AbstractRationaleCocaine 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.ObjectivesHere 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.MethodsAdult 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 five-day block of testing. Next, rats received daily systemic administration of the mGlu5 NAM MTEP (3 mg/kg), mGlu5 PAM CDPPB (30 mg/kg) or vehicle prior to DMS testing during a block of five days, followed by a 5-day washout DMS testing block.ResultsMTEP 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.ConclusionsThese 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.
The Effects of Extended-Access Cocaine Self-Administration on Working Memory Performance, Reversal Learning and Incubation of Cocaine-Seeking in Adult Male Rats
