The Pharmacology and Mechanism of Action of Zolpidemzolpidem, and its interaction with GABAA...

The Pharmacology and Mechanismof Action of Zolpidem

David J. Sanger and Henri Depoortere

Synthélabo Recherche, Bagneux, France

Key Words: Imidazopyridine–Insomnia—Sleep—Zolpidem.

INTRODUCTION

Each of us spends approximately one third of our life sleeping. Thanks to technological

advances in methods of evaluating the electrical activity of the brain during sleep and

wakefulness (polysomnography) we now know a great deal about the physiology of sleep

in humans and lower animals. We know less about the functions of sleep, however, al-

though there has never been any shortage of theory and speculation on this topic. The bio-

logical significance of sleep is emphasized by the important effects of sleep disturbances.

Sleep disorders are classified by the DSM IV into dyssomnias and parasomnias; the major

clinical problem in this area is probably primary insomnia.

Insomnia is not itself a disease and may or may not be considered a symptom of an-

other physical or psychiatric disorder. It is best characterized as a complaint of difficulty

in initiating or maintaining sleep or of sleep which is not satisfying or restorative. It is es-

sentially a subjective problem, therefore, although polysomnographic and other objective

methods may have important roles to play in evaluating the significance of the problem

and the effectiveness of treatments. Assessments of the prevalence of insomnia vary, but

all recent surveys indicate that it is a common problem. Ohayon (55), using a telephone in-

terviewing technique of a representative sample of the French population, reported that

18.6% of the sample complained of insomnia. This figure is, in fact, slightly lower than

those obtained in other populations (some surveys have reported that up to 40% of the

population may suffer from insomnia in a given year) (14,29,39,49). Marked differences

between different countries have also been reported (90). Complaints of insomnia increase

with age and are more common in women than in men (61,88). Using a figure for the

prevalence rate of insomnia in the population of the United States of 32 to 33%, Stoller

calculated that the economic costs associated with this disorder could be approximately

$100 billion (83). Although such calculations are necessarily estimates and subject to con-

troversy, it has also been proposed that the annual cost of accidents alone in the USA asso-

ciated with insomnia may be about $50 billion (45,96).

323

CNS Drug ReviewsVol. 4, No. 4, pp. 323–340© 1998 Neva Press, Branford, Connecticut

Address correspondence and reprint requests to Dr. D. J. Sanger, Synthélabo Recherche, 31 avenue Paul

Vaillant-Couturier, 92220 Bagneux, France. Fax: +33 (1) 45-36-20-70.

Much insomnia is associated with disturbances in patterns of living or disruptive lifeevents and is, therefore, transitory and may not require specific treatment. In other patientsthe problem may be solved by changes in behavior or lifestyle, usually referred to as goodsleep hygiene (35). For example, patients should be advised to maintain regular sleepingtimes, avoid stimulants such as coffee in the evenings and so on (50). For patients inwhom insomnia is a more intractable problem, however, treatment with hypnotic drugsmay be appropriate. Indeed, a significant number of people report that they self-medicatewith alcohol, herbal drinks, or over-the-counter sleep aids to assist sleep (16).

Over the last century, a variety of hypnotic agents have been introduced into medicineranging from the bromides and chloral hydrate through the barbiturates and thebenzodiazepines to the newer non-benzodiazepine agents. Although not even the neweragents probably achieve all the criteria of the “ideal” hypnotic as defined by Bartholini(6), progress has certainly been made in inducing and maintaining sleep while limiting un-wanted effects. Many brain mechanisms are undoubtedly involved in the regulation ofsleep but it is remarkable that the great majority of drugs used for sleep induction act by

potentiating the actions of the inhibitory neurotransmitter γ-aminobutyric acid (GABA).The present paper will summarize the pharmacology of the non-benzodiazepine hypnotic,zolpidem, and its interaction with GABAA receptors in the central nervous system.

CHEMISTRY

Zolpidem (N,N,6-trimethyl-2[4-methyl-phenyl]imidazo[1,2-a]pyridine-3-acetamidehemitartrate) is a stable, water-soluble, microcrystalline solid with a molecular weight of392.4 (weight of salt). Its structural formula is shown in Fig. 1 in comparison with twoother non-benzodiazepines, zopiclone, which is also used in the treatment of insomnia(54) and zaleplon which is in clinical development also as a hypnotic (8). The medicinalchemistry program that led to the discovery of zolpidem and other imidazopyridine deri-vates has been described by George et al. (34).

PRECLINICAL PHARMACOLOGY

The aim of the drug discovery program that led to zolpidem was to identify a non-ben-zodiazepine compound that would show a rapid-onset, short-duration hypnotic effect andwould bind to benzodiazepine (BZ) receptors. Zolpidem has these characteristics (24), butduring the course of the pharmacological evaluation of the compound it was found thatboth, its pharmacological profile and its mechanism of action, differed in potentially sig-nificant ways from those of the benzodiazepines themselves.

Since the objective of the research program was to synthesize and develop ligands forBZ receptors, the first level of primary screening necessarily involved a receptor-bindingassay. Many imidazopyridine derivatives were found to have high and selective affinitiesfor these sites, zolpidem displacing radiolabelled diazepam from preparations of rat brainmembranes with affinities of 27 nM in the cerebellum and 109 nM in the hippocampus(4). These in vitro studies were followed by investigation of the effects of zolpidem on the

CNS Drug Reviews, Vol. 4, No. 4, 1998

324 D. J. SANGER AND H. DEPOORTERE

EEG of rats and cats; it was found that the compound produced a rapid-onset, short-dura-

tion hypnotic effect (4,24).

Electrocorticographic (ECoG) measures in immobilized rats showed that zolpidem at

doses of 0.1 to 1.0 mg/kg by the intraperitoneal route, and doses approximately three

times higher when administered orally, produced a pattern of activity characterized by

slow waves (2 to 4 Hz) with only transient periods of fast activity (12 to 14 Hz) at high

doses (21,24). This was considered to be of particular interest because, in similar experi-

ments, benzodiazepines were typically observed to produce a greater degree of fast ac-

tivity which was thought not to correspond to a pattern of normal sleep (24). The hypnotic

effect of zolpidem, consisting of an increase in slow-wave or non-rapid eye movement

(NREM) sleep was confirmed with measures of the EEG in freely moving rats and cats. In

these studies, zolpidem produced a short-duration (∼ 3 h in rats, depending on dose) in-

crease in NREM sleep with little effect on the proportion of REM sleep except at high

doses (21,24,26).


ZOLPIDEM 325

Fig. 1. Structural formula of the imidazopyridine hypnotic zolpidem in comparison with those of two other

non-benzodiazepine hypnotics, zopiclone and zaleplon.

Recently, the analysis of the microstructural elements of sleep provided a novel ap-proach to the evaluation of the stability and quality of sleep. It is possible to model in-somnia in rats using a variety of methods, such as recording during the dark phase of thenocturnal cycle, depleting brain serotonin, or making lesions of certain brain regions suchas the olfactory bulbs. Using such techniques, it has been found that sleep patterns shownumerous periods of wakefulness and light sleep indicating poor sleep quality. In such ex-periments, zolpidem reduced sleep fragmentation and microarousals and induced a morestable overall pattern of sleep (22,23).

Behavioral Effects

The effects of zolpidem as measured by EEG were confirmed with behavioral experi-ments in rats and mice which showed decreases in locomotor activity and other uncondi-tioned and conditioned behaviors (24,56,74). Like other compounds acting as agonists atBZ receptors, zolpidem produced a variety of other behavioral and neuropharmacologicaleffects. These included anticonvulsant actions, motor incoordination, discriminativestimulus properties, anxiolytic-like effects, and actions on learning and memory. When thepotency of the drug to induce these different actions was analyzed in detail, however,zolpidem showed an unexpected profile.

One of the pharmacological tests most sensitive to benzodiazepines is convulsions in-duced in rats or mice by pentylenetetrazol; this test has been used as a screening procedurefor this type of drug. Zolpidem was found to antagonize pentylenetetrazol-induced sei-zures in mice at doses similar to those that blocked seizures produced by electroshock andhigher than doses that reduced locomotor activity, a presumed reflection of the drug’s sed-ative effect (56). These results are shown in Fig. 2, which emphasizes the difference be-tween the pattern of results obtained with zolpidem and those of quazepam, brotizotam,and zopiclone.

These findings were important since they indicate that in mice, as in rats (7,74), sed-ative effects seem to predominate over other actions of zolpidem (24). It is also of par-ticular interest that increases in muscle relaxation and motor incoordination (which are notparticularly desirable in a hypnotic drug) occurred only at the highest doses. Thesefindings are also of considerable theoretical interest, however. It had previously been as-sumed that all the pharmacological effects of benzodiazepines were mediated by activityat similar receptors, possibly situated in different regions of the CNS. The observation thatdifferent dose ranges of any particular benzodiazepine were necessary to give rise to dif-ferent effects was believed to be related to receptor reserve or the proportion of receptorsthat needed to be occupied to produce each effect. Thus, occupation of a relatively smallnumber of receptors was sufficient to block pentylenetetrazol-induced seizures, whereasmany more receptors would have to be occupied before sedation occurred (cf. brotizolamin Fig. 2). Of course, the observation of a profile such as that of zolpidem indicates thatthis hypothesis cannot be correct and such findings are more consistent with the idea thatdifferent effects of BZ-receptor agonists might be mediated by different receptor subtypes(69,101). The extent to which biochemical and electrophysiological results with zolpidemare consistent with this hypothesis is considered below.

Zolpidem has also been studied in a variety of other behavioral procedures and resultsgenerally show that sedative effects predominate and may mask other actions. The drug



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Fig. 2. Dose-related pharmacological effects of zolpidem, quazepam, brotizolam, and zopiclone in mice. Measures are: exploratory locomotor activity (EA), inhibition of sei-

zures induced by pentylenetetrazol (PTZ) and electroshock (MES), muscle relaxation as assessed by the hanging grid test (MYO), and ataxia as measured by a rotarod test

(ATA). From ref. 56.

has anxiolytic-like effects but only in a limited range of tests and only at doses that de-crease behavioral output (24,36,53,69). Similarly, increases in food and fluid intake in ro-dents, which are consistently reported with benzodiazepines, have been reported onlyrarely with zolpidem (15,18,56,74,81,100). An effect on the learning of an avoidance re-sponse was also found in mice only at sedative doses (71).

Like many psychotropic agents, agonists at BZ receptors can serve as discriminativestimuli and drug discrimination methods have been extensively used to characterize thebehavioral pharmacology of zolpidem. In rats there is only limited cross-substitution be-tween zolpidem and benzodiazepines (24,71) and these findings have been used to de-velop theories concerned with the role of receptor subtypes (69,70). The few studies thathave been carried out in this area with non-human primates suggest, however, that differ-ences between zolpidem and benzodiazepines may be less apparent in these species(37,65). In a recent drug discrimination experiment using human volunteers, the subjectswere able to learn a discrimination between zolpidem and triazolam (51).

Effects of Repeated Administration

Chronic administration of benzodiazepines, particularly at high doses, can lead to a de-crease in drug efficacy or potency (pharmacological tolerance) or the appearance of with-drawal or abstinence signs when drug treatment terminates (physiological dependence).The extent to which these phenomena occur under conditions of normal clinical use is ofcourse a cause of concern for both physicians and patients and there is evidence that phys-iological dependence does develop in the clinic with at least some benzodiazepines (99).

It is imperative, therefore, that, during the development of novel hypnotic or anxiolyticdrugs, studies are carried out to investigate the conditions under which tolerance or de-pendence may occur. A number of experiments have been described involving repeatedadministration of zolpidem to rats and mice and the results suggest that little pharmaco-logical tolerance develops to the anticonvulsant or sedative effects of the drug(21,57,73,75,77). Of particular interest is the finding that, when zolpidem was comparedwith equivalent doses of other BZ-receptor agonists, marked differences were observedbetween the different drugs. Fig. 3 shows that, while tolerance developed quite rapidly tothe depression of conditioned behavior produced by midazolam, little tolerance occurredwith equivalent doses of zolpidem (75). In contrast to these rodent experiments, a studyinvolving repeated administration of zolpidem to baboons showed apparent tolerance tothe ataxia produced by the drug occurring within a few days (37).

The development of pharmacological tolerance is presumably due to the entrainment ofcompensatory physiological mechanisms during chronic drug treatment and similar pro-cesses may underlie physiological dependence. It is not surprising, therefore, that severalexperiments with mice have reported that little spontaneous or precipitated withdrawal isobserved following repeated administration of zolpidem (57,93). Similarly, in a study in-volving squirrel monkeys, it was found that fewer signs of precipitated withdrawal oc-curred with zolpidem than with diazepam (64). However, precipitated withdrawal fromzolpidem was reported when very high doses were given to mice (300 mg/kg/d) (84) andseveral studies have reported withdrawal signs classified as mild or intermediate inzolpidem-treated baboons (37,97,98). It is likely, however, that the doses of zolpidem used



in these primate studies may have produced levels of receptor occupation much higher

than those ever likely to occur under normal clinical conditions (9,76).

This set of studies indicates that even at sedative doses of zolpidem little tolerance or

physiological dependence develops, at least in rodents. At high doses these phenomena

are more likely to occur, as would be expected, and there may also be significant differ-

ences among different species of laboratory animals. This research appears to provide a

good prediction of the clinical situation. Tolerance and dependence appear not to have

been reported during the normal clinical use of zolpidem at recommended doses, although

there are a very small number of reports that suggest tolerance and/or dependence in-

volving abnormally high doses (see refs. 17,66,82 for review).

MECHANISM OF ACTION

Binding to Native Receptors

As noted in an earlier section, zolpidem was originally selected for investigation and

ultimately clinical development because it was found to displace radiolabelled


ZOLPIDEM 329

Fig. 3. Dose-related effects of midazolam and zolpidem on rates of bar pressing in rats following of 10 daily in-

jections of saline, midazolam (3.0 mg/kg), or zolpidem (1.0 mg/kg). The rightward shift of the midazolam

dose-response curve indicates that pharmacological tolerance developed to the sedative effect of this drug. From

ref. 75.

benzodiazepines from their binding sites in the CNS. In addition, the pharmacological ef-fects of zolpidem are blocked by the BZ-receptor antagonist flumazenil (24,68), showingthat the drug exerts its actions through these sites. However, it soon became apparent that,as described in the preceding sections, the pharmacological effects of zolpidem after acuteand repeated administration showed certain interesting differences from those ofbenzodiazepines. Zolpidem’s mechanism of action was, therefore, investigated in greaterdetail. This was done using receptor-binding methods and several laboratories showed amore selective binding profile of zolpidem than that observed with the benzodiazepinesthemselves.

Zolpidem displaced the binding of different benzodiazepines from brain membranepreparations or brain sections in a regionally selective way (4,11,20,48,79). In particular,zolpidem displaced benzodiazepines more potently in the cerebellum than in the hippo-campus or the spinal cord, a pattern previously defined as selectivity for Type-1 or BZ1 re-

ceptors (80). (Some authors have proposed that the nomenclature ω should be used in

place of BZ — and therefore ω1 and ω2 in place of BZ1 and BZ2 — because many of thedrugs that bind to these sites do not have benzodiazepine structures. The receptors will,

therefore, be referred to as BZ(ω) for the remainder of the paper [43]). The appropriate no-menclature for these sites has recently been discussed in detail (5). Table 1 provides

several examples of the BZ1(ω1) selectivity of zolpidem.Studies involving the binding of labeled zolpidem itself also observed a more limited

and heterogeneous distribution of binding sites in the rat CNS than that found withbenzodiazepines (3,48). Autoradiographic studies with [3H]zolpidem in sections of



TABLE 1. Examples of the regional selectivity of biding of zolpidem

to BZ(w) receptors in rat brain membrane preparations in vitro

monkey and human brain showed that zolpidem binds with greater regional selectivitythan do benzodiazepines (20), although a recent study found that the patterns of selectivitywere not identical in rats and monkeys (25, but see also 76).

The binding of zolpidem to BZ(ω) receptors in different regions of the CNS has alsobeen investigated in vivo in rodents sacrificed after systemic administration of drug and la-beled ligand (10,11) and in baboons and humans using positron emission tomography(1,76). In the animal studies, the regional selectivity of zolpidem’s binding was again ap-parent (Table 2). However, the PET study in human volunteers found similar levels of re-ceptor occupation in different brain regions (mean of 29%) after administration ofzolpidem 20 mg. This is likely to be related to the CNS areas chosen for investigation andbecause the proportion of sites occupied was relatively low. On the basis of these results ithas been calculated that the clinical dose of zolpidem 10 mg would be expected to occupy

only 10 to 15% of the total population of BZ(ω) sites, a proportion considerably less thanthat seen with pharmacologically equivalent doses of benzodiazepines (9).

Activity at Recombinant GABAA Receptors

It has been known for some time that BZ(ω) binding sites are associated with theGABAA subtype of receptors for the inhibitory neurotransmitter GABA. Recent develop-ments in molecular biology have shown that GABAA receptors, like other receptors of theligand-gated ion-channel family, are made up of five subunits that occur in several fam-

ilies of polypeptides (α, β, γ, etc.) (47,52). The BZ(ω) binding sites are associated with the

α and γ subunits and functional recombinant GABAA receptors can be expressed in, for

example, human embryonic kidney (HEK) cells by combining α, β, and γ subunits. Suchpreparations can then be used in biochemical and electrophysiological experiments to in-vestigate the mode of action of different pharmacological agents (78).

Seeburg et al. (62) first reported that GABAA receptors consisting of an α1 subunit in

combination with β3 and γ2 subunits showed high affinity for zolpidem, whereas receptors


ZOLPIDEM 331

TABLE 2. Regional selectivity of displacement by zolpidem

of [3H]flumazenil binding in the rat CNS in vivo

2 2

with α2 or α3 subunits showed much lower affinity, and receptors containing α5 subunitsshowed no affinity at all (Table 3). These results indicated that GABAA receptors con-

taining α1 subunits correspond to the pharmacologically defined BZ1(ω1) receptor

whereas the BZ2(ω2) sites are probably heterogeneous, corresponding to GABAA re-

ceptors containing α2, α3, or α5 subunits. The selectivity of zolpidem has been confirmedin a number of subsequent studies which have also shown that, in contrast, most other

BZ(ω) site agonists bind to GABAA receptor subtypes with similar affinities (13,28,38).

That these differences in affinity between different GABAA receptor subunit combina-tions have functional significance has been shown using single-cell electrophysiological

recordings. When zolpidem is applied to receptors containing α1 subunits, low concentra-tions potentiate the effect of GABA whereas higher concentrations are required in re-

ceptors containing α2 or α3 subunits and there is little or no response in α5-containing re-ceptors (12,63,94). These findings are illustrated in Fig. 4, which also shows the lack ofselectivity of diazepam.

PHARMACOKINETICS AND METABOLISM

The pharmacokinetic and metabolic profiles of zolpidem have been investigated indetail in experimental animals and humans and several descriptions of this information areavailable (30,33,67). After oral administration, zolpidem is rapidly and completely ab-sorbed with bioavailabilities of 20% in the rat, < 10% in monkeys and 70% in humans.Peak plasma levels are reached after approximately 15 min in rats, 30 min in monkeys,and 1 h in humans. Elimination half-lives are of the order of 1.5 h in rats, 1 to 2 h inmonkeys and 1.5 to 3.0 h in humans. The drug rapidly crosses the blood-brain barrier.

Zolpidem metabolites have been identified and pharmacologically inactive (33). Themajor metabolite is a carboxylic-acid derivative that accounts for > 50% of the adminis-tered drug. In humans, biotransformation by cytochrome P450 (CYP) isoenzymes in-volves mainly CYP-3A4, although CYP-1A2 and CYP-2D6 also play minor roles (58).Experimental studies indicate that the risk of pharmacokinetic drug interactions in clinicalpractice is low (30,67) although co-administration with inducers of CYP enzymes mayresult in reduced plasma concentrations and decreased effectiveness of zolpidem (91).



TABLE 3. Displacement of [3H]flumazenil binding from recombinant

GABAA receptors with different subunit combinations

CLINICAL EXPERIENCE WITH ZOLPIDEM

Efficacy

Zolpidem was first introduced to the market as a short-term treatment for insomnia in

France in 1988. It has subsequently been registered in > 70 countries. It was first marketed


ZOLPIDEM 333

Fig. 4. Potentiation by diazepam and zolpidem of the GABA-induced Cl– current in cell lines transfected with

GABAA receptors containing α1 (�), α3 (p), or α5 (¢) subunits. Results are shown as the potentiation of the

maximum GABA-induced current in each cell line. Similar concentrations of diazepam were effective in the

three cell lines, whereas zolpidem showed selectivity of action at GABAA receptors containing α1 subunits.

From ref. 12.

in the United States in 1993. In some countries, zolpidem is the most widely prescribedand used hypnotic drug.

A large number of clinical studies of the efficacy of zolpidem in inducing and main-taining sleep, involving tens of thousands of patients, have been carried out and the resultshave been published. Several detailed reviews of this literature are available (44,59,95).Zolpidem’s activity has been evaluated using subjective assessments in which patients re-sponded to questionnaires concerning the latency, quality, and duration of their sleep. Insuch studies, zolpidem was reported to reduce sleep latency, increase duration, andproduce more satisfying sleep. These findings have been confirmed in trials using ob-jective polysomnographic methods in which sleep latency and noctural awakenings werereduced and sleep duration was increased. These studies have also reported that sleep ar-chitecture was not disrupted during a night of zolpidem-assisted sleep (95).

Analyses of the microstructure of sleep have also been carried out using measures ofthe cyclic alternating pattern (CAP). CAP rate is significantly correlated with the sub-jective appreciation of sleep quality even in the absence of significant macrostructural al-terations (87). Zolpidem was found to reduce the increased CAP rate shown in the dis-turbed sleep of insomniac patients and to attenuate the instability of the sleep patternsproduced by noise (85,86).

In seeking to develop zolpidem as a rapid-onset, short-duration hypnotic, a major aimwas to identify a drug that would not give rise to impairments in performance the day aftera night of drug-assisted sleep. Such next-day effects have been a significant cause forconcern with some hypnotic barbiturates and benzodiazepines. A number of studies weretherefore carried out to investigate next-day alertness and psychomotor performance withzolpidem (for review see refs. 19,89). The results of these studies showed that when ap-propriate doses of zolpidem (5 to 10 mg) were taken at bedtime there were minimal effectson cognitive or psychomotor performance or daytime drowsiness the next morning.

Safety

Before registration and marketing, zolpidem was tested in the appropriate toxicologicalscreens in experimental animals. The results showed that the compound was extremelywell tolerated with a large therapeutic ratio (31). In the clinic, controlled trials and post-marketing surveillance have confirmed the positive safety profile (2,17,60). Zolpidem isalso safe in overdose; Garnier et al. (32) reported in a review of 344 cases of intentional,acute overdose that the effects were generally benign, requiring no specific measuresexcept support and perhaps gastric lavage. In post-marketing surveys most reported ad-verse events were CNS related and not unexpected for a hypnotic drug (e.g., drowsiness orsedation). Gastrointestinal events such as nausea are also reported occasionally, particu-larly at higher doses (60). It has been suggested, in fact, that such effects may limit theabuse potential of zolpidem (27). Rebound insomnia following cessation of a course ofhypnotic treatment, which has been reported to be a problem with some other drugs in thisclass, is also of minimal significance when zolpidem is used at the correct doses and for anappropriate duration (92).



DISCUSSION

In the 10 years since it was first introduced to the market, zolpidem has become awidely used and successful hypnotic drug. When taken according to prescribing guide-lines it is a very effective and safe medicine. Zolpidem has also become an important ex-perimental tool for both laboratory workers interested in the neuropharmacology and be-havioral pharmacology of hypnotic drugs and researchers studying the structure andfunction of GABAA receptors. The selectivity of zolpidem for different GABAA-receptorsubtypes, particularly its lack of activity at receptors containing α5 subunits, makes it animportant chemical tool for research on the significance of GABAA-receptor heteroge-neity. Until more selective compounds are described, zolpidem is likely to remain a veryimportant drug for laboratory research.

The clinical profile of zolpidem also has a number of characteristics highly desirable inan agent used for the short-term treatment of insomnia. The extent to which the reporteddifferences in human experimental pharmacology and clinical actions show that zolpidemhas major clinical advantages over some other short-acting hypnotics, such as triazolam,remains a matter for debate (40,42,46). The more selective pharmacological profile andmechanism of action of zolpidem, however, suggest that, at least from a theoretical pointof view, it might offer potential advantages over other hypnotics. As summarized above,zolpidem acts selectively at certain subtypes of GABAA receptors, where it may also showa higher intrinsic efficacy than other agents (41). These characteristics mean that clinicallyactive doses of zolpidem would be expected to occupy a smaller proportion of the total

population of BZ(ω) sites associated with GABAA receptors than other drugs, as positronemission tomography (PET) studies in humans seem to confirm (9). Since zolpidem isclearly an effective agent in inducing sleep, the drug’s pharmacology would indicate that

this action is likely to involve GABAA receptors containing α1 subunits and that the addi-tional sites acted on by non-selective drugs are unnecessary for this effect. However, occu-pation of additional receptors might have significance for unwanted pharmacological ef-fects or for the development of pharmacological tolerance or physiological dependence(102). The good safety profile of zolpidem (17) may, therefore, be related to the drug’smore selective mechanism of action.

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