STEROID REGULATION OF ION CHANNELS

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DESCRIPTION: (Applicant's abstract) The long-term goal of this project is to establish that region-specific and gender-specific differences in the expression of structurally and functionally distinct GABA-A receptors contribute to the generation of gender-specific behaviors. It is well established that gonadal steroids act to induce permanent (organizational) sexual dimorphisms in regions of the mammalian brain that provide the neural architecture underlying the generation of sexual behaviors. Specifically, many studies have strongly implicated GABAergic synaptic transmission within steroid-sensitive areas of the ventromedial nucleus (VMN) of the hypothalamus and preoptic area (POA) as playing a key role in mediating adult sexual behavior. Although the sexually dimorphic nature of these nuclei and the importance of GABAergic transmission within them to the control of adult sexual behaviors is indisputable, no published study to date has characterized either GABAA receptor function or gender-specific differences in GABAA receptor expression within these regions. To establish whether the ability of GABAergic agents to modify sexual behavior resides in the expression of structurally distinct GABA-A receptors within the VMN and POA, in situ hybridization and immunocytochemical techniques will be employed to analyze GABA-A receptor mRNA and subunit expression. To determine if differences in the expression of structurally different receptors result in gender- and region-specific differences in receptor function, sensitivity of GABA-A-dependent currents to allosteric modulators, whose actions are dependent upon subunit composition, will be assessed by whole-cell patch clamp analysis of VMN and POA neurons in intact slices and acutely dissociated cells. Finally, it is clear that the ability of an animal to generate appropriate sexual behaviors depends upon transient (activational) changes in neural transmission evoked by cyclical changes in gonadal steroids. The GABA-A receptor has been implicated as a target for activational actions of steroids in the generation of sexual behaviors. To establish that behavioral receptivity in female rats, which is induced by activational changes in steroids, is correlated with transient changes in GABA-A receptor expression and function, in situ hybridization and patch clamp analysis of neurons from the VMN and POA will be made for receptive (proestrus) and nonreceptive (diestrus) adult female rats subsequent to behavioral testing. Data from these experiments will provide important information on the neural substrates that underlie normal sexual behaviors, and may elucidate, in part, the biological basis for complex human attributes such as sexual orientation and transsexuality. In addition, results from these experiments may provide important information relevant to understanding gender-dependent differences in cognitive states, such as postpartum depression, and diseases, such as epilepsy, in which GABA-A receptors play a pivotal role.