Sleep-inducing Properties Research Articles

Structural requirements for 5-HT2A and 5-HT1A serotonin receptor potentiation by the biologically active lipid oleamide.

Oleamide is an endogenous fatty acid primary amide that possesses sleep-inducing properties in animals and that has been shown to effect serotonergic receptor responses and block gap junction communication. Herein, the potentiation of the 5-HT1A receptor response is disclosed, and a study of the structural features of oleamide required for potentiation of the 5-HT2A and 5-HT1A response to serotonin (5-HT) is described. Of the naturally occurring fatty acids, the primary amide of oleic acid (oleamide) is the most effective at potentiating the 5-HT2A receptor response. The structural features required for activity were found to be highly selective. The presence, position, and stereochemistry of the delta9-cis double bond is required, and even subtle structural variations reduce or eliminate activity. Secondary or tertiary amides may replace the primary amide but follow a well defined relationship requiring small amide substituents, suggesting that the carboxamide serves as a hydrogen bond acceptor but not donor. Alternative modifications at the carboxamide as well as modifications of the methyl terminus or the hydrocarbon region spanning the carboxamide and double bond typically eliminate activity. A less extensive study of the 5-HT1A potentiation revealed that it is more tolerant and accommodates a wider range of structural modifications. An interesting set of analogs was identified that inhibit rather than potentiate the 5-HT2A, but not the 5-HT1A, receptor response, further suggesting that such analogs may permit the selective modulation of serotonin receptor subtypes and even have opposing effects on the different subtypes.

Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides.

Endogenous neuromodulatory molecules are commonly coupled to specific metabolic enzymes to ensure rapid signal inactivation. Thus, acetylcholine is hydrolysed by acetylcholine esterase and tryptamine neurotransmitters like serotonin are degraded by monoamine oxidases. Previously, we reported the structure and sleep-inducing properties of cis-9-octadecenamide, a lipid isolated from the cerebrospinal fluid of sleep-deprived cats. cis-9-Octadecenamide, or oleamide, has since been shown to affect serotonergic systems and block gap-junction communication in glial cells (our unpublished results). We also identified a membrane-bound enzyme activity that hydrolyses oleamide to its inactive acid, oleic acid. We now report the mechanism-based isolation, cloning and expression of this enzyme activity, originally named oleamide hydrolase, from rat liver plasma membranes. We also show that oleamide hydrolase converts anandamide, a fatty-acid amide identified as the endogenous ligand for the cannabinoid receptor, to arachidonic acid, indicating that oleamide hydrolase may serve as the general inactivating enzyme for a growing family of bioactive signalling molecules, the fatty-acid amides. Therefore we will hereafter refer to oleamide hydrolase as fatty-acid amide hydrolase, in recognition of the plurality of fatty-acid amides that the enzyme can accept as substrates.

New sleep-inducing brain lipids identified

Drugs for treating sleep disorders may result from a new family of naturally occurring, sleep-inducing brain lipids isolated and characterized by scientists at Scripps Research Institute, La Jolla, Calif. The Scripps team, led by institute president Richard A. Lerner, chemist Dale L. Boger, and neuropharmacologist Steven J. Henriksen, has found that the family of primary lipid amides induces sleep in rats. The findings suggest such lipid derivatives may represent a previously unrecognized class of biological signaling molecules [ Science , 268 , 1506 (1995)]. It is known that lipids have sleep-related properties, Henriksen notes. In humans, for example, lipid breakdown occurs predominantly at night. And people with lipid-restricted diets are less able to experience deep sleep. Also, lipid-related molecules like short-chain fatty acids and prostaglandins show sleep-inducing properties. The researchers isolated two fatty acid amides from the cerebrospinal fluid of sleep-deprived cats: cis -9,10-octadecenoam...

Do benzodiazepines induce sleep by a gabaergic mechanism?

In order to further characterize the possible role of GABA function in the sleep-inducing properties of benzodiazepines (BZs), we have administered the GABA agonist muscimol (0.05 and 0.1 mg/kg) and the GABA antagonist bicuculline (1.25 and 2.5 mg/kg) IP, alone and in combination with triazolam (0.8 mg/kg). There was no evidence of interaction of these compounds with triazolam vis a vis sleep. These data are consistent with an earlier report indicating a lack of interaction of muscimol with flurazepam, and suggest that non-GABAergic mechanisms may be involved in the hypnotic properties of benzodiazepines.

Steroid profiles of brown adipose tissue

In brown adipose tissue of alp-marmot ( Marmota marmota), badger ( Meles meles) and Wistar rats steroids of C 21- and C 19-type are identified and quantified. The detection of 3α-hydroxy-5α-pregnan-20-one, α-hydroxy-5β-pregnan-20-one, 3α,21-dihydroxy-5α-pregnan-20-one, 3α,21-dihydroxy-5β-pregnan-20-one and 3β,21-dihydroxy-5α-pregnan-20-one is of special interest since sleep-inducing properties have been described with these steroids.

Cholinergic drugs as diagnostic and therapeutic tools in affective disorders

The hypothesis of a significant involvement of the cholinergic system in the pathogenesis of affective disorders still lacks strong experimental support. This is mainly because of missing specific peripheral markers of the central nervous activity of the cholinergic system and the lack of specific cholinergic agonists and antagonists without severe peripheral side effects. As the direct cholinergic agonist RS 86 seems to be more suitable because of its minor side effects, long half-life and oral applicability, it was tested for its antimanic property and its effect on the hypothalamo-pituitary adrenal system and the rapid eye movement (REM) sleep-generating system. RS 86 exhibited antimanic and REM sleep-inducing properties, but failed to stimulate the cortisol system.

Sleep induction by an adrenal steroid in the rat.

The ring A reduced metabolites of deoxycorticosterone and progesterone, 3 alpha, 5 alpha-tetrahydrodeoxycorticosterone (THDOC) and 3 alpha-hydroxy-5 alpha-dihydroprogesterone (3 alpha-OH-DHP) have been shown to be potent barbiturate-like ligands of the benzodiazepine receptor complex. The former has also been reported to have anxiolytic effects in mice and rats. In the present study, sleep recordings were obtained on rats given 5 and 10 mg/kg of these steroids alone and in combination with flurazepam. THDOC, but not 3 alpha-OH-DHP, had potent dose-dependent sleep-inducing properties and increased nonREM sleep. Flurazepam had similar hypnotic effects and also reduced REM sleep. There were no significant interactions between THDOC and flurazepam, except in the case of REM latency, which tended to increase when the two compounds were given together. In summary, THDOC, a mineralocorticoid metabolite found in brain, has sedative properties and could conceivably play a role in stress responses.

Determination of bentazepam in plasma by high-performance liquid chromatography

Bentazepam (2,3-tetramethylene-4-phenyl-7-oxo-thiene), Fig. 1, is a derivative of thienodiazepine showing anxiolytic, tranquillizing, anticonvulsant, miorelaxing and sleep-inducing properties [ 11. Pre-clinical trials in volunteers have shown psychotropic activity for this drug such that the preparation may be considered as a tranquillizer with slight psychostimulatory properties. The drug also shows activity in combating symptoms of anxiety, restlessness, depression, difficulties in touch, sleep disorders [2] and in treatment of childhood anxiety [3]. Acute and chronic intolerance to the drug is rare at the clinical doses of 30-150 mg and is generally accompanied by side-effects similar to those displayed by several benzodiazepines. However these side-effects appear at doses greater than those normally used in clinical practice [4].

Effects of a new benzodiazepine hypnotic (quazepam—SCH 16134) on EEG synchronization and sleep-inducing mechanisms in cats

The sleep-inducing properties of a new benzodiazepine hypnotic (quazepam—SCH 16134) were evaluated in cats with transection at different levels of the brain stem structure. Effects observed after administration of doses ranging from 0.12 and 1 mg/kg given intravenously were compared with those of pentobarbital. In the encéphale isolé small doses of quazepam induced or increased the synchronized periods. The desynchronized electroencephalogram (EEG) pattern of midpontine pretrigeminal preparations was not modified by these small doses. Only larger doses induced a fast neocortical activity of high amplitude. In midpontine pretrigeminal hemisection the synchronization occurred exclusively or predominantly in the hemisphere contralateral to the lesion. In the cerveau isolé, quazepam did not influence the typical synchronized EEG pattern. The arousal threshold after mesencephalic and physiological stimulation was raised only in encéphale isolé animals. Pentobarbital provoked sustained synchronization in all preparations with a pattern quite different from that of the benzodiazepine. These results suggest that quazepam may act through facilitation of the EEG-synchronizing mechanisms localized in the lower brain stem which are involved in physiological EEG-synchronizing and sleepinducing processes.

A psychophysiological investigation of the long-term effects of clozapine upon sleep patterns of normal young adults

A 25-night single-blind cross over design was employed to determine the long-term effects of clozapine on the sleep patterns of six normal young adults. Subjects received 12.50 mg placebo on the first and last five nights, whereas on the intermediate 15 nights 12.5 mg clozapine was administered. The subjects slept in the laboratory on the third and fourth nights to obtain baseline recordings, and on the eight, twelfth, sixteenth, and twentieth nights to determine the effects of clozapine on sleep variables. Recordings on nights 21 and 25 were used to assess withdrawal effects. Percentage stage 1 sleep and indices of body movements during sleep were significantly reduced, suggesting that clozapine may have sleep-inducing properties. There were no significant rebound of stage REM sleep during drug withdrawal despite a small but significant reduction in stage REM during drug administration. Numerous side effects, indicative of sleepiness, were reported on the mornings following drug administration, and there was evidence of a rapid tolerance to clozapine. These findings may limit the efficacy of clozapine as an hypnotic agent over an extended period of time. Further research on insomniac subjects is therefore indicated.