title: Alpha-2 adrenergic modulation of sleep: time-of-day-dependent pharmacodynamic profiles of dexmedetomidine and clonidine in the rat.
abstract: 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 further investigate the role of this receptor in sleep-wake regulation, rats received injections i.p. either during their peak of activity (circadian time CT-18: 6 hr after lights out) or near the mid-point of their 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 mg/kg or the less selective alpha-2 agonist, clonidine 0.04 to 0.08 mg/kg, or vehicle. Clonidine and dMED showed remarkable overall similarities in their soporific profiles. Except for the lower dose of clonidine, 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 reduction of NREM sleep that was accompanied by locomotor activity and body temperature above control levels. After CT-5 treatments, this period of 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 after all treatments at both times of day, with elevated REM levels 18 to 30 hr posttreatment. Pre-treatment with the selective alpha-2 antagonist atipamezole (0.5 mg/kg) reversed the effects of CT-18 dMED 0.04 mg/kg except REM sleep suppression, which was only partially reversed. The NREM-inducing potency of dMED 0.02 mg/kg was greater when administered at CT-18 than at CT-5. Taken together with other evidence, these findings suggest that the profound NREM-inducing effects of dMED may be mediated by postsynaptic alpha-2 adrenoceptors. Furthermore, the pharmacodynamic action of alpha-2 adrenergic agonists, like many other sedative hypnotics (e.g., benzodiazepines), produce a hysteresis in sleep-wake regulation characterized by "rebound" waking after drug-induced sleep.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, California, USA.
authors.forename: W F
authors.initials: WF
authors.lastname: Seidel
authors.forename: M
authors.initials: M
authors.lastname: Maze
authors.forename: W C
authors.initials: WC
authors.lastname: Dement
authors.forename: D M
authors.initials: DM
authors.lastname: Edgar
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002940:Circadian Rhythm / Q000502:physiology*; D003000:Clonidine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004569:Electroencephalography / Q000187:drug effects; D006993:Hypnotics and Sedatives / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007093:Imidazoles / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008297:Male; D020926:Medetomidine; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology*; D012890:Sleep / Q000187:drug effects* / Q000502:physiology*; D012895:Sleep, REM / Q000187:drug effects
chemical_list: D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D006993:Hypnotics and Sedatives; D007093:Imidazoles; D018341:Receptors, Adrenergic, alpha-2; C050701:atipamezole; D003000:Clonidine; D020926:Medetomidine