ACTIVATION OF PROTEIN-KINASE-C IN THE HYPOTHALAMIC VENTROMEDIAL NUCLEUS OR THE MIDBRAIN CENTRAL GRAY FACILITATES LORDOSIS

Many neurotransmitters and neuropeptides can act through the hypothala mic ventromedial nucleus (VMN) or midbrain central gray (MCG) to facil itate lordosis. Since these lordosis-facilitating agents can also stim ulate the phosphoinositide (PI) second-messenger pathway, it was hypot hesized that direct activation of this pathway can also potentiate the behavior. To evaluate this possibility, a phorbol ester, TPA (12-O-te tradecanoyl phorbol 13-acetate), was used to activate a key enzyme, pr otein kinase C (PKC), of the PI pathway in ovariectomized (OVX) rats e ither primed or not primed with estrogen. These female rats were paire d with males for mating tests before and after an intracerebral infusi on of TPA, and both the lordosis quotient (LQ) and the lordosis streng th (LS) were measured. Bilateral infusion of TPA (5 mu g/0.5 mu l or 0 .2 mu g/0.2 mu l, but not 0.1 mu g/0.2 mu l/side) into the VMN or MCG of estrogen-primed subjects facilitated both LQ and LS in 30 min, peak ed at 60-90 min, and the facilitation lasted for more than 180 min. Th is facilitatory effect of TPA was: (1) not observed in OVX rats not pr imed with estrogen; (2) not observed if the infused TPA did not reach both sides of the VMN or MCG; (3) not mimicked by 4 alpha-phorbol 12,1 3-didecanoate, which does not activate PKC; (4) blocked by PKC inhibit ors (H7 10 mM or staurosporine 1 mu M, 0.2 mu l/side), which by themse lves did not facilitate lordosis; and (5) was not affected by pretreat ment of the progestin antagonist RU486. These observations indicate th at TPA facilitates lordosis in a dose-dependent fashion by activating, and not by depleting, PKC in the VMN or MCG, and that the TPA effect requires estrogen priming but not the activation of progestin receptor s. Thus, the PI pathway or the activation of PKC may be a common media tor for lordosis facilitation in these two brain regions; and the requ irement of estrogen priming further raises the possibility that this s econd-messenger system or its substrates in the VMN and MCG are modula ted by estrogen.