This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. There is a critical need to develop effective medications to treat cocaine addiction. Medication effectiveness in reducing cocaine use was determined in a nonhuman primate model of intravenous drug self-administration. The project continued to focus on the behavioral pharmacology and in vivo neurochemistry of monoamine transporter inhibitors as complementary approaches to characterize the neuropharmacology of cocaine. In addition, we have emphasized behavioral and neurochemical interactions between glutamate and dopamine. More recently, we have conducted studies with a variety of monoamine releasers having different affinity for dopamine and serotonin receptors. PAL-353, which is more selective for releasing dopamine relative to serotonin, induced robust behavioral-stimulant effects similar to those observed for amphetamine. In contrast, PAL-313, which is equipotent in releasing both dopamine and serotonin, did not induce behavioral-stimulant effects over a broad range of doses. These differences in profile of behavioral effects were evident even at drug doses that markedly increased extracellular dopamine, supporting the interpretation that an increase in serotonergic tone can have a postsynaptic inhibitory effects on motor behavior. We are currently characterizing the reinforcing effectiveness of several amphetamine analogs that differ in potency to release dopamine and serotonin. The results indicate that compounds with high potency for serotonin release have a behavioral profile of low abuse liability. The integration of in vivo neurochemistry and behavioral pharmacology in nonhuman primates will define neurochemical mechanisms that underlie the addictive properties of cocaine and related stimulants. The results obtained will direct efforts to treat cocaine abuse in humans.
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