Glutamate is believed to play an integral role in the behavioral effects of cocaine related to its abuse. Most previous research has focused on the contribution of ionotropic glutamate receptor (iGluR) mechanisms, but growing evidence suggests that metabotropic glutamate receptors (mGluRs) may play an unexpectedly important role. Recent studies from our laboratory and others have shown that pharmacological blockade or genetic deletion of the mGluR subtype 5 (mGluR5) can attenuate key behavioral effects of cocaine in mice and monkeys. Our proposed research will build on initial findings in squirrel monkeys with three specific aims.
Specific Aim 1 will use IV drug discrimination techniques to investigate the impact of mGluR5 antagonists and related drugs on the discriminative stimulus effects of cocaine. The contribution of dopamine (DA) and iGluR mechanisms in mGluR5 modulation of the discriminative stimulus effects of cocaine will be evaluated in drug interaction studies with direct and indirect DA agonists and NMDA and AMPA/kainate receptor antagonists.
Specific Aim 2 will investigate the effects of mGluR5 antagonists and related drugs on IV self-administration of cocaine under a second-order schedule of reinforcement. Parallel studies using a comparable schedule of food delivery will assess the selectivity with which drugs modulate the reinforcing effects of cocaine without producing a generalized suppression of operant behavior. Observational studies will monitor potential side effects of drugs that selectively attenuate cocaine self-administration.
Specific Aim 3 will use a reinstatement model of cocaine relapse to investigate the effects of mGluR5 antagonists and related drugs on cocaine-seeking behavior that has been extinguished and subsequently restored by cocaine priming and a cocaine-paired stimulus. The results will provide a needed empirical framework for evaluating mGluR5 and related glutamate receptor mechanisms in relevant nonhuman primate models of cocaine abuse and relapse. They should also provide new insights regarding mGluR5 as a potential target for the pharmacological management of cocaine addiction. ? ?
