title: Brain 5-HT deficiency increases stress vulnerability and impairs antidepressant responses following psychosocial stress.
abstract: Brain serotonin (5-HT) deficiency and exposure to psychosocial stress have both been implicated in the etiology of depression and anxiety disorders, but whether 5-HT deficiency influences susceptibility to depression- and anxiety-like phenotypes induced by psychosocial stress has not been formally established. Most clinically effective antidepressants increase the extracellular levels of 5-HT, and thus it has been hypothesized that antidepressant responses result from the reversal of endogenous 5-HT deficiency, but this hypothesis remains highly controversial. Here we evaluated the impact of brain 5-HT deficiency on stress susceptibility and antidepressant-like responses using tryptophan hydroxylase 2 knockin (Tph2KI) mice, which display 60-80% reductions in brain 5-HT. Our results demonstrate that 5-HT deficiency leads to increased susceptibility to social defeat stress (SDS), a model of psychosocial stress, and prevents the fluoxetine (FLX)-induced reversal of SDS-induced social avoidance, suggesting that 5-HT deficiency may impair antidepressant responses. In light of recent clinical and preclinical studies highlighting the potential of inhibiting the lateral habenula (LHb) to achieve antidepressant and antidepressant-like responses, we also examined whether LHb inhibition could achieve antidepressant-like responses in FLX-insensitive Tph2KI mice subjected to SDS. Our data reveal that using designer receptors exclusively activated by designer drugs (DREADDs) to inhibit LHb activity leads to reduced SDS-induced social avoidance behavior in both WT and Tph2KI mice. This observation provides additional preclinical evidence that inhibiting the LHb might represent a promising alternative therapeutic approach under conditions in which selective 5-HT reuptake inhibitors are ineffective.
authors: Departments of Cell Biology.
authors: Benjamin D
authors: BD
authors: Sachs
authors: Departments of Cell Biology.
authors: Jason R
authors: JR
authors: Ni
authors: Departments of Cell Biology, Neurobiology, and Medicine, Duke University Medical Center, Durham, NC 27710 marc.caron@dm.duke.edu.
authors: Marc G
authors: MG
authors: Caron
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004198:Disease Susceptibility; D005473:Fluoxetine / Q000494:pharmacology / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D012701:Serotonin / Q000172:deficiency* / Q000378:metabolism; D013315:Stress, Psychological / Q000188:drug therapy* / Q000378:metabolism*; D014365:Tryptophan Hydroxylase / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D005473:Fluoxetine; D012701:Serotonin; C487802:Tph2 protein, mouse; D014365:Tryptophan Hydroxylase
keywords: antidepressants; habenula; serotonin; stress