Influence of castration on the response of the rat vas deferens to fluoxetine.
Antidepressant drugs such as desipramine and fluoxetine increase norepinephrine (NE) contractile response in rat vas deferens by inhibiting neuronal amine uptake. Fluoxetine, unlike other antidepressants, also inhibits calcium fluxes, which results in an inhibition of maximal NE effect. Since the contractile response of the reproductive tract is under the influence of testosterone, the effect of fluoxetine could be modified according to the endocrine status of the animal. In the present study we evaluated the influence of castration and testosterone replacement (1 mg per 100 g body wt.) on the peripheral action of fluoxetine. Castration was followed by a decrease in vas deferens weight and the appearance of spontaneous activity. Testosterone replacement reversed these effects. Concentration-response curves to NE and calcium were obtained in the absence and the presence of fluoxetine in vasa deferentia from normal, castrated and testosterone-treated castrated rats. After castration the effect of fluoxetine on vas deferens contractility was markedly altered. The spontaneous activity that appears after castration was prevented by fluoxetine and the stimulatory effect on NE-induced contractions was not observed. In contrast, the inhibitory action of fluoxetine on maximal NE effect was increased. Testosterone replacement restored vas deferens response to NE in the presence of fluoxetine. Fluoxetine did not modify the binding parameters of [(3)H]prazosin in vasa deferentia from normal or castrated animals. Cocaine shifted the NE concentration-response curve to the left in all groups, suggesting that the changes in fluoxetine effect following castration were not the result of an alteration of the neuronal uptake mechanism. The nitric oxide synthase inhibitor l-NMMA did not modify vas deferens response to NE in castrated animals either in the absence or presence of fluoxetine. An increased sensitivity to the inhibitory effect of fluoxetine was observed in the calcium concentration-response curves in vasa deferentia from castrated rats, an effect that was reversed by testosterone replacement. The results suggest that the alteration in the responsiveness of vasa deferentia from castrated rats to calcium could be responsible for increased sensitivity to the inhibitory effect of fluoxetine. It is concluded that vas deferens contractile response is testosterone dependent and that this behaviour modifies the effect of drugs such as fluoxetine that have dual effect on contractility.
Busch
L
L
Department of Pharmacology, School of Dentistry, University of Buenos Aires, Marcelo T. de Alvear 2142 (1122), Buenos Aires, Argentina. lucila@farmaco.odon.uba.ar
Wald
M
M
Borda
E
E
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002369:Castration; D003042:Cocaine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005473:Fluoxetine / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013739:Testosterone / Q000502:physiology*; D014649:Vas Deferens / Q000187:drug effects* / Q000502:physiology; D019323:omega-N-Methylarginine / Q000494:pharmacology
D000317:Adrenergic alpha-Antagonists; D002118:Calcium; D003042:Cocaine; D004791:Enzyme Inhibitors; D005473:Fluoxetine; D019001:Nitric Oxide Synthase; D009638:Norepinephrine; D011224:Prazosin; D017367:Selective Serotonin Reuptake Inhibitors; D013739:Testosterone; D019323:omega-N-Methylarginine