in the United States of America, 36% of cocaine users are women. Accumulating evidence suggests that there are sex differences in the behavioral response to cocaine, where overall, female rats display more hyperactivity and exaggerated behavioral responses to cocaine as well as develop a longer-lasting and more robust behavioral sensitization to cocaine than male rats. These observations suggest that a complex process that depends on a wide range of physiological, neuronal, and hormonal interactions mediate cocaine-induced effects. Although great advances have been made in understanding molecular and behavioral adaptations after cocaine administration, very little is known about physiological and behavioral effects of cocaine in females. Females have a complex endocrinological profile; where sex/gonadal steroids (estrogen and progesterone) regulate the female's neuronal activity, many reproductive behaviors, and the synthesis and secretion of several neurotransmitters (including the opioid, monoamergic, and glutamatergic systems), affect neural circuitry during development and adulthood and control reward and motivational feedback systems. There is accumulating evidence which suggests that estrogen and progesterone affect cocaine-induced behavioral alterations. Our hypothesis is that estrogen and progesterone will potentiate or inhibit the behavioral, neurochemical, endocrinological and molecular responses to cocaine via activation of membrane and genomic receptor mediated mechanisms. Moreover, each steroid receptor isomer (beta - and alpha -estrogen receptor as well as A- and B-progesterone receptors) will differentially induce or inhibit cocaine responses. And this, in turn, regulates sex differences in the behavioral and subjective effects of cocaine. To test this postulate we propose two aims: (1) To allow us to use transgenic receptor knockout mice to examine the contributions of the various receptors, we will first determine whether the behavioral responses of female mice to cocaine are modulated by circulating gonadal steroids as they are in female monkeys, rats and humans. We will then use receptor knockout mice to determine how these genetic mutations affect females' responses to cocaine and the ability of estrogen and progesterone to modulate these responses. 2) Using different periods of steroid administration, different steroid antagonists, and steroid analogs, which do not activate intracellular receptors, we will examine whether these hormones are acting through membrane or classic intracellular steroid receptors. This study has obvious clinical implications since women's responses to cocaine may be modified by stage of the menstrual cycle, the use of hormone-containing drugs such as birth control pills, or whether she is menopausal. Variation in endocrine status may affect critical measures such as the tendency to administer an overdose and the development of tolerance and sensitization to cocaine. This important clinical issue in females needs further investigation.
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