Acute and long-term administration of citalopram desensitizes alpha2-adrenoceptors in the rat vas deferens.
The aim of this study was to investigate the effect of citalopram, a selective serotonin reuptake inhibitor, on the sensitivity of rat vas deferens alpha2-adrenoceptors and to compare it with the effects of serotonin and the dual noradrenaline-serotonin uptake inhibitor duloxetine. To this end, we studied the inhibitory effect of the alpha2-adrenoceptor agonist bromoxidine on the electrically induced contraction of the vas deferens. Citalopram (1, 3 x 10(3) and 3 x 10(4) nM) applied in-vitro significantly attenuated the concentration-response inhibition induced by activation of alpha2-adrenoceptors on the electrically evoked contraction of the vas deferens (concentration of the agonist required to promote 50% of the maximal effect, EC50, for bromoxidine increased by 232%, 421% and 818%, respectively). Similarly, serotonin also attenuated the concentration-response inhibition mediated by presynaptic alpha2-adrenoceptors (96% increase in EC50). Acute and long-term systemic administration of citalopram and duloxetine also produced a loss in the sensitivity of alpha2-adrenoceptors to bromoxidine (EC50 for bromoxidine increased by 97% and 144%, respectively, after citalopram, and by 214% and 167% after duloxetine). In addition, we observed that an increased fraction of receptors was required to be occupied to yield 50% of the inhibitory effect of bromoxidine after long-term administration of citalopram and duloxetine (KE increased by 142% and 83%). These results are indicative of early-onset and persistent down-regulation of peripheral alpha2-adrenoceptors by citalopram, which may account for some of its side effects.
Departamento de Farmacología, Universidad del País Vasco, E-48940 Leioa, Vizcaya, Spain.
Laura
L
Grandoso
Laura
L
García
Joseba
J
Pineda
Luisa
L
Ugedo
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D000068438:Brimonidine Tartrate; D015283:Citalopram / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D000068736:Duloxetine Hydrochloride; D004558:Electric Stimulation; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology; D014649:Vas Deferens / Q000187:drug effects* / Q000502:physiology
D018759:Adrenergic Uptake Inhibitors; D000316:Adrenergic alpha-Agonists; D000068438:Brimonidine Tartrate; D015283:Citalopram; D000068736:Duloxetine Hydrochloride; D011810:Quinoxalines; D018341:Receptors, Adrenergic, alpha-2; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D013876:Thiophenes; C547770:Adra2a protein, rat