The Dopamine D4 Receptor Regulates Gonadotropin-Releasing Hormone Neuron Excitability in Male Mice

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Abstract
Gonadotropin-releasing hormone (GnRH)-secreting neurons control fertility. The release of GnRH peptide regulates the synthesis and release of both LH and FSH from the anterior pituitary. While it is known that dopamine regulates GnRH neurons, the specific dopamine receptor subtype(s) involved remain unclear. Previous studies in adult rodents have reported juxtaposition of fibers containing tyrosine hydroxylase (TH), a marker of catecholaminergic cells, onto GnRH neurons and that exogenous dopamine inhibits GnRH neurons postsynaptically through dopamine D1-like and/or D2-like receptors. Our microarray data from GnRH neurons revealed a high level of Drd4 transcripts [i.e., dopamine D4 receptor (D4R)]. Single-cell RT-PCR and immunocytochemistry confirmed GnRH cells express the Drd4 transcript and protein, respectively. Calcium imaging identified changes in GnRH neuronal activity during application of subtype-specific dopamine receptor agonists and antagonists when GABAergic and glutamatergic transmission was blocked. Dopamine, dopamine with D1/5R-specific or D2/3R-specific antagonists or D4R-specific agonists decreased the frequency of calcium oscillations. In contrast, D1/5R-specific agonists increased the frequency of calcium oscillations. The D4R-mediated inhibition was dependent on Gi/o protein coupling, while the D1/5R-mediated excitation required Gs protein coupling. Together, these results indicate that D4R plays an important role in the dopaminergic inhibition of GnRH neurons. Significance Statement The convergence of information on neurons secreting gonadotropin-releasing hormone (GnRH) shape their secretory profile and consequently, fertility. Dopamine inhibits GnRH neurons, yet the specific dopamine receptor subtype(s) involved remain unclear. Using single RT-PCR, immunofluorescence, and dopamine receptor-specific pharmacological tools, we show here that dopamine D4 receptor (D4R) plays a role in the dopaminergic inhibition of GnRH neurons, adding a new tool for the modulation of reproductive function.

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