Despite substantial efforts, there are currently no FDA-approved pharmacotherapies available for the treatment of cocaine abuse or dependence. A prominent feature of cocaine use is the high rate of relapse among addicted individuals. Cocaine craving is thought to serve as an important event preceding relapse and can be elicited in human addicts via presentation of cocaine-associated cues. Similarly, cocaine-paired cues are capable of reinstating previously-extinguished cocaine-seeking behavior in experimental animals trained to self-administer cocaine. Recent evidence obtained in rodents has suggested that activation of group II metabotropic glutamate receptors (mGluRs) is capable of attenuating the ability of cocaine cues to induce reinstatement. Group II mGluRs include the mGluR2 and mGluRS subtypes and are Gi/o-coupled presynaptic receptors whose activation results in decreased synaptic release of glutamate, dopamine, and other neurotransmitters. These receptors are localized in brain regions known to be involved in the reinforcing effects of cocaine, such as the caudate nucleus, nucleus accumbens (NAcc), prefrontal cortex, and amygdala. The proposed experiments seek to translate and extend earlier findings from rodents to nonhuman primate models of cocaine use and relapse. Squirrel monkeys will be trained to self-administer intravenous cocaine in the presence of distinct environmental stimuli. Presentation of these stimuli during saline substitution tests will thus result in cocaine-seeking behavior initiated and maintained solely by the presentation of cocaine-paired cues and not by the direct pharmacological effects of cocaine itself. Animals will be pretreated with the highly-selective and potent group II mGluR agonist LY379268 prior to cue- presentation tests to determine if activation of these receptors can attenuate cue-induced drug-seeking behavior in primates with extensive histories of cocaine self-administration. Subsequently, animals will be implanted with guide cannulae targeting both the dorsal and ventral (NAcc) portions of the striatum. Cue- presentation test sessions will be conducted concurrently with microdialysis to assess any possible correlations between LY379268 effects on cocaine-seeking and its neuropharmacological effects on extracellular dopamine or glutamate levels within the dorsal and ventral striatum. The goal of this research is to better understand the mechanism(s) by which drug-associated cues are capable of eliciting drug-craving in cocaine-addicted individuals. As craving is a major factor preceding relapse to drug use, the results of these experiments may help identify new targets for anticraving and relapse-prevention medications development.
|Manvich, Daniel F; Kimmel, Heather L; Cooper, Debra A et al. (2012) The serotonin 2C receptor antagonist SB 242084 exhibits abuse-related effects typical of stimulants in squirrel monkeys. J Pharmacol Exp Ther 342:761-9|
|Manvich, Daniel F; Kimmel, Heather L; Howell, Leonard L (2012) Effects of serotonin 2C receptor agonists on the behavioral and neurochemical effects of cocaine in squirrel monkeys. J Pharmacol Exp Ther 341:424-34|