; Fukumoto, Kazuya; Yamada, Kiyofumi

2018-06-20

Patients suffering from neuropsychiatric disorders such as substance use and addiction disorders show impaired decision-making, which may be associated with their psychiatric disorders. Previously, using a gambling test for rodents, we demonstrated that methamphetamine-dependent rats showed alterations in their decision-making strategy. In this study, we investigated the effect of nicotine on impaired decision-making strategy in rats which have been treated repeatedly with methamphetamine. Nicotine has previously been shown to have therapeutic effects on attentional and cognitive abnormalities in psychosis. Rats were administered methamphetamine subcutaneously (sc) at 4 mg/kg once a day, for 30 days, and their decision-making was then assessed with a rodent gambling task. We found that methamphetamine-treated rats preferred the high-risk/high-return actions, which is consistent with our previous findings. Methamphetamine-induced impairment of decision-making was reversed by daily nicotine treatment (0.3 mg/kg, sc). This effect was associated with the reduction of lose-shift behavior after negative reward prediction error. Repeated treatment with nicotine had no effects on arm-choice behavior in naïve rats. Varenicline, an α4β2-nicotinic acetylcholine receptor partial agonist, also ameliorated the altered decision-making in methamphetamine-treated rats. Our findings suggest that nicotine treatment is useful for ameliorating the altered decision-making caused by methamphetamine treatment, and that the α4β2-nicotinic acetylcholine receptor is a therapeutic target for poor decision-making. Copyright © 2018. Published by Elsevier B.V.

Drug-induced parkinsonism following chronic methamphetamine use by a patient on haloperidol decanoate.

PubMed

Matthew, Binoj J; Gedzior, Joanna S

2015-01-01

This report attempts to highlight that use of an antipsychotic and concurrent chronic use of methamphetamine can cause drug-induced parkinsonism. Methamphetamine is usually not encountered in the list of agents that induce drug-induced parkinsonism and so its consideration particularly during chronic use by a patient who is also on an antipsychotic is worthwhile because of its popularity as an illegal narcotic. This case report describes just such a case of drug-induced parkinsonism which is a subacute syndrome that mimics Parkinson's disease. Although less alarming than dystonia, it is more common, more difficult to treat and can be the cause of significant disability during maintenance treatment especially in the elderly. In most cases, symptoms are reversible in days or weeks, but occasionally, especially in the elderly, or if long-acting injectable antipsychotics are used-as in this case-symptoms may last for weeks or months. The report also illustrates the neuronal workings due to chronic methamphetamine-use and the additive effects of dopamine blockade by antipsychotics such as haloperidol. © The Author(s) 2015.

Methamphetamine-induced increases in putamen gray matter associate with inhibitory control.

PubMed

Groman, Stephanie M; Morales, Angelica M; Lee, Buyean; London, Edythe D; Jentsch, James David

2013-10-01

Problematic drug use is associated with difficulty in exerting self-control over behaviors, and this difficulty may be a consequence of atypical morphometric characteristics that are exhibited by drug-experienced individuals. The extent to which these structural abnormalities result from drug use or reflect neurobiological risk factors that predate drug use, however, is unknown. The purpose of this study is to determine how methamphetamine affects corticostriatal structure and how drug-induced changes relate to alterations in inhibitory control. Structural magnetic resonance images and positron emission tomography (PET) scans, assessing dopamine D₂-like receptor and transporter availability, were acquired in monkeys trained to acquire, retain, and reverse three-choice visual discrimination problems before and after exposure to an escalating dose regimen of methamphetamine (or saline, as a control). Voxel-based morphometry was used to compare changes in corticostriatal gray matter between methamphetamine- and saline-exposed monkeys. The change in gray matter before and after the dosing regimen was compared to the change in the behavioral performance and in dopaminergic markers measured with PET. Methamphetamine exposure, compared to saline, increased gray matter within the right putamen. These changes were positively correlated with changes in performance of methamphetamine-exposed monkeys in the reversal phase, and were negatively correlated with alterations in D₂-like receptor and DAT availability. The results provide the first evidence that exposure to a methamphetamine dosing regimen that resembles human use alters the structural integrity of the striatum and that gray-matter abnormalities detected in human methamphetamine users are due, at least in part, to the pharmacological effects of drug experience.

Sigma receptor antagonists attenuate acute methamphetamine-induced hyperthermia by a mechanism independent of IL-1β mRNA expression in the hypothalamus

PubMed Central

Seminerio, Michael J.; Robson, Matthew J.; McCurdy, Christopher R.; Matsumoto, Rae R.

2013-01-01

Methamphetamine is currently one of the most widely abused drugs worldwide, with hyperthermia being a leading cause of death in methamphetamine overdose situations. Methamphetamine-induced hyperthermia involves a variety of cellular mechanisms, including increases in hypothalamic interleukin-1 beta (IL-1β) expression. Methamphetamine also interacts with sigma receptors and previous studies have shown that sigma receptor antagonists mitigate many of the behavioral and physiological effects of methamphetamine, including hyperthermia. The purpose of the current study was to determine if the attenuation of methamphetamine-induced hyperthermia by the sigma receptor antagonists, AZ66 and SN79, is associated with a concomitant attenuation of IL-1β mRNA expression, particularly in the hypothalamus. Methamphetamine produced doseand time-dependent increases in core body temperature and IL-1β mRNA expression in the hypothalamus, striatum, and cortex in male, Swiss Webster mice. Pretreatment with the sigma receptor antagonists, AZ66 and SN79, significantly attenuated methamphetamine-induced hyperthermia, but further potentiated IL-1β mRNA in the mouse hypothalamus when compared to animals treated with methamphetamine alone. These findings suggest sigma receptor antagonists attenuate methamphetamine-induced hyperthermia through a different mechanism from that involved in the modulation of hypothalamic IL-1β mRNA expression. PMID:22820108

Metabolite alterations in basal ganglia associated with methamphetamine-related psychiatric symptoms. A proton MRS study.

PubMed

Sekine, Yoshimoto; Minabe, Yoshio; Kawai, Masayoshi; Suzuki, Katsuaki; Iyo, Masaomi; Isoda, Haruo; Sakahara, Harumi; Ashby, Charles R; Takei, Nori; Mori, Norio

2002-09-01

Following the chronic use of methamphetamine, some individuals experience psychosis and anxiety. One reason may be the persistence of metabolite abnormalities in the brain of currently abstinent former methamphetamine users. In this study, N-acetylaspartate (NAA), creatine plus phosphocreatine (Cr+PCr), and choline-containing compound (Cho) levels were measured in the left and right basal ganglia using proton magnetic resonance spectroscopy (MRS) in 13 abstinent methamphetamine users and 11 healthy comparison subjects with no history of illicit drug use. The methamphetamine users showed a significantly reduced Cr+PCr/Cho ratio in the bilateral basal ganglia compared with the healthy comparison subjects. Furthermore, the reduction in the Cr+PCr/Cho ratio was significantly correlated with the duration of methamphetamine use and with the severity of residual psychiatric symptoms. NAA/Cho ratios in the bilateral basal ganglia did not significantly differ between methamphetamine users and comparison subjects. These findings suggest that protracted use of methamphetamine may cause metabolite alterations in the basal ganglia. Furthermore, residual psychiatric symptoms may be attributable to the metabolite alterations in the basal ganglia.

Methamphetamine-induced increases in putamen gray matter associate with inhibitory control

PubMed Central

Groman, Stephanie M.; Morales, Angelica M.; Lee, Buyean; London, Edythe D.; Jentsch, James David

2013-01-01

Rationale Problematic drug use is associated with difficulty in exerting self-control over behaviors, and this difficulty may be a consequence of atypical morphometric characteristics that are exhibited by drug-experienced individuals. The extent to which these structural abnormalities result from drug use or reflect neurobiological-risk factors that predate drug use, however, is unknown. Objectives To determine how methamphetamine affects corticostriatal structure and how drug-induced changes relate to alterations in inhibitory control. Methods Structural magnetic resonance images and positron emission tomography (PET) scans, assessing dopamine D2-like receptor and transporter availability, were acquired in monkeys trained to acquire, retain and reverse three-choice visual discrimination problems before and after exposure to an escalating dose regimen of methamphetamine (or saline, as a control). Voxel-based morphometry was used to compare changes in corticostriatal gray matter between methamphetamine and saline exposed monkeys. The change in gray matter before and after the dosing regimen was compared to the change in the behavioral performance and in dopaminergic markers measured with PET. Results Methamphetamine exposure, compared to saline, increased gray matter within the right putamen. These changes were positively correlated with changes in performance of methamphetamine-exposed monkeys in the reversal phase, and were negatively correlated with alterations in D2-like receptor and DAT availability. Conclusions The results provide the first evidence that exposure to a methamphetamine dosing regimen that resembles human use alters the structural integrity of the striatum and that gray-matter abnormalities detected in human methamphetamine users are due, at least in part, to the pharmacological effects of drug experience. PMID:23748383

Evidence-Based Guidelines for the Pharmacologic Management of Methamphetamine Dependence, Relapse Prevention, Chronic Methamphetamine-Related, and Comorbid Psychiatric Disorders in Post-Acute Settings.

PubMed

Härtel-Petri, Roland; Krampe-Scheidler, Anne; Braunwarth, Wolf-Dietrich; Havemann-Reinecke, Ursula; Jeschke, Peter; Looser, Winfried; Mühlig, Stephan; Schäfer, Ingo; Scherbaum, Norbert; Bothe, Lydia; Schaefer, Corinna; Hamdorf, Willem

2017-05-01

The increasing abuse of the street drug crystal meth (methamphetamine) in many countries worldwide has resulted in a growing demand to treat patients who have acquired a methamphetamine-related disorder. The results of a systematic literature search which led to the consensus-based recommendations by the Working Group of the German Agency for Quality in Medicine (Ärztliches Zentrum für Qualität in der Medizin - ÄZQ) are presented. Pharmacological treatments were reviewed in 58 out of the 103 publications included. They were mainly randomized controlled trials (RCT). Despite increased research activities, none of the medications studied demonstrated a convincing and consistent effect on abstinence rates, despite some having an impact on craving and retention rates or symptom control. In addition, as yet there is no sufficient evidence available for dopamine analogue treatment ("substitution") after the initial withdrawal-period. Methamphetamine-related, post-acute persistent or comorbid syndromes such as methamphetamine-associated psychosis (MAP), depressive syndromes, anxiety, and sleep disorders are usually treated in a symptom-oriented manner. Risks of interactions with methamphetamine have to be taken in account when prescribing medications with doubtful efficacy. Further research is warranted. © Georg Thieme Verlag KG Stuttgart · New York.

Role of high-mobility group box 1 in methamphetamine-induced activation and migration of astrocytes.

PubMed

Zhang, Yuan; Zhu, Tiebing; Zhang, Xiaotian; Chao, Jie; Hu, Gang; Yao, Honghong

2015-09-04

Mounting evidence has indicated that high-mobility group box 1 (HMGB1) is involved in cell activation and migration. Our previous study demonstrated that methamphetamine mediates activation of astrocytes via sigma-1 receptor (σ-1R). However, the elements downstream of σ-1R in this process remain poorly understood. Thus, we examined the molecular mechanisms involved in astrocyte activation and migration induced by methamphetamine. The expression of HMGB1, σ-1R, and glial fibrillary acidic protein (GFAP) was examined by western blot and immunofluorescent staining. The phosphorylation of cell signaling pathways was detected by western blot, and cell migration was examined using a wound-healing assay in rat C6 astroglia-like cells transfected with lentivirus containing red fluorescent protein (LV-RFP) as well as in primary human astrocytes. The role of HMGB1 in astrocyte activation and migration was validated using a siRNA approach. Exposure of C6 cells to methamphetamine increased the expression of HMGB1 via the activation of σ-1R, Src, ERK mitogen-activated protein kinase, and downstream NF-κB p65 pathways. Moreover, methamphetamine treatment resulted in increased cell activation and migration in C6 cells and primary human astrocytes. Knockdown of HMGB1 in astrocytes transfected with HMGB1 siRNA attenuated the increased cell activation and migration induced by methamphetamine, thereby implicating the role of HMGB1 in the activation and migration of C6 cells and primary human astrocytes. This study demonstrated that methamphetamine-mediated activation and migration of astrocytes involved HMGB1 up-regulation through an autocrine mechanism. Targeting HMGB1 could provide insights into the development of a potential therapeutic approach for alleviation of cell activation and migration of astrocytes induced by methamphetamine.

Cannabis-induced psychosis associated with high potency "wax dabs".

PubMed

Pierre, Joseph M; Gandal, Michael; Son, Maya

2016-04-01

With mounting evidence that the risk of cannabis-induced psychosis may be related to both dose and potency of tetrahydrocannbinol (THC), increasing reports of psychosis associated with cannabinoids containing greater amounts of THC are anticipated. We report two cases of emergent psychosis after using a concentrated THC extract known as cannabis "wax," "oil," or "dabs" raising serious concerns about its psychotic liability. Although "dabbing" with cannabis wax is becoming increasingly popular in the US for both recreational and "medicinal" intentions, our cases raise serious concerns about its psychotic liability and highlight the importance of understanding this risk by physicians recommending cannabinoids for purported medicinal purposes. Published by Elsevier B.V.

Psychomotor effect differences between l-methamphetamine and d-methamphetamine are independent of murine plasma and brain pharmacokinetics profiles.

PubMed

Nishimura, Tetsuya; Takahata, Kazue; Kosugi, Yuri; Tanabe, Takaaki; Muraoka, Shizuko

2017-05-01

l-Methamphetamine has been occasionally referred to as a stimulant similar to d-methamphetamine, probably owing to insufficient comparative studies. Here, we directly compared psychomotor efficacies and pharmacokinetics of methamphetamine enantiomers in mice. Only d-methamphetamine, but not l-methamphetamine, induced stereotypy and sensitization at 1-10 mg/kg. However, plasma pharmacokinetic parameters of 10 mg/kg l-methamphetamine were ≥tenfold those of 1 mg/kg d-methamphetamine. These results clearly indicate that differential psychomotor efficacies of methamphetamine enantiomers are independent of their pharmacokinetic profiles.

N-phenylpropyl-N´-substituted piperazines occupy sigma receptors and alter methamphetamine-induced hyperactivity in mice

PubMed Central

Miller, Dennis K.; Park, Eric S.; Lever, Susan Z.; Lever, John R.

2016-01-01

This study examined the effect of the N-phenylpropyl-N´-substituted piperazine ligands SA4503 (3,4-dimethoxyphenethyl), YZ-067 (4-methoxyphenethyl), YZ-185 (3-methoxyphenethyl) and Nahas-3h (4-methoxybenzyl) on methamphetamine-induced hyperactivity in mice. In a previous study in rats, SA4503 increased methamphetamine-induced hyperactivity at a lower ligand dose and enhanced it at a higher dose. The other ligands have not been investigated in this assay. Presently, mice were administered sigma ligands, and specific [125I]E-IA-DM-PE-PIPZE and [125I]RTI-121 binding was measured to determine σ1 sigma receptor and dopamine transporter occupancy, respectively. Mice were also administered sigma ligands followed by methamphetamine, and locomotor activity was measured. Each of the ligands occupied σ1 sigma receptors (ED50 = 0.2–0.6 µmol/kg) with similar potency, but none occupied the transporter (ED50 > 10 µmol/kg). At the highest dose tested (31.6 µmol/kg) all four sigma ligands significantly attenuated methamphetamine-induced hyperactivity. Interestingly, SA4503, YZ-067 and Nahas-3h, but not YZ-185, enhanced methamphetamine-induced hyperactivity at lower ligand doses (1–3.16 µmol/kg). These results suggest that these ligands function as stimulant agonists at lower doses and as antagonists at higher does, with subtle changes in the substitution pattern at the 3- and 4-positions of the phenethyl group contributing to the nature of the interactions. Overall, these data indicate a complex role for σ1 sigma receptor ligands in methamphetamine’s behavioral effects. PMID:27851908

Incubation of extinction responding and cue-induced reinstatement, but not context- or drug priming-induced reinstatement, after withdrawal from methamphetamine

PubMed Central

Adhikary, Sweta; Caprioli, Daniele; Venniro, Marco; Kallenberger, Paige; Shaham, Yavin; Bossert, Jennifer M.

2016-01-01

In rats trained to self-administer methamphetamine, extinction responding in the presence of drug-associated contextual and discrete cues progressively increases after withdrawal (incubation of methamphetamine craving). The conditioning factors underlying this incubation are unknown. Here, we studied incubation of methamphetamine craving under different experimental conditions to identify factors contributing to this incubation. We also determined whether the rats’ response to methamphetamine priming incubates after withdrawal. We trained rats to self-administer methamphetamine in a distinct context (context A) for 14 days (6-h/day). Lever presses were paired with a discrete light cue. We then tested groups of rats in context A or a different non-drug context (context B) after 1 day, 1 week, or 1 month for extinction responding with or without the discrete cue. Subsequently, we tested the rats for reinstatement of drug seeking induced by exposure to contextual, discrete cue, or drug priming (0, 0.25, and 0.5 mg/kg). Operant responding in the extinction sessions in contexts A or B was higher after 1 week and 1 month of withdrawal than after 1 day; this effect was context-independent. Independent of the withdrawal period, operant responding in the extinction sessions was higher when responding led to contingent delivery of the discrete cue. After extinction, discrete cue-induced reinstatement, but not context- or drug priming-induced reinstatement, progressively increased after withdrawal. Together, incubation of methamphetamine craving, as assessed in extinction tests, is primarily mediated by time-dependent increases in non-reinforced operant responding, and this effect is potentiated by exposure to discrete, but not contextual, cues. PMID:26989042

Neuroimmune Basis of Methamphetamine Toxicity

PubMed Central

Loftis, Jennifer M.; Janowsky, Aaron

2015-01-01

Although it is not known which antigen-specific immune responses (or if antigen-specific immune responses) are relevant or required for methamphetamine's neurotoxic effects, it is apparent that methamphetamine exposure is associated with significant effects on adaptive and innate immunity. Alterations in lymphocyte activity and number, changes in cytokine signaling, impairments in phagocytic functions, and glial activation and gliosis have all been reported. These drug-induced changes in immune response, particularly within the CNS, are now thought to play a critical role in the addiction process for methamphetamine dependence as well as for other substance use disorders. In Section 2, methamphetamine's effects on glial cell (e.g., microglia and astrocytes) activity and inflammatory signaling cascades are summarized, including how alterations in immune cell function can induce the neurotoxic and addictive effects of methamphetamine. Section 2 also describes neurotransmitter involvement in the modulation of methamphetamine's inflammatory effects. Section 3 discusses the very recent use of pharmacological and genetic animal models which have helped elucidate the behavioral effects of methamphetamine's neurotoxic effects and the role of the immune system. Section 4 is focused on the effects of methamphetamine on blood–brain barrier integrity and associated immune consequences. Clinical considerations such as the combined effects of methamphetamine and HIV and/or HCV on brain structure and function are included in Section 4. Finally, in Section 5, immune-based treatment strategies are reviewed, with a focus on vaccine development, neuroimmune therapies, and other anti-inflammatory approaches. PMID:25175865

Incubation of extinction responding and cue-induced reinstatement, but not context- or drug priming-induced reinstatement, after withdrawal from methamphetamine.

PubMed

Adhikary, Sweta; Caprioli, Daniele; Venniro, Marco; Kallenberger, Paige; Shaham, Yavin; Bossert, Jennifer M

2017-07-01

In rats trained to self-administer methamphetamine, extinction responding in the presence of drug-associated contextual and discrete cues progressively increases after withdrawal (incubation of methamphetamine craving). The conditioning factors underlying this incubation are unknown. Here, we studied incubation of methamphetamine craving under different experimental conditions to identify factors contributing to this incubation. We also determined whether the rats' response to methamphetamine priming incubates after withdrawal. We trained rats to self-administer methamphetamine in a distinct context (context A) for 14 days (6 hours/day). Lever presses were paired with a discrete light cue. We then tested groups of rats in context A or a different non-drug context (context B) after 1 day, 1 week or 1 month for extinction responding with or without the discrete cue. Subsequently, we tested the rats for reinstatement of drug seeking induced by exposure to contextual, discrete cue, or drug priming (0, 0.25 and 0.5 mg/kg). Operant responding in the extinction sessions in contexts A or B was higher after 1 week and 1 month of withdrawal than after 1 day; this effect was context-independent. Independent of the withdrawal period, operant responding in the extinction sessions was higher when responding led to contingent delivery of the discrete cue. After extinction, discrete cue-induced reinstatement, but not context- or drug priming-induced reinstatement, progressively increased after withdrawal. Together, incubation of methamphetamine craving, as assessed in extinction tests, is primarily mediated by time-dependent increases in non-reinforced operant responding, and this effect is potentiated by exposure to discrete, but not contextual, cues. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

The Central Amygdala Nucleus is Critical for Incubation of Methamphetamine Craving

PubMed Central

Li, Xuan; Zeric, Tamara; Kambhampati, Sarita; Bossert, Jennifer M; Shaham, Yavin

2015-01-01

Cue-induced methamphetamine seeking progressively increases after withdrawal but mechanisms underlying this ‘incubation of methamphetamine craving' are unknown. Here we studied the role of central amygdala (CeA), ventral medial prefrontal cortex (vmPFC), and orbitofrontal cortex (OFC), brain regions implicated in incubation of cocaine and heroin craving, in incubation of methamphetamine craving. We also assessed the role of basolateral amygdala (BLA) and dorsal medial prefrontal cortex (dmPFC). We trained rats to self-administer methamphetamine (10 days; 9 h/day, 0.1 mg/kg/infusion) and tested them for cue-induced methamphetamine seeking under extinction conditions during early (2 days) or late (4–5 weeks) withdrawal. We first confirmed that ‘incubation of methamphetamine craving' occurs under our experimental conditions. Next, we assessed the effect of reversible inactivation of CeA or BLA by GABAA+GABAB receptor agonists (muscimol+baclofen, 0.03+0.3 nmol) on cue-induced methamphetamine seeking during early and late withdrawal. We also assessed the effect of muscimol+baclofen reversible inactivation of vmPFC, dmPFC, and OFC on ‘incubated' cue-induced methamphetamine seeking during late withdrawal. Lever presses in the cue-induced methamphetamine extinction tests were higher during late withdrawal than during early withdrawal (incubation of methamphetamine craving). Muscimol+baclofen injections into CeA but not BLA decreased cue-induced methamphetamine seeking during late but not early withdrawal. Muscimol+baclofen injections into dmPFC, vmPFC, or OFC during late withdrawal had no effect on incubated cue-induced methamphetamine seeking. Together with previous studies, results indicate that the CeA has a critical role in incubation of both drug and non-drug reward craving and demonstrate an unexpected dissociation in mechanisms of incubation of methamphetamine vs cocaine craving. PMID:25475163

Effect of blonanserin on methamphetamine-induced disruption of latent inhibition and c-Fos expression in rats.

PubMed

Kuramashi, Aki; Abe, Hiroshi; Koganemaru, Go; Matsuo, Hisae; Ikeda, Tetsuya; Ebihara, Kosuke; Funahashi, Hideki; Takeda, Ryuichiro; Nishimori, Toshikazu; Ishida, Yasushi

2013-08-09

To clarify the psychopharmacological profile of blonanserin, a novel antipsychotic, we examined its effect on the methamphetamine-induced disruption of latent inhibition (LI) and the neural activation related to this effect in rats. To evaluate the LI, we used a conditioned emotional response in which a tone (conditioned stimulus) was paired with a mild foot shock (unconditioned stimulus). This paradigm was presented to rats licking water. Methamphetamine-induced (1.0mg/kg, i.p.) disruption of LI was significantly improved by the administration of a higher dose (3.0mg/kg, i.p.) of blonanserin and tended to be improved by 1.0-mg/kg blonanserin and 0.2-mg/kg haloperidol but not by a lower dose (0.3mg/kg) of blonanserin. Immunohistochemical examination showed blonanserin (3.0mg/kg, i.p.) increased c-Fos expression in the shell area but not in the core area of the nucleus accumbens while methamphetamine (3.0mg/kg, i.p.) produced the opposite expression pattern. Blonanserin also increased the number of c-Fos expressions in the central amygdala nucleus but not in the basolateral amygdala nucleus or the prefrontal cortex. Blonanserin ameliorates the methamphetamine-induced disruption of LI, as other antipsychotics do, and a neuronal activation and/or modulation of neurotransmission in the nucleus accumbens is related to the disruption of LI by methamphetamine and to its amelioration by blonanserin. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Comparisons of methamphetamine psychotic and schizophrenic symptoms: a differential item functioning analysis.

PubMed

Srisurapanont, Manit; Arunpongpaisal, Suwanna; Wada, Kiyoshi; Marsden, John; Ali, Robert; Kongsakon, Ronnachai

2011-06-01

The concept of negative symptoms in methamphetamine (MA) psychosis (e.g., poverty of speech, flatten affect, and loss of drive) is still uncertain. This study aimed to use differential item functioning (DIF) statistical techniques to differentiate the severity of psychotic symptoms between MA psychotic and schizophrenic patients. Data of MA psychotic and schizophrenic patients were those of the participants in the WHO Multi-Site Project on Methamphetamine-Induced Psychosis (or WHO-MAIP study) and the Risperidone Long-Acting Injection in Thai Schizophrenic Patients (or RLAI-Thai study), respectively. To confirm the unidimensionality of psychotic syndromes, we applied the exploratory and confirmatory factor analyses (EFA and CFA) on the eight items of Manchester scale. We conducted the DIF analysis of psychotic symptoms observed in both groups by using nonparametric kernel-smoothing techniques of item response theory. A DIF composite index of 0.30 or greater indicated the difference of symptom severity. The analyses included the data of 168 MA psychotic participants and the baseline data of 169 schizophrenic patients. For both data sets, the EFA and CFA suggested a three-factor model of the psychotic symptoms, including negative syndrome (poverty of speech, psychomotor retardation and flatten/incongruous affect), positive syndrome (delusions, hallucinations and incoherent speech) and anxiety/depression syndrome (anxiety and depression). The DIF composite indexes comparing the severity differences of all eight psychotic symptoms were lower than 0.3. The results suggest that, at the same level of syndrome severity (i.e., negative, positive, and anxiety/depression syndromes), the severity of psychotic symptoms, including the negative ones, observed in MA psychotic and schizophrenic patients are almost the same. Copyright © 2011 Elsevier Inc. All rights reserved.

Perinatal Asphyxia Reduces Dentate Granule Cells and Exacerbates Methamphetamine-Induced Hyperlocomotion in Adulthood

PubMed Central

Wakuda, Tomoyasu; Matsuzaki, Hideo; Suzuki, Katsuaki; Iwata, Yasuhide; Shinmura, Chie; Suda, Shiro; Iwata, Keiko; Yamamoto, Shigeyuki; Sugihara, Genichi; Tsuchiya, Kenji J.; Ueki, Takatoshi; Nakamura, Kazuhiko; Nakahara, Daiichiro; Takei, Nori; Mori, Norio

2008-01-01

Background Obstetric complications have been regarded as a risk factor for schizophrenia later in life. One of the mechanisms underlying the association is postulated to be a hypoxic process in the brain in the offspring around the time of birth. Hippocampus is one of the brain regions implicated in the late-onset dopaminergic dysfunction associated with hypoxic obstetric complications. Methodology/Principal Findings We used an animal model of perinatal asphyxia, in which rat pups were exposed to 15 min of intrauterine anoxia during Cesarean section birth. At 6 and 12 weeks after birth, the behavior of the pups was assessed using a methamphetamine-induced locomotion test. In addition, the histopathology of the hippocampus was examined by means of stereology. At 6 weeks, there was no change in the methamphetamine-induced locomotion. However, at 12 weeks of age, we found an elevation in methamphetamine-induced locomotor activity, which was associated with an increase of dopamine release in the nucleus accumbens. At the same age, we also found a reduction of the dentate granule cells of the hippocampus. Conclusions/Significance These results suggest that the dopaminergic dysregulation after perinatal asphyxia is associated with a reduction in hippocampal dentate granule cells, and this may partly contribute to the pathogenesis of schizophrenia. PMID:18985150

Effects of Circadian Disruption on Methamphetamine Consumption in Methamphetamine-Exposed Rats

PubMed Central

Doyle, Susan E.; Feng, Hanting; Garber, Garrett; Menaker, Michael; Lynch, Wendy J.

2015-01-01

Rationale A substantial number of clinical studies indicate associations between sleep abnormalities and drug abuse; however, the role played by the circadian system in the development of addiction is largely unknown. Objective The aim of this study was to examine the effects of experimentally induced chronic jet lag on methamphetamine consumption in a rat model of methamphetamine drinking. Methods Male Sprague-Dawley rats (n=32) were housed in running wheel cages in a 12:12 light:dark cycle. One group of rats (n=16) was given two weeks of forced methamphetamine consumption (0.01% in drinking water; meth pre-exposed) while a second group (n=16, not pre-exposed) received water only. This was followed by a two week abstinence period during which half of the animals from each group were exposed to 4 consecutive 6-hr advancing phase shifts of the light:dark cycle, while the other half remained on the original light:dark cycle. Methamphetamine consumption was assessed in all rats following the deprivation period using a two-bottle choice paradigm. Results Methamphetamine consumption was initially lower in methamphetamine pre-exposed vs. not pre-exposed rats. However, during the second week following abstinence, consumption was significantly higher in phase shifted rats of the methamphetamine pre-exposed group compared to all other groups. Conclusions These data reveal an effect of circadian rhythm disturbance on methamphetamine consumption, and suggest that dysregulation of the circadian system be considered in the etiology of relapse and addiction. PMID:25543849

Effects of circadian disruption on methamphetamine consumption in methamphetamine-exposed rats.

PubMed

Doyle, Susan E; Feng, Hanting; Garber, Garrett; Menaker, Michael; Lynch, Wendy J

2015-06-01

A substantial number of clinical studies indicate associations between sleep abnormalities and drug abuse; however, the role played by the circadian system in the development of addiction is largely unknown. The aim of this study was to examine the effects of experimentally induced chronic jet lag on methamphetamine consumption in a rat model of methamphetamine drinking. Male Sprague-Dawley rats (n = 32) were housed in running wheel cages in a 12:12 h light:dark cycle. One group of rats (n = 16) was given 2 weeks of forced methamphetamine consumption (0.01 % in drinking water; meth pre-exposed) while a second group (n = 16, not pre-exposed) received water only. This was followed by a 2-week abstinence period during which half of the animals from each group were exposed to four consecutive 6-h advancing phase shifts of the light:dark cycle, while the other half remained on the original light:dark cycle. Methamphetamine consumption was assessed in all rats following the deprivation period using a two-bottle choice paradigm. Methamphetamine consumption was initially lower in methamphetamine pre-exposed versus not pre-exposed rats. However, during the second week following abstinence, consumption was significantly higher in phase-shifted rats of the methamphetamine pre-exposed group compared to all other groups. These data reveal an effect of circadian rhythm disturbance on methamphetamine consumption and suggest that dysregulation of the circadian system be considered in the etiology of relapse and addiction.

Rates and features of methamphetamine-related presentations to emergency departments: An integrative literature review.

PubMed

Jones, Rikki; Woods, Cindy; Usher, Kim

2018-07-01

To review the clinical impact methamphetamine has on emergency departments by assessing the available research on the rates and features of methamphetamine-related presentations. Globally, methamphetamine availability, distribution and use have rapidly increased. As a result, the number of methamphetamine-related presentations to emergency departments has also increased. In this context, it is timely to review the rate and features of methamphetamine-related presentations to understand the impact of methamphetamine on emergency departments and facilitate the allocation of services, staff and resources. An integrative literature review. This study presents an integrated literature review, following the systematic review process as outlined in the PRISMA flow chart. Several databases were searched using a combination of search terms. Articles were measured against inclusion and exclusion criteria, and the final ten articles were subjected to quality appraisal and outcomes reported. Methamphetamine accounted for 2.3% or less of all emergency departments presentations. The majority of methamphetamine users presenting to emergency departments were males, with a mean age 31-37. Methamphetamine-related presentations to emergency departments were more likely to present with trauma, psychosis, and be placed on 24-hr psychiatric hold. Methamphetamine-related presentations were more likely to present with agitation, aggression and homicidal behaviour and present to emergency departments out of hours and accompanied by police compared with other emergency departments substance-related presentations. Several important themes were highlighted in this review that has an impact on emergency departments services, resources and staff. Understanding the rate and patterns of methamphetamine-related presentations can help to provide evidence for policy development and staff education in emergency departments. Methamphetamine-related presenters are more aggressive and agitated and more

Neonatal methamphetamine-induced corticosterone release in rats is inhibited by adrenal autotransplantation without altering the effect of the drug on hippocampal serotonin

PubMed Central

Grace, Curtis E.; Schaefer, Tori L.; Gudelsky, Gary A.; Williams, Michael T.; Vorhees, Charles V.

2010-01-01

Rat neonatal methamphetamine exposure results in corticosterone release and learning and memory impairments in later life; effects also observed after neonatal stress. Previous attempts to test the role of corticosterone release after methamphetamine using corticosterone inhibitors were unsuccessful and adrenalectomy caused reductions in hippocampal serotonin greater than those caused by methamphetamine alone. Here we tested whether adrenal autotransplantation could be used to attenuate methamphetamine-induced corticosterone release without also altering the effects of the drug on serotonin. Adrenal autotransplantation surgery occurred on postnatal day 9 followed by methamphetamine or saline treatment from postnatal day 11–20 (10 mg/kg/dose x 4/day). Plasma corticosterone and hippocampal serotonin and 5-hydroxyindoleacetic acid were determined 30 min following the first treatment on each day between postnatal days 11–20. Adrenal autotransplantation attenuated neonatal methamphetamine-induced corticosterone release by ~70% initially, ~55% midway through treatment, and ~25% by the end of treatment. Methamphetamine reduced serotonin and 5-hydroxyindoleacetic acid in the hippocampus to the same degree as in sham-surgery rats. The data show that neonatal adrenal autotransplantation is an effective method for partially reducing treatment-induce corticosterone release while providing sufficient corticosterone to sustain normal growth and development. The method should is applicable to other models of developmental stress/corticosterone release. PMID:20153424

Involvement of sigma-1 receptor in astrocyte activation induced by methamphetamine via up-regulation of its own expression.

PubMed

Zhang, Yuan; Lv, Xuan; Bai, Ying; Zhu, Xinjian; Wu, Xiaodong; Chao, Jie; Duan, Ming; Buch, Shilpa; Chen, Ling; Yao, Honghong

2015-02-17

Although it has been documented that methamphetamine induces astrocyte activation, the mechanism(s) underlying this effect remain poorly understood. We thus sought to examine the molecular mechanisms involved in methamphetamine-mediated activation of astrocytes with a focus on the role of sigma-1 receptor (σ-1R) in this process. The expression of σ-1R and glial fibrillary acidic protein (GFAP) was examined by reverse transcription PCR (RT-PCR), real-time PCR, Western blot, and immunofluorescent staining; phosphorylation of cell signaling pathways was detected by Western blot analysis. Immunoprecipitation was used to determine the interaction between σ-1R and p-Src. Chromatin immunoprecipitation (ChIP) assay was employed to discern the binding of cAMP-response element-binding protein (CREB) with the promoter of σ-1R. The role of σ-1R in astrocyte activation was further validated in σ-1R knockout (KO) mice by Western blot combined with immunofluorescent staining. Exposure of primary rat astrocytes to methamphetamine increased the expression of σ-1R via the activation of Src, ERK mitogen-activated protein kinase, and downstream CREB pathways. Subsequently, CREB translocated into nucleus and interacted with the promoter of σ-1R resulting in increased expression of σ-1R with a concomitant increase in expression of GFAP. This effect was inhibited in cells treated with the σ-1R antagonist-BD1047, thereby implicating the role of σ-1R in the activation of astrocytes. In vivo relevance of these findings was further corroborated in σ-1R KO mice that were administered methamphetamine. In the methamphetamine administered mice, there was a failure of the drug to induce activation of astrocytes, an effect that was evident in wild-type (WT) mice exposed to methamphetamine. The study presented herein demonstrates that methamphetamine-mediated activation of astrocytes involved up-regulation of σ-1R through a positive-feedback mechanism. Understanding the regulation of �

Stereotypic behaviors in mice selectively bred for high and low methamphetamine-induced stereotypic chewing.

PubMed

Atkins, A L; Helms, M L; O'Toole, L A; Belknap, J K

2001-08-01

At high doses, methamphetamine produces repetitive stereotypic behaviors, and the degree to which this occurs is heritable. Mice of a B6D2F2 genetic background were selectively bred for four generations for high (HMA) and low (LMA) numbers of stereotyped chewing episodes measured for 1 min at 33 min post-injection following 10 mg/kg methamphetamine (changed to 7 mg/kg for the high line and 15 mg/kg for the low line in the third selected generation to avoid ceiling and floor effects, respectively). We sought to determine whether stereotypic behaviors other than number of repetitive chewing episodes were altered by the selective breeding process. HMA and LMA mice of the third and fourth selected generations were tested for chewing stereotypy, for a number of other stereotypic behaviors previously observed in rodents, and for several other non-stereotypic responses to methamphetamine. Testing in the third selected generation was conducted by observing behaviors on videotape following 7 mg/kg methamphetamine. In the fourth selected generation, mice were also tested in automated activity monitors following 10 mg/kg methamphetamine and in climbing chimneys following 16 mg/kg methamphetamine. Dose-response curves with doses of 1, 2, 3.5, 7, 10, and 15 mg/kg methamphetamine were constructed for the most commonly observed behaviors. LMA mice, which exhibited low stereotyped chewing, exhibited high stereotyped circling and climbing, and the reverse was true for these behaviors for HMA mice. For most of the other behaviors measured, there were drug effects but no differences between selected lines. These results suggest that these three stereotyped behaviors, chewing, circling, and climbing, at least partly share the same mechanisms, and therefore are influenced by at least some of the same genes, since animals selectively bred for low methamphetamine-induced stereotyped chewing exhibited high amounts of circling and climbing when given methamphetamine. This also suggests

Role of microglia in methamphetamine-induced neurotoxicity

PubMed Central

Xu, Enquan; Liu, Jianuo; Liu, Han; Wang, Xiaobei; Xiong, Huangui

2017-01-01

Methamphetamine (Meth) is an addictive psychostimulant widely abused around the world. The chronic use of Meth produces neurotoxicity featured by dopaminergic terminal damage and microgliosis, resulting in serious neurological and behavioral consequences. Ample evidence indicate that Meth causes microglial activation and resultant secretion of pro-inflammatory molecules leading to neural injury. However, the mechanisms underlying Meth-induced microglial activation remain to be determined. In this review, we attempt to address the effects of Meth on human immunodeficiency virus (HIV)-associated microglia activation both in vitro and in-vivo. Meth abuse not only increases HIV transmission but also exacerbates progression of HIV-associated neurocognitive disorders (HAND) through activation of microglia. In addition, the therapeutic potential of anti-inflammatory drugs on ameliorating Meth-induced microglia activation and resultant neuronal injury is discussed. PMID:28694920

Attenuated microglial activation mediates tolerance to the neurotoxic effects of methamphetamine.

PubMed

Thomas, David M; Kuhn, Donald M

2005-02-01

Methamphetamine causes persistent damage to dopamine nerve endings of the striatum. Repeated, intermittent treatment of mice with low doses of methamphetamine leads to the development of tolerance to its neurotoxic effects. The mechanisms underlying tolerance are not understood but clearly involve more than alterations in drug bioavailability or reductions in the hyperthermia caused by methamphetamine. Microglia have been implicated recently as mediators of methamphetamine-induced neurotoxicity. The purpose of the present studies was to determine if a tolerance regimen of methamphetamine would attenuate the microglial response to a neurotoxic challenge. Mice treated with a low-dose methamphetamine tolerance regimen showed minor reductions in striatal dopamine content and low levels of microglial activation. When the tolerance regimen preceded a neurotoxic challenge of methamphetamine, the depletion of dopamine normally seen was significantly attenuated. The microglial activation that occurs after a toxic methamphetamine challenge was blunted likewise. Despite the induction of tolerance against drug-induced toxicity and microglial activation, a neurotoxic challenge with methamphetamine still caused hyperthermia. These results suggest that tolerance to methamphetamine neurotoxicity is associated with attenuated microglial activation and they further dissociate its neurotoxicity from drug-induced hyperthermia.

Molecular bases of methamphetamine-induced neurodegeneration.

PubMed

Cadet, Jean Lud; Krasnova, Irina N

2009-01-01

Methamphetamine (METH) is a highly addictive psychostimulant drug, whose abuse has reached epidemic proportions worldwide. The addiction to METH is a major public concern because its chronic abuse is associated with serious health complications including deficits in attention, memory, and executive functions in humans. These neuropsychiatric complications might, in part, be related to drug-induced neurotoxic effects, which include damage to dopaminergic and serotonergic terminals, neuronal apoptosis, as well as activated astroglial and microglial cells in the brain. Thus, the purpose of the present paper is to review cellular and molecular mechanisms that might be responsible for METH neurotoxicity. These include oxidative stress, activation of transcription factors, DNA damage, excitotoxicity, blood-brain barrier breakdown, microglial activation, and various apoptotic pathways. Several approaches that allow protection against METH-induced neurotoxic effects are also discussed. Better understanding of the cellular and molecular mechanisms involved in METH toxicity should help to generate modern therapeutic approaches to prevent or attenuate the long-term consequences of psychostimulant use disorders in humans.

Increased prevalence of self-reported psychotic illness predicted by crystal methamphetamine use: Evidence from a high-risk population.

PubMed

Lappin, Julia M; Roxburgh, Amanda; Kaye, Sharlene; Chalmers, Jenny; Sara, Grant; Dobbins, Timothy; Burns, Lucinda; Farrell, Michael

2016-12-01

The potential of methamphetamine, and high-potency crystal methamphetamine in particular, to precipitate psychotic symptoms and psychotic illness is the subject of much speculation internationally. Established psychotic illness is disabling for individuals and costly to society. The aim of this study was to investigate whether use of crystal methamphetamine was associated with greater prevalence of self-reported psychotic illness, compared to use of other forms of methamphetamine. The sample comprised participants interviewed as part of an annual cross-sectional survey of Australian people who inject drugs. Comparisons were made between groups according to the nature of their methamphetamine use: crystal methamphetamine or other forms of methamphetamine. Self-reported diagnoses of psychotic illness and other mental health problems were compared between groups. Predictors of self-reported psychotic illness were examined using multivariable logistic regression analyses. Self-reported psychotic illness was highly prevalent among users of crystal methamphetamine (12.0%), and significantly more so than among users of other forms of methamphetamine (3.9%) (OR=3.36; CI: 1.03-10.97). Significant predictors of self-reported psychosis in the cohort were: use of crystal methamphetamine; dependent use; lack of education beyond high school; and younger age. Highly increased prevalence of self-reported psychotic illness is associated with use of high-potency crystal methamphetamine in people who inject drugs, particularly where there is dependent use. There is an urgent need to develop effective interventions for dependent crystal methamphetamine use; and a need to monitor for symptoms of psychotic illness in drug-using populations. Copyright © 2016 Elsevier B.V. All rights reserved.

Sex differences in the acute locomotor response to methamphetamine in BALB/c mice.

PubMed

Ohia-Nwoko, Odochi; Haile, Colin N; Kosten, Therese A

2017-06-01

Women use methamphetamine more frequently than men and are more vulnerable to its negative psychological effects. Rodent models have been an essential tool for evaluating the sex-dependent effects of psychostimulants; however, evidence of sex differences in the behavioral responses to methamphetamine in mice is lacking. In the present study, we investigated acute methamphetamine-induced (1mg/kg and 4mg/kg) locomotor activation in female and male BALB/c mice. We also evaluated whether basal locomotor activity was associated with the methamphetamine-induced locomotor response. The results indicated that female BALB/c mice displayed enhanced methamphetamine-induced locomotor activity compared to males, while basal locomotor activity was positively correlated with methamphetamine-induced activity in males, but not females. This study is the first to show sex-dependent locomotor effects of methamphetamine in BALB/c mice. Our observations emphasize the importance of considering sex when assessing behavioral responses to methamphetamine. Copyright © 2017 Elsevier B.V. All rights reserved.

Assessment of Japanese stimulant control law offenders using the Addiction Severity Index--Japanese version: comparison with patients in treatment settings.

PubMed

Watanabe, Takashi; Ogai, Yasukazu; Koga, Takehiro; Senoo, Eiichi; Nakamura, Kazuhiko; Mori, Norio; Ikeda, Kazutaka

2009-12-01

The present study assessed problems in Japanese prisoners (inmates) who abused methamphetamine. Fifty-two male inmates were assessed in 2005-2007 using the Addiction Severity Index-Japanese version and compared with 55 male methamphetamine abusers in hospitals and recovery centers. The chi(2) and Mann-Whitney-Wilcoxon tests showed that the inmates had a significantly lower education level, more frequently had full-time jobs, had more experience living with a sexual partner, and more frequently had a history of juvenile delinquency and criminal records than patients. Although psychiatric symptoms, such as depression, anxiety, and hallucinations, were not common among inmates, suicidal behavior and trouble controlling violence were common in both groups.

Cocaine and methamphetamine induce opposing changes in BOLD signal response in rats.

PubMed

Taheri, Saeid; Xun, Zhu; See, Ronald E; Joseph, Jane E; Reichel, Carmela M

2016-07-01

Neuroimaging studies in psychostimulant addicts have reported functional neural activity changes in brain regions involved in relapse. However, the difference between the effects of the psychostimulants methamphetamine and cocaine on neuronal activity in a similar setting not been clarified. Since studies in humans are limited by the inability to study the initial impact of psychostimulant drugs, we addressed this issue in a rat model. Here, we report methamphetamine and cocaine-induced blood-oxygen-level dependent (BOLD) signal change using functional magnetic resonance imaging (fMRI) in rats receiving drug for the first time during the imaging session. Twenty-three male Long Evans rats underwent fMRI imaging and received an intravenous infusion of methamphetamine, cocaine, or saline. Anatomical and pharmacological fMRI (pfMRI) were performed on a 7T BioSpec dedicated research MR scanner under isoflurane gas (1.5-2%). After collecting baseline data for 10min, rats received drug over the next 10min for a total 40min scan time. Data were then preprocessed and statistically analyzed in anatomically defined regions of interest (ROIs) that have been implicated in persistent drug seeking and relapse. Methamphetamine during the imaging session resulted in a sustained negative BOLD signal change in key regions of the relapse circuit, except for the prefrontal cortex. In contrast, cocaine evoked a positive or unchanged BOLD signal in these same regions. In all of the investigated ROIs, there were no changes in BOLD signal following saline. Acute methamphetamine and cocaine have distinct patterns of functional activity as measured by pfMRI. Copyright © 2016 Elsevier B.V. All rights reserved.

Cocaine and methamphetamine induce opposing changes in BOLD signal response in rats

PubMed Central

See, Ronald E.; Joseph, Jane E.; Reichel, Carmela M.

2016-01-01

Background Neuroimaging studies in psychostimulant addicts have reported functional neural activity changes in brain regions involved in relapse. However, the difference between the effects of the psychostimulants methamphetamine and cocaine on neuronal activity in a similar setting not been clarified. Since studies in humans are limited by the inability to study the initial impact of psychostimulant drugs, we addressed this issue in a rat model. Objective Here, we report methamphetamine and cocaine-induced blood-oxygen-level dependent (BOLD) signal change using functional magnetic resonance imaging (fMRI) in rats receiving drug for the first time during the imaging session. Methods Twenty-three male Long Evans rats underwent fMRI imaging and received an intravenous infusion of methamphetamine, cocaine, or saline. Anatomical and pharmacological fMRI (pfMRI) were performed on a 7T BioSpec dedicated research MR scanner under isoflurane gas (1.5-2%). After collecting baseline data for 10 min, rats received drug over the next 10 min for a total 40 min scan time. Data were then preprocessed and statistically analyzed in anatomically defined regions of interest (ROIs) that have been implicated in persistent drug seeking and relapse. Results Methamphetamine during the imaging session resulted in a sustained negative BOLD signal change in key regions of the relapse circuit, except for the prefrontal cortex. In contrast, cocaine evoked a positive or unchanged BOLD signal in these same regions. In all of the investigated ROIs, there were no changes in BOLD signal following saline. Conclusion Acute methamphetamine and cocaine have distinct patterns of functional activity as measured by pfMRI. PMID:27103569

[Current situation of and the political measures for drug abuse/dependence].

PubMed

Wada, Kiyoshi; Ozaki, Shigeru; Kondo, Ayumi

2008-04-01

More than 10 years has passed since 1995 when the third epidemic of methamphetamine abuse started in Japan. We are now still in the third epidemic of methamphetamine abuse, thought the current situation of drug abuse/dependence has obviously changed from previously. Considering several kinds of nationwide surveys and censuses, the authors summarized the change as follows: a) obvious decrease in solvent abuse/dependence, b) stabilization of methamphetamine abuse/dependence, c) increase in abuse of such drugs as cannabis or MDMA which don't have high potential to cause drug-induced psychosis, and d) emergence of non-regulatory drugs represented by designer drugs. These imply the change a) from "hard drugs" to "soft drugs", b) from Japanese unique situation which is symbolized by solvent abuse to Western situation which is symbolized by cannabis abuse, and c) from "illicit drugs" to "non-regulatory drugs". These characteristics reveal that there is the limitation to the Japanese Government policy which has tried to control the drug issue mainly as criminal cases for many years and that it is time now to change its policy. The authors stress the necessities of development of medical treatment targeting drug dependence and of its social support system.

The relationship between crystalline methamphetamine use and methamphetamine dependence.

PubMed

McKetin, Rebecca; Kelly, Erin; McLaren, Jennifer

2006-12-01

The aim of the current study was to determine whether crystalline methamphetamine users are more dependent on methamphetamine than people who use other forms of the drug, and if so, whether this could be accounted for by their methamphetamine use history. A structured face-to-face interview was used to assess drug use patterns and demographics among a convenience sample of 309 regular methamphetamine users from Sydney, Australia. Dependence on methamphetamine in the past year was measured using the Severity of Dependence Scale. The use of crystalline methamphetamine in the past year was confirmed using a photographic identification sheet. Participants who had used crystalline methamphetamine in the past year were significantly more likely to be dependent on methamphetamine than participants who took only other forms of methamphetamine during this time (61% versus 39%). Methamphetamine dependence was also associated with injecting or smoking methamphetamine (67% and 58%, respectively versus 30% for intranasal or oral use), using methamphetamine more than weekly (68% versus 34%), having used the drug for more than 5 years (61% versus 36%), and having used 'base' methamphetamine in the past year (59% versus 39%). Crystalline methamphetamine use remained significantly associated with methamphetamine dependence after adjusting for these patterns of methamphetamine use. Methamphetamine users who took crystalline methamphetamine in the past year were more likely to be dependent than methamphetamine users who had not taken the crystalline form of the drug during this time.

Methamphetamine induces trace amine-associated receptor 1 (TAAR1) expression in human T lymphocytes: role in immunomodulation.

PubMed

Sriram, Uma; Cenna, Jonathan M; Haldar, Bijayesh; Fernandes, Nicole C; Razmpour, Roshanak; Fan, Shongshan; Ramirez, Servio H; Potula, Raghava

2016-01-01

The novel transmembrane G protein-coupled receptor, trace amine-associated receptor 1 (TAAR1), represents a potential, direct target for drugs of abuse and monoaminergic compounds, including amphetamines. For the first time, our studies have illustrated that there is an induction of TAAR1 mRNA expression in resting T lymphocytes in response to methamphetamine. Methamphetamine treatment for 6 h significantly increased TAAR1 mRNA expression (P < 0.001) and protein expression (P < 0.01) at 24 h. With the use of TAAR1 gene silencing, we demonstrate that methamphetamine-induced cAMP, a classic response to methamphetamine stimulation, is regulated via TAAR1. We also show by TAAR1 knockdown that the down-regulation of IL-2 in T cells by methamphetamine, which we reported earlier, is indeed regulated by TAAR1. Our results also show the presence of TAAR1 in human lymph nodes from HIV-1-infected patients, with or without a history of methamphetamine abuse. TAAR1 expression on lymphocytes was largely in the paracortical lymphoid area of the lymph nodes with enhanced expression in lymph nodes of HIV-1-infected methamphetamine abusers rather than infected-only subjects. In vitro analysis of HIV-1 infection of human PBMCs revealed increased TAAR1 expression in the presence of methamphetamine. In summary, the ability of methamphetamine to activate trace TAAR1 in vitro and to regulate important T cell functions, such as cAMP activation and IL-2 production; the expression of TAAR1 in T lymphocytes in peripheral lymphoid organs, such as lymph nodes; and our in vitro HIV-1 infection model in PBMCs suggests that TAAR1 may play an important role in methamphetamine -mediated immune-modulatory responses. © Society for Leukocyte Biology.

Partial MHC/Neuroantigen Peptide Constructs: A Potential Neuroimmune-Based Treatment for Methamphetamine Addiction

PubMed Central

Loftis, Jennifer M.; Wilhelm, Clare J.; Vandenbark, Arthur A.; Huckans, Marilyn

2013-01-01

Relapse rates following current methamphetamine abuse treatments are very high (∼40–60%), and the neuropsychiatric impairments (e.g., cognitive deficits, mood disorders) that arise and persist during remission from methamphetamine addiction likely contribute to these high relapse rates. Pharmacotherapeutic development of medications to treat addiction has focused on neurotransmitter systems with only limited success, and there are no Food and Drug Administration approved pharmacotherapies for methamphetamine addiction. A growing literature shows that methamphetamine alters peripheral and central immune functions and that immune factors such as cytokines, chemokines, and adhesion molecules play a role in the development and persistence of methamphetamine induced neuronal injury and neuropsychiatric impairments. The objective of this study was to evaluate the efficacy of a new immunotherapy, partial MHC/neuroantigen peptide construct (RTL551; pI-Ab/mMOG-35-55), in treating learning and memory impairments induced by repeated methamphetamine exposure. C57BL/6J mice were exposed to two different methamphetamine treatment regimens (using repeated doses of 4 mg/kg or 10 mg/kg, s.c.). Cognitive performance was assessed using the Morris water maze and CNS cytokine levels were measured by multiplex assay. Immunotherapy with RTL551 improved the memory impairments induced by repeated methamphetamine exposure in both mouse models of chronic methamphetamine addiction. Treatment with RTL551 also attenuated the methamphetamine induced increases in hypothalamic interleukin-2 (IL-2) levels. Collectively, these initial results indicate that neuroimmune targeted therapies, and specifically RTL551, may have potential as treatments for methamphetamine-induced neuropsychiatric impairments. PMID:23460798

A Rodent “Self-Report” Measure of Methamphetamine Craving? Rat Ultrasonic Vocalizations During Methamphetamine Self-Administration, Extinction, and Reinstatement

PubMed Central

Mahler, Stephen V.; Moorman, David E.; Feltenstein, Matthew W.; Cox, Brittney M.; Ogburn, Katelyn B.; Bachar, Michal; McGonigal, Justin T.; Ghee, Shannon M.; See, Ronald E.

2012-01-01

Rats emit ultrasonic vocalizations (USVs) in a variety of contexts, and it is increasingly clear that USVs reflect more complex information than mere positive and negative affect states. We sought to examine USVs in a common model of addiction and relapse, the self-administration/reinstatement paradigm, in order to gain insight into subjective states experienced by rats during various types of methamphetamine seeking. We measured three subtypes of “50kHz” USVs [flats, trills, and non-trill frequency modulated USVs (FMs)], as well as long and short duration “22kHz” USVs, during self-administration and extinction training, and during reinstatement elicited by cues, a methamphetamine prime, cues + prime, or the pharmacological stressor yohimbine. During self-administration and extinction, rats emitted many flats and FMs, (and short duration “22kHz” USVs on day 1 of self-administration), but few trills. In contrast, methamphetamine priming injections potently enhanced FMs and trills, and trill production was correlated with the degree of methamphetamine + cue-elicited reinstatement. Cues alone yielded increases only in flat USVs during reinstatement, though a subset of rats displaying strong cue-induced reinstatement also emitted long duration, aversion-related “22kHz” USVs. Although yohimbine administration caused reinstatement, it did not induce “22kHz” USVs in methamphetamine-experienced or methamphetamine-naïve rats (unlike footshock stress, which did induce long duration “22kHz” USVs). These findings demonstrate heterogeneity of rat USVs emitted during different types of methamphetamine seeking, and highlight their potential usefulness for gaining insight into the subjective states of rats in rodent models of drug addiction and relapse. PMID:22940018

Methamphetamine use and treatment in Iran: A systematic review from the most populated Persian Gulf country.

PubMed

Alam-mehrjerdi, Zahra; Mokri, Azarakhsh; Dolan, Kate

2015-08-01

Methamphetamine use is a new health concern in Iran, the most populated Persian Gulf country. However, there is no well-documented literature. The current study objectives were to systematically review all published English and Persian studies of the prevalence of methamphetamine use, the general physical and psychiatric-related harms and the availability of methamphetamine treatment and harm reduction services for adult users in Iran. A comprehensive search of the international peer-reviewed and gray literature was undertaken. Multiple electronic and scientific English and Persian databases were systematically searched from January 2002 to September 2014. Additionally, English and Persian gray literature on methamphetamine use was sought using online gray literature databases, library databases and general online searches over the same period of time. Nineteen thousand and two hundred and eight studies, reports and conference papers were identified but only 42 studies were relevant to the study objectives. They were mainly published in 2010-2014. The search results confirmed the seizures of methamphetamine (six studies), the prevalence of methamphetamine use among the general population (three studies), drug users (four studies), women (nine studies) and opiate users in opiate treatment programs (five studies). In addition, methamphetamine use had resulted in blood-borne viral infections (one study), psychosis and intoxication (ten studies). Different reasons had facilitated methamphetamine use. However, the Matrix Model, community therapy and harm reduction services (four studies) had been provided for methamphetamine users in some cities. The current situation of methamphetamine use necessitates more research on the epidemiology and health-related implications. These studies should help in identifying priorities for designing and implementing prevention and educational programs. More active models of engagement with Persian methamphetamine users and the

Assessment of Japanese Stimulant Control Law Offenders Using the Addiction Severity Index—Japanese Version: Comparison with Patients in Treatment Settings

PubMed Central

Watanabe, Takashi; Ogai, Yasukazu; Koga, Takehiro; Senoo, Eiichi; Nakamura, Kazuhiko; Mori, Norio; Ikeda, Kazutaka

2009-01-01

The present study assessed problems in Japanese prisoners (inmates) who abused methamphetamine. Fifty-two male inmates were assessed in 2005–2007 using the Addiction Severity Index-Japanese version and compared with 55 male methamphetamine abusers in hospitals and recovery centers. The χ2 and Mann-Whitney-Wilcoxon tests showed that the inmates had a significantly lower education level, more frequently had full-time jobs, had more experience living with a sexual partner, and more frequently had a history of juvenile delinquency and criminal records than patients. Although psychiatric symptoms, such as depression, anxiety, and hallucinations, were not common among inmates, suicidal behavior and trouble controlling violence were common in both groups. PMID:20049245

EXTENDED ACCESS TO METHAMPHETAMINE SELF-ADMINISTRATION AFFECTS SENSORIMOTOR GATING IN RATS

PubMed Central

Hadamitzky, Martin; Markou, Athina; Kuczenski, Ronald

2010-01-01

Disturbed information processing observed in neuropsychiatric disorders is reflected by deficient sensorimotor gating, measured as prepulse inhibition (PPI) of the acoustic startle response (ASR). Long-term, higher-dose methamphetamine (METH) abuse patterns are associated with cognitive impairments, mania and/or schizophrenia-like psychosis. The present study investigated in rats METH-induced impairment of sensorimotor gating using an intravenous self-administration (IVSA) escalating dose procedure. In this procedure, rats escalated drug intake during weekly extended access periods to METH IVSA (1, 3, and 6-h), where PPI was assessed after each access period and thus at various times of drug exposure. Despite increased drug intake over the course of extended access to METH, disruption of sensorimotor gating was only seen after the access period of 6-h. The data suggest that METH-induced impairment of sensorimotor gating in IVSA-tasks is rather attributed to continuous and higher-dose exposure than to actual amounts of drug present at the time of testing. IVSA procedures, comprising stepwise stimulant escalation may serve as a useful translational model in rats that approximate important aspects of human abuse pattern in the context of stimulant-induced cognitive and behavioral deficits. PMID:21070821

Naltrexone moderates the relationship between cue-induced craving and subjective response to methamphetamine in individuals with methamphetamine use disorder.

PubMed

Roche, Daniel J O; Worley, Matthew J; Courtney, Kelly E; Bujarski, Spencer; London, Edythe D; Shoptaw, Steven; Ray, Lara A

2017-07-01

Reductions in cue-induced craving and subjective response to drugs of abuse are commonly used as initial outcome measures when testing novel medications for the treatment of addiction. Yet neither the relationship between these two measures at the individual level nor the moderating effects of pharmacotherapies on this relationship has been examined. This secondary data analysis sought to examine (1) the predictive relationship between cue-induced craving and subsequent acute subjective response to methamphetamine (MA) and (2) whether the opioid-receptor antagonist naltrexone moderated this association in a sample of non-treatment-seeking individuals who met DSM-IV criteria for MA use disorder (abuse or dependence). Participants (n = 30) completed two 4-day medication regimens (oral naltrexone 50 mg or placebo, in a randomized, counterbalanced, and double-blind fashion). On day 4 of each medication regimen, participants completed a cue-reactivity paradigm followed by intravenous MA administration. Methamphetamine craving was assessed after the cue-reactivity paradigm, and subjective response to MA was assessed during MA infusion. Cue-induced craving for MA was positively associated with post-infusion subjective MA effects, including positive (i.e., stimulation, good effects, feel drug, high), negative (i.e., anxious and depressed), and craving-related (i.e., want more, would like access to drug, crave) responses. Naltrexone, vs. placebo, significantly reduced the association between cue-induced craving and positive subjective response to MA. The findings indicate that naltrexone moderates the predictive relationship between cue-induced craving and positive subjective effects of MA, thereby suggesting a behavioral mechanism by which naltrexone may be efficacious in treating MA use disorder.

Methamphetamine Induces Anhedonic-Like Behavior and Impairs Frontal Cortical Energetics in Mice.

PubMed

Fonseca, Raquel; Carvalho, Rui A; Lemos, Cristina; Sequeira, Ana C; Pita, Inês R; Carvalho, Fábio; Silva, Carlos D; Prediger, Rui D S; Jarak, Ivana; Cunha, Rodrigo A; Fontes Ribeiro, Carlos A; Köfalvi, Attila; Pereira, Frederico C

2017-02-01

We recently showed that a single high dose of methamphetamine (METH) induces a persistent frontal cortical monoamine depletion that is accompanied by helpless-like behavior in mice. However, brain metabolic alterations underlying both neurochemical and mood alterations remain unknown. Herein, we aimed at characterizing frontal cortical metabolic alterations associated with early negative mood behavior triggered by METH. Adult C57BL/6 mice were injected with METH (30 mg/kg, i.p.), and their frontal cortical metabolic status was characterized after probing their mood and anxiety-related phenotypes 3 days postinjection. Methamphetamine induced depressive-like behavior, as indicated by the decreased grooming time in the splash test and by a transient decrease in sucrose preference. At this time, METH did not alter anxiety-like behavior or motor functions. Depolarization-induced glucose uptake was reduced in frontocortical slices from METH-treated mice compared to controls. Consistently, astrocytic glucose transporter (GluT1) density was lower in the METH group. A proton high rotation magic angle spinning (HRMAS) spectroscopic approach revealed that METH induced a significant decrease in N-acetyl aspartate (NAA) and glutamate levels, suggesting that METH decreased neuronal glutamatergic function in frontal cortex. We report, for the first time, that a single METH injection triggers early self-care and hedonic deficits and impairs frontal cortical energetics in mice. © 2016 John Wiley & Sons Ltd.

Oral health of the methamphetamine abuser.

PubMed

Donaldson, Mark; Goodchild, Jason H

2006-11-01

The pharmacology of methamphetamine is reviewed, and the effects of methamphetamine use on oral health are described. Methamphetamine is a highly addictive amphetamine analogue, initially synthesized in 1919. Illicit methamphetamine use leads to devastating effects on health, particularly the dentition. Illegal production of methamphetamine has skyrocketed in recent years, as have the number of users. The chief complaint of methamphetamine users is xerostomia. Without the protective effects of saliva, caries development in these patients is rampant. The typical pattern of decay involves the facial and cervical areas of both the maxillary and mandibular teeth, with eventual progression to frank coronal involvement. The acidic substances used to manufacture this drug have also been implicated as a cause of tooth decay and wear in users, as has bruxism as a result of drug-induced hyperactivity. When possible, these patients should be referred to a dentist to improve their oral health status and minimize the potential for adverse cardiovascular sequelae. Other preventive measures for methamphetamine users include stimulating saliva flow and increasing fluoride supplementation. Pharmacists should also counsel users to avoid carbohydrate-rich soft drinks in favor of water. Oral moisturizers may also be effective. Methamphetamine use causes xerostomia secondary to sympathetic central nervous system activation, rampant caries caused by high-sugar intake in the absence of protective saliva, and bruxism as a result of hyperactivity. Practitioners should know how to recognize the signs of and manage the oral health of patients with a history of methamphetamine use.

Selective breeding for magnitude of methamphetamine-induced sensitization alters methamphetamine consumption

PubMed Central

Scibelli, Angela C.; McKinnon, Carrie S.; Reed, Cheryl; Burkhart-Kasch, Sue; Li, Na; Baba, Harue; Wheeler, Jeanna M.

2012-01-01

Rationale Genetically determined differences in susceptibility to drug-induced sensitization could be related to risk for drug consumption. Objectives Studies were performed to determine whether selective breeding could be used to create lines of mice with different magnitudes of locomotor sensitization to methamphetamine (MA). MA sensitization (MASENS) lines were also examined for genetically correlated responses to MA. Methods Beginning with the F2 cross of C57BL/6J and DBA/2J strains, mice were tested for locomotor sensitization to repeated injections of 1 mg/kg MA and bred based on magnitude of sensitization. Five selected offspring generations were tested. All generations were also tested for MA consumption, and some were tested for dose-dependent locomotor-stimulant responses to MA, consumption of saccharin, quinine, and potassium chloride as a measure of taste sensitivity, and MA clearance after acute and repeated MA. Results Selective breeding resulted in creation of two lines [MA high sensitization (MAHSENS) and MA low sensitization (MALSENS)] that differed in magnitude of MA-induced sensitization. Initially, greater MA consumption in MAHSENS mice reversed over the course of selection so that MALSENS mice consumed more MA. MAHSENS mice exhibited greater sensitivity to the acute stimulant effects of MA, but there were no significant differences between the lines in MA clearance from blood. Conclusions Genetic factors influence magnitude of MA-induced locomotor sensitization and some of the genes involved in magnitude of this response also influence MA sensitivity and consumption. Genetic factors leading to greater MA-induced sensitization may serve a protective role against high levels of MA consumption. PMID:21088960

Functional and Structural Brain Changes Associated with Methamphetamine Abuse

PubMed Central

Jan, Reem K.; Kydd, Rob R.; Russell, Bruce R.

2012-01-01

Methamphetamine (MA) is a potent psychostimulant drug whose abuse has become a global epidemic in recent years. Firstly, this review article briefly discusses the epidemiology and clinical pharmacology of methamphetamine dependence. Secondly, the article reviews relevant animal literature modeling methamphetamine dependence and discusses possible mechanisms of methamphetamine-induced neurotoxicity. Thirdly, it provides a critical review of functional and structural neuroimaging studies in human MA abusers; including positron emission tomography (PET) and functional and structural magnetic resonance imaging (MRI). The effect of abstinence from methamphetamine, both short- and long-term within the context of these studies is also reviewed. PMID:24961256

Methamphetamine-induced toxicity: an updated review on issues related to hyperthermia

PubMed Central

Matsumoto, Rae R.; Seminerio, Michael J.; Turner, Ryan C.; Robson, Matthew J.; Nguyen, Linda; Miller, Diane B.; O’Callaghan, James P.

2015-01-01

Reports of methamphetamine-related emergency room visits suggest that elevated body temperature is a universal presenting symptom, with lethal overdoses generally associated with extreme hyperthermia. This review summarizes the available information on methamphetamine toxicity as it pertains to elevations in body temperature. First, a brief overview of thermoregulatory mechanisms is presented. Next, central and peripheral targets that have been considered for potential involvement in methamphetamine hyperthermia are discussed. Finally, future areas of investigation are proposed, as further studies are needed to provide greater insight into the mechanisms that mediate the alterations in body temperature elicited by methamphetamine. PMID:24836729

Clinical Course of Methamphetamine-Induced Psychotic Disorder in a 3-Month Follow-Up.

PubMed

Javadian, Sakineh; Shabani, Amir; Shariat, Seyed Vahid

2016-11-03

To assess the clinical course of patients with methamphetamine-induced psychotic disorder (MIPD) and any possible predictors of the clinical course in a 3-month follow-up. This prospective cohort study included 50 patients (7 female, 43 male) with MIPD and was performed from September 2014 to October 2015. Patients were assessed during hospitalization and in a follow-up visit 3 months later. Diagnoses were made using interviews based on the Structured Clinical Interview for DSM-IV Axis I Disorders. Positive, negative, manic, and depressive symptoms were the main outcome measures that were assessed using the Scale for the Assessment of Positive Symptoms, Scale for the Assessment of Negative Symptoms, Young Mania Rating Scale, and Hamilton Depression Rating Scale, respectively. Paired t test and regression analysis were used to analyze the data. Forty-six patients (92%) were reassessed at follow-up. More than half of the patients relapsed to methamphetamine use, did not adhere to treatment, and were functionally impaired. Positive, negative, and manic symptoms, but not depressive symptoms, improved in abstinent patients (P < .001, P = .001, P < .001, and P = .395, respectively). The best predictor of depressive and negative symptoms at follow-up was the patients' respective baseline scores; but positive and manic symptoms were best predicted by reuse of methamphetamine during follow-up. Various symptom categories do not always change in the same direction during the course of the disorder, especially depressive symptoms that do not improve with abstinence but aggravate with frequency of methamphetamine use. Negative symptoms at baseline also seem to have a possible role in prediction of methamphetamine reuse in patients with MIPD. Physicians should be advised to independently address all of the symptom categories of their patients with MIPD at each follow-up visit. © Copyright 2016 Physicians Postgraduate Press, Inc.

Simultaneous use of alcohol with methamphetamine but not ecstasy linked with aggression among young adult stimulant users.

PubMed

Leslie, Ellen M; Smirnov, Andrew; Cherney, Adrian; Wells, Helene; Legosz, Margot; Kemp, Robert; Najman, Jake M

2017-07-01

Illicit stimulants are often combined with alcohol in nightlife entertainment districts, an environment where aggressive behaviour commonly occurs. While alcohol and methamphetamine use are each associated with aggressive behaviour, relatively little is known about the impact of the combined use of alcohol and amphetamine-type stimulants (i.e., ecstasy [MDMA] and methamphetamine) on aggression. Analysis of longitudinal data from a population-based sample of Australian young adult amphetamine-type stimulant users (n=248) to examine: (a) prevalence and timing of simultaneous alcohol and amphetamine-type stimulant use and (b) predictors of ecstasy- and methamphetamine-related aggression and hostility. Prediction models of ecstasy- and methamphetamine-related aggression and hostility were developed using multivariate logistic regression. Simultaneous alcohol consumption and amphetamine-type stimulant use was prevalent, with drinking generally occurring before consuming amphetamine-type stimulants and while 'high'. Methamphetamine-related aggression and hostility was significantly associated with recurrent risky simultaneous methamphetamine and alcohol use (Adjusted Odds Ratio [AOR] 2.74, 95% CI 1.09-6.89), a high frequency and increasing use methamphetamine trajectory (AOR 7.23, 95% CI 1.27-41.03), and high trait aggression (AOR 5.78, 95% CI 2.53-13.20). In contrast, only trait aggression (moderate: AOR 3.01, 95% CI 1.55-5.84; high: AOR 5.02, 95% CI 2.38-10.61) was associated with ecstasy-related aggression and hostility. These findings indicate a link between risky patterns of simultaneous alcohol and methamphetamine use and methamphetamine-related aggression and hostility, independent of separate use of alcohol, methamphetamine and cannabis, trait aggression, psychosis, and gender. The policy challenges of amphetamine-type stimulant and alcohol use require a targeted, multidisciplinary approach. Copyright © 2017 Elsevier Ltd. All rights reserved.

Cannabinoids and Psychosis.

PubMed

D'Souza, Deepak Cyril; Radhakrishnan, Rajiv; Sherif, Mohamed; Cortes-Briones, Jose; Cahill, John; Gupta, Swapnil; Skosnik, Patrick D; Ranganathan, Mohini

2016-01-01

There is growing interest in the relationship between cannabis and psychosis. The link between cannabis use and psychosis comprises three distinct relationships: acute psychosis associated with cannabis intoxication, acute psychosis that lasts beyond the period of acute intoxication, and persistent psychosis not time-locked to exposure. Experimental studies reveal that cannabis, tetrahydrocannabinol (THC) and synthetic cannabinoids reliably produce transient positive, negative, and cognitive symptoms in healthy volunteers. Case-studies indicate that cannabinoids can induce acute psychosis which lasts beyond the period of acute intoxication and persisting as long as a month. Exposure to cannabis in adolescence is associated with an increased risk for later psychotic disorder in adulthood; this association is consistent, somewhat specific, shows a dose-response, and is biologically plausible. The link between cannabinoids and psychosis is greater with earlier age of exposure to cannabinoids, childhood abuse and genetic vulnerability. However, cannabinoids are neither necessary nor sufficient to cause a persistent psychotic disorder. More likely cannabinoids are a 'component cause' interacting with other known (family history) and unknown factors to result in psychosis outcomes. While more research is needed to better understand the relationship between cannabinoid use and psychosis, and the neural underpinnings of this link, clinicians should be mindful of the potential risk of psychosis especially in vulnerable populations, including adolescents and those with a psychosis diathesis. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Expression of HIV gp120 protein increases sensitivity to the rewarding properties of methamphetamine in mice

PubMed Central

Kesby, James P.; Hubbard, David T.; Markou, Athina; Semenova, Svetlana

2012-01-01

Methamphetamine abuse and human immunodeficiency virus (HIV) infection induce neuropathological changes in corticolimbic brain areas involved in reward and cognitive function. Little is known about the combined effects of methamphetamine and HIV infection on cognitive and reward processes. The HIV/gp120 protein induces neurodegeneration in mice, similar to HIV-induced pathology in humans. We investigated the effects of gp120 expression on associative learning, preference for methamphetamine and non-drug reinforcers, and sensitivity to the conditioned rewarding properties of methamphetamine in transgenic (tg) mice expressing HIV/gp120 protein (gp120-tg). gp120-tg mice learned the operant response for food at the same rate as non-tg mice. In the two-bottle choice procedure with restricted access to drugs, gp120-tg mice exhibited greater preference for methamphetamine and saccharin than non-tg mice, whereas preference for quinine was similar between genotypes. Under conditions of unrestricted access to methamphetamine, the mice exhibited a decreased preference for increasing methamphetamine concentrations. However, male gp120-tg mice showed a decreased preference for methamphetamine at lower concentrations than non-tg male mice. gp120-tg mice developed methamphetamine-induced conditioned place preference at lower methamphetamine doses compared with non-tg mice. No differences in methamphetamine pharmacokinetics were found between genotypes. These results indicate that gp120-tg mice exhibit no deficits in associative learning or reward/motivational function for a natural reinforcer. Interestingly, gp120 expression resulted in increased preference for methamphetamine and a highly palatable non-drug reinforcer (saccharin) and increased sensitivity to methamphetamine-induced conditioned reward. These data suggest that HIV-positive individuals may have increased sensitivity to methamphetamine, leading to high methamphetamine abuse potential in this population. PMID

Determinants of cue-elicited craving and physiologic reactivity in methamphetamine-dependent subjects in the laboratory.

PubMed

Tolliver, Bryan K; McRae-Clark, Aimee L; Saladin, Michael; Price, Kimber L; Simpson, Annie N; DeSantis, Stacia M; Baker, Nathaniel L; Brady, Kathleen T

2010-03-01

Craving for methamphetamine is commonly reported by heavy users of the drug and may increase the risk of relapse in newly abstinent individuals. Exposure to methamphetamine-associated cues in the laboratory can elicit measureable craving and autonomic reactivity in some individuals with methamphetamine dependence. In this study, clinical and demographic correlates of methamphetamine craving and the optimal conditions for its measurement in the laboratory are explored. Subjective (craving) and physiologic (heart rate and skin conductance) reactivity to presentation of methamphetamine-associated photo, video, and paraphernalia cues were evaluated in 43 subjects with methamphetamine dependence. Association of cue reactivity with demographic and clinical characteristics including duration, frequency, amount, and recency of methamphetamine use were assessed. Craving was reported by fewer than half of subjects at baseline and by approximately 70% of subjects after methamphetamine cue exposure. Relative to baseline, subjective craving was increased by all three cue modalities to a similar extent. In general, physiological cue reactivity correlated poorly with cue-induced craving. Craving at baseline was strongly predictive of cue-induced craving. Differences in cue-induced craving were not associated with age, sex, education, employment, treatment status, or number of days using methamphetamine in the 60 days prior to study entry. In contrast, the degree of baseline craving was strongly associated with employment status and the number of days using methamphetamine in the past 60 days. Cue-induced craving for methamphetamine may be reliably measured in methamphetamine-dependent individuals in the laboratory. Further studies employing the cue reactivity paradigm in methamphetamine dependence are warranted.

HIV-1 TAT protein enhances sensitization to methamphetamine by affecting dopaminergic function.

PubMed

Kesby, James P; Najera, Julia A; Romoli, Benedetto; Fang, Yiding; Basova, Liana; Birmingham, Amanda; Marcondes, Maria Cecilia G; Dulcis, Davide; Semenova, Svetlana

2017-10-01

Methamphetamine abuse is common among humans with immunodeficiency virus (HIV). The HIV-1 regulatory protein TAT induces dysfunction of mesolimbic dopaminergic systems which may result in impaired reward processes and contribute to methamphetamine abuse. These studies investigated the impact of TAT expression on methamphetamine-induced locomotor sensitization, underlying changes in dopamine function and adenosine receptors in mesolimbic brain areas and neuroinflammation (microgliosis). Transgenic mice with doxycycline-induced TAT protein expression in the brain were tested for locomotor activity in response to repeated methamphetamine injections and methamphetamine challenge after a 7-day abstinence period. Dopamine function in the nucleus accumbens (Acb) was determined using high performance liquid chromatography. Expression of dopamine and/or adenosine A receptors (ADORA) in the Acb and caudate putamen (CPu) was assessed using RT-PCR and immunohistochemistry analyses. Microarrays with pathway analyses assessed dopamine and adenosine signaling in the CPu. Activity-dependent neurotransmitter switching of a reserve pool of non-dopaminergic neurons to a dopaminergic phenotype in the ventral tegmental area (VTA) was determined by immunohistochemistry and quantified with stereology. TAT expression enhanced methamphetamine-induced sensitization. TAT expression alone decreased striatal dopamine (D1, D2, D4, D5) and ADORA1A receptor expression, while increasing ADORA2A receptors expression. Moreover, TAT expression combined with methamphetamine exposure was associated with increased adenosine A receptors (ADORA1A) expression and increased recruitment of dopamine neurons in the VTA. TAT expression and methamphetamine exposure induced microglia activation with the largest effect after combined exposure. Our findings suggest that dopamine-adenosine receptor interactions and reserve pool neuronal recruitment may represent potential targets to develop new treatments for

Behavioral and growth effects induced by low dose methamphetamine administration during the neonatal period in rats

PubMed Central

Williams, Michael T.; Moran, Mary S.; Vorhees, Charles V.

2009-01-01

The investigation of methamphetamine exposure during neonatal development in rats has demonstrated that long-term spatial learning deficits are induced. A previous dose–response study showed that administration of 5 mg/kg methamphetamine, four times daily from postnatal days 11 to 20 produced these deficits, although the effects were not as severe as at higher doses of 10 or 15 mg/kg. This study examined concentrations of methamphetamine at or below 5 mg/kg given over the same period of time. Five different concentrations of methamphetamine (i.e., 5, 2.5, 1.25, 0.625, or 0) were administered every 2 h four times daily from postnatal days 11 to 20. Body weights, zero maze performance, and Morris water maze learning were examined. A dose-dependent decrease in body weight was observed during the period of methamphetamine administration and these lower weights continued throughout adulthood for the 5, 2.5, and 1.25 mg/kg concentrations, although the adult decreases were negligible. No differences were noted in the zero maze. In the Morris water maze during the acquisition period, dose-dependent differences in spatial orientation were seen, however non-dose related deficits were observed for other parameters. During the shifted platform phase (“reversal”), a similar dose-dependent difference in spatial orientation was observed, although no other effects were noted during this phase. Females performed worse than males regardless of treatment or the phase of learning in the Morris water maze. These data suggest that even lower doses of methamphetamine can alter learning and memory in adulthood, although with less consistent results than with doses higher than 5 mg/kg/dose. These data would caution against even casual use of methamphetamine by women during pregnancy since even low doses could alter the ability of the child to learn. PMID:15380827

Levetiracetam induced acute reversible psychosis in a patient with uncontrolled seizures

PubMed Central

Kumar, Nithin; Swaroop, H. S.; Chakraborty, Ananya; Chandran, Suhas

2014-01-01

Levetiracetam (LEV) is a relatively newer antiepileptic drug with novel mechanism of action. It was introduced to the market in the year 2000. Pre-marketing clinical trials of the drug reported good tolerability with a wide safety margin. On post-marketing updates, there are few reports of psychosis after treatment with the drug. Here, we report a case of 52-year-old epileptic man who developed acute, reversible psychosis within 3 days of initiation of treatment. The drug was prescribed at a dose of 500 mg per day. After 3 days of treatment, the patient developed visual hallucinations, mood swings, withdrawal and suspicious behavior. Delirium was ruled out as there was no fluctuation in his sensorium or focal neurological deficits. His lab investigations for electrolytes, renal function test, thyroid, liver function and other related tests levels were within normal limits. A diagnosis of LEV induced psychosis was reached based on clinical judgment and causality assessment. PMID:25298593

Stress-Induced Enzyme Compounds Methamphetamine Neurotoxicity

MedlinePlus

... two exposures. They implicate ketoprofen’s main target, the pro-inflammatory enzyme cyclooxygenase (COX-1/COX-2), in ... Illegal Drugs Inhalants K2/Spice Kratom LSD (Acid) Marijuana MDMA (Ecstasy) Methamphetamine Opioids Other Drugs Over-the- ...

Dose-related psychotic symptoms in chronic methamphetamine users: evidence from a prospective longitudinal study.

PubMed

McKetin, Rebecca; Lubman, Dan I; Baker, Amanda L; Dawe, Sharon; Ali, Robert L

2013-03-01

Methamphetamine is associated with psychotic phenomena, but it is not clear to what extent this relationship is due to premorbid psychosis among people who use the drug. To determine the change in the probability of psychotic symptoms occurring during periods of methamphetamine use. Longitudinal prospective cohort study. A fixed-effects analysis of longitudinal panel data, consisting of 4 noncontiguous 1-month observation periods, was used to examine the relationship between changes in methamphetamine use and the risk of experiencing psychotic symptoms within individuals over time. Sydney and Brisbane, Australia. A total of 278 participants 16 years of age or older who met DSM-IV criteria for methamphetamine dependence on entry to the study but who did not meet DSM-IV criteria for lifetime schizophrenia or mania. Clinically significant psychotic symptoms in the past month, defined as a score of 4 or more on any of the Brief Psychiatric Rating Scale items of suspiciousness, hallucinations, or unusual thought content. The number of days of methamphetamine use in the past month was assessed using the Opiate Treatment Index. There was a 5-fold increase in the likelihood of psychotic symptoms during periods of methamphetamine use relative to periods of no use (odds ratio [OR], 5.3 [95% CI, 3.4-8.3]; P < .001), this increase being strongly dose-dependent (1-15 days of methamphetamine use vs abstinence in the past month: OR, 4.0 [95% CI, 2.5-6.5]; ≥16 days of methamphetamine use vs abstinence in the past month: OR, 11.2 [95% CI, 5.9-21.1]). Frequent cannabis and/or alcohol use (≥16 days of use in the past month) further increased the odds of psychotic symptoms (cannabis: OR, 2.0 [95% CI, 1.1-3.5]; alcohol: OR, 2.1 [95% CI, 1.1-4.2]). There was a large dose-dependent increase in the occurrence of psychotic symptoms during periods of methamphetamine use among users of the drug.

Prefrontal glutamate correlates of methamphetamine sensitization and preference

PubMed Central

Lominac, Kevin D.; Quadir, Sema G.; Barrett, Hannah M.; McKenna, Courtney L.; Schwartz, Lisa M.; Ruiz, Paige N.; Wroten, Melissa G.; Campbell, Rianne R.; Miller, Bailey W.; Holloway, John J.; Travis, Katherine O.; Rajasekar, Ganesh; Maliniak, Dan; Thompson, Andrew B.; Urman, Lawrence E.; Kippin, Tod E.; Phillips, Tamara J.; Szumlinski, Karen K.

2016-01-01

Methamphetamine (MA) is a widely abused, highly addictive, psychostimulant that elicits pronounced deficits in neurocognitive function related to hypo-functioning of the prefrontal cortex (PFC). Our understanding of how repeated methamphetamine impacts excitatory glutamatergic transmission within the PFC is limited, as is information about the relation between PFC glutamate and addiction vulnerability/resiliency. In vivo microdialysis and immunoblotting studies characterized the effects of methamphetamine (10 injections of 2 mg/kg, IP) upon extracellular glutamate in C57BL/6J mice and upon glutamate receptor and transporter expression, within the medial PFC. Glutamatergic correlates of both genetic and idiopathic variance in MA preference/intake were determined through studies of high versus low MA-drinking selectively bred mouse lines (MAHDR versus MALDR, respectively) and inbred C57BL/6J mice exhibiting spontaneously divergent place-conditioning phenotypes. Repeated methamphetamine sensitized drug-induced glutamate release and lowered indices of NMDA receptor expression in C57BL/6J mice, but did not alter basal extracellular glutamate content or total protein expression of Homer proteins, or metabotropic or AMPA glutamate receptors. Elevated basal glutamate, blunted methamphetamine-induced glutamate release and ERK activation, as well as reduced protein expression of mGlu2/3 and Homer2a/b were all correlated biochemical traits of selection for high versus low methamphetamine drinking, and Homer2a/b levels were inversely correlated with the motivational valence of methamphetamine in C57BL/6J mice. These data provide novel evidence that repeated, low-dose, methamphetamine is sufficient to perturb pre- and post-synaptic aspects of glutamate transmission within the medial PFC and that glutamate anomalies within this region may contribute to both genetic and idiopathic variance in methamphetamine addiction vulnerability/resiliency. PMID:26742098

Prior stimulation of the endocannabinoid system prevents methamphetamine-induced dopaminergic neurotoxicity in the striatum through activation of CB2 receptors.

PubMed

Nader, Joëlle; Rapino, Cinzia; Gennequin, Benjamin; Chavant, Francois; Francheteau, Maureen; Makriyannis, Alexandros; Duranti, Andrea; Maccarrone, Mauro; Solinas, Marcello; Thiriet, Nathalie

2014-12-01

Methamphetamine toxicity is associated with cell death and loss of dopamine neuron terminals in the striatum similar to what is found in some neurodegenerative diseases. Conversely, the endocannabinoid system (ECS) has been suggested to be neuroprotective in the brain, and new pharmacological tools have been developed to increase their endogenous tone. In this study, we evaluated whether ECS stimulation could reduce the neurotoxicity of high doses of methamphetamine on the dopamine system. We found that methamphetamine alters the levels of the major endocannabinoids, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) in the striatum, suggesting that the ECS participates in the brain responses to methamphetamine. Δ(9)-tetrahydrocannabinol (THC), a cannabis-derived agonist of both CB1 and CB2 cannabinoid receptors, or inhibitors of the main enzymes responsible for the degradation of AEA and 2-AG (URB597 and JZL184, respectively), blunted the decrease in striatal protein levels of tyrosine hydroxylase induced by methamphetamine. In addition, antagonists of CB2, but not of CB1, blocked the preventive effects of URB597 and JZL184, suggesting that only the former receptor subtype is engaged in neuroprotection exerted by ECS stimulation. Finally, we found that methamphetamine increases striatal levels of the cytokine tumor necrosis factor alpha, an effect that was blocked by ECS stimulation. Altogether, our results indicate that stimulation of ECS prior to the administration of an overdose of methamphetamine considerably reduces the neurotoxicity of the drug through CB2 receptor activation and highlight a protective function for the ECS against the toxicity induced by drugs and other external insults to the brain. This article is part of the Special Issue entitled 'CNS Stimulants'. Copyright © 2014 Elsevier Ltd. All rights reserved.

Prior stimulation of the endocannabinoid system prevents methamphetamine-induced dopaminergic neurotoxicity in the striatum through activation of CB2 receptors

PubMed Central

Nader, Joëlle; Rapino, Cinzia; Gennequin, Benjamin; Chavant, Francois; Francheteau, Maureen; Makriyannis, Alexandros; Duranti, Andrea; Maccarrone, Mauro; Solinas, Marcello; Thiriet, Nathalie

2016-01-01

Methamphetamine toxicity is associated with cell death and loss of dopamine neuron terminals in the striatum similar to what is found in some neurodegenerative diseases. Conversely, the endocannabinoid system (ECS) has been suggested to be neuroprotective in the brain, and new pharmacological tools have been developed to increase their endogenous tone. In this study, we evaluated whether ECS stimulation could reduce the neurotoxicity of high doses of methamphetamine on the dopamine system. We found that methamphetamine alters the levels of the major endocannabinoids, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) in the striatum, suggesting that the ECS participates in the brain responses to methamphetamine. Δ9-tetrahydrocannabinol (THC), a cannabis-derived agonist of both CB1 and CB2 cannabinoid receptors, or inhibitors of the main enzymes responsible for the degradation of AEA and 2-AG (URB597 and JZL184, respectively), blunted the decrease in striatal protein levels of tyrosine hydroxylase induced by methamphetamine. In addition, antagonists of CB2, but not of CB1, blocked the preventive effects of URB597 and JZL184, suggesting that only the former receptor subtype is engaged in neuroprotection exerted by ECS stimulation. Finally, we found that methamphetamine increases striatal levels of the cytokine tumor necrosis factor alpha, an effect that was blocked by ECS stimulation. Altogether, our results indicate that stimulation of ECS prior to the administration of an overdose of meth-amphetamine considerably reduces the neurotoxicity of the drug through CB2 receptor activation and highlight a protective function for the ECS against the toxicity induced by drugs and other external insults to the brain. This article is part of the Special Issue entitled ‘CNS Stimulants’. PMID:24709540

Perceived Risk of Methamphetamine among Chinese Methamphetamine Users

PubMed Central

Kelly, Brian C; Liu, Tieqiao; Yang, Xiaozhao Yosef; Zhang, Guanbai; Hao, Wei; Wang, Jichuan

2014-01-01

Background Methamphetamine use has grown considerably in China in recent years. Information about perceptions of risk on methamphetamine is important to facilitate health promotion efforts. Methods Using both survey data and qualitative interview data, the authors evaluate the perceived risk of methamphetamine use among Chinese users using a mixed-methods approach. Through Respondent Driven Sampling, the authors recruited a sample of 303 methamphetamine users in Changsha, China. Results A majority (59.1%) perceive that infrequent methamphetamine use poses no risk to the user, while 11.2% perceive at least moderate risk for light use. A majority (56.7%) perceived at least moderate risk associated with regular methamphetamine use. Most (82.2%) also perceive methamphetamine to be easily obtainable. A path model indicates that perceived risk shapes intentions to use and expectations of future use, as does perceived availability. Qualitatively, while addiction was the most common risk discussed by users, they differed on whether they perceived the drug addictive. Other concerns raised by interviewees included impaired cognition, mental health problems, physical harm, and social dysfunction. Discussion While some users identify significant risks with methamphetamine, others do not perceive its use to be problematic. Collectively, these findings indicate that intervening upon perceptions of risk among Chinese methamphetamine users may be a means to influence intentions to use. PMID:24925820

Gender differences in the behavioral effects of methamphetamine.

PubMed

Schindler, Charles W; Bross, Joshua G; Thorndike, Eric B

2002-05-10

The effects of methamphetamine were tested in male and female rats on two different behavioral tasks. Following habituation to a locomotor activity chamber, female rats were more sensitive to the locomotor activating effect of i.p. methamphetamine (0.1-3.0 mg/kg) than were male rats. A similar effect has been observed for other psychomotor stimulants, including cocaine and amphetamine. However, males and females did not differ on methamphetamine-induced place preference following eight conditioning trials with a wide range of doses (0.1-5.6 mg/kg). These results suggest that males and females differ in their response to methamphetamine for only some behavioral tasks.

Methamphetamine fails to alter the noradrenergic integrity of the heart.

PubMed

Ruffoli, Riccardo; Soldani, Paola; Pasquali, Livia; Ruggieri, Stefano; Paparelli, Antonio; Fornai, Francesco

2008-10-01

The chronic use of methamphetamine leads to cardiomyopathy and a nigrostriatal dopamine deficiency that partly mimics what occurs in Parkinson's disease. This study examines the cardiac effects occurring after chronic administration of methamphetamine and parkinsonism-inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Despite the similarities concerning the nigrostriatal dopamine denervation, methamphetamine failed to produce chronic norepinephrine depletion in the heart, thus contrasting with what occurs in Parkinson's disease or after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. These data suggest that the chronic cardiovascular effects induced by methamphetamine rely on biochemical changes which differ from those activated by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or during the course of Parkinson's disease.

Fragment C Domain of Tetanus Toxin Mitigates Methamphetamine Neurotoxicity and Its Motor Consequences in Mice

PubMed Central

Mendieta, Liliana; Granado, Noelia; Aguilera, José; Tizabi, Yousef

2016-01-01

Background: The C-terminal domain of the heavy chain of tetanus toxin (Hc-TeTx) is a nontoxic peptide with demonstrated in vitro and in vivo neuroprotective effects against striatal dopaminergic damage induced by 1-methyl-4-phenylpyridinium and 6-hydoxydopamine, suggesting its possible therapeutic potential in Parkinson’s disease. Methamphetamine, a widely abused psychostimulant, has selective dopaminergic neurotoxicity in rodents, monkeys, and humans. This study was undertaken to determine whether Hc-TeTx might also protect against methamphetamine-induced dopaminergic neurotoxicity and the consequent motor impairment. Methods: For this purpose, we treated mice with a toxic regimen of methamphetamine (4mg/kg, 3 consecutive i.p. injections, 3 hours apart) followed by 3 injections of 40 ug/kg of Hc-TeTx into grastrocnemius muscle at 1, 24, and 48 hours post methamphetamine treatment. Results: We found that Hc-TeTx significantly reduced the loss of dopaminergic markers tyrosine hydroxylase and dopamine transporter and the increases in silver staining (a well stablished degeneration marker) induced by methamphetamine in the striatum. Moreover, Hc-TeTx prevented the increase of neuronal nitric oxide synthase but did not affect microglia activation induced by methamphetamine. Stereological neuronal count in the substantia nigra indicated loss of tyrosine hydroxylase-positive neurons after methamphetamine that was partially prevented by Hc-TeTx. Importantly, impairment in motor behaviors post methamphetamine treatment were significantly reduced by Hc-TeTx. Conclusions: Here we demonstrate that Hc-TeTx can provide significant protection against acute methamphetamine-induced neurotoxicity and motor impairment, suggesting its therapeutic potential in methamphetamine abusers. PMID:26945022

Psychosis: Atypical Limbic Epilepsy versus Limbic Hyperexcitability with Onset at Puberty?

PubMed Central

Sharp, Frank R.; Hendren, Robert L.

2009-01-01

Phencyclidine (PCP), Ketamine (Special K) and MK-801 are non-competitive NMDA antagonists that produce acute psychosis in humans. The psychosis produced by these psychomimetic drugs is indistinguishable from schizophrenia and includes both positive and negative symptoms. This drug-induced psychosis occurs after puberty in humans. This brief review argues that this psychosis is an atypical form of limbic epilepsy based upon MK-801 induced spike-and-wave activity in rats and based upon increased blood flow and metabolism in brain of patients with psychosis caused by these psychomimetics. Moreover, there is a specific limbic thalamcortical psychosis circuit that mediates cell injury in limbic cortex of rodents and may mediate this PCP-induced psychosis in humans. It is proposed that this thalamocortical psychosis circuit develops at puberty and can mediate psychosis at puberty and in adulthood by PCP and ketamine-induced psychosis, and possibly in schizophrenia, bipolar disease and other psychotic states. Finally, based upon this developmentally regulated psychosis-epilepsy related thalamocortical circuitry, it is proposed that anti-epileptic drugs that promote GABAergic mechanisms might decrease the probability of episodic psychosis from any cause. PMID:17416210

Fragment C Domain of Tetanus Toxin Mitigates Methamphetamine Neurotoxicity and Its Motor Consequences in Mice.

PubMed

Mendieta, Liliana; Granado, Noelia; Aguilera, José; Tizabi, Yousef; Moratalla, Rosario

2016-08-01

The C-terminal domain of the heavy chain of tetanus toxin (Hc-TeTx) is a nontoxic peptide with demonstrated in vitro and in vivo neuroprotective effects against striatal dopaminergic damage induced by 1-methyl-4-phenylpyridinium and 6-hydoxydopamine, suggesting its possible therapeutic potential in Parkinson's disease. Methamphetamine, a widely abused psychostimulant, has selective dopaminergic neurotoxicity in rodents, monkeys, and humans. This study was undertaken to determine whether Hc-TeTx might also protect against methamphetamine-induced dopaminergic neurotoxicity and the consequent motor impairment. For this purpose, we treated mice with a toxic regimen of methamphetamine (4mg/kg, 3 consecutive i.p. injections, 3 hours apart) followed by 3 injections of 40 ug/kg of Hc-TeTx into grastrocnemius muscle at 1, 24, and 48 hours post methamphetamine treatment. We found that Hc-TeTx significantly reduced the loss of dopaminergic markers tyrosine hydroxylase and dopamine transporter and the increases in silver staining (a well stablished degeneration marker) induced by methamphetamine in the striatum. Moreover, Hc-TeTx prevented the increase of neuronal nitric oxide synthase but did not affect microglia activation induced by methamphetamine. Stereological neuronal count in the substantia nigra indicated loss of tyrosine hydroxylase-positive neurons after methamphetamine that was partially prevented by Hc-TeTx. Importantly, impairment in motor behaviors post methamphetamine treatment were significantly reduced by Hc-TeTx. Here we demonstrate that Hc-TeTx can provide significant protection against acute methamphetamine-induced neurotoxicity and motor impairment, suggesting its therapeutic potential in methamphetamine abusers. © The Author 2016. Published by Oxford University Press on behalf of CINP.

Agmatine attenuates methamphetamine-induced hyperlocomotion and stereotyped behavior in mice.

PubMed

Kitanaka, Nobue; Kitanaka, Junichi; Hall, F Scott; Uhl, George R; Watabe, Kaname; Kubo, Hitoshi; Takahashi, Hitoshi; Tanaka, Koh-ichi; Nishiyama, Nobuyoshi; Takemura, Motohiko

2014-04-01

We investigated whether pretreatment with the neurotransmitter/neuromodulator agmatine (decarboxylated L-arginine) affected methamphetamine (METH)-induced hyperlocomotion and stereotypy in male ICR mice. Agmatine pretreatment alone had no effects on locomotion or stereotypy, but it produced a dose-dependent attenuation of locomotion and the total incidence of stereotyped behavior induced by a low dose of METH (5 mg/kg). The stereotypy induced by this dose was predominantly characterized by stereotyped sniffing. By contrast, agmatine did not affect the total incidence of stereotypy induced by a higher dose of METH (10 mg/kg). However, the nature of stereotypy induced by this dose of METH was substantially altered; agmatine pretreatment significantly reduced stereotyped biting but significantly increased stereotyped sniffing and persistent locomotion. Agmatine pretreatment therefore appears to produce a rightward shift in the dose-response curve for METH. Pretreatment of mice with piperazine-1-carboxamidine (a putative agmatinase inhibitor) had no effect on locomotion or stereotypy induced by a low dose of METH, suggesting that endogenous agmatine may not regulate the METH action.

Methamphetamine Vaccines: Improvement through Hapten Design.

PubMed

Collins, Karen C; Schlosburg, Joel E; Bremer, Paul T; Janda, Kim D

2016-04-28

Methamphetamine (MA) addiction is a serious public health problem, and current methods to abate addiction and relapse are currently ineffective for mitigating this growing global epidemic. Development of a vaccine targeting MA would provide a complementary strategy to existing behavioral therapies, but this has proven challenging. Herein, we describe optimization of both hapten design and formulation, identifying a vaccine that elicited a robust anti-MA immune response in mice, decreasing methamphetamine-induced locomotor activity.

Neuroleptic-induced deficit syndrome in bipolar disorder with psychosis

PubMed Central

Ueda, Satoshi; Sakayori, Takeshi; Omori, Ataru; Fukuta, Hajime; Kobayashi, Takashi; Ishizaka, Kousuke; Saijo, Tomoyuki; Okubo, Yoshiro

2016-01-01

Neuroleptics can induce not only physical adverse effects but also mental effects that produce deficit status in thought, affect, cognition, and behavior. This condition is known as neuroleptic-induced deficit syndrome (NIDS), which includes apathy, lack of initiative, anhedonia, indifference, blunted affect, and reduced insight into disease. Although this old concept now appears almost forgotten, neuroleptics, whether typical or atypical, can make depression or bipolar disorder resemble other more refractory conditions, readily leading to mistaken diagnosis and inappropriate treatment. The authors describe three cases of NIDS superimposed on depressive phase in bipolar disorder with psychosis, where the attending psychiatrist’s failure to recognize NIDS prevented patients from receiving effective treatment and achieving remission. All cases achieved remission after reduction of neuroleptics and intensive therapy, including electroconvulsive therapy, for bipolar depression. The concept of NIDS was originally introduced for schizophrenia, and it has rarely been highlighted in other diseases. In recent years, however, atypical antipsychotics are being more often administered to patients with bipolar disorder. Psychiatrists, therefore, should also remember and exercise caution regarding NIDS in the pharmacotherapy of bipolar disorder with and without psychosis. The authors believe that the concept of NIDS needs to be reappraised in current psychiatry. PMID:26893564

Methamphetamine Pills

MedlinePlus

... Careers Our People Staff Volunteers Board of Directors Science Advisory Board Newsroom Annual Report & Financials Frequently Asked Questions Contact Search for: Search Home Drug Guide Methamphetamine Pills Methamphetamine Pills Know the facts about methamphetamine pills and connect with help and ...

An experimental study of catechol-o-methyltransferase Val158Met moderation of delta-9-tetrahydrocannabinol-induced effects on psychosis and cognition.

PubMed

Henquet, Cécile; Rosa, Araceli; Krabbendam, Lydia; Papiol, Sergi; Fananás, Lourdes; Drukker, Marjan; Ramaekers, Johannes G; van Os, Jim

2006-12-01

Observational studies have suggested that psychometric psychosis liability and a functional polymorphism in the catechol-O-methyltransferase (COMT Val(158)Met) gene moderate the psychosis-inducing effect of cannabis. To replicate and extend this finding, a double-blind, placebo-controlled cross-over design was used in which patients with a psychotic disorder (n=30), relatives of patients with a psychotic disorder (n=12), and healthy controls (n=32) were exposed to Delta-9-tetrahydrocannabinol (Delta-9-THC, the principal component of cannabis) or placebo, followed by cognitive assessment and assessment of current psychotic experiences. Previous expression of psychometric psychosis liability was also assessed. Models of current psychotic experiences and cognition were examined with multilevel random regression analyses to assess (i) main effects of genotype and condition, (ii) interactions between condition and genotype, and (iii) three-way interactions between condition, genotype, and psychometric psychosis liability. Carriers of the Val allele were most sensitive to Delta-9-THC-induced psychotic experiences, but this was conditional on prior evidence of psychometric psychosis liability. Delta-9-THC impacted negatively on cognitive measures. Carriers of the Val allele were also more sensitive to Delta-9-THC-induced memory and attention impairments compared to carriers of the Met allele. Experimental effects of Delta-9-THC on cognition and psychosis are moderated by COMT Val(158)Met genotype, but the effects may in part be conditional on the additional presence of pre-existing psychosis liability. The association between cannabis and psychosis may represent higher order gene-environment and gene-gene interactions.

Increased blood 8-hydroxy-2-deoxyguanosine levels in methamphetamine users during early abstinence.

PubMed

Huang, Ming-Chyi; Lai, Ying-Ching; Lin, Shih-Ku; Chen, Chun-Hsin

2018-01-01

Reactive oxygen species (ROS) are thought to play a role in the adverse physical and mental consequences of methamphetamine usage. The oxidative DNA adduct 8-hydroxy-2'-deoxyguanosine (8-OHdG) is a well-known biomarker of ROS-induced DNA damage. Currently, there is insufficient clinical information about methamphetamine-induced oxidative DNA damage. This study examined differences in blood levels of 8-OHdG between methamphetamine users and non-users as well as alterations in 8-OHdG levels after 2 weeks of methamphetamine abstinence. We recruited 182 methamphetamine users (78.6% of male) and 71 healthy controls (95.8% of male). Baseline serum 8-OHdG levels were measured in both groups using a competitive enzyme-linked immunosorbent assay. In methamphetamine users, 8-OHdG levels were measured again 2 weeks after baseline measurement. The results showed that methamphetamine users had significantly higher 8-OHdG levels (0.34 ± 0.13 ng/mL) than healthy controls (0.30 ± 0.08 ng/mL) (p < 0.001). The 8-OHdG levels did not alter after 2 weeks of methamphetamine abstinence (0.32 ± 0.12 ng/mL, p = 0.051 compared to baseline measurement; p = 0.12 compared to healthy controls). No significant correlations were observed between baseline 8-OHdG levels in methamphetamine users and post-abstinence interval, age of the first methamphetamine use, duration of methamphetamine use, or history of frequent methamphetamine use. Our findings suggest that methamphetamine users had an enhanced level of oxidative damage, which did not normalize during early abstinence. Future studies are required to determine the effects of long-term methamphetamine abstinence and potential confounders on 8-OHdG levels in methamphetamine users.

Methamphetamine exposure during brain development alters the brain acetylcholine system in adolescent mice

PubMed Central

Siegel, Jessica A.; Park, Byung S.; Raber, Jacob

2013-01-01

Children exposed to methamphetamine during brain development as a result of maternal drug use have long-term hippocampus-dependent cognitive impairments, but the mechanisms underlying these impairments are not understood. The acetylcholine system plays an important role in cognitive function and potential methamphetamine-induced acetylcholine alterations may be related to methamphetamine-induced cognitive impairments. In this study, we investigated the potential long-term effects of methamphetamine exposure during hippocampal development on the acetylcholine system in adolescence mice on postnatal day 30 and in adult mice on postnatal day 90. Methamphetamine exposure increased the density of acetylcholine neurons in regions of the basal forebrain and the area occupied by acetylcholine axons in the hippocampus in adolescent female mice. In contrast, methamphetamine exposure did not affect the density of GABA cells or total neurons in the basal forebrain. Methamphetamine exposure also increased the number of muscarinic acetylcholine receptors in the hippocampus of adolescent male and female mice. Our results demonstrate for the first time that methamphetamine exposure during hippocampal development affects the acetylcholine system in adolescent mice and that these changes are more profound in females than males. PMID:21824143

Evaluation of the Cardiovascular and Subjective Effects of Rivastigmine In Combination With Methamphetamine in Methamphetamine-Dependent Human Volunteers

PubMed Central

De La Garza, R.; Shoptaw, S.; Newton, T. F.

2008-01-01

Acetylcholine (ACh) has been implicated in the reinforcing and locomotor activating effects produced by methamphetamine. Of interest, recent data suggest that acetylcholinesterase (AChE) inhibitors attenuate methamphetamine-seeking behavior in rats. We conducted this study in order to determine the safety (adverse events, mood changes, cardiovascular effects) and preliminary efficacy (subjective effects) of the AChE inhibitor rivastigmine when tested in combination with methamphetamine. Twenty-three non-treatment seeking methamphetamine-dependent participants resided in an inpatient unit at UCLA for two-weeks, and completed this double-blind, between-subjects, placebo-controlled study. Prior to randomization to study drug, infusions of saline (day 4; o mg) and methamphetamine (day 5; 30 mg, IV) were given to all participants at 11:30 a.m. in single-blinded fashion. On day 7 and continuing through day 11, participants were randomized to receive oral placebo (0 mg, N=7) or rivastigmine (1.5 mg, N=7; 3 mg, N=9). On day 11, the subjects received saline and methamphetamine infusions again (randomized to either 11:30 a.m. or 2:30 p.m.), under double-blind conditions. The data analyses compared across-study measures of adverse events and mood, and a post-randomization analysis of cardiovascular and subjective effects (on Day 11). The data reveal that rivastigmine was not associated with increased adverse events or alterations in mood. As expected, acute methamphetamine exposure (30 mg, IV) increased heart rate and blood pressure, as well as several positive subjective effects, ARCI ratings, and reported monetary value (p<0.05). The data indicated that rivastigmine, at 3 mg, significantly attenuated methamphetamine-induced increases in diastolic blood pressure, and self-reports of “anxious” and “desire” (p<0.05). Taken together, the findings in the current report suggest that pharmacological manipulations that enhance brain ACh warrant continued investigation as

The differential effects of alprazolam and oxazepam on methamphetamine self-administration in rats.

PubMed

Spence, Allyson L; Guerin, Glenn F; Goeders, Nicholas E

2016-09-01

Methamphetamine is the second most commonly used illicit drug in the world, and despite recent attempts by the Drug Enforcement Administration to combat this epidemic, methamphetamine use is still on the rise. As methamphetamine use increases so does polydrug use, particularly that involving methamphetamine and benzodiazepines. The present study was designed to examine the effects of two benzodiazepines on methamphetamine self-administration. Five doses of methamphetamine (0.0075, 0.015, 0.03, 0.09, and 0.12mg/kg/infusion) were tested, producing an inverted U-shaped dose-response curve. Rats were then pretreated with oxazepam, alprazolam, or vehicle prior to methamphetamine self-administration. To determine if the effects of these drugs were due to the GABAA receptor and/or translocator protein (TSPO), we also pretreated rats with an antagonist for the benzodiazepine-binding site on the GABAA receptor (i.e., flumazenil) and a TSPO antagonist (i.e., PK11195) prior to alprazolam or oxazepam administration. Oxazepam significantly reduced methamphetamine self-administration as demonstrated by a downward shift of the dose-response curve. In contrast, alprazolam significantly enhanced methamphetamine self-administration as evidenced by a leftward shift of the dose-response curve. Flumazenil completely blocked the effects of alprazolam on methamphetamine self-administration. When administered individually, both flumazenil and PK11195 partially reversed the effects of oxazepam on methamphetamine self-administration. However, when these two antagonists were combined, the effects of oxazepam were completely reversed. The GABAA receptor is responsible for the alprazolam-induced enhancement of methamphetamine self-administration, while the activation of both the GABAA receptor and TSPO are responsible for the oxazepam-induced reduction of methamphetamine self-administration. Published by Elsevier Ireland Ltd.

The role of hyperthermia and metabolism as mechanisms of tolerance to methamphetamine neurotoxicity.

PubMed

Johnson-Davis, Kamisha L; Fleckenstein, Annette E; Wilkins, Diana G

2003-12-15

Pretreatment with multiple methamphetamine injections prior to a high-dose methamphetamine challenge administration can attenuate long-term deficits in striatal and hippocampal serotonin content caused by the stimulant. The present data extend previous findings by demonstrating that rats pretreated with escalating doses methamphetamine did not exhibit dopamine deficits in the striatum, nor serotonin deficits in striatal, frontal cortical, or hippocampal tissues, 7 days after a challenge methamphetamine administration. This protection was not due to attenuation of methamphetamine-induced hyperthermia or altered brain methamphetamine concentrations. These data differ from previous findings thereby highlighting that different mechanisms contribute to the tolerance of the neurotoxic effects.

Methamphetamine

MedlinePlus

... 1016/j.drugalcdep.2014.10.027. Bassindale T. Quantitative analysis of methamphetamine in hair of children removed ... Highlight Do rats prefer palatable foods over meth? Research Report Metham-phetamine Provides an overview of the ...

Methamphetamine

MedlinePlus

... a tablet to take by mouth. If your child is taking methamphetamine for ADHD, it is usually ... often than prescribed by your doctor.If your child is taking methamphetamine for ADHD, the doctor will ...

Involvement of posterior cingulate cortex in ketamine-induced psychosis relevant behaviors in rats.

PubMed

Ma, Jingyi; Leung, L Stan

2018-02-15

The involvement of posterior cingulate cortex (PCC) on ketamine-induced psychosis relevant behaviors was investigated in rats. Bilateral infusion of muscimol, a GABA A receptor agonist, into the PCC significantly antagonized ketamine-induced deficit in prepulse inhibition of a startle reflex (PPI), deficit in gating of hippocampal auditory evoked potentials, and behavioral hyperlocomotion in a dose dependent manner. Local infusion of ketamine directly into the PCC also induced a PPI deficit. Systemic injection of ketamine (3mg/kg,s.c.) induced an increase in power of electrographic activity in the gamma band (30-100Hz) in both the PCC and the hippocampus; peak theta (4-10Hz) power was not significantly altered, but peak theta frequency was increased by ketamine. In order to exclude volume conduction from the hippocampus to PCC, inactivation of the hippocampus was made by local infusion of muscimol into the hippocampus prior to ketamine administration. Muscimol in the hippocampus effectively blocked ketamine-induced increase of gamma power in the hippocampus but not in the PCC, suggesting independent generation of gamma waves in PCC and hippocampus. It is suggested that the PCC is part of the brain network mediating ketamine-induced psychosis related behaviors. Copyright © 2017 Elsevier B.V. All rights reserved.

Investigation of the origin of ephedrine and methamphetamine by stable isotope ratio mass spectrometry: a Japanese experience.

PubMed

Makino, Y; Urano, Y; Nagano, T

2005-01-01

Illicit drug abuse is a serious global problem that can only be solved through international cooperation. In Asian countries, the abuse of methamphetamine is one of the most pressing problems. To assist in the control of methamphetamine, the authors investigated in detail the character of ephedrine, which is a key precursor for the illicit manufacture of methamphetamine. Commercial ephedrine is produced by one of three methods: (a) extraction from Ephedra plants, (b) full chemical synthesis or (c) via a semi-synthetic process involving the fermentation of sugar, followed by amination. Although chemically there is no difference between ephedrine samples from different origins (natural, synthetic or semi-synthetic), scientific and analytical tools such as drug-characterization and impurity-profiling programmes may provide valuable information for law enforcement and regulatory activities as part of precursor control strategies. During the research under discussion in the present article, in addition to classical impurity profiling of manufacturing by-products, the use of stable isotope ratio mass spectrometry was investigated for determining the origin of the ephedrine that had been used as a precursor in seized methamphetamine samples. The results of carbon and nitrogen stable isotope ratio (delta13C and delta15N) analysis of samples of crystalline methamphetamine seized in Japan suggested that the drug had been synthesized from either natural or semi-synthetic ephedrine and not from synthetic ephedrine. Stable isotope ratio analysis is expected to be a useful tool for tracing the origins of seized methamphetamine. It has attracted much interest from precursor control authorities in Japan and the East Asian region and may prove useful in the international control of precursors.

Neuroticism associated with cocaine-induced psychosis in cocaine-dependent patients: a cross-sectional observational study.

PubMed

Roncero, Carlos; Daigre, Constanza; Barral, Carmen; Ros-Cucurull, Elena; Grau-López, Lara; Rodríguez-Cintas, Laia; Tarifa, Nuria; Casas, Miguel; Valero, Sergi

2014-01-01

Cocaine consumption can induce transient psychotic symptoms, which has been correlated with more severe addiction and aggressive behavior. However, little is known about the nature of the relationship between personality traits and psychotic symptoms in cocaine-dependent patients. This study examined the relationship between neuroticism and cocaine-induced psychosis. A total of 231 cocaine-dependent patients seeking treatment were recruited to the study. Personality was evaluated by the Zuckerman-Kuhlman Personality Questionnaire. Cocaine-induced psychosis questionnaire, SCID-I, and SCID-II were used to evaluate comorbidity and clinical characteristics. Data analysis was performed in three steps: descriptive, bivariate, and multivariate analyses. Cocaine-induced psychosis was reported in 65.4% of the patients and some personality disorder in 46.8%. Two personality dimensions (Neuroticism-Anxiety and Aggression-Hostility) presented a significant effect on the risk of experiencing psychotic symptoms (t(229) = 2.69, p = 0.008; t(229) = 2.06, p = 0.004), and patients with psychotic symptoms showed higher scores in both variables. On the multivariate analysis, only Neuroticism remained as a significant personality factor independently associated with psychotic symptoms (Wald = 7.44, p<0.05, OR = 1.08, CI 95% 1.02-1.16) after controlling for age, gender and number of consumption substances. An association between high neuroticism scores and presence of psychotic symptoms induced by cocaine has been found, independently of other consumption variables. Personality dimensions should be evaluated in cocaine-dependent patients in order to detect high scores of neuroticism and warn patients about the risk of developing cocaine-induced psychotic symptoms.

A comparison of economic demand and conditioned-cued reinstatement of methamphetamine- or food-seeking in rats

PubMed Central

Galuska, Chad M.; Banna, Kelly M.; Willse, Lena Vaughn; Yahyavi-Firouz-Abadi, Noushin; See, Ronald E.

2011-01-01

The present study examined whether continued access to methamphetamine or food reinforcement changed economic demand for both. The relationship between demand elasticity and cue-induced reinstatement was also determined. Male Long-Evans rats lever-pressed under increasing fixed-ratio requirements for either food pellets or methamphetamine (20 μg/50 μl infusion). For two groups, demand curves were obtained before and after continued access (12 days, 2-hr sessions) to the reinforcer under a fixed-ratio 3 schedule. A third group was given continued access to methamphetamine between determinations of food demand and a fourth group abstained from methamphetamine between determinations. All groups underwent extinction sessions, followed by a cue-induced reinstatement test. Although food demand was less elastic than methamphetamine demand, continued access to methamphetamine shifted the methamphetamine demand curve upward and the food demand curve downward. In some rats, methamphetamine demand also became less elastic. Continued access to food had no effect on food demand. Reinstatement was higher after continued access to methamphetamine relative to food. For methamphetamine, elasticity and reinstatement measures were correlated. We conclude that continued access to methamphetamine – but not food – alters demand in ways suggestive of methamphetamine accruing reinforcing strength. Demand elasticity and reinstatement measures appear to be related indices of drug-seeking. PMID:21597363

Chronic methamphetamine exposure induces cardiac fas-dependent and mitochondria-dependent apoptosis.

PubMed

Liou, Cher-Ming; Tsai, Shiow-Chwen; Kuo, Chia-Hua; Williams, Timothy; Ting, Hua; Lee, Shin-Da

2014-06-01

Very limited information regarding the influence of chronic methamphetamine exposure on cardiac apoptosis is available. In this study, we evaluate whether chronic methamphetamine exposure will increase cardiac Fas-dependent (type I) and mitochondria-dependent (type II) apoptotic pathways. Thirty-two male Wistar rats at 3-4 months of age were randomly divided into a vehicle-treated group [phosphate-buffered saline (PBS) 0.5 ml SQ per day] and a methamphetamine-treated group (MA 10 mg/kg SQ per day) for 3 months. We report that after 3 months of exposure, abnormal myocardial architecture, more minor cardiac fibrosis and cardiac TUNEL-positive apoptotic cells were observed at greater frequency in the MA group than in the PBS group. Protein levels of TNF-α, Fas ligand, Fas receptor, Fas-associated death domain, activated caspase-8, and activated caspase-3 (Fas-dependent apoptosis) extracted from excised hearts were significantly increased in the MA group, compared to the PBS group. Protein levels of cardiac Bak, t-Bid, Bak to Bcl-xL ratio, activated caspase-9, and activated caspase-3 (mitochondria-dependent apoptosis) were significantly increased in the MA group, compared with the PBS group. The results from this study reveal that chronic methamphetamine exposure will activate cardiac Fas-dependent and mitochondria-dependent apoptotic pathways, which may indicate a possible mechanism for developing cardiac abnormalities in humans with chronic methamphetamine abuse.

PET studies of d-methamphetamine pharmacokinetics in primates: comparison with l-methamphetamine and ( --)-cocaine.

PubMed

Fowler, Joanna S; Kroll, Carsten; Ferrieri, Richard; Alexoff, David; Logan, Jean; Dewey, Stephen L; Schiffer, Wynne; Schlyer, David; Carter, Pauline; King, Payton; Shea, Colleen; Xu, Youwen; Muench, Lisa; Benveniste, Helene; Vaska, Paul; Volkow, Nora D

2007-10-01

The methamphetamine molecule has a chiral center and exists as 2 enantiomers, d-methamphetamine (the more active enantiomer) and l-methamphetamine (the less active enantiomer). d-Methamphetamine is associated with more intense stimulant effects and higher abuse liability. The objective of this study was to measure the pharmacokinetics of d-methamphetamine for comparison with both l-methamphetamine and (-)-cocaine in the baboon brain and peripheral organs and to assess the saturability and pharmacologic specificity of binding. d- and l-methamphetamine and (-)-cocaine were labeled with (11)C via alkylation of the norprecursors with (11)C-methyl iodide using literature methods. Six different baboons were studied in 11 PET sessions at which 2 radiotracer injections were administered 2-3 h apart to determine the distribution and kinetics of (11)C-d-methamphetamine in brain and peripheral organs. Saturability and pharmacologic specificity were assessed using pretreatment with d-methamphetamine, methylphenidate, and tetrabenazine. (11)C-d-Methamphetamine pharmacokinetics were compared with (11)C-l-methamphetamine and (11)C-(-)-cocaine in both brain and peripheral organs in the same animal. (11)C-d- and l-methamphetamine both showed high uptake and widespread distribution in the brain. Pharmacokinetics did not differ between enantiomers, and the cerebellum peaked earlier and cleared more quickly than the striatum for both. (11)C-d-Methamphetamine distribution volume ratio was not substantially affected by pretreatment with methamphetamine, methylphenidate, or tetrabenazine. Both enantiomers showed rapid, high uptake and clearance in the heart and lungs and slower uptake and clearance in the liver and kidneys. A comparison of (11)C-d-methamphetamine and (11)C-(-)-cocaine showed that (11)C-d-methamphetamine peaked later in the brain than did (11)C-(-)-cocaine and cleared more slowly. The 2 drugs showed similar behavior in all peripheral organs examined except the kidneys and

Morphometric abnormalities of the lateral ventricles in methamphetamine-dependent subjects☆

PubMed Central

Jeong, Hyeonseok S.; Lee, Sunho; Yoon, Sujung; Jung, Jiyoung J.; Cho, Han Byul; Kim, Binna N.; Ma, Jiyoung; Ko, Eun; Im, Jooyeon Jamie; Ban, Soonhyun; Renshaw, Perry F.; Lyoo, In Kyoon

2017-01-01

Background The presence of morphometric abnormalities of the lateral ventricles, which can reflect focal or diffuse atrophic changes of nearby brain structures, is not well characterized in methamphetamine dependence. The current study was aimed to examine the size and shape alterations of the lateral ventricles in methamphetamine-dependent subjects. Methods High-resolution brain structural images were obtained from 37 methamphetamine-dependent subjects and 25 demographically matched healthy individuals. Using a combined volumetric and surface-based morphometric approach, the structural variability of the lateral ventricles, with respect to extent and location, was examined. Results Methamphetamine-dependent subjects had an enlarged right lateral ventricle compared with healthy individuals. Morphometric analysis revealed a region-specific pattern of lateral ventricular expansion associated with methamphetamine dependence, which was mainly distributed in the areas adjacent to the ventral striatum, medial prefrontal cortex, and thalamus. Conclusions Patterns of shape decomposition in the lateral ventricles may have relevance to the structural vulnerability of the prefrontal-ventral striatal-thalamic circuit to methamphetamine-induced neurotoxicity. PMID:23769159

Nucleus accumbens hyperpolarization-activated cyclic nucleotide-gated channels modulate methamphetamine self-administration in rats.

PubMed

Cao, Dan-Ni; Song, Rui; Zhang, Shu-Zhuo; Wu, Ning; Li, Jin

2016-08-01

Methamphetamine addiction is believed to primarily result from increased dopamine release and the inhibition of dopamine uptake. Some evidence suggests that hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play important roles in the functional modulation of dopaminergic neurons and the pathophysiology of related diseases. However, little is known about the effects of HCN channels on methamphetamine addiction. The present study investigated the role of brain HCN channels in methamphetamine addiction. Acute intracerebroventricular (i.c.v.) injection or bilateral intra-accumbens microinjections of non-selective HCN channel blocker ZD7288 (0.3125 and 0.625 μg) significantly reduced both methamphetamine (0.0125 or 0.05 mg/kg/infusion)-induced self-administration under fixed ratio 2 reinforcement and the breakpoint of methamphetamine (0.05 mg/kg/infusion) under progressive ratio reinforcement in rats. Moreover, compared with i.c.v. injection, bilateral intra-accumbens microinjections of ZD7288 exerted stronger inhibitory effects, suggesting that blockade of HCN channels in the nucleus accumbens reduced the reinforcing effects of and motivation for methamphetamine. We also found that ZD7288 (0.625 and 1.25 μg, i.c.v.) significantly decreased methamphetamine (1 mg/kg, intraperitoneal (i.p.))-induced hyperactivity with no effect on the spontaneous activity in rats. Finally, in vivo microdialysis experiments showed that the HCN channel blockade using ZD7288 (0.625 and 1.25 μg, i.c.v.) decreased methamphetamine (1 mg/kg, i.p.)-induced elevation of extracellular dopamine levels in the nucleus accumbens. These results indicate that HCN channels in the nucleus accumbens are involved in the reinforcing properties of methamphetamine and highlight the importance of HCN channels in the regulation of dopamine neurotransmission underlying methamphetamine addiction.

Agmatine attenuates the discriminative stimulus and hyperthermic effects of methamphetamine in male rats.

PubMed

Thorn, David A; Li, Jiuzhou; Qiu, Yanyan; Li, Jun-Xu

2016-09-01

Methamphetamine abuse remains an alarming public heath challenge, with no approved pharmacotherapies available. Agmatine is a naturally occurring cationic polyamine that has previously been shown to attenuate the rewarding and psychomotor-sensitizing effects of methamphetamine. This study examined the effects of agmatine on the discriminative stimulus and hyperthermic effects of methamphetamine. Adult male rats were trained to discriminate 0.32 mg/kg methamphetamine from saline. Methamphetamine dose dependently increased drug-associated lever responding. The nonselective dopamine receptor antagonist haloperidol (0.1 mg/kg) significantly attenuated the discriminative stimulus effects of methamphetamine (5.9-fold rightward shift). Agmatine (10-100 mg/kg) did not substitute for methamphetamine, but significantly attenuated the stimulus effects of methamphetamine, leading to a maximum of a 3.5-fold rightward shift. Acute 10 mg/kg methamphetamine increased the rectal temperature by a maximum of 1.96±0.17°C. Agmatine (10-32 mg/kg) pretreatment significantly attenuated the hyperthermic effect of methamphetamine. Agmatine (10 mg/kg) also significantly reversed methamphetamine-induced temperature increase. Together, these results support further exploration of the value that agmatine may have for the treatment of methamphetamine abuse and overdose.

Agmatine attenuates the discriminative stimulus and hyperthermic effects of methamphetamine in male rats

PubMed Central

Thorn, David A.; Li, Jiuzhou; Qiu, Yanyan; Li, Jun-Xu

2016-01-01

Methamphetamine abuse remains an alarming public heath challenge with no approved pharmacotherapies available. Agmatine is a naturally-occurring cationic polyamine that has previously been shown to attenuate the rewarding and psychomotor-sensitizing effects of methamphetamine. This study examined the effects of agmatine on the discriminative stimulus and hyperthermic effects of methamphetamine. Adult male rats were trained to discriminate 0.32 mg/kg methamphetamine from saline. Methamphetamine dose-dependently increased drug-associated lever responding. The nonselective dopamine receptor antagonist haloperidol (0.1 mg/kg) significantly attenuated the discriminative stimulus effects of methamphetamine (5.9-fold rightward shift). Agmatine (10 –100 mg/kg) did not substitute for methamphetamine but significantly attenuated the stimulus effects of methamphetamine, leading to a maximum of 3.5-fold rightward shift. Acute 10 mg/kg methamphetamine increased the rectal temperature by a maximum of 1.96 ± 0.17 °C. Agmatine (10 – 32 mg/kg) pretreatment significantly attenuated the hyperthermic effect of methamphetamine. Agmatine (10 mg/kg) also significantly reversed methamphetamine-induced temperature increase. Together, these results support further exploration of the value that agmatine may have for treating methamphetamine abuse and overdose. PMID:27232669

THE EFFECT OF EARLY ENVIRONMENTAL MANIPULATION ON LOCOMOTOR SENSITIVITY AND METHAMPHETAMINE CONDITIONED PLACE PREFERENCE REWARD

PubMed Central

Hensleigh, E.; Pritchard, L. M.

2014-01-01

Early life stress leads to several effects on neurological development, affecting health and well-being later in life. Instances of child abuse and neglect are associated with higher rates of depression, risk taking behavior, and an increased risk of drug abuse later in life. This study used repeated neonatal separation of rat pups as a model of early life stress. Rat pups were either handled and weighed as controls or separated for 180 minutes per day during postnatal days 2-8. In adulthood, male and female rats were tested for methamphetamine conditioned place preference reward and methamphetamine induced locomotor activity. Tissue samples were collected and mRNA was quantified for the norepinephrine transporter in the prefrontal cortex and the dopamine transporter in the nucleus accumbens. Results indicated rats given methamphetamine formed a conditioned place preference, but there was no effect of early separation or sex. Separated males showed heightened methamphetamine-induced locomotor activity, but there was no effect of early separation for females. Overall females were more active than males in response to both saline and methamphetamine. No differences in mRNA levels were observed across any conditions. These results suggest early neonatal separation affects methamphetamine-induced locomotor activity in a sex-dependent manner but has no effects on methamphetamine conditioned place preference. PMID:24713150

Methamphetamine Accelerates Cellular Senescence through Stimulation of De Novo Ceramide Biosynthesis

PubMed Central

Astarita, Giuseppe; Avanesian, Agnesa; Grimaldi, Benedetto; Realini, Natalia; Justinova, Zuzana; Panlilio, Leight V.; Basit, Abdul; Piomelli, Daniele

2015-01-01

Methamphetamine is a highly addictive psychostimulant that causes profound damage to the brain and other body organs. Post mortem studies of human tissues have linked the use of this drug to diseases associated with aging, such as coronary atherosclerosis and pulmonary fibrosis, but the molecular mechanism underlying these findings remains unknown. Here we used functional lipidomics and transcriptomics experiments to study abnormalities in lipid metabolism in select regions of the brain and, to a greater extent, peripheral organs and tissues of rats that self-administered methamphetamine. Experiments in various cellular models (primary mouse fibroblasts and myotubes) allowed us to investigate the molecular mechanisms of systemic inflammation and cellular aging related to methamphetamine abuse. We report now that methamphetamine accelerates cellular senescence and activates transcription of genes involved in cell-cycle control and inflammation by stimulating production of the sphingolipid messenger ceramide. This pathogenic cascade is triggered by reactive oxygen species, likely generated through methamphetamine metabolism via cytochrome P450, and involves the recruitment of nuclear factor-κB (NF-κB) to induce expression of enzymes in the de novo pathway of ceramide biosynthesis. Inhibitors of NF-κB signaling and ceramide formation prevent methamphetamine-induced senescence and systemic inflammation in rats self-administering the drug, attenuating their health deterioration. The results suggest new therapeutic strategies to reduce the adverse consequences of methamphetamine abuse and improve effectiveness of abstinence treatments. PMID:25671639

Repeated methamphetamine administration differentially alters fos expression in caudate-putamen patch and matrix compartments and nucleus accumbens.

PubMed

Jedynak, Jakub P; Cameron, Courtney M; Robinson, Terry E

2012-01-01

The repeated administration of psychostimulant drugs produces a persistent and long-lasting increase ("sensitization") in their psychomotor effects, which is thought to be due to changes in the neural circuitry that mediate these behaviors. One index of neuronal activation used to identify brain regions altered by repeated exposure to drugs involves their ability to induce immediate early genes, such as c-fos. Numerous reports have demonstrated that past drug experience alters the ability of drugs to induce c-fos in the striatum, but very few have examined Fos protein expression in the two major compartments in the striatum--the so-called patch/striosome and matrix. In the present study, we used immunohistochemistry to investigate the effects of pretreatment with methamphetamine on the ability of a subsequent methamphetamine challenge to induce Fos protein expression in the patch and matrix compartments of the dorsolateral and dorsomedial caudate-putamen and in the ventral striatum (nucleus accumbens). Animals pretreated with methamphetamine developed robust psychomotor sensitization. A methamphetamine challenge increased the number of Fos-positive cells in all areas of the dorsal and ventral striatum. However, methamphetamine challenge induced Fos expression in more cells in the patch than in the matrix compartment in the dorsolateral and dorsomedial caudate-putamen. Furthermore, past experience with methamphetamine increased the number of methamphetamine-induced Fos positive cells in the patch compartment of the dorsal caudate putamen, but not in the matrix or in the core or shell of the nucleus accumbens. These data suggest that drug-induced alterations in the patch compartment of the dorsal caudate-putamen may preferentially contribute to some of the enduring changes in brain activity and behavior produced by repeated treatment with methamphetamine.

Are methamphetamine precursor control laws effective tools to fight the methamphetamine epidemic?

PubMed

Nonnemaker, James; Engelen, Mark; Shive, Daniel

2011-05-01

One of the most notable trends in illegal substance use among Americans over the past decade is the dramatic growth and spread of methamphetamine use. In response to the dramatic rise in methamphetamine use and its associated burden, a broad range of legislations has been passed to combat the problem. In this paper, we assess the impact of retail-level laws intended to restrict chemicals used to manufacture methamphetamine (methamphetamine precursor laws) in reducing indicators of domestic production, methamphetamine availability, and the consequences of methamphetamine use. Specifically, we examine trends in these indicators of methamphetamine supply and use over a period spanning the implementation of the federal Methamphetamine Anti-Proliferation Act (MAPA) (October 2000) and a more stringent state-level restriction enacted in California (January 2000). The results are mixed in terms of the effectiveness of legislative efforts to control methamphetamine production and use, depending on the strength of the legislation (California Uniform Controlled Substances Act versus federal MAPA), the specification of the comparison group, and the particular outcome of interest. Some evidence suggests that domestic production was impacted by these legislative efforts, but there is also evidence that prices fell, purities rose, and treatment episodes increased. Copyright © 2010 John Wiley & Sons, Ltd.

PET Studies of d-Methamphetamine Pharmacokinetics in Primates: Comparison with l-Methamphetamine and (—)-Cocaine

PubMed Central

Fowler, Joanna S.; Kroll, Carsten; Ferrieri, Richard; Alexoff, David; Logan, Jean; Dewey, Stephen L.; Schiffer, Wynne; Schlyer, David; Carter, Pauline; King, Payton; Shea, Colleen; Xu, Youwen; Muench, Lisa; Benveniste, Helene; Vaska, Paul; Volkow, Nora D.

2009-01-01

The methamphetamine molecule has a chiral center and exists as 2 enantiomers, d-methamphetamine (the more active enantiomer) and l-methamphetamine (the less active enantiomer). d-Methamphetamine is associated with more intense stimulant effects and higher abuse liability. The objective of this study was to measure the pharmacokinetics of d-methamphetamine for comparison with both l-methamphetamine and (—)-cocaine in the baboon brain and peripheral organs and to assess the saturability and pharmacologic specificity of binding. Methods d- and l-methamphetamine and (—)-cocaine were labeled with 11C via alkylation of the norprecursors with 11C-methyl iodide using literature methods. Six different baboons were studied in 11 PET sessions at which 2 radiotracer injections were administered 2–3 h apart to determine the distribution and kinetics of 11C-d-methamphetamine in brain and peripheral organs. Saturability and pharmacologic specificity were assessed using pretreatment with d-methamphetamine, methylphenidate, and tetrabenazine. 11C-d-Methamphetamine pharmacokinetics were compared with 11C-l-methamphetamine and 11C-(—)-cocaine in both brain and peripheral organs in the same animal. Results 11C-d- and l-methamphetamine both showed high uptake and widespread distribution in the brain. Pharmacokinetics did not differ between enantiomers, and the cerebellum peaked earlier and cleared more quickly than the striatum for both. 11C-d-Methamphetamine distribution volume ratio was not substantially affected by pretreatment with methamphetamine, methylphenidate, or tetrabenazine. Both enantiomers showed rapid, high uptake and clearance in the heart and lungs and slower uptake and clearance in the liver and kidneys. A comparison of 11C-d-methamphetamine and 11C-(—)-cocaine showed that 11C-d-methamphetamine peaked later in the brain than did 11C-(—)-cocaine and cleared more slowly. The 2 drugs showed similar behavior in all peripheral organs examined except the kidneys

Seasonal allergic conjunctivitis induced by Japanese pear pollen.

PubMed

Yanagisawa, S; Nagaki, Y; Hiraki, S; Kadoi, C; Hayasaka, S; Teranishi, H

1999-01-01

To evaluate the ocular findings in patients with Japanese pear (Pyrus pyrifolia Nakai) pollinosis. Twenty-two farmers working on artificial pollination in Japanese pear orchards were examined for ocular itching, conjunctival conditions, presence of eosinophils in the conjunctival specimen, and nasal symptoms. Serum IgE antibody to Japanese pear pollen was determined in 16 farmers. Of the 22 subjects, 3 (Nos. 3, 4, and 13) exhibited ocular itching, conjunctival hyperemia, eosinophils in the conjunctival specimen, and positive serum IgE antibodies to Japanese pear pollen. In these patients, the conjunctivitis disappeared after treatment with topical cromoglycate. The present study demonstrated that seasonal allergic conjunctivitis may be induced by Japanese pear pollen (entomophilous flower pollen).

Repeated exposure to methamphetamine induces sex-dependent hypersensitivity to ischemic injury in the adult rat heart

PubMed Central

Seeley, Sarah L.; Stoops, Thorne S.; D’Souza, Manoranjan S.

2017-01-01

Background We previously reported that adult female, but not male rats that were prenatally exposed to methamphetamine exhibit myocardial hypersensitivity to ischemic injury. However, it is unknown whether hypersensitivity to ischemic injury develops when rats are exposed to methamphetamine during adulthood. The goal of this study was to determine whether methamphetamine exposure during adulthood sensitizes the heart to ischemic injury. Methods Adult male and female rats received daily injections of methamphetamine (5 mg/kg) or saline for 10 days. Their hearts were isolated on day 11 and subjected to a 20 min ischemic insult on a Langendorff isolated heart apparatus. Cardiac contractile function was measured by an intraventricular balloon, and infarct size was measured by triphenyltetrazolium chloride staining. Results Hearts from methamphetamine-treated females exhibited significantly larger infarcts and suppressed postischemic recovery of contractile function compared to hearts from saline-treated females. In contrast, methamphetamine had no effect on infarct size or contractile recovery in male hearts. Subsequent experiments demonstrated that hypersensitivity to ischemic injury persisted in female hearts following a 1 month period of abstinence from methamphetamine. Myocardial protein kinase C-ε expression, Akt phosphorylation, and ERK phosphorylation were unaffected by adult exposure to methamphetamine. Conclusions Exposure of adult rats to methamphetamine sex-dependently increases the extent of myocardial injury following an ischemic insult. These data suggest that women who have a heart attack might be at risk of more extensive myocardial injury if they have a recent history of methamphetamine abuse. PMID:28575091

Repeated exposure to methamphetamine induces sex-dependent hypersensitivity to ischemic injury in the adult rat heart.

PubMed

Rorabaugh, Boyd R; Seeley, Sarah L; Stoops, Thorne S; D'Souza, Manoranjan S

2017-01-01

We previously reported that adult female, but not male rats that were prenatally exposed to methamphetamine exhibit myocardial hypersensitivity to ischemic injury. However, it is unknown whether hypersensitivity to ischemic injury develops when rats are exposed to methamphetamine during adulthood. The goal of this study was to determine whether methamphetamine exposure during adulthood sensitizes the heart to ischemic injury. Adult male and female rats received daily injections of methamphetamine (5 mg/kg) or saline for 10 days. Their hearts were isolated on day 11 and subjected to a 20 min ischemic insult on a Langendorff isolated heart apparatus. Cardiac contractile function was measured by an intraventricular balloon, and infarct size was measured by triphenyltetrazolium chloride staining. Hearts from methamphetamine-treated females exhibited significantly larger infarcts and suppressed postischemic recovery of contractile function compared to hearts from saline-treated females. In contrast, methamphetamine had no effect on infarct size or contractile recovery in male hearts. Subsequent experiments demonstrated that hypersensitivity to ischemic injury persisted in female hearts following a 1 month period of abstinence from methamphetamine. Myocardial protein kinase C-ε expression, Akt phosphorylation, and ERK phosphorylation were unaffected by adult exposure to methamphetamine. Exposure of adult rats to methamphetamine sex-dependently increases the extent of myocardial injury following an ischemic insult. These data suggest that women who have a heart attack might be at risk of more extensive myocardial injury if they have a recent history of methamphetamine abuse.

Methamphetamine neurotoxicity in dopamine nerve endings of the striatum is associated with microglial activation.

PubMed

Thomas, David M; Walker, Paul D; Benjamins, Joyce A; Geddes, Timothy J; Kuhn, Donald M

2004-10-01

Methamphetamine intoxication causes long-lasting damage to dopamine nerve endings in the striatum. The mechanisms underlying this neurotoxicity are not known but oxidative stress has been implicated. Microglia are the major antigen-presenting cells in brain and when activated, they secrete an array of factors that cause neuronal damage. Surprisingly, very little work has been directed at the study of microglial activation as part of the methamphetamine neurotoxic cascade. We report here that methamphetamine activates microglia in a dose-related manner and along a time course that is coincident with dopamine nerve ending damage. Prevention of methamphetamine toxicity by maintaining treated mice at low ambient temperature prevents drug-induced microglial activation. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), which damages dopamine nerve endings and cell bodies, causes extensive microglial activation in striatum as well as in the substantia nigra. In contrast, methamphetamine causes neither microglial activation in the substantia nigra nor dopamine cell body damage. Dopamine transporter antagonists (cocaine, WIN 35,428 [(-)-2-beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane 1,5-naphthalenedisulfonate], and nomifensine), selective D1 (SKF 82958 [(+/-)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide]), D2 (quinpirole), or mixed D1/D2 receptor agonists (apomorphine) do not mimic the effect of methamphetamine on microglia. Hyperthermia, a prominent and dangerous clinical response to methamphetamine intoxication, was also ruled out as the cause of microglial activation. Together, these data suggest that microglial activation represents an early step in methamphetamine-induced neurotoxicity. Other neurochemical effects resulting from methamphetamine-induced overflow of DA into the synapse, but which are not neurotoxic, do not play a role in this response.

A comparison of economic demand and conditioned-cued reinstatement of methamphetamine-seeking or food-seeking in rats.

PubMed

Galuska, Chad M; Banna, Kelly M; Willse, Lena Vaughn; Yahyavi-Firouz-Abadi, Noushin; See, Ronald E

2011-08-01

This study examined whether continued access to methamphetamine or food reinforcement changed economic demand for both. The relationship between demand elasticity and cue-induced reinstatement was also determined. Male Long-Evans rats were lever pressed under increasing fixed-ratio requirements for either food pellets or methamphetamine (20 μg/50 μl infusion). For two groups, demand curves were obtained before and after continued access (12 days, 2-h sessions) to the reinforcer under a fixed-ratio 3 schedule. A third group was given continued access to methamphetamine between determinations of food demand and a fourth group abstained from methamphetamine between determinations. All groups underwent extinction sessions, followed by a cue-induced reinstatement test. Although food demand was less elastic than methamphetamine demand, continued access to methamphetamine shifted the methamphetamine demand curve upward and the food demand curve downward. In some rats, methamphetamine demand also became less elastic. Continued access to food had no effect on food demand. Reinstatement was higher after continued access to methamphetamine relative to food. For methamphetamine, elasticity and reinstatement measures were correlated. Continued access to methamphetamine, but not food, alters demand in ways suggestive of methamphetamine accruing reinforcing strength. Demand elasticity thus provides a useful measure of abuse liability that may predict future relapse to renewed drug-seeking and drug use.

Actigraphy-based sleep parameters during the reinstatement of methamphetamine self-administration in rhesus monkeys.

PubMed

Berro, Laís F; Andersen, Monica L; Tufik, Sergio; Howell, Leonard L

2016-04-01

The objective of this study was to investigate nighttime activity of nonhuman primates during extinction and cue- and drug-primed reinstatement of methamphetamine self-administration. Adult rhesus monkeys (Macaca mulatta; n = 5) self-administered methamphetamine (0.01 mg/kg/injection, i.v.) under a fixed-ratio 20 schedule of reinforcement. Saline infusions were then substituted for methamphetamine and stimulus light (drug-conditioned stimulus presented during drug self-administration) withheld until subjects reached extinction criteria. Drug- and cue-induced reinstatement effects were evaluated after i.v. noncontingent priming injections of methamphetamine (0.03, 0.1, or 0.3 mg/kg). Activity-based sleep measures were evaluated with Actiwatch monitors a week before (baseline nighttime activity parameters) and throughout the protocol. Although methamphetamine self-administration did not significantly affect nighttime activity compared to baseline, sleeplike parameters were improved during extinction compared to self-administration maintenance. Priming injection of 0.1 mg/kg methamphetamine, but not 0.03 or 0.3 mg/kg, induced significant reinstatement effects. These behavioral responses were accompanied by nighttime outcomes, with increased sleep fragmentation and decreased sleep efficiency in the night following 0.1 mg/kg methamphetamine-induced reinstatement. In the absence of both drug and drug-paired cues (extinction conditions), nighttime activity decreased compared to self-administration maintenance. Additionally, effective reinstatement conditions impaired sleeplike measures. Our data indicate that the reintroduction of the stimulus light as a drug-paired cue increased nighttime activity. (c) 2016 APA, all rights reserved).

Methamphetamine-Associated Cardiomyopathy

PubMed Central

Won, Sekon; Hong, Robert A.; Shohet, Ralph V.; Seto, Todd B.; Parikh, Nisha I.

2015-01-01

Methamphetamine and related compounds are now the second most commonly used illicit substance worldwide, after cannabis. Reports of methamphetamine-associated cardiomyopathy (MAC) are increasing, but MAC has not been well reviewed. This analysis of MAC will provide an overview of the pharmacology of methamphetamine, historical perspective and epidemiology, a review of case and clinical studies, and a summary of the proposed mechanisms for MAC. Clinically, many questions remain, including the appropriate therapeutic interventions for MAC, the incidence and prevalence of cardiac pathology in methamphetamine users, risk factors for developing MAC, and prognosis of these patients. In conclusion, recognition of the significance of MAC among physicians and other medical caregivers is important given the growing use of methamphetamine and related stimulants worldwide. PMID:24037954

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.

Repeated Methamphetamine Administration Differentially Alters Fos Expression in Caudate-Putamen Patch and Matrix Compartments and Nucleus Accumbens

PubMed Central

Jedynak, Jakub P.; Cameron, Courtney M.; Robinson, Terry E.

2012-01-01

Background The repeated administration of psychostimulant drugs produces a persistent and long-lasting increase (“sensitization”) in their psychomotor effects, which is thought to be due to changes in the neural circuitry that mediate these behaviors. One index of neuronal activation used to identify brain regions altered by repeated exposure to drugs involves their ability to induce immediate early genes, such as c-fos. Numerous reports have demonstrated that past drug experience alters the ability of drugs to induce c-fos in the striatum, but very few have examined Fos protein expression in the two major compartments in the striatum—the so-called patch/striosome and matrix. Methodology/Principal Findings In the present study, we used immunohistochemistry to investigate the effects of pretreatment with methamphetamine on the ability of a subsequent methamphetamine challenge to induce Fos protein expression in the patch and matrix compartments of the dorsolateral and dorsomedial caudate-putamen and in the ventral striatum (nucleus accumbens). Animals pretreated with methamphetamine developed robust psychomotor sensitization. A methamphetamine challenge increased the number of Fos-positive cells in all areas of the dorsal and ventral striatum. However, methamphetamine challenge induced Fos expression in more cells in the patch than in the matrix compartment in the dorsolateral and dorsomedial caudate-putamen. Furthermore, past experience with methamphetamine increased the number of methamphetamine-induced Fos positive cells in the patch compartment of the dorsal caudate putamen, but not in the matrix or in the core or shell of the nucleus accumbens. Conclusions/Significance These data suggest that drug-induced alterations in the patch compartment of the dorsal caudate-putamen may preferentially contribute to some of the enduring changes in brain activity and behavior produced by repeated treatment with methamphetamine. PMID:22514626

Methamphetamine Causes Microglial Activation in the Brains of Human Abusers

PubMed Central

Sekine, Yoshimoto; Ouchi, Yasuomi; Sugihara, Genichi; Takei, Nori; Yoshikawa, Etsuji; Nakamura, Kazuhiko; Iwata, Yasuhide; Tsuchiya, Kenji J.; Suda, Shiro; Suzuki, Katsuaki; Kawai, Masayoshi; Takebayashi, Kiyokazu; Yamamoto, Shigeyuki; Matsuzaki, Hideo; Ueki, Takatoshi; Mori, Norio; Gold, Mark S.; Cadet, Jean L.

2008-01-01

Methamphetamine is a popular addictive drug whose use is associated with multiple neuropsychiatric adverse events and toxic to the dopaminergic and serotonergic systems of the brain. Methamphetamine-induced neuropathology is associated with increased expression of microglial cells that are thought to participate in either pro-toxic or protective mechanisms in the brain. Although reactive microgliosis has been observed in animal models of methamphetamine neurotoxicity, no study has reported on the status of microglial activation in human methamphetamine abusers. The present study reports on 12 abstinent methamphetamine abusers and 12 age-, gender-, education-matched control subjects who underwent positron emission tomography using a radiotracer for activated microglia, [11C](R)-(1-[2-chlorophenyl]-N-methyl-N-[1-methylpropyl]-3-isoquinoline carboxamide) ([11C](R)-PK11195). Compartment analysis was used to estimate quantitative levels of binding potentials of [11C](R)-PK11195 in brain regions with dopaminergic and/or serotonergic innervation. The mean levels of [11C](R)-PK11195 binding were higher in methamphetamine abusers than those in control subjects in all brain regions (> 250% higher, p < 0.01 for all). In addition, the binding levels in the midbrain, striatum, thalamus, and orbitofrontal and insular cortices (p < 0.05) correlated inversely with the duration of methamphetamine abstinence. These results suggest that chronic self-administration of methamphetamine can cause reactive microgliosis in the brains of human methamphetamine abusers, a level of activation that appears to subside over longer periods of abstinence. PMID:18509037

Methamphetamine causes microglial activation in the brains of human abusers.

PubMed

Sekine, Yoshimoto; Ouchi, Yasuomi; Sugihara, Genichi; Takei, Nori; Yoshikawa, Etsuji; Nakamura, Kazuhiko; Iwata, Yasuhide; Tsuchiya, Kenji J; Suda, Shiro; Suzuki, Katsuaki; Kawai, Masayoshi; Takebayashi, Kiyokazu; Yamamoto, Shigeyuki; Matsuzaki, Hideo; Ueki, Takatoshi; Mori, Norio; Gold, Mark S; Cadet, Jean L

2008-05-28

Methamphetamine is a popular addictive drug whose use is associated with multiple neuropsychiatric adverse events and toxic to the dopaminergic and serotonergic systems of the brain. Methamphetamine-induced neuropathology is associated with increased expression of microglial cells that are thought to participate in either pro-toxic or protective mechanisms in the brain. Although reactive microgliosis has been observed in animal models of methamphetamine neurotoxicity, no study has reported on the status of microglial activation in human methamphetamine abusers. The present study reports on 12 abstinent methamphetamine abusers and 12 age-, gender-, and education-matched control subjects who underwent positron emission tomography using a radiotracer for activated microglia, [(11)C](R)-(1-[2-chlorophenyl]-N-methyl-N-[1-methylpropyl]-3-isoquinoline carboxamide) ([(11)C](R)-PK11195). Compartment analysis was used to estimate quantitative levels of binding potentials of [(11)C](R)-PK11195 in brain regions with dopaminergic and/or serotonergic innervation. The mean levels of [(11)C](R)-PK11195 binding were higher in methamphetamine abusers than those in control subjects in all brain regions (>250% higher; p < 0.01 for all). In addition, the binding levels in the midbrain, striatum, thalamus, and orbitofrontal and insular cortices (p < 0.05) correlated inversely with the duration of methamphetamine abstinence. These results suggest that chronic self-administration of methamphetamine can cause reactive microgliosis in the brains of human methamphetamine abusers, a level of activation that appears to subside over longer periods of abstinence.

Glutamatergic neurometabolites during early abstinence from chronic methamphetamine abuse.

PubMed

O'Neill, Joseph; Tobias, Marc C; Hudkins, Matthew; London, Edythe D

2014-10-31

The acute phase of abstinence from methamphetamine abuse is critical for rehabilitation success. Proton magnetic resonance spectroscopy has detected below-normal levels of glutamate+glutamine in anterior middle cingulate of chronic methamphetamine abusers during early abstinence, attributed to abstinence-induced downregulation of the glutamatergic systems in the brain. This study further explored this phenomenon. We measured glutamate+glutamine in additional cortical regions (midline posterior cingulate, midline precuneus, and bilateral inferior frontal cortex) putatively affected by methamphetamine. We examined the relationship between glutamate+glutamine in each region with duration of methamphetamine abuse as well as the depressive symptoms of early abstinence. Magnetic resonance spectroscopic imaging was acquired at 1.5 T from a methamphetamine group of 44 adults who had chronically abused methamphetamine and a control group of 23 age-, sex-, and tobacco smoking-matched healthy volunteers. Participants in the methamphetamine group were studied as inpatients during the first week of abstinence from the drug and were not receiving treatment. In the methamphetamine group, small but significant (5-15%, P<.05) decrements (vs control) in glutamate+glutamine were observed in posterior cingulate, precuneus, and right inferior frontal cortex; glutamate+glutamine in posterior cingulate was negatively correlated (P<.05) with years of methamphetamine abuse. The Beck Depression Inventory score was negatively correlated (P<.005) with glutamate+glutamine in right inferior frontal cortex. Our findings support the idea that glutamatergic metabolism is downregulated in early abstinence in multiple cortical regions. The extent of downregulation may vary with length of abuse and may be associated with severity of depressive symptoms emergent in early recovery. © The Author 2015. Published by Oxford University Press on behalf of CINP.

Endoplasmic Reticulum Stress Mediates Methamphetamine-Induced Blood–Brain Barrier Damage

PubMed Central

Qie, Xiaojuan; Wen, Di; Guo, Hongyan; Xu, Guanjie; Liu, Shuai; Shen, Qianchao; Liu, Yi; Zhang, Wenfang; Cong, Bin; Ma, Chunling

2017-01-01

Methamphetamine (METH) abuse causes serious health problems worldwide, and long-term use of METH disrupts the blood–brain barrier (BBB). Herein, we explored the potential mechanism of endoplasmic reticulum (ER) stress in METH-induced BBB endothelial cell damage in vitro and the therapeutic potential of endoplasmic reticulum stress inhibitors for METH-induced BBB disruption in C57BL/6J mice. Exposure of immortalized BMVEC (bEnd.3) cells to METH significantly decreased cell viability, induced apoptosis, and diminished the tightness of cell monolayers. METH activated ER stress sensor proteins, including PERK, ATF6, and IRE1, and upregulated the pro-apoptotic protein CHOP. The ER stress inhibitors significantly blocked the upregulation of CHOP. Knockdown of CHOP protected bEnd.3 cells from METH-induced cytotoxicity. Furthermore, METH elevated the production of reactive oxygen species (ROS) and induced the dysfunction of mitochondrial characterized by a Bcl2/Bax ratio decrease, mitochondrial membrane potential collapse, and cytochrome c. ER stress release was partially reversed by ROS inhibition, and cytochrome c release was partially blocked by knockdown of CHOP. Finally, PBA significantly attenuated METH-induced sodium fluorescein (NaFluo) and Evans Blue leakage, as well as tight junction protein loss, in C57BL/6J mice. These data suggest that BBB endothelial cell damage was caused by METH-induced endoplasmic reticulum stress, which further induced mitochondrial dysfunction, and that PBA was an effective treatment for METH-induced BBB disruption. PMID:28959203

Delayed emergence of methamphetamine's enhanced cardiovascular effects in nonhuman primates during protracted methamphetamine abstinence.

PubMed

Vaupel, D B; Schindler, C W; Chefer, S; Belcher, A M; Ahmet, I; Scheidweiler, K B; Huestis, M A; Stein, E A

2016-02-01

Methamphetamine abuse is linked with brain abnormalities, but its peripheral effects constitute an integral aspect of long-term methamphetamine use. Eight male rhesus monkeys with long histories of intravenous methamphetamine self-administration were evaluated 1 day, and 1, 4, 12, 26, and 52 weeks after their last methamphetamine self-administration session. On test days, isoflurane-anesthetized animals received a 0.35 mg/kg IV methamphetamine challenge. A control group consisted of 10 age and gender matched drug naïve monkeys. Cardiovascular responses to methamphetamine were followed for 2.5h. Echocardiograms were acquired at 3 and 12 months of abstinence and in the control animals. No pre-methamphetamine baseline differences existed among 7 physiological measures across all conditions and controls. As expected, methamphetamine increased heart rate and blood pressure in controls. However, immediately following the self-administration period, the blood pressure response to methamphetamine challenge was reduced when compared to control monkeys. The peak and 150-min average heart rate increases, as well as peak blood pressure increases following methamphetamine were significantly elevated between weeks 12 to 26 of abstinence. These data indicate the development of tolerance followed by sensitization to methamphetamine cardiovascular effects. Echocardiography demonstrated decreased left ventricular ejection fraction and cardiac output at 3 months of abstinence. Importantly, both cardiovascular sensitization and cardiotoxicity appeared to be reversible as they returned toward control group levels after 1 year of abstinence. Enhanced cardiovascular effects may occur after prolonged abstinence in addicts relapsing to methamphetamine and may underlie clinically reported acute cardiotoxic events. Published by Elsevier Ireland Ltd.

N-Acetyl and Glutamatergic Neurometabolites in Perisylvian Brain Regions of Methamphetamine Users.

PubMed

Tang, Jinsong; O'Neill, Joseph; Alger, Jeffry R; Shen, Zhiwei; Johnson, Maritza C; London, Edythe D

2018-05-21

Methamphetamine induces neuronal N-acetyl-aspartate synthesis in preclinical studies. In a preliminary human proton magnetic resonance spectroscopic imaging investigation, we also observed that N-acetyl-aspartate+N-acetyl-aspartyl-glutamate in right inferior frontal cortex correlated with years of heavy methamphetamine abuse. In the same brain region, glutamate+glutamine is lower in methamphetamine users than in controls and is negatively correlated with depression. N-acetyl and glutamatergic neurochemistries therefore merit further investigation in methamphetamine abuse and the associated mood symptoms. Magnetic resonance spectroscopic imaging was used to measure N-acetyl-aspartate+N-acetyl-aspartyl-glutamate and glutamate+glutamine in bilateral inferior frontal cortex and insula, a neighboring perisylvian region affected by methamphetamine, of 45 abstinent methamphetamine-dependent and 45 healthy control participants. Regional neurometabolite levels were tested for group differences and associations with duration of heavy methamphetamine use, depressive symptoms, and state anxiety. In right inferior frontal cortex, N-acetyl-aspartate+N-acetyl-aspartyl-glutamate correlated with years of heavy methamphetamine use (r = +0.45); glutamate+glutamine was lower in methamphetamine users than in controls (9.3%) and correlated negatively with depressive symptoms (r = -0.44). In left insula, N-acetyl-aspartate+N-acetyl-aspartyl-glutamate was 9.1% higher in methamphetamine users than controls. In right insula, glutamate+glutamine was 12.3% lower in methamphetamine users than controls and correlated negatively with depressive symptoms (r = -0.51) and state anxiety (r = -0.47). The inferior frontal cortex and insula show methamphetamine-related abnormalities, consistent with prior observations of increased cortical N-acetyl-aspartate in methamphetamine-exposed animal models and associations between cortical glutamate and mood in human methamphetamine users.

σ Receptor antagonist attenuation of methamphetamine-induced neurotoxicity is correlated to body temperature modulation.

PubMed

Robson, Matthew J; Seminerio, Michael J; McCurdy, Christopher R; Coop, Andrew; Matsumoto, Rae R

2013-01-01

Methamphetamine (METH) causes hyperthermia and dopaminergic neurotoxicity in the rodent striatum. METH interacts with σ receptors and σ receptor antagonists normally mitigate METH-induced hyperthermia and dopaminergic neurotoxicity. The present study was undertaken because in two experiments, pretreatment with σ receptor antagonists failed to attenuate METH-induced hyperthermia in mice. This allowed us to determine whether the ability of σ receptor antagonists (AZ66 and AC927) to mitigate METH-induced neurotoxicity depends upon their ability to modulate METH-induced hyperthermia. Mice were treated using a repeated dosing paradigm and body temperatures recorded. Striatal dopamine was measured one week post-treatment. The data indicate that the ability of σ receptor antagonists to attenuate METH-induced dopaminergic neurotoxicity is linked to their ability to block METH-induced hyperthermia. The ability of σ receptor antagonists to mitigate METH-induced hyperthermia may contribute to its neuroprotective actions.

Current research on methamphetamine-induced neurotoxicity: animal models of monoamine disruption.

PubMed

Kita, Taizo; Wagner, George C; Nakashima, Toshikatsu

2003-07-01

Methamphetamine (METH)-induced neurotoxicity is characterized by a long-lasting depletion of striatal dopamine (DA) and serotonin as well as damage to striatal dopaminergic and serotonergic nerve terminals. Several hypotheses regarding the mechanism underlying METH-induced neurotoxicity have been proposed. In particular, it is thought that endogenous DA in the striatum may play an important role in mediating METH-induced neuronal damage. This hypothesis is based on the observation of free radical formation and oxidative stress produced by auto-oxidation of DA consequent to its displacement from synaptic vesicles to cytoplasm. In addition, METH-induced neurotoxicity may be linked to the glutamate and nitric oxide systems within the striatum. Moreover, using knockout mice lacking the DA transporter, the vesicular monoamine transporter 2, c-fos, or nitric oxide synthetase, it was determined that these factors may be connected in some way to METH-induced neurotoxicity. Finally a role for apoptosis in METH-induced neurotoxicity has also been established including evidence of protection of bcl-2, expression of p53 protein, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), activity of caspase-3. The neuronal damage induced by METH may reflect neurological disorders such as autism and Parkinson's disease.

Chronic methamphetamine exposure significantly decreases microglia activation in the arcuate nucleus.

PubMed

Lloyd, Steven A; Corkill, Beau; Bruster, Matthew C; Roberts, Rick L; Shanks, Ryan A

2017-07-01

Methamphetamine is a powerful psychostimulant drug and its use and abuse necessitates a better understanding of its neurobiobehavioral effects. The acute effects of binge dosing of methamphetamine on the neurons in the CNS are well studied. However, the long-term effects of chronic, low-dose methamphetamine are less well characterized, especially in other cell types and areas outside of the major dopamine pathways. Mice were administered 5mg/kg/day methamphetamine for ten days and brain tissue was analyzed using histochemistry and image analysis. Increased microglia activity in the striatum confirmed toxic effects of methamphetamine in this brain region using this dosing paradigm. A significant decrease in microglia activity in the arcuate nucleus of the hypothalamus was observed with no effect noted on dopamine neurons in the arcuate nucleus. Given the importance of this area in homeostatic and neuroendocrine regulation, the current study highlights the need to more fully understand the systemic effects of chronic, low-dose methamphetamine use. The novel finding of microglia downregulation after chronic methamphetamine could lead to advances in understanding neuroinflammatory responses towards addiction treatment and protection from psychostimulant-induced neurotoxicity. Copyright © 2017 Elsevier B.V. All rights reserved.

GABAA receptor positive allosteric modulators modify the abuse-related behavioral and neurochemical effects of methamphetamine in rhesus monkeys.

PubMed

Berro, Laís F; Andersen, Monica L; Tufik, Sergio; Howell, Leonard L

2017-09-01

GABA A receptor positive allosteric modulators (GABA A receptor modulators) are commonly used for the treatment of insomnia. Nevertheless, the effects of these compounds on psychostimulant-induced sleep impairment are poorly understood. Because GABA A receptor modulators have been shown to decrease the abuse-related effects of psychostimulants, the aim of the present study was to evaluate the effects of temazepam (0.3, 1.0 or 3.0 mg/kg) and eszopiclone (0.3, 1.0 or 3.0 mg/kg), two GABA A receptor modulators, on the behavioral neuropharmacology of methamphetamine in adult rhesus macaques (n = 5). Sleep-like measures and general daytime activity were evaluated with Actiwatch monitors. Methamphetamine self-administration (0.03 mg/kg/inf) was evaluated during morning sessions. Methamphetamine-induced dopamine overflow was assessed through in vivo microdialysis targeting the nucleus accumbens. Nighttime treatment with either temazepam or eszopiclone was ineffective in improving sleep-like measures disrupted by methamphetamine self-administration. Acute pretreatment with a low dose of temazepam before self-administration sessions increased methamphetamine self-administration without affecting normal daytime home-cage activity. At a high dose, acute temazepam pretreatment decreased methamphetamine self-administration and attenuated methamphetamine-induced increases in dopamine in the nucleus accumbens, without decreasing general daytime activity. Acute eszopiclone treatment exerted no effects on methamphetamine intake or drug-induced increases in dopamine. Our study suggests that treatments based on GABA A receptor modulators are not effective for the treatment of sleep disruption in the context of psychostimulant use. In addition, distinct GABA A receptor modulators differentially modulated the abuse-related effects of methamphetamine, with acute treatment with the high efficacy GABA A receptor modulator temazepam decreasing the behavioral and neurochemical effects

Δ9-tetrahydrocannabinol prevents methamphetamine-induced neurotoxicity.

PubMed

Castelli, M Paola; Madeddu, Camilla; Casti, Alberto; Casu, Angelo; Casti, Paola; Scherma, Maria; Fattore, Liana; Fadda, Paola; Ennas, M Grazia

2014-01-01

Methamphetamine (METH) is a potent psychostimulant with neurotoxic properties. Heavy use increases the activation of neuronal nitric oxide synthase (nNOS), production of peroxynitrites, microglia stimulation, and induces hyperthermia and anorectic effects. Most METH recreational users also consume cannabis. Preclinical studies have shown that natural (Δ9-tetrahydrocannabinol, Δ9-THC) and synthetic cannabinoid CB1 and CB2 receptor agonists exert neuroprotective effects on different models of cerebral damage. Here, we investigated the neuroprotective effect of Δ9-THC on METH-induced neurotoxicity by examining its ability to reduce astrocyte activation and nNOS overexpression in selected brain areas. Rats exposed to a METH neurotoxic regimen (4 × 10 mg/kg, 2 hours apart) were pre- or post-treated with Δ9-THC (1 or 3 mg/kg) and sacrificed 3 days after the last METH administration. Semi-quantitative immunohistochemistry was performed using antibodies against nNOS and Glial Fibrillary Acidic Protein (GFAP). Results showed that, as compared to corresponding controls (i) METH-induced nNOS overexpression in the caudate-putamen (CPu) was significantly attenuated by pre- and post-treatment with both doses of Δ9-THC (-19% and -28% for 1 mg/kg pre- and post-treated animals; -25% and -21% for 3 mg/kg pre- and post-treated animals); (ii) METH-induced GFAP-immunoreactivity (IR) was significantly reduced in the CPu by post-treatment with 1 mg/kg Δ9-THC1 (-50%) and by pre-treatment with 3 mg/kg Δ9-THC (-53%); (iii) METH-induced GFAP-IR was significantly decreased in the prefrontal cortex (PFC) by pre- and post-treatment with both doses of Δ9-THC (-34% and -47% for 1 mg/kg pre- and post-treated animals; -37% and -29% for 3 mg/kg pre- and post-treated animals). The cannabinoid CB1 receptor antagonist SR141716A attenuated METH-induced nNOS overexpression in the CPu, but failed to counteract the Δ9-THC-mediated reduction of METH-induced GFAP-IR both in the PFC and CPu. Our

Gray-matter volume, midbrain dopamine D2/D3 receptors and drug craving in methamphetamine users.

PubMed

Morales, A M; Kohno, M; Robertson, C L; Dean, A C; Mandelkern, M A; London, E D

2015-06-01

Dysfunction of the mesocorticolimbic system has a critical role in clinical features of addiction. Despite evidence suggesting that midbrain dopamine receptors influence amphetamine-induced dopamine release and that dopamine is involved in methamphetamine-induced neurotoxicity, associations between dopamine receptors and gray-matter volume have been unexplored in methamphetamine users. Here we used magnetic resonance imaging and [(18)F]fallypride positron emission tomography, respectively, to measure gray-matter volume (in 58 methamphetamine users) and dopamine D2/D3 receptor availability (binding potential relative to nondisplaceable uptake of the radiotracer, BPnd) (in 31 methamphetamine users and 37 control participants). Relationships between these measures and self-reported drug craving were examined. Although no difference in midbrain D2/D3 BPnd was detected between methamphetamine and control groups, midbrain D2/D3 BPnd was positively correlated with gray-matter volume in the striatum, prefrontal cortex, insula, hippocampus and temporal cortex in methamphetamine users, but not in control participants (group-by-midbrain D2/D3 BPnd interaction, P<0.05 corrected for multiple comparisons). Craving for methamphetamine was negatively associated with gray-matter volume in the insula, prefrontal cortex, amygdala, temporal cortex, occipital cortex, cerebellum and thalamus (P<0.05 corrected for multiple comparisons). A relationship between midbrain D2/D3 BPnd and methamphetamine craving was not detected. Lower midbrain D2/D3 BPnd may increase vulnerability to deficits in gray-matter volume in mesocorticolimbic circuitry in methamphetamine users, possibly reflecting greater dopamine-induced toxicity. Identifying factors that influence prefrontal and limbic volume, such as midbrain BPnd, may be important for understanding the basis of drug craving, a key factor in the maintenance of substance-use disorders.

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

A Role for D1 Dopamine Receptors in Striatal Methamphetamine-Induced Neurotoxicity

PubMed Central

Friend, Danielle M.; Keefe, Kristen A.

2015-01-01

Methamphetamine (METH) exposure results in long-term damage to the dopamine system in both human METH abusers and animal models. One factor that has been heavily implicated in this METH-induced damage to the dopaminergic system is the activation of D1 Dopamine (DA) receptors. However, a significant caveat to the studies investigating the role of the receptor in such toxicity is that genetic and pharmacological manipulations of the D1 DA receptor also mitigate METH-induced hyperthermia. Importantly, METH-induced hyperthermia is tightly associated with the neurotoxicity, such that simply cooling animals during METH exposure protects against the neurotoxicity. Therefore, it is difficult to determine whether D1 DA receptors per se play an important role in METH-induced neurotoxicity or whether the protection observed simply resulted from a mitigation of METH-induced hyperthermia. To answer this important question, the current study infused a D1 DA receptor antagonist into striatum during METH exposure while controlling for METH-induced hyperthermia. Here we found that even when METH-induced hyperthermia is maintained, the coadministration of a D1 DA receptor antagonist protects against METH-induced neurotoxicity, strongly suggesting that D1 DA receptors play an important role in METH-induced neurotoxicity apart from the mitigation of METH-induced hyperthermia. PMID:23994061

The Effects of Locus Coeruleus and Norepinephrine in Methamphetamine Toxicity

PubMed Central

Ferrucci, Michela; Giorgi, Filippo S; Bartalucci, Alessia; Busceti, Carla L; Fornai, Francesco

2013-01-01

The activity of locus coeruleus (LC) neurons has been extensively investigated in a variety of behavioural states. In fact this norepinephrine (NE)-containing nucleus modulates many physiological and pathological conditions including the sleep-waking cycle, movement disorders, mood alterations, convulsive seizures, and the effects of drugs such as psychostimulants and opioids. This review focuses on the modulation exerted by central NE pathways on the behavioural and neurotoxic effects produced by the psychostimulant methamphetamine, essentially the modulation of the activity of mesencephalic dopamine (DA) neurons. In fact, although NE in itself mediates some behavioural effects induced by methamphetamine, NE modulation of DA release is pivotal for methamphetamine-induced behavioural states and neurotoxicity. These interactions are discussed on the basis of the state of the art of the functional neuroanatomy of central NE- and DA systems. Emphasis is given to those brain sites possessing a remarkable overlapping of both neurotransmitters. PMID:23814540

Japan's hiropon panic: resident non-Japanese and the 1950s meth crisis.

PubMed

Alexander, Jeffrey W

2013-05-01

This qualitative historical policy analysis explores Japan's early postwar market for hiropon (methamphetamine/meth) and the impact of its anti-hiropon campaigns. The paper traces the origins of medical methamphetamine production in prewar Japan; known at that time by its former brand-name, 'Philopon' (pronounced hiropon), and argues that the anti-meth 'shock-horror' campaigns of the 1950s were exacerbated by long-simmering animosity toward non-Japanese residents - especially Koreans and Taiwanese. Through an analysis of both English- and Japanese-language source materials, the paper explores the gritty, frightening themes of Japan's 1950s-era anti-meth propaganda campaigns and the parallel effort by police to arrest, prosecute, and deport members of the resident Korean and Taiwanese communities. The author demonstrates that by incorporating a wider variety of contemporary Japanese-language sources such as news reports and anti-drug propaganda materials about the postwar hiropon trade, we may more fully appreciate the historic, underlying social tensions behind the swift and targeted public response. The author concludes that Japan's postwar federal and municipal governments, together with police and media agencies, cultivated a sensational 'drug panic' designed both to dissuade citizens from using hiropon and to fuel a concerted police campaign against non-Japanese involved in the meth trade. Published by Elsevier B.V.

[Control of craving for methamphetamine: development of scales for dependence and search for medicines for treatment].

PubMed

Ogai, Yasukazu; Haraguchi, Ayako; Kondo, Ayumi; Takamatsu, Yukio; Yamamoto, Hideko; Sendoo, Eiichi; Ikeda, Katzutaka

2005-10-01

Methamphetamine dependence presents a serious problem not only for patients but also for society. Medical treatment has mainly targeted psychotic symptoms such as hallucination and delusion, and ignored the symptoms of craving, which are the major cause of dependence. Therefore, the risk of lapse into methamphetamine reuse remains very high. Although development of both medicines and programs for treatment of craving is needed, progress has been hampered by the lack of appropriate scales for assessing the severity of dependence and craving. On the other hand, recent breakthroughs in genomic sciences and molecular medicine have made it possible to investigate the molecular mechanisms underlying craving in animals. This paper reviews studies on the development of scales for assessing the severity of methamphetamine dependence and craving, together with recent data on candidate medicines for craving treatment in animals. The reliability and validity of the revised Addiction Severity Index -Japanese version (ASI-J) was confirmed after its administration to 100 drug abuse patients. The Craving Index was also newly developed, and its validity for prediction of relapse was confirmed. In animal experiments, fluoxetine, a selective serotonin reuptake inhibitor, was recognized as a candidate medicine for treatment of methamphetamine dependence.

The neuronal nitric oxide synthase inhibitor, 7-nitroindazole, protects against methamphetamine-induced neurotoxicity in vivo.

PubMed

Itzhak, Y; Ali, S F

1996-10-01

The present study was undertaken to investigate whether the relatively selective neuronal nitric oxide synthase (NOS) inhibitor, 7-nitroindazole (7-NI), protects against methamphetamine (METH)-induced neurotoxicity. Male Swiss Webster mice received the following treatments (i.p.; q 3 h x 3): (a) vehicle/saline, (b) 7-NI (25 mg/kg)/saline, (c) vehicle/METH (5 mg/kg), and (d) 7-NI (25 mg/kg)/METH (5 mg/kg). On the second day, groups (a) and (b) received two vehicle injections, and groups (c) and (d) received two 7-NI injections (25 mg/kg, each). Administration of vehicle/METH resulted in 68, 44, and 55% decreases in the concentration of dopamine, 3,4-dihydroxyphenylacetic acid, and homovanillic acid, respectively, and a 48% decrease in the number of [3H]mazindol binding sites in the striatum compared with control values. Treatment with 7-NI (group d) provided full protection against the depletion of dopamine and its metabolites and the loss of dopamine transporter binding sites. Administration of 7-NI/saline (group b) affected neither the tissue concentration of dopamine and its metabolites nor the binding parameters of [3H] mazindol compared with control values. 7-NI had no significant effect on animals' body temperature, and it did not affect METH-induced hyperthermia. These findings indicate a role for nitric oxide in methamphetamine-induced neurotoxicity and also suggest that blockade of NOS may be beneficial for the management of Parkinson's disease.

Methamphetamine Use in Club Subcultures

PubMed Central

Kelly, Brian C.; LeClair, Amy; Parsons, Jeffrey T.

2014-01-01

In recent decades, methamphetamine developed a peculiar geographic distribution in the United States, with limited diffusion in the Northeast. While use within gay clubs received attention, methamphetamine in club subcultures more broadly remains less clear. Using quantitative and qualitative data, we provide a descriptive assessment of methamphetamine use in club subcultures. Methamphetamine use in club subcultures often has instrumental purposes. The context of initiation into methamphetamine use and its close connection to cocaine shape later patterns of use. Viewing meth solely as a gay party drug misses a significant part of the population and may misguide public health strategies to reduce methamphetamine use in the Northeast. PMID:23848380

Lamotrigine blocks repeated high-dose methamphetamine-induced behavioral sensitization to dizocilpine (MK-801), but not methamphetamine in rats.

PubMed

Nakato, Yasuya; Abekawa, Tomohiro; Inoue, Takeshi; Ito, Koki; Koyama, Tsukasa

2011-10-24

We recently proposed a new psychostimulant animal model of the progressive pathophysiological changes of schizophrenia. Studies using that model produced a treatment strategy for preventing progression. Lamotrigine (LTG) blocks repeated high-dosage methamphetamine (METH)-induced initiation and expression of prepulse inhibition deficit and development of apoptosis in the medial prefrontal cortex (mPFC). Moreover, it inhibits METH-induced increases in extracellular glutamate levels in the mPFC (Nakato et al., 2011, Neurosci. Lett.). Abnormal behavior induced by METH or NMDA receptor antagonists is regarded as an animal model of schizophrenia. This study examined the effects of LTG on the development of behavioral sensitization to METH and cross-sensitization to dizocilpine (MK-801) by repeated administration of high-dose METH (2.5mg/kg, 10 times s.c.). Rats were injected repeatedly with LTG (30mg/kg) after 120min METH administration (2.5mg/kg). Repeated co-administration of LTG blocked the development of behavioral cross-sensitization to MK-801 (0.15mg/kg), but it did not prevent behavioral sensitization to METH (0.2mg/kg). The LTG-induced prevention of increased glutamate by high-dose METH might be related to the former finding. Combined results of our previous studies and this study suggest that LTG is useful to treat schizophrenia, especially at a critical point in its progression. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Gray-Matter Volume, Midbrain Dopamine D2/D3 Receptors and Drug Craving in Methamphetamine Users

PubMed Central

Morales, Angelica A.; Kohno, Milky; Robertson, Chelsea L.; Dean, Andy C.; Mandelkern, Mark A.; London, Edythe D.

2015-01-01

Dysfunction of the mesocorticolimbic system plays a critical role in clinical features of addiction. Despite evidence suggesting that midbrain dopamine receptors influence amphetamine-induced dopamine release and that dopamine is involved in methamphetamine-induced neurotoxicity, associations between dopamine receptors and gray-matter volume have been unexplored in methamphetamine users. Here we used magnetic resonance imaging and [18F]fallypride positron emission tomography, respectively, to measure gray-matter volume (in 58 methamphetamine users) and dopamine D2/D3 receptor availability (binding potential relative to nondisplaceable uptake of the radiotracer, BPnd) (in 31 methamphetamine users and 37 control participants). Relationships between these measures and self-reported drug craving were examined. Although no difference in midbrain D2/D3 BPnd was detected between methamphetamine and control groups, midbrain D2/D3 BPnd was positively correlated with gray-matter volume in the striatum, prefrontal cortex, insula, hippocampus and temporal cortex in methamphetamine users, but not in control participants (group-by-midbrain D2/D3 BPnd interaction, p<0.05 corrected for multiple comparisons). Craving for methamphetamine was negatively associated with gray-matter volume in the insula, prefrontal cortex, amygdala, temporal cortex, occipital cortex, cerebellum, and thalamus (p<0.05 corrected for multiple comparisons). A relationship between midbrain D2/D3 BPnd and methamphetamine craving was not detected. Lower midbrain D2/D3 BPnd may increase vulnerability to deficits in gray-matter volume in mesocorticolimbic circuitry in methamphetamine users, possibly reflecting greater dopamine-induced toxicity. Identifying factors that influence prefrontal and limbic volume, such as midbrain BPnd, may be important for understanding the basis of drug craving, a key factor in the maintenance of substance use disorders. PMID:25896164

Boundary Conditions of Methamphetamine Craving

PubMed Central

Lopez, Richard B.; Onyemekwu, Chukwudi; Hart, Carl L.; Ochsner, Kevin N.; Kober, Hedy

2015-01-01

Methamphetamine use has increased significantly and become a global health concern. Craving is known to predict methamphetamine use and relapse following abstinence. Some have suggested that cravings are automatic, generalized, and uncontrollable, but experimental work addressing these claims is lacking. In two exploratory studies we tested the boundary conditions of methamphetamine craving by asking: (1) is craving specific to users’ preferred route of administration? and (2) can craving be regulated by cognitive strategies? Two groups of methamphetamine users were recruited. In Study 1, participants were grouped by their preferred route of administration (intranasal vs. smoking), and rated their craving in response to photographs and movies depicting methamphetamine use (via the intranasal vs. smoking route). In Study 2, methamphetamine smokers implemented cognitive regulation strategies while viewing photographs depicting methamphetamine smoking. Strategies involved either focusing on the positive aspects of smoking methamphetamine or the negative consequences of doing so – the latter strategy based on treatment protocols for addiction. In Study 1, we found a significant interaction between group and route of administration, such that participants who preferred to smoke methamphetamine reported significantly stronger craving for smoking stimuli, whereas those who preferred the intranasal route reported stronger craving for intranasal stimuli. In Study 2, participants reported significantly lower craving when focusing on the negative consequences associated with methamphetamine use. Taken together, these findings suggest that strength of craving for methamphetamine is moderated by users’ route of administration and can be reduced by cognitive strategies. This has important theoretical, methodological, and clinical implications. PMID:26302338

Chronic Nicotine Exposure Attenuates Methamphetamine-Induced Dopaminergic Deficits

PubMed Central

Vieira-Brock, Paula L.; McFadden, Lisa M.; Nielsen, Shannon M.; Ellis, Jonathan D.; Walters, Elliot T.; Stout, Kristen A.; McIntosh, J. Michael; Wilkins, Diana G.; Hanson, Glen R.

2015-01-01

Repeated methamphetamine (METH) administrations cause persistent dopaminergic deficits resembling aspects of Parkinson’s disease. Many METH abusers smoke cigarettes and thus self-administer nicotine; yet few studies have investigated the effects of nicotine on METH-induced dopaminergic deficits. This interaction is of interest because preclinical studies demonstrate that nicotine can be neuroprotective, perhaps owing to effects involving α4β2 and α6β2 nicotinic acetylcholine receptors (nAChRs). This study revealed that oral nicotine exposure beginning in adolescence [postnatal day (PND) 40] through adulthood [PND 96] attenuated METH-induced striatal dopaminergic deficits when METH was administered at PND 89. This protection did not appear to be due to nicotine-induced alterations in METH pharmacokinetics. Short-term (i.e., 21-day) high-dose nicotine exposure also protected when administered from PND 40 to PND 61 (with METH at PND 54), but this protective effect did not persist. Short-term (i.e., 21-day) high-dose nicotine exposure did not protect when administered postadolescence (i.e., beginning at PND 61, with METH at PND 75). However, protection was engendered if the duration of nicotine exposure was extended to 39 days (with METH at PND 93). Autoradiographic analysis revealed that nicotine increased striatal α4β2 expression, as assessed using [125I]epibatidine. Both METH and nicotine decreased striatal α6β2 expression, as assessed using [125I]α-conotoxin MII. These findings indicate that nicotine protects against METH-induced striatal dopaminergic deficits, perhaps by affecting α4β2 and/or α6β2 expression, and that both age of onset and duration of nicotine exposure affect this protection. PMID:26391161

3,4-Methylenedioxypyrovalerone prevents while methylone enhances methamphetamine-induced damage to dopamine nerve endings: β-ketoamphetamine modulation of neurotoxicity by the dopamine transporter

PubMed Central

Anneken, John H.; Angoa-Pérez, Mariana; Kuhn, Donald M.

2016-01-01

Methylone, 3,4-methylenedioxypyrovalerone (MDPV), and mephedrone are psychoactive ingredients of ‘bath salts’ and their abuse represents a growing public health care concern. These drugs are cathinone derivatives and are classified chemically as β-ketoamphetamines. Because of their close structural similarity to the amphetamines, methylone, MDPV, and mephedrone share most of their pharmacological, neurochemical, and behavioral properties. One point of divergence in their actions is the ability to cause damage to the CNS. Unlike methamphetamine, the β-ketoamphetamines do not damage dopamine (DA) nerve endings. However, mephedrone has been shown to significantly accentuate methamphetamine neurotoxicity. Bath salt formulations contain numerous different psychoactive ingredients, and individuals who abuse bath salts also coabuse other illicit drugs. Therefore, we have evaluated the effects of methylone, MDPV, mephedrone, and methamphetamine on DA nerve endings. The β-ketoamphetamines alone or in all possible two-drug combinations do not result in damage to DA nerve endings but do cause hyperthermia. MDPV completely protects against the neurotoxic effects of methamphetamine while methylone accentuates it. Neither MDPV nor methylone attenuates the hyperthermic effects of methamphetamine. The potent neuroprotective effects of MDPV extend to amphetamine-, 3,4-methylenedioxymethamphetamine-, and MPTP-induced neurotoxicity. These results indicate that β-ketoamphetamine drugs that are non-substrate blockers of the DA transporter (i.e., MDPV) protect against methamphetamine neurotoxicity, whereas those that are substrates for uptake by the DA transporter and which cause DA release (i.e., methylone, mephedrone) accentuate neurotoxicity. PMID:25626880

A potential role for N-acetylcysteine in the management of methamphetamine dependence.

PubMed

McKetin, Rebecca; Dean, Olivia M; Baker, Amanda L; Carter, Greg; Turner, Alyna; Kelly, Peter J; Berk, Michael

2017-03-01

Methamphetamine dependence is a growing problem in Australia and globally. Currently, there are no approved pharmacotherapy options for the management of methamphetamine dependence. N-acetylcysteine is one potential pharmacotherapy option. It has received growing attention as a therapy for managing addictions because of its capacity to restore homeostasis to brain glutamate systems disrupted in addiction and thereby reduce craving and the risk of relapse. N-acetylcysteine also has antioxidant properties that protect against methamphetamine-induced toxicity and it may therefore assist in the management of the neuropsychiatric and neurocognitive effects of methamphetamine. This commentary overviews the actions of N-acetylcysteine and evidence for its efficacy in treating addiction with a particular focus on its potential utility for methamphetamine dependence. We conclude that the preliminary evidence indicates a need for full-scale trials to definitively establish whether N-acetylcysteine has a therapeutic benefit and the nature of this benefit, for managing methamphetamine dependence. [McKetin R, Dean O, Baker A. L, Carter G, Turner A, Kelly P. J, Berk M. A potential role for N-acetylcysteine in the management of methamphetamine dependence. Drug Alcohol Rev 2017;36:153-159]. © 2016 Australasian Professional Society on Alcohol and other Drugs.

Methamphetamine-related brainstem haemorrhage.

PubMed

Chiu, Zelia K; Bennett, Iwan E; Chan, Patrick; Rosenfeld, Jeffrey V

2016-10-01

We report the case of an otherwise healthy 29-year-old woman who presented with a brainstem haemorrhage following intravenous methamphetamine use. Extensive investigation did not reveal an underlying pathology, and the development of symptoms was temporally related to methamphetamine injection. Although intracerebral haemorrhage secondary to methamphetamine use is well documented, this report describes a haemorrhage within the brainstem which is a rare location. While animal studies have demonstrated the potential of methamphetamines to produce brainstem haemorrhages, there has only been one previous report describing a haemorrhage in this location due to amphetamine use in humans. We conclude with a brief discussion of the clinical features and aetiology of methamphetamine-related stroke. Copyright © 2016 Elsevier Ltd. All rights reserved.

AMPA receptor plasticity in accumbens core contributes to incubation of methamphetamine craving

PubMed Central

Scheyer, Andrew F.; Loweth, Jessica A.; Christian, Daniel T.; Uejima, Jamie; Rabei, Rana; Le, Tuan; Dolubizno, Hubert; Stefanik, Michael T.; Murray, Connor H.; Sakas, Courtney; Wolf, Marina E.

2016-01-01

BACKGROUND The incubation of cue-induced drug craving in rodents provides a model of persistent vulnerability to craving and relapse in human addicts. After prolonged withdrawal, incubated cocaine craving depends on strengthening of nucleus accumbens (NAc) core synapses through incorporation of Ca2+-permeable AMPA receptors (CP-AMPARs). Through mGlu1-mediated synaptic depression, mGlu1 positive allosteric modulators (PAMs) remove CP-AMPARs from these synapses and thereby reduce cocaine craving. This study aimed to determine if similar plasticity accompanies incubation of methamphetamine craving. METHODS Rats self-administered saline or methamphetamine under extended-access conditions. Cue-induced seeking tests demonstrated incubation of methamphetamine craving. After withdrawal periods ranging from 1 to >40 days, rats underwent one of the following procedures: 1) whole-cell patch clamp recordings to characterize AMPAR transmission, 2) intra-NAc core injection of the CP-AMPAR antagonist 1-napthyl acetyl spermine (naspm) prior to a seeking test, or 3) systemic administration of an mGlu1 PAM prior to a seeking test. RESULTS Incubation of methamphetamine craving was associated with CP-AMPAR accumulation in NAc core, and both effects were maximal after ~1 week of withdrawal. Expression of incubated craving was decreased by intra-NAc naspm injection or systemic mGlu1 PAM administration. CONCLUSIONS These results are the first to demonstrate a role for the NAc in the incubation of methamphetamine craving and describe adaptations in synaptic transmission associated with this model. They establish that incubation of craving and associated CP-AMPAR plasticity occur much more rapidly during withdrawal from methamphetamine than cocaine. However, a common mGlu1-based therapeutic strategy may be helpful for recovering cocaine and methamphetamine addicts. PMID:27264310

Inhibiting effects of rhynchophylline on methamphetamine-dependent zebrafish are related with the expression of tyrosine hydroxylase (TH).

PubMed

Zhu, Chen; Liu, Wei; Luo, Chaohua; Liu, Yi; Li, Chan; Fang, Miao; Lin, Yingbo; Ou, Jinying; Chen, Minting; Zhu, Daoqi; Yung, Ken Kin-Lam; Mo, Zhixian

2017-03-01

In this study, to study the effect of rhynchophylline on TH in midbrain of methamphetamine-induced conditioned place preference (CPP) adult zebrafish, place preference adult zebrafish models were established by methamphetamine (40μg/g) and the expression of TH was observed by immunohistochemistry technique and Western blot. Ketamine (150μg/g), high dose of rhynchophylline (100μg/g) group can significantly reduce the place preference; immunohistochemistry results showed that the number of TH-positive neurons in midbrain was increased in the methamphetamine model group, whereas less TH-positive neurons were found in the ketamine group and high dosage rhynchophylline group. Western blot results showed that the expression of TH protein was significantly increased in the model group, whereas less expression was found in the ketamine group, high dosage rhynchophylline group. Our data pointed out that TH plays an important role in the formation of methamphetamine-induced place preference in adult zebrafish. Rhynchophylline reversed the expression of TH in the midbrain demonstrates the potential effect of mediates methamphetamine induced rewarding effect. Copyright © 2017 Elsevier B.V. All rights reserved.

Changes of sperm quality and hormone receptors in the rat testis after exposure to methamphetamine.

PubMed

Nudmamud-Thanoi, Sutisa; Sueudom, Wanvipa; Tangsrisakda, Nareelak; Thanoi, Samur

2016-10-01

Methamphetamine (METH) is known to damage neurons and induce psychosis. It can also induce apoptosis in seminiferous tubules and affect sperm quality. The present study was carried out to investigate the effect of a rat model of METH addiction on sperm quality and expression of progesterone receptors (PR) and estrogen receptors (ER) in the testis. Sperm quality parameters including sperm motility, sperm morphology and sperm concentration were examined. Protein and gene expressions PR, ERα and ERβ were studied using immunohistochemistry and reverse transcriptase-polymerase chain reaction, respectively. The percentages of normal sperm motility and normal sperm morphology were significantly decreased in animals receiving METH, especially in escalating dose (ED METH) and escalating dose-binge (ED-binge METH) groups when compared with control. In addition, sperm concentrations in ED METH and ED-binge METH groups were numerically decreased. PR, ERα and ERβ immunoreactive cells were significantly decreased in spermatogonia, spermatogenic cells and especially in Sertoli cells in all METH-treated groups. Furthermore, messenger RNA expression of PR, ERα and ERβ were also significantly decreased in all METH-treated animals. These results indicate that METH can induce abnormal sperm quality. These changes of sperm quality may relate to the reduction of PR, ERα and ERβ expressions in male germ cells and Sertoli cells which are essential for spermatogenesis and development of sperm.

Glial Reactivity in Resistance to Methamphetamine-Induced Neurotoxicity

PubMed Central

Friend, Danielle M.; Keefe, Kristen A.

2013-01-01

Neurotoxic regimens of methamphetamine (METH) result in reactive microglia and astrocytes in striatum. Prior data indicate that rats with partial dopamine (DA) loss resulting from prior exposure to METH are resistant to further decreases in striatal DA when re-exposed to METH 30 days later. Such resistant animals also do not show an activated microglia phenotype, suggesting a relation between microglial activation and METH-induced neurotoxicity. To date, the astrocyte response in such resistance has not been examined. Thus, this study examined glial-fibrillary acidic protein (GFAP) and CD11b protein expression in striata of animals administered saline or a neurotoxic regimen of METH on postnatal days 60 and/or 90 (Saline:Saline, Saline:METH, METH:Saline, METH:METH). Consistent with previous work, animals experiencing acute toxicity (Saline:METH) showed both activated microglia and astocytes, whereas those resistant to the acute toxicity (METH:METH) did not show activated microglia. Interestingly, GFAP expression remained elevated in rats exposed to METH at PND60 (METH:Saline), and was not elevated further in resistant rats treated for the second time with METH (METH:METH). These data suggest that astrocytes remain reactive up to 30 days post-METH exposure. Additionally, these data indicate that astrocyte reactivity does not reflect acute, METH-induced DA terminal toxicity, whereas microglial reactivity does. PMID:23414433

Δ9-Tetrahydrocannabinol Prevents Methamphetamine-Induced Neurotoxicity

PubMed Central

Castelli, M. Paola; Casu, Angelo; Casti, Paola; Scherma, Maria; Fattore, Liana; Fadda, Paola; Ennas, M. Grazia

2014-01-01

Methamphetamine (METH) is a potent psychostimulant with neurotoxic properties. Heavy use increases the activation of neuronal nitric oxide synthase (nNOS), production of peroxynitrites, microglia stimulation, and induces hyperthermia and anorectic effects. Most METH recreational users also consume cannabis. Preclinical studies have shown that natural (Δ9-tetrahydrocannabinol, Δ9-THC) and synthetic cannabinoid CB1 and CB2 receptor agonists exert neuroprotective effects on different models of cerebral damage. Here, we investigated the neuroprotective effect of Δ9-THC on METH-induced neurotoxicity by examining its ability to reduce astrocyte activation and nNOS overexpression in selected brain areas. Rats exposed to a METH neurotoxic regimen (4×10 mg/kg, 2 hours apart) were pre- or post-treated with Δ9-THC (1 or 3 mg/kg) and sacrificed 3 days after the last METH administration. Semi-quantitative immunohistochemistry was performed using antibodies against nNOS and Glial Fibrillary Acidic Protein (GFAP). Results showed that, as compared to corresponding controls (i) METH-induced nNOS overexpression in the caudate-putamen (CPu) was significantly attenuated by pre- and post-treatment with both doses of Δ9-THC (−19% and −28% for 1 mg/kg pre- and post-treated animals; −25% and −21% for 3 mg/kg pre- and post-treated animals); (ii) METH-induced GFAP-immunoreactivity (IR) was significantly reduced in the CPu by post-treatment with 1 mg/kg Δ9-THC1 (−50%) and by pre-treatment with 3 mg/kg Δ9-THC (−53%); (iii) METH-induced GFAP-IR was significantly decreased in the prefrontal cortex (PFC) by pre- and post-treatment with both doses of Δ9-THC (−34% and −47% for 1 mg/kg pre- and post-treated animals; −37% and −29% for 3 mg/kg pre- and post-treated animals). The cannabinoid CB1 receptor antagonist SR141716A attenuated METH-induced nNOS overexpression in the CPu, but failed to counteract the Δ9-THC-mediated reduction of METH-induced GFAP-IR both in the

Methamphetamine differentially affects BDNF and cell death factors in anatomically defined regions of the hippocampus

PubMed Central

Galinato, Melissa H.; Orio, Laura; Mandyam, Chitra D.

2014-01-01

Methamphetamine exposure reduces hippocampal long-term potentiation (LTP) and neurogenesis and these alterations partially contribute to hippocampal maladaptive plasticity. The potential mechanisms underlying methamphetamine-induced maladaptive plasticity were identified in the present study. Expression of brain-derived neurotrophic factor (BDNF; a regulator of LTP and neurogenesis), and its receptor tropomyosin-related kinase B (TrkB) were studied in the dorsal and ventral hippocampal tissue lysates in rats that intravenously self-administered methamphetamine in a limited access (1 h/day) or extended access (6 h/day) paradigm for 17 days post baseline sessions. Extended access methamphetamine enhanced expression of BDNF with significant effects observed in the dorsal and ventral hippocampus. Methamphetamine-induced enhancements in BDNF expression were not associated with TrkB receptor activation as indicated by phospho (p)-TrkB-706 levels. Conversely, methamphetamine produced hypophosphorylation of NMDA receptor subunit 2B (GluN2B) at Tyr-1472 in the ventral hippocampus, indicating reduced receptor activation. In addition, methamphetamine enhanced expression of anti-apoptotic protein Bcl-2 and reduced pro-apoptotic protein Bax levels in the ventral hippocampus, suggesting a mechanism for reducing cell death. Analysis of Akt, a pro-survival kinase that suppresses apoptotic pathways and pAkt at Ser-473 demonstrated that extended access methamphetamine reduces Akt expression in the ventral hippocampus. These data reveal that alterations in Bcl-2 and Bax levels by methamphetamine were not associated with enhanced Akt expression. Given that hippocampal function and neurogenesis vary in a subregion-specific fashion, where dorsal hippocampus regulates spatial processing and has higher levels of neurogenesis, whereas ventral hippocampus regulates anxiety-related behaviors, these data suggest that methamphetamine self-administration initiates distinct allostatic changes in

A role for D1 dopamine receptors in striatal methamphetamine-induced neurotoxicity.

PubMed

Friend, Danielle M; Keefe, Kristen A

2013-10-25

Methamphetamine (METH) exposure results in long-term damage to the dopamine system in both human METH abusers and animal models. One factor that has been heavily implicated in this METH-induced damage to the dopaminergic system is the activation of D1 dopamine (DA) receptors. However, a significant caveat to the studies investigating the role of the receptor in such toxicity is that genetic and pharmacological manipulations of the D1 DA receptor also mitigate METH-induced hyperthermia. Importantly, METH-induced hyperthermia is tightly associated with the neurotoxicity, such that simply cooling animals during METH exposure protects against the neurotoxicity. Therefore, it is difficult to determine whether D1 DA receptors per se play an important role in METH-induced neurotoxicity or whether the protection observed simply resulted from a mitigation of METH-induced hyperthermia. To answer this important question, the current study infused a D1 DA receptor antagonist into striatum during METH exposure while controlling for METH-induced hyperthermia. Here we found that even when METH-induced hyperthermia is maintained, the coadministration of a D1 DA receptor antagonist protects against METH-induced neurotoxicity, strongly suggesting that D1 DA receptors play an important role in METH-induced neurotoxicity apart from the mitigation of METH-induced hyperthermia. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

nNOS inhibitors attenuate methamphetamine-induced dopaminergic neurotoxicity but not hyperthermia in mice.

PubMed

Itzhak, Y; Martin, J L; Ail, S F

2000-09-11

Methamphetamine (METH)-induced dopaminergic neurotoxicity is associated with hyperthermia. We investigated the effect of several neuronal nitric oxide synthase (nNOS) inhibitors on METH-induced hyperthermia and striatal dopaminergic neurotoxicity. Administration of METH (5 mg/kg; q. 3 h x 3) to Swiss Webster mice produced marked hyperthermia and 50-60% depletion of striatal dopaminergic markers 72 h after METH administration. Pretreatment with the nNOS inhibitors S-methylthiocitrulline (SMTC; 10 mg/kg) or 3-bromo-7-nitroindazole (3-Br-7-NI; 20 mg/kg) before each METH injection did not affect the persistent hyperthermia produced by METH, but afforded protection against the depletion of dopaminergic markers. A low dose (25 mg/kg) of the nNOS inhibitor 7-nitroindazole (7-NI) did not affect METH-induced hyperthermia, but a high dose (50 mg/kg) produced significant hypothermia. These findings indicate that low dose of selective nNOS inhibitors protect against METH-induced neurotoxicity with no effect on body temperature and support the hypothesis that nitric oxide (NO) and peroxynitrite have a major role in METH-induced dopaminergic neurotoxicity.

17 β-Estradiol exacerbates methamphetamine-induced anxiety-like behavior in female mice.

PubMed

Rauhut, A S; Curran-Rauhut, M A

2018-05-20

The present experiment investigated the effect of 17 β-estradiol (E 2 ) on anxiety-like behavior following methamphetamine administration in female, Swiss-Webster mice. Mice underwent bilateral ovariectomy (OVX) followed by a subcutaneous implantation of a Silastic capsule containing either sesame oil (OVX + Oil) or E 2 (36 μg/ml; OVX + E 2 ). One week later, mice were placed in an open-field chamber for an 8-h session. During the first 3 h of the session, mice were permitted to run in the absence of any drug (baseline). Then, mice were injected intraperitoneally with methamphetamine (0.25, 0.5 or 1.0 mg/kg) or vehicle (physiological saline) and returned to the open-field chamber for the remaining five hours of the session. Mice were injected with vehicle or a different methamphetamine dose once a week for 4 weeks. Four measures of anxiety were assessed: distanced traveled, vertical counts, time in the center, and time resting in the perimeter of the chamber. OVX + E 2 were less active and spent less time in the center than OVX + Oil mice during Hour 1 at certain doses, but not during remaining baseline hours (Hours 2-3). Furthermore, group differences were not observed during the Stimulant Phase (Hour 4) following injection of any methamphetamine dose (0.25, 0.5 or 1.0 mg/kg) or the vehicle. However, OVX + E 2 mice were less active, spent less time in the center, and spent more time resting in the perimeter of the chamber compared to OVX + Oil mice during certain hours of the Clearance Phase (Hours 5-8) following injection of the high (1.0 mg/kg), but not the low (0.25 mg/kg) or moderate (0.5 mg/kg), methamphetamine doses. These results suggest that E 2 exacerbates anxiety-like behavior during acute clearance from a high methamphetamine dose in OVX female mice, perhaps indicating that E 2 contributes to drug relapse in women by worsening anxiety-related withdrawal symptoms. Copyright © 2018 Elsevier B.V. All rights reserved.

Cannabis-induced attenuated psychotic symptoms: implications for prognosis in young people at ultra-high risk for psychosis.

PubMed

McHugh, M J; McGorry, P D; Yung, A R; Lin, A; Wood, S J; Hartmann, J A; Nelson, B

2017-03-01

Cannabis use shows a robust dose-dependent relationship with psychosis risk among the general population. Despite this, it has been difficult to link cannabis use with risk for transitioning to a psychotic disorder among individuals at ultra-high risk (UHR) for psychosis. The present study examined UHR transition risk as a function of cannabis use characteristics which vary substantially between individuals including age of first use, cannabis abuse severity and a history of cannabis-induced attenuated psychotic symptoms (APS). Participants were 190 UHR individuals (76 males) recruited at entry to treatment between 2000 and 2006. They completed a comprehensive baseline assessment including a survey of cannabis use characteristics during the period of heaviest use. Outcome was transition to a psychotic disorder, with mean time to follow-up of 5.0 years (range 2.4-8.7 years). A history of cannabis abuse was reported in 58% of the sample. Of these, 26% reported a history of cannabis-induced APS. These individuals were 4.90 (95% confidence interval 1.93-12.44) times more likely to transition to a psychotic disorder (p = 0.001). Greater severity of cannabis abuse also predicted transition to psychosis (p = 0.036). However, this effect was mediated by higher abuse severity among individuals with a history of cannabis-induced APS. Findings suggest that cannabis use poses risk in a subpopulation of UHR individuals who manifest cannabis-induced APS. Whether this reflects underlying genetic vulnerability requires further study. Nevertheless, findings reveal an important early marker of risk with potentially significant prognostic utility for UHR individuals.

Prior nicotine self-administration attenuates subsequent dopaminergic deficits of methamphetamine in rats: Role of nicotinic acetylcholine receptors

PubMed Central

Baladi, Michelle G; Nielsen, Shannon M; McIntosh, J. Michael; Hanson, Glen R; Fleckenstein, Annette E

2015-01-01

Preclinical studies have demonstrated that oral nicotine exposure attenuates long-term dopaminergic damage induced by toxins, including repeated, high doses of methamphetamine. It is suggested that alterations in nicotinic acetylcholine receptor (nAChR) expression, including α4β2* and α6β2* subtypes, likely contribute to this protection. The current study extended these findings by investigating whether nicotine self-administration in male, Sprague-Dawley rats 1): attenuates short-term dopaminergic damage induced by methamphetamine and 2) causes alterations in levels of α4β2* and α6β2* nAChR subtypes. The findings indicate that nicotine self-administration (0.032 mg/kg/infusion for 14 days) per se did not alter α4β2* and α6β2* nAChR expression or dopamine transporter (DAT) expression and function. Interestingly, prior nicotine self-administration attenuated methamphetamine-induced decreases in DAT function when assessed 24 h, but not 1 h, after methamphetamine treatment (4 × 7.5 mg/kg/injection). The ability of nicotine to attenuate the effects of methamphetamine on DAT function corresponded with increases in α4β2*, but not α6β2*, nAChR binding density. Understanding the role of nAChRs in methamphetamine-induced damage has the potential to elucidate mechanisms underlying the etiology of disorders involving dopaminergic dysfunction, as well as to highlight potential new therapeutic strategies for prevention or reduction of dopaminergic neurodegeneration. PMID:26871405

Prior nicotine self-administration attenuates subsequent dopaminergic deficits of methamphetamine in rats: role of nicotinic acetylcholine receptors.

PubMed

Baladi, Michelle G; Nielsen, Shannon M; McIntosh, J Michael; Hanson, Glen R; Fleckenstein, Annette E

2016-08-01

Preclinical studies have demonstrated that oral nicotine exposure attenuates long-term dopaminergic damage induced by toxins, including repeated, high doses of methamphetamine. It is suggested that alterations in nicotinic acetylcholine receptor (nAChR) expression, including α4β2* and α6β2* subtypes, likely contribute to this protection. The current study extended these findings by investigating whether nicotine self-administration in male, Sprague-Dawley rats (a) attenuates short-term dopaminergic damage induced by methamphetamine and (b) causes alterations in levels of α4β2* and α6β2* nAChR subtypes. The findings indicate that nicotine self-administration (0.032 mg/kg/infusion for 14 days) per se did not alter α4β2* and α6β2* nAChR expression or dopamine transporter (DAT) expression and function. Interestingly, prior nicotine self-administration attenuated methamphetamine-induced decreases in DAT function when assessed 24 h, but not 1 h, after methamphetamine treatment (4×7.5 mg/kg/injection). The ability of nicotine to attenuate the effects of methamphetamine on DAT function corresponded with increases in α4β2*, but not α6β2*, nAChR binding density. Understanding the role of nAChRs in methamphetamine-induced damage has the potential to elucidate mechanisms underlying the etiology of disorders involving dopaminergic dysfunction, as well as to highlight potential new therapeutic strategies for prevention or reduction of dopaminergic neurodegeneration.

Risperidone for psychosis-induced aggression or agitation (rapid tranquillisation).

PubMed

Ostinelli, Edoardo G; Hussein, Mohsin; Ahmed, Uzair; Rehman, Faiz-Ur; Miramontes, Krista; Adams, Clive E

2018-04-10

Aggressive, agitated or violent behaviour due to psychosis constitutes an emergency psychiatric treatment where fast-acting interventions are required. Risperidone is a widely accessible antipsychotic that can be used to manage psychosis-induced aggression or agitation. To examine whether oral risperidone alone is an effective treatment for psychosis-induced aggression or agitation. We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials (up to April 2017); this register is compiled by systematic searches of major resources (including AMED, BIOSIS CINAHL, Embase, MEDLINE, PsycINFO, PubMed, and registries of clinical trials) and their monthly updates, handsearches, grey literature, and conference proceedings. There are no language, date, document type, or publication status limitations for inclusion of records into the register. Randomised controlled trials (RCTs) comparing rapid use of risperidone and other drugs, combinations of drugs or placebo for people exhibiting aggression or agitation (or both) thought to be due to psychosis. We independently inspected all citations from searches, identified relevant abstracts, and independently extracted data from all included studies. For binary data we calculated risk ratio (RR) and for continuous data we calculated mean difference (MD), all with 95% confidence intervals (CI) and used a fixed-effect model. We assessed risk of bias for the included studies and used the GRADE approach to produce a 'Summary of findings' tables. The review now contains data from nine trials (total n = 582) reporting on five comparisons. Due to risk of bias, small size of trials, indirectness of outcome measures and a paucity of investigated and reported 'pragmatic' outcomes, evidence was graded as very-low quality. None of the included studies provided useable data on our primary outcome 'tranquillisation or asleep' by 30 minutes, repeated need for tranquillisation or any economic outcomes. Data were available for our

Effect of melatonin on methamphetamine- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurotoxicity and methamphetamine-induced behavioral sensitization.

PubMed

Itzhak, Y; Martin, J L; Black, M D; Ali, S F

1998-06-01

Methamphetamine (METH)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity is thought to be associated with the formation of free radicals. Since evidence suggests that melatonin may act as a free radical scavenger and antioxidant, the present study was undertaken to investigate the effect of melatonin on METH- and MPTP-induced neurotoxicity. In addition, the effect of melatonin on METH-induced locomotor sensitization was investigated. The administration of METH (5 mg kg(-1) x 3) or MPTP (20 mg kg(-1) x 3) to Swiss Webster mice resulted in 45-57% depletion in the content of striatal dopamine and its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, and 57-59% depletion in dopamine transporter binding sites. The administration of melatonin (10 mg kg(-1)) before each of the three injections of the neurotoxic agents (on day 1), and thereafter for two additional days, afforded a full protection against METH-induced depletion of dopamine and its metabolites and dopamine transporter binding sites. In addition, melatonin significantly diminished METH-induced hyperthermia. However, the treatment with melatonin had no significant effect on MPTP-induced depletion of the dopaminergic markers tested. In the set of behavioral experiments, we found that the administration of 1 mg kg(-1) METH to Swiss Webster mice for 5 days resulted in marked locomotor sensitization to a subsequent challenge injection of METH, as well as context-dependent sensitization (conditioning). The pretreatment with melatonin (10 mg kg(-1)) prevented neither the sensitized response to METH nor the development of conditioned locomotion. Results of the present study indicate that melatonin has a differential effect on the dopaminergic neurotoxicity produced by METH and MPTP. Since it is postulated that METH-induced hyperthermia is related to its neurotoxic effect, while regulation of body temperature is unrelated to MPTP-induced neurotoxicity or METH-induced

Mechanisms involved in the neurotoxic and cognitive effects of developmental methamphetamine exposure.

PubMed

Jablonski, Sarah A; Williams, Michael T; Vorhees, Charles V

2016-06-01

Methamphetamine exposure in utero leads to a variety of higher-order cognitive deficits, such as decreased attention and working, and spatial memory impairments in exposed children (Piper et al., 2011; Roussotte et al., 2011; Kiblawi et al., 2011). As with other teratogens, the timing of methamphetamine exposure greatly determines its effects on both neuroanatomical and behavioral outcomes. Methamphetamine exposure in rodents during the third trimester human equivalent period of brain development results in distinct and long-lasting route-based and spatial navigation deficits (Williams et al., 2003; Vorhees et al., 2005, 2008, 2009;). Here, we examine the impact of neonatal methamphetamine-induced neurotoxicity on behavioral outcomes, neurotransmission, receptor changes, plasticity proteins, and DNA damage. Birth Defects Research (Part C) 108:131-141, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Aripiprazole-Induced Hypoprolactinemia in an Adult Male with First-Episode Psychosis.

PubMed

Propst, Alanna J; Jarvis, G Eric; Margolese, Howard C

2016-01-01

Aripiprazole is an atypical antipsychotic that acts as a partial agonist at dopamine D2 receptors. Compared to other atypical antipsychotics, aripiprazole has less metabolic side effects and is less likely to increase prolactin. Moreover, it has been shown to have a unique prolactin lowering effect. While aripiprazole has been associated with subnormal prolactin levels in children, no documented cases of hypoprolactinemia in adults exist thus far. Here we report a case of aripiprazole-induced hypoprolactinemia in an adult male with first-episode psychosis, and the possible effects of abnormally low prolactin are discussed.

Physiological and subjective effects of acute intranasal methamphetamine during extended-release alprazolam maintenance

PubMed Central

Lile, Joshua A.; Stoops, William W.; Glaser, Paul E.A.; Hays, Lon R.; Rush, Craig R.

2015-01-01

Background Medications development for methamphetamine dependence is ongoing, but no widely accepted, effective pharmacotherapy has been identified. Previous studies have demonstrated neurobiological perturbations to central GABAA activity following chronic stimulant use, and that positive modulation of GABAA receptors attenuates the neurochemical and behavioral response to stimulant drugs such as methamphetamine. Therefore, GABAA modulators could be useful as pharmacotherapies for stimulant-use disorders. Methods This study tested the hypothesis that intranasal methamphetamine would be safe and well tolerated during maintenance on extended-release alprazolam (XR), and that the effects of methamphetamine would be attenuated. Eight non-treatment-seeking, stimulant-dependent individuals completed an inpatient experiment in which ascending doses of intranasal methamphetamine (0, 5, 10, 20 and 30 mg) were administered after four days of alprazolam XR maintenance (0 and 1 mg/day). Results Intranasal methamphetamine produced prototypical effects (e.g., increased positive subjective ratings and elevated cardiovascular signs). The combination of intranasal methamphetamine and alprazolam XR was safe and well tolerated. Alprazolam XR produced small, but orderly, reductions in some of the subjective effects of methamphetamine, and performance impairment. Conclusions The present results demonstrate that methamphetamine use during alprazolam XR treatment would not pose a significant safety risk. Given the potential of GABAA positive modulators to manage certain aspects of stimulant abuse and dependence (i.e., drug-induced seizures, anxiety and stress), but the relatively small impact on the acute abuse-related effects of methamphetamine observed here, additional research with GABAA positive modulators is warranted, but should consider their use as an adjunct component of combination behavioral and/or drug treatment. PMID:21737214

Changes in Gray Matter Density, Regional Homogeneity, and Functional Connectivity in Methamphetamine-Associated Psychosis: A Resting-State Functional Magnetic Resonance Imaging (fMRI) Study.

PubMed

Zhang, Shengyu; Hu, Qiang; Tang, Tao; Liu, Chao; Li, Chengchong; Zang, Yin-Yin; Cai, Wei-Xiong

2018-06-13

BACKGROUND Using regional homogeneity (ReHo) blood oxygen level-dependent functional MR (BOLD-fMRI), we investigated the structural and functional alterations of brain regions among patients with methamphetamine-associated psychosis (MAP). MATERIAL AND METHODS This retrospective study included 17 MAP patients, 16 schizophrenia (SCZ) patients, and 18 healthy controls. Informed consent was obtained from all patients before the clinical assessment, the severity of clinical symptoms was evaluated prior to the fMRI scanning, and then images were acquired and preprocessed after each participant received 6-min fRMI scanning. The participants all underwent BOLD-fMRI scanning. Voxel-based morphometry was used to measure gray matter density (GMD). Resting-state fMRI (rs-fMRI) was conducted to analyze functional MR, ReHo, and functional connectivity (FC). RESULTS GMD analysis results suggest that MAP patients, SCZ patients, and healthy volunteers show different GMDs within different brain regions. Similarly, the ReHo analysis results suggest that MAP patients, SCZ patients, and healthy volunteers have different GMDs within different brain regions. Negative correlations were found between ReHo- and the PANSS-positive scores within the left orbital interior frontal gyrus (L-orb-IFG) of MAP patients. ReHo- and PANSS-negative scores of R-SFG were negatively correlated among SCZ patients. The abnormal FC of R-MFG showed a negative correlation with the PANSS score among MAP patients. CONCLUSIONS The abnormalities in brain structure and FC were associated with the development of MAP.

Methamphetamine and dopamine neurotoxicity: differential effects of agents interfering with glutamatergic transmission.

PubMed

Boireau, A; Bordier, F; Dubédat, P; Doble, A

1995-07-28

The effects of riluzole and lamotrigine, two agents which interfere with the release of glutamate (GLU), and MK-801, a blocker of N-methyl-D-aspartate (NMDA) receptors, were compared in the model of methamphetamine-induced depletion of dopamine (DA) levels in mice. Repeated injections with methamphetamine (4 x 5 mg/kg i.p.) markedly decreased levels of DA, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels. When mice were treated with riluzole (2 x 10 mg/kg p.o.), no protection was observed against the decrease in DA and the two metabolites. Lamotrigine (2 x 10 mg/kg p.o.) was also inactive. Treatment with MK-801 (2 x 2.5 mg/kg i.p.) antagonized the decrease in DA, DOPAC and HVA levels induced by the neurotoxin. Thus, unlike an NMDA blocker, drugs that interfere with GLU release did not antagonize the methamphetamine-induced DA neurotoxicity in mice. The consequences of this inactivity are discussed in terms of the reliability of this model to test new drugs with putative efficacy in the treatment of Parkinson's disease.

Randomized, placebo-controlled trial of bupropion in methamphetamine-dependent participants with less than daily methamphetamine use

PubMed Central

Heinzerling, Keith G.; Swanson, Aimee-Noelle; Hall, Timothy M.; Yi, Yi; Wu, Yingnian; Shoptaw, Steven J.

2014-01-01

Aims Two previous randomized trials found an effect for bupropion in reducing methamphetamine use in the subgroup with lower frequency of methamphetamine use at baseline. This study aimed to replicate these results by comparing bupropion versus placebo in methamphetamine dependent participants with less than daily methamphetamine use at baseline. Methods Methamphetamine dependent volunteers reporting methamphetamine use on ≤ 29 of past 30 days were randomized to bupropion 150mg twice daily (N=41) or placebo (N=43) and outpatient counseling for 12 weeks. The primary outcome was the proportion achieving end of treatment (EOT) methamphetamine abstinence (weeks 11 and 12) for bupropion versus placebo. A post hoc analysis compared EOT abstinence by medication adherence assessed via plasma bupropion/hydroxybupropion level. Results There was no significant difference in EOT abstinence between bupropion (29%, 12/41) and placebo (14%, 6/43; p = 0.087). Among participants receiving bupropion, EOT abstinence was significantly higher in participants assessed as medication adherent by plasma bupropion/hydroxybupropion levels (54%, 7/13) compared to non-adherent participants (18%, 5/28; p = 0.018). Medication adherence by plasma levels was low (32%). Conclusions Bupropion may be efficacious for methamphetamine dependence but only in a highly selected subgroup of medication adherent participants with less than daily baseline methamphetamine use. Even a single objective “snapshot” measure of medication adherence is highly associated with treatment outcomes. PMID:24894963

Methamphetamine - Multiple Languages

MedlinePlus

... Facts about Methamphetamine - العربية (Arabic) PDF Karen Chemical Dependency Taskforce of Minnesota Burmese (myanma bhasa) Expand Section ... about Methamphetamine - myanma bhasa (Burmese) MP3 Karen Chemical Dependency Taskforce of Minnesota Chinese, Traditional (Cantonese dialect) (繁體中文) ...

The methamphetamine problem

PubMed Central

Galbraith, Niall

2015-01-01

This paper introduces the reader to the characteristics of methamphetamine. Explored within are the drug's effects on those who consume it as well as the history and prevalence of its use. The highly addictive nature of methamphetamine is compounded by its affordability and the ease with which it is produced, with North America and East Asia having become established as heartlands for both consumption and manufacture. The paper discusses recent cultural depictions of the drug and also the role that mental health professionals may take in designing and delivering interventions to treat methamphetamine addiction. PMID:26755964

Cognitive deficits associated with combined HIV gp120 expression and chronic methamphetamine exposure in mice

PubMed Central

Kesby, James P.; Markou, Athina; Semenova, Svetlana

2014-01-01

Methamphetamine abuse is common among individuals infected by human immunodeficiency virus (HIV). Neurocognitive outcomes tend to be worse in methamphetamine users with HIV. However, it is unclear whether discrete cognitive domains are susceptible to impairment after combined HIV infection and methamphetamine abuse. The expression of HIV/gp120 protein induces neuropathology in mice similar to HIV-induced pathology in humans. We investigated the separate and combined effects of methamphetamine exposure and gp120 expression on cognitive function in transgenic (gp120-tg) and control mice. The mice underwent an escalating methamphetamine binge regimen and were tested in novel object/location recognition, object-in-place recognition, and Barnes maze tests. gp120 expression disrupted performance in the object-in-place test (i.e., similar time spent with all objects, regardless of location), indicating deficits in associative recognition memory. gp120 expression also altered reversal learning in the Barnes maze, suggesting impairments in executive function. Methamphetamine exposure impaired spatial strategy in the Barnes maze, indicating deficits in spatial learning. Methamphetamine-exposed gp120-tg mice had the lowest spatial strategy scores in the final acquisition trials in the Barnes maze, suggesting greater deficits in spatial learning than all of the other groups. Although HIV infection involves interactions between multiple proteins and processes, in addition to gp120, our findings in gp120-tg mice suggest that humans with the dual insult of HIV infection and methamphetamine abuse may exhibit a broader spectrum of cognitive deficits than those with either factor alone. Depending on the cognitive domain, the combination of both insults may exacerbate deficits in cognitive performance compared with each individual insult. PMID:25476577

Bupropion differentially impacts acquisition of methamphetamine self-administration and sucrose-maintained behavior

PubMed Central

Reichel, Carmela M.; Linkugel, Jessica D.; Bevins, Rick A.

2010-01-01

Bupropion reduces the subjective effects and cue-induced craving for methamphetamine in humans. Given these effects of bupropion on methamphetamine in humans and its widespread clinical use, a preclinical model of drug-taking was used to determine if pretreatment with bupropion would alter the acquisition of methamphetamine self-administration. During acquisition, rats were given saline or bupropion (30 or 60 mg/kg, IP) 5 min before a 60-min session. For the first 8 days, each response on the active lever produced an infusion of methamphetamine (0.025 mg/kg). Responding on the inactive lever had no programmed consequence. This FR1 schedule was then increased to an FR3 for 4 more days. In a parallel study, the identical procedures were used to test the impact of bupropion on sucrose-maintained responding. Bupropion pretreatment decreased the number of methamphetamine infusions and sucrose deliveries earned on an FR1 and FR3. However, bupropion pretreatment only delayed discrimination between the active and inactive levers in the methamphetamine self-administration rats. Discrimination between active and inactive levers was acquired in all groups in the sucrose experiment regardless of pretreatment condition. Combined, these results suggest that bupropion has a more general effect within the appetitive/reward system of the brain rather than having complete specificity for methamphetamine. PMID:18329085

The adverse health effects of synthetic cannabinoids with emphasis on psychosis-like effects.

PubMed

van Amsterdam, Jan; Brunt, Tibor; van den Brink, Wim

2015-03-01

Cannabis use is associated with an increased risk of psychosis in vulnerable individuals. Cannabis containing high levels of the partial cannabinoid receptor subtype 1 (CB1) agonist tetrahydrocannabinol (THC) is associated with the induction of psychosis in susceptible subjects and with the development of schizophrenia, whereas the use of cannabis variants with relatively high levels of cannabidiol (CBD) is associated with fewer psychotic experiences. Synthetic cannabinoid receptor agonists (SCRAs) are full agonists and often more potent than THC. Moreover, in contrast to natural cannabis, SCRAs preparations contain no CBD so that these drugs may have a higher psychosis-inducing potential than cannabis. This paper reviews the general toxicity profile and the adverse effects of SCRAs with special emphasis on their psychosis-inducing risk. The review shows that, compared with the use of natural cannabis, the use of SCRAs may cause more frequent and more severe unwanted negative effects, especially in younger, inexperienced users. Psychosis and psychosis-like conditions seem to occur relatively often following the use of SCRAs, presumably due to their high potency and the absence of CBD in the preparations. Studies on the relative risk of SCRAs compared with natural cannabis to induce or evoke psychosis are urgently needed. © The Author(s) 2015.

Striatal dopamine release in vivo following neurotoxic doses of methamphetamine and effect of the neuroprotective drugs, chlormethiazole and dizocilpine.

PubMed

Baldwin, H A; Colado, M I; Murray, T K; De Souza, R J; Green, A R

1993-03-01

1. Administration to rats of methamphetamine (15 mg kg-1, i.p.) every 2 h to a total of 4 doses resulted in a neurotoxic loss of striatal dopamine of 36% and of 5-hydroxytryptamine (5-HT) in the cortex (43%) and hippocampus (47%) 3 days later. 2. Administration of chlormethiazole (50 mg kg-1, i.p.) 15 min before each dose of methamphetamine provided complete protection against the neurotoxic loss of monoamines while administration of dizocilpine (1 mg kg-1, i.p.) using the same dose schedule provided substantial protection. 3. Measurement of dopamine release in the striatum by in vivo microdialysis revealed that methamphetamine produced an approximate 7000% increase in dopamine release after the first injection. The enhanced release response was somewhat diminished after the third injection but still around 4000% above baseline. Dizocilpine (1 mg kg-1, i.p.) did not alter this response but chlormethiazole (50 mg kg-1, i.p.) attenuated the methamphetamine-induced release by approximately 40%. 4. Dizocilpine pretreatment did not influence the decrease in the dialysate concentration of the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) produced by administration of methamphetamine while chlormethiazole pretreatment decreased the dialysate concentration of these metabolites still further. 5. The concentration of dopamine in the dialysate during basal conditions increased modestly during the course of the experiment. This increase did not occur in chlormethiazole-treated rats. HVA concentrations were unaltered by chlormethiazole administration. 6. Chlormethiazole (100-1000 microM) did not alter methamphetamine (100 microM) or K+ (35 mM)-evoked release of endogenous dopamine from striatal prisms in vitro. 7. Several NMDA antagonists prevent methamphetamine-induced neurotoxicity; however chlormethiazole is not an NMDA antagonist. Inhibition of striatal dopamine function prevents methamphetamine-induced toxicity of both dopamine and 5

Effect of the Novel Positive Allosteric Modulator of Metabotropic Glutamate Receptor 2 AZD8529 on Incubation of Methamphetamine Craving After Prolonged Voluntary Abstinence in a Rat Model.

PubMed

Caprioli, Daniele; Venniro, Marco; Zeric, Tamara; Li, Xuan; Adhikary, Sweta; Madangopal, Rajtarun; Marchant, Nathan J; Lucantonio, Federica; Schoenbaum, Geoffrey; Bossert, Jennifer M; Shaham, Yavin

2015-10-01

Cue-induced methamphetamine craving increases after prolonged forced (experimenter-imposed) abstinence from the drug (incubation of methamphetamine craving). Here, we determined whether this incubation phenomenon would occur under conditions that promote voluntary (self-imposed) abstinence. We also determined the effect of the novel metabotropic glutamate receptor 2 positive allosteric modulator, AZD8529, on incubation of methamphetamine craving after forced or voluntary abstinence. We trained rats to self-administer palatable food (6 sessions) and then to self-administer methamphetamine under two conditions: 12 sessions (9 hours/day) or 50 sessions (3 hours/day). We then assessed cue-induced methamphetamine seeking in extinction tests after 1 or 21 abstinence days. Between tests, the rats underwent either forced abstinence (no access to the food- or drug-paired levers) or voluntary abstinence (achieved via a discrete choice procedure between methamphetamine and palatable food; 20 trials per day) for 19 days. We also determined the effect of subcutaneous injections of AZD8529 (20 and 40 mg/kg) on cue-induced methamphetamine seeking 1 day or 21 days after forced or voluntary abstinence. Under both training and abstinence conditions, cue-induced methamphetamine seeking in the extinction tests was higher after 21 abstinence days than after 1 day (incubation of methamphetamine craving). AZD8529 decreased cue-induced methamphetamine seeking on day 21 but not day 1 of forced or voluntary abstinence. We introduce a novel animal model to study incubation of drug craving and cue-induced drug seeking after prolonged voluntary abstinence, mimicking the human condition of relapse after successful contingency management treatment. Our data suggest that positive allosteric modulators of metabotropic glutamate receptor 2 should be considered for relapse prevention. Published by Elsevier Inc.

METHAMPHETAMINE-INDUCED NEUROTOXICITY DISRUPTS NATURALLY OCCURRING PHASIC DOPAMINE SIGNALING

PubMed Central

Howard, Christopher D.; Daberkow, David P.; Ramsson, Eric S.; Keefe, Kristen A.; Garris, Paul A.

2013-01-01

Methamphetamine (METH) is a highly addictive drug that is also neurotoxic to central dopamine (DA) systems. Although striatal DA depletions induced by METH are associated with behavioral and cognitive impairments, the link between these phenomena remains poorly understood. Previous work in both METH-pretreated animals and the 6-hydroxydopamine model of Parkinson’s disease suggests that a disruption of phasic DA signaling, which is important for learning and goal-directed behavior, may be such a link. However, prior studies used electrical stimulation to elicit phasic-like DA responses and were also performed under anesthesia, which alters DA neuron activity and presynaptic function. Here we investigated the consequences of METH-induced DA terminal loss on both electrically evoked phasic-like DA signals and so-called “spontaneous” phasic DA transients measured by voltammetry in awake rats. Not ostensibly attributable to discrete stimuli, these sub-second DA changes may play a role in enhancing reward-cue associations. METH-pretreatment reduced tissue DA content in the dorsomedial striatum and nucleus accumbens by ~55%. Analysis of phasic-like DA responses elicited by reinforcing stimulation revealed that METH pretreatment decreased their amplitude and underlying mechanisms for release and uptake to a similar degree as DA content in both striatal subregions. Most importantly, characteristics of DA transients were altered by METH-induced DA terminal loss, with amplitude and frequency decreased and duration increased. These results demonstrate for the first time that denervation of DA neurons alters naturally occurring DA transients and are consistent with diminished phasic DA signaling as a plausible mechanism linking METH-induced striatal DA depletions and cognitive deficits. PMID:23574406

Effects of D2 or combined D1/D2 receptor antagonism on the methamphetamine-induced one-trial and multi-trial behavioral sensitization of preweanling rats

PubMed Central

Mohd-Yusof, Alena; Veliz, Ana; Rudberg, Krista N.; Stone, Michelle J.; Gonzalez, Ashley E.; McDougall, Sanders A.

2015-01-01

Rationale There is suggestive evidence that the neural mechanisms mediating one-trial and multi-trial behavioral sensitization differ, especially when the effects of various classes of dopamine (DA) agonists are examined. Objective The purpose of the present study was to determine the role of the D2 receptor for the induction of one-trial and multi-trial methamphetamine sensitization in preweanling rats. Methods In a series of experiments, rats were injected with saline or raclopride (a selective D2 receptor antagonist), either alone or in combination with SCH23390 (a selective D1 receptor antagonist), 15 min prior to treatment with the indirect DA agonist methamphetamine. Acute control groups were given two injections of saline. This pretreatment regimen occurred on either postnatal days (PD) 13–16 (multi-trial) or PD 16 (one-trial). On PD 17, rats were challenged with methamphetamine and locomotor sensitization was determined. Results Blockade of D2 or D1/D2 receptors reduced or prevented, respectively, the induction of multi-trial methamphetamine sensitization in young rats, while the same manipulations had minimal effects on one-trial behavioral sensitization. Conclusions DA antagonist treatment differentially affected the methamphetamine-induced sensitized responding of preweanling rats depending on whether a one-trial or multi-trial procedure was used. The basis for this effect is uncertain, but there was some evidence that repeated DA antagonist treatment caused nonspecific changes that produced a weakened sensitized response. Importantly, DA antagonist treatment did not prevent the one-trial behavioral sensitization of preweanling rats. The latter result brings into question whether DA receptor stimulation is necessary for the induction of psychostimulant-induced behavioral sensitization during early ontogeny. PMID:26650612

Physiological and subjective effects of acute intranasal methamphetamine during extended-release alprazolam maintenance.

PubMed

Lile, Joshua A; Stoops, William W; Glaser, Paul E A; Hays, Lon R; Rush, Craig R

2011-12-15

Medications development for methamphetamine dependence is ongoing, but no widely accepted, effective pharmacotherapy has been identified. Previous studies have demonstrated neurobiological perturbations to central GABA(A) activity following chronic stimulant use, and that positive modulation of GABA(A) receptors attenuates the neurochemical and behavioral response to stimulant drugs such as methamphetamine. Therefore, GABA(A) modulators could be useful as pharmacotherapies for stimulant-use disorders. This study tested the hypothesis that intranasal methamphetamine would be safe and well tolerated during maintenance on extended-release alprazolam (XR), and that the effects of methamphetamine would be attenuated. Eight non-treatment-seeking, stimulant-dependent individuals completed an inpatient experiment in which ascending doses of intranasal methamphetamine (0, 5, 10, 20 and 30 mg) were administered after four days of alprazolam XR maintenance (0 and 1mg/day). Intranasal methamphetamine produced prototypical effects (e.g., increased positive subjective ratings and elevated cardiovascular signs). The combination of intranasal methamphetamine and alprazolam XR was safe and well tolerated. Alprazolam XR produced small, but orderly, reductions in some of the subjective effects of methamphetamine, and performance impairment. The present results demonstrate that methamphetamine use during alprazolam XR treatment would not pose a significant safety risk. Given the potential of GABA(A) positive modulators to manage certain aspects of stimulant abuse and dependence (i.e., drug-induced seizures, anxiety and stress), but the relatively small impact on the acute abuse-related effects of methamphetamine observed here, additional research with GABA(A) positive modulators is warranted, but should consider their use as an adjunct component of combination behavioral and/or drug treatment. Copyright © 2011. Published by Elsevier Ireland Ltd.

Cholecystokinin-8 inhibits methamphetamine-induced neurotoxicity via an anti-oxidative stress pathway.

PubMed

Wen, Di; An, Meiling; Gou, Hongyan; Liu, Xia; Liu, Li; Ma, Chunling; Cong, Bin

2016-12-01

As a powerful addictive psychostimulant drug, coupled with its neurotoxicity, methamphetamine (METH) abuse may lead to long-lasting abnormalities in brain structure and function. We found that pretreatment of cholecystokinin-8 (CCK-8) inhibited METH-induced brain cellular dopaminergic (DA) damage in the striatum and substantia nigra, and related behavioural deficits and hyperthermia. However, the mechanism of CCK-8 action on METH-induced toxicity is not clear. The aim of this study was to explore whether the possible protective effect of CCK-8 on METH-induced neurotoxicity involved anti-oxidative stress mechanisms. The subtypes of CCK receptors mediating the regulatory action of CCK-8 were also investigated. The present results revealed that CCK-8 dose-dependently inhibited METH-induced cytotoxic effect by activating the CCK2 receptor subtype in PC12 cells and CCK2 receptor stable transfected-HEK293 cells. Pre-treatment of CCK-8 before METH stimulation significantly attenuated the generation of reactive oxygen species and NADPH oxidase activation in PC12 cells. In conclusion, our study demonstrated a protective effect of CCK-8 on METH-induced neurotoxicity in vitro and suggested that a possible mechanism of this action was dependent on the activation of the CCK2 receptor to reduce the neurotoxicity and oxidative stress induced by METH stimulation. Copyright © 2016 Elsevier B.V. All rights reserved.

Rating the severity and character of transient cocaine-induced delusions and hallucinations with a new instrument, the Scale for Assessment of Positive Symptoms for Cocaine-Induced Psychosis (SAPS-CIP).

PubMed

Cubells, Joseph F; Feinn, Richard; Pearson, Deborah; Burda, Jeffrey; Tang, Yilang; Farrer, Lindsay A; Gelernter, Joel; Kranzler, Henry R

2005-10-01

Cocaine can induce transient psychotic symptoms. We examined the phenomenology of such cocaine-induced psychosis (CIP) using a modified version of the Scale for Assessment of Positive Symptoms (SAPS), a well-validated instrument for the assessment of schizophrenic psychosis. We developed a new instrument, the Scale for Assessment of Positive Symptoms for Cocaine-Induced Psychosis (SAPS-CIP), based on the well-validated SAPS. We interviewed 243 unrelated cocaine-dependent adults using both the SAPS-CIP and an instrument for the identification of cocaine-induced paranoia, the Cocaine Experience Questionnaire (CEQ). One hundred and eighty-one (75%) of the subjects endorsed CIP using the CEQ. With the SAPS-CIP, hallucination (HAL) and delusion (DEL) scores correlated strongly, and the DEL domain showed excellent concurrent validity with the CEQ. We observed significant positive correlations, respectively, between severity of HAL and DEL, and lifetime number of episodes of cocaine use, and negative correlations with age at onset of cocaine use. The results suggest that CIP consists of transient delusional and hallucinatory symptoms, which tend to occur together and co-vary in severity. It appears that rating cocaine-induced paranoia alone (e.g., with the CEQ) can identify most subjects experiencing CIP. However, the SAPS-CIP is useful for quantifying the severity of CIP according to operational criteria. Our data provide additional evidence that CIP is a sensitizing response.

AMPA Receptor Plasticity in Accumbens Core Contributes to Incubation of Methamphetamine Craving.

PubMed

Scheyer, Andrew F; Loweth, Jessica A; Christian, Daniel T; Uejima, Jamie; Rabei, Rana; Le, Tuan; Dolubizno, Hubert; Stefanik, Michael T; Murray, Conor H; Sakas, Courtney; Wolf, Marina E

2016-11-01

The incubation of cue-induced drug craving in rodents provides a model of persistent vulnerability to craving and relapse in human addicts. After prolonged withdrawal, incubated cocaine craving depends on strengthening of nucleus accumbens (NAc) core synapses through incorporation of Ca 2+ -permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (CP-AMPARs). Through metabotropic glutamate receptor 1 (mGluR1)-mediated synaptic depression, mGluR1 positive allosteric modulators remove CP-AMPARs from these synapses and thereby reduce cocaine craving. This study aimed to determine if similar plasticity accompanies incubation of methamphetamine craving. Rats self-administered saline or methamphetamine under extended-access conditions. Cue-induced seeking tests demonstrated incubation of methamphetamine craving. After withdrawal periods ranging from 1 to >40 days, rats underwent one of the following procedures: 1) whole-cell patch clamp recordings to characterize AMPAR transmission, 2) intra-NAc core injection of the CP-AMPAR antagonist 1-naphthyl acetyl spermine followed by a seeking test, or 3) systemic administration of a mGluR1 positive allosteric modulator followed by a seeking test. Incubation of methamphetamine craving was associated with CP-AMPAR accumulation in NAc core, and both effects were maximal after ~1 week of withdrawal. Expression of incubated craving was decreased by intra-NAc core 1-naphthyl acetyl spermine injection or systemic mGluR1 positive allosteric modulator administration. These results are the first to demonstrate a role for the NAc in the incubation of methamphetamine craving and describe adaptations in synaptic transmission associated with this model. They establish that incubation of craving and associated CP-AMPAR plasticity occur much more rapidly during withdrawal from methamphetamine compared with cocaine. However, a common mGluR1-based therapeutic strategy may be helpful for recovering cocaine and methamphetamine

Mind Over Matter: Methamphetamine

MedlinePlus

... If a Person Uses Methamphetamine for a Long Time? Scientists are using brain imaging techniques, like positron emission tomography (called PET for short), to study the brains of human Methamphetamine users. They have ...

Cognitive deficits associated with combined HIV gp120 expression and chronic methamphetamine exposure in mice.

PubMed

Kesby, James P; Markou, Athina; Semenova, Svetlana

2015-01-01

Methamphetamine abuse is common among individuals infected by human immunodeficiency virus (HIV). Neurocognitive outcomes tend to be worse in methamphetamine users with HIV. However, it is unclear whether discrete cognitive domains are susceptible to impairment after combined HIV infection and methamphetamine abuse. The expression of HIV/gp120 protein induces neuropathology in mice similar to HIV-induced pathology in humans. We investigated the separate and combined effects of methamphetamine exposure and gp120 expression on cognitive function in transgenic (gp120-tg) and control mice. The mice underwent an escalating methamphetamine binge regimen and were tested in novel object/location recognition, object-in-place recognition, and Barnes maze tests. gp120 expression disrupted performance in the object-in-place test (i.e. similar time spent with all objects, regardless of location), indicating deficits in associative recognition memory. gp120 expression also altered reversal learning in the Barnes maze, suggesting impairments in executive function. Methamphetamine exposure impaired spatial strategy in the Barnes maze, indicating deficits in spatial learning. Methamphetamine-exposed gp120-tg mice had the lowest spatial strategy scores in the final acquisition trials in the Barnes maze, suggesting greater deficits in spatial learning than all of the other groups. Although HIV infection involves interactions between multiple proteins and processes, in addition to gp120, our findings in gp120-tg mice suggest that humans with the dual insult of HIV infection and methamphetamine abuse may exhibit a broader spectrum of cognitive deficits than those with either factor alone. Depending on the cognitive domain, the combination of both insults may exacerbate deficits in cognitive performance compared with each individual insult. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

The neurotoxic effects of methamphetamine on 5-hydroxytryptamine and dopamine in brain: evidence for the protective effect of chlormethiazole.

PubMed

Green, A R; De Souza, R J; Williams, J L; Murray, T K; Cross, A J

1992-04-01

Studies were undertaken in mice and rats on the neurotoxic effects of methamphetamine on dopaminergic and 5-hydroxytryptaminergic neurones in the brain and the neuroprotective action of chlormethiazole. In initial studies, mice were injected with methamphetamine (5 mg/kg, i.p.) at 2 hr intervals, to a total of 4 times. This procedure produced a 66% loss of striatal dopamine and a 50% loss of tyrosine hydroxylase activity 3 days later. Chlormethiazole (50 mg/kg, i.p.), given 15 min before each dose of methamphetamine, totally prevented the methamphetamine-induced loss of tyrosine hydroxylase activity and partly prevented the loss of dopamine. Phencyclidine (20 mg/kg, i.p.), given in place of chlormethiazole, also prevented the loss of tyrosine hydroxylase. Administration to rats of 4 doses of methamphetamine (15 mg/kg, i.p.) at 3 hr intervals resulted in a 75% loss of striatal dopamine 3 days later and a similar loss of 5-HT and 5-HIAA in cortex and hippocampus. Chlormethiazole (50 mg/kg, i.p.), given 15 min before each injection of methamphetamine, protected against the loss of dopamine and indoleamine content, in the respective regions. Pentobarbital (25 mg/kg, i.p.) also provided substantial protection but diazepam (2.5 mg/kg, i.p.) was without effect. Confirming earlier studies, dizocilpine (1 mg/kg) also provided substantial protection against the methamphetamine-induced neurotoxicity. Preliminary data indicated that chlormethiazole was not neuroprotective because of a hypothermic action. These data therefore demonstrate that chlormethiazole is an effective neuroprotective agent against methamphetamine-induced neurotoxicity and extend the evidence for the possible value of this drug in preventing neurodegeneration.

Protection against methamphetamine-induced neurotoxicity to neostriatal dopaminergic neurons by adenosine receptor activation.

PubMed

Delle Donne, K T; Sonsalla, P K

1994-12-01

Methamphetamine (METH)-induced neurotoxicity to nigrostriatal dopaminergic neurons in experimental animals appears to have a glutamatergic component because blockade of N-methyl-D-aspartate receptors prevents the neuropathologic consequences. Because adenosine affords neuroprotection against various forms of glutamate-mediated neuronal damage, the present studies were performed to investigate whether adenosine plays a protective role in METH-induced toxicity. METH-induced decrements in neostriatal dopamine content and tyrosine hydroxylase activity in mice were potentiated by concurrent treatment with caffeine, a nonselective adenosine antagonist that blocks both A1 and A2 adenosine receptors. In contrast, chronic treatment of mice with caffeine through their drinking water for 4 weeks, which increased the number of adenosine A1 receptors in the neostriatum and frontal cortex, followed by drug washout, prevented the neurochemical changes produced by the treatment of mice with METH treatment. In contrast, this treatment did not prevent 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine-induced dopaminergic neurotoxicity. Furthermore, concurrent administration of cyclopentyladenosine, an adenosine A1 receptor agonist, attenuated the METH-induced neurochemical changes. This protection by cyclopentyladenosine was blocked by cyclopentyltheophylline, an A1 receptor antagonist. These results indicate that activation of A1 receptors can protect against METH-induced neurotoxicity in mice.

Pharmacologic Treatment with GABAB Receptor Agonist of Methamphetamine-Induced Cognitive Impairment in Mice

PubMed Central

Mizoguchi, Hiroyuki; Yamada, Kiyofumi

2011-01-01

Methamphetamine (METH) is a highly addictive drug, and addiction to METH has increased to epidemic proportions worldwide. Chronic use of METH causes psychiatric symptoms, such as hallucinations and delusions, and long-term cognitive deficits, which are indistinguishable from paranoid schizophrenia. The GABA receptor system is known to play a significant role in modulating the dopaminergic neuronal system, which is related to behavioral changes induced by drug abuse. However, few studies have investigated the effects of GABA receptor agonists on cognitive deficits induced by METH. In the present review, we show that baclofen, a GABA receptor agonist, is effective in treating METH-induced impairment of object recognition memory and prepulse inhibition (PPI) of the startle reflex, a measure of sensorimotor gating in mice. Acute and repeated treatment with METH induced a significant impairment of PPI. Furthermore, repeated but not acute treatment of METH resulted in a long-lasting deficit of object recognition memory. Baclofen, a GABAB receptor agonist, dose-dependently ameliorated the METH-induced PPI deficits and object recognition memory impairment in mice. On the other hand, THIP, a GABAA receptor agonist, had no effect on METH-induced cognitive deficits. These results suggest that GABAB receptors may constitute a putative new target in treating cognitive deficits in chronic METH users. PMID:21886573

alpha-Phenyl-N-tert-butyl nitrone attenuates methamphetamine-induced depletion of striatal dopamine without altering hyperthermia.

PubMed

Cappon, G D; Broening, H W; Pu, C; Morford, L; Vorhees, C V

1996-10-01

Methamphetamine (MA) administration to adult rats (4 x 10 mg/kg s.c.) induces neurotoxicity predominately characterized by a persistent reduction of neostriatal dopamine (DA) content. Hyperthermia following MA administration potentiates the resulting DA depletion. DA-derived free radicals are postulated to be a mechanism through which MA-induced neurotoxicity is produced. The spin trapping agent PBN reacts with free radicals to form nitroxyl adducts, thereby preventing damaging free radical reactions with cellular substrates. MA with saline pretreatment (Sal-MA) reduced neostriatal DA by 55% (P < 0.01 vs. Sal-Sal). MA with PBN pretreatment (PBN-MA) at 36 or 60 mg/kg reduced neostriatal DA by 36 and 22%, respectively (P < 0.05 and P < 0.01 vs Sal-MA) indicating partial protection. PBN pretreatment did not alter MA-induced hyperthermia. Thus, PBN does not attenuate MA-induced neurotoxicity by reducing MA-induced hyperthermia. These results support a role for free radicals in the generation of MA-induced dopaminergic neurotoxicity.

Protective effects of pseudoginsenoside-F11 on methamphetamine-induced neurotoxicity in mice.

PubMed

Wu, Chun Fu; Liu, Yan Li; Song, Ming; Liu, Wen; Wang, Jin Hui; Li, Xian; Yang, Jing Yu

2003-08-01

In the present study, pseudoginsenoside-F(11) (PF(11)), a saponin that existed in American ginseng, was studied on its protective effect on methamphetamine (MA)-induced behavioral and neurochemical toxicities in mice. MA was intraperitoneally administered at the dose of 10 mg/kg four times at 2-h intervals, and PF(11) was orally administered at the doses of 4 and 8 mg/kg two times at 4-h intervals, 60 min prior to MA administration. The results showed that PF(11) did not significantly influence, but greatly ameliorated, the anxiety-like behavior induced by MA in the light-dark box task. In the forced swimming task, PF(11) significantly shortened the prolonged immobility time induced by MA. In the appetitively motivated T-maze task, PF(11) greatly shortened MA-induced prolonged latency and decreased the error counts. Similar results were also observed in the Morris water maze task. PF(11) significantly shortened the escape latency prolonged by MA. There were significant decreases in the contents of dopamine (DA), 3,4-dihydroxyphenacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoacetic acid (5-HIAA) in the brain of MA-treated mice. PF(11) could partially, but significantly, antagonize MA-induced decreases of DA. The above results demonstrate that PF(11) is effective in protection of MA-induced neurotoxicity and also suggest that natural products, such as ginseng, might be potential candidates for the prevention and treatment of the neurological disorders induced by MA abuse.

Impact of methamphetamine on dopamine neurons in primates is dependent on age: implications for development of Parkinson's disease

PubMed Central

Morrow, Bret A.; Roth, Robert H.; Redmond, D. Eugene; Elsworth, John D.

2011-01-01

Methamphetamine is a CNS stimulant with limited therapeutic indications, but is widely abused. Short-term exposure to higher doses, or long-term exposure to lower doses, of methamphetamine induces lasting damage to nigrostriatal dopamine neurons in man and animals. Strong evidence indicates that the mechanism for this detrimental effect on dopamine neurons involves oxidative stress exerted by reactive oxygen species. This study investigates the relative susceptibility of dopamine neurons in mid-gestation, young, and adult (not aged) monkeys to 4 treatments with methamphetamine over 2 days. Primate dopamine neurons undergo natural cell death at mid-gestation, and we hypothesized that during this event they are particularly vulnerable to oxidative stress. The results indicated that at mid-gestation and in adults, dopamine neurons were susceptible to methamphetamine-induced damage, as indicated by loss of striatal TH immunoreactivity and dopamine concentration. However, dopamine neurons in young animals appeared totally resistant to the treatment, despite this group having higher brain levels of methamphetamine 3 hours after administration than the adults. As a possible explanation for the protection, striatal GDNF levels were elevated in young animals 1-week after treatment, but not in adults following methamphetamine treatment. Implications of these primate studies are: 1) the susceptibility of dopamine neurons at mid-gestation to methamphetamine warns against the risk of exposing pregnant women to the drug or oxidative stressors, and supports the hypothesis of Parkinson's disease being associated with oxidative stress during development, 2) elucidation of the mechanism of resistance of dopamine neurons in the young animals to methamphetamine-induced oxidative stress may provide targets for slowing or preventing age- or disease-related loss of adult nigrostriatal DA neurons, and 3) the increased striatal production of GDNF in young animals, but not in adults, in

Dysregulation of D₂-mediated dopamine transmission in monkeys after chronic escalating methamphetamine exposure.

PubMed

Groman, Stephanie M; Lee, Buyean; Seu, Emanuele; James, Alex S; Feiler, Karen; Mandelkern, Mark A; London, Edythe D; Jentsch, J David

2012-04-25

Compulsive drug-seeking and drug-taking are important substance-abuse behaviors that have been linked to alterations in dopaminergic neurotransmission and to impaired inhibitory control. Evidence supports the notions that abnormal D₂ receptor-mediated dopamine transmission and inhibitory control may be heritable risk factors for addictions, and that they also reflect drug-induced neuroadaptations. To provide a mechanistic explanation for the drug-induced emergence of inhibitory-control deficits, this study examined how a chronic, escalating-dose regimen of methamphetamine administration affected dopaminergic neurochemistry and cognition in monkeys. Dopamine D₂-like receptor and dopamine transporter (DAT) availability and reversal-learning performance were measured before and after exposure to methamphetamine (or saline), and brain dopamine levels were assayed at the conclusion of the study. Exposure to methamphetamine reduced dopamine D₂-like receptor and DAT availability and produced transient, selective impairments in the reversal of a stimulus-outcome association. Furthermore, individual differences in the change in D₂-like receptor availability in the striatum were related to the change in response to positive feedback. These data provide evidence that chronic, escalating-dose methamphetamine administration alters the dopamine system in a manner similar to that observed in methamphetamine-dependent humans. They also implicate alterations in positive-feedback sensitivity associated with D₂-like receptor dysfunction as the mechanism by which inhibitory control deficits emerge in stimulant-dependent individuals. Finally, a significant degree of neurochemical and behavioral variation in response to methamphetamine was detected, indicating that individual differences affect the degree to which drugs of abuse alter these processes. Identification of these factors ultimately may assist in the development of individualized treatments for substance dependence.

Taurine protects methamphetamine-induced developmental angiogenesis defect through antioxidant mechanism

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

Shao, Xue; Hu, Zhengtao; Hu, Chunyan

Investigations have characterized addictive drug-induced developmental cardiovascular malformation in human, non-human primate and rodent. However, the underlying mechanism of malformation caused by drugs during pregnancy is still largely unknown, and preventive and therapeutic measures have been lacking. Using {sup 1}H NMR spectroscopy, we profiled the metabolites from human embryo endothelial cells exposed to methamphetamine (METH) and quantified a total of 226 peaks. We identified 11 metabolites modified robustly and found that taurine markedly increased. We then validated the hypothesis that this dramatic increase in taurine could attribute to its effect in inhibiting METH-induced developmental angiogenesis defect. Taurine supplement showed amore » more significant potential than other metabolites in protecting against METH-induced injury in endothelial cells. Taurine strongly attenuated METH-induced inhibition of proliferation and migration in endothelial cells. Furthermore, death rate and vessel abnormality of zebrafish embryos treated with METH were greatly reversed by taurine. In addition, taurine supplement caused a rapid decrease in reactive oxygen species generation and strongly attenuated the excitable arise of antioxidase activities in the beginning of METH exposure prophase. Dysregulations of NF-κB, p-ERK as well as Bax, which reflect apoptosis, cell cycle arrest and oxidative stress in vascular endothelium, were blocked by taurine. Our results provide the first evidence that taurine prevents METH-caused developmental angiogenesis defect through antioxidant mechanism. Taurine could serve as a potential therapeutic or preventive intervention of developmental vascular malformation for the pregnant women with drug use. Highlights: ► Metabonomics findings. ► Abnormal development. ► Dysregulations of key proteins.« less

Methamphetamine-induced neuronal necrosis: the role of electrographic seizure discharges

PubMed Central

Fujikawa, Denson G.; Pais, Emil S.; Aviles, Ernesto R.; Hsieh, Kung-Chiao; Bashir, Muhammad Tariq

2016-01-01

We have evidence that methamphetamine (METH)-induced neuronal death is morphologically necrotic, not apoptotic, as is currently believed, and that electrographic seizures may be responsible. We administered 40 mg/kg i.p. to 12 male C57BL/6 mice and monitored EEGs continuously and rectal temperatures every 15 min, keeping rectal temperatures <41.0 °C. Seven of the 12 mice had repetitive electrographic seizure discharges (RESDs) and 5 did not. The RESDs were often not accompanied by behavioral signs of seizures–i.e., they were often not accompanied by clonic forelimb movements. The 7 mice with RESDs had acidophilic neurons (the H&E light-microscopic equivalent of necrotic neurons by ultrastructural examination) in all of 7 brain regions (hippocampal CA1, CA2, CA3 and hilus, amygdala, piriform cortex and entorhinal cortex), the same brain regions damaged following generalized seizures, 24 h after METH administration. The 5 mice without RESDs had a few acidophilic neurons in 4 of the 7 brain regions, but those with RESDs had significantly more in 6 of the 7 brain regions. Maximum rectal temperatures were comparable in mice with and without RESDs, so that cannot explain the difference between the two groups with respect to METH-induced neuronal death. Our data show that METH-induced neuronal death is morphologically necrotic, that EEGs must be recorded to detect electrographic seizure activity in rodents without behavioral evidence of seizures, and that RESDs may be responsible for METH-induced neuronal death. PMID:26562800

Methamphetamine induces autophagy and apoptosis in a mesencephalic dopaminergic neuronal culture model: role of cathepsin-D in methamphetamine-induced apoptotic cell death.

PubMed

Kanthasamy, Arthi; Anantharam, V; Ali, Syed F; Kanthasamy, A G

2006-08-01

Autophagy is a phylogenetically conserved process that plays a critical role in the degradation of oxidatively damaged proteins and organelle turnover. The role of oxidative stress and apoptosis in methamphetamine (METH)-induced neurotoxicity is well known; however, the potential contribution of autophagy to METH-induced oxidative damage in dopaminergic neuronal systems remains unclear. The goals of the present article were twofold: (a) to develop an in vitro dopaminergic cell culture model to study cellular and molecular mechanisms underlying METH-induced autophagy and apoptosis, and (b) to determine whether lysosomal protease cathepsin-D activation, resulting from the loss of lysosomal membrane integrity, contributes to METH-induced apoptosis. To accomplish these goals, we characterized morphological and biochemical changes in an immortalized mesencephalic dopaminergic neuronal cell line (N27 cells) following treatment with METH. Exposure of METH (2 mM) to N27 cells resulted in the appearance of cytoplasmic vacuolar structures reminiscent of autophagic vacuoles within 3 h. In order to ascertain the identity of the vacuolar structures that are formed following METH exposure, immunohistochemical staining for markers of autophagy were performed. LAMP 2, a classical marker of autophagolysosomes, revealed an extensive punctuate pattern of distribution on the vacuolar membrane surface, with exclusive localization in the cytoplasm. Additionally, using DNA fragmentation analysis we showed a dose-dependent increase in fragmented DNA in METH treated N27 cells. Since METH-induced autophagy preceded DNA fragmentation, we tested whether dysfunction of the autophagolysosomal system contributes to nuclear damage. Immunofluorescence studies with cathepsin-d demonstrated a granular pattern of staining in untreated cells, whereas an increased cathepsin- D immunoreactivity with a globular pattern of staining was observed in METH-treated cells. Nevertheless, blockade of cathepsin

High ambient temperature increases intravenous methamphetamine self-administration on fixed and progressive ratio schedules in rats.

PubMed

Cornish, Jennifer L; Clemens, Kelly J; Thompson, Murray R; Callaghan, Paul D; Dawson, Bronwyn; McGregor, Iain S

2008-01-01

Methamphetamine is a drug that is often consumed at dance parties or nightclubs where the ambient temperature is high. The present study determined whether such high ambient temperatures alter intravenous methamphetamine self-administration in the rat. Male Hooded Wistar rats were trained to self-administer intravenous methamphetamine (0.1 mg/kg/infusion) under a fixed ratio 1 (FR1) or progressive ratio (PR) schedule of reinforcement at an ambient temperature of 23 +/- 1 degrees C. They were then given their daily self-administration session at a raised ambient temperature of 30 +/- 1 degrees C. Methamphetamine self-administration was increased at 30 degrees C under both FR1 and PR reinforcement schedules, with the latter effect indicating that heat enhances the motivation to obtain methamphetamine. High temperatures did not alter self-administration of the D1 receptor agonist SKF 82958 in methamphetamine-experienced rats suggesting some specificity in the methamphetamine effect. When rats were given access to drink isotonic saline solution during methamphetamine self-administration sessions they drank much more solution at 30 degrees C than 23 degrees C. However, availability of isotonic saline to drink did not alter the heat-induced facilitation of methamphetamine self-administration (PR schedule) indicating that the heat effect does not simply reflect increased motivation for intravenous fluids. Hyperthermia was evident in rats self-administering methamphetamine at high ambient temperatures and fluid consumption did not prevent this effect. Heat did not affect blood levels of methamphetamine, or its principal metabolite amphetamine indicating that the facilitatory effect of heat did not reflect altered methamphetamine pharmacokinetics. Overall, these results show that high ambient temperatures increase the reinforcing efficacy of methamphetamine and encourage higher levels of drug intake.

Methamphetamine and HIV-1 gp120 Effects on Lipopolysaccharide Stimulated Matrix Metalloproteinase-9 Production by Human Monocyte-Derived Macrophages

PubMed Central

Reynolds, Jessica L.; Mahajan, Supriya D.; Aalinkeel, Ravikumar; Nair, Bindukumar; Sykes, Donald E.; Schwartz, Stanley A.

2011-01-01

Monocytes/macrophages are a primary source of human immunodeficiency virus (HIV-1) in the central nervous system (CNS). Macrophages infected with HIV-1 produce a plethora of factors, including matrix metalloproteinase-9 (MMP-9) that may contribute to the development of HIV-1-associated neurocognitive disorders (HAND). MMP-9 plays a pivotal role in the turnover of the extracellular matrix (ECM) and functions to remodel cellular architecture. We have investigated the role of methamphetamine and HIV-1 gp120 in the regulation of lipopolysaccaride (LPS) induced-MMP-9 production in monocyte-derived macrophages (MDM). Here, we show that LPS-induced MMP-9 gene expression and protein secretion are potentiated by incubation with methamphetamine alone and gp120 alone. Further, concomitant incubation with gp120 and methamphetamine potentiated LPS-induced MMP-9 expression and biological activity in MDM. Collectively methamphetamine and gp120 effects on MMPs may modulate remodeling of the extracellular environment enhancing migration of monocytes/macrophages to the CNS. PMID:21425912

Ghrelin precursor gene polymorphism and methamphetamine dependence in the Korean population.

PubMed

Yoon, Su-Jung; Pae, Chi-Un; Lee, Heejin; Choi, Bomoon; Kim, Tae-Suk; Lyoo, In Kyoon; Kwon, Do-Hoon; Kim, Dai-Jin

2005-12-01

Ghrelin is a recently isolated brain-gut peptide that has growth hormone-releasing and appetite-inducing activities. Several recent studies have suggested that ghrelin plays a major role in the pathophysiology of drug-seeking behavior and anxiety. Therefore, we assessed the effect of the ghrelin precursor polymorphism on methamphetamine dependence in the Korean population. One hundred and eighteen patients with methamphetamine dependence, according to the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria, and the 144 healthy controls were enrolled in this study. Genotyping for the ghrelin precursor polymorphism was performed by the polymerase chain reaction-restriction fragment length polymorphism-based technique. The genotypic and allelic distributions of the ghrelin precursor polymorphism in the patients with methamphetamine dependence were not significantly different from those of the control subjects. However, the Met72 carriers were associated with the emotional problems of methamphetamine dependence. The patients with the Met72 allele were more depressed and anxious than the homozygous patients with the wild Leu72 allele. The present study suggests that the ghrelin precursor polymorphism may not confer a susceptibility to the development of methamphetamine dependence in the Korean population. However, the Leu72Met polymorphism could have a potential role in the emotional problems that are associated with this disease.

Association of dopamine transporter reduction with psychomotor impairment in methamphetamine abusers.

PubMed

Volkow, N D; Chang, L; Wang, G J; Fowler, J S; Leonido-Yee, M; Franceschi, D; Sedler, M J; Gatley, S J; Hitzemann, R; Ding, Y S; Logan, J; Wong, C; Miller, E N

2001-03-01

Methamphetamine is a popular and highly addictive drug of abuse that has raised concerns because it has been shown in laboratory animals to be neurotoxic to dopamine terminals. The authors evaluated if similar changes occur in humans and assessed if they were functionally significant. Positron emission tomography scans following administration of [(11)C]d-threo-methylphenidate (a dopamine transporter ligand) measured dopamine transporter levels (a marker of dopamine cell terminals) in the brains of 15 detoxified methamphetamine abusers and 18 comparison subjects. Neuropsychological tests were also performed to assess motor and cognitive function. Methamphetamine abusers showed significant dopamine transporter reduction in the striatum (mean differences of 27.8% in the caudate and 21.1% in the putamen) relative to the comparison subjects; this reduction was evident even in abusers who had been detoxified for at least 11 months. Dopamine transporter reduction was associated with motor slowing and memory impairment. These results provide evidence that methamphetamine at dose levels taken by human abusers of the drug leads to dopamine transporter reduction that is associated with motor and cognitive impairment. These results emphasize the urgency of alerting clinicians and the public of the long-term changes that methamphetamine can induce in the human brain.

[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

Epileptic peri-ictal psychosis, a reversible cause of psychosis.

PubMed

González Mingot, C; Gil Villar, M P; Calvo Medel, D; Corbalán Sevilla, T; Martínez Martínez, L; Iñiguez Martínez, C; Santos Lasaosa, S; Mauri Llerda, J A

2013-03-01

Epileptic psychoses are categorised as peri-ictal and interictal according to their relationship with the occurrence of seizures. There is a close temporal relationship between peri-ictal psychosis and seizures, and psychosis may present before (preictal), during (ictal) or after seizures (postictal). Epileptic psychoses usually have acute initial and final phases, with a short symptom duration and complete remission with a risk of recurrence. There is no temporal relationship between interictal or chronic psychosis and epileptic seizures. Another type of epileptic psychosis is related to the response to epilepsy treatment: epileptic psychosis caused by the phenomenon of forced normalisation (alternative psychosis), which includes epileptic psychosis secondary to epilepsy surgery. Although combination treatment with antiepileptic and neuroleptic drugs is now widely used to manage this condition, there are no standard treatment guidelines for epileptic psychosis. We present 5 cases of peri-ictal epileptic psychosis in which we observed an excellent response to treatment with levetiracetam. Good control was achieved over both seizures and psychotic episodes. Levetiracetam was used in association with neuroleptic drugs with no adverse effects, and our patients did not require high doses of the latter. Categorising psychotic states associated with epilepsy according to their temporal relationship with seizures is clinically and prognostically useful because it provides important information regarding disease treatment and progression. The treatment of peri-ictal or acute mental disorders is based on epileptic seizure control, while the treatment of interictal or chronic disorders has more in common with managing disorders which are purely psychiatric in origin. In addition to improving the patient's quality of life and reducing disability, achieving strict control over seizures may also prevent the development of interictal psychosis. For this reason, we believe that

Safety and efficacy of varenicline to reduce positive subjective effects produced by methamphetamine in methamphetamine-dependent volunteers

PubMed Central

Verrico, Christopher D.; Mahoney, James J.; Thompson-Lake, Daisy G. Y.; Bennett, Ryan S.; Newton, Thomas F.; De La Garza, Richard

2015-01-01

Methamphetamine use is increasing in the US. Although there are no Food and Drug Administration (FDA)-approved medications for methamphetamine dependence, preclinical and clinical studies suggest that methamphetamine users may benefit from treatments that enhance cholinergic neurotransmission. Consequently, we determined the safety and the efficacy of varenicline treatment, a partial agonist at α4β2 and a full agonist at α7 nicotinic acetylcholine receptors, to reduce positive subjective effects produced by smoked methamphetamine. Additionally, the effects of treatment with varenicline on the cardiovascular and reinforcing effects of methamphetamine were determined. We conducted a double-blind, placebo-controlled, within-subjects trial of varenicline vs. placebo in methamphetamine-dependent volunteers who were not seeking treatment. Participants were randomly assigned to receive one dose of varenicline (0, 1, or 2 mg) po BID, titrated up to the target dose over days 1–7, during each of three separate inpatient phases. Safety measures included the frequency, duration, severity, and relatedness of adverse events reported. Positive subjective effects included ‘Any drug effect’, ‘High’, ‘Good effects’, ‘Stimulated’, and ‘Drug liking’, which were rated by participants before and for 1 h after smoking methamphetamine (0, 10, and 30 mg). There were no serious adverse events and no differences in adverse events reported during the three phases. Varenicline (2 mg) significantly reduced ratings of ‘Any drug effect’ and ‘Stimulated’, as well as attenuated ratings of ‘High’, ‘Drug liking’, and ‘Good effects’, produced by methamphetamine (30 mg). The ability of varenicline to attenuate the positive subjective effects of methamphetamine in the laboratory suggests that varenicline should continue to be explored as a treatment for methamphetamine dependence. PMID:24393456

Intranasal insulin treatment alleviates methamphetamine induced anxiety-like behavior and neuroinflammation.

PubMed

Beirami, Elmira; Oryan, Shahrbanoo; Seyedhosseini Tamijani, Seyedeh Masoumeh; Ahmadiani, Abolhassan; Dargahi, Leila

2017-11-01

Insulin, as a peptide hormone, has recently gained attention for its pro-cognitive, anti-inflammatory and neuroprotective effects in the central nervous system (CNS). Most studies have indicated anxiogenic and neuroinflammatory effects of methamphetamine (MA) and other psychostimulants, even after periods of abstinence. The present study aimed to examine whether intranasal (IN) insulin treatment with high CNS bioavailability and minimal systemic side effects, can reverse the anxiety-like behavior and neuroinflammation induced by repeated MA administration. In male wistar rats, escalating doses of MA (1-10mg/kg, i.p.) were administrated twice a day for 10 consecutive days. IN insulin treatment (0.5IU/day, for 7days after MA discontinuation) attenuated MA-induced anxiety-like behavior in the elevated plus maze task, and significantly decreased the levels of glial cell markers (GFAP and Iba1), pro-inflammatory cytokines (TNF-α and IL-6) as well as COX2 and NF-κB players of neuroinflammation, in the hippocampus of MA-treated animals. These findings introduce insulin as a potential therapeutic approach for the treatment of MA aversive symptoms. Copyright © 2017 Elsevier B.V. All rights reserved.

The role of system Xc- in methamphetamine-induced dopaminergic neurotoxicity in mice.

PubMed

Dang, Duy-Khanh; Shin, Eun-Joo; Tran, Hai-Quyen; Kim, Dae-Joong; Jeong, Ji Hoon; Jang, Choon-Gon; Nah, Seung-Yeol; Sato, Hideyo; Nabeshima, Toshitaka; Yoneda, Yukio; Kim, Hyoung-Chun

2017-09-01

The cystine/glutamate antiporter (system Xc - , Sxc) transports cystine into cell in exchange for glutamate. Since xCT is a specific subunit of Sxc, we employed xCT knockout mice and investigated whether this antiporter affected methamphetamine (MA)-induced dopaminergic neurotoxicity. MA treatment significantly increased striatal oxidative burdens in wild type mice. xCT inhibitor [i.e., S-4-carboxy-phenylglycine (CPG), sulfasalazine] or an xCT knockout significantly protected against these oxidative burdens. MA-induced increases in Iba-1 expression and Iba-1-labeled microglial immunoreactivity (Iba-1-IR) were significantly attenuated by CPG or sulfasalazine administration or xCT knockout. CPG or sulfasalazine significantly attenuated MA-induced TUNEL-positive cell populations in the striatum of Taconic ICR mice. The decrease in excitatory amino acid transporter-2 (or glutamate transporter-1) expression and increase in glutamate release were attenuated by CPG, sulfasalazine or xCT knockout. In addition, CPG, sulfasalazine or xCT knockout significantly protected against dopaminergic loss (i.e., decreases in tyrosine hydroxylase expression and immunoreactivity, and an increase in dopamine turnover rate) induced by MA. However, CPG, sulfasalazine or xCT knockout did not significantly affect the impaired glutathione system [i.e., decrease in reduced glutathione (GSH) and increase in oxidized glutathione (GSSG)] induced by MA. Our results suggest that Sxc mediates MA-induced neurotoxicity via facilitating oxidative stress, microgliosis, proapoptosis, and glutamate-related toxicity. Copyright © 2017 Elsevier Ltd. All rights reserved.

Drug-Induced Psychosis: How to Avoid Star Gazing in Schizophrenia Research by Looking at More Obvious Sources of Light

PubMed Central

Paparelli, Alessandra; Di Forti, Marta; Morrison, Paul D.; Murray, Robin M.

2010-01-01

The prevalent view today is that schizophrenia is a syndrome rather than a specific disease. Liability to schizophrenia is highly heritable. It appears that multiple genetic and environmental factors operate together to push individuals over a threshold into expressing the characteristic clinical picture. One environmental factor which has been curiously neglected is the evidence that certain drugs can induce schizophrenia-like psychosis. In the last 60 years, improved understanding of the relationship between drug abuse and psychosis has contributed substantially to our modern view of the disorder suggesting that liability to psychosis in general, and to schizophrenia in particular, is distributed trough the general population in a similar continuous way to liability to medical disorders such as hypertension and diabetes. In this review we examine the main hypotheses resulting from the link observed between the most common psychotomimetic drugs (lysergic acid diethylamide, amphetamines, cannabis, phencyclidine) and schizophrenia. PMID:21267359

Methamphetamine: Putting the Brakes on Speed

ERIC Educational Resources Information Center

Gettig, Jacob P.; Grady, Sarah E.; Nowosadzka, Izabella

2006-01-01

In only recent history, illicit use of methamphetamine, once isolated to urban areas on the West Coast, has spread into rural areas of the Midwest and southern United States. Although past and current methamphetamine legislation has increased penalties for methamphetamine manufacturers and tightened restrictions on sales of known precursors, the…

Methamphetamine and Parkinson's Disease

PubMed Central

Granado, Noelia; Ares-Santos, Sara; Moratalla, Rosario

2013-01-01

Parkinson's disease (PD) is a neurodegenerative disorder predominantly affecting the elderly. The aetiology of the disease is not known, but age and environmental factors play an important role. Although more than a dozen gene mutations associated with familial forms of Parkinson's disease have been described, fewer than 10% of all cases can be explained by genetic abnormalities. The molecular basis of Parkinson's disease is the loss of dopamine in the basal ganglia (caudate/putamen) due to the degeneration of dopaminergic neurons in the substantia nigra, which leads to the motor impairment characteristic of the disease. Methamphetamine is the second most widely used illicit drug in the world. In rodents, methamphetamine exposure damages dopaminergic neurons in the substantia nigra, resulting in a significant loss of dopamine in the striatum. Biochemical and neuroimaging studies in human methamphetamine users have shown decreased levels of dopamine and dopamine transporter as well as prominent microglial activation in the striatum and other areas of the brain, changes similar to those observed in PD patients. Consistent with these similarities, recent epidemiological studies have shown that methamphetamine users are almost twice as likely as non-users to develop PD, despite the fact that methamphetamine abuse and PD have distinct symptomatic profiles. PMID:23476887

Dysregulation of D2-Mediated Dopamine Transmission in Monkeys after Chronic Escalating Methamphetamine Exposure

PubMed Central

Groman, S.M.; Lee, B.; Seu, E.; James, A.S.; Feiler, K.; Mandelkern, M.A.; London, E.D.; Jentsch, J.D.

2012-01-01

Compulsive drug-seeking and drug-taking are important substance-abuse behaviors that have been linked to alterations in dopaminergic neurotransmission and to impaired inhibitory control. Evidence supports the notions that abnormal D2 receptor-mediated dopamine transmission and inhibitory control may be heritable risk factors for addictions, and that they also reflect drug-induced neuroadaptations. To provide a mechanistic explanation for the drug-induced emergence of inhibitory-control deficits, this study examined how a chronic, escalating-dose regimen of methamphetamine administration affected dopaminergic neurochemistry and cognition in monkeys. Dopamine D2-like receptor and dopamine transporter (DAT) availability and reversal-learning performance were measured before and after exposure to methamphetamine (or saline), and brain dopamine levels were assayed at the conclusion of the study. Exposure to methamphetamine reduced dopamine D2-like receptor and DAT availability, and produced transient, selective impairments in the reversal of a stimulus-outcome association. Furthermore, individual differences in the change in D2-like receptor availability in the striatum were related to the change in response to positive feedback. These data provide evidence that chronic, escalating-dose methamphetamine administration alters the dopamine system in a manner similar to that observed in methamphetamine-dependent humans. They also implicate alterations in positive-feedback sensitivity associated with D2-like receptor dysfunction as the mechanism by which inhibitory control deficits emerge in stimulant-dependent individuals. Finally, a significant degree of neurochemical and behavioral variation in response to methamphetamine was detected, indicating that individual differences affect the degree to which drugs of abuse alter these processes. Identification of these factors ultimately may assist in the development of individualized treatments for substance dependence. PMID

Does methamphetamine use increase violent behaviour? Evidence from a prospective longitudinal study.

PubMed

McKetin, Rebecca; Lubman, Dan I; Najman, Jake M; Dawe, Sharon; Butterworth, Peter; Baker, Amanda L

2014-05-01

To determine whether violent behaviour increases during periods of methamphetamine use and whether this is due to methamphetamine-induced psychotic symptoms. A fixed-effects (within-subject) analysis of four non-contiguous 1-month observation periods from a longitudinal prospective cohort study. Sydney and Brisbane, Australia. A total of 278 participants aged 16 years or older who met DSM-IV criteria for methamphetamine dependence on entry to the study but who did not meet DSM-IV criteria for life-time schizophrenia or mania. Violent behaviour was defined as severe hostility in the past month on the Brief Psychiatric Rating Scale (BPRS) (corresponding to assault/damage to property). Days of methamphetamine and other substance use in the past month were assessed using the Opiate Treatment Index. Positive psychotic symptoms in the past month were identified using the BPRS. There was a dose-related increase in violent behaviour when an individual was using methamphetamine compared with when they were not after adjusting for other substance use and socio-demographics [cf. no use in the past month: 1-15 days of use odds ratio (OR) = 2.8, 95% confidence interval (CI) =1.6-4.9; 16+ days of use OR = 9.5, 95% CI = 4.8-19.1]. The odds of violent behaviour were further increased by psychotic symptoms (OR = 2.0, 95% CI = 1.1-3.6), which accounted for 22-30% of violent behaviour related to methamphetamine use. Heavy alcohol consumption also increased the risk of violent behaviour (OR = 3.1, 95% CI = 1.4-7.0) and accounted for 12-18% of the violence risk related to methamphetamine use. There is a dose-related increase in violent behaviour during periods of methamphetamine use that is largely independent of the violence risk associated with psychotic symptoms. © 2014 Society for the Study of Addiction.

Changes in gene expression linked to methamphetamine-induced dopaminergic neurotoxicity.

PubMed

Xie, Tao; Tong, Liqiong; Barrett, Tanya; Yuan, Jie; Hatzidimitriou, George; McCann, Una D; Becker, Kevin G; Donovan, David M; Ricaurte, George A

2002-01-01

The purpose of these studies was to examine the role of gene expression in methamphetamine (METH)-induced dopamine (DA) neurotoxicity. First, the effects of the mRNA synthesis inhibitor, actinomycin-D, and the protein synthesis inhibitor, cycloheximide, were examined. Both agents afforded complete protection against METH-induced DA neurotoxicity and did so independently of effects on core temperature, DA transporter function, or METH brain levels, suggesting that gene transcription and mRNA translation play a role in METH neurotoxicity. Next, microarray technology, in combination with an experimental approach designed to facilitate recognition of relevant gene expression patterns, was used to identify gene products linked to METH-induced DA neurotoxicity. This led to the identification of several genes in the ventral midbrain associated with the neurotoxic process, including genes for energy metabolism [cytochrome c oxidase subunit 1 (COX1), reduced nicotinamide adenine dinucleotide ubiquinone oxidoreductase chain 2, and phosphoglycerate mutase B], ion regulation (members of sodium/hydrogen exchanger and sodium/bile acid cotransporter family), signal transduction (adenylyl cyclase III), and cell differentiation and degeneration (N-myc downstream-regulated gene 3 and tau protein). Of these differentially expressed genes, we elected to further examine the increase in COX1 expression, because of data implicating energy utilization in METH neurotoxicity and the known role of COX1 in energy metabolism. On the basis of time course studies, Northern blot analyses, in situ hybridization results, and temperature studies, we now report that increased COX1 expression in the ventral midbrain is linked to METH-induced DA neuronal injury. The precise role of COX1 and other genes in METH neurotoxicity remains to be elucidated.

Methamphetamine Use and Violent Behavior: User Perceptions and Predictors

PubMed Central

Brecht, Mary-Lynn; Herbeck, Diane

2015-01-01

This study describes the extent to which methamphetamine users perceive that their methamphetamine use has resulted in violent behavior, and describes the level of self-reported prevalence of specific violent criminal behaviors irrespective of methamphetamine use. Predictors of these two violence-related indicators, in terms of potential correlates from substance use history, criminal history, and health risk domains are examined. Data are from extensive interviews of 350 methamphetamine users who received substance use treatment in a large California county. A majority (56%) perceived that their methamphetamine use resulted in violent behavior; 59% reported specific violent criminal behaviors. For more than half of those reporting violent criminal behavior, this behavior pattern began before methamphetamine initiation. Thus, for a subsample of methamphetamine users, violence may be related to factors other than methamphetamine use. Users' perceptions that their methamphetamine use resulted in violence appears strongest for those with the most severe methamphetamine-related problems, particularly paranoia. PMID:26594058

[Effect of rhynchophylline on behaviors of methamphetamine-dependent zebrafish and the mechanism].

PubMed

Chen, Yi-Fei; Peng, Ju; Fang, Miao; Liu, Yi; Nie, Ling-Hui; Mo, Zhi-Xian; Zhu, Ling-Ling

2016-11-20

To observe the effect of rhynchophylline on methamphetamine-dependent zebrafish and explore the possible mechanism. Zebrafish were divided into control group, amphetamine group, low- (50 mg/kg) and high (100 mg/kg)-dose rhynchophylline groups, and ketamine (150 mg/kg) group. Conditioned place preference (CPP) was induced in zebrafish with methamphetamine, and the staying time in the drug box and the tracking map of the zebrafish were observed with Noldus Ethovision XT system. The protein expressions of TH, NR2B and GLUR2 in the brain of zebrafish with CPP were detected with Western blotting. Compared with the control group, zebrafish in methamphetamine group showed significant variations in the staying time and swimming distance in the drug box after conditioning (P<0.05) with obvious alterations of NR2B, TH and GLUR2 expressions in the brain (P<0.05). Treatment of methamphetamine-dependent zebrafish with high-dose rhynchophylline significantly reduced the variations in the staying time and swimming distance in the drug box (P<0.05) and in the expressions of NR2B, TH and GLUR2 in the brain (P<0.05). Rhynchophylline can inhibit methamphetamine dependence in zebrafish, the mechanism of which may involve the expressions of TH, NR2B and GLUR2 proteins in the brain.

Special Medical Conditions Associated with Catatonia in the Internal Medicine Setting: Hyponatremia-Inducing Psychosis and Subsequent Catatonia

PubMed Central

Novac, Andrei A; Bota, Daniela; Witkowski, Joanne; Lipiz, Jorge; Bota, Robert G

2014-01-01

Diagnosis and treatment of catatonia in the psychiatry consultation service is not infrequent. Usually, the patient either presents to the Emergency Department or develops catatonia on the medical floor. This condition manifests with significant behavioral changes (from mildly decreased speech output to complete mutism) that interfere with the ability to communicate. After structural brain disorders are excluded, one of the diagnoses that always should be considered is catatonia. However, the causes of catatonia are numerous, ranging from psychiatric causes to a plethora of medical illnesses. Therefore, it is not surprising that there are many proposed underlying mechanisms of catatonia and that controversy persists about the etiology of specific cases. There are only 6 reports of hyponatremia-induced catatonia and psychosis in the literature. Here, we present the case of a 30-year-old woman with catatonia and psychosis induced by hyponatremia, and we use this report to exemplify the multitude of biologic causes of catatonia and to propose a new way to look at the neuroanatomical basis of processing, particularly the vertical processing systems we believe are involved in catatonia. PMID:25102520

Methamphetamine induces apoptosis in immortalized neural cells: protection by the proto-oncogene, bcl-2.

PubMed

Cadet, J L; Ordonez, S V; Ordonez, J V

1997-02-01

Methamphetamine (METH) is an amphetamine analog that produces degeneration of the dopaminergic system in mammals. The neurotoxic effects of the drug are thought to be mediated by oxygen-based free radicals. In the present report, we have used immortalized neural cells obtained from rat mesencephalon in order to further assess the role of oxidative stress in METH-induced neurotoxicity. We thus tested if the anti-death proto-oncogene, bcl-2 could protect against METH-induced cytotoxicity. METH caused dose-dependent loss of cellular viability in control cells while bcl-2-expressing cells were protected against these deleterious effects. Using flow cytometry, immunofluorescent staining, and DNA electrophoresis, we also show that METH exposure can cause DNA strand breaks, chromatin condensation, nuclear fragmentation, and DNA laddering. All these changes were prevented by bcl-2 expression. These observations provide further support for the involvement of oxidative stress in the toxic effects of amphetamine analogs. They also document that METH-induced cytotoxicity is secondary to apoptosis. These findings may be of relevance to the cause(s) of Parkinson's disease which involves degeneration of the nigrostriatal dopaminergic pathway.

Fatal Small Intestinal Ischemia Due to Methamphetamine Intoxication: Report of a Case With Autopsy Results.

PubMed

Attaran, Hamid

2017-05-01

Methamphetamine is one of the most common abused drugs, so its various effects on different body organs should be familiar to all physicians. Regarding its gastrointestinal sequels, there are few reports of ischemic colitis induced by its vasoconstrictive effects. This is the first report of isolated small intestinal infarction resulting in death following methamphetamine toxicity. A 40-year-old woman with a past history of medical treatment for obesity referred to hospital with severe chest and back pain, perspiration, nausea, agitation, high blood pressure, bradycardia and subsequent lethargy and vasomotor instability. Cardiac evaluations were normal, and a toxicologic urinalysis revealed methamphetamine. Later, abdominal pain predominated, and ultrasonography revealed signs of bowel infarction. She did not consent to surgery and succumbed afterward. At autopsy gangrene and perforation of distal ileum were found. The cause of death was determined as intestinal gangrene following methamphetamine toxicity. Methamphetamine has anorectic effects and so is used in some "diet pills"; Consumers may not even know they are using methamphetamine. Hence in cases of either known MA abuse or those using unknown weight reduction drugs presenting with gastrointestinal complaints or abdominal pain, intestinal ischemia should be kept in mind and if plausible, intervened promptly.

Neurotoxicity induced by methamphetamine-heroin combination in PC12 cells.

PubMed

Tian, Xiang; Ru, Qin; Xiong, Qi; Yue, Kai; Chen, Lin; Ma, Baomiao; Gan, Weimin; Si, Yuanren; Xiao, Huqiao; Li, Chaoying

2017-04-24

Simultaneous administration of psychostimulants and opioids is a major drug abuse problem worldwide. The combination of psychostimulants and opioids produces more serious effects than either drug alone and is responsible for numerous deaths. In recent years, owing to its increased use, methamphetamine (METH), a psychostimulant, has become a popular choice for use in combination with opioids, especially heroin. However, little is known about the neurotoxicity of METH/heroin combination. The aims of this study were to evaluate whether METH/heroin combination was more neurotoxic than either drug alone and analyze the possible neurotoxic mechanisms using rat pheochromocytoma (PC12) cells. Our data showed that METH/heroin combination exhibited a significant decrease in cell viability than either drug alone, and the coefficient of drug interaction (CDI) indicated that the combination appeared to produce synergistic effects. Further studies showed that METH/heroin combination induced apoptosis and decreased the mitochondrial potential significantly, compared to either drug alone. This was demonstrated by a significant decrease in the expression of Bcl-2 and an increase in expression of Bax, accompanied by increase in the activities of caspase-3 and caspase-9. These results suggest that the combination of METH and heroin is more neurotoxic than either drug alone, and it induces apoptosis via the mitochondrial apoptotic pathway. Copyright © 2017 Elsevier B.V. All rights reserved.

Retrotransposition of Long Interspersed Element 1 Induced by Methamphetamine or Cocaine*

PubMed Central

Okudaira, Noriyuki; Ishizaka, Yukihito; Nishio, Hajime

2014-01-01

Long interspersed element 1 (L1) is a retroelement constituting ∼17% of the human genome. A single human cell has 80–100 copies of L1 capable of retrotransposition (L1-RTP), ∼10% of which are “hot L1” copies, meaning they are primed for “jumping” within the genome. Recent studies demonstrated induction of L1 activity by drugs of abuse or low molecular weight compounds, but little is known about the underlying mechanism. The aim of this study was to identify the mechanism and effects of methamphetamine (METH) and cocaine on L1-RTP. Our results revealed that METH and cocaine induced L1-RTP in neuronal cell lines. This effect was found to be reverse transcriptase-dependent. However, METH and cocaine did not induce double-strand breaks. RNA interference experiments combined with add-back of siRNA-resistant cDNAs revealed that the induction of L1-RTP by METH or cocaine depends on the activation of cAMP response element-binding protein (CREB). METH or cocaine recruited the L1-encoded open reading frame 1 (ORF1) to chromatin in a CREB-dependent manner. These data suggest that the cellular cascades underlying METH- and cocaine-induced L1-RTP are different from those behind L1-RTP triggered by DNA damage; CREB is involved in drug-induced L1-RTP. L1-RTP caused by drugs of abuse is a novel type of genomic instability, and analysis of this phenomenon might be a novel approach to studying substance-use disorders. PMID:25053411

A systematic review of methamphetamine precursor regulations.

PubMed

McKetin, Rebecca; Sutherland, Rachel; Bright, David A; Norberg, Melissa M

2011-11-01

To assess the effectiveness of methamphetamine precursor regulations in reducing illicit methamphetamine supply and use. A systematic review of 12 databases was used to identify studies that had evaluated the impact of methamphetamine precursor regulations on methamphetamine supply and/or use. The guidelines of the Effective Practice and Organization of Care Group (EPOC) of The Cochrane Collaboration were used to determine which study designs were included and assess their quality. Ten studies met the inclusion criteria. These studies evaluated 15 interventions (13 regulations and two related interdiction efforts), all of which were located in North America. Interventions had consistent impacts across various indicators of methamphetamine supply and use. Seven of the 15 interventions produced reductions in methamphetamine indicators (ranging from 12% to 77%). Two of the largest impacts were seen following interdiction efforts, involving the closure of rogue pharmaceutical companies. There was no evidence of a shift into other types of drug use, or injecting use, although the impact on the synthetic drug market was not examined. Null effects were related largely to the existence of alternative sources of precursor chemicals or the availability of imported methamphetamine. Methamphetamine precursor regulations can reduce indicators of methamphetamine supply and use. Further research is needed to determine whether regulations can be effective outside North America, particularly in developing countries, and what impact they have on the broader synthetic drug market. Improved data on precursor diversion are needed to facilitate the evaluation of precursor regulations. © 2011 The Authors, Addiction © 2011 Society for the Study of Addiction.

Glial dysfunction in abstinent methamphetamine abusers

PubMed Central

Sailasuta, Napapon; Abulseoud, Osama; Harris, Kent C; Ross, Brian D

2010-01-01

Persistent neurochemical abnormalities in frontal brain structures are believed to result from methamphetamine use. We developed a localized 13C magnetic resonance spectroscopy (MRS) assay on a conventional MR scanner, to quantify selectively glial metabolic flux rate in frontal brain of normal subjects and a cohort of recovering abstinent methamphetamine abusers. Steady-state bicarbonate concentrations were similar, between 11 and 15 mmol/L in mixed gray-white matter of frontal brain of normal volunteers and recovering methamphetamine-abusing subjects (P>0.1). However, glial 13C-bicarbonate production rate from [1-13C]acetate, equating with glial tricarboxylic acid (TCA) cycle rate, was significantly reduced in frontal brain of abstinent methamphetamine-addicted women (methamphetamine 0.04 μmol/g per min (N=5) versus controls 0.11 μmol/g per min (N=5), P=0.001). This is equivalent to 36% of the normal glial TCA cycle rate. Severe reduction in glial TCA cycle rate that normally comprises 10% of total cerebral metabolic rate may impact operation of the neuronal glial glutamate cycle and result in accumulation of frontal brain glutamate, as observed in these recovering methamphetamine abusers. Although these are the first studies to define directly an abnormality in glial metabolism in human methamphetamine abuse, sequential studies using analogous 13C MRS methods may determine ‘cause and effect' between glial failure and neuronal injury. PMID:20040926

Clinical characteristics of synthetic cannabinoid-induced psychosis in relation to schizophrenia: a single-center cross-sectional analysis of concurrently hospitalized patients.

PubMed

Altintas, Merih; Inanc, Leman; Oruc, Gamze Akcay; Arpacioglu, Selim; Gulec, Huseyin

2016-01-01

This study aimed to evaluate synthetic cannabinoid (SC)-induced psychosis in terms of patient profile and clinical characteristics with reference to concurrently hospitalized schizophrenic patients. A total of 81 male patients diagnosed with psychotic disorder induced by the use of SCs (n=50; mean (standard deviation [SD]) age: 25.9 (5.5) years) or with schizophrenia (n=31, mean (SD) age: 42.9 (11.6) years) based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, diagnosis criteria who were concurrently hospitalized at Erenköy Mental and Neurological Diseases Training and Research Hospital were included in this cross-sectional study. Data on sociodemographic characteristics, Brief Psychiatric Rating Scale (BPRS), Positive and Negative Syndrome Scale (PANSS), Frontal Assessment Battery (FAB), Hamilton Rating Scale for Depression (HRSD), and Hamilton Anxiety Rating Scale (HAM-A) were recorded in all the patients. Mean (SD) age at disease onset in SC-induced psychosis patients was 22.3 (5.6) years; 26.0% had suicidal ideation and 58.4% were hospitalized involuntarily. Marijuana was the most common first used substance (72.0%), and solitary use of SC was noted in 38.0% of patients. SC-induced psychosis patients had similar PANSS positive, BPRS, HRSD, and FAB scores and significantly lower PANSS negative scores (18.0 [6.5] vs 22.3 [6.0], P=0.004) than patients with schizophrenia, while they had similar HAM-A scores (17.8 [10.3] vs 21.6 [5.5], P=0.085) as young schizophrenics. Age at onset for SC (r=0.364, P=0.05) or substance (r=0.395, P=0.01) use was correlated positively with total FAB scores. In conclusion, our findings revealed SC-induced psychosis to influence young individuals and be associated with remarkable rates of suicidal ideation and involuntary hospitalization as well as similar clinical picture with schizophrenia in terms of PANSS positive, BPRS, HRSD, HAM-A, and FAB scores. Younger age at onset was associated with poorer

Late-life effects of chronic methamphetamine exposure during puberty on behaviour and corticostriatal mono-amines in social isolation-reared rats.

PubMed

Strauss, Laetitia; Brink, Christiaan B; Möller, Marisa; Stein, Dan J; Harvey, Brian H

2014-01-01

Chronic methamphetamine (MA) abuse results in an acute psychosis indistinguishable from paranoid schizophrenia. However, less is known of the interaction between MA use and environmental insults, and how this contributes to late-onset psychopathology. Using social isolation rearing (SIR), a neurodevelopmental animal model of schizophrenia, we investigated the association between changes in corticostriatal mono-amines and putative behaviours related to MA-induced psychosis in isolation and group-housed rats following chronic MA or saline exposure. Weaned male offspring of MA-naive female Wistar rats, either group- or isolation-housed from postnatal day (PND) +21, received saline (2 ml/kg s.c. b.i.d.) or an escalating dose of MA (0.2-6 mg/kg s.c. b.i.d.) for 16 days from PND +35 to +50. On PND +78, offspring were tested for deficits in social interactive behaviour (SIB) and prepulse inhibition (PPI) of startle, with frontal cortex and striatum harvested for the assessment of mono-amine concentrations. SIR significantly reduced rearing time, staying together, approaching and anogenital sniffing (outward-directed SIB), but increased self-grooming and locomotor activity (self-directed SIB), and also induced profound deficits in PPI. Pubertal MA exposure in group-housed animals also induced similar alterations in outward- and self-directed SIB and reduced PPI. Combined MA+SIR exposure evoked a similarly intense behavioural response as SIR or MA separately, with no exacerbation evident. Neither treatment separately nor together affected corticostriatal serotonin or noradrenaline levels, although frontal cortical dopamine (DA) levels were significantly increased in SIR and MA+group-housed animals. A trend towards further elevated frontal cortical DA was noted in the MA+SIR treatment group. Striatal DA was unaltered by all treatments. This study provides the first evidence that chronic pubertal MA exposure evokes postpubertal psychosis-like behaviours in rats of similar

Antipsychotic-Induced Dopamine Supersensitivity Psychosis: Pharmacology, Criteria, and Therapy.

PubMed

Chouinard, Guy; Samaha, Anne-Noël; Chouinard, Virginie-Anne; Peretti, Charles-Siegfried; Kanahara, Nobuhisa; Takase, Masayuki; Iyo, Masaomi

2017-01-01

The first-line treatment for psychotic disorders remains antipsychotic drugs with receptor antagonist properties at D2-like dopamine receptors. However, long-term administration of antipsychotics can upregulate D2 receptors and produce receptor supersensitivity manifested by behavioral supersensitivity to dopamine stimulation in animals, and movement disorders and supersensitivity psychosis (SP) in patients. Antipsychotic-induced SP was first described as the emergence of psychotic symptoms with tardive dyskinesia (TD) and a fall in prolactin levels following drug discontinuation. In the era of first-generation antipsychotics, 4 clinical features characterized drug-induced SP: rapid relapse after drug discontinuation/dose reduction/switch of antipsychotics, tolerance to previously observed therapeutic effects, co-occurring TD, and psychotic exacerbation by life stressors. We review 3 recent studies on the prevalence rates of SP, and the link to treatment resistance and psychotic relapse in the era of second-generation antipsychotics (risperidone, paliperidone, perospirone, and long-acting injectable risperidone, olanzapine, quetiapine, and aripiprazole). These studies show that the prevalence rates of SP remain high in schizophrenia (30%) and higher (70%) in treatment-resistant schizophrenia. We then present neurobehavioral findings on antipsychotic-induced supersensitivity to dopamine from animal studies. Next, we propose criteria for SP, which describe psychotic symptoms and co-occurring movement disorders more precisely. Detection of mild/borderline drug-induced movement disorders permits early recognition of overblockade of D2 receptors, responsible for SP and TD. Finally, we describe 3 antipsychotic withdrawal syndromes, similar to those seen with other CNS drugs, and we propose approaches to treat, potentially prevent, or temporarily manage SP. © 2017 S. Karger AG, Basel.

Single nucleotide polymorphism near CREB1, rs7591784, is associated with pretreatment methamphetamine use frequency and outcome of outpatient treatment for methamphetamine use disorder

PubMed Central

Heinzerling, Keith G.; Demirdjian, Levon; Wu, Yingnian; Shoptaw, Steven

2016-01-01

Although stimulant dependence is highly heritable, few studies have examined genetic influences on methamphetamine dependence. We performed a candidate gene study of 52 SNPs and pretreatment methamphetamine use frequency among 263 methamphetamine dependent Hispanic and Non-Hispanic White participants of several methamphetamine outpatient clinical trials in Los Angeles. One SNP, rs7591784 was significantly associated with pretreatment methamphetamine use frequency following Bonferroni correction (p < 0.001) in males but not females. We then examined rs7591784 and methamphetamine urine drug screen results during 12 weeks of outpatient treatment among males with treatment outcome data available (N = 94) and found rs7591784 was significantly associated with methamphetamine use during treatment controlling for pretreatment methamphetamine use. rs7591784 is near CREB1 and in a linkage disequilibrium block with rs2952768, previously shown to influence CREB1 expression. The CREB signaling pathway is involved in gene expression changes related to chronic use of multiple drugs of abuse including methamphetamine and these results suggest that variability in CREB signaling may influence pretreatment frequency of methamphetamine use as well as outcomes of outpatient treatment. Medications targeting the CREB pathway, including phosphodiesterase inhibitors, warrant investigation as pharmacotherapies for methamphetamine use disorders. PMID:26736037

Cannabis and psychosis: an update on course and biological plausible mechanisms.

PubMed

Linszen, Don; van Amelsvoort, Therese

2007-03-01

Cannabis use is the most commonly abused illicit substance. Its relation with psychosis remains a topic of debate. Epidemiological studies suggest that cannabis is a component cause accounting for approximately 10% of cases. An increasing number of studies have been published on neurobiological effects of cannabis and vulnerability of psychosis. Acute cannabis administration can induce memory impairments, sometimes persisting months following abstinence. There is no evidence that residual effects on cognition remain after years of abstinence. The scarce literature on neuro-imaging mainly done in nonpsychotic populations, show little evidence that cannabis has effects on brain anatomy. Acute effects of cannabis include increases of cerebral blood flow, whereas long-term effects of cannabis include attenuation of cerebral blood flow. In animals Delta9-tetrahydrocannabinol enhances dopaminergic neurotransmission in brain regions known to be implicated in psychosis. Studies in humans show that genetic vulnerability may add to increased risk of developing psychosis and cognitive impairments following cannabis consumption. Delta9-tetrahydrocannabinol induces psychotic like states and memory impairments in healthy volunteers. Simultaneously with increasing understanding of neurobiological cannabis effects, there is a lack of studies in people with psychosis. There are plausible mechanisms that might explain the psychotogenic effects of cannabis.

Methamphetamine enhances Hepatitis C virus replication in human hepatocytes

PubMed Central

Ye, L.; Peng, J. S.; Wang, X.; Wang, Y. J.; Luo, G. X.; Ho, W. Z.

2009-01-01

SUMMARY Very little is known about the interactions between hepatitis C virus (HCV) and methamphetamine, which is a highly abused psychostimulant and a known risk factor for human immunodeficiency virus (HIV)/HCV infection. This study examined whether methamphetamine has the ability to inhibit innate immunity in the host cells, facilitating HCV replication in human hepatocytes. Methamphetamine inhibited intracellular interferon alpha expression in human hepatocytes, which was associated with the increase in HCV replication. In addition, methamphetamine also compromised the anti-HCV effect of recombinant interferon alpha. Further investigation of mechanism(s) responsible for the methamphetamine action revealed that methamphetamine was able to inhibit the expression of the signal transducer and activator of transcription 1, a key modulator in interferon-mediated immune and biological responses. Methamphetamine also down-regulated the expression of interferon regulatory factor-5, a crucial transcriptional factor that activates the interferon pathway. These in vitro findings that methamphetamine compromises interferon alpha-mediated innate immunity against HCV infection indicate that methamphetamine may have a cofactor role in the immunopathogenesis of HCV disease. PMID:18307590

Cortical ionotropic glutamate receptor antagonism protects against methamphetamine-induced striatal neurotoxicity.

PubMed

Gross, N B; Duncker, P C; Marshall, J F

2011-12-29

Binge administration of the psychostimulant drug, methamphetamine (mAMPH), produces long-lasting structural and functional abnormalities in the striatum. mAMPH binges produce nonexocytotic release of dopamine (DA), and mAMPH-induced activation of excitatory afferent inputs to cortex and striatum is evidenced by elevated extracellular glutamate (GLU) in both regions. The mAMPH-induced increases in DA and GLU neurotransmission are thought to combine to injure striatal DA nerve terminals of mAMPH-exposed brains. Systemic pretreatment with either competitive or noncompetitive N-methyl-D-aspartic acid (NMDA) antagonists protects against mAMPH-induced striatal DA terminal damage, but the locus of these antagonists' effects has not been determined. Here, we applied either the NMDA receptor antagonist, (dl)-amino-5-phosphonovaleric acid (AP5), or the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, dinitroquinoxaline-2,3-dione (DNQX), directly to the dura mater over frontoparietal cortex to assess their effects on mAMPH-induced cortical and striatal immediate-early gene (c-fos) expression. In a separate experiment we applied AP5 or DNQX epidurally in the same cortical location of rats during a binge regimen of mAMPH and assessed mAMPH-induced striatal dopamine transporter (DAT) depletions 1 week later. Our results indicate that both ionotropic glutamate receptor antagonists reduced the mAMPH-induced Fos expression in cerebral cortex regions near the site of epidural application and reduced Fos immunoreactivity in striatal regions innervated by the affected cortical regions. Also, epidural application of the same concentration of either antagonist during a binge mAMPH regimen blunted the mAMPH-induced striatal DAT depletions with a topography similar to its effects on Fos expression. These findings demonstrate that mAMPH-induced dopaminergic injury depends upon cortical NMDA and AMPA receptor activation and suggest the involvement of the

Role of oxidative stress in methamphetamine-induced dopaminergic toxicity mediated by protein kinase Cδ

PubMed Central

Nguyen, Xuan-Khanh Thi; Li, Zhengyi; Bing, Guoying; Bach, Jae-Hyung; Park, Dae Hun; Nakayama, Keiichi; Ali, Syed F.; Kanthasamy, Anumantha G.; Cadet, Jean Lud; Nabeshima, Toshitaka; Kim, Hyoung-Chun

2014-01-01

This study examined the role of protein kinase C (PKC) isozymes in methamphetamine (MA)-induced dopaminergic toxicity. Multiple-dose administration of MA did not significantly alter PKCα, PKCβI, PKCβII, or PKCζ expression in the striatum, but did significantly increase PKCδ expression. Gö6976 (a co-inhibitor of PKCα and -β), hispidin (PKCβ inhibitor), and PKCζ pseudosubstrate inhibitor (PKCζ inhibitor) did not significantly alter MA-induced behavioral impairments. However, rottlerin (PKCδ inhibitor) significantly attenuated behavioral impairments in a dose-dependent manner. In addition, MA-induced behavioral impairments were not apparent in PKCδ knockout (–/–) mice. MA-induced oxidative stress (i.e., lipid peroxidation and protein oxidation) was significantly attenuated in rottlerin-treated mice and was not apparent in PKCδ (–/–) mice. Consistent with this, MA-induced apoptosis (i.e., terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive apoptotic cells) was significantly attenuated in rottlerin-treated mice. Furthermore, MA-induced increases in the dopamine (DA) turnover rate and decreases in tyrosine hydroxylase (TH) activity and the expression of TH, dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT2) were not significantly observed in rottlerin-treated or PKCδ (–/–) mice. Our results suggest that PKCδ gene expression is a key mediator of oxidative stress and dopaminergic damage induced by MA. Thus, inhibition of PKCδ may be a useful target for protection against MA-induced neurotoxicity. PMID:22512859

Role of oxidative stress in methamphetamine-induced dopaminergic toxicity mediated by protein kinase Cδ.

PubMed

Shin, Eun-Joo; Duong, Chu Xuan; Nguyen, Xuan-Khanh Thi; Li, Zhengyi; Bing, Guoying; Bach, Jae-Hyung; Park, Dae Hun; Nakayama, Keiichi; Ali, Syed F; Kanthasamy, Anumantha G; Cadet, Jean Lud; Nabeshima, Toshitaka; Kim, Hyoung-Chun

2012-06-15

This study examined the role of protein kinase C (PKC) isozymes in methamphetamine (MA)-induced dopaminergic toxicity. Multiple-dose administration of MA did not significantly alter PKCα, PKCβI, PKCβII, or PKCζ expression in the striatum, but did significantly increase PKCδ expression. Gö6976 (a co-inhibitor of PKCα and -β), hispidin (PKCβ inhibitor), and PKCζ pseudosubstrate inhibitor (PKCζ inhibitor) did not significantly alter MA-induced behavioral impairments. However, rottlerin (PKCδ inhibitor) significantly attenuated behavioral impairments in a dose-dependent manner. In addition, MA-induced behavioral impairments were not apparent in PKCδ knockout (-/-) mice. MA-induced oxidative stress (i.e., lipid peroxidation and protein oxidation) was significantly attenuated in rottlerin-treated mice and was not apparent in PKCδ (-/-) mice. Consistent with this, MA-induced apoptosis (i.e., terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive apoptotic cells) was significantly attenuated in rottlerin-treated mice. Furthermore, MA-induced increases in the dopamine (DA) turnover rate and decreases in tyrosine hydroxylase (TH) activity and the expression of TH, dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT2) were not significantly observed in rottlerin-treated or PKCδ (-/-) mice. Our results suggest that PKCδ gene expression is a key mediator of oxidative stress and dopaminergic damage induced by MA. Thus, inhibition of PKCδ may be a useful target for protection against MA-induced neurotoxicity. Copyright © 2012 Elsevier B.V. All rights reserved.

Methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxypyrovalerone (MDPV) induce differential cytotoxic effects in bovine brain microvessel endothelial cells.

PubMed

Rosas-Hernandez, Hector; Cuevas, Elvis; Lantz, Susan M; Rice, Kenner C; Gannon, Brenda M; Fantegrossi, William E; Gonzalez, Carmen; Paule, Merle G; Ali, Syed F

2016-08-26

Designer drugs such as synthetic psychostimulants are indicative of a worldwide problem of drug abuse and addiction. In addition to methamphetamine (METH), these drugs include 3,4-methylenedioxy-methamphetamine (MDMA) and commercial preparations of synthetic cathinones including 3,4-methylenedioxypyrovalerone (MDPV), typically referred to as "bath salts." These psychostimulants exert neurotoxic effects by altering monoamine systems in the brain. Additionally, METH and MDMA adversely affect the integrity of the blood-brain barrier (BBB): there are no current reports on the effects of MDPV on the BBB. The aim of this study was to compare the effects of METH, MDMA and MDPV on bovine brain microvessel endothelial cells (bBMVECs), an accepted in vitro model of the BBB. Confluent bBMVEC monolayers were treated with METH, MDMA and MDPV (0.5mM-2.5mM) for 24h. METH and MDMA increased lactate dehydrogenase release only at the highest concentration (2.5mM), whereas MDPV induced cytotoxicity at all concentrations. MDMA and METH decreased cellular proliferation only at 2.5mM, with similar effects observed after MDPV exposures starting at 1mM. Only MDPV increased reactive oxygen species production at all concentrations tested whereas all 3 drugs increased nitric oxide production. Morphological analysis revealed different patterns of compound-induced cell damage. METH induced vacuole formation at 1mM and disruption of the monolayer at 2.5mM. MDMA induced disruption of the endothelial monolayer from 1mM without vacuolization. On the other hand, MDPV induced monolayer disruption at doses ≥0.5mM without vacuole formation; at 2.5mM, the few remaining cells lacked endothelial morphology. These data suggest that even though these synthetic psychostimulants alter monoaminergic systems, they each induce BBB toxicity by different mechanisms with MDPV being the most toxic. Published by Elsevier Ireland Ltd.

Effects of light, food, and methamphetamine on the circadian activity rhythm in mice.

PubMed

Pendergast, Julie S; Yamazaki, Shin

2014-04-10

The circadian rhythm of locomotor activity in mice is synchronized to environmental factors such as light and food availability. It is well-known that entrainment of the activity rhythm to the light-dark cycle is attained by the circadian pacemaker in the suprachiasmatic nucleus (SCN). Locomotor activity is also controlled by two extra-SCN oscillators; periodic food availability entrains the food-entrainable oscillator (FEO) and constant consumption of low-dose methamphetamine reveals the output of the methamphetamine-sensitive circadian oscillator (MASCO). In this study, we sought to investigate the relationship between the SCN, FEO, and MASCO by examining the combinatorial effects of light, food restriction, and/or methamphetamine on locomotor activity. To investigate coupling between the SCN and FEO, we tested whether food anticipatory activity, which is the output of the FEO, shifted coordinately with phase shifts of the light-dark cycle. We found that the phase of food anticipatory activity was phase-delayed or phase-advanced symmetrically with the respective shift of the light-dark cycle, suggesting that the FEO is strongly coupled to the SCN and the phase angle between the SCN and FEO is maintained during ad libitum feeding. To examine the effect of methamphetamine on the output of the FEO, we administered methamphetamine to mice undergoing restricted feeding and found that food-entrained activity was delayed by methamphetamine treatment. In addition, restricted feeding induced dissociation of the MASCO and SCN activity rhythms during short-term methamphetamine treatment, when these rhythms are typically integrated. In conclusion, our data suggest that the outputs of the SCN, FEO and MASCO collectively drive locomotor activity. Copyright © 2014 Elsevier Inc. All rights reserved.

Electrolytic lesions of the bilateral ventrolateral orbital cortex inhibit methamphetamine-associated contextual memory formation in rats.

PubMed

Zhao, Yan; Liu, Peng; Chu, Zheng; Liu, Fei; Han, Wei; Xun, Xi; Dang, Yong-Hui

2015-10-22

The memories that are formed between rewarding and drug-associated contextual cues have been suggested to contribute to drug addiction relapse. Recent evidence has indicated that the ventrolateral orbital cortex (VLO) plays important roles in reward-based learning and reversal learning. However, whether the VLO is required for methamphetamine-induced contextual memory formation is not well understood. In the present study, a three-phase methamphetamine-induced conditioned place preference (CPP) model was used to investigate the effects of VLO lesions on the formation of drug-associated contextual memories in rats. We found that the VLO lesions themselves elicited no observable effects on place preferences. However, the VLO lesions delayed the acquisition and extinction phases of CPP without affecting the expression level. Furthermore, the VLO lesions did not have an obvious influence on CPP reinstatement. These results indicate that electrolytic lesions of the bilateral ventrolateral orbital cortex can inhibit the formation of methamphetamine-induced contextual memories in rats. Moreover, VLO may not be critically involved in memory storage and retrieval. Copyright © 2015 Elsevier B.V. All rights reserved.

Role of Dorsomedial Striatum Neuronal Ensembles in Incubation of Methamphetamine Craving after Voluntary Abstinence

PubMed Central

Venniro, Marco; Zhang, Michelle; Bossert, Jennifer M.; Warren, Brandon L.; Hope, Bruce T.

2017-01-01

We recently developed a rat model of incubation of methamphetamine craving after choice-based voluntary abstinence. Here, we studied the role of dorsolateral striatum (DLS) and dorsomedial striatum (DMS) in this incubation. We trained rats to self-administer palatable food pellets (6 d, 6 h/d) and methamphetamine (12 d, 6 h/d). We then assessed relapse to methamphetamine seeking under extinction conditions after 1 and 21 abstinence days. Between tests, the rats underwent voluntary abstinence (using a discrete choice procedure between methamphetamine and food; 20 trials/d) for 19 d. We used in situ hybridization to measure the colabeling of the activity marker Fos with Drd1 and Drd2 in DMS and DLS after the tests. Based on the in situ hybridization colabeling results, we tested the causal role of DMS D1 and D2 family receptors, and DMS neuronal ensembles in “incubated” methamphetamine seeking, using selective dopamine receptor antagonists (SCH39166 or raclopride) and the Daun02 chemogenetic inactivation procedure, respectively. Methamphetamine seeking was higher after 21 d of voluntary abstinence than after 1 d (incubation of methamphetamine craving). The incubated response was associated with increased Fos expression in DMS but not in DLS; Fos was colabeled with both Drd1 and Drd2. DMS injections of SCH39166 or raclopride selectively decreased methamphetamine seeking after 21 abstinence days. In Fos-lacZ transgenic rats, selective inactivation of relapse test-activated Fos neurons in DMS on abstinence day 18 decreased incubated methamphetamine seeking on day 21. Results demonstrate a role of DMS dopamine D1 and D2 receptors in the incubation of methamphetamine craving after voluntary abstinence and that DMS neuronal ensembles mediate this incubation. SIGNIFICANCE STATEMENT In human addicts, abstinence is often self-imposed and relapse can be triggered by exposure to drug-associated cues that induce drug craving. We recently developed a rat model of incubation

Role of Dorsomedial Striatum Neuronal Ensembles in Incubation of Methamphetamine Craving after Voluntary Abstinence.

PubMed

Caprioli, Daniele; Venniro, Marco; Zhang, Michelle; Bossert, Jennifer M; Warren, Brandon L; Hope, Bruce T; Shaham, Yavin

2017-01-25

We recently developed a rat model of incubation of methamphetamine craving after choice-based voluntary abstinence. Here, we studied the role of dorsolateral striatum (DLS) and dorsomedial striatum (DMS) in this incubation. We trained rats to self-administer palatable food pellets (6 d, 6 h/d) and methamphetamine (12 d, 6 h/d). We then assessed relapse to methamphetamine seeking under extinction conditions after 1 and 21 abstinence days. Between tests, the rats underwent voluntary abstinence (using a discrete choice procedure between methamphetamine and food; 20 trials/d) for 19 d. We used in situ hybridization to measure the colabeling of the activity marker Fos with Drd1 and Drd2 in DMS and DLS after the tests. Based on the in situ hybridization colabeling results, we tested the causal role of DMS D 1 and D 2 family receptors, and DMS neuronal ensembles in "incubated" methamphetamine seeking, using selective dopamine receptor antagonists (SCH39166 or raclopride) and the Daun02 chemogenetic inactivation procedure, respectively. Methamphetamine seeking was higher after 21 d of voluntary abstinence than after 1 d (incubation of methamphetamine craving). The incubated response was associated with increased Fos expression in DMS but not in DLS; Fos was colabeled with both Drd1 and Drd2 DMS injections of SCH39166 or raclopride selectively decreased methamphetamine seeking after 21 abstinence days. In Fos-lacZ transgenic rats, selective inactivation of relapse test-activated Fos neurons in DMS on abstinence day 18 decreased incubated methamphetamine seeking on day 21. Results demonstrate a role of DMS dopamine D 1 and D 2 receptors in the incubation of methamphetamine craving after voluntary abstinence and that DMS neuronal ensembles mediate this incubation. In human addicts, abstinence is often self-imposed and relapse can be triggered by exposure to drug-associated cues that induce drug craving. We recently developed a rat model of incubation of methamphetamine

Mephedrone Does not Damage Dopamine Nerve Endings of the Striatum but Enhances the Neurotoxicity of Methamphetamine, Amphetamine and MDMA

PubMed Central

Angoa-Pérez, Mariana; Kane, Michael J.; Briggs, Denise I.; Francescutti, Dina M.; Sykes, Catherine E.; Shah, Mrudang M.; Thomas, David M.; Kuhn, Donald M.

2012-01-01

Mephedrone (4-methylmethcathinone) is a β-ketoamphetamine stimulant drug of abuse with close structural and mechanistic similarities to methamphetamine. One of the most powerful actions associated with mephedrone is the ability to stimulate dopamine (DA) release and block its reuptake through its interaction with the dopamine transporter (DAT). Although mephedrone does not cause toxicity to DA nerve endings, its ability to serve as a DAT blocker could provide protection against methamphetamine-induced neurotoxicity like other DAT inhibitors. To test this possibility, mice were treated with mephedrone (10, 20 or 40 mg/kg) prior to each injection of a neurotoxic regimen of methamphetamine (4 injections of 2.5 or 5.0 mg/kg at 2 hr intervals). The integrity of DA nerve endings of the striatum was assessed through measures of DA, DAT and tyrosine hydroxylase levels. The moderate to severe DA toxicity associated with the different doses of methamphetamine was not prevented by any dose of mephedrone but was, in fact, significantly enhanced. The hyperthermia caused by combined treatment with mephedrone and methamphetamine was the same as seen after either drug alone. Mephedrone also enhanced the neurotoxic effects of amphetamine and MDMA on DA nerve endings. In contrast, nomifensine protected against methamphetamine-induced neurotoxicity. Because mephedrone increases methamphetamine neurotoxicity, the present results suggest that it interacts with the DAT in a manner unlike that of other typical DAT inhibitors. The relatively innocuous effects of mephedrone alone on DA nerve endings mask a potentially dangerous interaction with drugs that are often co-abused with it, leading to heightened neurotoxicity. PMID:23205838

Mirtazapine to Reduce Methamphetamine Use

PubMed Central

Colfax, Grant N.; Santos, Glenn-Milo; Das, Moupali; Santos, Deirdre McDermott; Matheson, Tim; Gasper, James; Shoptaw, Steve; Vittinghoff, Eric

2012-01-01

Context No approved pharmacologic treatments for methamphetamine dependence exist. Methamphetamine use is associated with high morbidity and is a major cofactor in the human immunodeficiency virus epidemic among men who have sex with men (MSM). Objective To determine whether mirtazapine would reduce methamphetamine use among MSM who are actively using methamphetamine. Design Double-blind, randomized, controlled, 12-week trial of mirtazapine vs placebo conducted from September 5, 2007, to March 4, 2010. Setting San Francisco Department of Public Health. Participants Participants were actively using, methamphetamine-dependent, sexually active MSM seen weekly for urine sample collection and substance use counseling. Interventions Random assignment to daily oral mirtazapine (30 mg) or placebo; both arms included 30-minute weekly substance use counseling. Main Outcome Measures The primary study outcome was reduction in methamphetamine-positive urine test results. Secondary outcomes were study medication adherence (by self-report and medication event monitoring systems) and sexual risk behavior. Results Sixty MSM were randomized, 85% of follow-up visits were completed, and 56 participants (93%) completed the final visit. In the primary intent-to-treat analysis, participants assigned to the mirtazapine group had fewer methamphetamine-positive urine test results compared with participants assigned to the placebo group (relative risk, 0.57; 95% CI, 0.35–0.93, P = .02). Urine positivity decreased from 67% (20 of 30 participants) to 63% (17 of 27) in the placebo arm and from 73% (22 of 30) to 44% (12 of 27) in the mirtazapine arm. The number needed to treat to achieve a negative weekly urine test result was 3.1. Adherence was 48.5% by medication event monitoring systems and 74.7% by self-report; adherence measures were not significantly different between arms (medication event monitoring systems, P = .82; self-report, P = .92). Most sexual risk behaviors decreased

The impact of comorbid cannabis and methamphetamine use on mental health among regular ecstasy users.

PubMed

Scott, Laura A; Roxburgh, Amanda; Bruno, Raimondo; Matthews, Allison; Burns, Lucy

2012-09-01

Residual effects of ecstasy use induce neurotransmitter changes that make it biologically plausible that extended use of the drug may induce psychological distress. However, there has been only mixed support for this in the literature. The presence of polysubstance use is a confounding factor. The aim of this study was to investigate whether regular cannabis and/or regular methamphetamine use confers additional risk of poor mental health and high levels of psychological distress, beyond regular ecstasy use alone. Three years of data from a yearly, cross-sectional, quantitative survey of Australian regular ecstasy users was examined. Participants were divided into four groups according to whether they regularly (at least monthly) used ecstasy only (n=936), ecstasy and weekly cannabis (n=697), ecstasy and weekly methamphetamine (n=108) or ecstasy, weekly cannabis and weekly methamphetamine (n=180). Self-reported mental health problems and Kessler Psychological Distress Scale (K10) were examined. Approximately one-fifth of participants self-reported at least one mental health problem, most commonly depression and anxiety. The addition of regular cannabis and/or methamphetamine use substantially increases the likelihood of self-reported mental health problems, particularly with regard to paranoia, over regular ecstasy use alone. Regular cannabis use remained significantly associated with self reported mental health problems even when other differences between groups were accounted for. Regular cannabis and methamphetamine use was also associated with earlier initiation to ecstasy use. These findings suggest that patterns of drug use can help identify at risk groups that could benefit from targeted approaches in education and interventions. Given that early initiation to substance use was more common in those with regular cannabis and methamphetamine use and given that this group had a higher likelihood of mental health problems, work around delaying onset of initiation

Increased self-reported impulsivity in methamphetamine users maintaining drug abstinence.

PubMed

Jones, Hannah W; Dean, Andy C; Price, Kimberly A; London, Edythe D

2016-09-01

Impulsivity has been proposed as an important factor in the initiation and maintenance of addiction. Indirect evidence suggests that some methamphetamine users report less impulsivity when they are using methamphetamine compared to when abstaining from drug use, but this hypothesis has not been directly tested. In this study, self-reports of impulsivity were obtained from 32 methamphetamine-dependent (DSM-IV) research participants and 41 healthy control subjects, using the Barratt Impulsiveness Scale-11. The methamphetamine users were assessed during an active period of methamphetamine use, as determined through urinalysis, and again after approximately 1 week of confirmed abstinence. Control subjects likewise completed two assessments. A subset of participants also completed serial assessments of the Beck Depression Inventory (Methamphetamine Group, N = 17, Control Group, N = 38) and the Methamphetamine Withdrawal Questionnaire (Methamphetamine Group, N = 12). There was a significant interaction of group with time on impulsivity (p = 0.044), reflecting a significant increase from the first to the second assessment in the methamphetamine users (p = 0.013), but no change among healthy control subjects. In contrast, depressive and withdrawal symptoms significantly decreased between the first and second assessments in the methamphetamine users (ps ≤0.01). Change in impulsivity in methamphetamine users was not significantly correlated with change in withdrawal or depression (ps >0.05). These findings suggest that methamphetamine users report more impulsivity when abstaining from drug use, an effect that is not significantly related to methamphetamine withdrawal. Attenuation of impulsivity may reinforce continued methamphetamine use in these individuals.

Protective effect of gallic acid in experimental model of ketamine-induced psychosis: possible behaviour, biochemical, neurochemical and cellular alterations.

PubMed

Yadav, Monu; Jindal, Deepak Kumar; Dhingra, Mamta Sachdeva; Kumar, Anil; Parle, Milind; Dhingra, Sameer

2018-04-01

Gallic acid has been reported to possess a number of psychopharmacological activities. These activities are attributed to the antioxidant potential due to the presence of phenolic moeity. The present study was carried out to investigate the protective effects of gallic acid in an experimental model of ketamine-induced psychosis in mice. Ketamine (50 mg/kg, i.p.) was used to induce stereotyped psychotic behavioural symptoms in mice. Behavioural studies (locomotor activity, stereotype behaviour, immobility duration and memory retention) were carried out to investigate the protective of gallic acid on ketamine-induced psychotic symptoms, followed by biochemical and neurochemical changes and cellular alterations in the brain. Chronic treatment with gallic acid for 15 consecutive days significantly attenuated stereotyped behavioural symptoms in mice. Biochemical estimations revealed that gallic acid reduced the lipid peroxidation and restored the total brain proteins. Furthermore, gallic acid remarkably reduced the dopamine levels, AChE activity and inflammatory surge (serum TNF-α), and increased the levels of GABA and increased glutathione in mice. The study revealed that gallic acid could ameliorate psychotic symptoms and biochemical changes in mice, indicating protective effects in psychosis.

Methamphetamine craving induced in an online virtual reality environment.

PubMed

Culbertson, Christopher; Nicolas, Sam; Zaharovits, Itay; London, Edythe D; De La Garza, Richard; Brody, Arthur L; Newton, Thomas F

2010-10-01

The main aim of this study was to assess self-reported craving and physiological reactivity in a methamphetamine virtual reality (METH-VR) cue model created using Second Life, a freely available online gaming platform. Seventeen, non-treatment seeking, individuals that abuse methamphetamine (METH) completed this 1-day, outpatient, within-subjects study. Participants completed four test sessions: 1) METH-VR, 2) neutral-VR, 3) METH-video, and 4) neutral-video in a counterbalanced (Latin square) fashion. The participants provided subjective ratings of urges to use METH, mood, and physical state throughout each cue presentation. Measures of physiological reactivity (heart rate variability) were also collected during each cue presentation and at rest. The METH-VR condition elicited the greatest change in subjective reports of "crave METH", "desire METH", and "want METH" at all time points. The "high craving" participants displayed more high frequency cardiovascular activity while the "low craving" participants displayed more low frequency cardiovascular activity during the cue conditions, with the greatest difference seen during the METH-VR and METH-video cues. These findings reveal a physiological divergence between high and low craving METH abusers using heart rate variability, and demonstrate the usefulness of VR cues for eliciting subjective craving in METH abusers, as well as the effectiveness of a novel VR drug cue model created within an online virtual world. (c) 2010 Elsevier Inc. All rights reserved.

Methamphetamine Craving Induced in an Online Virtual Reality Environment

PubMed Central

Culbertson, Christopher; Nicolas, Sam; Zaharovits, Itay; London, Edythe D.; De La Garza, Richard; Brody, Arthur L.; Newton, Thomas F.

2010-01-01

The main aim of this study was to assess self-reported craving and physiological reactivity in a methamphetamine virtual reality (METH-VR) cue model created using Second Life, a freely available online gaming platform. Seventeen, non-treatment seeking, individuals that abuse methamphetamine (METH) completed this one-day, outpatient, within-subjects study. Participants completed four test sessions: 1) METH-VR 2) neutral-VR 3) METH-video 4) neutral-video in a counterbalanced (latin square) fashion. The participants provided subjective ratings of urges to use METH, mood, and physical state throughout each cue presentation. Measures of physiological reactivity (heart rate variability) were also collected during each cue presentation and at rest. The METH-VR condition elicited the greatest change in subjective reports of “crave METH”, “desire METH”, and “want METH” at all time points. The “high craving” participants displayed more high frequency cardiovascular activity while the “low craving” participants displayed more low frequency cardiovascular activity during the cue conditions, with the greatest difference seen during the METH-VR and METH-video cues. These findings reveal a physiological divergence between high and low craving METH abusers using heart rate variability, and demonstrate the usefulness of VR cues for eliciting subjective craving in METH abusers, as well as the effectiveness of a novel VR drug cue model created within an online virtual world. PMID:20643158

Nrf2 deficiency potentiates methamphetamine-induced dopaminergic axonal damage and gliosis in the striatum.

PubMed

Granado, Noelia; Lastres-Becker, Isabel; Ares-Santos, Sara; Oliva, Idaira; Martin, Eduardo; Cuadrado, Antonio; Moratalla, Rosario

2011-12-01

Oxidative stress that correlates with damage to nigrostriatal dopaminergic neurons and reactive gliosis in the basal ganglia is a hallmark of methamphetamine (METH) toxicity. In this study, we analyzed the protective role of the transcription factor Nrf2 (nuclear factor-erythroid 2-related factor 2), a master regulator of redox homeostasis, in METH-induced neurotoxicity. We found that Nrf2 deficiency exacerbated METH-induced damage to dopamine neurons, shown by an increase in loss of tyrosine hydroxylase (TH)- and dopamine transporter (DAT)-containing fibers in striatum. Consistent with these effects, Nrf2 deficiency potentiated glial activation, indicated by increased striatal expression of markers for microglia (Mac-1 and Iba-1) and astroglia (GFAP) one day after METH administration. At the same time, Nrf2 inactivation dramatically potentiated the increase in TNFα mRNA and IL-15 protein expression in GFAP+ cells in the striatum. In sharp contrast to the potentiation of striatal damage, Nrf2 deficiency did not affect METH-induced dopaminergic neuron death or expression of glial markers or proinflammatory molecules in the substantia nigra. This study uncovers a new role for Nrf2 in protection against METH-induced inflammatory and oxidative stress and striatal degeneration. Copyright © 2011 Wiley‐Liss, Inc.

Postpartum Psychosis

MedlinePlus

... of postpartum psychosis never had delusions containing violent commands. Delusions take many forms, and not all of them are destructive. Most women who experience postpartum psychosis do not harm themselves or anyone else. However, there ...

The role of dopamine receptors in the neurotoxicity of methamphetamine.

PubMed

Ares-Santos, S; Granado, N; Moratalla, R

2013-05-01

Methamphetamine is a synthetic drug consumed by millions of users despite its neurotoxic effects in the brain, leading to loss of dopaminergic fibres and cell bodies. Moreover, clinical reports suggest that methamphetamine abusers are predisposed to Parkinson's disease. Therefore, it is important to elucidate the mechanisms involved in methamphetamine-induced neurotoxicity. Dopamine receptors may be a plausible target to prevent this neurotoxicity. Genetic inactivation of dopamine D1 or D2 receptors protects against the loss of dopaminergic fibres in the striatum and loss of dopaminergic neurons in the substantia nigra. Protection by D1 receptor inactivation is due to blockade of hypothermia, reduced dopamine content and turnover and increased stored vesicular dopamine in D1R(-/-) mice. However, the neuroprotective impact of D2 receptor inactivation is partially dependent on an effect on body temperature, as well as on the blockade of dopamine reuptake by decreased dopamine transporter activity, which results in reduced intracytosolic dopamine levels in D2R(-/-) mice. © 2013 The Association for the Publication of the Journal of Internal Medicine.

Acute psychosis as an initial manifestation of hypothyroidism: a case report.

PubMed

Ueno, Shinichi; Tsuboi, Satoko; Fujimaki, Motoki; Eguchi, Hiroto; Machida, Yutaka; Hattori, Nobutaka; Miwa, Hideto

2015-11-17

Hypothyroidism is one of the most important causes of treatable dementia, and psychosis occasionally associated with it is known as myxedema madness. We report a case of a 90-year-old patient who developed myxedema madness acutely without overt clinical symptoms and signs suggestive of hypothyroidism. A 90-year-old Japanese man, a general practitioner, was admitted to our emergency room because of acute-onset lethargy, delusions, and hallucinations. He had been actively working until 3 days before the admission. Upon admission, his general physical examination was unremarkable. However, a blood investigation showed the presence of hypothyroidism, and computed tomography revealed pleural effusion and ascites. Electroencephalography revealed diffuse slow waves with a decrease of α-wave activity. A single-photon emission computed tomography scan revealed a decrease of cerebral blood flow in both frontal lobes. The patient was soon treated with thyroid hormone replacement therapy. Following normalization of his thyroid function, both pleural effusion and ascites diminished and his electroencephalographic activity improved simultaneously; however, he did not recover from his psychosis. Myxedema madness should be kept in mind in the differential diagnosis of acute psychosis in elderly patients, particularly the oldest patients as in our case, because manifestations of hypothyroidism often may be indistinguishable from the aging process.

On the Role of Imitation on Adolescence Methamphetamine Abuse Dynamics.

PubMed

Mushanyu, J; Nyabadza, F; Muchatibaya, G; Stewart, A G R

2017-03-01

Adolescence methamphetamine use is an issue of considerable concern due to its correlation with later delinquency, divorce, unemployment and health problems. Understanding how adolescents initiate methamphetamine abuse is important in developing effective prevention programs. We formulate a mathematical model for the spread of methamphetamine abuse using nonlinear ordinary differential equations. It is assumed that susceptibles are recruited into methamphetamine use through imitation. An epidemic threshold value, [Formula: see text], termed the abuse reproduction number, is proposed and defined herein in the drug-using context. The model is shown to exhibit the phenomenon of backward bifurcation. This means that methamphetamine problems may persist in the population even if [Formula: see text] is less than one. Sensitivity analysis of [Formula: see text] was performed to determine the relative importance of different parameters in methamphetamine abuse initiation. The model is then fitted to data on methamphetamine users less than 20 years old reporting methamphetamine as their primary substance of abuse in the treatment centres of Cape Town and parameter values that give the best fit are chosen. Results show that the proportion of methamphetamine users less than 20 years old reporting methamphetamine as their primary substance of abuse will continue to decrease in Cape Town of South Africa. The results suggest that intervention programs targeted at reducing adolescence methamphetamine abuse, are positively impacting methamphetamine abuse.

Correlates of Trading Sex for Methamphetamine in a Sample of HIV-Negative Heterosexual Methamphetamine Users

PubMed Central

Semple, Shirley J.; Strathdee, Steffanie A.; Zians, Jim; Patterson, Thomas L.

2012-01-01

While many studies have examined correlates of trading sex for money, few have examined factors associated with exclusive trading of sex for drugs. We identified sociodemographic, behavioral, and psychological correlates of trading sex for methamphetamine in a sample of HIV-negative heterosexual men and women who were enrolled in a sexual risk reduction intervention in San Diego, California. Of 342 participants, 26% overall (21% of males and 31% of females) reported trading sex for methamphetamine in the past two months. Multiple logistic regression analysis revealed that recently trading sex for methamphetamine was independently associated with being female, homeless, binging on methamphetamine, sexual victimization in the past two months, engaging in anal sex 24 or more times in the past two months, and higher sexual compulsivity scores. Effective interventions for this high-risk population should consider gender-focused counseling for sexual abuse, motivational enhancement therapy, social-cognitive skills training, as well as enhanced access and utilization of social services, including drug treatment. PMID:21858954

Correlates of trading sex for methamphetamine in a sample of HIV-negative heterosexual methamphetamine users.

PubMed

Semple, Shirley J; Strathdee, Steffanie A; Zians, Jim; Patterson, Thomas L

2011-01-01

While many studies have examined correlates of trading sex for money, few have examined factors associated with exclusive trading of sex for drugs. We identified sociodemographic, behavioral, and psychological correlates of trading sex for methamphetamine in a sample of HIV-negative heterosexual men and women who were enrolled in a sexual risk reduction intervention in San Diego, California. Of 342 participants, 26% overall (21% of males and 31% of females) reported trading sex for methamphetamine in the past two months. Multiple logistic regression analysis revealed that recently trading sex for methamphetamine was independently associated with being female, homeless, binging on methamphetamine, sexual victimization in the past two months, engaging in anal sex 24 or more times in the past two months, and higher sexual compulsivity scores. Effective interventions for this high-risk population should consider gender-focused counseling for sexual abuse, motivational enhancement therapy, social-cognitive skills training, as well as enhanced access and utilization of social services, including drug treatment.

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

Methamphetamine-induced behavioral sensitization in a rodent model of posttraumatic stress disorder.

PubMed

Eagle, Andrew L; Perrine, Shane A

2013-07-01

Single prolonged stress (SPS) is a rodent model of posttraumatic stress disorder (PTSD)-like characteristics. Given that PTSD is frequently comorbid with substance abuse and dependence, including methamphetamine (METH), the current study sought to investigate the effects of SPS on METH-induced behavioral sensitization. In experiment 1, Sprague-Dawley rats were subject to SPS or control treatment and subsequently tested across four sessions of an escalating METH dosing paradigm. METH was injected (i.p.) in escalating doses (0, 0.032, 0.1, 0.32, 1.0, and 3.2mg/kg; dissolved in saline) every 15min and ambulatory activity was recorded. In experiment 2, SPS and control treated rats were injected (i.p.) with either saline or METH (5mg/kg) for five consecutive daily sessions and tested for stereotypy as well as ambulatory activity. Two days later, all animals were injected with a challenge dose of METH (2.5mg/kg) and again tested for activity. No differences in the acute response to METH were observed between SPS and controls. SPS enhanced METH induced ambulatory activity across sessions, compared to controls. METH-induced stereotypy increased across sessions, indicative of behavioral sensitization; however, SPS attenuated, not enhanced, this effect suggesting that SPS may prevent the development of stereotypy sensitization. Collectively, results show that SPS increases repeated METH-induced ambulatory activity while preventing the transition across sessions from ambulatory activity to stereotypy. These findings suggest that SPS alters drug-induced neuroplasticity associated with behavioral sensitization to METH, which may reflect an effect on the shared neurocircuitry underlying PTSD and substance dependence. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

COMT ValMet moderation of cannabis-induced psychosis: a momentary assessment study of 'switching on' hallucinations in the flow of daily life.

PubMed

Henquet, C; Rosa, A; Delespaul, P; Papiol, S; Fananás, L; van Os, J; Myin-Germeys, I

2009-02-01

A functional polymorphism in the catechol-o-methyltransferase gene (COMT Val(158)Met) may moderate the psychosis-inducing effects of cannabis. In order to extend this finding to dynamic effects in the flow of daily life, a momentary assessment study of psychotic symptoms in response to cannabis use was conducted. The experience sampling technique was used to collect data on cannabis use and occurrence of symptoms in daily life in patients with a psychotic disorder (n = 31) and healthy controls (n = 25). Carriers of the COMT Val(158)Met Val allele, but not subjects with the Met/Met genotype, showed an increase in hallucinations after cannabis exposure, conditional on prior evidence of psychometric psychosis liability. The findings confirm that in people with psychometric evidence of psychosis liability, COMT Val(158)Met genotype moderates the association between cannabis and psychotic phenomena in the flow of daily life.

Mephedrone does not damage dopamine nerve endings of the striatum, but enhances the neurotoxicity of methamphetamine, amphetamine, and MDMA.

PubMed

Angoa-Pérez, Mariana; Kane, Michael J; Briggs, Denise I; Francescutti, Dina M; Sykes, Catherine E; Shah, Mrudang M; Thomas, David M; Kuhn, Donald M

2013-04-01

Mephedrone (4-methylmethcathinone) is a β-ketoamphetamine stimulant drug of abuse with close structural and mechanistic similarities to methamphetamine. One of the most powerful actions associated with mephedrone is the ability to stimulate dopamine (DA) release and block its re-uptake through its interaction with the dopamine transporter (DAT). Although mephedrone does not cause toxicity to DA nerve endings, its ability to serve as a DAT blocker could provide protection against methamphetamine-induced neurotoxicity like other DAT inhibitors. To test this possibility, mice were treated with mephedrone (10, 20, or 40 mg/kg) prior to each injection of a neurotoxic regimen of methamphetamine (four injections of 2.5 or 5.0 mg/kg at 2 h intervals). The integrity of DA nerve endings of the striatum was assessed through measures of DA, DAT, and tyrosine hydroxylase levels. The moderate to severe DA toxicity associated with the different doses of methamphetamine was not prevented by any dose of mephedrone but was, in fact, significantly enhanced. The hyperthermia caused by combined treatment with mephedrone and methamphetamine was the same as seen after either drug alone. Mephedrone also enhanced the neurotoxic effects of amphetamine and 3,4-methylenedioxymethamphetamine on DA nerve endings. In contrast, nomifensine protected against methamphetamine-induced neurotoxicity. As mephedrone increases methamphetamine neurotoxicity, the present results suggest that it interacts with the DAT in a manner unlike that of other typical DAT inhibitors. The relatively innocuous effects of mephedrone alone on DA nerve endings mask a potentially dangerous interaction with drugs that are often co-abused with it, leading to heightened neurotoxicity. © 2012 International Society for Neurochemistry.

Paliperidone for the treatment of ketamine-induced psychosis: a case report.

PubMed

Zuccoli, M L; Muscella, A; Fucile, C; Carrozzino, R; Mattioli, F; Martelli, A; Orengo, S

2014-01-01

Ketamine is an anaesthetic and analgesic drug synthesized in the 1960s from phencyclidine. The recreational use of ketamine increased among the dance culture of techno and house music, in particular in clubs, discotheques, and rave parties. The psychotropic effects of ketamine are now well known and they range from dissociation to positive, negative, and cognitive schizophrenia-like symptoms. We report a case of a chronic oral consumption of ketamine which induced agitation, behavioral abnormalities, and loss of contact with reality in a poly-drug abuser; these symptoms persisted more than two weeks after the drug consumption had stopped. Antipsychotic treatment with paliperidone led to a successful management of the psychosis, getting a complete resolution of the clinical picture. Paliperidone has proven to be very effective in the treatment of ketamine-induced disorders. Moreover, the pharmacological action and metabolism of paliperidone are poorly dependent from the activity of liver enzymes, so that it seems to be one of the best second generation antipsychotics for the treatment of smokers and alcohol abusers.

Haloperidol plus promethazine for psychosis-induced aggression.

PubMed

Huf, Gisele; Alexander, Jacob; Gandhi, Pinky; Allen, Michael H

2016-11-25

Health services often manage agitated or violent people, and such behaviour is particularly prevalent in emergency psychiatric services (10%). The drugs used in such situations should ensure that the person becomes calm swiftly and safely. To examine whether haloperidol plus promethazine is an effective treatment for psychosis-induced aggression. On 6 May 2015 we searched the Cochrane Schizophrenia Group's Register of Trials, which is compiled by systematic searches of major resources (including MEDLINE, EMBASE, AMED, BIOSIS, CINAHL, PsycINFO, PubMed, and registries of clinical trials) and their monthly updates, handsearches, grey literature, and conference proceedings. All randomised clinical trials with useable data focusing on haloperidol plus promethazine for psychosis-induced aggression. We independently extracted data. For binary outcomes, we calculated risk ratio (RR) and its 95% confidence interval (CI), on an intention-to-treat basis. For continuous data, we estimated the mean difference (MD) between groups and its 95% CI. We employed a fixed-effect model for analyses. We assessed risk of bias for included studies and created 'Summary of findings' tables using GRADE. We found two new randomised controlled trials (RCTs) from the 2015 update searching. The review now includes six studies, randomising 1367 participants and presenting data relevant to six comparisons.When haloperidol plus promethazine was compared with haloperidol alone for psychosis-induced aggression for the outcome not tranquil or asleep at 30 minutes, the combination treatment was clearly more effective (n=316, 1 RCT, RR 0.65, 95% CI 0.49 to 0.87, high-quality evidence). There were 10 occurrences of acute dystonia in the haloperidol alone arm and none in the combination group. The trial was stopped early as haloperidol alone was considered to be too toxic.When haloperidol plus promethazine was compared with olanzapine, high-quality data showed both approaches to be tranquillising. It was

Developmental stress elicits preference for methamphetamine in the spontaneously hypertensive rat model of attention-deficit/hyperactivity disorder.

PubMed

Womersley, Jacqueline S; Mpeta, Bafokeng; Dimatelis, Jacqueline J; Kellaway, Lauriston A; Stein, Dan J; Russell, Vivienne A

2016-06-17

Developmental stress has been hypothesised to interact with genetic predisposition to increase the risk of developing substance use disorders. Here we have investigated the effects of maternal separation-induced developmental stress using a behavioural proxy of methamphetamine preference in an animal model of attention-deficit/hyperactivity disorder, the spontaneously hypertensive rat, versus Wistar Kyoto and Sprague-Dawley comparator strains. Analysis of results obtained using a conditioned place preference paradigm revealed a significant strain × stress interaction with maternal separation inducing preference for the methamphetamine-associated compartment in spontaneously hypertensive rats. Maternal separation increased behavioural sensitization to the locomotor-stimulatory effects of methamphetamine in both spontaneously hypertensive and Sprague-Dawley strains but not in Wistar Kyoto rats. Our findings indicate that developmental stress in a genetic rat model of attention-deficit/hyperactivity disorder may foster a vulnerability to the development of substance use disorders.

Dissociation of corticotropin-releasing factor receptor subtype involvement in sensitivity to locomotor effects of methamphetamine and cocaine.

PubMed

Giardino, William J; Mark, Gregory P; Stenzel-Poore, Mary P; Ryabinin, Andrey E

2012-02-01

Enhanced sensitivity to the euphoric and locomotor-activating effects of psychostimulants may influence an individual's predisposition to drug abuse and addiction. While drug-induced behaviors are mediated by the actions of several neurotransmitter systems, past research revealed that the corticotropin-releasing factor (CRF) system is important in driving the acute locomotor response to psychostimulants. We previously reported that genetic deletion of the CRF type-2 receptor (CRF-R2), but not the CRF type-1 receptor (CRF-R1) dampened the acute locomotor stimulant response to methamphetamine (1 mg/kg). These results contrasted with previous studies implicating CRF-R1 in the locomotor effects of psychostimulants. Since the majority of previous studies focused on cocaine, rather than methamphetamine, we set out to test the hypothesis that these drugs differentially engage CRF-R1 and CRF-R2. We expanded our earlier findings by first replicating our previous experiments at a higher dose of methamphetamine (2 mg/kg), and by assessing the effects of the CRF-R1-selective antagonist CP-376,395 (10 mg/kg) on methamphetamine-induced locomotor activity. Next, we used both genetic and pharmacological tools to examine the specific components of the CRF system underlying the acute locomotor response to cocaine (5-10 mg/kg). While genetic deletion of CRF-R2 dampened the locomotor response to methamphetamine (but not cocaine), genetic deletion and pharmacological blockade of CRF-R1 dampened the locomotor response to cocaine (but not methamphetamine). These findings highlight the differential involvement of CRF receptors in acute sensitivity to two different stimulant drugs of abuse, providing an intriguing basis for the development of more targeted therapeutics for psychostimulant addiction.

Duration of active psychosis and first-episode psychosis negative symptoms.

PubMed

Lyne, John; Joober, Ridha; Schmitz, Norbert; Lepage, Martin; Malla, Ashok

2017-02-01

Duration of untreated psychosis (DUP) has been associated with negative symptoms in several studies; however, longitudinal findings have been inconsistent. No previous study has accounted for active psychosis after presentation, although this could impact on outcomes in a manner similar to DUP. We measured Scale for the Assessment of Positive Symptoms at frequent intervals during the 12 months after initial presentation to determine the active psychosis duration for 230 individuals with first-episode psychosis. This duration was added to DUP prior to presentation to create a new variable, duration of active psychosis (DAP). Negative symptoms were divided into expressivity and motivation/pleasure domains as measured by Scale for the Assessment of Negative Symptoms (SANS). The relationship of DUP and DAP with negative symptoms at 24-month follow up was determined and confounders controlled for using regression analysis. When DUP and DAP were compared as binary variables with long and short groups, 25.2% of individuals had differing category membership. DAP had a significant uncorrected association with both expressivity domain and motivation/pleasure domains at 24 months; however, relationship with DUP was not significant. DAP remained a significant predictor of 24-month expressivity domain after controlling for potential confounders. Active psychosis after presentation is substantial, which is a limitation of DUP studies if active psychosis is considered as the key factor within DUP. DAP is a better predictor of negative symptoms than DUP at 2-year follow up, which suggests this concept requires further research. © 2015 Wiley Publishing Asia Pty Ltd.

Effects of Housing on Methamphetamine-Induced Neurotoxicity and Spatial Learning and Memory.

PubMed

Gutierrez, Arnold; Jablonski, Sarah A; Amos-Kroohs, Robyn M; Barnes, Anna C; Williams, Michael T; Vorhees, Charles V

2017-07-19

Severe stress potentiates methamphetamine (MA) neurotoxicity. However, whether moderate stress increases or decreases the neurotoxic effects of MA is unknown. We assessed the effects of MA (4 × 10 mg/kg at 2 h intervals) in combination with prior barren-cage housing in adult male Sprague-Dawley rats on monoamines and glial fibrillary acid protein (GFAP) in one cohort and spatial learning and memory in the Morris water maze in another cohort. MA reduced dopamine (DA) and serotonin (5-HT) in the neostriatum and nucleus accumbens, 5-HT in the hippocampus, and increased GFAP in neostriatum and nucleus accumbens compared with saline controls. In neostriatum, barren-cage housing protected against MA-induced increases in GFAP, but it did not prevent DA and 5-HT reductions, although it did increase hippocampal norepinephrine. MA impaired spatial learning during acquisition, reversal, and shift phases and impaired reference memory on reversal and shift probe trials. Barren-cage housing enhanced performance during acquisition but not during reversal or shift or on probe trials. The data indicate that prior barren-cage housing moderates MA-induced neostriatal astrogliosis and initial spatial learning, but has no protective effect when the platform is smaller and relocated and therefore requires cognitive flexibility in relearning.

Mir143-BBC3 cascade reduces microglial survival via interplay between apoptosis and autophagy: Implications for methamphetamine-mediated neurotoxicity

PubMed Central

Zhang, Yuan; Shen, Kai; Bai, Ying; Lv, Xuan; Huang, Rongrong; Zhang, Wei; Chao, Jie; Nguyen, Lan K.; Hua, Jun; Gan, Guangming; Hu, Gang; Yao, Honghong

2016-01-01

ABSTRACT BBC3 (BCL2 binding component 3) is a known apoptosis inducer; however, its role in microglial survival remains poorly understood. In addition to the classical transcription factor TRP53, Mir143 is involved in BBC3 expression at the post-transcriptional level. Here, we identify unique roles of Mir143-BBC3 in mediating microglial survival via the regulation of the interplay between apoptosis and autophagy. Autophagy inhibition accelerated methamphetamine-induced apoptosis, whereas autophagy induction attenuated the decrease in microglial survival. Moreover, anti-Mir143-dependent BBC3 upregulation reversed the methamphetamine-induced decrease in microglial survival via the regulation of apoptosis and autophagy. The in vivo relevance of these findings was confirmed in mouse models, which demonstrated that the microinjection of anti-Mir143 into the hippocampus ameliorated the methamphetamine-induced decrease in microglia as well as that observed in heterozygous Mir143+/− mice. These findings provide new insight regarding the specific contributions of Mir143-BBC3 to microglial survival in the context of drug abuse. PMID:27464000

Trace amine-associated receptor 1 regulation of methamphetamine-induced neurotoxicity.

PubMed

Miner, Nicholas B; Elmore, Josh S; Baumann, Michael H; Phillips, Tamara J; Janowsky, Aaron

2017-12-01

Trace amine-associated receptor 1 (TAAR1) is activated by methamphetamine (MA) and modulates dopaminergic (DA) function. Although DA dysregulation is the hallmark of MA-induced neurotoxicity leading to behavioral and cognitive deficits, the intermediary role of TAAR1 has yet to be characterized. To investigate TAAR1 regulation of MA-induced neurotoxicity, Taar1 transgenic knock-out (KO) and wildtype (WT) mice were administered saline or a neurotoxic regimen of 4 i.p. injections, 2h apart, of MA (2.5, 5, or 10mg/kg). Temperature data were recorded during the treatment day. Additionally, striatal tissue was collected 2 or 7days following MA administration for analysis of DA, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and tyrosine hydroxylase (TH) levels, as well as glial fibrillary acidic protein (GFAP) expression. MA elicited an acute hypothermic drop in body temperature in Taar1-WT mice, but not in Taar1-KO mice. Two days following treatment, DA and TH levels were lower in Taar1-KO mice compared to Taar1-WT mice, regardless of treatment, and were dose-dependently decreased by MA. GFAP expression was significantly increased by all doses of MA at both time points and greater in Taar1-KO compared to Taar1-WT mice receiving MA 2.5 or 5mg/kg. Seven days later, DA levels were decreased in a similar pattern: DA was significantly lower in Taar1-KO compared to Taar1-WT mice receiving MA 2.5 or 5mg/kg. TH levels were uniformly decreased by MA, regardless of genotype. These results indicate that activation of TAAR1 potentiates MA-induced hypothermia and TAAR1 confers sustained neuroprotection dependent on its thermoregulatory effects. Published by Elsevier B.V.

Effect of an electronic control device exposure on a methamphetamine-intoxicated animal model.

PubMed

Dawes, Donald M; Ho, Jeffrey D; Cole, Jon B; Reardon, Robert F; Lundin, Erik J; Terwey, Karen S; Falvey, Dan G; Miner, James R

2010-04-01

demonstrated cardiac capture during ECD exposure consistent with previous animal studies. In the larger animals, none of the methamphetamine-intoxicated animals demonstrated cardiac capture. Two control sheep showed evidence of capture similar to the smaller animals. No ventricular fibrillation occurred after the exposure in any animal. In smaller animals (32 kg or less), ECD exposure exacerbated atrial and ventricular irritability induced by methamphetamine intoxication, but this effect was not seen in larger, adult-sized animals. There were no episodes of ventricular fibrillation after exposure associated with ECD exposure in methamphetamine-intoxicated sheep.

When acute-stage psychosis and substance use co-occur: differentiating substance-induced and primary psychotic disorders.

PubMed

Caton, C L; Samet, S; Hasin, D S

2000-09-01

Substances such as alcohol, cocaine, amphetamine, and cannabis can produce psychotic reactions in individuals who are otherwise free of serious mental illness. However, persons with primary psychotic disorders, such as schizophrenia and bipolar disorder, who use these substances often present for treatment with signs and symptoms similar to those whose psychosis resulted from the use of drugs alone. While it is often difficult to distinguish substance-induced from primary psychoses, especially early in the course of treatment, this differential diagnosis has important implications for treatment planning. To help clinicians distinguish these two types of presentations, the authors first review the types of psychotic symptoms that can co-occur with substance use. They discuss the prevalence and patterns of substance use that have been found in patients with schizophrenia and other primary psychotic disorders and review the negative outcomes associated with substance use in this population. The prevalence of and types of symptoms and problems associated with psychotic symptoms that occur as a result of substance use alone are also reviewed. The authors describe assessment procedures for differentiating substance-induced and primary psychotic disorders. They stress the importance of accurately establishing the temporal relationship between the substance use and the onset and continuation of psychotic symptoms in making a differential diagnosis, as well as the importance of being familiar with the types of psychological symptoms that can occur with specific substances. The authors review the utility and limitations of a number of diagnostic instruments for assessing patients with co-occurring psychosis and substance use problems, including The Addiction Severity Index, The Michigan Alcohol Screening Test, and diagnostic interviews such as the Schedule for Affective Disorders and Schizophrenia and the Structured Clinical Interview for DSM. They then discuss the

Is an Abnormal ECG Just the Tip of the ICE-berg? Examining the Utility of Electrocardiography in Detecting Methamphetamine-Induced Cardiac Pathology.

PubMed

Paratz, Elizabeth D; Zhao, Jessie; Sherwen, Amanda K; Scarlato, Rose-Marie; MacIsaac, Andrew I

2017-07-01

Methamphetamine use is escalating in Australia and New Zealand, with increasing emergency department attendance and mortality. Cardiac complications play a large role in methamphetamine-related mortality, and it would be informative to assess the frequency of abnormal electrocardiograms (ECGs) amongst methamphetamine users. To determine the frequency and severity of ECG abnormalities amongst methamphetamine users compared to a control group. We conducted a retrospective cohort analysis on 212 patients admitted to a tertiary hospital (106 patients with methamphetamine use, 106 age and gender-matched control patients). Electrocardiograms were analysed according to American College of Cardiology guidelines. Mean age was 33.4 years, with 73.6% male gender, with no significant differences between groups in smoking status, ECG indication, or coronary angiography rates. Methamphetamine users were more likely to have psychiatric admissions (22.6% vs 1.9%, p<0.0001). Overall, ECG abnormalities were significantly more common (71.7% vs 32.1%, p<0.0001) in methamphetamine users, particularly tachyarrhythmias (38.7% vs 26.4%, p<0.0001), right axis deviation (7.5% vs 0.0%, p=0.004), left ventricular hypertrophy (26.4% vs 4.7%, p<0.0001), P pulmonale pattern (7.5% vs 0.9%, p=0.017), inferior Q waves (10.4% vs 0.0%, p=0.001), lateral T wave inversion (3.8% vs 0.0%, p=0.043), and longer QTc interval (436.41±31.61ms vs 407.28±24.38ms, p<0.0001). Transthoracic echocardiogram (n=24) demonstrated left ventricular dysfunction (38%), thrombus (8%), valvular lesions (17%), infective endocarditis (17%), and pulmonary hypertension (13%). Electrocardiograms were only moderately sensitive at predicting abnormal TTE. Electrocardiographic abnormalities are more common in methamphetamine users than age and gender-matched controls. Due to the high frequency of abnormalities, ECGs should be performed in all methamphetamine users who present to hospital. Methamphetamine users with abnormal ECGs

Role of Mitochondria in Methamphetamine-Induced Dopaminergic Neurotoxicity: Involvement in Oxidative Stress, Neuroinflammation, and Pro-apoptosis-A Review.

PubMed

Shin, Eun-Joo; Tran, Hai-Quyen; Nguyen, Phuong-Tram; Jeong, Ji Hoon; Nah, Seung-Yeol; Jang, Choon-Gon; Nabeshima, Toshitaka; Kim, Hyoung-Chun

2018-01-01

Methamphetamine (MA), an amphetamine-type psychostimulant, is associated with dopaminergic toxicity and has a high abuse potential. Numerous in vivo and in vitro studies have suggested that impaired mitochondria are critical in dopaminergic toxicity induced by MA. Mitochondria are important energy-producing organelles with dynamic nature. Evidence indicated that exposure to MA can disturb mitochondrial energetic metabolism by inhibiting the Krebs cycle and electron transport chain. Alterations in mitochondrial dynamic processes, including mitochondrial biogenesis, mitophagy, and fusion/fission, have recently been shown to contribute to dopaminergic toxicity induced by MA. Furthermore, it was demonstrated that MA-induced mitochondrial impairment enhances susceptibility to oxidative stress, pro-apoptosis, and neuroinflammation in a positive feedback loop. Protein kinase Cδ has emerged as a potential mediator between mitochondrial impairment and oxidative stress, pro-apoptosis, or neuroinflammation in MA neurotoxicity. Understanding the role and underlying mechanism of mitochondrial impairment could provide a molecular target to prevent or alleviate dopaminergic toxicity induced by MA.

The rise of methamphetamine in Southeast and East Asia.

PubMed

McKetin, Rebecca; Kozel, Nicholas; Douglas, Jeremy; Ali, Robert; Vicknasingam, Balasingam; Lund, Johannes; Li, Jih-Heng

2008-05-01

Southeast and East Asia has become a global hub for methamphetamine production and trafficking over the past decade. This paper describes the rise of methamphetamine supply and to what extent use of the drug is occurring in the region. The current review uses data collected through the Drug Abuse Information Network for Asia and the Pacific (DAINAP) and other available sources to analyse retrospectively methamphetamine trends within Southeast and East Asia. Southeast and East Asia has experienced a methamphetamine epidemic in the past decade which began around 1997 and peaked in 2000-2001. While the situation has since stabilised in many countries, methamphetamine trafficking and use are still increasing in parts of the Mekong region and there is evidence of large-scale manufacture in Cambodia, Indonesia, Malaysia and the Philippines. Methamphetamine is typically smoked or ingested, but injection of the drug is apparent. While the peak of the methamphetamine epidemic has passed in parts of Southeast and East Asia, attention is needed to minimise the potential consequences of spreading methamphetamine production, trafficking and use in the Mekong region and in the peninsular and archipelago of Southeast Asia.

Influencing Antibody-Mediated Attenuation of Methamphetamine CNS Distribution through Vaccine Linker Design.

PubMed

Gooyit, Major; Miranda, Pedro O; Wenthur, Cody J; Ducime, Alex; Janda, Kim D

2017-03-15

Active vaccination examining a single hapten engendered with a series of peptidic linkers has resulted in the production of antimethamphetamine antibodies. Given the limited chemical complexity of methamphetamine, the structure of the linker species embedded within the hapten could have a substantial effect on the ultimate efficacy of the resulting vaccines. Herein, we investigate linker effects by generating a series of methamphetamine haptens that harbor a linker with varying amino acid identity, peptide length, and associated carrier protein. Independent changes in each of these parameters were found to result in alterations in both the quantity and quality of the antibodies induced by vaccination. Although it was found that the consequence of the linker design was also dependent on the identity of the carrier protein, we demonstrate overall that the inclusion of a short, structurally simple, amino acid linker benefits the efficacy of a methamphetamine vaccine in limiting brain penetration of the free drug.

Imipenem-cilastatin-induced psychosis: a case report.

PubMed

Ninan, Jacob; George, Gemy Maria

2016-04-27

Elderly patients, in particular, have been reported to develop psychiatric side effects from antibiotics. Clarithromycin, quinolones, sulfamethoxazole-trimethoprim, isoniazid, penicillin, and cephalosporins have been reported to cause psychosis. This case report bridges a void in the medical literature with regards to the psychiatric adverse effects of imipenem-cilastatin. A 64-year-old Hispanic man in septic shock due to urinary tract infection was initiated on imipenem-cilastatin and mechanically ventilated, following admission to hospital. His mentation was normal for 72 hours after extubation and discontinuation of sedatives and opioids, following which he was noted to be in acute psychosis. Our patient's imipenem-cilastatin dose had been increased 24 hours prior to his violent visual and auditory hallucinations because his renal function had improved. The physical examination and laboratory tests did not reveal evidence of a new central nervous infection or endocrinopathy. His mentation improved after his antibiotic was switched to ceftriaxone, based on culture and sensitivity testing. Similar psychiatric symptoms developed 2 months later when he was treated with imipenem for a recurrent urinary tract infection. His symptoms again resolved with modification of his antibiotic regimen. Endocrine dysfunctions (thyroid, adrenal, and pituitary disorders) and toxic ingestions are medical disorders known to cause brief psychotic episodes. Fluoroquinolones, penicillins, and trimethoprim-sulfamethoxazole are common antibiotics associated with this rare adverse effect. Several pharmacokinetic hypotheses have been proposed for this adverse effect: (1) N-methyl-D-aspartate receptor hypofunctioning, (2) sequential blockade of folic acid production, (3) inhibition of prostaglandin E2 and proinflammatory cytokine production, (4) increased central dopamine turnover, and (5) accumulation of toxic levels of the drug. Pre-existing psychopathology, relevant comorbidities, slow

Modulation of methamphetamine-induced nitric oxide production by neuropeptide Y in the murine striatum.

PubMed

Yarosh, Haley L; Angulo, Jesus A

2012-11-05

Methamphetamine (METH) is a potent stimulant that induces both acute and long-lasting neurochemical changes in the brain including neuronal cell loss. Our laboratory demonstrated that the neuropeptide substance P enhances the striatal METH-induced production of nitric oxide (NO). In order to better understand the role of the striatal neuropeptides on the METH-induced production of NO, we used agonists and antagonists of the NPY (Y1R and Y2R) receptors infused via intrastriatal microinjection followed by a bolus of METH (30 mg/kg, ip) and measured 3-NT immunofluorescence, an indirect index of NO production. One striatum received pharmacological agent while the contralateral striatum received aCSF and served as control. NPY receptor agonists dose dependently attenuated the METH-induced production of striatal 3-NT. Conversely, NPY receptor antagonists had the opposite effect. Moreover, METH induced the accumulation of cyclic GMP and activated caspase-3 in approximately 18% of striatal neurons, a phenomenon that was attenuated by pre-treatment with NPY2 receptor agonist. Lastly, METH increased the levels of striatal preproneuropeptide Y mRNA nearly five-fold 16 h after injection as determined by RT-PCR, suggesting increased utilization of the neuropeptide. In conclusion, NPY inhibits the METH-induced production of NO in striatal tissue. Consequently, production of this second messenger induces the accumulation of cyclic GMP and activated caspase-3 in some striatal neurons, an event that may precede the apoptosis of some striatal neurons. Copyright © 2012 Elsevier B.V. All rights reserved.

The impact of age, HIV serostatus and seroconversion on methamphetamine use.

PubMed

Montoya, Jessica L; Cattie, Jordan; Morgan, Erin; Woods, Steven Paul; Cherner, Mariana; Moore, David J; Atkinson, J Hampton; Grant, Igor

2016-03-01

Characterizing methamphetamine use in relation to age, HIV serostatus and seroconversion is pertinent given the increasingly older age of the population with HIV and the intertwined epidemics of methamphetamine use and HIV. Study aims were to investigate whether (i) methamphetamine use differs by age and HIV serostatus, and (ii) receiving an HIV diagnosis impacts methamphetamine use among younger and older persons with HIV. This study examined methamphetamine use characteristics among 217 individuals with a lifetime methamphetamine dependence diagnosis who completed an in-person study assessment. Multivariable regressions revealed that HIV serostatus uniquely attenuates methamphetamine use, such that persons with HIV report a smaller cumulative quantity (β = -0.16, p = 0.01) and a fewer number of days (β = -0.18, p = 0.004) of methamphetamine use than persons without HIV. Among the HIV+ sample, all participants persisted in methamphetamine use after receiving an HIV diagnosis, with about 20% initiating use after seroconversion. Repeated measures analysis of variance indicated that density of methamphetamine use (i.e. grams per day used) was greater among the younger, relative to the older, HIV+ group (p = 0.02), and increased for both age groups following seroconversion (p < 0.001). These analyses indicate that although HIV serostatus may attenuate methamphetamine use behaviors, many people with HIV initiate, or persist in, methamphetamine use after receiving an HIV diagnosis. These findings raise the question of whether tailoring of prevention and intervention strategies might reduce the impact of methamphetamine and HIV across the age continuum.

Psychosis

PubMed Central

Arciniegas, David B.

2015-01-01

Purpose of Review: Psychosis is a common and functionally disruptive symptom of many psychiatric, neurodevelopmental, neurologic, and medical conditions and an important target of evaluation and treatment in neurologic and psychiatric practice. The purpose of this review is to define psychosis, communicate recent changes to the classification of and criteria for primary psychotic disorders described in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), and summarize current evidence-based approaches to the evaluation and management of primary and secondary psychoses. Recent Findings: The DSM-5 classification of and criteria for primary psychotic disorders emphasize that these conditions occur along a spectrum, with schizoid (personality) disorder and schizophrenia defining its mild and severe ends, respectively. Psychosis is also identified as only one of several dimensions of neuropsychiatric disturbance in these disorders, with others encompassing abnormal psychomotor behaviors, negative symptoms, cognitive impairments, and emotional disturbances. This dimensional approach regards hallucinations and delusions as arising from neural systems subserving perception and information processing, thereby aligning the neurobiological framework used to describe and study such symptoms in primary psychotic disorders with those used to study psychosis associated with other neurologic conditions. Summary: This article provides practicing neurologists with updates on current approaches to the diagnosis, evaluation, and treatment of primary and secondary psychoses. PMID:26039850

Association between cytochrome P450 2D6 polymorphisms and body fluid methamphetamine concentrations in Japanese forensic autopsy cases.

PubMed

Matsusue, Aya; Ikeda, Tomoya; Tani, Naoto; Waters, Brian; Hara, Kenji; Kashiwagi, Masayuki; Takayama, Mio; Ikematsu, Natsuki; Kubo, Shin-Ichi; Ishikawa, Takaki

2018-05-18

Methamphetamine (MA) is an illicit stimulant that affects the central nervous system. Cytochrome P450 2D6 (CYP2D6) plays an important role in MA metabolism. Numerous allelic variants confer substantial variation in CYP2D6 activity among individuals. In the present study, we examined the frequencies of CYP2D6 alleles, including CYP2D6*1, *2, *4, *5, *10, *14A, *14B, *18, and *36, and multiplication, in 82 forensic autopsy cases of MA abusers and 567 autopsy cases in which MA was not detected (controls). Ultrarapid metabolizer (UM), extensive metabolizer (EM), intermediate metabolizer (IM), and poor metabolizer (PM) phenotypes were predicted from CYP2D6 genotypes. Of MA abusers, 64 subjects were predicted to be EM, 17 were IM, and 1 was UM. No MA abuser had the predicted PM phenotype. No significant differences in CYP2D6 phenotype frequencies were found between MA abusers and controls. MA and amphetamine (AMP) concentrations were measured in the right heart blood, left heart blood, peripheral external iliac blood, urine, pericardial fluid, and bone marrow of MA abusers. MA concentrations in urine and bone marrow were significantly higher in IM than in EM. AMP concentration was not associated with CYP2D6 phenotype in any body fluid. These results suggest that the MA concentration in body fluids is influenced by CYP2D6 phenotypes in the Japanese population. Copyright © 2018 Elsevier B.V. All rights reserved.

Effects of the NMDA antagonist memantine on human methamphetamine discrimination.

PubMed

Hart, Carl L; Haney, Margaret; Foltin, Richard W; Fischman, Marian W

2002-12-01

The discriminative stimulus effects of N-methyl- D-aspartate (NMDA) antagonists have been assessed in laboratory animals. To date, no published study has assessed their ability to alter methamphetamine-related discriminative stimulus effects in humans. This study investigated the discriminative stimulus, subjective (e.g. "Good Drug Effect"), psychomotor performance, and cardiovascular effects (e.g. blood pressure) of oral methamphetamine following acute oral memantine (a non-competitive NMDA antagonist) in humans. Initially, participants were trained to discriminate 10 mg methamphetamine from placebo using a standard two-response procedure (drug versus placebo). Then, the effects of memantine (0, 40 mg) on methamphetamine discrimination were examined across several methamphetamine doses (0, 5, 10, 20 mg) using a novel-response procedure (drug versus placebo versus novel). Following placebo pretreatment, 10 mg methamphetamine produced 99% methamphetamine-appropriate responding and placebo produced 75% placebo-appropriate responding. Following memantine pretreatment, participants responded as if they had been given a novel compound, although memantine did not significantly alter most subjective-effects ratings following methamphetamine. Memantine alone produced "positive" subjective effects and novel drug-appropriate responding. These data indicate that the memantine-methamphetamine combination produced novel discriminative stimulus effects and that memantine produced some stimulant-like subjective effects.

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.

Methamphetamine use and dependence in vulnerable female populations.

PubMed

Kittirattanapaiboon, Phunnapa; Srikosai, Soontaree; Wittayanookulluk, Apisak

2017-07-01

The study reviews recent publications on methamphetamine use and dependence women in term of their epidemic, physical health impact, psychosocial impacts, and also in the identified vulnerable issues. Studies of vulnerable populations of women are wide ranging and include sex workers, sexual minorities, homeless, psychiatric patients, suburban women, and pregnant women, in which amphetamine type stimulants (ATSs) are the most commonly reported illicit drug used among them. The prenatal exposure of ATS demonstrated the small for gestational age and low birth weight; however, more research is needed on long-term studies of methamphetamine-exposed children. Intimate partner violence (IPV) is commonly reported by female methamphetamine users as perpetrators and victims. However, statistics and gendered power dynamics suggest that methamphetamine-related IPV indicates a higher chance of femicide. Methamphetamine-abusing women often have unresolved childhood trauma and are introduced to ATS through families or partners. Vulnerable populations of women at risk of methamphetamine abuse and dependence. Impacts on their physical and mental health, IPV, and pregnancy have been reported continuing, which guide that empowering and holistic substance abuse are necessary for specific group.

The War on Drugs: Methamphetamine, Public Health, and Crime.

PubMed

Dobkin, Carlos; Nicosia, Nancy

2009-03-01

In mid-1995, a government effort to reduce the supply of methamphetamine precursors successfully disrupted the methamphetamine market and interrupted a trajectory of increasing usage. The price of methamphetamine tripled and purity declined from 90 percent to 20 percent. Simultaneously, amphetaminerelated hospital and treatment admissions dropped 50 percent and 35 percent, respectively. Methamphetamine use among arrestees declined 55 percent. Although felony methamphetamine arrests fell 50 percent, there is no evidence of substantial reductions in property or violent crime. The impact was largely temporary. The price returned to its original level within four months; purity, hospital admissions, treatment admissions, and arrests approached preintervention levels within eighteen months. (JEL I12, K42).

Suicidality in first episode psychosis is associated with insight and negative beliefs about psychosis.

PubMed

Barrett, Elizabeth A; Sundet, Kjetil; Faerden, Ann; Agartz, Ingrid; Bratlien, Unni; Romm, Kristin Lie; Mork, Erlend; Rossberg, Jan Ivar; Steen, Nils Eiel; Andreassen, Ole A; Melle, Ingrid

2010-11-01

Suicidal behaviour is prevalent in psychotic disorders. Insight has been found to be associated with increased risk for suicidal behaviour, but not consistently. A possible explanation for this is that insight has different consequences for patients depending on their beliefs about psychosis. The present study investigated whether a relationship between insight, negative beliefs about psychosis and suicidality was mediated by depressive symptoms, and if negative beliefs about psychosis moderated the relationship between insight and suicidality in patients with a first episode of psychosis (FEP). One hundred ninety-four FEP-patients were assessed with a clinical interview for diagnosis, symptoms, functioning, substance use, suicidality, insight, and beliefs about psychosis. Nearly 46% of the patients were currently suicidal. Depressive symptoms, having a schizophrenia spectrum disorder, insight, and beliefs about negative outcomes for psychosis were independently associated with current suicidality; contradicting a mediating effect of depressive symptoms. Negative beliefs about psychosis did not moderate the effect of insight on current suicidality. The results indicate that more depressive symptoms, higher insight, and negative beliefs about psychosis increase the risk for suicidality in FEP-patients. The findings imply that monitoring insight should be part of assessing the suicide risk in patients with FEP, and that treating depression and counteracting negative beliefs about psychosis may possibly reduce the risk for suicidality. Copyright © 2010 Elsevier B.V. All rights reserved.

Relationship between menarche and psychosis onset in women with first episode of psychosis.

PubMed

Rubio-Abadal, Elena; Usall, Judith; Barajas, Anna; Carlson, Janina; Iniesta, Raquel; Huerta-Ramos, Elena; Baños, Iris; Dolz, Montserrat; Sánchez, Bernardo; Ochoa, Susana

2016-10-01

The aim of this study was to explore the relationship between age at menarche and age at first episode of psychosis, as well as clinical severity and outcome, in a population of women with first-episode psychosis. Clinical and socio-demographical data, age at menarche and at first-episode psychosis, parental history of psychosis and cannabis-use habits were obtained from 42 subjects with a first episode of psychosis. Positive and Negative Syndrome Scale, Clinical Global Impression, Global Assessment Function, Disability Assessment Schedule, Wechsler Adult Intelligence Scale and Wechsler Intelligence Scale for Children, European Quality of Life, and Lewis and Murray Obstetric Complication Scales were administered. Statistical analysis was performed by means of zero-order correlations and Mann-Whitney U and Kruskal-Wallis tests using SPSS version 17.0. We found no significant correlation between age at menarche and age at first-episode psychosis, or with the clinical scores performed. We observed that subjects with earlier age at menarche had more parental history of psychosis. Our negative results do not support the theory of a possible protective role of oestrogen, which seems to be more complex than previously thought. We would suggest that further research is needed to investigate developmental influences of sex steroids on the onset of psychosis and potentially therapeutic benefits based upon oestrogen. © 2014 Wiley Publishing Asia Pty Ltd.

Histopathological study of cardiac lesions in methamphetamine poisoning-related deaths.

PubMed

Akhgari, Maryam; Mobaraki, Homeira; Etemadi-Aleagha, Afshar

2017-02-17

Methamphetamine abuse is a worldwide health concern. Methamphetamine causes health hazards in many vital organs. It can cause damage to cardiac tissue via catecholamines release. Methamphetamine related deaths are becoming one of the most important problems in Iran. The purpose of the present study was to determine cardiac pathology in methamphetamine poisoning-related deaths. The study included 100 cases of methamphetamine poisoning-related deaths and 100 cases as control group. Toxicology analysis of liver, gastric content, bile, urine, blood and vitreous humor were conducted to detect drugs, poisons and alcohols using thin layer chromatography, gas chromatography/mass spectrometry, and high performance liquid chromatography. Positive toxicology analysis results except for amphetamine and methamphetamine were excluded from the study in order to omit interfering factors. The most striking features of cardiac damage were observed by light microscopy. Methamphetamine and amphetamine were detected in either urine or gastric content samples. In all of the cases methamphetamine toxicity was determined to be a direct cause of death by forensic medicine practitioner. Cardiovascular pathology was noted in 68% of studied cases. The most common histopathologic features were myocardial fiber hypertrophy, mild, moderate to severe atherosclerosis and focal degeneration/necrosis. The results of the present study indicate that cardiotoxicity is one of the major contributing factors in methamphetamine poisoning related deaths. Overall, the current study highlights the fact that cardiotoxic effects of methamphetamine can explain increasing reports of heart failure and consequently death in young abusers. Not applicable. Histopathological study of cardiac lesions in methamphetamine poisoning-related deaths.

The Vesicular Monoamine Transporter-2: An Important Pharmacological Target for the Discovery of Novel Therapeutics to Treat Methamphetamine Abuse

PubMed Central

Nickell, Justin R.; Siripurapu, Kiran B.; Vartak, Ashish; Crooks, Peter A.; Dwoskin, Linda P.

2014-01-01

Methamphetamine abuse escalates, but no approved therapeutics are available to treat addicted individuals. Methamphetamine increases extracellular dopamine in reward-relevant pathways by interacting at vesicular monoamine transporter-2 (VMAT2) to inhibit dopamine uptake and promote dopamine release from synaptic vesicles, increasing cytosolic dopamine available for reverse transport by the dopamine transporter (DAT). VMAT2 is the target of our iterative drug discovery efforts to identify pharmacotherapeutics for methamphetamine addiction. Lobeline, the major alkaloid in Lobelia inflata, potently inhibited VMAT2, methamphetamine-evoked striatal dopamine release, and methamphetamine self-administration in rats but exhibited high affinity for nicotinic acetylcholine receptors (nAChRs). Defunctionalized, unsaturated lobeline analog, meso-transdiene (MTD), exhibited lobeline-like in vitro pharmacology, lacked nAChR affinity, but exhibited high affinity for DAT, suggesting potential abuse liability. The 2,4-dicholorophenyl MTD analog, UKMH-106, exhibited selectivity for VMAT2 over DAT, inhibited methamphetamine-evoked dopamine release, but required a difficult synthetic approach. Lobelane, a saturated, defunctionalized lobeline analog, inhibited the neurochemical and behavioral effects of methamphetamine; tolerance developed to the lobelane-induced decrease in methamphetamine self-administration. Improved drug-likeness was afforded by the incorporation of a chiral N-1,2-dihydroxypropyl moiety into lobelane to afford GZ-793A, which inhibited the neurochemical and behavioral effects of methamphetamine, without tolerance. From a series of 2,5-disubstituted pyrrolidine analogs, AV-2-192 emerged as a lead, exhibiting high affinity for VMAT2 and inhibiting methamphetamine-evoked dopamine release. Current results support the hypothesis that potent, selective VMAT2 inhibitors provide the requisite preclinical behavioral profile for evaluation as pharmacotherapeutics for

PKCδ-dependent p47phox activation mediates methamphetamine-induced dopaminergic neurotoxicity.

PubMed

Dang, Duy-Khanh; Shin, Eun-Joo; Kim, Dae-Joong; Tran, Hai-Quyen; Jeong, Ji Hoon; Jang, Choon-Gon; Ottersen, Ole Petter; Nah, Seung-Yeol; Hong, Jau-Shyong; Nabeshima, Toshitaka; Kim, Hyoung-Chun

2018-02-01

Protein kinase C (PKC) has been recognized to activate NADPH oxidase (PHOX). However, the interaction between PKC and PHOX in vivo remains elusive. Treatment with methamphetamine (MA) resulted in a selective increase in PKCδ expression out of PKC isoforms. PKCδ co-immunoprecipitated with p47phox, and facilitated phosphorylation and membrane translocation of p47phox. MA-induced increases in PHOX activity and reactive oxygen species were attenuated by knockout of p47phox or PKCδ. In addition, MA-induced impairments in the Nrf-2-related glutathione synthetic system were also mitigated by knockout of p47phox or PKCδ. Glutathione-immunoreactivity was co-localized in Iba-1-labeled microglial cells and in NeuN-labeled neurons, but not in GFAP-labeled astrocytes, reflecting the necessity for self-protection against oxidative stress by mainly microglia. Buthionine-sulfoximine, an inhibitor of glutathione biosynthesis, potentiated microglial activation and pro-apoptotic changes, leading to dopaminergic losses. These neurotoxic processes were attenuated by rottlerin, a pharmacological inhibitor of PKCδ, genetic inhibitions of PKCδ [i.e., PKCδ knockout mice (KO) and PKCδ antisense oligonucleotide (ASO)], or genetic inhibition of p47phox (i.e., p47phox KO or p47phox ASO). Rottlerin did not exhibit any additive effects against the protective activity offered by genetic inhibition of p47phox. Therefore, we suggest that PKCδ is a critical regulator for p47phox activation induced by MA, and that Nrf-2-dependent GSH induction via inhibition of PKCδ or p47phox, is important for dopaminergic protection against MA insult. Copyright © 2017 Elsevier Inc. All rights reserved.

The Impact of Age, HIV Serostatus and Seroconversion on Methamphetamine Use

PubMed Central

Montoya, Jessica L.; Cattie, Jordan; Morgan, Erin; Woods, Steven Paul; Cherner, Mariana; Moore, David J.; Atkinson, J. Hampton; Grant, Igor

2016-01-01

Background Characterizing methamphetamine use in relation to age, HIV serostatus and seroconversion is pertinent given the increasingly older age of the population with HIV and the intertwined epidemics of methamphetamine use and HIV. Objectives Study aims were to investigate whether 1) methamphetamine use differs by age and HIV serostatus and 2) receiving an HIV diagnosis impacts methamphetamine use among younger and older persons with HIV. Methods This study examined methamphetamine use characteristics among 217 individuals with a lifetime methamphetamine dependence diagnosis who completed an in-person study assessment. Results Multivariable regressions revealed that HIV serostatus uniquely attenuates methamphetamine use, such that persons with HIV report a smaller cumulative quantity (β = −.16, p = .01) and a fewer number of days (β = −.18, p = .004) of methamphetamine use than persons without HIV. Among the HIV+ sample, all participants persisted in methamphetamine use after receiving an HIV diagnosis, with about 20% initiating use after seroconversion. Repeated measures analysis of variance indicated that density of methamphetamine use (i.e., grams per day used) was greater among the younger, relative to the older, HIV+ group (p = .02), and increased for both age groups following seroconversion (p < .001). Conclusion These analyses indicate that although HIV serostatus may attenuate methamphetamine use behaviors, many people with HIV initiate, or persist in, methamphetamine use after receiving an HIV diagnosis. These findings raise the question of whether tailoring of prevention and intervention strategies might reduce the impact of methamphetamine and HIV across the age continuum. PMID:26837461

HIV Prevalence and Risk among Heterosexual Methamphetamine Injectors in California

PubMed Central

Kral, Alex H.; Lorvick, Jennifer; Martinez, Alexis; Lewis, Megan A.; Orr, Alexander; Anderson, Rachel; Flynn, Neil; Bluthenthal, Ricky N.

2013-01-01

This CDC-funded study compares HIV prevalence and risk behavior among heterosexual methamphetamine (n=428) and non-methamphetamine (n=878) injectors in California, USA during 2001–2003. While HIV was not highly prevalent among methamphetamine injectors (3%), sexual and injection risk behaviors were highly prevalent (ranging from 21% to 72%). In multivariate analyses, methamphetamine injectors had higher odds than non-methamphetamine injectors of unprotected vaginal intercourse and sex with five or more sexual partners in the past six months, and of distributive and receptive syringe sharing in the past thirty days. There was no significant difference in HIV sero-status by methamphetamine use. Suggestions are made for designing HIV prevention programs. PMID:21391786

Methamphetamine Use: Hazards and Social Influences.

ERIC Educational Resources Information Center

Wermuth, Laurie

2000-01-01

Presents data on methamphetamine use in the United States and the economic and social pressures that may partially explain expanded methamphetamine use. Recommends a policy response that utilizes a public health approach, including prevention campaigns, harm-reduction outreach and treatment approaches, and pharmacologic and abstinence-based drug…

[Japanese epidemiologic investigation for non-steroidal anti-inflammatory drugs-induced ulcers].

PubMed

Miyake, Kazumasa; Sakamoto, Choitsu

2011-06-01

This review summaried epidemiologic investigation for non-steroidal anti-inflammatory drugs (NSAIDs)-induced ulcers to focus on the Japanese evidence. In Japan, national health insurance does not cover procedures that prevent or lower the risk for NSAIDs-induced ulcer. In NSAIDs treatment to patients with risk factors, it is desirable to administer antiulcer agents. However, in Japan, there are no large-scale studies on the efficacy of co-medication such as proton pump inhibitors, prostaglandin analogs (misoprostol) or histamine-H2 receptor antagonists or on the effectiveness of H. pylori eradication or selective COX-2 antagonists. In the future, large-scale clinical studies should be conducted to accumulate high quality evidence including cost-effectiveness and overall safety including cardiovascular events, because Japanese differ from Westerners in several genetical or acquired factors.

Methamphetamine-associated dysregulation of the hypothalamic-pituitary-thyroid axis.

PubMed

Jones, Deborah L; Carrico, Adam W; Babayigit, Suat; Rodriguez, Violeta J; Aguila, Carlos; Kumar, Mahendra

2018-05-17

Methamphetamine and HIV impair thyroid function, but few studies have investigated their combined effects on thyroid dysregulation. This study examined the associations of methamphetamine use alone and in combination with HIV on thyroid function among men in South Florida. Measures of thyroid function in methamphetamine-using, HIV-infected (METH+HIV+; n = 127) and HIV-negative (METH+HIV-; n = 46) men who have sex with men (MSM) were compared to non-methamphetamine-using, HIV-negative men (METH-HIV-; n = 136). Thyroid function was dysregulated in methamphetamine-using MSM, irrespective of HIV status. Both meth-using groups had greater odds of abnormal thyroid stimulating hormone levels and significantly higher mean free triiodothyronine (T3) levels. Elevated free T3 was associated with greater depressive symptoms. Overall, outcomes have important implications for assessment of thyroid function in methamphetamine users, particularly among those presenting with depression.

Capillary microextraction: A new method for sampling methamphetamine vapour.

PubMed

Nair, M V; Miskelly, G M

2016-11-01

Clandestine laboratories pose a serious health risk to first responders, investigators, decontamination companies, and the public who may be inadvertently exposed to methamphetamine and other chemicals used in its manufacture. Therefore there is an urgent need for reliable methods to detect and measure methamphetamine at such sites. The most common method for determining methamphetamine contamination at former clandestine laboratory sites is selected surface wipe sampling, followed by analysis with gas chromatography-mass spectrometry (GC-MS). We are investigating the use of sampling for methamphetamine vapour to complement such wipe sampling. In this study, we report the use of capillary microextraction (CME) devices for sampling airborne methamphetamine, and compare their sampling efficiency with a previously reported dynamic SPME method. The CME devices consisted of PDMS-coated glass filter strips inside a glass tube. The devices were used to dynamically sample methamphetamine vapour in the range of 0.42-4.2μgm -3 , generated by a custom-built vapour dosing system, for 1-15min, and methamphetamine was analysed using a GC-MS fitted with a ChromatoProbe thermal desorption unit. The devices showed good reproducibility (RSD<15%), and a curvilinear pre-equilibrium relationship between sampling times and peak area, which can be utilised for calibration. Under identical sampling conditions, the CME devices were approximately 30 times more sensitive than the dynamic SPME method. The CME devices could be stored for up to 3days after sampling prior to analysis. Consecutive sampling of methamphetamine and its isotopic substitute, d-9 methamphetamine showed no competitive displacement. This suggests that CME devices, pre-loaded with an internal standard, could be a feasible method for sampling airborne methamphetamine at former clandestine laboratories. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Targeting oxidative stress, acetylcholinesterase, proinflammatory cytokine, dopamine and GABA by eucalyptus oil (Eucalyptus globulus) to alleviate ketamine-induced psychosis in rats.

PubMed

Yadav, Monu; Jindal, Deepak Kumar; Parle, Milind; Kumar, Anil; Dhingra, Sameer

2018-02-20

Essential oil of eucalyptus species is among the most common traded essential oils in the world. There is an increasing interest in the application of eucalyptus oil as a natural additive in food and pharmaceutical industry. The present study was undertaken to identify the phytoconstituents present in the essential oil of Eucalyptus globulus leaves (EO) and ascertain their protective effect against ketamine-induced psychosis in rats. GC-MS technique was used for analysis of phytoconstituents present in EO. Ketamine (50 mg/kg, i.p.) was used to induce psychosis in rats. Photoactometer, forced swim test and pole climb avoidance test were used to evaluate the protective effects of the EO (500, 1000 and 2000 mg/kg, p.o.) on acute and chronic administration. Bar test was used to test the side effect of EO. Biochemical and neurochemical estimations were carried out to explore the possible mechanism of action. GC-MS analysis of EO showed the presence of a number of biologically active compounds. EO at the dose of 500, 1000 and 2000 mg/kg, p.o. on acute and chronic administration, decreased locomotor activity, immobility duration and latency to climb the pole. EO was effective to facilitate the release of GABA, increase GSH levels, inhibit dopamine neurotransmission and decrease TNF-α levels as well as diminish AChE activity in different regions of the brain. EO at the dose of 500, 1000 mg/kg did not produce cataleptic behavior in rats. EO at the dose of 500, 1000 mg/kg produced protective effects against ketamine-induced psychosis and can be further explored clinically against neuropsychiatric disorders.

Alterations in malondialdehyde levels and laboratory parameters among methamphetamine abusers.

PubMed

Suriyaprom, Kanjana; Tanateerabunjong, Rossukon; Tungtrongchitr, Anchalee; Tungtrongchitr, Rungsunn

2011-12-01

To determine the concentrations of malondialdehyde, biochemical, and hematological parameters among methamphetamine abusers compared with a healthy control group and to evaluate the association between malondialdehyde and biochemical-hematological parameters. The concentrations of malondialdehyde, lipids, liver enzymes, albumin, blood urea nitrogen, creatinine, and hematological measurements were determined in 60 methamphetamine abusers and 60 controls. Significantly higher levels of malondialdehyde were found in the methamphetamine abusers than the controls [2.45 (2.12-2.81) vs. 1.41 (1.15-2.08)]. The levels ofalanine aminotransferase and alkaline phosphatase and white blood cell and platelet counts of the methamphetamine abusers were significantly elevated (p-value < 0.05) compared with the controls. Meanwhile, the levels of hemoglobin, hematocrit, albumin and body mass index were significantly lower among the methamphetamine-abusing group than the control group (p-value < 0.05). It was found that higher numbers of methamphetamine tablets per day were associated with higher malondialdehyde concentrations in methamphetamine abusers, and that malondialdehyde concentration inversely correlated with albumin level (r = -0.458, p-value < 0.05). Stepwise multiple regression analysis revealed that number of methamphetamine tablets per day, white blood cell count and albumin level were independent predictors of malondialdehyde level (p-value < 0.05). Methamphetamine abuse is related to increased lipid peroxidation, changes in inflammatory marker level, increase in liver enzymes, and decrease in hemoglobin and hematocrit concentrations. These effects may be early signs of the development of diseases associated with methamphetamine abuse.

Stroke and methamphetamine use in young adults: a review.

PubMed

Lappin, Julia M; Darke, Shane; Farrell, Michael

2017-12-01

Methamphetamine use and stroke are significant public health problems. Strokes among people aged below 45 years are much less common than in older age groups but have significant mortality and morbidity. Methamphetamine is a putative cause of strokes among younger people. A review of methamphetamine-related strokes was conducted. Bibliographic databases were searched until February 2017 for articles related to methamphetamine and stroke. Both haemorrhagic and ischaemic strokes were considered. Of 370 articles screened, 77 were selected for inclusion. There were 81 haemorrhagic and 17 ischaemic strokes reported in case reports and series. Both types were approximately twice as common in males. Route of administration associated with haemorrhagic stroke was typically oral or injecting, but for ischaemic stroke inhalation was most common. Haemorrhagic stroke was associated with vascular abnormalities in a third of cases. One quarter of individuals completely recovered, and a third died following haemorrhagic stroke. One-fifth completely recovered, and one-fifth died following ischaemic stroke. There is a preponderance of haemorrhagic strokes associated with methamphetamine use in young people, and methamphetamine-related stroke is associated with poor clinical outcomes. Mechanisms of methamphetamine-associated stroke include hypertension, vasculitis, direct vascular toxicity and vasospasm. In a period of rising worldwide methamphetamine use, the incidence of methamphetamine-related stroke will increase, with a consequent increase in the burden of disease contributed by such events. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Higher cortical and lower subcortical metabolism in detoxified methamphetamine abusers.

PubMed

Volkow, N D; Chang, L; Wang, G J; Fowler, J S; Franceschi, D; Sedler, M J; Gatley, S J; Hitzemann, R; Ding, Y S; Wong, C; Logan, J

2001-03-01

Methamphetamine has raised concerns because it may be neurotoxic to the human brain. Although prior work has focused primarily on the effects of methamphetamine on dopamine cells, there is evidence that other neuronal types are affected. The authors measured regional brain glucose metabolism, which serves as a marker of brain function, to assess if there is evidence of functional changes in methamphetamine abusers in regions other than those innervated by dopamine cells. Fifteen detoxified methamphetamine abusers and 21 comparison subjects underwent positron emission tomography following administration of [(18)F]fluorodeoxyglucose. Whole brain metabolism in the methamphetamine abusers was 14% higher than that of comparison subjects; the differences were most accentuated in the parietal cortex (20%). After normalization for whole brain metabolism, methamphetamine abusers exhibited significantly lower metabolism in the thalamus (17% difference) and striatum (where the differences were larger for the caudate [12%] than for the putamen [6%]). Statistical parametric mapping analyses corroborated these findings, revealing higher metabolism in the parietal cortex and lower metabolism in the thalamus and striatum of methamphetamine abusers. The fact that the parietal cortex is a region devoid of any significant dopaminergic innervation suggests that the higher metabolism seen in this region in the methamphetamine abusers is the result of methamphetamine effects in circuits other than those modulated by dopamine. In addition, the lower metabolism in the striatum and thalamus (major outputs of dopamine signals into the cortex) is likely to reflect the functional consequence of methamphetamine in dopaminergic circuits. These results provide evidence that, in humans, methamphetamine abuse results in changes in function of dopamine- and nondopamine-innervated brain regions.

Methamphetamine intoxication in a dog: case report.

PubMed

Pei, Zengyang; Zhang, Xu

2014-06-24

Methamphetamine abuse has undergone a dramatic worldwide increase, and represents a significant and global issue for public health. Incidents of methamphetamine intoxication and death in humans are relatively commonplace. Because of its increasing illicit availability, together with legitimate use in human medicine, accidental or intentional exposure to methamphetamine in dogs is becoming a more likely scenario. A 3-year-old, 3.7 kg intact female Miniature Poodle who had been intentionally fed an unknown amount of a crystalline-like substance developed extreme agitation, seizures, tachycardia, hyperthermia, hypertension, disseminated intravascular coagulation (DIC), bloody diarrhea, and dilated pupils. Blood work revealed leukocytosis, erythropenia, lymphocytosis, thrombocytopenia, coagulation abnormalities, but all to a mild extent, together with mild elevation in both alanine aminotranferease (ALT) and alkaline phosphatase (ALKP), and a mild decreased in glucose. Radiologic diagnosis revealed generalized, severe distension of the stomach and small intestinal tract with air. Immunochromatographic screening tests and gas chromatography mass spectrometry analysis confirmed methamphetamine intoxication and revealed concentrations of methamphetamine in blood and urine of 0.32 μg/mL and 2.35 μg/mL respectively. The dog demonstrated progressive improvement after supportive care, with the high fever resolved over the initial 24 hours of hospitalization, and agitation was successfully controlled beyond 48 hours after initial hospitalization. Hemostatic abnormalities were progressive improved after heparin therapy and supportive care. By the sixth day of hospitalization the dog was clinically well, and all laboratory data had returned to normal with the exception of a mild elevateion of ALKP. To the authors' knowledge, this is the second case report of methamphetamine intoxication in dogs presented in veterinary practice in open literature so far. Although rare

Increased /sup 3/H-spiperone binding sites in mesolimbic area related to methamphetamine-induced behavioral hypersensitivity

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

Akiyama, K.; Sato, M.; Otsuki, S.

1982-02-01

The specific /sup 3/H-spiperone binding to membrane homogenates of the striatum, mesolimbic area, and frontal cortex was examined in two groups of rats pretreated once daily with saline or 4 mg/kg of methamphetamine (MAP) for 14 days. At 7 days following cessation of chronic pretreatment, all rats received an injection of 4 mg/kg of MAP and were decapitated 1 hr after the injection. In the chronic saline-pretreatment group, the single administration of MAP induced significant changes in the number (Bmax) of specific /sup 3/H-spiperone binding sites (a decrease in the striatum and an increase in the mesolimbic area and frontalmore » cortex), but no significant changes in the affinity (KD) in any brain area. The chronic MAP pretreatment markedly augmented the changes in Bmax in the striatum and mesolimbic area. The increase in specific /sup 3/H-spiperone binding sites in the mesolimbic area is discussed in relation to MAP-induced behavioral hypersensitivity.« less

Obstacles to care in first-episode psychosis patients with a long duration of untreated psychosis.

PubMed

Bay, Nina; Bjørnestad, Jone; Johannessen, Jan O; Larsen, Tor K; Joa, Inge

2016-02-01

This qualitative study is a sub-study of the early 'Treatment and Intervention in Psychosis Study' (TIPS-2), a program for early intervention strategies for people experiencing a first episode of psychosis. We aimed to improve knowledge about factors that prevent or delay patients with a long duration of psychosis from accessing psychiatric health-care services at an earlier illness stage and their personal views on the impact of ongoing informational campaigns (ICs) on help-seeking behaviour. Following an interpretative-phenomenological approach, eight consecutive TIPS-2 patients with duration of untreated psychosis lasting for more than 6 months were interviewed. The interviews were analysed using a meaning condensation procedure. Five main themes were identified: (i) participants' failure to recognize symptoms of psychosis; (ii) difficulties expressing their experiences; (iii) concerns about stigma; (iv) poor psychosis detection skills among health-care professionals; and (v) participants' lack of awareness or understanding of ICs. The five themes identified may suggest that despite exposure to the targeted ICs, participants were unable to recognize or understand the severity of their symptoms. Further, although family members or others sometimes recognized the initial symptoms of psychosis development, these symptoms were attributed to reasons other than psychosis. Participants reported that health-care personnel also had trouble identifying emerging signs of psychosis. The ICs need to be carefully crafted to relay information to people who do not consider themselves as currently experiencing signs of psychosis. © 2014 Wiley Publishing Asia Pty Ltd.

Pharmacotherapeutic agents in the treatment of methamphetamine dependence.

PubMed

Morley, Kirsten C; Cornish, Jennifer L; Faingold, Alon; Wood, Katie; Haber, Paul S

2017-05-01

Methamphetamine use is a serious public health concern in many countries and is second to cannabis as the most widely abused illicit drug in the world. Effective management for methamphetamine dependence remains elusive and the large majority of methamphetamine users relapse following treatment. Areas covered: Progression in the understanding of the pharmacological basis of methamphetamine use has provided us with innovative opportunities to develop agents to treat dependence. The current review summarizes relevant literature on the neurobiological and clinical correlates associated with methamphetamine use. We then outline agents that have been explored for potential treatments in preclinical studies, human laboratory phase I and phase II trials over the last ten years. Expert opinion: No agent has demonstrated a broad and strong effect in achieving MA abstinence in Phase II trials. Agents with novel therapeutic targets appear promising. Advancement in MA treatment, including translation into practice, faces several clinical challenges.

A critical role of striatal A2A R-mGlu5 R interactions in modulating the psychomotor and drug-seeking effects of methamphetamine.

PubMed

Wright, Sherie R; Zanos, Panos; Georgiou, Polymnia; Yoo, Ji-Hoon; Ledent, Catherine; Hourani, Susanna M; Kitchen, Ian; Winsky-Sommerer, Raphaelle; Bailey, Alexis

2016-07-01

Addiction to psychostimulants is a major public health problem with no available treatment. Adenosine A2A receptors (A2A R) co-localize with metabotropic glutamate 5 receptors (mGlu5 R) in the striatum and functionally interact to modulate behaviours induced by addictive substances, such as alcohol. Using genetic and pharmacological antagonism of A2A R in mice, we investigated whether A2A R-mGlu5 R interaction can regulate the locomotor, stereotypic and drug-seeking effect of methamphetamine and cocaine, two drugs that exhibit distinct mechanism of action. Genetic deletion of A2A R, as well as combined administration of sub-threshold doses of the selective A2A R antagonist (SCH 58261, 0.01 mg/kg, i.p.) with the mGlu5 R antagonist, 3-((2-methyl-4-thiazolyl)ethynyl)pyridine (0.01 mg/kg, i.p.), prevented methamphetamine- but not cocaine-induced hyperactivity and stereotypic rearing behaviour. This drug combination also prevented methamphetamine-rewarding effects in a conditioned-place preference paradigm. Moreover, mGlu5 R binding was reduced in the nucleus accumbens core of A2A R knockout (KO) mice supporting an interaction between these receptors in a brain region crucial in mediating addiction processes. Chronic methamphetamine, but not cocaine administration, resulted in a significant increase in striatal mGlu5 R binding in wild-type mice, which was absent in the A2A R KO mice. These data are in support of a critical role of striatal A2A R-mGlu5 R functional interaction in mediating the ambulatory, stereotypic and reinforcing effects of methamphetamine but not cocaine-induced hyperlocomotion or stereotypy. The present study highlights a distinct and selective mechanistic role for this receptor interaction in regulating methamphetamine-induced behaviours and suggests that combined antagonism of A2A R and mGlu5 R may represent a novel therapy for methamphetamine addiction. © 2015 Society for the Study of Addiction.

Pharmacological characterization of psychosis-like behavior in the MPTP-lesioned nonhuman primate model of Parkinson's disease.

PubMed

Visanji, Naomi P; Gomez-Ramirez, Jordi; Johnston, Tom H; Pires, Donna; Voon, Valerie; Brotchie, Jonathan M; Fox, Susan H

2006-11-01

Investigation of the pathophysiology of psychosis in Parkinson's disease (PD), as well as the assessment of potential novel therapeutics, has been limited by the lack of a well-validated animal model. MPTP-lesioned primates exhibit abnormal behaviors that are distinct from dyskinesia and parkinsonism and may represent behavioral correlates of neural processes related to psychosis in PD. Here we assess four types of behavior--agitation, hallucinatory-like responses to nonapparent stimuli, obsessive grooming, and stereotypies that are termed "psychosis-like"--and define their pharmacology using a psychosis-like behavior rating scale. By assessing the actions of drugs known to enhance or attenuate psychosis in PD patients, we find that the pharmacology of these behaviors recapitulates, in several respects, the pharmacology of psychosis in PD. Thus, levodopa and apomorphine elicited psychosis-like behaviors. Amantadine significantly decreased levodopa-induced dyskinesia but exacerbated psychosis-like behaviors. Haloperidol reduced psychosis-like behaviors but at the expense of increased parkinsonian disability while the atypical neuroleptics clozapine and quetiapine reduced psychosis-like behaviors without significant effect on parkinsonian disability. The response of different components of the psychotomimetic behavior suggested the involvement of both dopaminergic and nondopaminergic mechanisms in their expression.

The newly synthesized pool of dopamine determines the severity of methamphetamine-induced neurotoxicity.

PubMed

Thomas, David M; Francescutti-Verbeem, Dina M; Kuhn, Donald M

2008-05-01

The neurotransmitter dopamine (DA) has long been implicated as a participant in the neurotoxicity caused by methamphetamine (METH), yet, its mechanism of action in this regard is not fully understood. Treatment of mice with the tyrosine hydroxylase (TH) inhibitor alpha-methyl-p-tyrosine (AMPT) lowers striatal cytoplasmic DA content by 55% and completely protects against METH-induced damage to DA nerve terminals. Reserpine, by disrupting vesicle amine storage, depletes striatal DA by more than 95% and accentuates METH-induced neurotoxicity. l-DOPA reverses the protective effect of AMPT against METH and enhances neurotoxicity in animals with intact TH. Inhibition of MAO-A by clorgyline increases pre-synaptic DA content and enhances METH striatal neurotoxicity. In all conditions of altered pre-synaptic DA homeostasis, increases or decreases in METH neurotoxicity paralleled changes in striatal microglial activation. Mice treated with AMPT, l-DOPA, or clorgyline + METH developed hyperthermia to the same extent as animals treated with METH alone, whereas mice treated with reserpine + METH were hypothermic, suggesting that the effects of alterations in cytoplasmic DA on METH neurotoxicity were not strictly mediated by changes in core body temperature. Taken together, the present data reinforce the notion that METH-induced release of DA from the newly synthesized pool of transmitter into the extracellular space plays an essential role in drug-induced striatal neurotoxicity and microglial activation. Subtle alterations in intracellular DA content can lead to significant enhancement of METH neurotoxicity. Our results also suggest that reactants derived from METH-induced oxidation of released DA may serve as neuronal signals that lead to microglial activation early in the neurotoxic process associated with METH.

Baclofen facilitates the extinction of methamphetamine-induced conditioned place preference in rats

PubMed Central

Voigt, Robin M.; Herrold, Amy A.; Napier, T. Celeste

2011-01-01

The powerful, long-lasting association between the rewarding effects of a drug and contextual cues associated with drug administration can be studied using conditioned place preference (CPP). The GABAB receptor agonist baclofen facilitates the extinction of morphine-induced CPP in mice. The current study extended this work by determining if baclofen could enhance the extinction of methamphetamine (Meth) CPP. CPP was established using a six day conditioning protocol wherein Meth-pairings were alternated with saline-pairings. Rats were subsequently administered baclofen (2mg/kg i.p. or vehicle) immediately after each daily forced extinction session, which consisted of a saline injection immediately prior to being placed into the previously Meth- or saline-paired chamber. One extinction training cycle, consisted of six once-daily forced extinction sessions, mimicking the alternating procedure established during conditioning, followed by a test for preference (Ext test). CPP persisted for at least four extinction cycles in vehicle-treated rats. In contrast, CPP was inhibited following a single extinction training cycle. These data indicate that Meth-induced CPP was resistant to extinction, but extinction training was rendered effective when the training was combined with baclofen. These findings converge with the prior demonstration of baclofen facilitating the extinction of morphine-induced CPP indicating that GABAB receptor actions are independent of the primary (unconditioned) stimulus (i.e., the opiate or the stimulant) and likely reflect mechanisms engaged by extinction learning processes per se. Thus, baclofen administered in conjunction with extinction training may be of value for addiction therapy regardless of the class of drug being abused. PMID:21463025

Korsakoff's psychosis due to massive beer intake provoked by diabetes insipidus.

PubMed

Farr, R W; Blankenship, D C; Viti, A; Albrink, M J

1988-05-01

Posttraumatic diabetes insipidus, acute pancreatitis, and Wernicke's encephalopathy and Korsakoff's psychosis in a 33-year-old white male alcohol abuser resulted in near-fatal cardiovascular collapse. The Wernicke's encephalopathy and Korsakoff's psychosis resulted from drinking massive quantities of beer to satisfy the thirst induced by diabetes insipidus. Although the diabetes insipidus was controlled with vasopressin, and the need for vasopressin resolved two months after diagnosis, the Wernicke-Korsakoff syndrome had not resolved by six months.

An evolving problem: methamphetamine production and trafficking in the United States.

PubMed

Shukla, Rashi K; Crump, Jordan L; Chrisco, Emelia S

2012-11-01

Methamphetamine is a serious illicit drug problem in the United States and globally. For decades, methamphetamine has been supplied to the illicit market through local clandestine manufacturing and trafficking. In the early stages, illicit methamphetamine was produced and trafficked by motorcycle gangs and Mexican criminal groups. Over time, local clandestine manufacturing increasingly contributed to the illicit supply and broader methamphetamine problem. This review examines the evolution of the illicit methamphetamine supply in the U.S. A review of the literature on methamphetamine production and trafficking was conducted. Information was obtained from numerous sources including governmental reports, books and academic articles. Attempts to control the supply of methamphetamine have only led to short term disruptions in availability. Clandestine manufacturing and trafficking have undergone significant changes over the past several decades. Shifts in local production have regularly been counterbalanced by changes in production and trafficking from criminal organizations in Mexico. Transnational criminal organizations now control much of the methamphetamine supply in the U.S. and methamphetamine remains widely available. The supply of methamphetamine in the United States is dynamic. Producers and traffickers have adapted to control efforts and the problem continues. Control efforts focused on eliminating supply are limited at best. Copyright © 2012 Elsevier B.V. All rights reserved.

Impaired arterial smooth muscle cell vasodilatory function in methamphetamine users.

PubMed

Nabaei, Ghaemeh; Oveisgharan, Shahram; Ghorbani, Askar; Fatehi, Farzad

2016-11-15

Methamphetamine use is a strong risk factor for stroke. This study was designed to evaluate arterial function and structure in methamphetamine users ultrasonographically. In a cross-sectional study, 20 methamphetamine users and 21 controls, aged between 20 and 40years, were enrolled. Common carotid artery intima-media thickness (CCA-IMT) marker of early atherogenesis, flow-mediated dilatation (FMD) determinants of endothelium-dependent vasodilation, and nitroglycerine-mediated dilatation (NMD) independent marker of vasodilation were measured in two groups. There were no significant differences between the two groups regarding demographic and metabolic characteristics. The mean (±SD) CCA-IMT in methamphetamine users was 0.58±0.09mm, versus 0.59±0.07mm in the controls (p=0.84). Likewise, FMD% was not significantly different between the two groups [7.6±6.1% in methamphetamine users vs. 8.2±5.1% in the controls; p=0.72], nor were peak flow and shear rate after hyperemia. However, NMD% was considerably decreased in the methamphetamine users [8.5±7.8% in methamphetamine users vs. 13.4±6.2% in controls; p=0.03]. According to our results, NMD is reduced among otherwise healthy methamphetamine users, which represents smooth muscle dysfunction in this group. This may contribute to the high risk of stroke among methamphetamine users. Copyright © 2016 Elsevier B.V. All rights reserved.

Neuroprotective targets through which 6-acetyl-3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one (SN79), a sigma receptor ligand, mitigates the effects of methamphetamine in vitro

PubMed Central

Kaushal, Nidhi; Robson, Matthew J.; Rosen, Abagail; McCurdy, Christopher R.; Matsumoto, Rae R.

2014-01-01

Exposure to high or repeated doses of methamphetamine can cause hyperthermia and neurotoxicity, which are thought to increase the risk of developing a variety of neurological conditions. Sigma receptor antagonism can prevent methamphetamine-induced hyperthermia and neurotoxicity, but the underlying cellular targets through which the neuroprotection is conveyed remain unknown. Differentiated NG108-15 cells were thus used as a model system to begin elucidating the neuroprotective mechanisms targeted by sigma receptor antagonists to mitigate the effects of methamphetamine. In differentiated NG108-15 cells, methamphetamine caused the generation of reactive oxygen/nitrogen species, an increase in PERK-mediated endoplasmic reticulum stress and the activation of caspase-3, -8 and -9, ultimately resulting in apoptosis at micromolar concentrations, and necrotic cell death at higher concentrations. The sigma receptor antagonist, 6-acetyl-3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one (SN79), attenuated methamphetamine-induced increases in reactive oxygen/nitrogen species, activation of caspase-3,-8 and-9 and accompanying cellular toxicity. In contrast, 1,3-di(2-tolyl)-guanidine (DTG), a sigma receptor agonist, shifted the dose response curve of methamphetamine-induced cell death towards the left. To probe the effect of temperature on neurotoxicity, NG108-15 cells maintained at an elevated temperature (40 °C) exhibited a significant and synergistic increase in cell death in response to methamphetamine, compared to cells maintained at a normal cell culture temperature (37 °C). SN79 attenuated the enhanced cell death observed in the methamphetamine-treated cells at 40 °C. Together, the data demonstrate that SN79 reduces methamphetamine-induced reactive oxygen/nitrogen species generation and caspase activation, thereby conveying neuroprotective effects against methamphetamine under regular and elevated temperature conditions. PMID:24380829

Transcriptional and epigenetic substrates of methamphetamine addiction and withdrawal: evidence from a long-access self-administration model in the rat.

PubMed

Cadet, Jean Lud; Brannock, Christie; Jayanthi, Subramaniam; Krasnova, Irina N

2015-04-01

Methamphetamine use disorder is a chronic neuropsychiatric disorder characterized by recurrent binge episodes, intervals of abstinence, and relapses to drug use. Humans addicted to methamphetamine experience various degrees of cognitive deficits and other neurological abnormalities that complicate their activities of daily living and their participation in treatment programs. Importantly, models of methamphetamine addiction in rodents have shown that animals will readily learn to give themselves methamphetamine. Rats also accelerate their intake over time. Microarray studies have also shown that methamphetamine taking is associated with major transcriptional changes in the striatum measured within a short or longer time after cessation of drug taking. After a 2-h withdrawal time, there was increased expression of genes that participate in transcription regulation. These included cyclic AMP response element binding (CREB), ETS domain-containing protein (ELK1), and members of the FOS family of transcription factors. Other genes of interest include brain-derived neurotrophic factor (BDNF), tyrosine kinase receptor, type 2 (TrkB), and synaptophysin. Methamphetamine-induced transcription was found to be regulated via phosphorylated CREB-dependent events. After a 30-day withdrawal from methamphetamine self-administration, however, there was mostly decreased expression of transcription factors including junD. There was also downregulation of genes whose protein products are constituents of chromatin-remodeling complexes. Altogether, these genome-wide results show that methamphetamine abuse might be associated with altered regulation of a diversity of gene networks that impact cellular and synaptic functions. These transcriptional changes might serve as triggers for the neuropsychiatric presentations of humans who abuse this drug. Better understanding of the way that gene products interact to cause methamphetamine addiction will help to develop better pharmacological

Bupropion for the treatment of methamphetamine dependence.

PubMed

Elkashef, Ahmed M; Rawson, Richard A; Anderson, Ann L; Li, Shou-Hua; Holmes, Tyson; Smith, Edwina V; Chiang, Nora; Kahn, Roberta; Vocci, Frank; Ling, Walter; Pearce, Valerie J; McCann, Michael; Campbell, Jan; Gorodetzky, Charles; Haning, William; Carlton, Barry; Mawhinney, Joseph; Weis, Dennis

2008-04-01

Bupropion was tested for efficacy in increasing weeks of abstinence in methamphetamine-dependent patients, compared to placebo. This was a double-blind placebo-controlled study, with 12 weeks of treatment and a 30-day follow-up. Five outpatient substance abuse treatment clinics located west of the Mississippi participated in the study. One hundred and fifty-one treatment-seekers with DSM-IV diagnosis of methamphetamine dependence were consented and enrolled. Seventy-two participants were randomized to placebo and 79 to sustained-release bupropion 150 mg twice daily. Patients were asked to come to the clinic three times per week for assessments, urine drug screens, and 90-min group psychotherapy. The primary outcome was the change in proportion of participants having a methamphetamine-free week. Secondary outcomes included: urine for quantitative methamphetamine, self-report of methamphetamine use, subgroup analyses of balancing factors and comorbid conditions, addiction severity, craving, risk behaviors for HIV, and use of other substances. The generalized estimating equation regression analysis showed that, overall, the difference between bupropion and placebo groups in the probability of a non-use week over the 12-week treatment period was not statistically significant (p=0.09). Mixed model regression was used to allow adjustment for baseline factors in addition to those measured (site, gender, level of baseline use, and level of symptoms of depression). This subgroup analysis showed that bupropion had a significant effect compared to placebo, among male patients who had a lower level of methamphetamine use at baseline (p<0.0001). Comorbid depression and attention-deficit/hyperactivity disorder did not change the outcome. These data suggest that bupropion, in combination with behavioral group therapy, was effective for increasing the number of weeks of abstinence in participants with low-to-moderate methamphetamine dependence, mainly male patients, regardless of

Methamphetamine-induced sensitization differentially alters pCREB and DeltaFosB throughout the limbic circuit of the mammalian brain.

PubMed

McDaid, John; Graham, Martin P; Napier, T Celeste

2006-12-01

Enhancements in behavior that accompany repeated, intermittent administration of abused drugs (sensitization) endure long after drug administration has ceased. Such persistence reflects changes in intracellular signaling cascades and associated gene transcription factors in brain regions that are engaged by abused drugs. This process is not characterized for the most potent psychomotor stimulant, methamphetamine. Using motor behavior as an index of brain state in rats, we verified that five once-daily injections of 2.5 mg/kg methamphetamine induced behavioral sensitization that was demonstrated (expressed) 3 and 14 days later. Using immunoblot procedures, limbic brain regions implicated in behavioral sensitization were assayed for extracellular signal-regulated kinase and its phosphorylated form (pERK/ERK, a signal transduction kinase), cAMP response element binding protein and its phosphorylated form (pCREB/CREB, a constitutively expressed transcriptional regulator), and DeltaFosB (a long-lasting transcription factor). pERK, ERK, and CREB levels were not changed for any region assayed. In the ventral tegmental area, pCREB and DeltaFosB also were not changed. pCREB (activated CREB) was elevated in the frontal cortex at 3 days withdrawal, but not at 14 days. pCREB levels were decreased at 14 days withdrawal in the nucleus accumbens and ventral pallidum. Accumbal and pallidal levels of DeltaFosB were increased at 3 days withdrawal, and this increase persisted to 14 days in the pallidum. Thus, only the ventral pallidum showed changes in molecular processes that consistently correlated with motor sensitization, revealing that this region may be associated with this enduring behavioral phenotype initiated by methamphetamine. The present findings expand our understanding of the neuroanatomical and molecular substrates that may play a role in the persistence of druginduced sensitization.

Heroin and Methamphetamine Injection: An Emerging Drug Use Pattern.

PubMed

Al-Tayyib, Alia; Koester, Stephen; Langegger, Sig; Raville, Lisa

2017-07-03

We sought to describe an emerging drug use pattern characterized by injection of both methamphetamine and heroin. We examined differences in drug injection patterns by demographics, injection behaviors, HIV and HCV status, and overdose. Persons who inject drugs (PWID) were recruited as part of the National HIV Behavioral Surveillance (NHBS) system in Denver, Colorado. We used chi-square statistics to assess differences between those who reported only heroin injection, only methamphetamine injection, and combined heroin and methamphetamine injection. We used generalized linear models to estimate unadjusted and adjusted prevalence ratios to describe the association between drug injection pattern and reported nonfatal overdose in 2015. We also examined changes in the drug reported as most frequently injected across previous NHBS cycles from 2005, 2009, and 2012. Of 592 participants who completed the survey in 2015, 173 (29.2%) reported only injecting heroin, 123 (20.8%) reported only injecting methamphetamine, and 296 (50.0%) reported injecting both drugs during the past 12 months. Injecting both heroin and methamphetamine was associated with a 2.8 (95% confidence interval: 1.7, 4.5) fold increase in reported overdose in the past 12 months compared with only injecting heroin. The proportion of those reporting methamphetamine as the most frequently injected drug increased from 2.1% in 2005 to 29.6% in 2015 (p < 0.001). The rapid increase in methamphetamine injection, and the emergence of combining methamphetamine with heroin, may have serious public health implications.

Alternative Reinforcer Response Cost Impacts Methamphetamine Choice in Humans

PubMed Central

Bennett, J. Adam; Stoops, William W.; Rush, Craig R.

2012-01-01

Methamphetamine use disorders are a persistent public health concern. Behavioral treatments have demonstrated that providing access to non-drug alternative reinforcers reduces methamphetamine use. The purpose of this human laboratory experiment was to determine how changes in response cost for non-drug alternative reinforcers influenced methamphetamine choice. Seven subjects with past year histories of recreational stimulant use completed a placebo-controlled, crossover, double-blind protocol in which they first sampled doses of oral methamphetamine (0, 8 or 16 mg) and completed a battery of subject-rated and physiological measures. During subsequent sessions, subjects then made eight discrete choices between 1/8th of the sampled dose and an alternative reinforcer ($0.25). The response cost to earn a methamphetamine dose was always 500 responses (FR500). The response cost for the alternative reinforcer varied across sessions (FR500, FR1000, FR2000, FR3000). Methamphetamine functioned as a positive reinforcer and produced prototypical stimulant-like effects (e.g., elevated blood pressure, increased ratings of “Stimulated”). Choice for doses over money was sensitive to changes in response cost for alternative reinforcers in that more doses were taken at higher FR values than at lower FR values. Placebo choices changed as a function of alternative reinforcer response cost to a greater degree than active methamphetamine choices. These findings suggest that manipulating the effort necessary to earn alternative reinforcers could impact methamphetamine use. PMID:23046851

Cannabis and Neuropsychiatry, 2: The Longitudinal Risk of Psychosis as an Adverse Outcome.

PubMed

Andrade, Chittaranjan

2016-06-01

Psychosis is one of the most serious among the adverse effects associated with cannabis use. The association between cannabis use and psychosis has been variously explored in a series of recent meta-analyses. The results of these meta-analyses show that persons who develop psychosis experience onset of psychosis about 2-3 years earlier if they are cannabis users; this effect is not observed with alcohol or other substance use. Higher levels of cannabis use are associated with greater risk of psychosis. Current cannabis abuse or dependence (but not past use or lower levels of current use) increases the risk of transition into psychosis in persons at ultrahigh risk of psychosis. About a third of patients with first-episode psychosis are cannabis users, and, at follow-up, about half of these users are found to continue their cannabis use. Continued cannabis use (in those who are treated after developing psychosis) is associated with higher risk of relapse into psychosis, and discontinuation of cannabis use reduces the risk of relapse to that in cannabis nonusers. Finally, persons with psychosis who continue to use cannabis have more severe positive symptoms and poorer levels of functioning. Because experimental studies in humans show that cannabinoids and cannabis can induce psychotic symptoms, it is reasonable to assume that the epidemiologic data indicate a causal effect of cannabis in anticipating, triggering, or exacerbating psychosis in vulnerable individuals and in worsening the course and outcome of the illness in those who continue to use the substance. Given the public health implications of these findings, the trend to legalize medical marijuana must be viewed with concern, and efforts are necessary to educate patients and the public about the serious mental and physical health risks associated with cannabis use and abuse. © Copyright 2016 Physicians Postgraduate Press, Inc.

Evaluating Exercise as a Therapeutic Intervention for Methamphetamine Addiction-Like Behavior1

PubMed Central

Somkuwar, Sucharita S.; Staples, Miranda C.; Fannon, McKenzie J.; Ghofranian, Atoosa; Mandyam, Chitra D.

2015-01-01

Abstract The need for effective treatments for addiction and dependence to the illicit stimulant methamphetamine in primary care settings is increasing, yet no effective medications have been FDA approved to reduce dependence [1]. This is partially attributed to the complex and dynamic neurobiology underlying the various stages of addiction [2]. Therapeutic strategies to treat methamphetamine addiction, particularly the relapse stage of addiction, could revolutionize methamphetamine addiction treatment. In this context, preclinical studies demonstrate that voluntary exercise (sustained physical activity) could be used as an intervention to reduce methamphetamine addiction. Therefore, it appears that methamphetamine disrupts normal functioning in the brain and this disruption is prevented or reduced by engaging in exercise. This review discusses animal models of methamphetamine addiction and sustained physical activity and the interactions between exercise and methamphetamine behaviors. The review highlights how methamphetamine and exercise affect neuronal plasticity and neurotoxicity in the adult mammalian striatum, hippocampus, and prefrontal cortex, and presents the emerging mechanisms of exercise in attenuating intake and in preventing relapse to methamphetamine seeking in preclinical models of methamphetamine addiction. PMID:29765835

Cycloserine Induced Late Onset Psychosis and Ethambutol Induced Peripheral Neuropathy Associated with MDR-TB Treatment in an Indian Patient- A Rare Case Report.

PubMed

Holla, Sadhana; Amberkar, Mohan Babu; Bhandarypanambur, Rajeshkrishna; Kamalkishore, Meenakumari; Janardhanan, Manju

2015-02-01

Adverse reactions and toxicity inevitably accompany all treatment courses for drug-resistant TB. Our case underscores the importance of awareness regarding neuropsychiatric adverse reactions due to MDR-TB therapy and reversible nature of it. Cycloserine induced psychosis is most life threatening complication and sometimes could be fatal. A 42-year-old male on MDR-TB therapy got admitted for his persistent psychotic complaints like hallucinations, delusions and suicidal ideations, despite being treated with quetiapine/olanzapine. Eventually patient was rehabilitated, cycloserine was stopped and psychotic events regressed slowly. Other culprit drugs like ethambutol and levofloxacin causing psychosis was ruled out because there was no relapse of psychotic events despite being continued with these drugs. He also complained of tingling, numbness, swaying, pain and weakness. On examination, he had distal motor weakness in lower limbs, tandem gait positive, altered position sense, and tenderness over toes and positive Romberg's sign with ataxia. He was diagnosed to have drug induced sensorimotor peripheral neuropathy. All these symptoms persisted after stopping cycloserine and patient continued to have neuropathy with ethambutol and ethionamide. Considering the nature of neuropathy which was mild, mixed sensorimotor and resolved completely after 2-3 weeks of stopping, it was more in favour of ethambutol. However, we could not rule out the possibility of ethionamide or (ethionamide + ethambutol) causing neuropathy or both could have accelerated the neurotoxic effects of cycloserine which remained elusive.

Long-term protective effects of methamphetamine preconditioning against single-day methamphetamine toxic challenges.

PubMed

Hodges, A B; Ladenheim, B; McCoy, M T; Beauvais, G; Cai, N; Krasnova, I N; Cadet, J L

2011-03-01

Methamphetamine (METH) use is associated with neurotoxic effects which include decreased levels of dopamine (DA), serotonin (5-HT) and their metabolites in the brain. We have shown that escalating METH dosing can protect against METH induced neurotoxicity in rats sacrificed within 24 hours after a toxic METH challenge. The purpose of the current study was to investigate if the protective effects of METH persisted for a long period of time. We also tested if a second challenge with a toxic dose of METH would cause further damage to monoaminergic terminals. Saline-pretreated rats showed significant METH-induced decreases in striatal DA and 5-HT levels in rats sacrificed 2 weeks after the challenge. Rats that received two METH challenges showed no further decreases in striatal DA or 5-HT levels in comparison to the single METH challenge. In contrast, METH-pretreated rats showed significant protection against METH-induced striatal DA and 5-HT depletion. In addition, the METH challenge causes substantial decreases in cortical 5-HT levels which were not further potentiated by a second drug challenge. METH preconditioning provided almost complete protection against METH -induced 5-HT depletion. These results are consistent with the idea that METH pretreatment renders the brain refractory to METH-induced degeneration of brain monoaminergic systems.

In vivo evidence of methamphetamine induced attenuation of brain tissue oxygenation as measured by EPR oximetry

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

Weaver, John, E-mail: jmweaver@salud.unm.edu; Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131; Yang, Yirong

2014-03-01

Abuse of methamphetamine (METH) is a major and significant societal problem in the US, as a number of studies have suggested that METH is associated with increased cerebrovascular events, hemorrhage or vasospasm. Although cellular and molecular mechanisms involved in METH-induced toxicity are not completely understood, changes in brain O{sub 2} may play an important role and contribute to METH-induced neurotoxicity including dopaminergic receptor degradation. Given that O{sub 2} is the terminal electron acceptor for many enzymes that are important in brain function, the impact of METH on brain tissue pO{sub 2}in vivo remains largely uncharacterized. This study investigated striatal tissuemore » pO{sub 2} changes in male C57BL/6 mice (16–20 g) following METH administration using EPR oximetry, a highly sensitive modality to measure pO{sub 2}in vivo, in situ and in real time. We demonstrate that 20 min after a single injection of METH (8 mg/kg i.v.), the striatal pO{sub 2} was reduced to 81% of the pretreatment level and exposure to METH for 3 consecutive days further attenuated striatal pO{sub 2} to 64%. More importantly, pO{sub 2} did not recover fully to control levels even 24 h after administration of a single dose of METH and continual exposure to METH exacerbates the condition. We also show a reduction in cerebral blood flow associated with a decreased brain pO{sub 2} indicating an ischemic condition. Our findings suggests that administration of METH can attenuate brain tissue pO{sub 2}, which may lead to hypoxic insult, thus a risk factor for METH-induced brain injury and the development of stroke in young adults. - Highlights: • Explored striatal tissue pO{sub 2}in vivo after METH administration by EPR oximetry. • pO{sub 2} was reduced by 81% after a single dose and 64% after 3 consecutive daily doses. • pO{sub 2} did not recover fully to control levels even 24 h after a single dose. • Decrease in brain tissue pO{sub 2} may be associated with a

The advent of a new pseudoephedrine product to combat methamphetamine abuse.

PubMed

Brzeczko, Albert W; Leech, Ronald; Stark, Jeffrey G

2013-09-01

The personal and societal effects of methamphetamine abuse are well documented. The ease of accessibility to methamphetamine and the quality of the "high" it produces makes the drug highly desired by its abusers. Over time, many methamphetamine users will also become methamphetamine cooks, where pseudoephedrine in over-the-counter cold products is converted to methamphetamine through a simple, albeit extremely dangerous, process. New laws limiting access to these products have had limited success. No existing commercial pseudoephedrine products offer significant impediments to slow or limit the extraction and conversion of pseudoephedrine in clandestine methamphetamine laboratories. A new pseudoephedrine 30 mg tablet product using Impede technology (Nexafed®) to deter methamphetamine production has recently been introduced into the marketplace. Using methods designed to mimic clandestine laboratory processes, the ability of this product to disrupt extraction and conversion of pseudoephedrine to methamphetamine yet provide therapeutic effectiveness was evaluated. Impede™ technology tablets limited the extraction and/or conversion of pseudoephedrine to methamphetamine when compared to a commercially marketed pseudoephedrine product (Sudafed®). Nexafed® tablets were also shown to be bioequivalent to the same control product, thus ensuring therapeutic equivalence. With the advent of new pseudoephedrine products in the marketplace with features to limit the extraction and conversion of pseudoephedrine to methamphetamine, new tools are now available to minimize the clandestine manufacture of the drug and potentially limit its social impact.

RNA interference targeting α-synuclein attenuates methamphetamine-induced neurotoxicity in SH-SY5Y cells.

PubMed

Chen, Ling; Huang, Enping; Wang, Huijun; Qiu, Pingming; Liu, Chao

2013-07-12

The protein α-synuclein (α-syn) is abundant in neurons and has been claimed to play critical roles in the pathophysiology of Parkinson's disease. Overexpression of α-syn has been shown to be toxicity in methamphetamine (METH)-induced model in vivo and in vitro which has Parkinson's-like pathology. However, the exact mechanisms underlying toxicity of α-syn mediated METH-induced neuron remain unknown. In the present study, human dopaminergic-like neuroblastoma SH-SY5Y cells were used as METH-induced model in vitro. Cell viability was found to be dramatically increased after silencing α-syn expression followed by METH treatment compared with a-syn wild-type cells and the morphological damage to cells after METH treatment was abated through knockdown of α-syn expression in this model. The expression levels of tyrosine hydroxylase (TH), dopamine transporter (DAT) and vesicular monoamine transporter 2(VMAT-2) were significantly decreased and the activity/levels of reactive oxygen species (ROS), nitric oxide synthase (NOS) and nitrogen (NO) were notably increased after METH treatment. However, the changes of these expression levels were reversed in cells transfected with α-syn-shRNA. These results suggested that TH, DAT, VMAT-2, ROS and NOS maybe involved in α-syn mediated METH-induced neuronal toxicity. Copyright © 2013 Elsevier B.V. All rights reserved.

Characterization of white matter integrity deficits in cocaine-dependent individuals with substance-induced psychosis compared with non-psychotic cocaine users.

PubMed

Willi, Taylor S; Barr, Alasdair M; Gicas, Kristina; Lang, Donna J; Vila-Rodriguez, Fidel; Su, Wayne; Thornton, Allen E; Leonova, Olga; Giesbrecht, Chantelle J; Procyshyn, Ric M; Rauscher, Alexander; MacEwan, William G; Honer, William G; Panenka, William J

2017-05-01

With sufficient drug exposure, some individuals develop transient psychotic symptoms referred to as 'substance-induced psychosis' (SIP), which closely resemble the symptoms observed in schizophrenia spectrum disorders. The comparability in psychotic presentation between SIP and the schizophrenias suggests that similar underlying neural deficits may contribute to the emergence of psychosis across these disorders. Only a small number of studies have investigated structural alterations in SIP, and all have been limited to volumetric imaging methods, with none controlling for the effects of chronic drug exposure. To investigate white matter abnormalities associated with SIP, diffusion tensor imaging was employed in a group of individuals with cocaine-associated psychosis (CAP; n = 24) and a cocaine-dependent non-psychotic (CDN) group (n = 43). Tract-based spatial statistics was used to investigate group differences in white matter diffusion parameters. The CAP group showed significantly lower fractional anisotropy values than the CDN group (p < 0.05) in voxels within white matter tracts of fronto-temporal, fronto-thalamic and interhemispheric pathways. The greatest differences in white matter integrity were present in the corpus callosum, corona radiata, bilateral superior longitudinal fasciculi and bilateral inferior longitudinal fasciculi. Additionally, the CAP group had voxels of significantly higher radial diffusivity in a subset of the previously mentioned pathways. These results are the first description of white matter integrity abnormalities in a SIP sample and indicate that differences in these pathways may be a shared factor in the expression of different forms of psychosis. © 2016 Society for the Study of Addiction.

Methamphetamine intoxication in a dog: case report

PubMed Central

2014-01-01

Background Methamphetamine abuse has undergone a dramatic worldwide increase, and represents a significant and global issue for public health. Incidents of methamphetamine intoxication and death in humans are relatively commonplace. Because of its increasing illicit availability, together with legitimate use in human medicine, accidental or intentional exposure to methamphetamine in dogs is becoming a more likely scenario. Case presentation A 3-year-old, 3.7 kg intact female Miniature Poodle who had been intentionally fed an unknown amount of a crystalline-like substance developed extreme agitation, seizures, tachycardia, hyperthermia, hypertension, disseminated intravascular coagulation (DIC), bloody diarrhea, and dilated pupils. Blood work revealed leukocytosis, erythropenia, lymphocytosis, thrombocytopenia, coagulation abnormalities, but all to a mild extent, together with mild elevation in both alanine aminotranferease (ALT) and alkaline phosphatase (ALKP), and a mild decreased in glucose. Radiologic diagnosis revealed generalized, severe distension of the stomach and small intestinal tract with air. Immunochromatographic screening tests and gas chromatography mass spectrometry analysis confirmed methamphetamine intoxication and revealed concentrations of methamphetamine in blood and urine of 0.32 μg/mL and 2.35 μg/mL respectively. The dog demonstrated progressive improvement after supportive care, with the high fever resolved over the initial 24 hours of hospitalization, and agitation was successfully controlled beyond 48 hours after initial hospitalization. Hemostatic abnormalities were progressive improved after heparin therapy and supportive care. By the sixth day of hospitalization the dog was clinically well, and all laboratory data had returned to normal with the exception of a mild elevateion of ALKP. Conclusion To the authors’ knowledge, this is the second case report of methamphetamine intoxication in dogs presented in veterinary practice in

Child loss and psychosis onset: evidence for traumatic experience as an etiological factor in psychosis.

PubMed

Devylder, Jordan E; Wang, Julia S-H; Oh, Hans Y; Lukens, Ellen P

2013-01-30

Previous research suggests that trauma may contribute to psychosis onset. In this study, we examine the effect of parental loss of a child on the onset of psychotic experience using data from the National Comorbidity Survey Replication, hypothesizing that child loss will precede the onset of psychosis and will be associated with a later age of onset. We likewise tested this association for six other psychiatric conditions to demonstrate specificity for psychosis. Individuals with a psychotic disorder who had lost a child had a significantly later age of onset, particularly in males, even when controlling for demographic variables and co-occurring substance abuse and psychiatric disorders. Psychosis onset frequently occurred within a year of child loss. No associations were found between child loss and onset of other psychiatric conditions, supporting specificity of the effect on psychosis. The presented findings implicate child loss as an etiological factor in the onset of psychosis, providing converging evidence with previous studies demonstrating associations between more widely studied trauma exposures (abuse, neglect, and assault) and psychosis. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Early psychosis workforce development: Core competencies for mental health professionals working in the early psychosis field.

PubMed

Osman, Helen; Jorm, Anthony F; Killackey, Eoin; Francey, Shona; Mulcahy, Dianne

2017-08-09

The aim of this study was to identify the core competencies required of mental health professionals working in the early psychosis field, which could function as an evidence-based tool to support the early psychosis workforce and in turn assist early psychosis service implementation and strengthen early psychosis model fidelity. The Delphi method was used to establish expert consensus on the core competencies. In the first stage, a systematic literature search was conducted to generate competency items. In the second stage, a panel consisting of expert early psychosis clinicians from around the world was formed. Panel members then rated each of the competency items on how essential they are to the clinical practice of all early psychosis clinicians. In total, 1023 pieces of literature including textbooks, journal articles and grey literature were reviewed. A final 542 competency items were identified for inclusion in the questionnaire. A total of 63 early psychosis experts participated in 3 rating rounds. Of the 542 competency items, 242 were endorsed as the required core competencies. There were 29 competency items that were endorsed by 62 or more experts, and these may be considered the foundational competencies for early psychosis practice. The study generated a set of core competencies that provide a common language for early psychosis clinicians across professional disciplines and country of practice, and potentially are a useful professional resource to support early psychosis workforce development and service reform. © 2017 John Wiley & Sons Australia, Ltd.

A qualitative study of methamphetamine initiation in Cape Town, South Africa

PubMed Central

Hobkirk, Andréa L.; Watt, Melissa H.; Myers, Bronwyn; Skinner, Donald; Meade, Christina S.

2015-01-01

Background Despite a significant rise in methamphetamine use in low- and middle-income countries, there has been little empirical examination of the factors that contribute to individuals’ initiation of methamphetamine use in these settings. The goal of this study was to qualitatively examine factors associated with methamphetamine initiation in South Africa. Methods In-depth interviews were conducted with 30 active methamphetamine users (13 women and 17 men) in Cape Town, South Africa. Interviews included narrative descriptions of the circumstances surrounding methamphetamine initiation. Interviews were audio recorded, transcribed, and translated. Transcripts were analyzed with document memos, data display matrices, and a constant comparison technique to identify themes. Results On average, participants began regularly using methamphetamine around age 21 and had used for seven years. Four major themes emerged related to the initiation of methamphetamine use. The prevalence of methamphetamine users and distributors made the drug convenient and highly accessible to first time users. Methamphetamine has increased in popularity and is considered “trendy”, which contributes to social pressure from friends, and less often, family members to initiate use. Initiation is further fueled by a lack of opportunities for recreation and employment, which leads to boredom and curiosity about the rumored positive effects of the drug. Young people also turn to methamphetamine use and distribution through gang membership as an attempt to generate income in impoverished communities with limited economic opportunities. Finally, participants described initiating methamphetamine as a means of coping with the cumulative stress and psychological burden provoked by the high rates of violence and crime in areas of Cape Town. Conclusion The findings highlight the complex nature of methamphetamine initiation in low- and middle-income countries like South Africa. There is a need for

A qualitative study of methamphetamine initiation in Cape Town, South Africa.

PubMed

Hobkirk, Andréa L; Watt, Melissa H; Myers, Bronwyn; Skinner, Donald; Meade, Christina S

2016-04-01

Despite a significant rise in methamphetamine use in low- and middle-income countries, there has been little empirical examination of the factors that contribute to individuals' initiation of methamphetamine use in these settings. The goal of this study was to qualitatively examine factors associated with methamphetamine initiation in South Africa. In-depth interviews were conducted with 30 active methamphetamine users (13 women and 17 men) in Cape Town, South Africa. Interviews included narrative descriptions of the circumstances surrounding methamphetamine initiation. Interviews were audio recorded, transcribed, and translated. Transcripts were analyzed with document memos, data display matrices, and a constant comparison technique to identify themes. On average, participants began regularly using methamphetamine around age 21 and had used for seven years. Four major themes emerged related to the initiation of methamphetamine use. The prevalence of methamphetamine users and distributors made the drug convenient and highly accessible to first time users. Methamphetamine has increased in popularity and is considered "trendy", which contributes to social pressure from friends, and less often, family members to initiate use. Initiation is further fueled by a lack of opportunities for recreation and employment, which leads to boredom and curiosity about the rumored positive effects of the drug. Young people also turn to methamphetamine use and distribution through gang membership as an attempt to generate income in impoverished communities with limited economic opportunities. Finally, participants described initiating methamphetamine as a means of coping with the cumulative stress and psychological burden provoked by the high rates of violence and crime in areas of Cape Town. The findings highlight the complex nature of methamphetamine initiation in low- and middle-income countries like South Africa. There is a need for community-level interventions to address the

Loneliness in psychosis: a systematic review.

PubMed

Lim, Michelle H; Gleeson, John F M; Alvarez-Jimenez, Mario; Penn, David L

2018-03-01

The aim of the review is to understand the relationships between loneliness and related psychological and social factors in individuals with psychosis. Loneliness is poorly understood in people with psychosis. Given the myriad of social challenges facing individuals with psychosis, these findings can inform psychosocial interventions that specifically target loneliness in this vulnerable group. We adhered to the PRISMA guidelines and systematically reviewed empirical studies that measured loneliness either as a main outcome or as an associated variable in individuals with psychosis. A total of ten studies examining loneliness in people diagnosed with a psychotic disorder were examined. Heterogeneity in the assessment of loneliness was found, and there were contradictory findings on the relationship between loneliness and psychotic symptomatology. In individuals with psychosis, loneliness may be influenced by psychological and social factors such as increased depression, psychosis, and anxiety, poor social support, poor quality of life, more severe internalised stigma and perceived discrimination, and low self-esteem. The relationship between loneliness and psychosis remains poorly understood due to a lack of rigorous studies. Although having strong social relationships is crucial to facilitate recovery from serious mental illness, psychosocial interventions that specifically target loneliness in individuals with psychosis are lacking and sorely needed. Interventions targeting loneliness in those with psychosis will also need to account for additional barriers associated with psychosis (e.g., social skill deficits, impoverished social networks, and negative symptoms).

Acute Modafinil Effects on Attention and Inhibitory Control in Methamphetamine-Dependent Humans*

PubMed Central

Dean, Andy C.; Sevak, Rajkumar J.; Monterosso, John R.; Hellemann, Gerhard; Sugar, Catherine A.; London, Edythe D.

2011-01-01

Objective: Individuals who are methamphetamine dependent exhibit higher rates of cognitive dysfunction than healthy people who do not use methamphetamine, and this dysfunction may have a negative effect on the success of behavioral treatments for the disorder. Therefore, a medication that improves cognition, such as modafinil (Provigil), may serve as a useful adjunct to behavioral treatments for methamphetamine dependence. Although cognitive-enhancing effects of modafinil have been reported in several populations, little is known about the effects of modafinil in methamphetamine-dependent individuals. We thus sought to evaluate the effects of modafinil on the cognitive performance of methamphetamine-dependent and healthy individuals. Method: Seventeen healthy subjects and 24 methamphetamine-dependent subjects participated in this randomized, double-blind, placebo-controlled, crossover study. Effects of modafinil (200 mg, single oral dose) were assessed on participants’ performance on tests of inhibitory control, working memory, and processing speed/attention. Results: Across subjects, modafinil improved performance on a test of sustained attention, with no significant improvement on any other cognitive tests. However, within the methamphetamine-dependent group only, participants with a high baseline frequency of methamphetamine use demonstrated a greater effect of modafinil on tests of inhibitory control and processing speed than those participants with low baseline use of methamphetamine. Conclusions: Although modafinil produced limited effects across all participants, methamphetamine-dependent participants with a high baseline use of methamphetamine demonstrated significant cognitive improvement on modafinil relative to those with low baseline methamphetamine use. These results add to the findings from a clinical trial that suggested that modafinil may be particularly useful in methamphetamine-dependent subjects who use the drug frequently. PMID:22051208

The advent of a new pseudoephedrine product to combat methamphetamine abuse

PubMed Central

Leech, Ronald; Stark, Jeffrey G.

2013-01-01

Background: The personal and societal effects of methamphetamine abuse are well documented. The ease of accessibility to methamphetamine and the quality of the “high” it produces makes the drug highly desired by its abusers. Over time, many methamphetamine users will also become methamphetamine cooks, where pseudoephedrine in over-the-counter cold products is converted to methamphetamine through a simple, albeit extremely dangerous, process. New laws limiting access to these products have had limited success. No existing commercial pseudoephedrine products offer significant impediments to slow or limit the extraction and conversion of pseudoephedrine in clandestine methamphetamine laboratories. Objective and Methods: A new pseudoephedrine 30 mg tablet product using Impede technology (Nexafed®) to deter methamphetamine production has recently been introduced into the marketplace. Using methods designed to mimic clandestine laboratory processes, the ability of this product to disrupt extraction and conversion of pseudoephedrine to methamphetamine yet provide therapeutic effectiveness was evaluated. Results: Impede™ technology tablets limited the extraction and/or conversion of pseudoephedrine to methamphetamine when compared to a commercially marketed pseudoephedrine product (Sudafed®). Nexafed® tablets were also shown to be bioequivalent to the same control product, thus ensuring therapeutic equivalence. Conclusions: With the advent of new pseudoephedrine products in the marketplace with features to limit the extraction and conversion of pseudoephedrine to methamphetamine, new tools are now available to minimize the clandestine manufacture of the drug and potentially limit its social impact. PMID:23968171

Brain serotonin transporter density and aggression in abstinent methamphetamine abusers.

PubMed

Sekine, Yoshimoto; Ouchi, Yasuomi; Takei, Nori; Yoshikawa, Etsuji; Nakamura, Kazuhiko; Futatsubashi, Masami; Okada, Hiroyuki; Minabe, Yoshio; Suzuki, Katsuaki; Iwata, Yasuhide; Tsuchiya, Kenji J; Tsukada, Hideo; Iyo, Masaomi; Mori, Norio

2006-01-01

In animals, methamphetamine is known to have a neurotoxic effect on serotonin neurons, which have been implicated in the regulation of mood, anxiety, and aggression. It remains unknown whether methamphetamine damages serotonin neurons in humans. To investigate the status of brain serotonin neurons and their possible relationship with clinical characteristics in currently abstinent methamphetamine abusers. Case-control analysis. A hospital research center. Twelve currently abstinent former methamphetamine abusers (5 women and 7 men) and 12 age-, sex-, and education-matched control subjects recruited from the community. The brain regional density of the serotonin transporter, a structural component of serotonin neurons, was estimated using positron emission tomography and trans-1,2,3,5,6,10-beta-hexahydro-6-[4-(methylthio)phenyl]pyrrolo-[2,1-a]isoquinoline ([(11)C](+)McN-5652). Estimates were derived from region-of-interest and statistical parametric mapping methods, followed by within-case analysis using the measures of clinical variables. The duration of methamphetamine use, the magnitude of aggression and depressive symptoms, and changes in serotonin transporter density represented by the [(11)C](+)McN-5652 distribution volume. Methamphetamine abusers showed increased levels of aggression compared with controls. Region-of-interest and statistical parametric mapping analyses revealed that the serotonin transporter density in global brain regions (eg, the midbrain, thalamus, caudate, putamen, cerebral cortex, and cerebellum) was significantly lower in methamphetamine abusers than in control subjects, and this reduction was significantly inversely correlated with the duration of methamphetamine use. Furthermore, statistical parametric mapping analyses indicated that the density in the orbitofrontal, temporal, and anterior cingulate areas was closely associated with the magnitude of aggression in methamphetamine abusers. Protracted abuse of methamphetamine may reduce

Distribution and pharmacokinetics of methamphetamine in the human body: clinical implications.

PubMed

Volkow, Nora D; Fowler, Joanna S; Wang, Gene-Jack; Shumay, Elena; Telang, Frank; Thanos, Peter K; Alexoff, David

2010-12-07

Methamphetamine is one of the most toxic of the drugs of abuse, which may reflect its distribution and accumulation in the body. However no studies have measured methamphetamine's organ distribution in the human body. Positron Emission Tomography (PET) was used in conjunction with [(11)C]d-methamphetamine to measure its whole-body distribution and bioavailability as assessed by peak uptake (% Dose/cc), rate of clearance (time to reach 50% peak-clearance) and accumulation (area under the curve) in healthy participants (9 Caucasians and 10 African Americans). Methamphetamine distributed through most organs. Highest uptake (whole organ) occurred in lungs (22% Dose; weight ∼1246 g), liver (23%; weight ∼1677 g) and intermediate in brain (10%; weight ∼1600 g). Kidneys also showed high uptake (per/cc basis) (7%; weight 305 g). Methamphetamine's clearance was fastest in heart and lungs (7-16 minutes), slowest in brain, liver and stomach (>75 minutes), and intermediate in kidneys, spleen and pancreas (22-50 minutes). Lung accumulation of [(11)C]d-methamphetamine was 30% higher for African Americans than Caucasians (p<0.05) but did not differ in other organs. The high accumulation of methamphetamine, a potent stimulant drug, in most body organs is likely to contribute to the medical complications associated with methamphetamine abuse. In particular, we speculate that methamphetamine's high pulmonary uptake could render this organ vulnerable to infections (tuberculosis) and pathology (pulmonary hypertension). Our preliminary findings of a higher lung accumulation of methamphetamine in African Americans than Caucasians merits further investigation and questions whether it could contribute to the infrequent use of methamphetamine among African Americans.

Distribution and pharmacokinetics of methamphetamine in the human body: clinical implications

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

Volkow, N.D.; Fowler, J.; Volkow, N.D.

2010-12-01

Methamphetamine is one of the most toxic of the drugs of abuse, which may reflect its distribution and accumulation in the body. However no studies have measured methamphetamine's organ distribution in the human body. Positron Emission Tomography (PET) was used in conjunction with [{sup 11}C]d-methamphetamine to measure its whole-body distribution and bioavailability as assessed by peak uptake (% Dose/cc), rate of clearance (time to reach 50% peak-clearance) and accumulation (area under the curve) in healthy participants (9 Caucasians and 10 African Americans). Methamphetamine distributed through most organs. Highest uptake (whole organ) occurred in lungs (22% Dose; weight {approx}1246 g), livermore » (23%; weight {approx}1677 g) and intermediate in brain (10%; weight {approx}1600 g). Kidneys also showed high uptake (per/cc basis) (7%; weight 305 g). Methamphetamine's clearance was fastest in heart and lungs (7-16 minutes), slowest in brain, liver and stomach (>75 minutes), and intermediate in kidneys, spleen and pancreas (22-50 minutes). Lung accumulation of [{sup 11}C]d-methamphetamine was 30% higher for African Americans than Caucasians (p < 0.05) but did not differ in other organs. The high accumulation of methamphetamine, a potent stimulant drug, in most body organs is likely to contribute to the medical complications associated with methamphetamine abuse. In particular, we speculate that methamphetamine's high pulmonary uptake could render this organ vulnerable to infections (tuberculosis) and pathology (pulmonary hypertension). Our preliminary findings of a higher lung accumulation of methamphetamine in African Americans than Caucasians merits further investigation and questions whether it could contribute to the infrequent use of methamphetamine among African Americans.« less

Distribution and Pharmacokinetics of Methamphetamine in the Human Body: Clinical Implications

PubMed Central

Volkow, Nora D.; Fowler, Joanna S.; Wang, Gene-Jack; Shumay, Elena; Telang, Frank; Thanos, Peter K.; Alexoff, David

2010-01-01

Background Methamphetamine is one of the most toxic of the drugs of abuse, which may reflect its distribution and accumulation in the body. However no studies have measured methamphetamine's organ distribution in the human body. Methods Positron Emission Tomography (PET) was used in conjunction with [11C]d-methamphetamine to measure its whole-body distribution and bioavailability as assessed by peak uptake (% Dose/cc), rate of clearance (time to reach 50% peak-clearance) and accumulation (area under the curve) in healthy participants (9 Caucasians and 10 African Americans). Results Methamphetamine distributed through most organs. Highest uptake (whole organ) occurred in lungs (22% Dose; weight ∼1246 g), liver (23%; weight ∼1677 g) and intermediate in brain (10%; weight ∼1600 g). Kidneys also showed high uptake (per/cc basis) (7%; weight 305 g). Methamphetamine's clearance was fastest in heart and lungs (7–16 minutes), slowest in brain, liver and stomach (>75 minutes), and intermediate in kidneys, spleen and pancreas (22–50 minutes). Lung accumulation of [11C]d-methamphetamine was 30% higher for African Americans than Caucasians (p<0.05) but did not differ in other organs. Conclusions The high accumulation of methamphetamine, a potent stimulant drug, in most body organs is likely to contribute to the medical complications associated with methamphetamine abuse. In particular, we speculate that methamphetamine's high pulmonary uptake could render this organ vulnerable to infections (tuberculosis) and pathology (pulmonary hypertension). Our preliminary findings of a higher lung accumulation of methamphetamine in African Americans than Caucasians merits further investigation and questions whether it could contribute to the infrequent use of methamphetamine among African Americans. PMID:21151866

Initiation into Methamphetamine Use For Young Gay and Bisexual Men

PubMed Central

Parsons, Jeffrey T.; Kelly, Brian C.; Weiser, Jonathan D.

2007-01-01

Research over the past ten years has suggested that methamphetamine use has become a significant problem and is associated with risky sexual behaviors among gay and bisexual men. In order to better understand initiation into methamphetamine use among gay and bisexual men, qualitative analyses were performed on a sample of young gay and bisexual men (ages 18-29) in New York City. Participants were recruited as part of a larger study which used time-space sampling to enroll club-going young adults who indicated recent club-drug (ecstasy, ketamine, GHB, methamphetamine, cocaine, and/or LSD) use. The data for this paper are derived from the qualitative interviews of 54 gay and bisexual male methamphetamine users. At initiation (1) Methamphetamine was used in a social, non-sexual setting for a majority of the participants; (2) participants expressed limited knowledge of methamphetamine; and (3) many participants used cocaine as a basis for comparison when describing various effects of the drug. The understanding that at initiation methamphetamine was not solely used as a sexual enhancement for members of this community may enable health workers to more accurately target potential users when putting forth intervention efforts. Future research should aim to gain a better understanding into the role that methamphetamine plays in non-sexual contexts, particularly among gay and bisexual men who may not be part of the club “scene.” The relationship between attitudes towards methamphetamine and other drugs, particularly cocaine, among gay and bisexual men should be explored. PMID:17398040

Failure of surgical treatment in methamphetamine body-stuffers.

PubMed

Bahrami-Motlagh, Hooman; Hassanian-Moghaddam, Hossein; Behnam, Behdad; Arab-Ahmadi, Mehran

2015-05-01

Body stuffing is defined as ingestion of unpackaged or packaged illicit drugs in a quick process. The drugs have usually been wrapped loosely in cellophane, plastic bags, paper, or aluminum foil. Methamphetamine toxicity is a dangerous state that occurs during methamphetamine leakage from the ingested packages in the gastrointestinal tract. This is usually occurring with cocaine and heroin, but methamphetamine body stuffing may less commonly happen, as well. Accordingly, management of methamphetamine body-stuffers is an important subject that has remained a controversy in clinical and legal aspects. We have reported two body-stuffer cases who underwent exploratory laparotomy. Although surgery was done, it was not useful to exit packs and even led to severe methamphetamine toxicity. These cases show that surgical treatment may be ineffective and even harmful in body-stuffers. On the other hand, this report suggests that pre and post-operation abdominal CT-scan is necessary for evaluating surgical treatment in patients who are still symptomatic. Copyright © 2015 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.

Methamphetamine abuse and “meth mouth” in Europe

PubMed Central

Boyd, Geraldine-A.; Mancinelli, Luca; Pagano, Stefano; Eramo, Stefano

2015-01-01

With easy chemical synthesis from its precursor, methamphetamine (MA) is now widespread in many countries. The abuse of methamphetamine is associated with several negative effects on health, because MA is a neurotoxin and a dangerous central nervous system stimulant. It changes levels of neurotransmitters in the brain, releasing dopamine and inhibiting nor epinephrine uptake which increases sympathetic nervous system activity and can lead to cardiac arrhythmia, hypertension and tachypnea. The consequences of MA abuse are clearly manifested in oral diseases (like “meth mouth”) which is characterised by extensive caries, teeth grinding with ensuing dental wear and trismus. The present review was designed to fill the gap in knowledge about methamphetamine abuse in the European Union (EU) and to illustrate the main clinical effects of prolonged use. After describing the pharmacology and systemic effects of methamphetamine and concentrating on its effects on the mouth, the present review compares the epidemiology and incidence of abuse in the world, particularly the USA and the EU. Key words:Methamphetamine, “Meth mouth”, drug abuse, oral health. PMID:25662544

DARK Classics in Chemical Neuroscience: Methamphetamine.

PubMed

Abbruscato, Thomas J; Trippier, Paul C

2018-04-06

Methamphetamine has the second highest prevalence of drug abuse after cannabis, with estimates of 35 million users worldwide. The ( S)-(+)-enantiomer is the illicit drug, active neurostimulant, and eutomer, while the ( R)-(-)-enantiomer is contained in over the counter decongestants. While designated a schedule II drug in 1970, ( S)-(+)-methamphetamine is available by prescription for the treatment of attention-deficit disorder and obesity. The illicit use of ( S)-(+)-methamphetamine results in the sudden "rush" of stimulation to the motivation, movement, pleasure, and reward centers in the brain, caused by rapid release of dopamine. In this review, we will provide an overview of the synthesis, pharmacology, adverse effects, and drug metabolism of this widely abused psychostimulant that distinguish it as a DARK classic in Chemical Neuroscience.

Psychosis in Parkinson's Disease.

PubMed

Ffytche, Dominic H; Aarsland, Dag

2017-01-01

Although illusions, hallucinations and delusions did not play a prominent role in James Parkinson's original clinical descriptions, the longitudinal view of disease progression he advocated has important lessons for the study of such symptoms today. A focus on longitudinal progression rather than individual symptoms led to the concept of PD psychosis-a spectrum of positive symptoms in Parkinson's disease. The publication of criteria for PD psychosis in 2007 helped unify the disparate set of symptoms, raising their profile and resulting in a rapid expansion of literature focussing on clinical aspects, mechanisms, and treatment. Here we review this literature and the evolving view of PD psychosis. Adding to previous evidence of a prospective risk for dementia and the move to supervised care, key recent developments include: recognition of prevalence increase with disease duration; a broadening of symptoms included in PD psychosis; better characterization of higher visual and cognitive dysfunction risk factors; structural, functional, and neurotransmitter imaging biomarker evidence; and approval of pimavanserin in the United States for the treatment of PD psychosis. The accumulating evidence raises novel questions and directions for future research that promise a better understanding of the clinical management of PD psychosis and its role as a biomarker for PD stage and progression. © 2017 Elsevier Inc. All rights reserved.

Perceptions of disadvantage, ethnicity and psychosis.

PubMed

Cooper, Claudia; Morgan, Craig; Byrne, Majella; Dazzan, Paola; Morgan, Kevin; Hutchinson, Gerard; Doody, Gillian A; Harrison, Glynn; Leff, Julian; Jones, Peter; Ismail, Khalida; Murray, Robin; Bebbington, Paul; Fearon, Paul

2008-03-01

People from Black ethnic groups (African-Caribbean and Black African) are more prone to develop psychosis in Western countries. This excess might be explained by perceptions of disadvantage. To investigate whether the higher incidence of psychosis in Black people is mediated by perceptions of disadvantage. A population-based incidence and case-control study of first-episode psychosis (Aetiology and Ethnicity in Schizophrenia and Other Psychoses (AESOP)). A total of 482 participants answered questions about perceived disadvantage. Black ethnic groups had a higher incidence of psychosis (OR= 4.7, 95% CI 3.1-7.2). After controlling for religious affiliation, social class and unemployment, the association of ethnicity with psychosis was attenuated (OR=3.0, 95% CI 1.6-5.4) by perceptions of disadvantage. Participants in the Black non-psychosis group often attributed their disadvantage to racism, whereas Black people in the psychosis group attributed it to their own situation. Perceived disadvantage is partly associated with the excess of psychosis among Black people living in the UK. This may have implications for primary prevention.

Distinct Neurochemical Adaptations Within the Nucleus Accumbens Produced by a History of Self-Administered vs Non-Contingently Administered Intravenous Methamphetamine

PubMed Central

Lominac, Kevin D; Sacramento, Arianne D; Szumlinski, Karen K; Kippin, Tod E

2012-01-01

Methamphetamine is a highly addictive psychomotor stimulant yet the neurobiological consequences of methamphetamine self-administration remain under-characterized. Thus, we employed microdialysis in rats trained to self-administer intravenous (IV) infusions of methamphetamine (METH-SA) or saline (SAL) and a group of rats receiving non-contingent IV infusions of methamphetamine (METH-NC) at 1 or 21 days withdrawal to determine the dopamine and glutamate responses in the nucleus accumbens (NAC) to a 2 mg/kg methamphetamine intraperitoneal challenge. Furthermore, basal NAC extracellular glutamate content was assessed employing no net-flux procedures in these three groups at both time points. At both 1- and 21-day withdrawal points, methamphetamine elicited a rise in extracellular dopamine in SAL animals and this effect was sensitized in METH-NC rats. However, METH-SA animals showed a much greater sensitized dopamine response to the drug challenge compared with the other groups. Additionally, acute methamphetamine decreased extracellular glutamate in both SAL and METH-NC animals at both time-points. In contrast, METH-SA rats exhibited a modest and delayed rise in glutamate at 1-day withdrawal and this rise was sensitized at 21 days withdrawal. Finally, no net-flux microdialysis revealed elevated basal glutamate and increased extraction fraction at both withdrawal time-points in METH-SA rats. Although METH-NC rats exhibited no change in the glutamate extraction fraction, they exhibited a time-dependent elevation in basal glutamate levels. These data illustrate for the first time that a history of methamphetamine self-administration produces enduring changes in NAC neurotransmission and that non-pharmacological factors have a critical role in the expression of these methamphetamine-induced neurochemical adaptations. PMID:22030712

Methamphetamine blocks exercise effects on Bdnf and Drd2 gene expression in frontal cortex and striatum.

PubMed

Thompson, Andrew B; Stolyarova, Alexandra; Ying, Zhe; Zhuang, Yumei; Gómez-Pinilla, Fernando; Izquierdo, Alicia

2015-12-01