ALPHA-2-ADRENERGIC MODULATION OF SLEEP - TIME-OF-DAY-DEPENDENT PHARMACODYNAMIC PROFILES OF DEXMEDETOMIDINE AND CLONIDINE IN THE RAT

Alpha adrenergic agonists such as clonidine are widely used for their antihypertensor effects, but they also cause sedation. The mechanisms underlying soporific effects of such compounds are poorly understood, but appear to involve the alpha-2 adrenergic receptor sub-type. To fur ther investigate the role of this receptor in sleep-wake regulation, r ats received injections i.p. either during their peak of activity (cir cadian time CT-18: 6 hr after lights out) or near the mid-point of the ir sleep-dominated phase (CT-5: 5 hr after lights on) with either the highly selective alpha-2 agonist dexmedetomidine (dMED) 0.02 to 0.04 m g/kg or the less selective alpha-2 agonist, clonidine 0.04 to 0.08 mg/ kg, or vehicle. Clonidine and dMED showed remarkable overall similarit ies in their soporific profiles. Except for the lower dose of clonidin e, both CT-5 and CT-18 treatments increased the percent of time spent in non-REM (NREM) sleep. The increase in NREM was followed by a reduct ion of NREM sleep that was accompanied by locomotor activity and body temperature above control levels. After CT-5 treatments, this period o f reduced NREM sleep was followed by a secondary increase in NREM 7 to 10 hr posttreatment. REM sleep was markedly reduced for 9 to 10 hr af ter all treatments at both times of day, with elevated REM levels 18 t o 30 hr posttreatment. Pre-treatment with the selective alpha-2 antago nist atipamezole (0.5 mg/kg) reversed the effects of CT-18 dMED 0.04 m g/kg except REM sleep suppression, which was only partially reversed. The NREM-inducing potency of dMED 0.02 mg/kg was greater when administ ered at CT-18 than at CT-5. Taken together with other evidence, these findings suggest that the profound NREM-inducing effects of dMED may b e mediated by postsynaptic alpha-2 adrenoceptors, Furthermore, the pha rmacodynamic action of alpha-2 adrenergic agonists, like many other se dative hypnotics (e.g., benzodiazepines), produce a hysteresis in slee p-wake regulation characterized by ''rebound'' waking after drug-induc ed sleep.