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PubMed2003

Influences of a light-dark profile and the pineal gland on the hypnotic activity of melatonin in mice and rats.

We have investigated the influences of the light-dark cycle and the pineal gland on the hypnotic activity of melatonin in rats and mice. The results showed that melatonin significantly shortened time to sleep onset and wakefulness time, increased slow wave sleep, paradoxical sleep, and total sleep time in rats during the light phase of a 12-h light:12-h dark cycle, by electroencephalogram recording. However, during the dark phase it had almost no significant sleep-promoting effect except shortened time to sleep onset. Melatonin exhibited more potent sleep-promoting effect in rats exposed to constant light compared with rats exposed to 12:12-h light:dark at 2000 h. Melatonin markedly prolonged sleeping time in the mice exposed to constant illumination. It was found that pinealectomy was an important factor that influenced the hypnotic activity of melatonin. When melatonin was administered to pinealectomized mice, the hypnotic activity of melatonin was more intense compared with sham-operated mice. These results demonstrated that the hypnotic activity of melatonin displayed a light-dependence manner. These results suggested that light exposure and the functional state of the pineal gland could substantially impact the hypnotic activity of melatonin at pharmacological dosage.

Administration, Oral↗
PubMed2002

Pharmacological properties and SAR of new 1,4-disubstituted piperazine derivatives with hypnotic-sedative activity.

Preparation, pharmacological properties and structure-activity relationships of new pyrimidyl-piperazine derivatives, exhibiting sedative and hypnotic activity in mice, are reported. The hypnotic activity of the compounds was comparable with that of zopiclone (the known hypnotic-sedative agent), their interaction with ethanol, however, being much lower. The obtained results suggested that zopiclone and pyrimidylpiperazines 2, 4 and 5 exerted their pharmacological activity through a different mechanism - zopiclone through the interaction with benzodiazepine receptors and compounds 2, 4 and 5 through an unidentified molecular target. The pharmacological properties of compound 3 could be the result of a mixed mechanism of action, combining the properties of zopiclone and those of compounds 2, 4 and 5. A common feature of zopiclone and compounds 2 and 3 was that, after their systemic administration, independently of mechanism of action, together with the hypnotic effect a reduction of the 5-HT turnover in the mouse brain was observed. Minimum structural requirements for the hypnotic activity were formulated. Structural considerations have shown that removing the alpha-carbonyl group did not influence the drug's ability to inhibit the locomotor activity. However, it did influence its ability to disturb motor coordination or abolish the righting reflex within non-lethal doses.

Animals↗
PubMed1998

Synthesis and sedative-hypnotic effects of N3-allyl- and N1-allyl-5,6-substituted 2-thiouracil derivatives in mice.

Twenty four thiouracil derivatives, including N3-allyl- (19) and N1-allyl-2-thiouracil (20) were synthesized and their pharmacological effects [sedative-hypnotic activity (loss of righting reflex and spontaneous activity), convulsant activity, effect on pentobarbital (PB)-induced sleep and mortality] were evaluated in mice at doses of 320 mg/kg, i.p. and 2 mumol/mouse by intracerebroventricular (i.c.v.) injections, respectively. N3-Allyl-6-propyl-2-thiouracil (3), N3-allyl-5,6-dimethyl-2-thiouracil (10), N3-allyl-1,2,3,4,5,6,7,8,9-nonahydro-4-oxo-2-thiocyclohepta [d]pyrimidine (16) and N3-allyl-5-methyl-2-thiouracil (18) exhibited sedative-hypnotic activity, whereas N3-allyl-6-ethyl-5-methyl-2-thiouracil (11), N1-allyl-5-methyl-2-thiouracil (21), N1-allyl-1,2,3,4,5,6,7,8,9-nonahydro-4-oxo-2-thiocyclohepta[ d]pyrimidine (23) and N1-allyl-5,6-dimethyl-2-thiouracil (24) conversely displayed clonic- and/or tonic-convulsant seizures. N3-Allyl-6-propyl-2-thiouracil (3) and N3-allyl-5-methyl-2-thiouracil (18) decreased spontaneous activity. Other compounds examined were inactive, or only slightly active in the sedative-hypnotic assay even at high doses. Fifteen compounds (1-4, 7, 10, 11, 14-16, 18-21, and 23) significantly prolonged the PB-induced sleeping time. Interestingly, only N1-allyl-5,6-dimethyl-2-thiouracil (24) shortened the PB-induced sleeping time. These results showed that these thiouracils possessed many different effects such as sedative-hypnotic, anticonvulsant and/or convulsant, and that N3-allyl-5-methyl-2-thiouracil (18) and N1-allyl-5,6-dimethyl-2-thiouracil (24) had the most potent hypnotic activity and antagonistic effect against PB, respectively.

Animals↗
PubMed1998

Concomitant prescribing of tranquilizers and hypnotics among patients receiving antidepressant prescriptions.

OBJECTIVE: To evaluate concomitant prescribing of tranquilizers and hypnotics in antidepressant treatment with particular focus on the relationship to drug class in patients prescribed antidepressant treatment for depressive disorders. DESIGN AND METHODS: Repeated cross-sectional surveys of Swedish physicians in ambulatory care from 1991 to 1996, including specialty practices. The participation rate was 65-70%. RESULTS: Tranquilizers and hypnotics were prescribed in 36.1% of the visits in which the intention was to treat depression. Concomitant prescribing increased with the patient's age for all antidepressant drug classes. Women received more concomitant prescriptions than men when treated with nonselective monoamine-reuptake inhibitors (NSMRI), mainly tricyclic compounds. Psychiatrists prescribed more concomitant tranquilizers and hypnotics than other physicians, and general practitioners fewer, when treating depression with selective serotonin-reuptake inhibitors (SSRIs), mainly citalopram. A logistic regression model showed that the risk for concomitant prescribing was higher when an NSMRI was prescribed than with other antidepressants. CONCLUSIONS: Concomitant prescribing of tranquilizers and hypnotics was common among antidepressant-treated patients. The most plausible reasons for the high rate of concomitant prescribing were the symptoms of the depression itself and/or the common comorbidity with anxiety disorders seen in this group of patients. The results of this study indicate that the concern about increased tranquilizer and hypnotic use among patients treated with SSRIs suggested in other studies seems to be unfounded in Sweden.

Adult↗
PubMed1976

Hypnotic and minor tranquilizer use among inpatients and after discharge.

A major concern in prescribing hypnotics and minor tranquilizers in the hospital is that long-term habituation might develop. Former psychiatric inpatients were surveyed to assess hypnotic and minor tranquilizer use following discharge. Patients who used flurazepam and chloral hydrate as inpatients were no more likely to use these hypnotics as outpatients than patients who received no hypnotics as inpatients. There was a significant association between inpatient and outpatient use of minor tranquilizers. Outpatient use of minor tranquilizers was also significantly associated with outpatient hypnotic use.

Aftercare↗
PubMed2000

Hypnotics. Options to help your patients stop.

BACKGROUND: There are a wide range of reasons why hypnotic agents may be started, but there is substantive evidence that they are often overused or misused. OBJECTIVE: To review the reasons for stopping hypnotic agents, how to detect their use, how to facilitate the decision to withdraw and how to most effectively achieve withdrawal. In this article, the target group is using but not intentionally abusing hypnotic agents. DISCUSSION: In many cases it is possible for patients to permanently stop using hypnotic drugs. Withdrawal can generally be achieved in the community, using a gradual taper regimen, although it is often a difficult process and is more effective when the patient is aware of the health benefits to be gained from withdrawal. Once withdrawn, other approaches to maintain sleep need to be reinforced to reduce the risk of recommencing hypnotic therapy.

Aged↗
PubMed2000

Mortality in elderly men with low psychosocial coping resources using anxiolytic-hypnotic drugs.

OBJECTIVE: Insufficient coping with stress may lead to increased susceptibility for disease and death. Use of anxiolytic-hypnotic drugs has been suggested as a coping strategy, and some opinions have proposed their use as preventive medication. The aim of this study was to estimate if use of anxiolytic-hypnotic drugs counters the increased mortality observed in individuals lacking other coping strategies such as emotional support and social participation. METHODS: A population based cohort study with 10-year (1982/83-1993) survival analysis was performed in 491 men born in 1914, living in the Swedish city of Malmö. RESULTS: Compared with men with a high level of psychosocial coping resources who did not use anxiolytic-hypnotic drugs, men with a low level of psychosocial coping resources had a higher risk of death irrespective whether they used anxiolytic-hypnotic drugs, RR = 1.7 (95% CI 1.1-2.6) or not RR = 1.8 (95%: 1.3-2.5). CONCLUSION: Anxiolytic-hypnotic drugs do not seem to counter increased mortality in elderly men with low psychosocial coping resources.

Adaptation, Psychological↗
PubMed2001

Effectiveness and safety of rocuronium-hypnotic sequence for rapid-sequence induction.

BACKGROUND: Either succinylcholine or rocuronium administered after a hypnotic is the current technique for rapid-sequence induction. It is assumed that rocuronium administered before a hypnotic (Rocuronium-hypnotic sequence) may equally provide an acceptable intubation condition as well as a shorter period of apnea in rapid-sequence induction. We designed a prospective, randomized study to evaluate the effectiveness and safety of the technique in a similar rapid-sequence induction. METHODS: Ninety adult patients receiving elective surgeries were enrolled in this study. In all patients the procedure in the study began with i.v. injection of fentanyl 2 micrograms/kg, followed by preoxygenation with 100% O2 for 2 min. Afterward, the patients were randomly allocated to 3 groups with each group consisting of 30 patients. In Rocuronium-thiopental (Ro-Th) group the patients received rocuronium 0.6 mg/kg and then thiopental 5 mg/kg; in Th-Ro group the patients received thiopental 5 mg/kg and then rocuronium 0.6 mg/kg; and in Thiopental-Succinylcholine (Th-Sx) group, the control group, the patients received thiopental 5 mg/kg and then succinylcholine 1 mg/kg. Laryngoscopy and endotracheal intubation were performed 60 s after the injection of the muscle relaxant. The intubation condition, the apneal time before laryngoscopy, the intubation time, and total apneal time were investigated and compared. Presence of injection pain, sense of paralysis, SpO2 less than 95% during induction, and any unexpected adverse event were also recorded. RESULTS: Six patients (1 in Ro-Th group, 2 in Th-Ro group, and 3 in Th-Sx group, respectively) were excluded from the study. The intubation conditions were acceptable in all patients of three groups who completed the study, and as to excellent intubation condition there was no difference between the three groups. In Ro-Th group both the apneal time before laryngoscopy (32.4 +/- 5.4 s) and total apneal time (48.5 +/- 11.0 s) were the shortest. Th-Ro group (53.2 +/- 5.8 and 67.5 +/- 8.3 s, respectively) and Th-Sx group (54.4 +/- 5.8 and 68.4 +/- 7.7 s, respectively) were similar in both aspects. With respect to intubation time there was no significant difference among the three groups. Five patients in Ro-Th group and one patient in Th-Sx group felt mild injection pain. Three patients in Ro-Th group were noted to have diminished breathing during induction, which was not recalled during enquiry in the postoperative visit. One patient in Ro-Th group saw a fall of SpO2 down below 95% (94% the minimal) during the apnea period. CONCLUSIONS: Compared with traditional hypnotic-rocuronium or hypnotic-succinylcholine sequence, rocuronium (0.6 mg)-thiopental sequence can provide a similar intubation condition but cause a much shorter apneal period in rapid-sequence induction. In carrying out recuronium-thiopental sequence induction, maintaining a patent infusion line is essential to avoid drug precipitation and awareness of muscular weakness as a result of ill-timed action of thiopental.

Adult↗
PubMed2001

The use of analgesics and hypnotics in relation to self-rated health and disability pension--a prospective study of middle-aged men.

AIMS: This cohort study on urban middle-aged men investigates the association between the use of analgesics and hypnotics, self-rated health (SRH) and disability pension. METHODS: Five birth-year cohorts of middle-aged, urban, Swedish men were invited to a screening programme and were followed for approximately 11 years. RESULTS: Out of all the subjects (n = 5798), 12.4% received a disability pension during follow-up, 27.0% rated their health as less than perfect, 10.6% used analgesics and 2.9% used hypnotics. Compared with non-users of analgesics and hypnotics, the adjusted hazard ratio of disability pension for the simultaneous use of both drugs was 7.0 (95% CI: 4.3, 11.6) and the adjusted odds ratio of poor SRH was 16.5 (6.3, 43.5). Thus, the use of analgesics and hypnotics was positively related to poor SRH and predicted award of a disability pension within an 11-year follow-up. This may reflect that the use of analgesics and hypnotics is a proxy of disease but an independent negative effect on health cannot be excluded. CONCLUSIONS: Information on the use of these drugs could be used to predict the award of a disability pension, such as in different geographical areas or population groups.

Adaptation, Psychological↗
PubMed2001

Relationship of brain ethanol metabolism to the hypnotic effect of ethanol. II: Studies in selectively bred rats and mice.

BACKGROUND: To clarify the role of brain acetaldehyde in the hypnotic effect of ethanol, we compared the ethanol-oxidizing capacity (rate of acetaldehyde accumulation) and catalase and aldehyde dehydrogenase activity in the brains of animals genetically selected for different sensitivities to the hypnotic effect of ethanol. METHODS: We used high, low, or control alcohol-sensitive rats (HAS, LAS, and CAS) and short- and long-sleep mice (SS and LS), as well as SS x LS recombinant inbred mice with known strain differences in mean duration of ethanol-induced sleep. We studied the rate of accumulation of acetaldehyde from ethanol in brain homogenates of these animals and correlated those values with their hypnotic sensitivity to ethanol. RESULTS: Acetaldehyde accumulation from ethanol was significantly higher in the brain homogenates from HAS rats and LS mice with high sensitivity to the hypnotic effect of ethanol in vivo, compared with LAS rats and SS mice with low sensitivity to ethanol. A correlation was found between the duration of ethanol-induced sleep and the in vitro rate of accumulation of ethanol-derived acetaldehyde in the brains of recombinant SS x LS mice strains. There was no correlation of sleep time with brain catalase levels. There were no line differences in brain catalase or aldehyde dehydrogenase or in alcohol or aldehyde dehydrogenase activity in livers of LAS, CAS, and HAS rats or in SS and LS mice. CONCLUSIONS: A correlation between the brain acetaldehyde accumulation, but not catalase levels, and the central effect of ethanol was demonstrated in animals genetically differing in initial sensitivity to the hypnotic effect of ethanol.

Acetaldehyde↗
PubMed2001

Neurotensin levels in specific brain regions and hypnotic sensitivity to ethanol and pentobarbital as a function of time after haloperidol administration in selectively bred rat lines.

Evidence indicates that sensitivity to ethanol is a good predictor of the development of alcoholism. Thus, identification of neuronal processes that regulate ethanol sensitivity has been the subject of much recent research. The present studies were designed to further test the hypothesis that neurotensinergic processes mediate, in part, hypnotic sensitivity to ethanol. Single doses of haloperidol were administered to lines of rats [selectively bred for high and low sensitivity (HAS and LAS, respectively) to hypnotic effects of ethanol] to produce increases in neurotensin (NT) levels in brain regions. At 20 h after administration, haloperidol produced dose-dependent increases in NT immunoreactivity levels in nucleus accumbens (NA) and caudate putamen (CP) in both HAS and LAS lines. Levels of NT in NA and CP returned to control values at 48 h after 4 mg/kg haloperidol. These studies used two measures of hypnotic sensitivity to ethanol: duration of loss of righting reflex (sleep time) and blood ethanol concentration at regain of righting reflex (BECRR). At 20 h, but not 48 h, after haloperidol treatment, both HAS and LAS rats displayed increases in ethanol-induced sleep time with concomitant decreases in BECRR. Pentobarbital-induced sleep time was not increased 20 h after administration of 4 mg/kg haloperidol; however, hypnotic sensitivity to both pentobarbital and ethanol was increased by acute (30-min) pretreatment with 1 mg/kg. These results suggest that NT levels in NA, acting via NT receptors, enhance hypnotic sensitivity to ethanol, but not pentobarbital.

Alcoholic Intoxication↗
PubMed2002

Hypnotic activity of melatonin: involvement of semicarbazide hydrochloride, blocker of synthetic enzyme for GABA.

AIM: To assess the effect of semicarbazide hydrochloride (SCZ), the blocker of synthetic enzyme for GABA, on the hypnotic activity of melatonin. METHODS: Righting reflex method in mice and electroencephalography (EEG) in rats were used to determine effects of SCZ on sleep and hypnotic activity of melatonin. RESULTS: Melatonin displayed a marked hypnotic activity both in righting reflex experiment and EEG recording. SCZ had no influence on sleep parameters in mice and rats when it was used alone. However, it blocked the sleep-potentiation effect of melatonin in mice. SCZ also inhibited melatonin-induced increase in total sleep time, slow wave sleep time, and paradoxical sleep time, and prevented melatonin-induced decrease in awake time in rats. CONCLUSION: SCZ antagonized the hypnotic activity of melatonin. It is thought that the hypnotic activity of melatonin is mediated by GABAergic system.

Animals↗
PubMed1992

Comparative clinical profiles of triazolam versus other shorter-acting hypnotics.

The efficacy, safety, and performance of triazolam was compared with those of other shorter-acting hypnotics acting on the gamma-aminobutyric acid (GABA) receptor--zopiclone, zolpidem, midazolam, brotizolam, temazepam, lormetazepam, and loprazolam. In all, 5506 patients participated in 38 clinical and epidemiologic studies, of whom 2462 were treated with triazolam in parallel-design and crossover studies. To provide clinically relevant comparisons, only studies using comparator agents in doses equipotent to the triazolam doses were included. Two general findings emerged. First, "serious" central nervous system side effects, such as excitement and violence, were not demonstrated for any of the hypnotic agents, including triazolam. Other central nervous system side effects, such as depression and irritability, were reported with equal frequencies for all the hypnotics reviewed. Rebound insomnia, reported intermittently with most of these agents, was short-lived and not clinically significant. So-called early morning insomnia was noted only once and does not appear to be a valid clinical entity. Daytime anxiety was not observed in large numbers of triazolam-treated subjects studied, which is contrary to claims that the drug is anxiogenic. Second, a remarkable similarity was found among all of these shorter-acting agents in terms of efficacy, side effects, and performance-related effects. This was particularly of note for zopiclone and zolpidem. Although claims have been made suggesting differences, evaluation of the studies herein showed that these nonbenzodiazepine hypnotics were indistinguishable from triazolam and other benzodiazepine hypnotics in their clinical and pharmacologic activity. Thus, different chemical structures did not a priori predict different clinical profiles when drugs share a similar mechanism of action.

Azabicyclo Compounds↗
PubMed2003

Pharmacokinetics and drug interactions of the sedative hypnotics.

Sleep complaints are common among patients and may be associated with mild to severe clinical symptoms. The use of hypnotic agents to improve the onset and quality of sleep has a history dating back centuries. Currently, several benzodiazepines and nonbenzodiazepines are widely used as sedative hypnotic drugs. The pharmacokinetic and pharmacodynamic profiles of these agents vary substantially, allowing them to be chosen for different clinical situations and tailored to specific sleep complaints. The short-acting benzodiazepines and benzodiazepine agonists have become the most widely prescribed sedative hypnotics because of their short to ultrashort half-life, and low tendency to impair cognitive and psychomotor performance on the day following nighttime use. In the current review, we summarize the pharmacokinetic and drug interaction profiles of the Food and Drug Administration-approved benzodiazepine sedative hypnotics: estazolam, flurazepam, quazepam, temazepam, and triazolam. In addition, alprazolam is included because of its popularity for this use, and 2 benzodiazepine receptor agonists, zolpidem and zaleplon, are reviewed. The presented data will provide clinicians with insight into the pharmacokinetic profiles of several popular sedative hypnotic agents, and provide guidelines to help them recognize or avoid drug interactions.

Benzodiazepines↗
PubMed2003

Psychological treatment for insomnia in the management of long-term hypnotic drug use: a pragmatic randomised controlled trial.

OBJECTIVE: To evaluate the clinical and cost impact of providing cognitive behaviour therapy (CBT) for insomnia (comprising sleep hygiene, stimulus control, relaxation and cognitive therapy components) to long-term hypnotic drug users in general practice. DESIGN: A pragmatic randomised controlled trial with two treatment arms (a CBT treated 'sleep clinic' group, and a 'no additional treatment' control group), with post-treatment assessments commencing at 3 and 6 months. SETTING: Twenty-three general practices in Sheffield, UK. PARTICIPANTS: Two hundred and nine serially referred patients aged 31-92 years with chronic sleep problems who had been using hypnotic drugs for at least 1 month (mean duration = 13.4 years). RESULTS: At 3- and 6-month follow-ups patients treated with CBT reported significant reductions in sleep latency, significant improvements in sleep efficiency, and significant reductions in the frequency of hypnotic drug use (all P<0.01). Among CBT treated patients SF-36 scores showed significant improvements in vitality at 3 months (P<0.01). Older age presented no barrier to successful treatment outcomes. The total cost of service provision was 154.40 per patient, with a mean incremental cost per quality-adjusted life-year of 3416 (at 6 months). However, there was evidence of longer term cost offsets owing to reductions in sleeping tablet use and reduced utilisation of primary care services. CONCLUSIONS: In routine general practice settings, psychological treatments for insomnia can improve sleep quality and reduce hypnotic consumption at a favourable cost among long-term hypnotic users with chronic sleep difficulties.

Adult↗
PubMed2005

Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds.

Hypnotic drugs, including benzodiazepine receptor ligands, barbiturates, antihistamines, and melatonin receptor ligands, are useful in treating insomnia, but clinicians should consider the relative abuse liability of these drugs when prescribing them. Two types of problematic hypnotic self-administration are distinguished. First, recreational abuse occurs when medications are used purposefully for the subjective "high." This type of abuse usually occurs in polydrug abusers, who are most often young and male. Second, chronic quasi-therapeutic abuse is a problematic use of hypnotic drugs in which patients continue long-term use despite medical recommendations to the contrary. Relative abuse liability is defined as an interaction between the relative reinforcing effects (i.e., the capacity to maintain drug self-administration behavior, thereby increasing the likelihood of nonmedical problematic use) and the relative toxicity (i.e., adverse effects having the capacity to harm the individual and/or society). An algorithm is provided that differentiates relative likelihood of abuse and relative toxicity of 19 hypnotic compounds: pentobarbital, methaqualone, diazepam, flunitrazepam, lorazepam, GHB (gamma-hydroxybutyrate, also known as sodium oxybate), temazepam, zaleplon, eszopiclone, triazolam, zopiclone, flurazepam, zolpidem, oxazepam, estazolam, diphenhydramine, quazepam, tra-zodone, and ramelteon. Factors in the analysis include preclinical and clinical assessment of reinforcing effects, preclinical and clinical assessment of withdrawal, actual abuse, acute sedation/memory impairment, and overdose lethality. The analysis shows that both the likelihood of abuse and the toxicity vary from high to none across these compounds. The primary clinical implication of the range of differences in abuse liability is that concern about recreational abuse, inappropriate long-term use, or adverse effects should not deter physicians from prescribing hypnotics when clinically indicated.

Animals↗
PubMed1991

[Reduction of the use of hypnotics by health education. Results from a controlled intervention study in a local community].

The object of this investigation was to study the effect of a wide informative campaign on the sale of hypnotics in Holbaek. An informative health campaign was carried out via the media and the general practitioners for a period of 16 weeks. The campaign in the media consisted of a weekly article by the journalists in the local newspaper, a weekly advertisement in the daily and weekly newspapers, mention in the local radio daily and in the weekly medical programme and a leaflet about sleep handed out by the general practitioners. Twelve general practitioners elected to participate in the intervention programme: all patients who sought hypnotics had to come to an interview about the sleep problem. The control consisted of the remaining eight general practitioners in Holbaek. The sale of hypnotics was registered by the pharmacists during five weeks prior to, six weeks during and three and 15 months after the campaign. Five weeks before the campaign, the sale of hypnotics was 2.05 defined daily doses per patient (1.69 in the intervention group and 2.49 in the control group). During the last five weeks of the campaign, the sale had declined by 24% and by 29% in the follow up period. The decline commenced immediately in the intervention group but was only partly stable. After approximately eight weeks of the campaign, stable declines had occurred in both groups. Fifteen months later, the sale of hypnotics was approximately 39% lower than at the commencement of the campaign.

Denmark↗
PubMed1990

The activity of zolpidem and other hypnotics within the gamma-aminobutyric acid (GABAA) receptor supramolecular complex, as determined by 35S-t-butylbicyclophosphorothionate (35S-TBPS) binding to rat cerebral cortex membranes.

The present study compares the effects of different hypnotics acting at omega 1/omega 2 sites (zolpidem, zopiclone, flunitrazepam and triazolam) on 35S-t-butylbicyclophosphorothionate (35S-TBPS) binding to well-washed rat cerebral membranes, in the presence of 1M NaCl. Under these conditions, all compounds enhanced 35S-TBPS binding in the 0.05 to 10 microM range with EC50 values and maximal enhancement of: zolpidem, 84 nM and 36%; flunitrazepam, 8 nM and 41%; zopiclone, 171 nM and 51%; triazolam, 2 nM and 42%. Under these conditions, gamma-aminobutyric acid enhanced 35S-TBPS binding with an EC50 of 240 nM and a 38% maximal increase. The EC50 values for the stimulation of 35S-TBPS binding are well correlated, with (r = 0.97) the affinity of these compounds at omega 1/omega 2 sites, and are in the same concentration range. This enhanced binding was due to an altered apparent affinity for the 35S-TBPS recognition site without any change in the number of sites (Scatchard analysis). The effect of zolpidem and other hypnotics was antagonized by flumazenil. This was an apparently competitive antagonism in the case of zolpidem or flunitrazepam, whereas for zopiclone, increasing the concentration of the hypnotic did not overcome the antagonism. Bicuculline only partially antagonized the hypnotic-induced enhancement of 35S-TBPS binding. This antagonism was more effective for zopiclone (-57%) than for either zolpidem (-33%) or flunitrazepam (-30%). Zolpidem and the other hypnotics studied induced a fast component of dissociation which was not observed in the control membranes. These findings are consistent with the hypothesis that omega 1/omega 2 agonists increase the frequency of openings of the chloride ionophore, with both gamma-aminobutyric acid-A receptor-dependent and -independent mechanisms.

Animals↗