Tolerance and rebound insomnia with rapidly eliminated hypnotics: a meta-analysis of sleep laboratory studies.

Differences in development of tolerance and occurrence of rebound insomnia have been well established between rapidly and slowly eliminated benzodiazepine hypnotics. Based on meta-analytic methodology, this study assesses whether there are such differences among the rapidly eliminated benzodiazepine and benzodiazepine-like hypnotics (brotizolam, midazolam, triazolam, zolpidem and zopiclone). All sleep laboratory studies of these drugs (n = 137) published from 1966 to 1997 were obtained, mainly through a MEDLINE search. Rigorous selection criteria resulted in the inclusion of 75 studies employing 1276 individuals (804 insomniacs and 472 healthy volunteers). Using a mixed effects regression model, reliable estimation of the effects on insomniacs of the recommended dose of each drug could be obtained. All five rapidly eliminated hypnotics showed statistically significant initial efficacy. Tolerance with intermediate and long-term use was clearly developed with triazolam and was only marginal with midazolam and zolpidem; it could not be estimated for brotizolam or zopiclone because of insufficient data. Rebound insomnia on the first withdrawal night was intense with triazolam and mild with zolpidem; data were unavailable for brotizolam and inadequate for midazolam and zopiclone. In conclusion, there are differences among the rapidly eliminated hypnotics with respect to tolerance and rebound insomnia suggesting that, in addition to short elimination half-life, other pharmacological properties are implicated in the mechanisms underlying these side-effects.     

Limited anxiolytic-like effects of non-benzodiazepine hypnotics in rodents

The present experiments compared the anxiolytic-like effects of the benzodiazepine (BZD) hypnotic triazolam with those of four non-BZD hypnotics including one non-selective (zopiclone) and three omega1-BZD selective (zolpidem, zaleplon and SX-3228) receptor ligands, in classical animal models including conflict tests (punished lever pressing and punished drinking tests in rats) and exploratory models (elevated plus-maze test in rats and light/dark choice test in mice), and a recently developed mouse defence test battery (MDTB) which has been validated for the screening of anxiolytic drugs. Results from both conflict procedures showed that zopiclone (0.3-10 mg/kg) produced anxiolytic-like effects comparable to those of triazolam (0.1-3 mg/kg), whereas the selective omega1-BZD receptor hypnotics zolpidem (0.3-3 mg/kg), zaleplon (0.1-3 mg/kg) and SX-3228 (0.1-1 mg/kg) displayed weaker and/or non-specific anxiolytic-like effects. Similarly, in the light/dark test in mice, zolpidem (0.1-1 mg/kg), zaleplon (0.3-10 mg/kg) and SX-3228 (0.03-0.3 mg/kg) showed a reduced potential to produce anxiolytic-like effects as compared to the non-selective omega-BZD receptor hypnotics triazolam (0.03-1 mg/kg) and zopiclone (1-30 mg/kg). In the elevated plus-maze test, zopiclone (1-10 mg/kg), zolpidem (0.1-1 mg/kg), zaleplon (0.3-3 mg/kg) and SX-3228 (0.1-1 mg/kg) displayed anxiolytic-like activity at doses close to those producing behavioural impairment, whereas triazolam (0.03-1 mg/kg) exhibited anxiolytic-like effects over a wide dose range in the absence of decreases in general activity. In the MDTB, zaleplon (0.3-10 mg/kg) decreased all defensive responses, a profile which was similar to that of triazolam (0.03-1 mg/kg), while zopiclone (1-30 mg/kg), zolpidem (0.3-10 mg/kg) and SX-3228 (0.03-1 mg/kg) had fewer effects on defensive behaviours with several effects occurring only at motor-impairing doses. Taken together, these results demonstrate that, although selective omega1-BZD receptor hypnotics display anxiolytic-like activity, the effects are generally weaker than those observed with non-selective omega-BZD receptor selective hypnotics such as triazolam or zopiclone. In particular, the anxiety-reducing potential of the omega1-BZD receptor selective compounds is limited to certain anxiety measures and may be confounded and/or masked by behavioural suppression.     

Pharmacological profiles of benzodiazepinergic hypnotics and correlations with receptor subtypes]

We examined the behavioral pharmacological properties of six benzodiazepine (omega) receptor ligands including brotizoram, nitrazepam, quazepam, rilmazafone, zolpidem and zopiclone and the binding of these drugs with omega receptor subtypes. Behavioral tests were performed at the time of the maximal effects induced by each drug following its oral administration to mice. All of these drugs dose-dependently induced impairment of motor coordination as rotarod performance and potentiation of thiopental-induced anesthesia as hypnotic effect. The hypnotic effects of rilmazafone, whose major metabolites were bound to both omega1 and omega2 receptors with high affinity, and omega1 selective quazepam were about 20 times more effective than the induction of motor impairments when compared with ED50 values. However, there was no difference between the ED50 values of omega1 selective zolpidem alone in these two tests. An antianxiety efficacy of zolpidem was relatively weak unlike that of other drugs in the elevated plus-maze. It has been reported that omega2, but not omega1, receptors are associated with motor impairment and anxiolytic effect. The weak anxiolytic effect of zolpidem supports the previous hypothesis. However, the strong motor incoordination of zolpidem suggests that not only omega2 but also omega1 receptors are related to motor impairment unlike the previous hypothesis.     

The interaction between zolpidem and beta-CMC: a clue to the identification of receptor sites involved in the sedative effect of zolpidem

The interaction of beta-CMC, an amino beta-carboline recently described as a selective antagonist of the sedative effect of diazepam, with zolpidem, an imidazopyridine hypnotic, which like beta-CMC binds preferentially to the omega 1 (BZ-1) site of the GABA benzodiazepine chloride channel receptor complex, was investigated. In mice, beta-CMC antagonized the effect of zolpidem against isoniazid-induced convulsions without affecting its activity against convulsions induced by pentylenetetrazole or electroshock. beta-CMC also antagonized the decrease in locomotor activity and the impairment in muscle strength provoked by zolpidem. In rats trained to discriminate zolpidem, beta-CMC antagonized both the interoceptive stimulus and the decrease in the rate of lever pressing produced by zolpidem. This selective antagonism, inhibition of effects of zolpidem exerted by low doses (locomotor activity and isoniazid-induced convulsions) as well as effects produced by high doses (muscle strength) but not those provoked by intermediate doses (pentylenetetrazole and electroshock-induced convulsions), could not be explained by a receptor occupancy hypothesis. These results suggest that the anticonvulsant and sedative effects of zolpidem do not involve the same receptor subtype and that the hypnoselective properties of zolpidem may be linked to its selectivity for the omega 1 (BZ-1) site of the GABAA receptor.     

Specificity within the GABAA receptor supramolecular complex: a consideration of the new omega 1-receptor selective imidazopyridine hypnotic zolpidem

The relative contribution of different recognition sites within the GABAA receptor supramolecular complex (GRSC) to the pharmacological effects of anxiolytic and hypnotic drugs is unknown. The development of the omega 1 (ex BZ1) specific hypnotic zolpidem allows a more direct approach to the problem. In contrast to many benzodiazepine hypnotic/anxiolytics (e.g., flunitrazepam, diazepam), zolpidem shows a specificity for GABAergic function, e.g., selectively reversing isoniazide-induced seizures. Furthermore, zolpidem produces a highly specific hypnotic action as compared to myorelaxant or amnesic effects (ratio of ED50's greater than 4.0 for zolpidem; less than 1 for flunitrazepam). Zolpidem exerts its action within the GRSC as it enhances 35S-TBPS binding, as do mixed omega 1/omega 2 compounds or GABA agonists. Both the in vivo and in vitro actions of zolpidem are reversed by flumazenil and the enhanced 35S-TBPS binding is also bicuculline-sensitive. Thus, omega 1 recognition site stimulation (e.g., by zolpidem) is sufficient to produce potent pharmacological effects and modulation of the GABAA receptor-gated chloride ionophore.     

Comparison of short- and long-acting benzodiazepine-receptor agonists with different receptor selectivity on motor coordination and muscle relaxation following thiopental-induced anesthesia in mice

In this study, we compared the effects of Type I benzodiazepine receptor-selective agonists (zolpidem, quazepam) and Type I/II non-selective agonists (zopiclone, triazolam, nitrazepam) with either an ultra-short action (zolpidem, zopiclone, triazolam) or long action (quazepam, nitrazepam) on motor coordination (rota-rod test) and muscle relaxation (traction test) following the recovery from thiopental-induced anesthesia (20 mg/kg) in ddY mice. Zolpidem (3 mg/kg), zopiclone (6 mg/kg), and triazolam (0.3 mg/kg) similarly caused an approximately 2-fold prolongation of the thiopental-induced anesthesia. Nitrazepam (1 mg/kg) and quazepam (3 mg/kg) showed a 6- or 10-fold prolongation of the anesthesia, respectively. Zolpidem and zopiclone had no effect on the rota-rod and traction test. Moreover, zolpidem did not affect motor coordination and caused no muscle relaxation following the recovery from the thiopental-induced anesthesia. However, zopiclone significantly impaired the motor coordination at the beginning of the recovery. Triazolam significantly impaired the motor coordination and muscle relaxant activity by itself, and these impairments were markedly exacerbated after the recovery from anesthesia. Nitrazepam and quazepam significantly impaired motor coordination, and the impairments were exacerbated after the recovery. These results suggest that the profile of recovery of motor coordination and muscle flaccidity after co-administration of benzodiazepine-receptor agonists and thiopental is related to the half-life and selectivity for the benzodiazepine-receptor subtypes.     

Interaction of the hypnotic lormetazepam with central benzodiazepine receptor subtypes omega 1, omega 2 and omega 3]

To clarify the action of lormetazepam, 3-hydroxybenzodiazepine, on the benzodiazepine (BZ) receptor subtypes, effects of lormetazepam on motor performance in the traction test and hexobarbital-induced loss of righting reflex in mice and the binding to BZ receptor subtypes were investigated in comparison with those of other BZ hypnotics. Lormetazepam prolonged the duration of hexobarbital-induced loss of righting reflex. The minimal effective dose (1 mg/kg, p.o.) was higher than that of flunitrazepam, lower than those of diazepam and zopiclone, and the same as those of triazolam and brotizolam. Lormetazepam showed the ataxic effect at 10 mg/kg, p.o., but the separation between its effective doses for the hypnotic and ataxic effects was the largest among the hypnotics tested. In the displacement study on [3H]flumazenil binding to cerebellar and spinal cord membranes, lormetazepam bound with a higher affinity to omega 1 receptor (Ki = 10 nM) than to omega 2 receptor (Ki = 29 nM). The GABA-ratios of lormetazepam to omega 1 and omega 2 receptors were 3.9 and 4.0, respectively; and they were higher and lower than those of flunitrazepam to omega 1 and omega 2 receptors, respectively. In the displacement study on [3H] Ro5-4864 binding to kidney membranes, lormetazepam bound with a lower affinity to the omega 3 receptor (Ki = 213 nM) than flunitrazepam. Thus, lormetazepam was suggested to be a potent hypnotic with weaker ataxic effects than other BZ hypnotics, which may be due to its selective and potent agonistic action on central omega 1 receptors.     

The effects of benzodiazepine (triazolam), cyclopyrrolone (zopiclone) and imidazopyridine (zolpidem) hypnotics on the frequency of hippocampal theta activity and sleep structure in rats.

In order to investigate the relative efficacy and safety of zopiclone and zolpidem, we compared the effects of higher doses of zopiclone and zolpidem on the frequency of hippocampal theta activity and sleep structure with that of triazolam. Rats were divided into triazolam treatment group (1 mg/kg, 5 mg/kg), zopiclone treatment group (20 mg/kg, 100 mg/kg) and zolpidem treatment group (20 mg/kg, 100 mg/kg). Rats were injected intraperitoneally with these drugs or their vehicle. Polygraphic sleep recording and visual frequency analysis of the hippocampal EEG activity in REM sleep were carried out for 6 h after each injection. Zolpidem, unlike triazolam and zopiclone, had a much milder reducing-effect on the frequency of hippocampal theta activity and suppressing-effect on REM sleep. These results suggest that zolpidem may prove to be a safer hypnotic drug which has fewer or milder side effects than are benzodiazepine and cyclopyrrolone hypnotics.     

Pharmacological profile and clinical effect of zolpidem (Myslee tablets), a hypnotic agent

Zolpidem is a non-benzodiazepine hypnotic agent with a chemical structure of imidazopyridine. In vitro and in vivo binding studies, zolpidem exhibits selectivity to omega 1 receptors (GABAA-receptor subtypes containing alpha 1 subunits). Unlike benzodiazepines, zolpidem produces sedative effects in preference to anxiolytic, anticonvulsant and myorelaxant effects in behavioral experiments using mice. Double-blind comparative studies with reference drugs such as triazolam and zopiclone show that zolpidem is an effective and highly safe drug for the treatment of insomnia. In addition, zolpidem does not produce next-day residual effects, rebound insomnia and tolerance. This clinical profile of zolpidem may be related to its selectivity and high intrinsic activity for omega 1 receptors.     

Modulation of synaptic GABAA receptor function by zolpidem in substantia nigra pars reticulata

AIM: The substantia nigra pars reticulata (SNr) constitutes one of the output centers of the basal ganglia, and its abnormal activity is believed to contribute to some basal ganglia motor disorders. Different lines of evidence revealed a major contribution of GABAA receptor-mediated synaptic inhibition in controlling the activity of SNr. The benzodiazepine binding site within the GABAA receptor is a modulation site of significant clinical interest. A high density of benzodiazepine binding sites has been reported in the rat SNr. In the present study, we investigate the effects of activating benzodiazepine binding sites in the SNr. METHODS: Whole-cell patch-clamp recordings and motor behavior were applied. RESULTS: Superfusion of zolpidem, a benzodiazepine binding agonist, at 100 nmol/L significantly prolonged the decay time of GABAA receptor-mediated postsynaptic currents. The prolongation on decay time induced by zolpidem was sensitive to the benzodiazepine antagonist flumazenil, confirming the specificity on the benzodiazepine site. Zolpidem at 1 micromol/L exerted a stronger prolongation on the decay time. A further experiment was performed on behaving rats. A unilateral microinjection of zolpidem into the rat SNr caused a robust contralateral rotation, which was significantly different from that of control animals receiving the vehicle injection. CONCLUSION: The present in vitro and in vivo findings that zolpidem significantly potentiated GABA currents and thus inhibited the activity of the SNr provide a rationale for further investigations into its potential in the treatment of basal ganglia disorders.     

Evaluation of anxiolytic-like effects of some short-acting benzodiazepine hypnotics in mice

Anxiolytic-like effects of some short-acting benzodiazepine hypnotics were examined with experimental paradigms of anxiety using an elevated plus-maze in male ICR mice. Diazepam was used as a positive control. The drug at a dose of 1 mg/kg significantly increased the percentage of time spent in the open arms and percentage of the number of open arm entries in the elevated plus-maze. Triazolam, brotizolam, rilmazafone, and lormetazepam also showed an anxiolytic-like effect as indicated by the significant increase in the percentage of time spent in the open arms and percentage of the number of open arm entries. Effects of short-acting benzodiazepine hypnotics used in the study were more potent than those of diazepam. In addition, the doses affecting the elevated plus-maze by benzodiazepine hypnotics were much smaller than those that showed muscle-relaxant activity measured by the rotarod test, indicating that anxiolytic-like effects of benzodiazepine hypnotics had high specificity and selectivity.     

Effects of benzodiazepines receptor agonists on the hypothalamic-pituitary-adrenocortical axis

Previous studies have demonstrated that classical benzodiazepines decrease hypothalamic-pituitary-adrenocortical cortex (HPA) axis activity. Paradoxically, high doses of benzodiazepines also stimulate basal circulating corticosterone levels in some conditions. Because benzodiazepine agonists display little selectivity to any of the alpha subtypes of the gamma-amino butyric acid (GABA)(A) receptor to which they bind, we propose that the unequivocal results are due to an alpha subtype-dependent modulation of the hypothalamic-pituitary-adrenocortical cortex axis output. To test this, basal hormonal output and induction of Fos in the hypothalamic paraventricular nucleus were measured after administration of various benzodiazepine ligands in mice. Zolpidem, a selective alpha1 subtype agonist, produced a very strong increase in plasma adrenocorticotropic hormone and corticosterone whereas the inverse agonist FG7142 induced a small rise in plasma corticosterone. More surprisingly, the non-selective full agonists diazepam and zopiclone induced a lower increase in circulating corticosterone than after zolpidem. In contrast, the alpha(2,3,5)-selective benzodiazepine agonist and alpha1 antagonist L-838,417 had no effect on corticosterone levels. Strong induction of Fos in the paraventricular nucleus was found in response to zolpidem, diazepam, and zopiclone, but not after L-838,417. Finally, pre-administration of L-838,417 prior to zolpidem strongly inhibited the effect of zolpidem on corticosterone. Likewise, the non-selective agonists diazepam and zopiclone at a dose that alone had no effect on corticosterone also inhibited the effect of zolpidem. Taken together, these results suggest that benzodiazepine ligands modulate the hypothalamic-pituitary-adrenocortical cortex axis through partly opposite mechanisms; and that the net effect is dependent on the composition of the GABA(A) receptor subunits to which they bind.     

Benzodiazepine-induced intestinal motor disturbances in rats: mediation by omega 2 (BZ2) sites on capsaicin-sensitive afferent neurones.

1. The central and peripheral effects of the omega (benzodiazepine) site ligands, clonazepam, alpidem, zolpidem, triazolam, flumazenil, ethyl beta carboline-3-carboxylate (beta-CCE) and N-methyl beta carboline-3-carboxylate (beta-CCM) on intestinal myoelectrical activity were evaluated in conscious rats, chronically fitted with Nichrome electrodes implanted on the duodenum and jejunum. The localization of the omega (benzodiazepine) receptors involved in these effects was evaluated by use of systemic and perivagal capsaicin treatments. 2. When administered intraperitoneally (i.p.) the omega site inverse agonists beta-CCE and beta-CCM, and the omega site antagonist flumazenil, did not affect the duodeno-jejunal motility. Alpidem and zolpidem, two selective omega 1 site agonists induced an inhibition of migrating myoelectric complexes (MMCs) only at a high dose (5 mg kg-1). In contrast, clonazepam (a mixed omega 1/omega 2 agonist) and triazolam (a preferential omega 2 site agonist) disrupted the MMC-pattern at doses as low as 0.05 mg kg-1, the effect of trizolam being of much longer duration than that of clonazepam. None of these drugs altered MMC-pattern when administered centrally (i.c.v.). 3. Administered i.p. or i.c.v. prior to triazolam, alpidem blocked the effect of triazolam on duodenojejunal spike activity. Administered i.p. prior to triazolam, flumazenil suppressed the triazolam-induced MMC-disruption. Previous systemic but not perivagal capsaicin treatment suppressed the effects of clonazepam on MMCs. 4. It is concluded that omega-site agonists but not, antagonist or inverse agonists, administered systemically induced intestinal motor disturbances which may be linked to activation of omega 2 (BZ2) sites located on nonvagal capsaicin-sensitive afferent neurones.     

Imidazenil: a low efficacy agonist at alpha1- but high efficacy at alpha5-GABAA receptors fail to show anticonvulsant cross tolerance to diazepam or zolpidem

Whereas advances in the molecular biology of GABA(A) receptor complex using knock-out and knock-in mice have been valuable in unveiling the structure, composition, receptor assembly, and several functions of different GABA(A) receptor subtypes, the mechanism(s) underlying benzodiazepine (BZ) tolerance and withdrawal remain poorly understood. Studies using specific GABA(A) receptor subunit knock-in mice suggest that tolerance to sedative action of diazepam requires long-term activation of alpha1 and alpha5 GABA(A) receptor subunits. We investigated the role of long-term activation of these GABA(A) receptor subunits during anticonvulsant tolerance using high affinity and high intrinsic efficacy ligands for GABA(A) receptors expressing the alpha5 subunit (imidazenil) or alpha1 subunit (zolpidem), and a non-selective BZ recognition site ligand (diazepam). We report here that long-term activation of GABA(A) receptors by zolpidem and diazepam but not by imidazenil elicits anticonvulsant tolerance. Although anticonvulsant cross-tolerance occurs between diazepam and zolpidem, there is no cross-tolerance between imidazenil and diazepam or zolpidem. Furthermore, diazepam or zolpidem long-term treatment decreased the expression of mRNA encoding the alpha1 GABA(A) receptor subunit in prefrontal cortex by 43% and 20% respectively. In addition, diazepam but not zolpidem long-term treatment produced a 30% increase in the expression of the alpha5 GABA(A) receptor subunit mRNA in prefrontal cortex. In contrast, imidazenil which is devoid of anticonvulsant tolerance does not elicit significant changes in the expression of alpha1 or alpha5 GABA(A) receptor subunit. These findings suggest that long-term activation of GABA(A) receptors containing the alpha1 or other subunits but not the alpha5 receptor subunit is essential for the induction of anticonvulsant tolerance.     

Benzodiazepine receptor binding of benzodiazepine hypnotics: receptor and ligand specificity.

Benzodiazepine (BDZ) hypnotics bind at a specific receptor located on postsynaptic neurons. Some data support specificity of binding for several hypnotics to receptor subtypes. We evaluated BDZ receptor binding in cerebral cortical membranes using agonist, antagonist, and subtype-specific ligands for commonly used hypnotics and their metabolites. All hypnotics competed similarly at BDZ1 and BDZ2 receptor subtypes except quazepam and its metabolite 2-oxo-quazepam and to a lesser extent hydroxyethyl flurazepam (EtOH) flurazepam. These compounds had relative specificity for the BDZ1 site. Triazolam, estazolam, and flurazepam bound equally to sites labeled by agonists and antagonists but desalkylflurazepam, EtOH flurazepam, temazepam, quazepam, and 2-oxo-quazepam did not; in addition, these four compounds did not bind to the "peripheral" BDZ site labeled by Ro 5-4864. BDZ hypnotics differ in their receptor subtype and ligand binding characteristics.     

Enhancement of GABAergic transmission by zolpidem, an imidazopyridine with preferential affinity for type I benzodiazepine receptors

The effect of zolpidem, an imidazopyridine derivative with high affinity at the type I benzodiazepine recognition site, on the function of the GABAA/ionophore receptor complex was studied in vitro. Zolpidem, mimicking the action of diazepam, increased [3H]GABA binding, enhanced muscimol-stimulated 36Cl- uptake and reduced [35S]TBPS binding in rat cortical membrane preparations. Zolpidem was less effective than diazepam on the above parameters. Zolpidem induced a lower increase of [3H]GABA binding (23 vs. 35%) and muscimol-stimulated 36Cl- uptake (22 vs. 40%) and a smaller decrease of [35S]TBPS binding (47 vs. 77%) than diazepam. The finding that zolpidem enhanced the function of GABAergic synapses with an efficacy qualitatively and quantitatively different from that of diazepam suggests that this compound is a partial agonist at the benzodiazepine recognition site. Thus, our results are consistent with the view that the biochemical and pharmacological profile of a benzodiazepine recognition site ligand reflects its efficacy to enhance GABAergic transmission. Whether the preferential affinity of zolpidem at the type I site is involved in its atypical biochemical and pharmacological profile remains to be clarified.     

Zopiclone. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy as an hypnotic

Zopiclone is the first of the cyclopyrrolones, a new class of psychotherapeutic agents possessing a pharmacological profile of high efficacy and low toxicity similar to that of the benzodiazepines. Binding is thought to occur to the benzodiazepine receptor complex, or to a site closely linked to this complex. Although zopiclone exhibits anticonvulsant, muscle relaxant and anxiolytic properties in animals, it finds better use as an hypnotic because of marked sedating effects. In clinical trials, zopiclone (usually 7.5 mg) improved sleep in chronic insomniacs similarly to nitrazepam 5 mg, flurazepam 15 to 30 mg, triazolam 0.5 mg and temazepam 20 mg, but in a single study was slightly less effective than flunitrazepam 2 mg in some evaluation criteria. Sleep induction before surgical procedures in hospitalised patients is satisfactory with zopiclone, but when the drugs are administered a few hours before surgery, diazepam appears to be more effective in alleviating preoperative anxiety. Minimal impairment of psychomotor skills and mental acuity occurs in the morning after a bedtime dose of zopiclone, which has a short half-life of about 5 hours and no long acting metabolites. No serious side effects have been reported in the relatively small number of patients studied to date; the development of 'bitter taste' does not deter patients from continuing therapy. Thus, with its short duration of action zopiclone is a useful alternative to other hypnotics, especially in patients intolerant of residual effects the morning after taking an hypnotic.     

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.     

New hypnotic agents: clinical studies in general practice

The type of sleep problem should be determined so that the most appropriate hypnotic can be used, and in this respect duration of action is an important property. The benzodiazepine hypnotics are adequate for this purpose, but problems may arise due to daytime after-effects and the possibility of dependence developing. Non-benzodiazepine hypnotics may be useful alternatives and our group has undertaken double-blind comparative trials with two such compounds, namely zopiclone and zolpidem. Zopiclone was compared to temazepam in a cross-over trial on 36 patients and similar hypnotic effects were recorded. In a parallel group study, zolpidem 10 mg was compared to zolpidem 20 mg and placebo in 88 patients. Both doses of zolpidem were significantly better than placebo on a number of the parameters recorded, side-effects were negligible and there was no evidence of any rebound insomnia during the final control week.