An elucidation of the neural mechanisms of action of cocaine is required if we are to identify medications which might block its psychotropic and toxic effects. While the focus has been on dopamine (DA) mesolimbic involvement, cocaine also interferes with serotonin (5-HT) function; specific alterations in 5-HT control of DA,: mesolimbic systems may in part affect the consequences of acute and chronic cocaine. The goals of the present proposal are: (1) to assess the role of 5-HT in the behavioral effects of cocaine (i.e., discriminative stimulus effects, hyperactivity, stereotypy and sensitization); (2) to study further the mechanism(s) by which acute and chronic cocaine interact with 5-HT raphe systems; and (3) to characterize 5-HT modulatory control of DA mesolimbic systems. The behavioral effects of cocaine will be quantified following systemic and intracranial administration of 5-HT agonists and antagonists as well as 5- HT lesions. Single unit recording, microiontophoresis and stimulation techniques will be used to characterize the cellular effects of cocaine on 5-HT-containing neurons which project to DA neurons of the ventral tegmental area (VTA) or their limbic terminals in accumbens. We will also analyze the electrophysiological effects of 5-HT on DA-containing VTA neurons and assess whether acute and/or chronic cocaine modify the normal action of 5-HT on DA neurons. In addition to this continuing theme, we have initiated a study of the role of female steroid hormones in the regulation of central 5-HT systems and how this 5-HT-steroid interrelationship determines the neural response to cocaine. Importantly, this research is designed to provide fundamental knowledge about 5-HT-DA and 5-HT-steroid interactions and how these interactions are altered by cocaine, perhaps suggesting new strategies for pharmacological intervention in abusers. The lack of 5-HT compounds which exhibit selectivity for specific 5-HT receptors has been a significant limitation to this field. However, antisense oligonucleotides have proven to be useful tools for blocking production of specific receptors following central microinjection. Under this RSDA, I propose to gain training in molecular biology in order to implement the use of this antisense strategy as a potentially powerful approach to address the goals of this grant and, hopefully, obviate the need for receptor-specific drugs. Training is also sought in (1) in situ hybridization as one approach to colocalize 5-HT and DA receptors in monoamine cell bodies and their terminal neurons and (2) Northern analysis in order to establish the impact of cocaine and hormone treatments on steady state levels of mRNA for 5-HT transporters and receptors. With this RSDA, release time and salary support would be provided for development of these new methodologies necessary for enhancement of my ongoing research program.
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