Behavioral and Functional Evidence of Metabotropic Glutamate Receptor 2/3 and Metabotropic Glutamate Receptor 5 Dysregulation in Cocaine-Escalated Rats: Factor in the Transition to Dependence

doi:10.1016/j.biopsych.2010.02.011

Biological Psychiatry

Volume 68, Issue 3, 1 August 2010, Pages 240-248

https://doi.org/10.1016/j.biopsych.2010.02.011 Get rights and content

Background

Rats with extended daily cocaine access show escalating cocaine self-administration and behavioral signs of dependence. Regulation of glutamatergic transmission by metabotropic glutamate receptors has emerged as a mechanism in the addictive actions of drugs of abuse. We examined here whether neuroadaptive dysregulation of metabotropic glutamate receptor function is a factor in escalating cocaine self-administration.

Methods

Rats with 1 hour daily cocaine access (short access [ShA]) versus 6-hour access (long access [LgA]) were tested for differences in the effects of the metabotropic glutamate receptor 2/3 (mGluR2/3) agonist (−)-2-oxa-4-aminobicylco(3.1.0)hexane-4,6-dicarboxylic acid (LY379268) and the metabotropic glutamate receptor 5 (mGluR5) antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP) on cocaine-reinforced progressive-ratio responding and differences in expression levels and functional activity of mGluR2/3 and mGluR5.

Results

The LgA groups showed higher progressive-ratio breakpoints than ShA groups. LY379268 (0–3 mg/kg subcutaneous) dose-dependently lowered breakpoints in the LgA group but reduced breakpoints only at 3 mg/kg in the ShA group. Consistent with this behavioral effect, functional mGluR2/3 activity was significantly elevated following LgA cocaine exposure. MTEP (0–3 mg/kg intraperitoneal) reduced breakpoints in the ShA group only. Long access cocaine exposure was associated with decreased mGluR5 expression, accompanied by reduced functional mGluR5 activity in the nucleus accumbens. A downward trend developed in mGluR5 protein expression in the medial prefrontal cortex and hippocampus.

Conclusions

Functional upregulation of mGluR2/3 and downregulation of mGluR5 are likely factors in the transition to cocaine dependence. The differential behavioral effects of LY379268 and MTEP in rats with a history of long access to cocaine have implications for the treatment target potential of mGluR2/3 and mGluR5.

Section snippets

Animals

Male Wistar rats (200 – 250 g, Charles River, Wilmington, Massachusetts) were maintained on a 12-hour/12-hour light/dark cycle (lights off at 18:00). Food and water were available ad libitum. All procedures were conducted in strict adherence to the National Institutes of Health Guide for the Care and Use of Laboratory Animals (23) and were approved by the Institutional Animal Care and Use Committee of The Scripps Research Institute.

Cocaine Self-Administration Training

Rats (n = 55) were surgically prepared with indwelling silastic

Escalation of Cocaine Self-Administration

Cocaine self-administration progressively increased in the LgA group. Escalation of cocaine intake was observed beginning with session 7 in terms of responding over the entire 6-hour session [p < .01 vs. session 1 following one-way ANOVA, F(21,546) = 8.43, p < .001; Figure 1A, left panel] and session 5 in terms of first-hour responding [p < .01 vs. session 1 following one-way ANOVA, F(21,546) = 7.40, p < .001; Figure 1A, right panel] until session 22. In contrast, cocaine self-administration in

Discussion

In the present study, two agents known to dampen excitatory glutamatergic transmission by activating presynaptic and perisynaptic autoregulatory mGluR2/3 (LY379268) or by antagonizing excitatory postsynaptic mGluR5 (MTEP) attenuated the reinforcing effects of cocaine on a PR schedule. In rats showing escalated cocaine intake, the ability of the mGluR2/3 agonist LY379268 to diminish cocaine-maintained PR performance increased, whereas the effect of the mGluR5 antagonist MTEP was blunted. This

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Citation Excerpt :
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Archival ReportBehavioral and Functional Evidence of Metabotropic Glutamate Receptor 2/3 and Metabotropic Glutamate Receptor 5 Dysregulation in Cocaine-Escalated Rats: Factor in the Transition to Dependence

Background

Methods

Results

Conclusions

Section snippets

Animals

Cocaine Self-Administration Training

Escalation of Cocaine Self-Administration

Discussion

Neuropsychopharmacology

Neurosci Biobehav Rev

Neuropharmacology

Trends Pharmacol Sci

Eur J Pharmacol

J Neurosci Methods

Neuropharmacology

Trends Pharmacol Sci

Brain Res

Brain Res

Behav Brain Res

Neuroscience

Cell

Neurosci Lett

Neuron

Neuron

Brain Res Brain Res Rev

Drug abuse and addiction treatment researchThe next generation

Arch Gen Psychiatry

Transition from moderate to excessive drug intake: Change in hedonic set point

Science

Metabotropic glutamate 5 receptor antagonist MPEP decreased nicotine and cocaine self-administration but not nicotine and cocaine-induced facilitation of brain reward function in rats

Ann N Y Acad Sci

Group II metabotropic and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kainate glutamate receptors regulate the deficit in brain reward function associated with nicotine withdrawal in rats

J Pharmacol Exp Ther

Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice

Nat Neurosci

Attenuation of behavioral effects of cocaine by the metabotropic glutamate receptor 5 antagonist 2-methyl-6-(phenylethynyl)-pyridine in squirrel monkeys: Comparison with dizocilpine

J Pharmacol Exp Ther

Preferential effects of the metabotropic glutamate 2/3 receptor agonist LY379268 on conditioned reinstatement versus primary reinforcement: Comparison between cocaine and a potent conventional reinforcer

J Neurosci

Activation of group II metabotropic glutamate receptors in the nucleus accumbens shell attenuates context-induced relapse to heroin seeking

Neuropsychopharmacology

Unveiling the functions of presynaptic metabotropic glutamate receptors in the central nervous system

J Pharmacol Exp Ther

Metabotropic glutamate receptors

Cell Tissue Res

Presynaptic glutamate receptors: Physiological functions and mechanisms of action

Nat Rev Neurosci

A role of ventral tegmental area glutamate in contextual cue-induced relapse to heroin seeking

J Neurosci

Archival Report
Behavioral and Functional Evidence of Metabotropic Glutamate Receptor 2/3 and Metabotropic Glutamate Receptor 5 Dysregulation in Cocaine-Escalated Rats: Factor in the Transition to Dependence