Pharmacologic Evidence that a D2 Receptor Subtype Mediates Dopaminergic Stimulation of Prolactin Secretion from the Anterior Pituitary Gland

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Abstract
The ability of low concentrations of dopamine (DA) to stimulate the secretion of prolactin (PRL) was examined in perifused or monolayer cultures of anterior pituitary cells. In cultures perifused with media containing 100 nM DA, changing the DA concentration to either 1 or 100 pM caused a significant dose-dependent stimulatory PRL secretory response within 6 min when compared to the PRL secretory response to removal of DA altogether. Picomolar concentrations of DA caused a biphasic PRL secretory response. This response is characterized by an immediate increase in the rate of PRL secretion similar to that seen when the cells were treated with 100 nM thyrotropin-releasing hormone followed by a decrease in the rate of PRL secretion to levels comparable to cells receiving media alone. In a monolayer culture system DA, at concentrations between 10 nM and 1.0 pM, caused significant stimulation of PRL secretion relative to media alone. Maximal stimulation occurred at nanomolar concentrations of DA (approximately 60% greater than control). Although the D2 agonists, bromocriptine and 2-(N-phenethyl-N-propyl)-amino-5-hydroxytetralin hydrochloride (PPHT) caused significant (p M to 1 µM. These data suggest that DA not only inhibitis PRL secretion in vitro, but also stimulates PRL secretion at relatively low concentrations. Stimulation is mediated by a DA receptor which is neither recognized by D2 nor D1 agonists, suggesting a possible third DA receptor subtype. The identity of the DA receptor mediating dopaminergic stimulation (Ds) of PRL secretion was further examined using the highly specific D2 receptor antagonist Eticlopride (EΗ). EΗ (1–10 nM) caused significant dose-dependent antagonism of the inhibitory effects of DA, bromocriptine, and PPHT. In addition, EΗ (1–10 nM) caused a significant dose-dependent blockade of the stimulatory effects of DA on PRL secretion. EΗ, itself, exerted no effect on PRL secretion over the concentration range of 1–100 nM. The inability of bromocriptine and PPHT to stimulate PRL secretion provides evidence for a DA-specific receptor mediating dopaminergic stimulation of PRL secretion which is distinct from the receptor mediating dopaminergic inibition of PRL secretion. Since EΗ antagonizes both stimulation and inhibition of PRL secretion by DA, EΗ recognizes both the Ds receptor mediating stimulation of PRL secretion and the D2 receptor mediating inhibition of PRL secretion. Taken together, these data suggest that DA, at low concentrations, can stimulate PRL secretion and that this stimulation is mediated by a receptor which is similar yet distinct from the D2 receptor based on its interactions with bromocriptine, PPHT, and EΗ.

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