The cognitive cost of reducing relapse to cocaine-seeking with mGlu5 allosteric modulators
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Cocaine use disorder (CUD) remains difficult to treat with no FDA-approved medications to reduce relapse. Antagonism of metabotropic glutamate receptor 5 (mGlu5) has been demonstrated to decrease cocaine-seeking but may also further compromise cognitive function in long-term cocaine users.
Here we assessed the effect of repeated administration of negative or positive allosteric modulators (NAM or PAM) of mGlu5 on both cognitive performance and (context+cue)-primed cocaine-seeking after prolonged abstinence (≥ 45 days).
Adult male Sprague-Dawley rats underwent 6 days of short-access (1 h/day) and 12 days of long-access (6 h/day) cocaine self-administration. Rats were then trained and tested in a delayed match-to-sample (DMS) task to establish baseline working memory performance over a 5-day block of testing. Next, rats received daily systemic administration of the mGlu5 NAM 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine hydrochloride (MTEP; 3 mg/kg), the mGlu5 PAM 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB; 30 mg/kg) or vehicle prior to DMS testing during a block of 5 days, followed by a 5-day washout DMS testing block.
MTEP and CDPPB decreased drug-seeking in response to cocaine-associated cues after prolonged abstinence. However, repeated treatment with MTEP impaired working memory, while CDPPB had no effects on performance.
These results emphasize the relevance of evaluating cognitive function within the context of investigating pharmacotherapies to treat CUD. Further research is needed to determine how two mechanistically different pharmacological compounds can exert the same behavioral effects to reduce cocaine-seeking.
KeywordsAddiction Self-administration Cocaine Relapse Working memory mGlu5 receptor
The authors thank Dr. Jennifer Bizon and Dr. Joseph McQuail for their input on the design of the DMS task and Dr. Lori Knackstedt for her valuable comments during manuscript preparation. We also thank Mr. Spencer Berman, Mr. Kyle Fontaine, Ms. Carly Wallace, and Ms. Vera Monlux for their assistance with conducting behavioral studies.
This research was supported by the University of Florida McKnight Brain Institute pilot award (MS).
Compliance with ethical standards
All experimental protocols were approved by the University of Florida Institutional Animal Care and Use Committee and consistent with guidelines of the NIH Guide for the Care and Use of Laboratory Animals.
Conflict of interest
The authors declare that they have no conflicts of interest.
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