Role of the GABAA system in behavioral, motoric, and cerebellar protection by estrogen during ethanol withdrawal

Rewal, Mridula; Jung, Marianna E.; Wen, Yi; Brun-Zinkernagel, Anne-Marie; Simpkins, James W.

doi:10.1016/j.alcohol.2003.07.005

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Volume 31, Issue 1 , Pages 49-61, August 2003

Role of the GABA_A system in behavioral, motoric, and cerebellar protection by estrogen during ethanol withdrawal

Mridula Rewal
- Department of Pharmacology and Neuroscience, University of North Texas HSC at Fort Worth, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107-2699, USA
- Corresponding author. Tel.: +1-817-735-0156; fax: +1-817-735-2091.
Marianna E. Jung
- Department of Pharmacology and Neuroscience, University of North Texas HSC at Fort Worth, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107-2699, USA
Yi Wen
- Department of Pharmacology and Neuroscience, University of North Texas HSC at Fort Worth, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107-2699, USA
Anne-Marie Brun-Zinkernagel
- Department of Pathology and Anatomy, University of North Texas HSC at Fort Worth, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107-2699, USA
James W. Simpkins
- Department of Pharmacology and Neuroscience, University of North Texas HSC at Fort Worth, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107-2699, USA

Received 19 February 2003; received in revised form 16 June 2003; accepted 6 July 2003.

Editor: T.R. Jerrells

Abstract

Results of studies from our laboratory have shown that administration of 17β-estradiol (E₂) 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 E₂ against the EW syndrome. To test this hypothesis, we examined the effects of GABAergic drugs, with and without E₂, on EW sign scores, motoric capacity, and caspase activation. Ovariectomized rats implanted with an E₂ 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 E₂ lowered EW sign scores and improved initial as well as subsequent rotarod latencies compared with findings without treatment with E₂ (control group). These effects of E₂ 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 E₂ and exacerbated by bicuculline. Bicuculline also caused partial antagonism of the protective effect of E₂. 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 E₂ against the EW syndrome.