This is an application for a NIDA Research Scientist Award. A program of research is proposed that focuses on psychostimulant drugs but has implications for other drugs of abuse. The three general areas funded by NIDA that will be explored are as follows. 1. Medications development. A group of unique phenyltropane compounds will be characterized so that several candidates for substitute medications can be identified. The compounds will be screened in behavioral assays in rodents and nonhuman primates so as to find compounds that are active in vivo, not overtly toxic, potent and long-acting, effective in reducing cocaine self- administration, and have a low abuse liability. 2. Mechanisms controlling synthesis and degradation of transporters. Dopamine and serotonin transporters are targets or """"""""receptors"""""""" for drugs of abuse as well as for many therapeutically useful drugs. Since the levels of these proteins are dependent on a balance between synthesis and degradation, and because factors controlling levels need to be understood, methods for determining these factors will be developed and refined. 3. Physiology of CART peptides. CART peptides are novel neuropeptides that are highly concentrated in areas of the brain implicated in mechanisms of drug abuse. These areas include the nucleus accumbens, ventral pallidum, amygdala and midbrain ventral tegmentum. Preliminary data show that these peptides have physiologic effects. Their precise role in the mechanisms of action of drugs of abuse will be examined. An interdisciplinary team will focus on these problems. Several predoc as well as post doctoral fellows will be trained during this work.
