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PubMed1986

Neuroanatomical site of the inhibitory influence of anxiolytic drugs on central serotonergic transmission.

The neuroanatomical site of the inhibitory influence of anxiolytics on central serotonergic transmission has been investigated in the rat by studying the effect of systemic or intracerebral administration of these drugs on cerebral serotonin (5-HT) synthesis. Systemic administration of diazepam (3 mg/kg s.c.) or flunitrazepam (1 mg/kg, s.c.) caused a reduction of 5-HT synthesis (as measured by the accumulation of 5-hydroxytryptophan after inhibition of aromatic amino acid decarboxylase) in the hippocampus but not in the cerebral cortex, striatum, cerebellum or spinal cord of the rat. Zopiclone (22 mg/kg, s.c.) decreased the amine synthesis in hippocampus, striatum and prefrontal cortex. The decrease of hippocampal 5-HT synthesis induced by diazepam (5 mg/kg, s.c.) was antagonized by the benzodiazepine antagonist Ro 15-1788 (2 X 30 mg/kg, s.c.) but not by bicuculline (2 X 1 mg/kg, s.c.). Acute cerebral hemitransection or electrolytic lesion of the fasciculus retroflexus did not prevent the ability of diazepam (5 mg/kg, i.p.) to diminish hippocampal 5-HT synthesis. Local infusion of diazepam (15 micrograms) of flurazepam (1.5 micrograms) into the hippocampus of conscious rats (via indwelling cannulae) markedly reduced 5-HT synthesis in this brain area whereas infusion of these drugs into the raphé medianus (origin of the serotonergic afferents to the hippocampus) failed to affect hippocampal 5-HT synthesis. In contrast, local injection of muscimol (25-150 ng) into the raphé medianus reduced 5-HT synthesis in the hippocampus. This effect of muscimol was potentiated by a systemic administration of diazepam or an intra-raphé medianus infusion of flurazepam (at doses or concentrations which exhibited no intrinsic activity). It is concluded from these data that anxiolytic drugs exert an inhibitory influence on hippocampal serotonergic neurons which is mediated primarily via GABA-independent benzodiazepine receptors located in the vicinity of serotonergic nerve terminals.

Animals↗
PubMed1984

Benzodiazepine receptor ligand actions on GABA responses. Benzodiazepines, CL 218872, zopiclone.

The effects on GABA (4-aminobutyric acid) responses of several benzodiazepine and nonbenzodiazepine benzodiazepine receptor ligands were examined using mouse spinal cord neurons in dissociated cell culture. Diazepam, clonazepam and nitrazepam enhanced GABA responses potently at low nanomolar concentrations. Diazepam and clonazepam were most potent with significant enhancement at 1 nM and peak enhancement of 80.7 and 50.2% at 10 nM respectively. Nitrazepam was least potent with no significant enhancement at 1 nM and enhancement of only 20.7% at 10 nM. The benzodiazepine antagonist, Ro 15-1788, blocked enhancement by diazepam but also weakly enhanced GABA responses at low micromolar concentrations, suggesting partial agonist activity. The convulsant benzodiazepine, Ro 5-4864, did not enhance GABA responses at any concentration tested but antagonized GABA responses at 1 microM and above. Diazepam shifted GABA dose-response curves to the left by decreasing the apparent KD but without altering the apparent Vmax (Lineweaver-Burk analysis). Two nonbenzodiazepine anxiolytic/anticonvulsants, CL 218872 and zopiclone, were weak enhancers of GABA responses at high nanomolar concentrations. These results with benzodiazepines, CL 218872 and zopiclone are consistent with their anxiolytic and anticonvulsant profile in vivo and with studies of their effects upon low affinity GABA binding in vitro.

Animals↗
PubMed1996

Separation of enantiomers of drugs by capillary electrophoresis. III. Beta-cyclodextrin as chiral solvating agent.

Enantiomer separation by capillary zone electrophoresis was studied for a set of 34 chiral drugs. Keeping the concentration of beta-cyclodextrin as a chiral solvating agent as constant as possible led to the separation of seven enantiomeric pairs. Carvedilol, Tetryzoline, Tropicamide and Zopiclone gave a baseline separation, Chlorphenamine, Ketamine, and Orciprenaline a partial separation. Statistical analysis revealed that the best separation factors were observed for a medium degree of interaction with the cyclodextrin. A theory explaining this effect provides a helpful guideline for further optimization.

Azabicyclo Compounds↗
PubMed1993

Alleviating sleep-related discontinuance symptoms associated with benzodiazepine withdrawal: a new approach.

There is limited information on the time course of recovery of sleep architecture in patients withdrawn from benzodiazepines (BDZ). This study examined the effects of substituting a new class of hypnotic drugs, namely the cyclopyrrolones, for current BDZs in patients presenting with BDZ dependence. The results indicated a clear improvement in a variety of sleep parameters after commencing with a cyclopyrrolone (zopiclone). These changes remained to some extent after zopiclone was discontinued. Also, the absence of certain withdrawal effects (i.e. rebound insomnia) upon discontinuation of zopiclone allows for patients to be carried through a potentially difficult period after stopping BDZs, while expediting the eventual discontinuation of all hypnotic medication.

Adult↗
PubMed1983

Novel non-benzodiazepine anxiolytics.

Several new non-benzodiazepine anxiolytics are reported. These include tracazolate, zopiclone, CL218,872, CGS9896, buspirone, MK-801 and fenobam. A comparison of anticonflict effects and propensity to cause sedation and potentiate the actions of ethanol is given as well as their effects upon the binding of [3H]flunitrazepam in vitro. Their anxiolytic properties after treatment with the benzodiazepine antagonist, RO15-1788, are reported also. Tracazolate shows a wide separation between anxiolytic activity and ability to cause sedation and to potentiate alcohol. It enhanced binding of [3H]-flunitrazepam in contrast to benzodiazepines which displace it. Buspirone was without anticonflict activity and had no effect on benzodiazepine binding while fenobam and MK-801, also without effect on binding, showed large and small differences on causing sedation and potentiating alcohol respectively. Among the displacers of [3H]flunitrazepam zopiclone showed diminished sedation liability, compared to diazepam, as did CL218,872 and CGS9896. Zopiclone caused potentiation of ethanol however, at doses close to anxiolytic doses, while CL218,872 and CGS9896 showed a wider safety margin for potentiation of ethanol compared to anxiolytic doses. The drug RO15-1788 antagonised the anticonflict effects of benzodiazepine displacers and had no effects upon the other agents studied.

Animals↗
PubMed1991

Involvement of the dorsal hippocampus in mediation of the antianxiety action of tandospirone, a 5-hydroxytryptamine1A agonistic anxiolytic.

The effect of tandospirone, a 5-hydroxytryptamine (5-HT)1A agonist/anxiolytic, injected directly into dorsal hippocampus, on Vogel-type conflict behavior in rats was investigated and the findings were compared with the effects of diazepam and zopiclone. Tandospirone (30 micrograms/2 microliters and 60 micrograms/2 microliters) and diazepam (40 micrograms/2 microliters) but not zopiclone (20 micrograms/2 microliters), produced a potent anticonflict action in rats. The anticonflict action of tandospirone (30 micrograms/2 microliters), injected into the dorsal hippocampus, was significantly blocked by (-)-propranolol (5 mg/kg i.p.). The present findings provide evidence that suggests that tandospirone has an antianxiety action, presumably by stimulating 5-HT1A receptors in the dorsal hippocampus.

Animals↗
PubMed1992

Differential development of tolerance to the depressant effects of benzodiazepine and non-benzodiazepine agonists at the omega (BZ) modulatory sites of GABAA receptors.

In a previous study, it was found that both the benzodiazepine hypnotic, midazolam, and the imidazopyridine hypnotic, zolpidem, which has selective affinity for a sub-population of omega (benzodiazepine, BZ) modulatory sites of GABA(A) receptors, produced similar decreases in rates of food-reinforced lever pressing in rats. However, during 10 days of repeated administration, marked tolerance developed to the depressant effect of midazolam but little tolerance developed with zolpidem. It was found in the present study that, with a within-subject design similar to that used previously, tolerance developed to the response rate-decreasing activity of the benzodiazepine, triazolam and the cyclopyrrolone, zopiclone but not to that of the triazolopyridazine, CL 218,872. In another experiment, using a between-groups design, tolerance developed to the effect of midazolam, even if the injections were not associated with daily test sessions, providing no evidence for a drug-environment interaction. The lack of tolerance to zolpidem was confirmed in two experiments. There was little indication of tolerance to the depressant effect of zolpidem, even after 19 days administration of daily doses, up to 30 mg/kg, a dose 10 times greater than that which completely suppressed responding. These results showed that the extent to which tolerance develops to the effects of drugs with affinity for omega (BZ) modulatory sites can show wide variations which may be related to differences in mechanisms of action.

Animals↗
PubMed1983

Correlations among measures of response to benzodiazepines in man.

A retrospective analysis of five studies using benzodiazepines and one using a benzodiazepine-like drug, zopiclone, and involving 61 subjects in toto was carried out. All used a placebo control and all acute studies incorporated pre-treatment values as well. Eight variables which have previously been shown to be sensitive to benzodiazepine action and which covered a range of physiological, psychological and subjective measures were chosen. Within-subject correlations between drug minus placebo values for these variables were computed to examine relationships between the measures while the subjects were taking benzodiazepines. It was found that closely related measures within system were significantly correlated but other correlations were sparse. However under limited conditions, i.e., several doses of one drug in the same subjects as in the zopiclone study, a consistent pattern of effects was shown across measures, resulting in half of the possible correlations showing statistical significance. A similar pattern was shown in patients after 2-4 weeks treatment with benzodiazepines.

Anti-Anxiety Agents↗
PubMed1985

Benzodiazepine-induced hyperphagia in the nondeprived rat: comparisons with CL 218,872, zopiclone, tracazolate and phenobarbital.

Nondeprived male rats were familiarized with 30 min daily access to a highly palatable diet. Clonazepam, midazolam and chlordiazepoxide each produced significant dose-dependent increases in food consumption. Clonazepam was the most potent, and a significant hyperphagic effect was detected following 0.078 mg/kg (IP). Amongst novel non-benzodiazepine anxiolytics, zopiclone and CL 218,872 also produced significant increases in food intake. The smallest doses to produce significant hyperphagia for these two drugs were 10.0 and 2.5 mg/kg (IP) respectively. In contrast, tracazolate caused only a reduction in feeding, evident at 20 and 40 mg/kg (IP). Previous reports indicate that although benzodiazepines, zopiclone and CL 218,872 displace [3H] flunitrazepam binding in rat cerebral cortex preparations, tracazolate enhances the binding. Our results are consistent with the drug-induced hyperphagia depending upon agonist actions at high-affinity benzodiazepine sites. They also provide pharmacological evidence for a dissociation between hyperphagic and anxiolytic drug effects. Phenobarbital (2.5-40.0 mg/kg), like the benzodiazepines, produced a strong stimulation of food intake, indicating that drug action at an alternative site in the benzodiazepine receptor-GABA receptor-chloride channel complex can also lead to hyperphagia.

Animals↗
PubMed1987

Differential effects of benzodiazepine receptor ligands on isotonic saline and water consumption in water-deprived rats.

Water-deprived male rats were adapted to a 30 min test of water or saline drinking in a single-bottle acceptance test. The potent benzodiazepine agonist, clonazepam, produced significant increases in both water and saline consumption. Increases in the consumption of both were also obtained with the non-benzodiazepine agonist, zopiclone (a cyclopyrrolone), but not with the pyrazoloquinoline agonist, CGS 9896. Hence, some, but not all, benzodiazepine receptor agonists enhance drinking responses. The benzodiazepine receptor antagonists, Ro15-1788 and CGS 8216, had no significant effect on the intake of either isotonic saline or water. In contrast, the beta-carboline FG 7142, which has been described as an inverse agonist acting at benzodiazepine receptors, reduced both saline and water drinking at 10 and 20 mg/kg. Although the baseline level of saline drinking was considerably higher than that of water, there was no general indication that any drug effect on consumption interacted with the type of fluid in the drinking test. However, in the case of agonist-induced increases in consumption, peak effects occurred at different doses; they were lower for saline- than for water-drinking.

Animals↗
PubMed1987

A new method for screening anxiolytic drugs in rats.

In order to evaluate the anxiolytic action of drugs, a simple experimental procedure using a corridor-type runway was designed. In this apparatus, five food pellets were set in a row on a plastic platform. Rats with one day food-deprivation take a food pellet and then usually return to the start box. The time required to take 5 pellets (total time) and the number of returns were recorded. Diazepam (DZP) at 1-3.2 mg/kg and zopiclone (ZOP) at 10 mg/kg caused decreases in both parameters. These effects were blocked by the benzodiazepine receptor blocker, Ro15-1788, at 10 mg/kg. However, tracazolate failed to produce any change in both parameters. Haloperidol and imipramine prolonged the total time while reducing the number of returns. In contrast to DZP and ZOP, pentetrazol, well known to possess an anxiogenic effect, prolonged the total time. These results suggest that decreases in both the total time and the number of returns produced by DZP and ZOP may be related to their anxiolytic action which is mediated by a benzodiazepine receptor. Therefore, this procedure would be a simple and selective method for detecting benzodiazepine-type anxiolytics.

Animals↗
PubMed1988

Zopiclone, a cyclopyrrolone hypnotic: review of properties.

Zopiclone is a non-benzodiazepine hypnotic with a pharmacological spectrum of activity which resembles that of the benzodiazepines (BZD), but it binds to the GABA complex at a site different from the BZD receptor. Pharmacokinetic properties class ZPC in the category of hypnotics with intermediate-short half-life (5-7 hours) and explain the low incidence of unwanted effects reported. The influence of zopiclone 7.5 mg on sleep architecture is minimal. In healthy volunteers, the amount of deep sleep is increased. No depressant effect on respiratory function and no rebound effect has been demonstrated.

Azabicyclo Compounds↗
PubMed1990

Drug discrimination in rats successively trained to discriminate diazepam and pentobarbital.

In Phase 1, rats were trained to discriminate either diazepam or pentobarbital from the no-drug condition. Diazepam, pentobarbital, triazolam, meprobamate, and zopiclone occasioned 100% drug-lever responding in tests under both training conditions; but the generalization gradients determined under the pentobarbital training condition were shifted to the right of those determined under the diazepam training condition. In Phase 2, the training drugs were reversed for the two groups, as well as which lever was paired with drug or no drug, in an effort to produce greater specificity of the Phase 2 discrimination. In Phase 2 tests, the Phase 1 training drug occasioned responding on the Phase 2 drug lever in all rats, suggesting that retraining overrode the Phase 1 discrimination. There were indications, however, that Phase 1 training influenced Phase 2 responding: 1) Rats ceased responding partway through no-drug training sessions using the former drug lever, and criterion performance was somewhat more difficult to maintain in Phase 2. 2) In Phase 2, dose-effect curves determined under pentobarbital training were shifted even further to the right of those determined under diazepam training than in Phase 1.

Animals↗
PubMed1990

Zopiclone.

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Azabicyclo Compounds↗
PubMed1990

Zopiclone.

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Azabicyclo Compounds↗
PubMed1992

Effects of zopiclone on subjective evaluation of sleep and daytime alertness and on psychomotor and physical performance tests in athletes.

1. In a double-blind cross-over study 8 athletes received during 2 sessions of 2 nights zopiclone (7.5 mg) or placebo. 2. Residual effects on subsequent daytime functions were evaluated both subjectively by visual analogue scales as well as objectively by a test battery measuring psychomotor and physical skills. 3. Zopiclone had some favourable effects on self-estimated sleep quality and daytime sleepiness. 4. Psychomotor and physical performance tests did not show any significant difference between zopiclone and placebo. 5. We conclude that zopiclone has useful hypnotic activity without significant adverse effects on athletic performance.

Adult↗
PubMed1993

Effects of zopiclone, flunitrazepam, triazolam and levomepromazine on the transient change in sleep-wake schedule: polygraphic study, and the evaluation of sleep and daytime condition.

1. The effects of zopiclone 10mg (ZP), flunitrazepam 1mg (FN), triazolam 0.25mg (TZ) and levomepromazine 5mg (LP) on two models of sleep-wake schedule change-6 hours advanced shift: (A-shift), and 6 hours delayed: (D-shift)--were investigated in 6 healthy volunteers using polysomnography. 2. In A-shift with placebo, TST, SEI, %SR and REM/NREM decreased. ZP, FN and TZ shortened SL. All drugs increased TST and SEI. TZ and LP increased %SR and REM/NREM. 3. In D-shift with placebo, TST decreased, SWSL was prolonged, %S3+4 decreased, and %SR and REM/NREM increased. All drugs increased TST. ZP and LP shortened SWSL. All drugs increased %SWS. ZP, FN and TZ decreased %SR. ZP and FN decreased REM/NREM. 4. Daytime mental and physical conditions were worse than usual on more than half of the days in A- and D-shift. LP and FN caused some inadequate conditions on the following days. Significantly higher REM/NREM was observed in the nights before the days with worse mental conditions in D-shift, and lower REM/NREM in the nights before the days with worse physical conditions in A-shift. 5. It is concluded that TZ and ZP are superior to the others for A-shift and D-shift, respectively.

Adult↗