The long-term objective of this project is to gain an understanding of how differences in receptor reserve (RR; spare receptors) and in the relative efficacies of agonists for dopamine (DA) D2 and serotonin 5-HT1A receptor sites in the brain relate to differences in the functional effects mediated by these agonists. Previous studies demonstrated that differences in RR at pre- and postsynaptic D2 receptors explain why certain DA agonists elicit functional responses mediated by pre- but not postsynaptic D2 receptors. Preliminary studies indicate that this approach may provide insights into the mechanism of action of new nonbenzodiazepine anxiolytics (e.g. buspirone) which are selective 5-HT1A agonists. Three main hypotheses will be tested: 1) Receptor sensitivity changes which accompany drug-induced up- and downregulation are related to changes in RR; 2) The similar sensitivity to DA agonists of brain D2 presynaptic receptors, and pituitary D2 receptors regulating prolactin (PRL) secretion, is due to a similar, large RR at both sites; furthermore, the differential PRL response of male and female rats is due to differences in RR; and 3) A differential RR at pre- vs. postsynaptic 5-HT1A receptors accounts for their differential sensitivity to 5-HT-1A agonists. To test these hypotheses we will: 1) determine the effects of various chronic drug treatments (haloperidol, reserpine, DA agonists), rat strain (F344 and Buffalo), developmental age (2-60 days postnatal) and pertussis toxin treatment on the extent of RR at pre- and postsynaptic D2 receptors. presynaptic D2 (auto) receptor function will be assessed using the GBL model; postsynaptic D2 receptor function will be assessed by examining DA agonist-induced elevation of striatal ACh levels; 2) determine the extent of RR for various DA agonists at the pituitary D2 receptor in male and female rats by measuring their suppression of serum PRL levels. The effects of chronic estrogen and reserpine treatment will also be examined; 3) determine the extent of RR at pre- and postsynaptic 5-HT1A receptors for various selective 5-HT1A agonists (e.g. 8-OH-DPAT, buspirone, gepirone, ipsapirone); biochemical (5- HT synthesis inhibition), physiological (hypothermia) and collaborative electrophysiological (extracellular single unit recording) methods will be employed. The studies with DA agonists have important clinical implications for the design and use of these agents in the treatment of schizophrenia, Parkinson's disease, tardive dyskinesia and Tourette's syndrome; the studies with 5-HT1A agonists have similar implications for the therapy of anxiety disorders.
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