Sleep produced by clonidine (2‐(2,6‐dichlorophenylamino)‐2‐imidazoline hydrochloride)

Abstract

Summary1. The dose of clonidine (given intravenously) required to elicit sleep in the young chick is 1/25th to 1/50th of an equiactive dose of noradrenaline. The approximate ED50 is 0-01 umol/kg. Phentolamine (10-15 mg/kg, but not 5 mg/kg) antagonizes the action of both clonidine and noradrenaline. 2. Intensive treatment with p-chlorophenylalanine (700 mg/kg for 3-4 days) does not prevent the hypnotic effect of clonidine in the chick, although brain 5-HT is reduced to 15% of normal. Neither is natural sleep modified.3. Sleep after clonidine is not affected by methysergide (0 1-1 ,umol/kg, i.m.), but prevented by LSD (0-1-03 Amol/kg). The effect of LSD is interpreted-as a physiological antagonism. 4. Clonidine (50 mg/kg) injected intravenously into adult rats causes sleep which is not abolished by phentolamine (5 mg/kg) or by p-chlorophenylalanine in doses which interfere with natural sleep. 5. When, per kg body weight, the same dose of clonidine is injected into the lateral cerebral ventricle of rats, sleep ensues in more than half the animals, and persistent eating in about a third; only one -of seventeen rats showed no change in behaviour. Eating and sleeping remained unaltered after p-chlorophenylalanine. The actual dose of clonidine injected into the lateral ventricle was 0 037 ,umol, amounting to about 0 15 ptmol/kg or 15 times the dose required intravenously in the chick. Noradrenaline 0S15 ttmol per (intraventricular) injection caused eating but no sleep, whereas higher doses produced ataxia and paresis. 6. The work suggests that clonidine does not elicit sleep by an action requiring the integrity of the 5-HT-containing neurones arising in the raphe nuclei, and that its action is not on tryptamine receptors. In the chick, sleep appears to be produced by a central sympathomimetic effect; it is possible, but not certain, that this also holds for the rat. 7. The intravenous hypnotic dose of clonidine for the cat is about the same as that for the rat, but injection is not accompanied by signs of peripheral sympathetic stimulation.

HISTAMINE H2‐RECEPTORS IN THE BRAIN AND SLEEP PRODUCED BY CLONIDINE

“…In an earlier paper (Holman, Shillito & Vogt, 1971) an attempt was made to determine whether the sleep induced in chicks by intravenous injection of clonidine (Zaimis, 1970) can be considered to be an effect on central noradrenaline receptors. Although the results were compatible with that view, the antagonism between clonidine and blockers of a-adrenoceptors was only partial, a dose of phentolamine 40 jmol/kg reducing, but not abolishing, the effect of clonidine 0.04 gmol.…”

Central Effects of Clonidine 2‐(2,6‐dichlorophenylamino)‐2‐imidazoline Hydrochloride in Fowls

“…It readily crosses the blood-brain barrier chickens. Intravenous clonidine induced sleep in and given intravenously, induced sleep in adult rats young chicks (Zaimis, 1970) indistinguishable and cats (Holman et al, 1971). This was an from normal sleep and that elicited by intravenous important finding because of the controversy as to noradrenaline or adrenaline (Holman et al, 1971); the hypnotic potency of clonidine was 25 or 30 times that of noradrenaline.…”

“…Intravenous clonidine induced sleep in and given intravenously, induced sleep in adult rats young chicks (Zaimis, 1970) indistinguishable and cats (Holman et al, 1971). This was an from normal sleep and that elicited by intravenous important finding because of the controversy as to noradrenaline or adrenaline (Holman et al, 1971); the hypnotic potency of clonidine was 25 or 30 times that of noradrenaline. Effects of intraventricular clonidine on body temperature of sheep and goats, exposed to different ambient temperatures, were similar to those resulting with larger intraventricular doses of noradrenaline (Maskrey, Vogt & Bligh, 1970).…”

“…Indeed, sleep with slow wave electrocortical activity was induced in fowls both by centrally applied noradrenaline (Grunden & Marley, 1970;Marley & Stephenson, 1970;Marley & Nistico, 1972) or 5-hydroxytryptamine (Marley & Nistico, 1975;Marley & Whelan, 1975a), providing grounds for assuming involvement of noradrenergic as well as 5-hydroxytryptaminergic systems. Since clonidine elicited sleep in rats previously rendered awake by p-chlorophenylalanine, Holman et al (1971) concluded it was not mediated through the ascending 5-hydroxytryptaminergic system. 'Wakefulness' induced by p-chlorophenylalanine is one of the strongest pieces of evidence for implicating 5-hydroxytryptamine in electrocortical slow wave sleep; however, any assumption that this can be equated with normal wakefulness has been vigorously criticized (Rechtschaffen, Lovell, Freedman, Whitehead & Aldrich, 1973), and to complicate interpretation, p-chlorophenylalanine has pharmacological actions other than tryptophan hydroxylase inhibition (Marley & Whelan, 1975b Deighton & Hutchinson, 1940).…”

“…Clonidine has sympathomimetic properties the significance of sleep produced by norascribed to an action on peripheral and central adrenaline given into the brain; noradrenaline also ca-adrenoceptors (Nayler, Price, Swann, McInnes, acts on peripheral a-adrenoceptors but does not Race & Lowe, 1968;Holman, Shillito & Vogt, cross the blood-brain barrier, except in young 1971). It readily crosses the blood-brain barrier chickens.…”