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  • Title: The role of glutamate mGlu5 and adenosine A2a receptor interactions in regulating working memory performance and persistent cocaine seeking in rats.
    Author: Hámor PU, Gobin CM, Schwendt M.
    Journal: Prog Neuropsychopharmacol Biol Psychiatry; 2020 Dec 20; 103():109979. PubMed ID: 32470496.
    Abstract:
    Cocaine use disorder (CUD) is associated with neurobehavioral deficits that are resistant to current treatments. While craving and high rates of relapse are prominent features of CUD, persistent cognitive impairments are common and linked to poorer treatment outcomes. Here we sought to develop an animal model to study post-cocaine changes in drug seeking and working memory, and to evaluate 'therapeutic' effects of combined glutamate mGlu5 and adenosine A2a receptor blockade. As mGlu5 antagonists reduce drug seeking, and A2a blockade ameliorates working memory impairment, we hypothesized that mGlu5 + A2a antagonist cocktail would reduce both cocaine relapse and post-cocaine working memory deficits. Adult male Sprague-Dawley rats were first trained and tested in an operant delayed match-to-sample (DMS) task to establish the working memory baseline, followed by 6 days of limited and 12 days of extended access cocaine self-administration. Chronic cocaine reduced working memory performance (abstinence day 30-40) and produced robust time-dependent cocaine seeking at 45-, but not 120-days of abstinence. Systemic administration of A2a antagonist KW-6002 (0.125 and 1 mg/kg) failed to rescue post-cocaine working memory deficit. It also failed to reverse working memory impairment produced by mGlu5 NAM MTEP (1 mg/kg). Finally, KW-6002 prevented the ability of MTEP to reduce cocaine seeking and increased locomotor behavior. Thus, despite mGlu5 and A2a being exclusively co-localized in the striatum and showing behavioral synergism towards reducing cocaine effects in some studies, our findings advocate against the use of mGlu5 + A2a antagonist cocktail as it may further compromise cognitive deficits and augment drug craving in CUD.
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