The acute and chronic effects of psychostimulants, such as cocaine and amphetamine derivatives, are more pronounced in females than males. There is evidence to suggest that these gender differences are hormonally, rather than developmentally, based. The long-term goal of this project is to determine the cellular and molecular substrates that underlie the modulation of stimulant-induced behaviors by the female sex hormones estrogen (E) and progesterone (P). In the present proposal, we will test the hypothesis that the interaction of sex hormones with serotonin (5-HT) function lays the foundation for the behavioral response to cocaine; the actions of cocaine to inhibit 5-HT reuptake contribute to its behavioral effects while inhibition of dopamine (DA) reuptake is defined as a primary mediator. Hormone levels will be controlled experimentally using groups of female rats that have undergone ovariectomy (OVX), with or without replacement with E and P.
In Specific Aim 1, molecular biology approaches will be used to assess the impact of ovarian steroids on steady-state levels of the 5-HT transporter mRNA in midbrain and 5-HT1A, 5-HT1B, and 5-HT2c receptor mRNA in reward-relevant brain areas. The concomitant effects of these treatments on levels of mRNA for DA transporter, DA1 and DA2 receptors, and E and P receptors will also be determined. Behavioral and pharmacological tools will be used to assess the relative contribution of 5-HT1A, 5-HT1B, and 5-HT2C receptors to the locomotor stimulation (Specific Aim 2) and sensitization (Specific Aim 3) induced by cocaine in the face of given hormone environments.
In Specific Aim 4, the functional significance of sex hormone and 5-HT interactions will be assessed in the drug discrimination paradigm to provide an animal model of the """"""""subjective"""""""" effects of cocaine. Intact or OVX female rats will be trained to discriminate cocaine from saline and the neuropharmacological profile will be investigated using specific 5-HT and DA agonists and antagonists in the absence and presence of ovarian hormones. A comparative study of the locomotor stimulatory, sensitization and discriminative stimulus effects of the abused amphetamine derivative (+/-)-3,4-methylenedioxymethamphetamine (MDMA) will be conducted in parallel groups of rats to assess the generality of hormonal regulation to another psychostimulant, one whose behavioral effects are thought to be mediated in large part by 5-HT mechanisms. The results of these studies will provide important information concerning the fundamental mechanisms underlying both steroid-5-HT interactions and gender differences in the responsivity to psychostimulants. As a consequence, new insight into potential therapeutic strategies for drug dependence in women as well as the enhanced vulnerability of women to mood and anxiety disorders will be obtained.
