10 Brain Research, 413 (1987) 10- 14 Elsevier BRE 12605 Further evidence for endogenous hypothalamic serotonergic neurons involved in the cimetidine-induced prolactin release in the rat Esteban Kertesz, Gustavo M. Somoza, Jos6 L. D'Eramo and Carlos Libertun lnstituto de Biologia y Medicina Experimental, Buenos Aires (Argentina) (Accepted 28 October 1986) Key words: Intrahypothalamic; Cimetidine; Serotonin; Prolactin; Luteinizing hormonc( LH ) The aim of the present work was to further explore the possible relationship between the prolactin-releasing effect of cimetidinc and hypothalamic serotonergic neurons controlling pituitary hormone secretion. In a first approach, the prolactin-releasing effect of the drug was determined in adult male rats with total deafferentation of the hypothalamus. Cimetidine injection (60 mg/kg) produced a significant rise in prolactin, but not in luteinizing hormone (LH), both in deafferented rat and in sham-operated controls; by 15 rain there was a 5-6 fold increase in prolactin titers. Methysergide, a serotonin receptor blocker, used in a dosc (2.5 mg/kg), route (i.p.) and time (50 min earlier) which did not modify the hormone basal level in rats with total deafferentation of the hypothalamus, was able to prevent completely the prolactin release evoked by cimetidine. The same preventive effect on prolactin release was observed with the serotonin receptor blocker ketanserin (5 mg/kg, i.p., 30 min earlier). It is concluded that the prolactin-releasing effect of cimeti- dine is located at a hypothalamic level related to serotonergic neurons. INTRODUCTION The prolactin releasing effect of some H2-hista- mine receptor antagonists was first described in the rat using metiamide 2 and then confirmed in man with cimetidine ~2. A considerable body of literature, both on rodents and on humans, supports this concept 1 5, 9-11A8,21,22,26,28-30.35-38,41 However, the precise site and mechanism of action by which these drugs exert this effect are still not totally known. Concerning the site of action, it was postulated that the cimetidine- induced prolactin release involved a brain locus l'ls although the precise area remains obscure. A brain- mediated effect for the prolactin-releasing action of cimetidine could encompass either a direct effect on prolactin inhibiting and/or releasing factors, or the involvement of brain neurotransmitters which pro- vide the link between the brain and neurosecretory neurons which control prolactin. For example, recent data have been published indicating that seroton- ergic neurons are involved in the cimetidine-induced prolactin release in the rat 4 and in man 26. In the pres- ent study, we explore the possible interaction of ci- metidine with hypothalamic serotonergic neurons controlling pituitary prolactin release. MATERIALS AND METHODS Animals Male Wistar rats of the strain of the Instituto de Biologia y Medicina Experimental were housed in an air-conditioned room (22 °C) with lights on at 07.00 and off at 19.00 h and given free access to laboratory chow and tap water. Experiments were always per- formed between 09.00 h and 11.30 h to prevent varia- tion due to the circadian pattern of hormone secre- tion. To gain information concerning the site of action of the cimetidine-induced prolactin release, adult (300-350 g) males were deafferented according to Correspondence: C. Libertun, Instituto de Biologia y Medicina Experimental, Obligado 2490, 1428 Buenos Aires, Argentina.