BENZODIAZEPINE ABUSE--HORMONES AND ELECTROPHYSIOLOGY

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The purpose of this study is to test the pharmacology of electrophysiological changes due to bendodiazepine (BDZ) administration after progesterone (P) withdrawal in female rats, a physiological model of PMs anxiety. The abuse potential for BDZs is two- to three times higher for women than men according to epidemiological studies, a phenomenon which may be related to female hormone effects on BDZ actions. A compelling reason to study BDZ effects during hormone withdrawal is that a metabolite of P, 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP or allopregnanolone) is one of the most potent modulators of the GABA-A/BDZ receptor complex reported to date, as revealed by results from this lab and others. A recent report from this lab has also demonstrated that withdrawal from P produces an increase in anxiety in a similar manner to withdrawal from other GABA-active drugs such as BDZ. For this study, cells from CA1 hippocampus will be acutely isolated from female rats chronically treated and withdrawn from P. BDZ modulation of GABA currents will then be compared across hormone state. In addition, the effects of BDZ inverse agonists and antagonists on GABA/BDZ current will also be examined during P withdrawal, as BDZ withdrawal has been associated with changes in responses to all three classes of BDZ drugs. In some cases, rats will be injected with an antagonist of the benzodiazepine, GABA-A or dihyroperidine calcium channel site in order to better elucidate the mechanism of action of P withdrawal on GABA-A/BDZ currents. Results will be compared with those from oil controls and from male rats. In addition, sedative potency and anxiolytic effects of BDZs such as lorazepam will also be compared before and after P withdrawal as a behavioral validation of the electrophysiological changes observed. Hippocampal levels of neuroactive metabolites such as 3alpha,5alpha-ThP will be assessed by RIA, and levels of GABA and serotonin in hip-campus will be assessed using chronic microdialysis techniques before and after progesterone withdrawal, as two collaborative efforts. Preliminary results suggest that P withdrawal reverses the normally potentiating effect of BDZ administration to an inhibitory effect at 24 but not 72 hs after P withdrawal. These results suggest that alterations in endogenous circulating steroid hormones may influence the abuse potential for BDZ in females.