UCSF

The dopamine neurons of the ventral tegmental area (VTA) are involved with motivated behaviors and locomotion. Interestingly, stress stimulates the release of dopamine in brain regions receiving dense VTA input, which could be important in promoting escape from threatening situations. The mechanism by which stress activates the dopamine system is unknown, but many lines of evidence suggest a role for the stress-released neuropeptide, corticotropin-releasing factor (CRF). The effect of CRF on VTA dopamine neurons is not well characterized and is the major topic of this dissertation.

In order to address the effect of CRF on VTA dopamine neurons in brain slice recordings, I needed a method to confidently identify dopamine neurons. In contrast to the rat, I found that the presence of the hyperpolarization-activated, cyclic nucleotide-regulated cation current (Ih) is a reliable electrophysiological measure to identify dopamine neurons in the mouse. Furthermore, I demonstrated that CRF increased the firing of VTA dopamine neurons through a mechanism involving the CRF-receptor 1 (CRF-R1), the phospholipase C - protein kinase C (PLC - PKC pathway), and the Ih. I also found that CRF enhanced the Ih through a PKC-dependent mechanism, which did not involve changes in the voltage-dependence of activation for the Ih. Because of the role of the VTA and dopamine release in motor behaviors, I examined the effect of CRF in the VTA on the locomotor activity of rats. Mirroring my findings from brain slice recordings, I found that intra-VTA injections of CRF-R1 agonists required PKC and Ih to increase locomotor activity. Together, these studies examined the excitatory role of CRF on VTA dopamine neurons from ion currents to behavior and further the knowledge regarding stress-related neuropeptide modulation of the dopamine system.