DRUG RECEPTORS, NEUROTRANSMITTERS AND ADDICTION

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The focus of this project is on certain specific components of addiction, namely the repetitive use of drugs, the long-term effects of drugs, and the biochemical mechanisms underlying addictive behavior. In other projects, we have developed a mouse model for the in vivo labeling of dopamine transporters by binding ligands. In some components of this project, we utilize this model to examine the in vivo binding potency of various novel cocaine analogs as well as the rate at which compounds can enter the brain and occupy cocaine receptors-dopamine transporters. In in vivo receptor binding studies, we found that several cocaine analogs that displayed high potency in vitro also displayed high potency in vivo. Moreover, evidence suggests that maximal locomotor effects of these analogs occur with doses resulting in near maximal occupancy of transporter sites. Also, these compounds substituted for cocaine in rats trained to discriminate cocaine from saline. The compounds were from six to thirteen times more potent than cocaine in producing cocaine appropriate responding. Thus, these data support the notion that dopamine uptake inhibition is a component of behavioral effects of cocaine and its analogs. It is commonly said that drugs that enter the brain more rapidly are more addicting. By utilizing in vivo receptor binding models, it is possible to quantify how rapidly drugs enter the brain and occupy receptors by looking at the rat of displacement of ligand binding in vivo by various drugs. By using radiolabeled WIN-35,428 in vivo, it was possible to show that cocaine occupies its receptors more rapidly than GBR-12909 while mazindol was the slowest. These studies are a reasonable first step to being able to quantify how rapidly drugs enter the brain and to assess the role of this factor on the addiction liability of these compounds.