Effects of methoxamine, an alpha‐1 adrenoceptor agonist, and prazosin, an alpha‐1 antagonist, on the stages of the sleep—waking cycle in the cat

Abstract

In these experiments the effects of alpha 1-adrenoceptor agonism and antagonism were studied on the stages of the sleep-waking cycle of the cat, in order to determine optimal levels of alpha 1-adrenergic transmission for these stages. Polygraphic 16-h recordings showed that prazosin, an alpha 1-adrenoceptor antagonist, at 1 mg/kg i.p., increased paradoxical sleep (PS) time from 15.3% to 26.4% (p less than 0.001) of total time, and the number of PS episodes from 30.4 to 43.6 (p less than 0.001). The effect was prompt, reaching a maximum during the first 4 h with a shortening of PS latency from 40.4 min to 11.0 min (p less than 0.001). Prazosin at doses of 0.5 and 3.0 though not at 10.0 mg/kg also slightly, but significantly, increased PS. Methoxamine, and alpha 1-adrenoceptor agonist, at doses of 0.5 and 3.0 mg/kg, increased aroused waking time (low voltage mixed frequency EEG) during the first 4 h from 23.5% to 33.3% (p less than 0.05) and to 50.3% (p less than 0.01), and decreased PS. Prazosin potentiated dose-dependently clonidine-induced drowsiness ( hypersynchronized 4-8 Hz EEG), whereas the decrease in deep slow wave sleep and PS were potentiated only at the largest dose of it. These results indicate that moderate inhibition of cerebral alpha 1-adrenergic transmission facilitates paradoxical sleep in the cat. Furthermore, they suggest that the level of cerebral alpha 1-adrenergic transmission is high during aroused waking and low during drowsy waking.

Relationships between REM sleep findings and PTSD symptoms during the early aftermath of trauma

“…Targeting REM sleep disruption may be important for having therapeutic impact on sleep disturbance in the aftermath of trauma. This hypothesis is supported by recent observations of that prazosin, a medication that interferes with suppression of REM sleep from noradrenergic stimulation in an animal model (Hilakivi & Leppavuori, 1984), alleviates traumarelated nightmares and sleep disruption in chronic PTSD (Raskind et al, 2003). The similar benefits documented for treatment involving exposure and habituation to recurrent nightmare content (Krakow et al, 2001) could also involve reducing arousals from REM sleep.…”

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).…”

Distribution of ?1A adrenergic receptor m RNA in the rat brain visualized by in situ hybridization

“…Any of the three ␣ 1 receptor subtypes potentially could participate in these modulatory effects on cortical cellular activity and transmission. At a more behavioral level, the widespread cortical expression of ␣ 1 receptors is also most likely responsible for the activation of cortical EEG and the behaviorally arousing effects of ␣ 1 receptor stimulation, and conversely for the sedative effects of ␣ 1 receptor blockade (Guo et al, 1991;Hilakivi and Leppavuori, 1984;Hilakivi-Clarke et al, 1991). While specific roles for the different ␣ 1 receptor subtypes in modulating neocortical activity cannot be inferred from their similarly diffuse distribution, in the more primitive piriform cortex there is an apparently exclusive expression of the ␣ 1A receptor message as compared to the ␣ 1B and ␣ 1D receptor subtypes (McCune et al, 1993;Pieribone et al, 1994).…”