Membrane actions of progestins at dopamine type 1-like and GABAA receptors involve downstream signal transduction pathways

In the ventral tegmental area (VTA), progestins facilitate lordosis via rapid actions at membrane dopamine Type 1-like (D1) and/or GABAA receptors (GBRs), rather than via cognate, intracellular progestin receptors (PRs). Downstream signal transduction pathways involved in these effects were investigated using lordosis as a bioassay. If progestins’ actions at D1 and/or GBRs in the VTA require activation of G-proteins, adenylyl cyclase, cyclic AMP-dependent protein kinase A (PKA), phospholipase C (PLC), and/or PKC, then pharmacologically blocking these pathways would be expected to attenuate progestin-facilitated lordosis and its enhancement by D1 and GBR activity. Ovariectomized, estradiol-primed rats were infused first with vehicle or signal transduction inhibitor, and second with vehicle, a D1 or GBR agonist, and then with vehicle or progestins to the VTA. Rats were tested for lordosis following infusions. Results indicated that initiation of G-proteins, adenylyl cyclase, PKA, PLC, or PKC in the VTA is required for rapid effects of progestins through D1 and/or GBRs to facilitate lordosis. As well, progestins’ actions at n-methyl-d-aspartate receptors (NMDARs) may modulate activity at D1 and/or GBRs and mitogen activated protein kinase (MAPK) may be a common signaling pathway. Findings from a microarray study demonstrated that there was upregulation of genes associated with steroid metabolism, GBRs, D1, NMDARs and signal transduction factors in the midbrain VTA of naturally receptive mated compared to non-mated rats. Thus, in the VTA, progestins have rapid membrane-mediated actions via D1, GBRs, NMDARs and their downstream signal transduction pathways.