Serotonin 1B Autoreceptors Originating in the Caudal Dorsal Raphe Nucleus Reduce Expression of Fear and Depression-Like Behavior

Background Serotonin 1B (5-HT1B ) autoreceptors regulate release of serotonin from terminals of dorsal raphe nucleus (DRN) projections. Expression of 5-HT1B in the DRN inversely correlates with behavioral measures of emotion, and viral-mediated overexpression of 5-HT1B receptors in the middle DRN inversely reduces measures of fear and anxiety in unstressed rats. Because the caudal subregion of the DRN is important in translating stress into emotional dysregulation, we explored behavioral functions of 5-HT1B autoreceptors in the caudal DRN. Methods We manipulated 5-HT1B autoreceptor function in rats using either viral-mediated gene transfer into the caudal DRN or systemic injections of the 5-HT1B agonist 3-(1,2,5,6-tetrahydro-4-pyridyl)-5-propoxypyrrolo[3,2-b]pyridine (CP-94253). Rats were tested in forced swim test, open field test, and contextual fear conditioning. Results Overexpression of 5-HT1B in the caudal DRN increased swimming in the forced swim test. It did not alter locomotion or thigmotaxis in the open field test but did reduce conditioned freezing. Freezing was reduced when 5-HT1B overexpression was present only during testing but not training. The CP-94253 exerted an inverted U-shaped dose response curve on conditioned freezing, with most pronounced effects seen at 1 mg/kg. At this dose, CP-94253 administered before a fear retention test reduced freezing both during that session and in subsequent drug-free testing, but only when drug was paired with re-exposure to the fear context. Conclusions The 5-HT1B autoreceptors originating in the caudal DRN regulate behavioral expression of helplessness and fear. Because systemic pharmacologic treatment with a 5-HT1B agonist facilitates reductions in fear, 5-HT1B receptors may be a target for the treatment of certain anxiety disorders.