Role of Progesterone Receptor and Src Kinase in Methamphetamine-mediated Proceptive Behavior

Abstract

Methamphetamine (Meth) is a psychomotor stimulant strongly associated with increases in sexual drive and impulse in both men and women. These changes in sexual motivation have a greater impact on women due to their likelihood of facing the greater burden of unplanned pregnancies and an increased risk for psychiatric co-morbidities. We have previously established a rodent model of Meth-induced increases in sexual motivation. Using this model, we have demonstrated that in the presence of ovarian steroids, Meth-induced increase in behavior requires activation of the dopamine type-1 receptors and progesterone receptors (PR) in the medial amygdala (MePD). However, the mechanisms through which Meth is interacting with the PR signaling system remain unknown. The work presented here furthers our understanding of the potential mechanism by which Meth-activated pathways and ovarian steroids interact in the MePD to increase proceptive behaviors. First, using a cell-specific lesion technique, DAUN02 inactivation, we identified a behaviorally relevant cell population in the MePD required for Meth-induced increases in proceptivity. Furthermore, we demonstrated that within the MePD, Meth increases PR phosphorylation at Ser294 (pSer294-PR). This site is a target of both ERK1/2 and Src kinases, which have both been implicated in the cellular mechanisms underlying female sexual behavior. Indeed, the combined administration of Meth and ovarian hormones increased the phosphorylation of both ERK1/2 and Src kinases suggesting a role for these proteins in Meth-induced increases in PR phosphorylation and proceptivity. To test the possible role of each kinase, pharmacological inhibitors of either Src-family kinases or ERK1/2 were independently infused directly into the MePD. While separately inhibiting both kinases attenuated Meth-induced increases in proceptivity, ERK1/2 inhibition was unable to block the Meth-induced phosphorylation of Ser294-PR. Using shRNA to specifically knockdown the expression of Src in the MePD resulted in an attenuation of the Meth-induced proceptivity and a blockade of Meth-induced pERK1/2 and pSer-294-PR supporting the possibility that Src is a nexus linking Meth induced signaling to PR activation. These findings suggest that in the presence of ovarian steroids, Meth increases Src kinase signaling within the MePD, which subsequently increases pSer294-PR and pERK1/2, which are necessary for Meth-facilitated proceptive behavior.