Major depression is a serious mental disorder characterized by cognitive and neurovegetative symptoms although it's pathophysiology is incompletely understood. We have been testing the hypothesis that excessive activity of the 5-HTIB terminal autoreceptors in forebrain projections from dorsal raphe neurons is involved in some of the symptoms of depression and are selectively down regulated by SSRI antidepressants. However, 5-HT1B receptors are also located in many non serotonergic neurons throughout the central nervous system, thus it is crucial to discriminate between presynaptic autoreceptors and heteroreceptors in nonserotonergic neurons. This is a challenging problem, since serotonergic neurons are few in number and project diffusely, making it very difficult to gain experimental access to this specific subpopulation of 5-HTIB receptors. Therefore, we propose to use an innovative new technique to make experimental manipulations in 5-HT1b autoreceptors only in dorsal raphe neurons by using viral mediated gene transfer. We plan to either increase or decrease 5-HTIB mRNA levels in these neurons by injecting replication defective Herpes Simplex Virus carrying 5-HT1b """"""""transgene"""""""" cDNA directly into rat dorsal raphe nucleus and carefully validate changes in gene expression and 5-HT1b terminal autoreceptor activity in 5-HT projections to forebrain. In order to consider transgene induced depressive-like symptoms and antidepressant reversal, we will use several behavioral models of depression to determine whether 5-HTIB autoreceptors induce depressive-like behavioral changes. We will test an antisense knockdown RNA, also introduced by viral mediated gene transfer into dorsal raphe, for antidepressant effects. We will also test whether viral mediated gene transfer of the 5-HT1A somatodendritic autoreceptor into dorsal raphe nucleus produces comparable effects. It is our objective that these experiments will shed light on the role of serotonin autoreceptors in depression and its treatment, and will be an opportunity to extend the use of viral mediated gene transfer as a research technique in the study of mental illnesses using animal behavioral models.
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