Psychopharmacology (1994) 114:635-643 Psychopharmacology © Springer-Verlag 1994 Effect of pindolol on the L-5-I-ITP-induced increase in plasma prolactin and cortisol concentrations in man Herbert Y. Meltzer, Michael Maes, Laboratory of BiologicalPsychiatry,Case Western Reserve University,Cleveland,OH 44106, USA Received: 13 April 1993 / Final version: 23 August 1993 Abstract. Previous studies with direct-acting serotonin (5-HT) agonists and antagonists have demonstrated that stimulation of 5-HT~A, 5-HTlc and 5-HT2 receptors may promote cortisol and prolactin (PRL) secretion in man. There is also evidence that 5-HTlc/2 receptor stimulation contributes to the cortisol and PRL responses following administration of the 5-HT precursor, L-5-hydroxytryp- tophan (L-5-HTP), in man. To clarify the possible contri- bution of 5-HT1A receptor stimulation to the ability of L-5-HTP to stimulate cortisoI and PRL secretion in man, the effect of pindolol, a beta adrenoceptor antagonist that is also a 5-HT1A partial agonist, on the L-5-HTP-induced increases in cortisol and PRL secretion, was examined in 12 normal male volunteers. Pretreatment with pindolol, 30 mg orally, significantly inhibited the PRL but not the cortisot response to L-5-HTP, 200 mg PO. Pindolol alone decreased basal plasma PRL levels and increased basal plasma cortisol levels, possibly due to 5-HTIA antagonist and agonists effects, respectively. These data, coupled with observations from other studies, suggest that the L-5- HTP-induced increase in PRL but not cortisol secretion requires 5-HT 1Areceptor activation. PRL secretion due to 5-HT formed from exogenous L-5-HTP may require the availability of both intact 5-HT1A and 5-HT2/5-HTlc receptors, since blockade of either receptor type inhibited the PRL response to L-5-HTP. The implication of this synergistic effect for interpretation of neuroendocrine studies involving the serotonergic system in man is dis- cussed. Key words: 5-Hydroxytryptophan - Pindolol - Prolactin Cortisol - 5-HT~A - 5-HT2 and 5-HT~c receptors There is extensive evidence that serotonin (5-HT) can stimulate the secretion of prolactin (PRL) and corticos- teroids in man and laboratory animals. In vivo studies of Correspondence to." H.Y. Meltzer, Department of Psychiatry, University Hospitals of Cleveland, Hanna Pavilion, B-68, 2040 Abington Road, Cleveland,OH 44106-5000, USA the effect on PRL and corticosteroid secretion of direct- acting 5-HT agonists or of 5-HT precursors such as L- 5-hydroxytryptophan (L-5-HTP) or L-tryptophan (L-TRP) following pretreatment with a variety of 5-HT antagonists with relative specificity for particular subtypes of 5-HT receptors have suggested that the 5-HT receptors which are most important for PRL and corticosteroid secretion are the 5-HT1A, 5-HTlc, 5-HT2 and 5-HT3 receptor sub- types (see Mettzer et at. 1982; Meltzer and Nash 1988; Fuller 1992; Jorgensen et al. 1992; Levy and Van de Kar 1992 for reviews). The potential interactions between multiple subtypes of 5-HT receptors which may stimulate the secretion of PRL or corticosteroids have not been adequately investi- gated. Thus, it is not known whether the corticosteroid- stimulating effects of 5-HT1A agonists (Simonovic et al. 1984; Aulakh et al. 1988; Koenig et al. 1988; Matheson et al. 1989; Przegalinski et al. 1989; Di Sciullo et al. 1990), 5-HTIc/2 agonists (Koenig et al. 1987; King et al. 1989; Aulakh et al. 1992), or 5-HT3 agonists (Jorgensen et al. 1992) in rodents are entirely independent or whether their effects are interrelated. This is of particular interest with regard to the effect of precursors of 5-HT on hormone secretion, since 5-HT itself should be able to stimulate all potential mechanisms which are effective in modulating secretion of either hormone. Li et al. (1992) concluded that they could not detect evidence for a functional interaction between the 5-HT2- and 52HT~A-mediated increase in ACTH, corticosterone or PRL secretion in rodents. These findings will be discussed subsequently. By contrast, Jor- gensen et al. (1992) reported that 5-HTI, 5-HT2 and 5- HT3 antagonists blocked the PRL response to L-5-HTP in fluoxetine-treated rats alone and together. Based upon the degree of inhibition of the response by each type of antag- onist as well as various combinations, they concluded that combined activation of all three 5-HT receptor subtypes was required to obtain a maximal stimulation by 5-HT. There is conflicting data concerning which 5-HT re- ceptors mediate the ability of L-5-HTP or L-TRP to stimu- late PRL or cortisol secretion in man. Charig et al. (1986) reported that the acute administration of 40 mg ritanserin, a 5-HT2/lC antagonist (Awouters et al. 1982; Hoyer et al. 1988) enhanced the PRL response to an I.-TRP infusion. It was suggested that the PRL response to L-TRP was