title: Sexual side effects of serotonergic antidepressants: mediated by inhibition of serotonin on central dopamine release?
abstract: Antidepressant-induced sexual dysfunction adversely affects the quality of life of antidepressant users and reduces compliance with treatment. Animal models provide an instructive approach for examining potential sexual side effects of novel drugs. This review discusses the stability and reproducibility of our standardized test procedure that assesses the acute, subchronic and chronic effects of psychoactive compounds in a 30 minute mating test. In addition, we present an overview of the effects of several different (putative) antidepressants on male rat sexual behavior, as tested in our standardized test procedure. By comparing the effects of these mechanistically distinct antidepressants (paroxetine, venlafaxine, bupropion, buspirone, DOV 216,303 and S32006), this review discusses the putative mechanism underlying sexual side effects of antidepressants and their normalization. This review shows that sexual behavior is mainly inhibited by antidepressants that increase serotonin neurotransmission via blockade of serotonin transporters, while those that mainly increase the levels of dopamine and noradrenaline are devoid of sexual side effects. Those sexual disturbances cannot be normalized by simultaneously increasing noradrenaline neurotransmission, but are normalized by increasing both noradrenaline and dopamine neurotransmission. Therefore, it is hypothesized that the sexual side effects of selective serotonin reuptake inhibitors may be mediated by their inhibitory effects on dopamine signaling in sex brain circuits. Clinical development of novel antidepressants should therefore focus on compounds that simultaneously increase both serotonin and dopamine signaling.
authors.affiliation: Utrecht Institute for Pharmaceutical Sciences and Rudolf Magnus Institute of Neuroscience, Utrecht University, Universiteitsweg 99, 3584 CGUtrecht, The Netherlands.
authors.forename: Elisabeth Y
authors.initials: EY
authors.lastname: Bijlsma
authors.affiliation: Utrecht Institute for Pharmaceutical Sciences and Rudolf Magnus Institute of Neuroscience, Utrecht University, Universiteitsweg 99, 3584 CGUtrecht, The Netherlands.
authors.forename: Johnny S W
authors.initials: JS
authors.lastname: Chan
authors.affiliation: Utrecht Institute for Pharmaceutical Sciences and Rudolf Magnus Institute of Neuroscience, Utrecht University, Universiteitsweg 99, 3584 CGUtrecht, The Netherlands.
authors.forename: Berend
authors.initials: B
authors.lastname: Olivier
authors.affiliation: Utrecht Institute for Pharmaceutical Sciences and Rudolf Magnus Institute of Neuroscience, Utrecht University, Universiteitsweg 99, 3584 CGUtrecht, The Netherlands; Department of Anatomy, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.
authors.forename: Jan G
authors.initials: JG
authors.lastname: Veening
authors.affiliation: Institut de Recherches Servier, Psychopharmacology Department, 125 Chemin de Ronde, 78290 Croissy-sur-Seine, France.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Millan
authors.affiliation: Utrecht Institute for Pharmaceutical Sciences and Rudolf Magnus Institute of Neuroscience, Utrecht University, Universiteitsweg 99, 3584 CGUtrecht, The Netherlands.
authors.forename: Marcel D
authors.initials: MD
authors.lastname: Waldinger
authors.affiliation: Utrecht Institute for Pharmaceutical Sciences and Rudolf Magnus Institute of Neuroscience, Utrecht University, Universiteitsweg 99, 3584 CGUtrecht, The Netherlands.
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Oosting
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000009:adverse effects*; D001372:Aza Compounds / Q000009:adverse effects; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000009:adverse effects; D016642:Bupropion / Q000009:adverse effects; D002065:Buspirone / Q000009:adverse effects; D003511:Cyclohexanols / Q000009:adverse effects; D004195:Disease Models, Animal; D004298:Dopamine / Q000502:physiology; D005260:Female; D006801:Humans; D007211:Indoles / Q000009:adverse effects; D008297:Male; D009638:Norepinephrine / Q000502:physiology; D017374:Paroxetine / Q000009:adverse effects; D011725:Pyridines / Q000009:adverse effects; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000502:physiology; D017367:Selective Serotonin Reuptake Inhibitors / Q000009:adverse effects*; D012726:Sexual Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D012735:Sexual Dysfunction, Physiological / Q000139:chemically induced / Q000503:physiopathology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D000069470:Venlafaxine Hydrochloride
chemical_list: D000928:Antidepressive Agents; D001372:Aza Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D016642:Bupropion; D002065:Buspirone; D003511:Cyclohexanols; D004298:Dopamine; D007211:Indoles; D009638:Norepinephrine; D017374:Paroxetine; D011725:Pyridines; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D000069470:Venlafaxine Hydrochloride; C474071:1-(3,4-dichlorophenyl)-3-azabicyclo-(3.1.0)hexane hydrochloride; C533966:S32006
keywords: Animal model; Antidepressants; Drug-induced; Ejaculation; Sexual behavior; Sexual dysfunction