? This is an application for a NIDA Research Scientist Award. A long-term research objective is to delineate the neurochemical events that underlie drug abuse and dependence. In other words, drugs produce their effects through neurochemicals in the brain, and when taken repeatedly, drugs change the chemical makeup of the brain. The long-term neurochemical changes form the basis of dependence and relapse. When these changes become known, novel strategies for treatments and medications can be developed. ? ? The specific goals of this proposal focus on relatively new and relevant neurochemicals, the CART peptides. These peptide neurotransmitters are: found in brain regions related to reward and reinforcement, mobilized by psychostimulant drugs, and appear to mediate or modulate the actions of these drugs by interacting with mesolimbic dopamine. Mesolimbic dopamine is involved in reward and reinforcement for most or all drugs of abuse. ? ? Having shown that CART peptides can both mimic or blunt the actions of cocaine, depending on their site of action, and having shown that neurons containing CART interact with mesolimbic dopamine containing neurons, two aims of this project are to elucidate many aspects of the CART-dopamine interaction.
The first aim will test the hypotheses that CART in the VTA can release accumbal dopamine, can be stimulated by dopamine and if CART peptides and dopamine receptors are found on the same cells in the nucleus accumbens. Given the evidence that psychostimulants can rapidly modulate CART gene expression in the accumbens, the second aim will identify transcription factor binding sites in the proximal promoter of the CART gene that regulate expression of the CART gene. Finally, because of the need to study the CART receptors, the last aim will attempt to identify the receptor(s) by binding techniques. Taken together, these studies will: clarify the interaction of dopamine and CART, elucidate the regulation of the CART gene in the brain, and hopefully open a new area for study of the CART receptors. Preliminary data indicate that this work is feasible. Since CART peptides are important for stress and feeding and other processes, the findings in these studies will impact other areas as well. ? ? ? ?
