The dorsal and median raphe nuclei, the source nuclei of forebrain serotonergic innervation, contain corticotropin releasing factor (CRF) receptor mRNA and are densely innervated with CRF-immunoreactive fibers. Taken with recent findings that demonstrate biphasic effects of CRF on striatal serotonin (5-HT) release and inhibitory effects of CRF on neuronal activity of putative 5-HT neurons in the dorsal raphe nucleus, it is possible that CRF, or a related family member, regulates the activity of the 5-HT system. The objective of this proposal is to examine the physiological interactions between the brain CRF system and the raphe nuclei serotonergic system. Since CRF and 5-HT have been independently implicated in stress and stress-related psychiatric disorders, such as depression and anxiety, we hypothesize that interactions between CRF and 5-HT may be important in mediating the effects of particular stressors. This hypothesis will be tested by the following specific aims: 1) Determine the local mechanism of CRF control of 5-HT release. Pharmacological analysis using CRF receptor agonists and antagonists will be performed. These studies will be used to determine whether CRF-5-HT interactions occur at the level of 5-HT cell bodies. 2) Determine whether CRF effects on forebrain 5-HT release are regionally specific. Dose-response curves for the effects of CRF, administered intracerebroventricularly on 5-HT release in lateral septum, amygdala, nucleus accumbens, and hypothalamus will be generated. 3) Determine physiological conditions during which endogenous CRF affects the forebrain 5-HT system. The ability of a CRF receptor antagonist to block alterations in 5-HT release in terminal regions during physiological stressors will be determined.
This aim will provide functional significance for CRF-5-HT interactions and reveal situations in which endogenous CRF interacts with the forebrain 5-HT system.
