A HYPNOTIC RESPONSE TO DEXMEDETOMIDINE, AN ALPHA-2 AGONIST, IS MEDIATED IN THE LOCUS-CERULEUS IN RATS

Dexmedetomidine, the highly selective alpha-2-adrenergic agonist, produces a dose-dependent hypnotic response in rats through a central mechanism. Because the locus coeruleus (LC) contains pathways involved in the maintenance of vigilance and a high prevalence of alpha-2-adrenoceptors, we investigated the role of this brainstem nucleus in the hypnotic response to dexmedetomidine. The experimental model consisted of chronic, stereotactically cannulated rats (n = 157) in which the hypnotic response to dexmedetomidine was assessed by the duration of the loss of their righting reflex. Correct placement of the cannula was confirmed histologically at necropsy. The hypnotic response to dexmedetomidine 0.3 - 333.3-mu-g administered into the LC increased in a dose-dependent fashion. Dexmedetomidine 6.6-mu-g injected 2 mm lateral to the LC did not cause the animals to lose their righting response. Atipamezole 0.07-mu-g - 12-mu-g, a selective alpha-2-adrenergic antagonist, blocked the hypnotic response to dexmedetomidine 6.6-mu-g when both were administered into th, LC. Also, atipamezole 0.7 - 30-mu-g, administered into the LC, blocked in a dose-dependent manner the hypnotic response to intraperitoneal (ip) dexmedetomidine 50-mu-g.kg-1. Atipamezole injected into the LC did not block the hypnotic response to pentobarbital 40 mg.kg-1 ip. Prazosin, an alpha-1-adrenergic antagonist, 4.2-mu-g into the LC or 1.0 mg.kg-1 ip, did not alter the hypnotic response to dexmedetomidine 6.6-mu-g into the LC. The present data suggest that alpha-2-adrenergic receptors in the LC appear to be a major site for the hypnotic action of dexmedetomidine. This discrete region can now be probed with specific toxins in order to define the postreceptor molecular components involved in the transduction mechanism for the hypnotic response to alpha-2-adrenergic agonists.