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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.

ABSTRACT: Metabotropic glutamate receptors (mGluRs) have been implicated in regulating anxiety, stress responses, and the neurobehavioral effects of psychostimulants. The present study sought to determine whether group II mGluR activation by the potent mGlu2/3 receptor agonist, (-)-2-oxa-4-aminobicylco hexane-4,6-dicarboxylic acid (LY379268), antagonizes reinstatement of cocaine-seeking induced by cocaine-related stimuli and whether this effect extends to behavior induced by stimuli conditioned to a potent conventional reinforcer, sweetened condensed milk (SCM). Also, we tested whether the suppressant effects of LY379268 on conditioned reinstatement extend to the primary reinforcing effects of cocaine or SCM. Rats were trained to associate discriminative stimuli (S(D)) with the availability of cocaine or SCM versus non-reward and then subjected to repeated extinction sessions during which the respective reinforcers and S(D) were withheld. Subsequent reexposure to the cocaine or SCM S(D), but not the non-reward S(D), produced recovery of responding at the previously active lever. LY379268 (0.3-3.0 mg/kg, s.c.) dose-dependently attenuated recovery of cocaine seeking but reduced conditioned reinstatement by the SCM S(D) only at the highest dose. LY379268 did not alter responding reinforced directly by SCM, and only the highest LY379268 dose reduced cocaine self-administration. The results suggest that the effects of LY379268 are selective for behavior maintained by cocaine as opposed to palatable conventional reinforcers. More importantly, the results show that LY379268 suppresses behavior motivated by stimuli conditioned to cocaine or SCM more effectively than consummatory behavior maintained by the unconditioned effects of these substances. As such, the results identify group II mGluRs as a pharmacotherapeutic target for craving and relapse prevention associated with cocaine cue exposure.

SUBMITTER: Baptista MA

PROVIDER: S-EPMC6729475 | biostudies-literature | 2004 May

REPOSITORIES: biostudies-literature

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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.

Baptista Marco A S MA Martin-Fardon Rémi R Weiss Friedbert F

The Journal of neuroscience : the official journal of the Society for Neuroscience 20040501 20

Metabotropic glutamate receptors (mGluRs) have been implicated in regulating anxiety, stress responses, and the neurobehavioral effects of psychostimulants. The present study sought to determine whether group II mGluR activation by the potent mGlu2/3 receptor agonist, (-)-2-oxa-4-aminobicylco hexane-4,6-dicarboxylic acid (LY379268), antagonizes reinstatement of cocaine-seeking induced by cocaine-related stimuli and whether this effect extends to behavior induced by stimuli conditioned to a poten ...[more]

PMID: 15152032

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Project description:Metabotropic glutamate receptors (mGluRs) are G protein coupled receptors that play important roles in synaptic plasticity and other neuro-physiological and pathological processes. Allosteric mGluR ligands are particularly promising drug targets because of their modulatory effects--enhancing or suppressing the response of mGluRs to glutamate. The mechanism by which this modulation occurs is not known. Here, we propose the hypothesis that positive and negative modulators will differentially stabilize the active and inactive conformations of the receptors, respectively. To test this hypothesis, we have generated computational models of the transmembrane regions of different mGluR subtypes in two different conformations. The inactive conformation was modeled using the crystal structure of the inactive, dark state of rhodopsin as template and the active conformation was created based on a recent model of the light-activated state of rhodopsin. Ligands for which the nature of their allosteric effects on mGluRs is experimentally known were docked to the modeled mGluR structures using ArgusLab and Autodock softwares. We find that the allosteric ligand binding pockets of mGluRs are overlapping with the retinal binding pocket of rhodopsin, and that ligands have strong preferences for the active and inactive states depending on their modulatory nature. In 8 out of 14 cases (57%), the negative modulators bound the inactive conformations with significant preference using both docking programs, and 6 out of 9 cases (67%), the positive modulators bound the active conformations. Considering results by the individual programs only, even higher correlations were observed: 12/14 (86%) and 8/9 (89%) for ArgusLab and 10/14 (71%) and 7/9 (78%) for AutoDock. These findings strongly support the hypothesis that mGluR allosteric modulation occurs via stabilization of different conformations analogous to those identified in rhodopsin where they are induced by photochemical isomerization of the retinal ligand--despite the extensive differences in sequences between mGluRs and rhodopsin.

Dataset Information

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.

Publications

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.

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