title: Serotonin and Antidepressant SSRIs Inhibit Rat Neuroendocrine Dopamine Neurons: Parallel Actions in the Lactotrophic Axis.
abstract: Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for depression, but sexual side effects often compromise compliance. These reproductive dysfunctions are likely mediated by elevations of the hormone prolactin. Yet, how serotonin (5-HT) and SSRIs cause changes in prolactin secretion is not known. Here, using in vitro whole-cell patch-clamp recordings, we show that 5-HT hyperpolarizes and abolishes phasic discharge in rat neuroendocrine tuberoinfundibular dopamine (TIDA) neurons, the main inhibitor of prolactin secretion. This process is underpinned by 5-HT1A receptor-mediated activation of G-protein-coupled inwardly rectifying K(+)-like currents. We further demonstrate that the SSRIs, fluoxetine and sertraline, directly suppress TIDA neuron activity through parallel effects, independent of 5-HT transmission. This inhibition involves decreased intrinsic excitability and a slowing of TIDA network rhythms. These findings indicate that SSRIs may inhibit neuroendocrine dopamine release through both 5-HT-dependent and -independent actions, providing a mechanistic explanation for, and potential molecular targets for the amelioration of, the hyperprolactinemia and sexual dysfunction associated with these drugs.
  
  
  
  Depression affects approximately one-tenth of the population and is commonly treated with selective serotonin reuptake inhibitors (SSRIs; e.g., Prozac). Yet, many patients withdraw from SSRI therapy due to sexual side effects (e.g., infertility, menstrual disturbances, and impotence). Although it is generally accepted that sexual side effects are due to the ability of these drugs to elevate blood levels of the hormone prolactin, the mechanism for this hormonal imbalance is not known. Here, we show that SSRIs can inhibit hypothalamic dopamine neurons that normally suppress the secretion of prolactin. Intriguingly this inhibition can be explained both by increased serotonin activity and also by parallel serotonin-independent actions.
authors.affiliation: Rowett Institute of Nutrition and Health, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, United Kingdom david.lyons@abdn.ac.uk Christian.Broberger@ki.se.
authors.forename: David J
authors.identifier: 0000-0002-3391-5878
authors.initials: DJ
authors.lastname: Lyons
authors.affiliation: Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden, and.
authors.forename: Rachida
authors.identifier: 0000-0002-1736-6063
authors.initials: R
authors.lastname: Ammari
authors.affiliation: Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden, and.
authors.forename: Arash
authors.initials: A
authors.lastname: Hellysaz
authors.affiliation: Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden, and david.lyons@abdn.ac.uk Christian.Broberger@ki.se.
authors.forename: Christian
authors.identifier: 0000-0002-7050-8809
authors.initials: C
authors.lastname: Broberger
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001111:Arcuate Nucleus of Hypothalamus / Q000166:cytology*; D059290:Dopaminergic Neurons / Q000187:drug effects*; D004558:Electric Stimulation; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D052682:Lactotrophs / Q000187:drug effects*; D008297:Male; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D018683:Excitatory Amino Acid Agents; D011985:Receptors, Serotonin; D012701:Serotonin; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; D026941:Sodium Channel Blockers; D013764:Tetrahydronaphthalenes; D013779:Tetrodotoxin; D014446:Tyrosine 3-Monooxygenase; C083828:8-hydroxy-2-(N-n-propyl-N-(3'-iodo-2'-propenyl)amino)tetralin
keywords: depression; dopamine; fluoxetine; neuroendocrine; prolactin; tuberoinfundibular