title: Expression of the 5-HT1A serotonin receptor in the hippocampus is required for social stress resilience and the antidepressant-like effects induced by the nicotinic partial agonist cytisine.
abstract: Nicotinic acetylcholine receptor (nAChR) blockers potentiate the effects of selective serotonin reuptake inhibitors (SSRIs) in some treatment-resistant patients; however, it is not known whether these effects are independent, or whether the two neurotransmitter systems act synergistically. We first determined that the SSRI fluoxetine and the nicotinic partial agonist cytisine have synergistic effects in a mouse model of antidepressant efficacy, whereas serotonin depletion blocked the effects of cytisine. Using a pharmacological approach, we found that the 5-HT1A agonist 8-OH-DPAT also potentiated the antidepressant-like effects of cytisine, suggesting that this subtype might mediate the interaction between the serotonergic and cholinergic systems. The 5-HT1A receptors are located both presynaptically and postsynaptically. We therefore knocked down 5-HT1A receptors in either the dorsal raphe (presynaptic autoreceptors) or the hippocampus (a brain area with high expression of 5-HT1A heteroreceptors sensitive to cholinergic effects on affective behaviors). Knockdown of 5-HT1A receptors in hippocampus, but not dorsal raphe, significantly decreased the antidepressant-like effect of cytisine. This study suggests that serotonin signaling through postsynaptic 5-HT1A receptors in the hippocampus is critical for the antidepressant-like effects of a cholinergic drug and begins to elucidate the molecular mechanisms underlying interactions between the serotonergic and cholinergic systems related to mood disorders.
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Yann S
authors.initials: YS
authors.lastname: Mineur
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Emily B
authors.initials: EB
authors.lastname: Einstein
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Bentham
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Mattis B
authors.initials: MB
authors.lastname: Wigestrand
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Sam
authors.initials: S
authors.lastname: Blakeman
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Sylvia A
authors.initials: SA
authors.lastname: Newbold
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Marina R
authors.initials: MR
authors.lastname: Picciotto
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000470:Alkaloids / Q000627:therapeutic use*; D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use*; D001392:Azocines / Q000627:therapeutic use; D004195:Disease Models, Animal; D004357:Drug Synergism; D005473:Fluoxetine / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D019417:Hindlimb Suspension; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007398:Interpersonal Relations; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D011807:Quinolizines / Q000627:therapeutic use; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use; D013315:Stress, Psychological / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D000093843:Quinolizidine Alkaloids
chemical_list: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000470:Alkaloids; D000928:Antidepressive Agents; D001392:Azocines; D005473:Fluoxetine; D011807:Quinolizines; D044282:Receptor, Serotonin, 5-HT1A; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; C004712:cytisine; D000093843:Quinolizidine Alkaloids