Methamphetamine Administration Increases Proceptive Behavior by Activating Src Kinase and Upregulating Progesterone Receptor in the Medial Amygdala

Abstract

Methamphetamine, a psychostimulant drug of abuse, increases sexual motivation both in humans and in rodent models. The activation of dopamine type-1 receptors (D1Rs) within the medial amygdala, in the presence of ovarian hormones (EB+P), are both necessary and sufficient for increases in proceptive, or sexually motivated, behaviors. Here, we demonstrate that methamphetamine increases progesterone receptor expression in the medial amygdala independently of D1R activation, and that lentiviral overexpression of the progesterone receptor was able to recapitulate the methamphetamine-induced enhancement of proceptive behaviors. Furthermore, we found that within the medial amygdala, these progesterone receptors show an increase in phosphorylation of serine 294 of the progesterone receptor in a region-specific manner. The involvement of this phosphorylation site suggests a role for cytosolic kinases, which may be responsible for enhanced progesterone receptor action. The phosphorylation of serine 294 is blocked by D1R antagonists, and by inhibiting cSrc and ERK1/2, downstream of D1R signaling, we identified that Src and ERK1/2 are required for enhanced proceptive behavior. Taken together, we propose that within the medial amygdala, methamphetamine enhances progesterone receptors sensitivity to its cognate ligand via interaction with cSrc kinase and ERK1/2, as well as an increase total progesterone receptors, thus leading to enhanced proceptive behaviors in the rat.