Striatal 5-HT6 receptors: Roles in cocaine reinforcement and neuronal primary cilia

Thesis (Ph.D.)--University of Washington, 2016-03Serotonin (5-HT) is neurotransmitter that modulates a range of emotional behaviors and is involved in mediating behaviors related to reinforcement learning. Disturbances of the 5-HT system are implicated in psychiatric conditions such as post-traumatic stress disorder, depression, and anxiety. Of the 14 described 5-HT receptors, 5-HT6 receptors have been implicated in a variety of cognitive processes and have generated interest due to increasing evidence for their role in feeding, obesity, anxiety, depression and cognition. The 5-HT6 receptor is an excitatory GS coupled receptor that is found almost exclusively in the brain and is localized abundantly on the primary cilia of neurons, especially in the striatum. Primary cilia are sensory organelles found on most neurons that receive both chemical and mechanical signals from the surrounding environment. The striatum is a brain region of the basal ganglia that mediates a variety of neural functions including movement, learning, and cognition. From their subcellular localization on primary cilia to their pathway specific role in the striatum, this thesis dissertation will describe my work on understanding the underlying function of 5-HT6 receptors. My work shows 5-HT6 receptors in the striatum can alter normal cocaine reward conditioning, and explores the effect of 5-HT6 receptors on neuronal primary cilia. In particular, I show that increased expression of 5-HT6 receptors in the indirect pathway medium spiny neurons (MSNs) but not direct pathway MSNs of the ventral striatum lead to an increase in the sensitivity to the reinforcing properties of cocaine. I also show that the activity of 5-HT6 receptors affects the morphology of primary cilia in striatal neurons and that the amount of heterologous receptor expressed affects the subsequent subcellular receptor localization. Together my results continue to implicate an important role of 5-HT6 receptors in animal behavior and indicate a need for further analysis of 5-HT6 receptors in both a sub region and subcellular-specific manner