Department of Pharmacology, University of Medical Sciences in Poznan, Fredry 10, 61701 Poznan, Poland
Received 24 December 1997; in revised form 5 November 1998; accepted 11 December 1998
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ABSTRACT |
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INTRODUCTION |
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The present experiments were designed to use our chronically ethanol-treated animals known to be alcohol non-preferring (under the two-bottle, free-choice paradigm), because of their stronger behavioural responses in different pharmacodynamic tests, compared to preferring or control Wistar rats, in particular their stronger response to the hypnotic action of ethanol and their more anxiogenic behaviour) (Mikolajczak et al., 1995, 1997
). This behaviour of non-preferring rats was in agreement with the data of others (Moller et al., 1997
; Overstreet et al., 1997
; McMillen et al., 1998
). Because there are some suggestions that preferring animals represent a genetic model of alcoholism (Colombo, 1997
; Hammoumi et al., 1997
) and correspond to Type 2 alcoholism (Cloninger, 1987
) it is tempting to speculate that non-preferring rats may represent the other type of alcoholism and would be more sensitive [contrary to preferring AA rats (Wegelius et al., 1994
)] to the anxiolytic effects of BZ-like agonists.
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MATERIALS AND METHODS |
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Alcohol
The rats were given ethanol (12% solution) in an average dose of 9 g/kg/day during the first 8 weeks of the experiment as the only source of drinking fluids (Okulicz-Kozaryn et al., 1992). After this period, the animals could drink ethanol on a free-choice basis for 2 weeks and the preference was measured as the percentage of ethanol to the total volume of liquids drunk by the rats (Daoust et al., 1987
). Only animals for whom alcohol solution constituted <50% of all liquids were selected for the experiment (non-preferring rats) (Daoust et al., 1987
; Lin and Hubbard, 1994
). During behavioural experiments, the animals had free access to water and ethanol, and their ethanol consumption was 1.2 ± 0.2 g/kg/24 h, therefore the possible effects of withdrawal could be excluded. Rats of the same age which were not given ethanol formed the control groups.
Zolpidem
The animals were given one (1x) or multiple (10x) doses of zolpidem tartrate orally (Stilnox, 10 mg tablets, Synthelabo, Le Plessis Robinson, France) in doses of 1.0 mg/kg and 2.0 mg/kg; tablets were ground and suspended in 1% solution of methylcellulose (MC). The control groups were given the corresponding volume of 1% MC.
Effects on spontaneous locomotor activity: the actimeter
The test was conducted using PAN (Polska Akademia Nauk), a licensed activity meter, by placing animals in the centre of the apparatus and recording activity of rats by electromechanical counters. The data were expressed as signals corresponding to spontaneous locomotor movements during 5 min (Chodera et al., 1994). The locomotor activity was measured in control animals 15 min after a single zolpidem (1.0, 2.0 and 3.5 mg/kg, p.o.) or MC (control 1% MC) treatment.
The effect of zolpidem on hypnotic action of ethanol
The effects of zolpidem on the hypnotic action of ethanol were assessed after administering one dose or 10 doses (for 10 consecutive days) of zolpidem. At 15 min after drug administration (Thenot et al., 1988; Garrigou-Gadenne et al., 1989
; Rowlett and Woolverton, 1997
), ethanol was administered intraperitoneally (20% v/v solution) in a dose of 3.0 g/kg (Okulicz-Kozaryn et al., 1992
) and the duration of sleep time was measured (in minutes); it being expressed as the time from the loss until the first return of the righting reflex, as described in our earlier report (Okulicz-Kozaryn et al., 1992
).
Passive avoidance test
Passive avoidance behaviour was studied in a learning step-through situation which relies on the natural preference of rats for darkness. After 2 min of habituation to a dark compartment (425x404x 456 mm) the rat was placed on an illuminated (100 W) platform and allowed to enter the dark compartment (Ader et al., 1972). Two more approach trials were given on the following day with a 2 min interval between them. At the end of the second trial, an unavoidable scrambled electric footshock [500 µA AC (alternating current), 3 s] was delivered through the grid floor of the dark compartment (learning trial). Retention of the passive avoidance response (task) was tested 48 h later by placing the animal on the platform and measuring the latency in re-entering the dark compartment to maximum time of 180 s (Mikolajczak et al., 1994
). A preliminary selection of the rats was made before the experiments (pretest procedure without any acoustic or pain stimulus): in order to select arbitrarily those rats where latency values were <180 s.
The assessment of the effect of a single administration of zolpidem on latency was done 48 h after the electric footshock and 24 h after zolpidem was administered orally. Multiple administration of zolpidem was carried out for 9 consecutive days. On the 10th day, the test was carried out, the tenth drug administration took place on the 11th day of the experiment (Mikolajczak et al., 1994) and latency was measured 48 h after electric footshock was applied.
Statistical analysis
The results obtained were expressed as the arithmetic means ± SEM. Statistical analyses were carried out using one-way analysis of variance (ANOVA) and NewmanKeuls post-hoc test or unpaired t-test for analysis of data on locomotor activity or hypnotic effects of ethanol. Kruskal Wallis and MannWhitney tests were used for memory task data analysis.
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RESULTS AND DISCUSSION |
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Moreover, comparing the duration of ethanol-induced sleep after multiple administration of zolpidem with the duration after a single dose, it was observed that the effect of the drug administered in a dose of 1.0 mg/kg was significantly weaker, whereas a dose of 2.0 mg/kg produced a statistically significantly stronger effect (Fig. 3).
Chronic administration of ethanol to rats results in developing tolerance towards the duration of ethanol-induced sleep (P < 0.01, unpaired t-test, both for 1x and 10x 1% MC) (Figs 2 and 3). We have observed this phenomenon earlier (Okulicz-Kozaryn et al., 1992
; Mikolajczak et al., 1995
) and it corresponds with the results of research on tolerance development towards the sedative, hypothermic and anxiolytic effects of chronic administration of ethanol to animals (Samson and Harris, 1992
).
This tolerance seems to be responsible for the potentiation of the previously observed, weaker effect of ethanol action after single administration of 2.0 mg/kg of zolpidem to chronically ethanol-treated rats, when compared with the 1.0 mg/kg dose (Fig. 3). It is possible that, at this point, the interaction between zolpidem, the selective agonist of BZ
1 GABAA receptors, with ethanol, at the level of GABAA receptor subunits has some significance (Thielen et al., 1993
; Khan et al., 1994
; Mhatre and Ticku, 1994
; Sanger, 1997
). However, the mechanism of zolpidem-binding to different subunits of GABAA in chronically ethanol-treated animals is not fully clear (Mhatre and Ticku, 1994
; Devaud and Morrow, 1994
; Criswell et al., 1995
; Chen et al., 1997
). Therefore the prolongation of ethanol-induced sleep, observed after multiple administration of zolpidem, particularly at the dose of 2.0 mg/kg in chronically ethanol-treated rats, might be interpreted either as the effect of interaction of other neurotransmitting systems which may condition the development of ethanol tolerance (Khanna et al., 1991
; Samson and Harris, 1992
; Morrisett and Swartzwelder, 1993
; Freund and Anderson, 1996
; Hoffman and Tabakoff, 1996
) or as a result of changes in cross-tolerance between GABAA/BZ/chloride-channel complex function and ethanol activity (Toki et al., 1996
). So it is possible that, in the course of longer administration of the higher dose of zolpidem, the symptoms of alcohol tolerance are suppressed to the extent that the duration of alcohol-induced sleep in chronically ethanol-treated rats was similar to values observed in the control animals which did not receive zolpidem (Figs 2 and 3
). One might suggest that this effect of zolpidem could also be explained in terms of the partial substitution of the ethanol cue produced by this drug in ethanol discrimination tests (Shelton and Balster, 1994
; Sanger, 1997
).
Figures 4 and 5 depict the effects of zolpidem upon the change of latency to the dark compartment, 48 h after the moment the negative stimulus was applied, in the passive avoidance test, both for control (ethanol-naive) and chronically ethanol-treated rats respectively. The results show that zolpidem alters the latency observed both in control (ethanol-naive) (Fig. 4
) and in chronically ethanol-treated animals (Fig. 5
) (KruskalWallis test [H(5,35) = 22.12, P < 0.01] and [H(5,35) =10.57, P < 0.07], respectively).
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In chronically ethanol-treated and ethanol-naive (control) rats, the multiple 1% MC treatment led to prolongation of latency in comparison to its single administration (P < 0.05, MannWhitney test) (Fig. 5). After multiple administration of zolpidem at a 2.0 mg/kg dose to chronically ethanol-treated rats, a higher latency value was obtained, in comparison with the 10x 1% methylcellulose administration (P < 0.05, MannWhitney test) (Fig. 5
). This significantly prolonged latency time during which the animals remained on the platform could be the result of increased sedation, which was also observed in the experiments examining the hypnotic effect of ethanol in an analogous group of animals (Fig. 3
).
Therefore it seems that the passive avoidance test used in this work to study the effects of zolpidem on memory in chronically ethanol-treated animals may give misleading results due to the impossibility of ruling out the sedative or anxiolytic component (Okulicz-Kozaryn et al., 1995; Griebel et al., 1996
).
In conclusion, because multiple zolpidem treatment of chronically ethanol-treated rats resulted in similar values of sleep-time to those observed in zolpidem-non-treated control animals, it is possible that multiple administration of zolpidem partially inhibits the tolerance resulting from chronic ethanol treatment.
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FOOTNOTES |
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REFERENCES |
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![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Allain, H. and Monti, J. (1997) General safety profile of zolpidem: safety in elderly, overdose and rebound effects. European Psychiatry 12 (Suppl. 1), 21s29s.
Benavides, J., Peny, B., Dubois, A., Perrrault, G., Morel, E., Zivkovic, B. and Scatton, B. (1988) In vivo interaction of zolpidem with central benzodiazepine (BZD) binding sites (as labelled by [3H]Ro-1788) in the mouse brain. Preferential affinity of zolpidem for the 1(BZD1) subtype. Journal of Pharmacology and Experimental Therapeutics 245, 10331041.[Abstract]
Berline, I., Warot, D., Hergueta, T., Molinier, P., Bagot, C. and Puech, A. J. (1993) Comparison of the effects of zolpidem and triazolam on memory functions, psychomotor performances, and postural sway in healthy subjects. Journal of Clinical Psychopharmacology 13, 100106.[ISI][Medline]
Bottlender, R., Schultz, C., Moller, H. J. and Soyka, M. (1997) Zolpidem dependence in a patient with former polysubstance abuse. Pharmacopsychiatry 30, 108.[ISI][Medline]
Boyle, A. E., Segal, R., Smith, B. R. and Amit, Z. (1993) Bidirectional effects of GABAergic agonists and antagonists on maintenance of voluntary ethanol intake in rats. Pharmacology, Biochemistry and Behavior 46, 179182.[ISI][Medline]
Burt, D. R. and Kamatchi, G. L. (1991) GABAA receptor subtypes: from pharmacology to molecular biology. FASEB Journal 5, 29162923.
Cavallaro, R., Regazzetti, M. G., Covelli, G. and Smeraldi, E. (1993) Tolerance and withdrawal with zolpidem. Lancet 342, 374375.[ISI][Medline]
Chen, F., Rezvani, A., Jarrott, B. and Lawrence, A. J. (1997) [3H]Zolpidem binding in alcohol-preferring and non-preferring rat brain. Neuroscience Letters 238, 103106.[ISI][Medline]
Chodera, A., Nowakowska, E. and Bartczak, G. (1994) Tolerance to a new class of non-benzodiazepine anxiolytics. Polish Journal of Pharmacology 46, 479 481.
Cloninger, C. R. (1987) Neurogenetic adaptive mechanisms in alcoholism. Science 236, 410416.[ISI][Medline]
Colombo, G. (1997) Ethanol drinking behaviour in Sard-inian alcohol-preferring rats. Alcohol and Alcoholism 32, 443453.[Abstract]
Criswell, H. E., Simson, P. E., Duncan, G. E., McCown, J., Herbert, J. S., Morrow, A. L. and Breese, G. R. (1993) Molecular basis for regionally specific action of ethanol on GABA-A receptors: Generalization to other ligand-gated ion channels. Journal of Pharmacology and Experimental Therapeutics 267, 522537.[Abstract]
Criswell, H. E., Simson, P. E., Knapp, D. J., Devaud, L. L., McCown, T. J. and Duncan, G. E. (1995) Effect of zolpidem on gamma-amino-butyric acid (GABA)-induced inhibition predicts the interaction of ethanol with GABA on individual neurons in several rat brain regions. Journal of Pharmacology and Experimental Therapeutics 273, 526536.[Abstract]
Curran, H. V. (1986) Tranquillising memories: a review of the effect of benzodiazepines on human memory. Biological Psychology 23, 179213.[ISI][Medline]
Daoust, M., Lhuintre, J. P., Moore, N., Saligaut, C., Flipo, J. L. and Boismare, F. (1987) Is initial sensitivity to ethanol correlated with alcohol preference in alcohol-drinking and non-drinking rats? Alcohol and Alcoholism 22, 409414.[ISI][Medline]
Depoortere, H., Zivkovic, B., Lloyd, K. G., Sanger, D. J., Perrault, G., Langer, S. Z. and Bartholini, G. (1986) Zolpidem, a novel nonbenzodiazepine hypnotic. I. Neuropharmacological and behavioral effects. Journal of Pharmacology and Experimental Therapeutics 237, 649658.[Abstract]
Devaud, L. L. and Morrow, A. L. (1994) Effects of chronic ethanol administration on [3H]zolpidem binding in rat brain. European Journal of Pharmacology (Molecular Pharmacology Section) 267, 243247.[Medline]
De Witte, P. (1996) The role of neurotransmitters in alcohol dependence: animal research. Alcohol and Alcoholism 31 (Suppl. 1), 1316.
Duncan, G. E., Breese, G. R., Criswell, H. E., McCown, T. J., Herbert, J. S., Devaud, L. L. and Morrow, A.L. (1995) Distribution of [3H]zolpidem binding sites in relation to messenger RNA encoding the 1, ß2, and
2 subunits of GABAA receptors in rat brain. Neuroscience 64, 11131128.[ISI][Medline]
Evans, S. M., Funderburk, F. R. and Griffiths, R. R. (1990) Zolpidem and triazolam in humans: behavioral and subjective effects and abuse liability. Journal of Pharmacology and Experimental Therapeutics 255, 12461255.[Abstract]
Freund, G. and Anderson, K. J. (1996) Glutamate receptors in the frontal cortex of alcoholics. Alcoholism: Clinical and Experimental Research 20, 11651172.[ISI][Medline]
Garrigou-Gadenne, D., Burke, J. T., Durand, A., Depoortere, H., Thenot, J. P. and Morseli, P. L. (1989) Pharmacokinetics, brain distribution and pharmaco-electrocorticographic profile of zolpidem, a new hypnotic, in the rat. Journal of Pharmacology and Experimental Therapeutics 248, 12831288.[Abstract]
Grant, K. A. (1994) Emerging neurochemical concepts in the actions of ethanol at ligand-gated ion channels. Behavioural Pharmacology 5, 383404.[ISI][Medline]
Griebel, G., Sanger, D. J. and Perrault, G. (1996) The use of the rat elevated plus-maze to discriminate between non-selective and BZ-1 (1) selective, benzodiazepine receptor ligands. Psychopharmacology 124, 245254.[ISI][Medline]
Hammoumi, S., Naassila, M. and Daoust, M. (1997) Experimental findings in the study of the reduction of alcohol intake. European Neuropsychopharmacology 7 (Suppl. 3), S337S340.
Hoffman, P. L. and Tabakoff, B. (1996) Alcohol dependence: a commentary on mechanisms. Alcohol and Alcoholism 31, 333340.[Abstract]
Itier, V., Depoortere, H., Scatton, B. and Avenet, P. (1996) Zolpidem functionally discriminates subtypes of naive GABAA receptors in acutely dissociated rat striatal and cerebral neurons. Neuropharmacology 35, 137145.[ISI][Medline]
Izquierdo, I. and Medina, J. H. (1991) GABA receptor modulation of memory: the role of endogenous benzodiazepines. Trends in Pharmacological Sciences 12, 260265.[ISI][Medline]
Izquierdo, I. and Medina, J. H. (1995) Correlation between the pharmacology of long-potentiation and the pharmacology of memory. Neurobiology of Learning and Memory 63, 1932.[ISI][Medline]
Kalueff, A. and Nutt, D. J. (19961997) Role of GABA in memory and anxiety. Depression and Anxiety 4, 100 110.[Medline]
Khan, Z. U., Gutierrez, A. S. and De Blas, A. L. (1994) Short and long form 2 subunits of the GABAA/ benzodiazepine receptors. Journal of Neurochemistry 63, 14661476.[ISI][Medline]
Khanna, J. M., Wu, P. H., Weiner, J. and Kalant, H. (1991) NMDA antagonist inhibits rapid tolerance to ethanol. Brain Research Bulletin 26, 643645.[ISI][Medline]
Korpi, E. S. (1994) Role of GABAA receptors in the actions of alcohol and in alcoholism: recent advances. Alcohol and Alcoholism 29, 115129.[Abstract]
Lader, M. (1994) Anxiolytic drugs: dependence, addiction and abuse. European Neuropsychopharmacology 4, 8591.[ISI][Medline]
Langer, S. Z. and Arbilla, S. (1988) Limitations of the benzodiazepine receptor nomenclature: a proposal for a pharmacological classification as omega receptor subtypes. Fundamental and Clinical Pharmacology 2, 159170.[ISI][Medline]
Lewis, M. J. (1996) Alcohol reinforcement and neuropharmacological therapeutics. Alcohol and Alcoholism 31 (Suppl. 1), 1725.
Lin, N. and Hubbard, J. I. (1994) The increased ethanol preference in rats induced by choice, darkness, or drugs is reduced by ritanserin. Brain Research Bulletin 33, 633638.[ISI][Medline]
Lister, R. G. (1975) The amnesic action of benzodiazepines in man. Neuroscience and Biobehavioral Reviews 9, 8794.
Mayo-Smith, M. F. (1997) Pharmacological management of alcohol withdrawal a meta-analysis and evidence-based practice guideline. Journal of the American Medical Association 278, 144151.[Abstract]
McMillen, B. A., Means, L. W. and Matthews, J. D. (1998) Comparison of the alcohol-preferring P rat to the Wistar rat in behavioral tests of impulsivity and anxiety. Physiology and Behavior 63, 371375.[ISI][Medline]
McNamara, R. K. and Skelton, R. W. (1993) The pharmacological and neurochemical basis of place learning in the Morris water maze. Brain Research Review 18, 3349.[ISI][Medline]
Mhatre, M. and Ticku, M.K. (1994) Chronic ethanol treatment upregulates the GABA receptor ß subunit expression. Molecular Brain Research 23, 246252.[ISI][Medline]
Mikolajczak, P., Okulicz-Kozaryn, I., Kaminska, E. and Filipowski, R. (1994) Nimodipine and Nifedipine effect on performance of passive avoidance tasks in 2- and 6-month old rats. Canadian Journal of Physiology and Pharmacology 72 (Suppl. 1), 407.
Mikolajczak, P., Okulicz-Kozaryn, I. and Kaminska, E. (1995) Effects of Acamprosate and Baclofen on ethanol hypnotic action in chronically ethanol treated rats. Alcohol and Alcoholism 30, 550.
Mikolajczak, P., Okulicz-Kozaryn, I., Kaminska, E. and Skolozdrzych, K. (1997) Multiple acamprosate administration effect on learning and memory in chronically ethanol treated rats. Alcohol and Alcoholism 32, 365.
Moller, C., Wiklund, L., Thorsell, A., Hyytia, P. and Heilig, M. (1997) Decreased measures of experimental anxiety in rats bred for high alcohol preference. Alcoholism: Clinical and Experimental Research 21, 656 660.[ISI][Medline]
Monti, J. M., Monti, D., Estevez F. and Giusti, M. (1997) Sleep in patients with chronic primary insomnia during long-term zolpidem administration. Biological Psychiatry 42, 116S, 39151.
Morrisett, R. A. and Swartzwelder, H. S. (1993) Attenuation of hippocampal long-term potentiation by ethanol: a patch clamp analysis of glutamatergic and GABAergic mechanisms. Journal of Neuroscience 13, 22642272.[Abstract]
Okulicz-Kozaryn, I., Mikolajczak, P. and Kaminska, E. (1992) Tolerance to hypothermia and hypnotic action of ethanol in 3 and 14 months old rats. Pharmacology Research 25 (Suppl. 2), 6364.
Okulicz-Kozaryn, I., Mikolajczak, P., Kaminska, E. and Rosol, A. (1995) Influence of Nimodipine on performance of passive avoidance tasks in rats chronically treated with ethanol. Polish Journal of Pharmacology 47, 549550.
Overstreet, D. H., Halikas, J. A., Seredenin, S. B., Kampov-Polevoy, A., Viglinskaya, I. V., Kashevskaya, O., Badishtov, B. A., Knapp, D. J., Mormede, P., Kiianmaa, K., Li, Ting-Kai and Rezvani, A. H. (1997) Behavioral similarities and differences among alcohol-preferring and -nonpreferring rats: confirmation by factor analysis and extension by additional groups. Alcoholism: Clinical and Experimental Research 21, 840848.[ISI][Medline]
Palminteri, R. and Narbonne, G. (1988) Safety profile of zolpidem. In Imidazopyridines in Sleep Disorders, Sauvanet, J.P., Langer, S.Z. and Morselli, P.L. eds, pp. 351361. Raven Press, New York.
Patat, A., Le Coz, F., Thebault, C., Allain H. and Gandon, J. M. (1996) Effects of Zopiclone, Zolpidem and Flunitrazepam on nocturnal psychomotor and cognitive functions in normal young subjects. European Neuropsychopharmacology 6 (Suppl. 3), 101.
Perrault, G., Morel, E., Sanger, D. J. and Zivkovic, B. (1992) Lack of tolerance and physical dependence upon repeated treatment with the novel hypnotic zolpidem. Journal of Pharmacology and Experimental Therapeutics 263, 298303.[Abstract]
Plaznik, A. (1995) Pharmacology of tolerance to benzodiazepine receptor ligands. Polish Journal of Pharmacology 47, 489499.[Medline]
Rowlett, J. K. and Woolverton, W. L. (1997) Discriminative stimulus effects of zolpidem in pentobarbital-trained subjects: I. Comparison with triazolam in rhesus monkeys and rats. Journal of Pharmacology and Experimental Therapeutics 280, 162173.
Samson, H. H. and Harris, R. A. (1992) Neurobiology of alcohol abuse. Trends in Pharmacological Sciences 13, 206211.[ISI][Medline]
Sanger, D. J. (1997) The effects of new hypnotic drugs in rats trained to discriminate ethanol. Behavioural Pharmacology 8, 287292.[ISI][Medline]
Sanger, D. J. and Zivkovic, B. (1992) Differential development of tolerance to the depressant effects of benzodiazepine and non-benzodiazepine agonists at the omega (BZ) modulatory sites of GABA-A receptors. Neuropharmacology 31, 693700.[ISI][Medline]
Schmid, L., Bottlaender, M., Fuseau, C., Fournier, D., Brouillet, E. and Maziere, M. (1995) Zolpidem displays heterogeneity in its binding to the human primate benzodiazepine receptor in vivo. Journal of Neurochemistry 65, 18801886.[ISI][Medline]
Shelton, K. L. and Balster, R. L. (1994) Ethanol drug discrimination in rats: substitution with GABA agonists and NMDA antagonists. Behavioural Pharmacology 5, 441450.[ISI][Medline]
Tabakoff, B. (1995) Ethanol's action on the GABA-A receptor: is there a requirement for parsimony? Alcoholism: Clinical and Experimental Research 19, 15971598.[ISI][Medline]
Thenot, J. P., Hermann, P., Durand, A., Burke, J. T., Allen, J., Garrigou, D., Vajta, S., Albin, H., Thebault, J. J., Olive, G. and Warrington, S. J. (1988) Pharmacokinetics and metabolism of zolpidem in various animal species and in humans. In Imidazopyridines in Sleep Disorders, Sauvanet, J.P., Langer, S.Z. and Morselli, P.L. eds, pp. 139153. Raven Press, New York.
Thielen, R. J., McBridge, J., Lumeng, L. and Li, T. K. (1993) Housing conditions alter GABA-A receptor of alcohol-preferring and -nonpreferring rats. Pharmacology, Biochemistry and Behavior 46, 723727.[ISI][Medline]
Toki, S., Saito, T., Nabeshima, A., Hatta, S., Watanabe, M. and Takahata, N. (1996) Changes in GABAA receptor function and cross-tolerance to ethanol in diazepam-dependent rats. Alcoholism: Clinical and Experimental Research 20 (Suppl. 1), 40A44A.
Watsky, E. (1996) Management of zolpidem withdrawal. Journal of Clinical Psychopharmacology 16, 459.[ISI][Medline]
Weerts, E. M. and Griffiths, R. R. (1998) Zolpidem self-injection with concurrent physical dependence under conditions of long-term continuous availability in baboons. Behavioural Pharmacology 9, 285297.[ISI][Medline]
Wegelius, K., Honkanen, A. and Korpi, E. R. (1994) Benzodiazepine receptor ligands modulate ethanol drinking in alcohol-preferring rats. European Journal of Pharmacology 263, 141147.[ISI][Medline]
Wesensten, N.J., Balkin, T.J. and Belenky, G.I. (1995) Effects of daytime administration of zolpidem versus triazolam on memory. European Journal of Clinical Pharmacology 48, 115122.[ISI][Medline]
Wilkinson, C.J. (1995) The acute effects of zolpidem administered alone and with alcohol, on cognitive and psychomotor function. Journal of Clinical Psychiatry 56, 309318.[ISI][Medline]
Wilkinson, C.J. and Allard S. (1994) Zolpidem: Abuse potential with and without alcohol. Neuropsychopharmacology 10, 3S.