Methamphetamine-enhanced female sexual motivation is dependent on dopamine and progesterone signaling in the medial amygdala

Abstract

Methamphetamine (METH) is a psychomotor stimulant strongly associated with increases in sexual drive and impulsive sexual behaviors that often lead to unsafe sexual practices. In women METH users, such practices have been associated with increases in unplanned pregnancies and sexually transmitted diseases. Despite this significant heath concern, the neural mechanisms underlying this drug-sex association are not known. We previously established a rodent model of METH-facilitated female sexual behavior in which estradiol and progesterone interact with METH to increase motivational components of female behavior and neuronal activation in the posterodorsal medial amygdala (MePD) (Holder et al., 2010; Holder and Mong, 2010). The current study more directly examines the mechanisms underlying the drug-sex interaction. Here, we hypothesize that METH-induced increases in MePD dopamine signaling bridge the METH-hormone interaction. In support of this hypothesis, we found that excitotoxic lesions targeted to the MePD attenuated the METH-induced increases in proceptive behavior. Furthermore, infusion of a D1 agonist into the MePD increased proceptive behavior, while infusion of a D1 antagonist blocked the ability of METH to increase proceptive behaviors. Additionally, we found that METH-treatment increased progesterone receptor (PR)- immunoreactivity in the MePD, suggesting an interaction between dopamine and progesterone signaling. Indeed, infusions of the PR antagonist, RU486, prevented METH-induced increases in sexual behavior. Thus, taken together, the current findings suggest dopamine in the MePD modulates enhanced sexual motivation via an amplification of progesterone signaling and contributes to a better understanding of the neurobiology of drug-enhanced sexual behaviors.

The Role of Ovarian Hormones and the Medial Amygdala in Sexual Motivation

“…The MePD neurons express dopamine type 1 receptors (D 1 R) and α 1 noradrenergic receptors (102–104). Increased activation of D 1 R, in the MePD increases proceptive behaviors by 2.4 fold, similar to that displayed by animals that receive METH (96). Activation of either dopamine type 2 (D 2 R) receptors or α 1 receptors fails to increase proceptive behaviors.…”

“…Consistent with this role of enhancing the incentive salience, neurons of the MePD encode the intensity of the sexual stimulus in a graded manner (99, 100). In addition, lesions of the MePD do not abolish proceptive behaviors or approach behaviors in a paced-mating paradigm (96, 101). …”

“…In addition, the administration of ovarian hormones increases tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis, in the MePD (92). The MePD is necessary for the METH-induced enhancements of proceptive behaviors (96) and the display of ‘super-solicitational’ behaviors such the mounting the male rat in a naturally-occurring variant of Long Evans rats (97). Furthermore, within the MePD specific populations of neurons capable of responding to both METH and ovarian hormones mediate the heightened, but not baseline, sexually motivated behaviors (98).…”

“…Activation of either dopamine type 2 (D 2 R) receptors or α 1 receptors fails to increase proceptive behaviors. Ovarian hormones are also critical to increase the central sexual motivational state, and the combination of METH and ovarian hormones increases progestin receptors (PR) in the MePD (96). Activation of these PRs in the MePD is also necessary for the METH-induced heightened sexual motivation (96).…”

“…Ovarian hormones are also critical to increase the central sexual motivational state, and the combination of METH and ovarian hormones increases progestin receptors (PR) in the MePD (96). Activation of these PRs in the MePD is also necessary for the METH-induced heightened sexual motivation (96). Taken together, these data suggest that the MePD is a key region in a central state influenced by non-specific, or generalized, arousal and ovarian hormones that leads to increased sexual motivation.…”