Regulation of extracellular concentrations of serotonin by 5-HT(1A) and 5-HT(1B) autoreceptors in mice

The somatodendritic 5-HT1A autoreceptor and the terminal 5-HT1B autoreceptor are both able to alter extracellular levels of 5-HT by regulating its release from 5-HT nerve terminals. The studies in this thesis developed a novel application for the technique of in vivo microdialysis in order to investigate the fundamental differences between these two autoreceptors. The first set of studies examined the pharmacological differences between the 5-HT1A and 5-HT1B autoreceptors in mice. These studies characterized the novel 5-HT1A receptor agonist R-8-OH-PIPAT and the novel 5-HT1B receptor agonist CP 94,253. It was determined that both the 5-HT1A and 5-HT1B autoreceptors are able to regulate 5-HT release in the striatum of wild-type (129/SVEM) mice but through distinct pharmacological means. In addition, these initial studies determined that in vivo microdialysis is a viable technique in mice. The regional specificity for autoreceptor regulation of 5-HT release was then explored. These studies utilized 5-HT1A or 5-HT1B receptor knockout mice. It was determined that systemic administration of fluoxetine elicited a significantly greater increase in extracellular 5-HT in the striatum, a dorsal raphe innervated brain region, of 5-HT1A receptor knockout mice as compared to wild-type. A significantly greater increase in extracellular 5-HT in the ventral hippocampus, a median raphe innervated brain region, of the 5-HT1B receptor knockout mice as compared to wild-type was also observed. This indicated a distinct regional hierarchy for autoreceptor regulation of 5-HT release. These effects were not due to developmental alterations in the receptor knockout mice because parallel studies in wild-type mice using receptor antagonists produced the same pattern of effects. In the final set of studies, the physiological reorganization that occurs in response to genetic deletion of a 5-HT autoreceptor was determined. It was discovered that 5-HT1B receptors in the striatum of 5-HT 1A receptor knockout Mice bad an increased responsiveness, whereas the responsiveness of the 5-HT1A receptors measured in the ventral hippocampus, of the 5-HT1B receptor knockout mice was decreased. These experiments determined that the 5-HT1A and 5-HT 1B autoreceptors have distinct pharmacological means and topographical hierarchy for regulating 5-HT release, and genetic deletion of each of these autoreceptors results in distinct physiological reorganization