mGluR5 antagonism attenuates methamphetamine reinforcement and prevents reinstatement of methamphetamine-seeking behavior in rats

摘要

Addiction to methamphetamine is a significant public health problem, and there are currently no pharmacological agents that are approved for the treatment of addiction to this powerful psychostimulant. Chronic methamphetamine use leads to cognitive dysfunction as well as numerous psychiatric, neurological, and cardiovascular complications. There is a growing body of literature implicating an important role for glutamate neurotransmission in psychostimulant addiction. In the present study, we examined the effects of the selective type 5 metabotropic glutamate receptor (mGluR5) antagonist 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP) on intravenous self-administration of methamphetamine and reinstatement of methamphetamine-seeking behavior. Adult male Sprague-Dawley rats were trained to respond for intravenous methamphetamine (0.1 or 0.2 mg/kg/infusion) or food pellets and were subsequently administered vehicle or MTEP (0.3-3 mg/kg) prior to drug or food self-administration on a fixed-ratio 1 (FR1) schedule of reinforcement or a progressive ratio (PR) schedule of reinforcement. We also examined the effects of vehicle or MTEP (0.3-3 mg/kg) on cue- and drug-induced reinstatement of methamphetamine-seeking behavior as well as cue-induced reinstatement of food-seeking behavior. Our results show that MTEP dose-dependently reduced the reinforcing effects of methamphetamine under an FR1 and PR schedule of reinforcement without altering overall responding for food. MTEP also dose-dependently prevented cue and drug-induced reinstatement of methamphetamine-seeking behavior, but did not alter cue-induced reinstatement of food-seeking behavior. Together, these results indicate the mGluR5 receptors play an important role in methamphetamine reinforcement and methamphetamine-seeking behavior, and that pharmacological inhibitors of mGluR5 receptor function may represent a novel class of potential therapeutic agents for the treatment of methamphetamine addiction.