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

Abstract

Background 5-HT1B autoreceptors regulate release of serotonin from terminals of dorsal raphe nucleus (DRN) projections. 5-HT1B expression in the DRN correlates with behavioral measures of emotion, and viral-mediated overexpression of 5-HT1B receptors in the middle DRN reduces measures of fear and anxiety in unstressed rats. Since 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-94,253). Rats were tested in forced swim test, open field test, and contextual fear conditioning. Results 5-HT1B overexpression 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. CP-94,253 exerted an inverted U-shaped dose response curve on conditioned freezing, with most pronounced effects seen at 1 mg/kg. At this dose, CP-94,253 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 5-HT1B autoreceptors originating in the caudal DRN regulate behavioral expression of helplessness and fear. Since systemic pharmacological treatment with a 5-HT1B agonist facilitates reductions in fear, 5-HT1B receptors may be a target for the treatment of certain anxiety disorders.

Habenular kisspeptin modulates fear in the zebrafish

“…We also found that Kiss1 administration increased mRNA levels of 5-HT-related genes (pet1 and slc6a4a) in AS-exposed fish, suggesting the potential role of Kiss1 in serotonin modulation, as we reported previously (7). 5-HT has been widely implicated in the development and expression of fear and depression-like behavior (30,31). The mammalian lHb plays a pivotal role in escape behavior by influencing the activity of 5-HT neurons (32).…”

Dopamine D3 and 5-HT1B receptor dysregulation as a result of psychostimulant intake and forced abstinence: Implications for medications development

“…In contrast, others report anxiolytic-like effects in the EPM and Vogel conflict-drinking test following administration of similar doses of CP94253 (Tatarczynska et al, 2004). Furthermore, CP94253 dose-dependently reduces the expression of conditioned freezing (McDevitt et al, 2011), suggesting that 5-HT 1B R agonists attenuate conditioned anxiety. Clinical research investigating the effects of the triptan class of 5-HT 1 R agonists on anxiety has yielded mixed result with some studies reporting no effects of acute administration of sumatriptan, a 5-HT 1A/1B/1D R agonist (Pian et al, 1998), or zolmitriptan, a 5-HT 1B/1D/1F R agonist (Boshuisen and den Boer, 2000) in patients with obsessive-compulsive disorder (OCD).…”

Optogenetics in preclinical neuroscience and psychiatry research: recent insights and potential applications

“…Collectively, these optogenetic and pharmacological studies support the provocative conclusion that acute decreases in serotonin function are capable of producing antidepressant-like effects. Similar behavioral effects have been demonstrated by reducing serotonin function via dorsal raphe nucleus negative-feedback autoreceptor activation55 or overexpression 56. These findings go against studies in humans in which acute depletion of serotonin synthesis decreases mood in people with a history of major depressive disorder.…”