mGluR5 Antagonism Attenuates Methamphetamine Reinforcement and Prevents Reinstatement of Methamphetamine-Seeking Behavior in Rats

Gass, Justin T.; Osborne, Megan P. H.; Watson, Noreen L; Brown, Jordan L; Olive, M. Foster

doi:10.1038/npp.2008.140

Cited by 114 publications

(108 citation statements)

References 76 publications

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“…Our study also lends mechanistic confidence to previous reports that have used pharmacological tools to identify a role of mGluR5 in behaviors maintained by reward-paired stimuli (Tessari et al, 2004;Bespalov et al, 2005;Bäckström and Hyytiä, 2006;Schroeder et al, 2008;Gass et al, 2009;Kumaresan et al, 2009;MartinFardon et al, 2009;O'Connor et al, 2010), since these reports could have reflected off-target (Olive, 2009), anhedonic (Bäckström and Hyytiä, 2007) or reinforcing (van der Kam et al, 2009) effects of the pharmacological tools used.…”

Section: Discussionmentioning

confidence: 67%

Incentive Learning Underlying Cocaine-Seeking Requires mGluR5 Receptors Located on Dopamine D1 Receptor-Expressing Neurons

Novák¹,

Halbout²,

O’Connor³

et al. 2010

J. Neurosci.

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Understanding the psychobiological basis of relapse remains a challenge in developing therapies for drug addiction. Relapse in cocaine addiction often occurs following exposure to environmental stimuli previously associated with drug taking. The metabotropic glutamate receptor, mGluR5, is potentially important in this respect; it plays a central role in several forms of striatal synaptic plasticity proposed to underpin associative learning and memory processes that enable drug-paired stimuli to acquire incentive motivational properties and trigger relapse. Using cell type-specific RNA interference, we have generated a novel mouse line with a selective knock-down of mGluR5 in dopamine D1 receptor-expressing neurons. Although mutant mice self-administer cocaine, we show that reinstatement of cocaineseeking induced by a cocaine-paired stimulus is impaired. By examining different aspects of associative learning in the mutant mice, we identify deficits in specific incentive learning processes that enable a reward-paired stimulus to directly reinforce behavior and to become attractive, thus eliciting approach toward it. Our findings show that glutamate signaling through mGluR5 located on dopamine D1 receptor-expressing neurons is necessary for incentive learning processes that contribute to cue-induced reinstatement of cocaineseeking and which may underpin relapse in drug addiction.

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Section: Discussionmentioning

confidence: 67%

Incentive Learning Underlying Cocaine-Seeking Requires mGluR5 Receptors Located on Dopamine D1 Receptor-Expressing Neurons

Novák¹,

Halbout²,

O’Connor³

et al. 2010

J. Neurosci.

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“…Second, other neurotransmitters not investigated in the current study are probably involved in Meth-induced alterations. In particular, glutamate is involved in Methinduced toxicity (Quinton and Yamamoto, 2006), Meth reward, and reinforcement (Kim and Jang, 1997; Gass et al, 2009) and reinstatement of Meth seeking (Gass et al, 2009).…”

Section: Pfcmentioning

confidence: 99%

Extended Methamphetamine Self-Administration in Rats Results in a Selective Reduction of Dopamine Transporter Levels in the Prefrontal Cortex and Dorsal Striatum Not Accompanied by Marked Monoaminergic Depletion

Schwendt

Rocha²,

See³

et al. 2009

J Pharmacol Exp Ther

115

123

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Chronic abuse of methamphetamine leads to cognitive dysfunction and high rates of relapse, paralleled by significant changes of brain dopamine and serotonin neurotransmission. Previously, we found that rats with extended access to methamphetamine self-administration displayed enhanced methamphetamine-primed reinstatement of drug-seeking and cognitive deficits relative to limited access animals. The present study investigated whether extended access to methamphetamine self-administration produced abnormalities in dopamine and serotonin systems in rat forebrain. Rats self-administered methamphetamine (0.02-mg/i.v. infusion) during daily 1-h sessions for 7 to 10 days, followed by either short-(1-h) or longaccess (6-h) self-administration for 12 to 14 days. Lever responding was extinguished for 2 weeks before either reinstatement testing or rapid decapitation and tissue dissection. Tissue levels of monoamine transporters and markers of methamphetamine-induced toxicity were analyzed in several forebrain areas. Long-access methamphetamine self-administration resulted in escalation of daily drug intake (ϳ7 mg/kg/ day) and enhanced drug-primed reinstatement compared with the short-access group. Furthermore, long-, but not shortaccess to self-administered methamphetamine resulted in persistent decreases in dopamine transporter (DAT) protein levels in the prefrontal cortex and dorsal striatum. In contrast, only minor alterations in the tissue levels of dopamine or its metabolites were found, and no changes in markers specific for dopamine terminals or glial cell activation were detected. Our findings suggest that persistent methamphetamine seeking is associated with region-selective changes in DAT levels without accompanying monoaminergic neurotoxicity. Greater understanding of the neuroadaptations underlying persistent methamphetamine seeking and cognitive deficits could yield targets suitable for future therapeutic interventions.Methamphetamine (Meth) abuse in humans can quickly develop into a chronic relapsing disorder, accompanied by a wide range of neuropsychological deficits. For example, Meth addicts display impairments in memory functions, cognitive and psychomotor performance, as well as increased impulsivity and aggressive behavior (for reviews, see Nordahl et al., 2003;Scott et al., 2007). Human brain imaging studies provide evidence that these neuropsychological deficits are paralleled by significant changes in brain dopaminergic and serotonergic neurotransmitter systems, as well as altered general metabolic activity in basal ganglia and frontal cortices (for review, see Chang et al., 2007). In particular, chronic Meth abuse reduces the density of dopamine transporters (DAT) in the striatum and (to a lesser extent) in the frontal Article, publication date, and citation information can be found at

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“…21 Moreover, selfadministration and reinstatement of cocaine, nicotine, alcohol, methamphetamine, and heroin was attenuated by mGluR5 antagonists. [22][23][24][25][26][27][28][29][30][31][32] Therefore, much effort is being undertaken to develop 4 pharmacological compounds with the ability to block mGluR5s, which is assumed to be one efficacious way to treat psychostimulant-addiction.…”

Section: Introductionmentioning

confidence: 99%

Smoking but not cocaine use is associated with lower cerebral metabotropic glutamate receptor 5 density in humans

et al. 2013

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Long-lasting neuroadaptations in the glutamatergic corticostriatal circuitry have been suggested to be responsible for the persisting nature of drug addiction. In particular, animal models have linked the metabotropic glutamate receptor 5 (mGluR5) to drug-seeking behavior and extinction learning. Accordingly, blocking mGluR5s attenuated self-administration of cocaine and other addictive drugs in rats. How these animal findings extend to humans remains unclear. Therefore, we investigated if human cocaine users (CU) exhibit altered mGluR5 availability compared with drug-naïve control subjects. Seventeen male controls (11 smokers) and 18 male cocaine users (13 smokers) underwent positron emission tomography with 11C-ABP688 to quantify mGluR5 availability in 12 volumes of interest in addiction-related brain areas. Drug use was assessed by self-report and quantitative hair toxicology. CU and controls did not significantly differ in regional mGluR5 availability. In contrast, smokers (n=24) showed significantly lower mGluR5 density throughout the brain (mean 20%) compared with non-smokers (n=11). In terms of effect sizes, lower mGluR5 availability was most pronounced in the caudate nucleus (d=1.50, 21%), insula (d=1.47, 20%), and putamen (d=1.46, 18%). Duration of smoking abstinence was positively associated with mGluR5 density in all brain regions of interest, indicating that lower mGluR5 availability was particularly pronounced in individuals who had smoked very recently. Specifically tobacco smoking was associated with lower mGluR5 availability in both CU and controls, while cocaine use was not linked to detectable mGluR5 alterations. These findings have important implications regarding the development of novel pharmacotherapies aimed at facilitating smoking cessation. AbstractLong-lasting neuroadaptations in the glutamatergic corticostriatal circuitry have been suggested to be responsible for the persisting nature of drug addiction. In particular, animal models have linked the metabotropic glutamate receptor 5 (mGluR5) to drug-seeking behavior and extinction learning. Accordingly, blocking mGluR5s attenuated self-administration of cocaine and other addictive drugs in rats. How these animal findings extend to humans remains unclear. Therefore, we investigated if human cocaine users exhibit altered mGluR5 availability compared to drug-naïve control subjects.Seventeen male controls (11 smokers) and 18 male cocaine users (13 smokers) underwent positron emission tomography with 11 C-ABP688 to quantify mGluR5 availability in 12 volumes of interest in addiction-related brain areas. Drug use was assessed by self-report and quantitative hair toxicology.Cocaine users and controls did not significantly differ in regional mGluR5 availability. In contrast, smokers (n=24) showed significantly lower mGluR5 density throughout the brain (mean 20%) compared to non-smokers (n=11). In terms of effect sizes, lower mGluR5 availability was most pronounced in the caudate nucleus (d=1.50, 21%), insula (d=1.47, 20%), and putamen ...

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mGluR5 Antagonism Attenuates Methamphetamine Reinforcement and Prevents Reinstatement of Methamphetamine-Seeking Behavior in Rats

Cited by 114 publications

References 76 publications

Incentive Learning Underlying Cocaine-Seeking Requires mGluR5 Receptors Located on Dopamine D1 Receptor-Expressing Neurons

Incentive Learning Underlying Cocaine-Seeking Requires mGluR5 Receptors Located on Dopamine D1 Receptor-Expressing Neurons

Extended Methamphetamine Self-Administration in Rats Results in a Selective Reduction of Dopamine Transporter Levels in the Prefrontal Cortex and Dorsal Striatum Not Accompanied by Marked Monoaminergic Depletion

Smoking but not cocaine use is associated with lower cerebral metabotropic glutamate receptor 5 density in humans

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