Synergistic behavioral interaction between ethanol and clonidine in rats: role of alpha-2 adrenoceptors.
Activation of central alpha-2 adrenoceptor leads to a sleep-like state. The present study investigated the effect of ethanol on the loss of the righting reflex (LORR) and hypotension evoked by clonidine in Sprague-Dawley rats. Clonidine at 30 micrograms/kg had no effect on righting reflex, but a higher dose (60 micrograms/kg) elicited variable LORR that averaged 6.5 +/- 4.1 min. Similarly, 0.5 g/kg of ethanol elicited little effect (0.17 +/- 0.17 min), but a higher dose (1 g/kg) produced 2.5 +/- 1.1 min of LORR. Ethanol (0.5 g/kg), combined with the lower dose of clonidine, still had little effect on LORR, but when combined with the higher dose of clonidine the LORR (34.8 +/- 6.5 min) became significantly (P < .01) greater than the sum of the individual effects. Similarly, rats that received a combination of the higher dose (1 g/kg) of ethanol and lower dose (30 micrograms/kg) of clonidine exhibited significantly (P < .01) greater LORR (18.6 +/- 2.5 min) than the sum of individual effects. These findings suggest a synergistic interaction that is dose-related. The alpha-2 adrenoceptor antagonist yohimbine (1 mg/kg), or a mixed antagonist of imidazoline and alpha-2 adrenoceptors, idazoxan (60 micrograms/kg), counteracted the synergistic interaction between ethanol and clonidine on LORR; yohimbine was more effective than idazoxan, but the difference was not significant. Ethanol counteracted the hypotensive effect of clonidine and significantly (P < .05) increased blood pressure to levels higher than preclonidine and corresponding control values. Therefore, the synergistic interaction on LORR cannot be accounted for by an enhanced hypotensive response to clonidine. Furthermore, idazoxan counteracted the hypotensive response to clonidine more effectively than did yohimbine. Taken together, the findings suggest: 1) ethanol differentially influences the sedative (synergistic interaction) and hypotensive (antagonistic interaction) effects of clonidine; 2) the synergistic behavioral interaction is dose-related and involves, at least in part, central alpha-2 adrenoceptors; and 3) the hypotensive effect of clonidine is primarily mediated via imidazoline receptors.
Mao
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Department of Pharmacology, School of Medicine, East Carolina University, Greenville, North Carolina, USA.
Abdel-Rahman
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D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects; D003000:Clonidine / Q000494:pharmacology*; D004357:Drug Synergism; D000431:Ethanol / Q000494:pharmacology*; D019329:Idazoxan / Q000494:pharmacology; D054755:Imidazoline Receptors; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000502:physiology*; D011955:Receptors, Drug / Q000502:physiology; D012018:Reflex / Q000187:drug effects; D015016:Yohimbine / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D054755:Imidazoline Receptors; D018341:Receptors, Adrenergic, alpha-2; D011955:Receptors, Drug; D015016:Yohimbine; D000431:Ethanol; D003000:Clonidine; D019329:Idazoxan