Evidence for central alpha-2 adrenoceptors, not imidazoline binding sites, mediating the ethanol-attenuating properties of alpha-2 adrenoceptor antagonists.
The role of central adrenoceptors in the ethanol-attenuating effects of alpha-2 adrenoceptor blockers was investigated in mice; the centrally active antagonist atipamezole was compared with L 659,066, which penetrates the brain poorly. L 659,066 (1-10 mg/kg) had no effect on the hypothermia induced by ethanol (2 g/kg) or ethanol ataxia (2.4 g/kg), whereas atipamezole (1 mg/kg) significantly attenuated both ethanol-induced hypothermia and ataxia. Atipamezole (1-3 mg/kg) significantly attenuated the ethanol-induced reduction in exploratory head-dipping in a holeboard test whereas L 659,066 was only effective at a dose of 1 mg/kg, higher doses (3 and 10 mg/kg) and a lower dose (0.3 mg/kg) were ineffective. Atipamezole was without effect on ethanol's locomotor stimulant effect in the holeboard but L 659,066 attenuated this effect at doses less than 3 mg/kg Many alpha-2 adrenoceptor ligands also have affinity for nonadrenergic imidazoline-binding sites. The role these sites may play in attenuating ethanol's effects was investigated by comparing RX 821002 (methoxy idazoxan), which has little or no affinity for imidazoline-binding sites with atipamezole. Both atipamezo 1 e (1 mg/kg) and RX 821002 (0.06-0.2 mg/kg) significantly attenuated ethanol-induced hypothermia, ataxia and reduction in head-dipping, but were without effect on ethanol-induced locomotor stimulation. These results suggest that nonadrenergic imidazoline-binding sites are not implicated in the ethanol-attenuating properties of alpha-2 adrenoceptor antagonists.
Laboratory of Clinical Studies, National Institute on Alcohol Abuse & Alcoholism, Bethesda, Maryland.
M J
MJ
Durcan
R G
RG
Lister
M
M
Linnoila
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001259:Ataxia / Q000139:chemically induced; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D004146:Dioxanes / Q000494:pharmacology; D000431:Ethanol / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D019329:Idazoxan / Q000031:analogs & derivatives; D007093:Imidazoles / Q000494:pharmacology*; D054755:Imidazoline Receptors; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D011807:Quinolizines / Q000494:pharmacology*; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects* / Q000502:physiology; D011955:Receptors, Drug / Q000187:drug effects* / Q000502:physiology
D000317:Adrenergic alpha-Antagonists; D004146:Dioxanes; D007093:Imidazoles; D054755:Imidazoline Receptors; D011807:Quinolizines; D011942:Receptors, Adrenergic, alpha; D011955:Receptors, Drug; C050701:atipamezole; C055732:vatinoxan; D000431:Ethanol; C058525:2-methoxyidazoxan; D019329:Idazoxan