Role of dorsomedial striatum neuronal ensembles in incubation of methamphetamine craving after voluntary abstinence

Abstract 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 of methamphetamine craving after choice-based voluntary abstinence. Here, we used classical pharmacology, in situ hybridization, immunohistochemistry, and the Daun02 inactivation procedure to demonstrate a critical role of dorsomedial striatum neuronal ensembles in this new form of incubation of drug craving

Pilot Safety Evaluation of Varenicline for the Treatment of Methamphetamine Dependence.

Despite the worldwide extent of methamphetamine dependence, no medication has been shown to effectively treat afflicted individuals. One relatively unexplored approach is modulation of cholinergic system function. Animal research suggests that enhancement of central cholinergic activity, possibly at nicotinic acetylcholine receptors (nAChRs), can reduce methamphetamine-related behaviors. Further, preliminary findings indicate that rivastigmine, a cholinesterase inhibitor, may reduce craving for methamphetamine after administration of the drug in human subjects. We therefore performed a double-blind, placebo-controlled, crossover pilot study of the safety and tolerability of varenicline in eight methamphetamine-dependent research subjects. Varenicline is used clinically to aid smoking cessation, and acts as a partial agonist at α4β2 nAChRs with full agonist properties at α7 nAChRs. Oral varenicline dose was titrated over 1 week to reach 1 mg bid, and then was co-administered with 30 mg methamphetamine, delivered in ten intravenous infusions of 3 mg each. Varenicline was found to be safe in combination with IV methamphetamine, producing no cardiac rhythm disturbances or alterations in vital sign parameters. No adverse neuropsychiatric sequelae were detected either during varenicline titration or following administration of methamphetamine. The results suggest that varenicline warrants further investigation as a potential treatment for methamphetamine dependence

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

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

The clinical pharmacology of intranasal l-methamphetamine.

BackgroundWe studied the pharmacology of l-methamphetamine, the less abused isomer, when used as a nasal decongestant.Methods12 subjects self-administered l-methamphetamine from a nonprescription inhaler at the recommended dose (16 inhalations over 6 hours) then at 2 and 4 (32 and 64 inhalations) times this dose. In a separate session intravenous phenylephrine (200 microg) and l-methamphetamine (5 mg) were given to define alpha agonist pharmacology and bioavailability. Physiological, cardiovascular, pharmacokinetic, and subjective effects were measured.ResultsPlasma l-methamphetamine levels were often below the level of quantification so bioavailability was estimated by comparing urinary excretion of the intravenous and inhaled doses, yielding delivered dose estimates of 74.0 +/- 56.1, 124.7 +/- 106.6, and 268.1 +/- 220.5 microg for ascending exposures (mean 4.2 +/- 3.3 microg/inhalation). Physiological changes were minimal and not dose-dependent. Small decreases in stroke volume and cardiac output suggesting mild cardiodepression were seen.ConclusionInhaled l-methamphetamine delivered from a non-prescription product produced minimal effects but may be a cardiodepressant

Role of dopamine D1-like receptors in methamphetamine locomotor responses of D2 receptor knockout mice

Behavioral sensitization to psychostimulants manifests as an increased locomotor response with repeated administration. Dopamine systems are accepted to play a fundamental role in sensitization, but the role of specific dopamine receptor subtypes has not been completely defined. This study used the combination of dopamine D2 receptor-deficient mice and a D1-like antagonist to examine dopamine D1 and D2 receptor involvement in acute and sensitized locomotor responses to methamphetamine. Absence of the dopamine D2 receptor resulted in attenuation of the acute stimulant effects of methamphetamine. Mutant and wild-type mice exhibited sensitization that lasted longer within the time period of the challenge test in the mutant animals. Pretreatment with the D1-like receptor antagonist SCH 23390 produced more potent reductions in the acute and sensitized locomotor responses to methamphetamine in D2 receptor-deficient mice than in wild-type mice; however, the expression of locomotor sensitization when challenged with methamphetamine alone was equivalently attenuated by previous treatment with SCH 23390. These data suggest that dopamine D2 receptors play a key role in the acute stimulant and sensitizing effects of methamphetamine and act in concert with D1-like receptors to influence the acquisition of methamphetamine-induced behavioral sensitization, traits that may influence continued methamphetamine use.Fil: Kelly, M. A.. Oregon Health And Science University; Estados UnidosFil: Low, M. J.. Oregon Health And Science University; Estados UnidosFil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; ArgentinaFil: Phillips, T. J.. Oregon Health And Science University; Estados Unido

Evaluating drug law enforcement interventions directed towards methamphetamine in Australia

This report presents a preliminary analysis comparing the costs and impacts different types of law enforcement have on methamphetamine use. Methamphetamine belongs in the class of stimulant drugs referred to as Amphetamine Type Stimulants (ATS). The category of ATS includes ecstasy, amphetamine and methamphetamine. This research project concerned itself with the amphetamine and methamphetamine class and excluded ecstasy (and henceforth we use the generic term methamphetamine). In Australia, methamphetamine is available in three forms—powder, base and crystal. Methamphetamine is associated with significant harms and is an important drug policy priority. The National Amphetamine-Type Stimulants Strategy (2008–2011) articulates the following priority areas in relation to methamphetamine: improve community awareness and understanding of amphetamine-type stimulant use and related problems; reduce the supply of amphetamine-type stimulants; develop specific strategies to prevent and reduce amphetamine type stimulant use; and develop organisational and system capacity to prevent and respond to amphetamine-type stimulant problems This research concerns the second priority area—reducing the supply of methamphetamine. The specific aims of the research were twofold: to provide a rich description of the Australian methamphetamine supply chains in order to inform drug law enforcement interventions; and to conduct an initial economic evaluation comparing law enforcement interventions directed at the methamphetamine market. The work focused on the methamphetamine market(s) and supply chains in Australia above the retail level. Previous research has examined retail methamphetamine markets in Australia. Governments and policymakers are interested in determining which interventions are more or less effective than others, such that the scarce funding resources can be allocated in the most efficient manner possible. There is scant research available to law enforcement to guide such decisions. The main impediments to such research are the fundamental methodological challenges inherent in such an undertaking. This project is an attempt to conduct a preliminary analysis comparing the costs and impacts of different types of law enforcement. It is a ground-breaking study as this has not been previously attempted and it should be seen as the initial development of a methodological approach that can be improved upon with subsequent research. The project aimed to determine the relative cost-to-impact ratios of different law enforcement strategies aimed at reducing methamphetamine production and distribution. In an environment focused on efficiency in resource allocation, it is hoped that this research will provide the impetus for further research on the effectiveness of drug law enforcement. As the results of such research accumulate, it is hoped that policymakers will be able to use the information to improve decision making on law enforcement investment

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

Background: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. Methods: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. Results: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). Conclusions: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

Findings from the DUMA program: methamphetamine drug market trends

Introduction Methamphetamine is a drug of national concern, with the Australian Crime Commission assessing it to be the illicit drug posing the greatest risk to the Australian community. The Australian Institute of Health and Welfare’s (AIHW) 2013 National Drug Strategy Household Survey (NDSHS) reported that approximately 400,000 Australians had used meth/amphetamines in the previous 12 months. The NDSHS reported a stable rate of meth/amphetamine use in the general community from 2010 to 2013 of 2.1 percent. However, there was a shift in the type of meth/amphetamine used, from powder to purer forms like ice or crystal methamphetamine. Specifically, powder meth/amphetamine use among recent users decreased from 51 percent to 29 percent, while ice use more than doubled from 22 percent to 50 percent. In line with this, the frequency of methamphetamine use among injecting drug users in Melbourne remained consistent from 2008 to 2014, but users reported transitioning from powder to crystal forms of methamphetamine. Frequency of use of methamphetamine has also changed across the 2010 to 2013 period. In 2013, 15.5 percent of recent meth/amphetamine users reported daily or weekly use, compared with 9.3 percent in the 2010 survey. When examining use by form, approximately a quarter of users who mainly used ice reported using it at least weekly, compared with 2.2 percent of powder users who reported weekly use. Scott et al.’s study of injecting drug users in Melbourne found that those already using methamphetamine were starting to purchase the drug more frequently in 2013 compared with 2011

Meth in Allegan County -- Spreading to West Michigan?

According to the Office of National Drug Policy, White House, about 1.3 million people used meth in the year 2002. Moreover, in 2001, 607,000 people used methamphetamine. The University of Arkansas reports that businesses in Benton County were losing an estimated $21 million annually because of meth, mainly due to absenteeism and lost productivity. Methamphetamine is a profoundly addictive drug that seriously affects health, families, businesses, social services, and the environment. Why is meth use on the increase

An Empirical Examination of the Associations Among Crystal Methamphetamine Use History, Posttraumatic Stress Symptom Severity, and Perceived Social Support

Social support functions as a protective factor against the development of posttraumatic stress disorder (PTSD). Crystal methamphetamine use, however, is associated with a decrease in Social functioning. This is noteworthy as people with PTSD endorse elevated rates of crystal methamphetamine use. The current study proposed to look at perceived Social support as it relates to crystal methamphetamine use among individuals endorsing a wide range of posttraumatic stress symptoms. Questionnaires measuring perceived Social support and posttraumatic stress symptom severity were administered to 98 traumatic event-exposed adults (Mage = 48.5, SD =7.74) recruited from the San Francisco bay area who were participating in a larger study focused on human immunodeficiency virus treatment adherence. Regression analyses were employed to test three interrelated hypotheses based on the general prediction that posttraumatic stress and crystal methamphetamine use will evidence unique and combined relations with perceived Social support. While posttraumatic stress symptom severity was negatively related to perceived Social support (B = -.145, β = -.322, sr 2 = .104, t(93) = -3.299, p = .001), neither the extent of previous crystal methamphetamine use, or the interaction between posttraumatic stress symptom severity and crystal methamphetamine use were associated with decreased levels of perceived Social support. Secondary analyses revealed a significant interaction between avoidance symptoms and crystal methamphetamine use, but upon further investigation, it appears that this relationship is only significant for those who deny previous crystal methamphetamine use. Similarly, an analysis of marital status indicated no significant relation between PTSD, crystal methamphetamine use, and marital status. Taken together, these results replicated research linking PTSD symptoms to Social support, but do not suggest that crystal methamphetamine use further impact Social support level