Modification of certain pharmacological effects of ethanol by lipophilic alpha-1 adrenergic agonists

The influence of four centrally-acting alpha-1 adrenoceptor agonists, namely, 2(2-chloro-5-trifluoromethylphenylimino) imidazolidine (St 587), cirazoline, (-) 1,2,3,4-tetrahydro-8-methoxy-5-methylthio-2-naphthalenamine ((-)SKF 89748A) and 2-(2-methylindazol-4-imino)imidazolidine (Sgd 101/75) on the pharmacological effects of ethanol was investigated. All four drugs reduced the duration of ethanol-induced hypnosis in C57B1/6 mice, this effect being proportional to their relative potencies to exert central alpha-1 agonism. In prazosin-pretreated mice, St 587 failed to reduce the hypnotic effect of ethanol, which provided strong evidence for the role of alpha-1 agonism for the hypnosis reducing effect of St 587. Hyperactivity induced in C57B1/6 mice by a subhypnotic dose of ethanol and St 587 was reported earlier. In the present study, St 587, cirazoline and (-)SKF 89748A produced similar response, but no correlation between this effect and ethanol hypnosis blockade could be established. Interestingly, this hyperactivity response was not exhibited by Swiss-Webster, BALB/c or DBA-2 mice--strains in which St 587 exerted little or no antagonism to ethanol-induced hypnosis. Of the alpha-1 agonists, only St 587 reduced the ethanol-induced hypothermia in C57B1/6 mice. St 587 also blocked this effect of ethanol in BALB/c mice in which this drug failed to reduce the ethanol-induced hypnosis. It was concluded that ethanol-induced hypothermia and hypnosis are not interrelated. None of the alpha-1 agonists modified the pentobarbitone-induced hypnosis or the rate of elimination of ethanol in C57B1/6 mice. In this strain, the reduction of the duration of ethanol-induced hypnosis by the alpha-1 agonists is a selective and centrally-mediated response.