Methamphetamine Self-administration In Rats Research Articles

Inhibition of GSDMD-dependent pyroptosis decreased methamphetamine self-administration in rats

It is widely believed that the activation of the central dopamine (DA) system is crucial to the rewarding effects of methamphetamine (METH) and to the behavioral outcomes of METH use disorder. It was reported that METH exposure induced gasdermin D (GSDMD)-dependent pyroptosis in rats. The membrane pore formation caused by METH-induced pyroptosis may also contribute to the overflow of DA into the extracellular space and subsequently increase the DA levels in the brain. The present study firstly investigated whether the membrane pore information induced by GSDMD-dependent pyroptosis was associated with the increased DA levels in the ventral tegmental area (VAT) and nucleus accumbens (NAc) of rats self-administering METH and SY-SH5Y cells treated by METH. Subsequently, the effect of pore formation blockade or genetic inhibition of GSDMD on the reinforcing and motivational effect of METH was determined in rats, using the animal model of METH self-administration (SA). METH exposure significantly increased the activity of NLRP1/Cas-1/GSDMD pathway and the presence of pyroptosis, accompanied by the significantly increased DA levels in VTA and NAc. Moreover, intraperitoneal injections of disulfiram (DSF) or microinjection of rAAV-shGSDMD into VTA/NAc significantly reduced the reinforcing and motivational effect of METH, accompanied by the decreased level of DA in VTA and NAc. The results provided novel evidence that METH-induced pyroptosis could increase DA release in VTA and NAc via the NLRP1/Cas-1/GSDMD pathway. Additionally, membrane pores or GSDMD blockade could significantly reduce the reinforcing and motivational effect of METH. In conclusion, blocking GSDMD and membrane pore formation could be a promising potential target for the development of agents to treat METH use disorder

Vesicular monoamine transporter-2 inhibitor JPC-141 prevents methamphetamine-induced dopamine toxicity and blocks methamphetamine self-administration in rats

Previous research has demonstrated therapeutic potential for VMAT2 inhibitors in rat models of methamphetamine use disorder. Here, we report on the neurochemical and behavioral effects of 1-(2-methoxyphenethyl)-4-phenethypiperazine (JPC-141), a novel analog of lobelane. JPC-141 potently inhibited (Ki = 52 nM) [3H]dopamine uptake by VMAT2 in striatal vesicles with 50 to 250-fold greater selectivity for VMAT2 over dopamine, norepinephrine and serotonin plasmalemma transporters. Also, JPC-141 was 57-fold more selective for inhibiting VMAT2 over [3H]dofetilide binding to hERG channels expressed by HEK293, suggesting relatively low potential for cardiotoxicity. When administered in vivo to rats, JPC-141 prevented the METH-induced reduction in striatal dopamine content when given either prior to or after a high dose of METH, suggesting a reduction in METH-induced dopaminergic neurotoxicity. In behavioral assays, JPC-141 decreased METH-stimulated locomotor activity in METH-sensitized rats at doses of JPC-141 which did not alter locomotor activity in the saline control group. Moreover, JPC-141 specifically decreased iv METH self-administration at doses that had no effect on food-maintained responding. These findings support the further development of VMAT2 inhibitors as pharmacotherapies for individuals with methamphetamine use disorder.

Mitochondrial dysfunction and autophagy activation are associated with cardiomyopathy developed by extended methamphetamine self-administration in rats

The recent rise in illicit use of methamphetamine (METH), a highly addictive psychostimulant, is a huge health care burden due to its central and peripheral toxic effects. Mounting clinical studies have noted that METH use in humans is associated with the development of cardiomyopathy; however, preclinical studies and animal models to dissect detailed molecular mechanisms of METH-associated cardiomyopathy development are scarce. The present study utilized a unique very long-access binge and crash procedure of METH self-administration to characterize the sequelae of pathological alterations that occur with METH-associated cardiomyopathy. Rats were allowed to intravenously self-administer METH for 96 h continuous weekly sessions over 8 weeks. Cardiac function, histochemistry, ultrastructure, and biochemical experiments were performed 24 h after the cessation of drug administration. Voluntary METH self-administration induced pathological cardiac remodeling as indicated by cardiomyocyte hypertrophy, myocyte disarray, interstitial and perivascular fibrosis accompanied by compromised cardiac systolic function. Ultrastructural examination and native gel electrophoresis revealed altered mitochondrial morphology and reduced mitochondrial oxidative phosphorylation (OXPHOS) supercomplexes (SCs) stability and assembly in METH exposed hearts. Redox-sensitive assays revealed significantly attenuated mitochondrial respiratory complex activities with a compensatory increase in pyruvate dehydrogenase (PDH) activity reminiscent of metabolic remodeling. Increased autophagy flux and increased mitochondrial antioxidant protein level was observed in METH exposed heart. Treatment with mitoTEMPO reduced the autophagy level indicating the involvement of mitochondrial dysfunction in the adaptive activation of autophagy in METH exposed hearts. Altogether, we have reported a novel METH-associated cardiomyopathy model using voluntary drug seeking behavior. Our studies indicated that METH self-administration profoundly affects mitochondrial ultrastructure, OXPHOS SCs assembly and redox activity accompanied by increased PDH activity that may underlie observed cardiac dysfunction.

Cannabidiol but not cannabidiolic acid reduces behavioural sensitisation to methamphetamine in rats, at pharmacologically effective doses

RationaleCannabidiol (CBD) and cannabidiolic acid (CBDA) are non-psychoactive components of the cannabis plant. CBD has been well characterised to have anxiolytic and anticonvulsant activity, whereas the behavioural effects of CBDA are less clear. Preclinical and clinical data suggests that CBD has antipsychotic properties and reduces methamphetamine self-administration in rats. An animal model that is commonly used to mimic the neurochemical changes underlying psychosis and drug dependence is methamphetamine (METH) sensitisation, where repeated administration of the psychostimulant progressively increases the locomotor effects of METH.ObjectiveThe aim of this study was to determine whether CBD or CBDA attenuate METH-induced sensitisation of locomotor hyperactivity in rats.MethodsEighty-six male Sprague Dawley rats underwent METH sensitisation protocol where they were subjected to daily METH (1 mg/kg on days 2 and 8, 5 mg/kg on days 3–7; i.p.) injections for 7 days. After 21 days of withdrawal, rats were given a prior injection of CBD (0, 40 and 80 mg/kg; i.p.) or CBDA (0, 0.1, 10 and 1000 µg/kg; i.p.) and challenged with acute METH (1 mg/kg; i.p.). Locomotor activity was then measured for 60 min.ResultsRats displayed robust METH sensitisation as evidenced by increased locomotor activity to METH challenge in METH-pretreated versus SAL-pretreated rats. CBD (40 and 80 mg/kg) reduced METH-induced sensitisation. There was no effect of any CBDA doses on METH sensitisation or acute METH-induced hyperactivity.ConclusionThese results demonstrate that CBD, but not CBDA, reduces METH sensitisation of locomotor activity in rats at pharmacologically effective doses, thus reinforcing evidence that CBD has anti-addiction and antipsychotic properties.

NBQX attenuates relapse of nicotine seeking but not nicotine and methamphetamine self-administration in rats

Objective Pharmacological manipulations of glutamatergic ionotropic receptors have been suggested as a promising target for addiction treatment. Antagonists of AMPA/kainate receptors were shown to reduce alcohol intake or alcohol-seeking in various animal models. In this study, we evaluated the effect of NBQX, an AMPA/kainate receptor antagonist, on methamphetamine (METH) and nicotine self-administration in rats. Methods Male Wistar rats were trained to self-administer METH (0.08 mg/kg per infusion, session of 90 min) and nicotine (0.03 mg/kg per infusion, session of 60 min) under the fixed ratio 1 schedule of reinforcement. The maintenance training was 2 weeks. During the second week, NBQX was injected subcutaneously at doses of 5 or 10 mg/kg 20 min before the session or intravenously (IV) at doses of 1 and 5 mg/kg 10 min before the session. Following the maintenance training, rats were subjected to forced abstinence for 2 weeks and 1 day of the drug-free relapse-like session with IV NBQX treatment performed as before. Results Although NBQX did not affect nicotine maintenance, it significantly suppressed the drug-paired responding in the relapse session. Regarding METH, NBQX did not exert a significant effect at either phase of the study. Conclusions These findings suggest selective involvement of AMPA/kainate receptors in the relapse of nicotine seeking after a period of forced abstinence.

Effects of nicotine conditioning history on alcohol and methamphetamine self-administration in rats

BackgroundSmoking constitutes a significant public health risk. Alcohol and methamphetamine use disorders are also highly co-morbid with smoking, further increasing negative health outcomes. An important question in determining the underlying neurobiology of nicotine poly-drug use is understanding whether having a positive history with nicotine effects alters later drug-taking behavior. MethodsThe current experiments sought to elucidate whether having an appetitive nicotine conditioning history would affect later alcohol or methamphetamine self-administration. Adult male and female Long-Evans rats were first trained on a discriminated goal-tracking task in which the interoceptive effects of nicotine predicted sucrose reinforcement. As a control, pseudo-conditioned groups were included that had equated nicotine and sucrose experience. Rats were then shifted to either alcohol self-administration or methamphetamine self-administration. ResultsNicotine conditioning history had no effect on acquisition or maintenance of alcohol self-administration in males or females. In contrast, an appetitive nicotine conditioning history decreased methamphetamine self-administration in female rats, but not males. ConclusionsIn female, but not male, rats, an appetitive conditioning history with nicotine decreases methamphetamine, but not alcohol, self-administration. This dissociation suggests that the effects may be due to a specific increase in the reinforcing value of methamphetamine. This may have implications for better understanding the progression of drug use from nicotine to methamphetamine.

New Scaffold for Lead Compounds to Treat Methamphetamine Use Disorders.

Despite increased methamphetamine use worldwide, pharmacotherapies are not available to treat methamphetamine use disorder. The vesicular monoamine transporter-2 (VMAT2) is an important pharmacological target for discovery of treatments for methamphetamine use disorder. VMAT2 inhibition by the natural product, lobeline, reduced methamphetamine-evoked dopamine release, methamphetamine-induced hyperlocomotion, and methamphetamine self-administration in rats. Compared to lobeline, lobelane exhibited improved affinity and selectivity for VMAT2 over nicotinic acetylcholine receptors. Lobelane inhibited neurochemical and behavioral effects of methamphetamine, but tolerance developed to its behavioral efficacy in reducing methamphetamine self-administration, preventing further development. The lobelane analog, R-N-(1,2-dihydroxypropyl)-2,6-cis-di-(4-methoxyphenethyl)piperidine hydrochloride (GZ-793A), potently and selectively inhibited VMAT2 function and reduced neurochemical and behavioral effects of methamphetamine. However, GZ-793A exhibited potential to induce ventricular arrhythmias interacting with human-ether-a-go-go (hERG) channels. Herein, a new lead, R-3-(4-methoxyphenyl)-N-(1-phenylpropan-2-yl)propan-1-amine (GZ-11610), from the novel scaffold (N-alkyl(1-methyl-2-phenylethyl)amine) was evaluated as a VMAT2 inhibitor and potential therapeutic for methamphetamine use disorder. GZ-11610 was 290-fold selective for VMAT2 over dopamine transporters, suggesting that it may lack abuse liability. GZ-11610 was 640- to 3500-fold selective for VMAT2 over serotonin transporters and nicotinic acetylcholine receptors. GZ-11610 exhibited > 1000-fold selectivity for VMAT2 over hERG, representing a robust improvement relative to our previous VMAT2 inhibitors. GZ-11610 (3-30mg/kg, s.c. or 56-300mg/kg, oral) reduced methamphetamine-induced hyperactivity in methamphetamine-sensitized rats. Thus, GZ-11610 is a potent and selective inhibitor of VMAT2, may have low abuse liability and low cardiotoxicity, and after oral administration is effective and specific in inhibiting the locomotor stimulant effects of methamphetamine, suggesting further investigation as a potential therapeutic for methamphetamine use disorder.

Atypical dopamine transporter inhibitors attenuate compulsive-like methamphetamine self-administration in rats

Methamphetamine (METH) is a highly addictive drug, but no pharmacological treatment is yet available for METH use disorders. Similar to METH, the wake-promoting drug (R)-modafinil (R-MOD) binds to the dopamine transporter (DAT). Unlike METH, R-MOD is not a substrate for transport by DAT and has low abuse potential. We tested the hypothesis that the atypical DAT inhibitor R-MOD and compounds that are derived from modafinil would decrease METH intake by reducing the actions of METH at the DAT. We tested the effects of systemic injections of R-MOD and four novel modafinil-derived ligands with increased DAT affinity (JJC8-016, JJC8-088, JJC8-089, and JJC8-091) on intravenous (i.v.) METH self-administration in rats that were allowed short access (ShA; 1 h) or long access (LgA; 6 h) to the drug. ShA rats exhibited stable METH intake over sessions, whereas LgA rats exhibited an escalation of drug intake. R-MOD decreased METH self-administration in ShA and LgA rats (in the 1st hour only). JJC8-091 and JJC8-016 decreased METH self-administration in both ShA and LgA rats. JJC8-089 decreased METH self-administration in LgA rats only, whereas JJC8-088 had no effect on METH self-administration in either ShA or LgA rats. These findings support the potential of atypical DAT inhibitors for the treatment of METH use disorders and suggest several novel compounds as candidate drugs.

Methamphetamine abuse impairs motor cortical plasticity and function

Exposure to addictive drugs triggers synaptic plasticity in reward-related brain regions, such as the midbrain, nucleus accumbens and the prefrontal cortex. Effects of chronic drug exposure on other brain areas have not been fully investigated. Here, we characterize synaptic plasticity in motor cortex after methamphetamine self-administration in rats. We show that this causes a loss of corticostriatal plasticity in rat brain slices and impaired motor learning in the rotarod task. These findings are paralleled by the observation of a lack of transcranial magnetic stimulation-induced potentiation or depression of motor evoked potentials in human patients with addiction, along with poor performance in rotary pursuit task. Taken together, our results suggest that chronic methamphetamine use can affect behavioral performance via drug-evoked synaptic plasticity occluding physiological motor learning.

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

BackgroundMethamphetamine 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. MethodsFive 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. ResultsOxazepam 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. ConclusionsThe 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.

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

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 0.625μg) significantly reduced both methamphetamine (0.0125 or 0.05mg/kg/infusion)-induced self-administration under fixed ratio 2 reinforcement and the breakpoint of methamphetamine (0.05mg/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 1.25μg, i.c.v.) significantly decreased methamphetamine (1mg/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 1.25μg, i.c.v.) decreased methamphetamine (1mg/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.

Early life stress and chronic variable stress in adulthood interact to influence methamphetamine self-administration in male rats.

Early life stress interacts with adult stress to differentially modulate neural systems and vulnerability to various psychiatric illnesses. However, the effects of early life stress and adult stress on addictive behaviors have not been sufficiently investigated. We examined the effects of early life stress in the form of prolonged maternal separation, followed in early adulthood by either 10 days of chronic variable stress or no stress, on methamphetamine self-administration, extinction, and cue-induced reinstatement. We observed that chronic variable stress in adulthood reduced methamphetamine self-administration in rats with a history of early life stress. These findings add to an emerging body of literature suggesting interactions between early life and early adulthood stressors on adult behavioral phenotypes.

Proteomics Analysis of Dorsal Striatum Reveals Changes in Synaptosomal Proteins following Methamphetamine Self-Administration in Rats.

Methamphetamine is a widely abused, highly addictive drug. Regulation of synaptic proteins within the brain’s reward pathway modulates addiction behaviours, the progression of drug addiction and long-term changes in brain structure and function that result from drug use. Therefore, using large scale proteomics studies we aim to identify global protein expression changes within the dorsal striatum, a key brain region involved in the modulation of addiction. We performed LC-MS/MS analyses on rat striatal synaptosomes following 30 days of methamphetamine self-administration (2 hours/day) and 14 days abstinence. We identified a total of 84 differentially-expressed proteins with known roles in neuroprotection, neuroplasticity, cell cytoskeleton, energy regulation and synaptic vesicles. We identify significant expression changes in stress-induced phosphoprotein and tubulin polymerisation-promoting protein, which have not previously been associated with addiction. In addition, we confirm the role of amphiphysin and phosphatidylethanolamine binding protein in addiction. This approach has provided new insight into the effects of methamphetamine self-administration on synaptic protein expression in a key brain region associated with addiction, showing a large set of differentially-expressed proteins that persist into abstinence. The mass spectrometry proteomics data are available via ProteomeXchange with identifier PXD001443.

Methamphetamine self-administration in rats is diminished by wheel access in the prior 22 h

Methamphetamine self-administration in rats is diminished by wheel access in the prior 22 h

Dopamine receptors and the persistent neurovascular dysregulation induced by methamphetamine self-administration in rats.

Recently abstinent methamphetamine (Meth) abusers showed neurovascular dysregulation within the striatum. The factors that contribute to this dysregulation and the persistence of these effects are unclear. The current study addressed these knowledge gaps. First, we evaluated the brains of rats with a history of Meth self-administration following various periods of forced abstinence. Micro-computed tomography revealed a marked reduction in vessel diameter and vascular volume uniquely within the striatum between 1 and 28 days after Meth self-administration. Microvessels showed a greater impairment than larger vessels. Subsequently, we determined that dopamine (DA) D2 receptors regulated Meth-induced striatal vasoconstriction via acute noncontingent administration of Meth. These receptors likely regulated the response to striatal hypoxia, as hypoxia inducible factor 1α was elevated. Acute Meth exposure also increased striatal levels of endothelin receptor A and decreased neuronal nitric oxide synthase. Collectively, the data provide novel evidence that Meth-induced striatal neurovascular dysregulation involves DA receptor signaling that results in vasoconstriction via endothelin receptor A and nitric oxide signaling. As these effects can lead to hypoxia and trigger neuronal damage, these findings provide a mechanistic explanation for the selective striatal toxicity observed in the brains of Meth-abusing humans.

Active vaccination inhibits the acquisition of methamphetamine self-administration in rats

Active vaccination inhibits the acquisition of methamphetamine self-administration in rats

Preclinical efficacy of N-substituted benztropine analogs as antagonists of methamphetamine self-administration in rats.

Atypical dopamine-uptake inhibitors have low abuse potential and may serve as leads for development of cocaine-abuse treatments. Among them, the benztropine (BZT) derivatives, N-butyl (JHW007), N-allyl (AHN2-005), and N-methyl (AHN1-055) analogs of 3α-[bis(4'-fluorophenyl)methoxy]-tropane dose-dependently decreased cocaine self-administration without effects on food-maintained responding. Our study examined selectivity by assessing their effects on self-administration of other drugs. As with cocaine, each BZT analog (1.0-10.0 mg/kg i.p.) dose-dependently decreased maximal self-administration of d-methamphetamine (0.01-0.32 mg/kg/infusion) but was inactive against heroin (1.0-32.0 µg/kg/infusion) and ketamine (0.032-1.0 mg/kg/infusion) self-administration. Further, standard dopamine indirect-agonists [WIN35,428 ((-)-3β-(4-fluorophenyl)-tropan-2-β-carboxylic acid methyl ester tartrate), d-amphetamine (0.1-1.0 mg/kg i.p., each)] dose-dependently left-shifted self-administration dose-effect curves for d-methamphetamine, heroin, and ketamine. Noncompetitive NMDA-glutamate receptor/channel antagonists [(+)-MK-801 (0.01-0.1 mg/kg i.p.), memantine (1.0-10.0 mg/kg i.p.)] also left-shifted dose-effect curves for d-methamphetamine and ketamine (but not heroin) self-administration. The µ-agonists [dl-methadone and morphine (1.0-10.0 mg/kg i.p., each)] dose-dependently decreased maximal self-administration of µ-agonists (heroin, remifentanil) but not d-methamphetamine or ketamine self-administration. The µ-agonist-induced decreases were similar to the effects of BZT analogs on stimulant self-administration and effects of food prefeeding on responding maintained by food reinforcement. Radioligand-binding and behavioral studies suggested that inhibition of dopamine transporters and σ receptors were critical for blocking stimulant self-administration by BZT-analogs. Thus, the present results suggest that the effects of BZT analogs on stimulant self-administration are similar to effects of µ-agonists on µ-agonist self-administration and food prefeeding on food-reinforced responding, which implicates behavioral mechanisms for these effects and further supports development of atypical dopamine uptake inhibitors as medications for stimulant abuse.

Oral administration of GZ-793A, a VMAT2 inhibitor, decreases methamphetamine self-administration in rats

Despite the high prevalence of use of methamphetamine (METH), there is no FDA-approved pharmacological treatment available currently for METH addiction. The vesicular monoamine transporter (VMAT2) has been proposed as a novel target to treat METH abuse. GZ-793A, a lobelane analog and selective VMAT2 inhibitor, has been shown previously to decrease METH self-administration specifically when administered via the subcutaneous route in rats. Since oral administration is the preferred clinical route, the present experiments determined if oral administration of GZ-793A would decrease specifically METH self-administration. Experiments 1 and 2 assessed the dose-effect functions of oral administration of GZ-793A (30–240mg/kg) on intravenous METH self-administration and food-maintained responding, respectively. Experiments 3 and 4 assessed the time-course (20–180min pretreatment) of oral administration of GZ-793A on METH self-administration and food-maintained responding, respectively. Oral administration of GZ-793A dose-dependently decreased METH self-administration, with the highest dose (240mg/kg) producing an 85% decrease compared to control baseline. The decrease in METH self-administration produced by GZ-793A (120mg/kg) lasted at least 180min. In contrast, GZ-793A failed to alter food-maintained responding at any of the doses or pretreatment intervals tested. The oral effectiveness and the specificity of GZ-793A to decrease methamphetamine self-administration support the feasibility of developing VMAT2 inhibitors as treatments for METH abuse.

GZ‐793A, a lobelane analog, interacts with the vesicular monoamine transporter‐2 to inhibit the effect of methamphetamine

(R)-3-[2,6-cis-Di(4-methoxyphenethyl)piperidin-1-yl]propane-1,2-diol (GZ-793A) inhibits methamphetamine-evoked dopamine release from striatal slices and methamphetamine self-administration in rats. GZ-793A potently and selectively inhibits dopamine uptake at the vesicular monoamine transporter-2 (VMAT2). This study determined GZ-793A's ability to evoke [³H]dopamine release and inhibit methamphetamine-evoked [³H]dopamine release from isolated striatal synaptic vesicles. Results show GZ-793A concentration-dependent [³H]dopamine release; nonlinear regression revealed a two-site model of interaction with VMAT2 (High- and Low-EC₅₀ = 15.5 nM and 29.3 μM, respectively). Tetrabenazine and reserpine completely inhibited GZ-793A-evoked [³H]dopamine release, however, only at the High-affinity site. Low concentrations of GZ-793A that interact with the extravesicular dopamine uptake site and the High-affinity intravesicular DA release site also inhibited methamphetamine-evoked [³H]dopamine release from synaptic vesicles. A rightward shift in the methamphetamine concentration-response was evident with increasing concentrations of GZ-793A, and the Schild regression slope was 0.49 ± 0.08, consistent with surmountable allosteric inhibition. These results support a hypothetical model of GZ-793A interaction at more than one site on the VMAT2 protein, which explains its potent inhibition of dopamine uptake, dopamine release via a High-affinity tetrabenazine- and reserpine-sensitive site, dopamine release via a Low-affinity tetrabenazine- and reserpine-insensitive site, and a low-affinity interaction with the dihydrotetrabenazine binding site on VMAT2. GZ-793A inhibition of the effects of methamphetamine supports its potential as a therapeutic agent for the treatment of methamphetamine abuse.

The group II metabotropic glutamate receptor agonist, LY379268, decreases methamphetamine self-administration in rats

BackgroundGiven the problems associated with the escalation in methamphetamine (METH) use, the identification of more effective treatment strategies is essential. Group II metabotropic glutamate receptors (mGluRs) have been suggested to be a novel therapeutic target for psychostimulant addiction. We sought to test the ability of the selective group II mGluR agonist LY379268 to reduce METH self-administration in rats. MethodsRats were trained to self-administer METH on a progressive ratio (PR) schedule. Animals were then switched to fixed ratio responding and given daily extended access (6h/day) to METH self-administration for 14 days. Rats were then re-tested on the PR schedule. The effect of LY379268 on METH-reinforced PR responding was determined before and after 14 days of extended access. To test for non-specific effects, a separate group of animals received LY379268 prior to a sucrose pellet-reinforced PR schedule. ResultsAnimals escalated their daily intake of METH during extended access. PR responding did not change as a function of extended access. LY379268 significantly attenuated METH reinforced responding, both before and after extended access. The degree of attenuation did not change as a function of extended access. LY379268 had no effect on sucrose pellet-reinforced responding at any dose. ConclusionsLY379268 selectively reduced the motivation to self-administer METH. In contrast to data with other compounds, the sensitivity to the effects of LY379268 did not change following extended access to METH self-administration. Group II mGluR agonists, therefore, may represent a relatively new class of compounds for the development of pharmacotherapies for METH addiction.