Daniel Monti

Sleep and waking during acute histamine H3 agonist BP 2.94 or H3 antagonist carboperamide (MR 16155) administration in rats.

The present study evaluated the effects of histamine H3 receptor agonist BP 2.94 or H3 receptor antagonist carboperamide (MR 16155) given by oral route on sleep and waking in rats surgically prepared for long-term recordings.BP 2.94 produced a significant increase of slow-wave sleep (SWS) that was related to slight decreases of waking, light sleep, and REM sleep. Carboperamide significantly increased waking and decreased SWS and REM sleep. Pretreatment with carboperamide prevented the effect of BP 2.94 on SWS.It is suggested that the effects of BP 2.94 or carboperamide on sleep and waking could depend on changes in the availability of histamine at the postsynaptic H1 receptor. Alternatively, activation or blockade of the H3 heteroreceptors found in the central catecholamine, indolamine, and acetylcholine nerve endings could inhibit or increase the release of noradrenaline, serotonin, dopamine, and acetylcholine. This would secondarily result in changes of sleep variables.

The effects of moclobemide on nocturnal sleep of depressed patients.

The effect of moclobemide, a short-acting, reversible, preferential type-A MAO inhibitor (300 mg daily in three divided doses), on the sleep of eight depressed patients was assessed by polysomnographic recordings in a 4-week therapeutic trial. Six patients showed an improvement greater than 50% on the Hamilton Depression Rating Scale. Compared to placebo, patients receiving moclobemide showed improved sleep continuity as judged by the decrease in wake time after sleep onset and total wake time, particularly during the intermediate and late stages of drug administration. Total sleep time increase was comprised of larger amounts of stage 2 NREM sleep. REM sleep latency was significantly increased and REM sleep % decreased during the drug administration period. However, in contrast to the older, non-selective and selective MAOIs, moclobemide had a mild REM sleep suppressant effect.

Effects of selective activation of the 5-HT1B receptor with CP-94,253 on sleep and wakefulness in the rat.

The effects of the 5-HT1B receptor agonist CP-94,253 were compared with those of the mixed beta-adrenoceptor and 5-HT1A/B receptor antagonist (+/-)pindolol in rats implanted for chronic sleep recordings. CP-94,253 (5.0-10.0 mg/kg) significantly increased waking and reduced slow wave sleep (SWS) and REM sleep (REMS). At 2.0-4.0 mg/kg (+/-)pindolol reduced REMS. Pretreatment with (+/-)pindolol (2.0-4.0 mg/kg) reversed the effect of CP-94,253 on waking and SWS, while REMS remained suppressed. It is suggested that the 5-HT1B receptor together with other 5-HT receptor subtypes may have a direct regulatory action on sleep and waking in the rat.

Pharmacological Treatment of Chronic Insomnia

SummaryInsomnia is defined as the inability to get the amount or quality of sleep necessary for optimal functioning and well being. Long term or chronic insomnia has been conventionally considered to be that lasting for at least 21 to 30 nights; however, it usually persists for months or years. It is more frequent in women than in men, and becomes more pronounced with age.Chronic insomnia is associated with mental disorders, psychophysiological conditions, inadequate sleep hygiene, neurological disorders and drug dependency. The most prevalent diagnosis is chronic insomnia associated with psychiatric disorders, followed in precedence by psychophysiological conditions.In chronic psychophysiological insomnia, idiopathic insomnia and insomnia associated with generalised anxiety, nonpharmacological strategies and sleeppromoting medication (e.g. hypnotics) are indicated. In patients with chronic insomnia associated with major depressive disorders, antidepressants that induce acute sedation (e.g. amitriptyline, doxepin, trazodone) represent the primary drug treatments of choice. When necessary, hypnotics can be added.Currently used hypnotics include benzodiazepine derivatives, the cyclopyrrolone zopiclone and the imidazopyridine zolpidem. Hypnotics with a short halflife show the best profile of efficacy versus adverse effects with regard to morning awakening and daytime functioning. In patients with chronic insomnia, hypnotics reduce sleep-onset latency, decrease the number of nocturnal awakenings and reduce the time spent awake. The increase in total sleep time is related to greater amounts of non-rapid eye movement (NREM) sleep.Few differences exist between benzodiazepines, zopiclone and zolpidem in terms of effectiveness in inducing and maintaining sleep. However, in contrast to the benzodiazepines and zopiclone, zolpidem does not suppress slow-wave sleep. Sleep laboratory and clinical studies tend to indicate that benzodiazepines are only effective when administered for relatively short periods of time in patients with chronic insomnia. Furthermore, a rebound insomnia has been described for short- and intermediate-acting benzodiazepines and zopiclone, and a withdrawal syndrome, denoting the presence of psychological and physical dependence, follows the abrupt cessation ofbenzodiazepine administration. In contrast, no evidence of tolerance or rebound insomnia has been observed in relation to zolpidem administration.

p-SPA, a peripheral adenosine A1 analogue, reduces sleep apneas in rats

The actions of N6-p-sulfophenyladenosine (p-SPA), a novel peripherally selective adenosine A1 agonist, were assessed on spontaneous and postsigh central sleep apneas in freely moving, unanesthetized rats by simultaneously monitoring sleep and respiration. Intraperitoneal administration of 0.1, 0.3, and 1.0 mg/kg of the drug significantly decreased postsigh and spontaneous sleep apnea index (AI). This effect persisted throughout the 6-h recording period. Doses of 0.1 and 0.3 mg/kg did not affect sleep efficiency, whereas 1.0 mg/kg of p-SPA reduced it to 60% of baseline value.

Increased waking after intra-accumbens injection of m-chlorophenylbiguanide: prevention with serotonin or dopamine receptor antagonists.

Bilateral injection of the selective 5-HT3 receptor agonist m-chlorophenylbiguanide (5.0-40.0 micrograms) into the nucleus accumbens of the rat significantly increased waking and decreased slow wave sleep. Rapid eye movement (REM) sleep remained unchanged. Pretreatment with the 5-HT3 receptor antagonist MDL 72222 (1aH,3a,5a, H-tropan-3-yl-3,5-dichloro-benzoate) (0.5 mg/kg s.c.) reversed the effects of m-chlorophenylbiguanide (10.0-20.0 micrograms) on sleep and waking. Blockade of the dopamine D1 or D2 receptor with (+)-SCH 23390 (0.25 mg/kg s.c.) or YM-09151-2 (cis-N-(1-benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4- methylaminobenzamide) (0.5 mg/kg s.c.), respectively antagonized the increase of waking and reduction of slow wave sleep induced by m-chloro-phenylbiguanide (10.0 micrograms). Our results tend to indicate that the increase of wakefulness after injection of the selective 5-HT3 receptor agonist m-chlorophenylbiguanide into the nucleus accumbens is partly related to the release of endogenous dopamine. In addition, they suggest that concomitant stimulation of both accumbens dopamine D1 and D2 receptor-related mechanisms is a necessary prerequisite to increase wakefulness.

Histamine H1 receptor antagonists in the treatment of insomnia : Is there a rational basis for use?

Neuroanatomical, neurochemical and neuropharmacological studies support a role for histamine in the control of the waking state. In this respect, the histamine H1 receptor plays a predominant role. Acute administration of first-generation H1 receptor antagonists [chlorphenamine (chlorpheniramine), diphenhydramine, mepyramine (pyrilamine) and triprolidine] produces somnolence, an increased likelihood of falling asleep and reduced concentration. These effects led to the use of these drugs as over-the-counter medications to promote sleep. The widespread use of sedative antihistamines as sleep aids stems from inappropriate attempts by undiagnosed and untreated patients with insomnia to resolve their sleep disturbance.The limited number of studies directed at disclosing the effects of first-generation antihistamines on sleep in patients with insomnia tend to suggest that these compounds are effective for the treatment of chronic insomnia; however, methodological flaws limit the validity of their conclusions. In addition, the development of acute tolerance to the sedative effects of first-generation H1 receptor antagonists further calls into question their effectiveness as sleep aids in transient, short or long term insomnia.Despite their widespread use, current evidence suggests that sedative antihistamines compare unfavourably with the benzodiazepine, cyclopyrrolone (zopiclone), imidazopyridine (zolpidem) and pyrazolopyrimidine (zaleplon) hypnotics, which consistently improve the difficulty falling asleep or maintaining sleep that is experienced by individuals with chronic insomnia.

Effect of the reversible monoamine oxidase-A inhibitor moclofoemide on sleep of depressed patients

The effect of moclobemide, a short-acting, reversible, preferential monoamine oxidase-A inhibitor in a 4-week therapeutic trial, on the sleep of ten depressed patients, was assessed by polysomnographic recordings. Compared with their time on placebo, patients receiving moclobemide showed improved sleep continuity, particularly during the intermediate and late stages of drug administration. The total increase in sleep time was comprised of larger amounts of stage 2 non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep. Withdrawal of moclobemide was followed by a further increase of REM sleep, although values did not surpass those sometimes observed in adults with normal sleep. In these patients, the symptoms of depression were rated as being significantly improved during the study period.