Elsevier

Biological Psychiatry

Volume 65, Issue 8, 15 April 2009, Pages 717-720
Biological Psychiatry

Brief Report
Positive Allosteric Modulation of mGluR5 Receptors Facilitates Extinction of a Cocaine Contextual Memory

https://doi.org/10.1016/j.biopsych.2008.11.001Get rights and content

Background

The perseverance of the motivational salience of drug-associated memories is an obstacle to the successful treatment of drug addiction and is often a causative factor in triggering relapse.

Methods

This study was intended to determine whether potentiation of type 5 metabotropic glutamate receptors (mGluR5), which are biochemically and structurally coupled to N-methyl-D-aspartate (NMDA) receptors, would facilitate the extinction of a cocaine-associated contextual memory as assessed by the conditioned place preference (CPP) paradigm in rats. Following the establishment of a cocaine CPP, rats were treated with the mGluR5 positive allosteric modulator 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB; 0.3, 3 and 30 mg/kg) before extinction test sessions. Additional groups of animals received 30 mg/kg CDPPB in combination with the mGluR5 antagonist 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP, 1 mg/kg) or the NMDA receptor antagonist MK-801 (.1 mg/kg).

Results

CDPPB dose-dependently facilitated the extinction of cocaine CPP, and these effects were not observed when animals were coadministered MTEP or MK-801. CDPPB failed to produce any evidence of neurotoxicity as assessed by FluoroJade C staining.

Conclusions

Positive allosteric modulation of mGluR5 function facilitates the extinction of a cocaine-associated contextual memory, which may represent a novel approach toward enhancing extinction learning in the context of drug addiction.

Section snippets

Animals

All procedures were conducted with the approval of an Institutional Animal Care and Use Committee. Male Sprague-Dawley rats (200–275 g, Harlan, Indianapolis, Indiana) were maintained on a 12 hour light-dark cycle (lights off at 7:00 am), and all experimentation was conducted during the dark phase. Rats were given ad libitum access to food and water throughout all procedures except during behavioral testing.

Apparatus

The CPP apparatus (Med Associates, St. Albans, Vermont) consisted of two adjacent

Results

Conditioning with cocaine (10 mg/kg) produced a significant place preference in all groups, as evidenced by a significant increase in the percent time spent in the initial nonpreferred side (Figures 1A and 1C). Cocaine CPP was observed to extinguished during the extinction test sessions as follows: vehicle (E5), .3 mg/kg CDPPB (E4), 3 mg/kg CDPPB (E1), 30 mg/kg CDPPB (E2), 30 mg/kg CDPPB + 1 mg/kg MTEP (E5), 30 mg/kg CDPPB + .1 mg/kg MK-801 (CPP was not extinguished after 5 days of extinction

Discussion

We found that the systemically active mGluR5 positive allosteric modulator CDPPB dose-dependently facilitated the extinction of a cocaine contextual memory, as evidenced by fewer extinction test sessions required to reach extinction criteria. This effect appeared to be mediated by both mGluR5 and NMDA receptors, because the effect of the highest dose of CDPPB tested was reversed by coadministration of MTEP and MK-801, respectively. CDPPB did not influence locomotor activity, nor did it exhibit

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    The responsiveness of drug-seeking behavior to PAMs may be affected by changes in mGlu5 receptor expression and subcellular distribution, which occur in rats undergoing methamphetamine withdrawal after methamphetamine-induced place-conditioning (Herrold et al., 2011) and behavioral sensitization to methamphetamine (Herrold, Persons, & Napier, 2013). Considering the efficacy of mGlu5 PAMs for facilitating inhibitory learning under both cocaine-induced place-conditioning (Gass & Olive, 2009) and cocaine self-administration procedures (Cleva et al., 2011), further work is warranted to understand (1) how re-exposure to methamphetamine-associated cues/contexts influences mGlu5 receptor function to impact PAM efficacy and (2) how stimulating mGlu5 receptor function impacts control of drug-seeking behavior by methamphetamine-associated cues and contexts. These findings with CDPPB, coupled with data from GRM5 knockout mice (Chesworth et al., 2013), point to a role of mGlu5 receptor signaling in the maintenance and recall of methamphetamine-context associations.

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