Related Experiment Video
Updated: Sep 15, 2025
BS3 Chemical Crosslinking Assay: Evaluating the Effect of Chronic Stress on Cell Surface GABAA Receptor Presentation in the Rodent Brain
Published on: May 26, 2023
Post-methamphetamine working memory decline predicts relapse vulnerability in rats and is rescued by mGlu3 receptor
Cassandra G Modrak1,2,3, Peter U Hámor4, Marek Schwendt5,6,7
1Psychology Department, University of Florida, 114 Psychology Building, 945 Center Drive, Gainesville, FL, 32611-2250, USA.
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.
Insights
Methamphetamine use impairs working memory and increases drug-seeking behavior. Metabotropic glutamate receptor 3 (mGlu3) activation shows potential for treating cognitive deficits associated with methamphetamine use disorder.
Area of Science:
- Neuroscience
- Pharmacology
- Behavioral Science
Background:
- Methamphetamine (meth) misuse is a global health crisis with high relapse and overdose rates.
- Chronic meth use leads to cognitive deficits, complicating treatment and recovery.
- Metabotropic glutamate receptor 3 (mGlu3) activation shows promise in preclinical models for attenuating drug-seeking and improving cognition.
Purpose of the Study:
- To investigate working memory and meth-seeking behaviors following abstinence in rats.
- To determine the effects of mGlu3 activation on these behaviors.
Main Methods:
- Rats underwent operant delayed match-to-sample (DMS) task for working memory assessment.
- Methamphetamine self-administration models (short and long access) were employed.
- Abstinence periods were followed by re-testing on DMS and relapse tests for meth-seeking.
- The mGlu3 activator 2-PMPA was administered to assess its effects.
Main Results:
- Methamphetamine self-administration resulted in working memory impairment in both sexes.
- Impaired working memory performance predicted the intensity of subsequent meth-seeking behavior.
- 2-PMPA administration improved working memory in a subset of impaired rats but did not directly affect meth-seeking.
Conclusions:
- Chronic meth self-administration in rats induces concurrent working memory deficits and significant meth-seeking, mirroring aspects of meth use disorder (MUD).
- mGlu3 manipulation presents a potential therapeutic strategy for addressing cognitive impairments linked to meth use.
