Post-methamphetamine working memory decline predicts relapse vulnerability in rats and is rescued by mGlu3 receptor activation.

Rationale: Widespread methamphetamine (meth) misuse remains a worldwide public health issue that lacks effective clinical treatment. Besides the high relapse and overdose rates, chronic meth use produces a spectrum of cognitive deficits that further complicate treatment and recovery. Activation of metabotropic glutamate receptor 3 (mGlu3) attenuates drug-seeking behavior and/or improves cognition in several animal models, though its ability to improve meth-associated behavioral deficits has not been explored.

Objectives: Here, we evaluated working memory and meth-seeking following abstinence and the effects of mGlu3 activation on such behaviors.

Methods: Adult male and female Sprague-Dawley rats were first trained and tested on the operant delayed match-to-sample (DMS) working memory task. Rats then underwent 7 days of short-access (1 h/day) and 14 days of long-access (6 h/day) self-administration or served as drug-naïve controls. During the first 3 weeks of abstinence, rats were re-tested on the DMS task and underwent relapse tests to evaluate meth-seeking behavior. Additionally, the effects of indirect mGlu3 activator 2-PMPA (30 mg/kg, i.p.) on both behavioral measures were assessed.

Results: Meth self-administration produced working memory impairment in both sexes. Significantly, the decline in DMS task performance predicted the magnitude of subsequent meth-seeking. 2-PMPA treatment improved DMS task performance in a cognitively impaired subgroup of rats but had no immediate effects on meth-seeking.

Conclusions: The current study shows that chronic meth self-administration in rats produces co-occurring working memory deficits and robust meth-seeking, akin to meth use disorder (MUD), and that mGlu3 manipulation holds promise in the treatment of meth-associated cognitive deficits.