Serotonin Receptors in the Central Nervous System
Because it is one of the earliest neurotransmitter to appear in evolution, it is not surprising that serotonin, or 5-HT, has been coopted for a large number of physiological roles in both the brain and periphery. The many actions of sertonin have in recent years been shown to be mediated by a correspondingly impressive number of receptor subtypes, now known to be at least fourteen. This lab is concerned with identifying mammalian sertonin receptor subtypes and their structural variant, establishing their cellular effects, and seeking causal connections between the actions of specific subtypes and aspects of psychiatric disorders and their treatments. We are focusing on two groups of serotonin receptors which in some areas may have opposing actions -- the 5-HT 1B and 5-HT 1D receptors, which among other actions effect the inhibition of adenylyl cyclase via Gi proteins, and the 5-HT6 and 5-HT7 receptors, which stimulate adenylyl cyclase through Gs proteins.
In studies done in collaboration with Dr. John Neumaier in the Department of Psychiatry, we have shown that 5-HT1B receptors are upregulated in an animal model of depression, and down regulated by the antidepressant fluoxetine. Since other workers have shown that 5-HT1B and 5-HT1D receptors serve as key control points in regulating 5-HT release from serotonergic neurons, our findings are consistent with the long-standing hypothesis that clinical depression may in party be mediated by a decrease in serotonergic tone in key brain areas. More importantly, these results suggest approaches to dissect the molecular events leading to serotonergic disregulation. Current work includes studies of the involvement of the hypothalamic-pituitary-adrenal axis in these effects and the development of transgenic tools to further study the role of 5-HT1B receptors in behavior.
The actions of 5-HT6 and 5-HT7 receptors have been identified only more recently. We are now involved in characterizing structural variants of Gs coupled serotonin receptors and differences among variants in their second messenger coupling and regulation. Our studies of these receptors have suggested alternatice pharmacological approaches for the treatment of psychotic conditions such as schizophrenia.