TY - JOUR
T1 - Role of the GABAA system in behavioral, motoric, and cerebellar protection by estrogen during ethanol withdrawal
AU - Rewal, Mridula
AU - Jung, Marianna E.
AU - Wen, Yi
AU - Brun-Zinkernagel, Anne Marie
AU - Simpkins, James W.
N1 - Funding Information:
This work was supported by the Pharmacology & Neuroscience Department at the University of North Texas Health Science Center at Fort Worth.
PY - 2003
Y1 - 2003
N2 - 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 (GABAA) 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 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 Results also showed that ethanol-withdrawn rats had more caspase-3-positive cells than observed for the dextrin diet-fed group in a manner reversed by E2 and exacerbated by bicuculline. Bicuculline also caused partial antagonism of the protective effect of E2. These findings support the suggestion that GABAA agonists ameliorate, and GABAA antagonists exacerbate, EW signs, cerebellar neuronal damage, and motoric impairment in ethanol-withdrawn rats.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.
AB - 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 (GABAA) 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 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 E2 and exacerbated by bicuculline. Bicuculline also caused partial antagonism of the protective effect of E2. These findings support the suggestion that GABAA agonists ameliorate, and GABAA 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.
KW - 17β-Estradiol
KW - Ethanol withdrawal
KW - GABA system
UR - http://www.scopus.com/inward/record.url?scp=0242690901&partnerID=8YFLogxK
U2 - 10.1016/j.alcohol.2003.07.005
DO - 10.1016/j.alcohol.2003.07.005
M3 - Article
C2 - 14615011
AN - SCOPUS:0242690901
SN - 0741-8329
VL - 31
SP - 49
EP - 61
JO - Alcohol
JF - Alcohol
IS - 1-2
ER -