Effects of Methoxamine and a-Adrenoceptor Antagonists, Prazosin and Yohimbine, on the Sleep-Wake Cycle of the Rat

Abstract

Summary: A study was carried out on the effects of methoxamine, prazosin, and yohimbine on the sleep-wake cycle in rats prepared for chronic sleep recordings. Methoxamine (4-8 mg/kg), an al-adrenoceptor agonist, induced a doserelated increase in wakefulness (W) and a decrease in slow-wave sleep (SWS) and REM sleep (REMS). Prazosin (0.125-1 mg/kg), which selectively blocks aladrenoceptors, modified only slightly the amount of time spent in Wand SWS, and consistently decreased REMS values. Prazosin (0.5 mg/kg) reversed the effects of methoxamine, decreasing Wand increasing sleep. Yohimbine (3 mg/kg), which blocks a2-adrenoceptors, augmented Wand diminished sleep. Methoxamine (4 mg/kg) in animals pretreated with yohimbine (3 mg/kg) induced a further decrease of SWS and REMS and an increase of W Thus, pharmacological activation of al-or blocking of a2-adrenoceptors appears to decrease sleep and increase W Further, blocking of al-adrenoceptors decreases REMS. Rapid eye movement sleep depression by the aI-agonist or the aI-antagonist is tentatively ascribed to a critical change in noradrenergic transmission in the brain. Key Words:Waking-Sleep--Methoxamine-Prazosin-Yohimbine.Intraventricular administration of adrenergic agonists of al-and a2-adrenoceptors (norepinephrine, epinephrine) produces a state of prolonged wakefulness (W) (I). Compounds that indirectly activate both noradrenergic and dopaminergic receptors (amphetamine, methylphenidate) also profoundly affect the sleep-wake cycle. As a result, slow-wave sleep (SWS) and REM sleep (REMS) are decreased and W is increased (2,3). Several other compounds including methoxamine also induce an increase of waking electroencephalography (EEG), which has been related to selective activation of al-adrenoceptors (4).The present study quantifies the effect of methoxamine on the sleep-wake cycle of the rat and attempts to ascertain the role of al-and a2-receptors in the methoxamine-induced disruption of the sleep-wake cycle. The effects of methoxamine were assessed after pretreatment with either prazosin, which selectively blocks al-adrenoceptors, or yohimbine, which behaves as an antagonist of a2-adrenoceptors.

Prazosin Effects on Objective Sleep Measures and Clinical Symptoms in Civilian Trauma Posttraumatic Stress Disorder: A Placebo-Controlled Study

“…These prazosin effects on sleep physiology are consistent with several studies in animals. Disruption of REM sleep by the alpha-1 adrenoreceptor agonist methoxamine was reversed by prazosin in several studies (27,28,29). REM sleep disruption induced by increasing CNS adrenergic activity with the NE reuptake inhibitor desipramine was reversed by prazosin but not by the beta adrenoreceptor antagonist propranolol (30).…”

Sleep loss and recovery after administration of drugs related to different arousal systems in rats

“…Systemic administration of excitatory α 1 -adrenoceptor antagonists, like prazosin (58), or agonists of the inhibitory α 2 -adrenoceptors, like guanfacine facilitate sleep (66). By contrast, antagonists of the α 2 -adrenoceptor, such as yohimbine, delay and suppress sleep (58), most likely by blocking the α 2 -type autoreceptors on NAerg neurons and enhancing NA release (68).…”

“…All drugs were dissolved in 0.4% methyl cellulose (Methocel F4M, Dow Chemical Company, USA) as vehicle. Drug doses were selected on the basis of previous literature data (49,58,72).…”

Prazosin for the Treatment of PTSD

“…Alpha-1 AR stimulation by NE increases release of the anxiogenic neuropeptide corticotrophin releasing factor (CRF) [23], decreases prefrontal cortex inhibition of "fight or flight" cognitive set [24], and increases acoustic startle response [25]. Stimulation of CNS alpha-1 AR disrupts REM sleep stage continuity, shortens REM and slow wave sleep durations, and increases stages 1 and 2 light sleep [11,12]. These effects of alpha-1 AR stimulation on sleep physiology favor emergence of trauma nightmares and reduction of restorative sleep [11,12,[26][27][28].…”

“…When stimulated by NE released from the diffuse projections of the pontine locus ceruleus, these central alpha-1 AR increase attention (especially to novel stimuli), level of arousal, and wakefulness [10]. When noradrenergic stimulation of alpha-1 AR is excessive, the results are hypervigilance, anxiety, irritability, lowered threshold for "fight or flight" cognitions and behaviors, reduced sleep duration, and rapid eye movement (REM) sleep disruption [11][12][13].…”