Changes in ovarian hormones across the menstrual cycle can impact upon responses to cocaine in women. Studies have shown that responses to cocaine are dampened during the luteal phase of the menstrual cycle, when estrogen and progesterone concentrations are high, relative to the other phases of the cycle, when concentrations of these hormones are relatively low. We have posited that the basis for attenuated responses to cocaine is the dopamine-antagonist effects of progesterone. As a first step to confirming our hypothesis, the proposed studies will examine the effects of exogenously administered progesterone, alone and in combination with estrogen, on subjective and physiological responses to smoked cocaine in women. Exogenous progesterone and estrogen will be administered during the follicular phase, which will enable us to examine their effects relatively unconfounded by possible interactions with endogenous hormones. Two studies are being proposed in this revised application. The first study will be a mixed within- and between-subjects, placebo-controlled inpatient study designed to characterize the effects of 0, 200 mg and 400 mg micronized progesterone on responses to and self-administration of placebo, 0.2 mg/kg and 0.4 mg/kg smoked cocaine in 36 women who abuse cocaine. The second study will also be a mixed within- and between-subjects experiment (N=36), in which responses to cocaine will be evaluated after pretreatment with progesterone (dose determined by Experiment 1) in combination with estrogen (0, 0.05 mg/day and 0.10 mg /day) in female cocaine abusers. The effects of estrogen alone will also be studied. We predict that progesterone will attenuate and estrogen will enhance responses to cocaine, and furthermore expect that the effects of progesterone may be more apparent in the presence of estrogen. The results of these studies, taken together, are expected to provide insight into the basis of menstrual cycle phase and perhaps gender differences on responses to cocaine, and may be relevant to the development of treatments targeted to female cocaine abusers.
