Activity of protein kinase C is important for 3α,5α-THP's actions at dopamine type 1-like and/or GABAA receptors in the ventral tegmental area for lordosis of rats

Abstract

In the ventral tegmental area, progestogens facilitate sexual receptivity of rodents via actions at dopamine type 1-like and/or γ-aminobutyric type A receptors and activation of downstream signal transduction molecules. In the present study, we investigated whether effects of progesterone's metabolite, 3α,5α-THP, to enhance lordosis via actions at these receptors in the ventral tegmental area requires phospholipase C-dependent protein kinase C. The objective of this study was to test the hypothesis that: if progestogens' actions through dopamine type 1-like and/or γ-aminobutyric type A receptors in the ventral tegmental area for lordosis require protein kinase C, then inhibiting protein kinase C in the ventral tegmental area should reduce 3α,5α-THP-facilitated lordosis and its enhancement by dopamine type 1-like or γ-aminobutyric type A receptor agonists. Ovariectomized, E 2 (10 μg s.c. at hr 0)-primed rats were tested for their baseline lordosis responses and then received a series of three infusions to the ventral tegmental area: first, bisindolylmaleimide (75 nM/side) or vehicle; second, SKF38393 (100 ng/side), muscimol (100 ng/side), or vehicle; third, 3α,5α-THP (100, 200 ng) or vehicle. Rats were pre-tested for lordosis and motor behavior and then tested for lordosis after each infusion and 10 and 60 mins after the last infusion. Rats were tested for motor behavior following their last lordosis test. As has been previously demonstrated, 3α,5α-THP infusions to the ventral tegmental area increased lordosis and effects were further enhanced by infusions of SKF38393 and muscimol. Infusions of bisindolylmaleimide to the ventral tegmental area attenuated 3α,5α-THP-, SKF38393-, and/or muscimol-facilitated lordosis. Effects on lordosis were not solely due to changes in general motor behavior. Thus, 3α,5α-THP's actions in the ventral tegmental area through membrane receptors may require activity of protein kinase C.

Mechanisms responsible for progesterone's protection against lordosis-inhibiting effects of restraint II. Role of progesterone metabolites

“…Allopregnanolone has been reported to activate PKA (Gonzalez-Flores et al, 2006; Mani et al, 2000) and MAPK (Etgen and Acosta-Martinez, 2003; Frye and Walf, 2008) and can increase Src kinase dependent Ca 2+ influx (Blackmore, 2008). Of relevance to the current findings is that allopregnanolone’s facilitation of lordosis can be blocked by PKC inhibitors (Gonzalez-Flores et al, 2006) or MAPK (Gonzalez-Flores et al, 2004).…”

“…Progesterone also increases cAMP (Mani et al, 2000) and inhibition of PKA attenuates progesterone’s facilitation of lordosis behavior (Gonzalez-Flores et al, 2006). Lordosis-facilitating effects of allopregnanolone are less vulnerable to PKA inhibition (Gonzalez-Flores et al, 2006) but may, instead, involve PKC (Frye and Walf, 2008; Gonzalez-Flores et al, 2006) and/or potentiation of the GABAergic system (Frye et al, 2006) which has also been reported to attenuate inhibitory effects of 5-HT 1A receptors on lordosis behavior (Guptarak et al, 2004). Therefore, the collective evidence is consistent with the occurrence of considerable cross-talk among progesterone’s multiple signaling cascades and its ability to attenuate effects of mild stress on female rat sexual behavior.…”

Allopregnanolone's attenuation of the lordosis-inhibiting effects of restraint is blocked by the antiprogestin, CDB-4124

“…Many of these signaling pathways (e.g. cAMP, PKC, PKA, MAPK, Src kinase) are also altered by allopregnanolone (Blackmore, 2008; Etgen and Acosta-Martinez, 2003; Frye and Walf, 2008; Gonzalez-Flores et al, 2006; Mani et al, 2000; Pluchino et al, 2006; Thomas and Pang, 2012) and allopregnanolone’s facilitation of lordosis can be blocked by PKC inhibitors (Gonzalez-Flores et al, 2006) or inhibitors of MAPK (Gonzalez-Flores et al, 2004). Therefore, allopregnanolone may indirectly activate intracellular progesterone by activation of intracellular signaling pathways.…”

Activation of progestin receptors in female reproductive behavior: Interactions with neurotransmitters

“…It has been recognized that in addition to steroid hormones, several neurotransmitters and neuropeptides influence female reproductive behavior in rodents. While the effects of acetylcholine, norepinephrine, serotonin (acting via 5-HT 2 , receptor subtype), DA (acting via receptor subtype D 1 ) and the neuropeptides GnRH, TRH, prolactin, oxytocin, substance P, and GABA A are considered facilitatory, serotonin (acting receptor subtype 5-HT 1A ), DA (acting through receptor subtype D 2 ), opioids, CRF, α-MSH, ACTH, β-endorphin, neuropeptide Y, cholecystokinin and glutamate are considered inhibitory on sexual behavior [26, 76, 93, 210, 250, 258]. …”