Role of the GABAA system in behavioral, motoric, and cerebellar protection by estrogen during ethanol withdrawal.
Results of studies from our laboratory have shown that administration of 17beta-estradiol (E(2)) reduces cerebellar neuronal damage during ethanol withdrawal (EW). In the current study, we investigated whether the GABAergic system is involved in the protective effects of E(2) against the EW syndrome. To test this hypothesis, we examined the effects of GABAergic drugs, with and without E(2), on EW sign scores, motoric capacity, and caspase activation. Ovariectomized rats implanted with an E(2) or an oil pellet received liquid ethanol [7.5% weight/volume (wt./vol.)] for 5 weeks or dextrin diet, followed by 2 weeks of EW. A gamma-aminobutyric acid type A (GABA(A)) agonist, muscimol (0.125 or 0.25 mg/kg), and antagonist, bicuculline (1.25 mg/kg), were administered (intraperitoneally; three times a day for 4 days) starting 1 day before the onset of EW. On termination of chronic administration of ethanol diet, rats were tested for overt withdrawal signs and latency to fall from a rotarod. The initial latency was measured separately to assess motoric capacity before learning occurred. Cerebelli were subsequently collected for immunohistochemistry to detect caspase activation. Results showed that treatment with E(2) lowered EW sign scores and improved initial as well as subsequent rotarod latencies compared with findings without treatment with E(2) (control group). These effects of E(2) were enhanced by combined treatment with muscimol and diminished by bicuculline. Results also showed that ethanol-withdrawn rats had more caspase-3-positive cells than observed for the dextrin diet-fed group in a manner reversed by E(2) and exacerbated by bicuculline. Bicuculline also caused partial antagonism of the protective effect of E(2). These findings support the suggestion that GABA(A) agonists ameliorate, and GABA(A) antagonists exacerbate, EW signs, cerebellar neuronal damage, and motoric impairment in ethanol-withdrawn rats. Also, results of the current study provide indirect evidence that the GABAergic system is involved in protective effects of E(2) against the EW syndrome.