Mechanism of action of dopamine on the in vitro release of gonadotropin-releasing hormone.
Controversy exists on whether dopamine (DA) stimulates or inhibits GnRH secretion and whether its effects are mediated via alpha-adrenergic receptors or dopaminergic receptors. As a means to examine this conflict, we have utilized an in vitro superfusion system to study the effects of DA, norepinephrine (NE), phentolamine (alpha-antagonist), pimozide (DA antagonist), and two DA agonists (apomorphine and bromocryptine) on GnRH release from isolated mediobasal hypothalami from adult male rats. In this dynamic system, graded concentrations of both NE and DA (2.0 nM to 2.0 microM) led to a dose-dependent increase in GnRH output during the 10 min interval that followed each pulse dose of NE (P less than 0.02) or DA (P less than 0.05). The DA-induced GnRH release was reproducible, consistent, and significant over five successive pulses (20 microM) at 30-min intervals (P less than 0.02). Coinfusion of phentolamine (20 microM) prevented the DA (20 microM) induced release of GnRH (P less than 0.03), but pimozide (20 microM) had no significant effect on DA-induced GnRH release (P greater than 0.3). The two DA agonists, apomorphine and bromocryptine, at doses up to 2.0 microM and 200 nM, respectively, had no significant effect on GnRH release. To determine whether DA was causing a direct stimulation of alpha-adrenergic receptors or being enzymatically converted to NE which could then stimulate alpha-receptors to induce GnRH release, rats were injected with sodium diethyldithiocarbamate (DDC) (550 mg/kg BW) ip, 1 h before death. DDC blocks the enzymatic conversion of DA to NE, and this was reflected by a 37% decrease in hypothalamic NE efflux during the superfusion. However, pulses of DA, even in the presence of DDC, were associated with a marked dose-dependent increase in hypothalamic NE efflux, and DDC failed to prevent the subsequent stimulation of GnRH release. We conclude that the apparent DA-induced release of GnRH is most probably attributable to DA-induced release of hypothalamic NE which, in turn, acts through alpha-adrenergic receptors on peptidergic neurons to stimulate GnRH release.
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001971:Bromocriptine / Q000494:pharmacology; D004298:Dopamine / Q000494:pharmacology*; D004299:Dopamine beta-Hydroxylase / Q000037:antagonists & inhibitors; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D007033:Hypothalamus, Middle / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D010646:Phentolamine / Q000494:pharmacology; D010868:Pimozide / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D011954:Receptors, Dopamine / Q000502:physiology*
D011942:Receptors, Adrenergic, alpha; D011954:Receptors, Dopamine; D010868:Pimozide; D007987:Gonadotropin-Releasing Hormone; D001971:Bromocriptine; D004299:Dopamine beta-Hydroxylase; D001058:Apomorphine; D004298:Dopamine; D009638:Norepinephrine; D010646:Phentolamine