Prolactin-lowering ability of (+/-)-idazoxan may be linked to a central noradrenergic-serotonergic interplay

2-[2-(1,4-benzodioxanyl)-2-imidazoline] (idazoxan) sometimes lowers basal prolactin levels in the male adult rat, but strongly inhibits hyperprolactinemia in suckling rats. A possible antido paminergic drug effect is not involved, due to its inability to modify prolactin release from superfused pituitary in vitro as well as rat haloperidol hyperprolactinemia in vivo. On the contrary, in the rat idazoxan counteracts hyperprolactinemias due to central presynaptic serotonergic neurotransmission increase (5-hydroxytryptophan, D-fenfluramine and fluoxetine) but not those related to direct agonists at 5-hydroxytryptamine (5-HT) receptor (6-chloro-2-[1-piperazinyl] pyrazine, MK 212; 1-(2,5-dimethoxy-4-iodophenyl)2-aminopropane, DOI). (+/-)-Idazoxan does not modify [3H]-5-HT release from isolated hypothalamic synaptosomes. It displays an affinity for alpha-2 adrenergic autoreceptors about 250-fold more than for alpha-2 heteroreceptors located on 5-HT nerve terminals in the central nervous system (pA2 value 9.99, equivalent to a Kb of 0.1 nM vs. pA2 7.60 equivalent to a Kb of 2.5 nM). The noradrenergic outflow selectively induced by idazoxan in the brain may negatively modulate the 5-HT release from the relevant nerve endings, thus preventing prolactin release due to an activation of presynaptic serotonergic axons induced both physiologically (lactation) and pharmacologically (5-hydroxytryptophan, D-fenfluramine and fluoxetine) without influencing hyperprolactinemias related to a direct activation of serotonergic receptors (MK 212 and DOI). Other blocking agents, strong but less selective than (+/-)-idazoxan for noradrenergic brain neurotransmission, do not modify or increase blood prolactin.(ABSTRACT TRUNCATED AT 250 WORDS)