Antiaggressive Effects of Zolpidem and Zopiclone in Agonistic Encounters Between Male Mice
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AGGRESSIVE BEHAVIOR
Volume 28, pages 416–425 (2002)
Antiaggressive Effects of Zolpidem
and Zopiclone in Agonistic Encounters
Between Male Mice
Mercedes Martı́n-López, José Francisco Navarron
Department of Psychobiology, Faculty of Psychology, University of Málaga, Spain
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The effects of benzodiazepines on various types of aggression have been extensively studied. These
substances produce their pharmacological effects by allosterically modulating the action of GABA via
specific recognition sites on the GABAA receptor called omega 1 and omega 2. The antiaggressive
profile of non-benzodiazepine compounds that also act at omega sites, such as zopiclone (a non-selective
omega 1 and 2 ligand) and zolpidem (a selective omega 1 ligand) has been scarcely explored. In this
study, we examined the action of zolpidem (0.75-3 mg/kg, intraperitoneally) and zopiclone (1.5-6 mg/
kg), administered acutely or subchronically for 10 days, on agonistic behavior elicited by isolation in
male mice. Individually housed mice were exposed to anosmic ‘‘standard opponents’’ 30 min after drug
administration, and the encounters were videotaped and evaluated using an ethologically based
analysis. Acute treatment with zopiclone produced a marked antiaggressive effect, reducing offensive
behaviors (threat and attack) at all doses used (1.5, 3, and 6 mg/kg) without affecting immobility.
Likewise, the intermediate dose of zolpidem (1.5 mg/kg) significantly decreased aggression in a specific
manner, without altering immobility, whereas the highest dose (3 mg/kg) provoked a reduction of
aggression accompanied by a weak (but significant) increase of immobility. With repeated treatment,
no tolerance to the antiaggressive effects of zopiclone and zolpidem was developed. It is concluded that
omega sites at the GABAA receptor could be involved in the control of aggression. Aggr. Behav.
28:416–425, 2002. r 2002 Wiley-Liss, Inc.
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Keywords: aggression; zolpidem; zopiclone; GABA; subchronic treatment; mice
INTRODUCTION
Aggressive behavior of animals is controlled or modulated by a variety of different
neurotransmitter systems in the brain, such as serotonine [Bell and Hobson, 1994; Navarro
and Maldonado, 1999; Sánchez et al., 1993], dopamine [Manzaneque and Navarro, 1999;
Navarro and Manzaneque, 1997; Navarro et al., 2000], opiates [Espert et al., 1993; Navarro
and Dávila, 1997], or nitric oxide [Nelson et al., 1995; Navarro et al., 1997]. However, it is
now recognized that aggression may be also influenced by the GABAergic system. Thus,
many substances that act on the GABAA/BDZ/Cl receptor complex provoke marked effects
on aggressive behavior. Benzodiazepines produce their pharmacological effects by
n
Correspondence to: José Francisco Navarro, Department of Psychobiology, Faculty of Psychology, University of
Málaga, Campus de Teatinios, 29071 Málaga, Spain. E-mail: navahuma@uma.es
Received 13 May 2001; amended version accepted 26 June 2001
r 2002 Wiley-Liss, Inc.
DOI 10.1002/ab.80013Zolpidem, Zopiclone, and Aggression in Mice 417 allosterically modulating the action of GABA via specific recognition sites on the GABAA receptor called omega 1 and omega 2 [Langer and Arbilla, 1988]. In animal studies, benzodiazepines such as diazepam [Martı́n-López and Navarro, 1997], clobazam [Martı́n- López and Navarro, 1996], midazolam [Martı́n-López and Navarro, 1999], and bentazepam [Martı́n-López and Navarro, 1998] have been demonstrated to possess antiaggressive properties using different animal models of aggression. This antiaggressive activity seems to be reverted by flumazenil administration [Miczek et al., 1994; Olivier et al., 1991]. Overall, these data underlie a significant role for the GABAA receptor in modulating of aggressive behavior. During the past few years, several compounds chemically unrelated to benzodiazepines that also act at omega sites associated with GABAA receptor have been developed, such as zopiclone and zolpidem. Zopiclone is a new class of hypnotic agent belonging to the cyclopyrrolone family that shows pharmacological properties similar to those of benzodiazepines (anxiolytic, sedative/hypnotic, anticonvulsant, anticonflict). This compound interacts with high affinity and efficacy at both omega 1 and omega 2 receptors, differing from hypnotic benzodiazepines by its lower miorelaxant activity and its propensity to induce physical dependence [Goa and Heel, 1986; Piot et al., 1990]. In concordance with the behavioral profile of benzodiazepines, zopiclone exhibits an antiaggressive action in rats [Ueki, 1987] and mice [Julou et al., 1983, Martı́n-López et al., 1994]. On the other hand, zolpidem is an imidazapyridine with a selective affinity only for the omega 1 receptor subtype, which corresponds with GABAA receptors containing a1b2g2 subunits [McKernan and Whiting, 1996]. In contrast to benzodiazepines, which produce sedative effects with equal or lower potency than anticonvulsant and miorelaxant effects, zolpidem is strongly sedative, showing lower anxiolytic, miorelaxant, and anticonvulsant activity [Holm and Goa, 2000]. Likewise, zolpidem develops less tolerance to their sedative and anticonvulsant effects after repeated administration in rodents [Sanger and Depoortere, 1998]. In this sense, it has been reported that increased convulsant sensitivity occurs during spontaneous and flumazenil- precipitated withdrawal after repeated administration of benzodiazepines but not zolpidem, suggesting that this compound may not produce benzodiazepine-like physical dependence [Perrault et al., 1992]. Although the antiaggressive profile of zopiclone (a non-selective omega 1 and 2 ligand) has been explored [Julou et al., 1983; Martı́n-López et al., 1994; Ueki, 1987], there is no evidence with respect to the antiaggressive properties of zolpidem (a selective omega 1 ligand). Therefore, this study was designed to assess the acute and subchronic effects of zopiclone (experiment 1) and zolpidem (experiment 2) on agonistic encounters in isolated male mice using an ethopharmacological approach. The term agonistic behavior encompasses threats and aggressive acts as well as defensive, submissive, and flight behaviors. The ethological analyses of these social encounters seems to be an appropriate technique to distinguish between specific and non-specific drug-induced changes. MATERIALS AND METHODS Animals A total of 336 albino male mice of the OF.1 strain (provided by CRIFFA, Barcelona, Spain) weighing 25 to 30 g were used. Animals were housed under standardized lighting conditions (white lights on: 20:00-8:00) at a constant temperature (211C), and food and tap
418 Martı´n-López and Navarro water were available ad libitum, except during behavioral trials. On arrival in the laboratory, the subjects were allocated to two different categories. Half were housed individually in transparent plastic cages (24 13.5 13 cm) as experimental animals. The remainder were housed in groups of five to be used as ‘‘standard opponents’’ and were rendered temporally anosmic by intranasal lavage with 4% zinc sulfate solution (Sigma Laboratories) on both 1 and 3 days before testing. Fighting in mice, as in most rodents, is closely related to olfaction. We used this type of opponent because it elicits attack but never initiates such behavior [Brain et al., 1981]. These animals very rarely direct spontaneous attacks toward the test animals, and, consequently, fighting is always unidirectional, being easily quantified. All the experimental animals underwent an isolation period of 30 days before the behavioral test (isolation-induced aggression model). Social isolation is an effective form of increasing the level of aggressiveness in different species of animals. This phenomenon is particularly well demonstrated in laboratory mice [Navarro, 1997; Valzelli, 1969]. Experimental Design Seven groups of mice were used in each experiment. Individually housed animals were allocated randomly to one control group receiving vehicle and six experimental groups (n ¼ 12 each) receiving acute or subchronic zopiclone (experiment 1) or zolpidem (experiment 2) injections. Drug administration consisted of (1) acute treatment: each animal received vehicle for 9 consecutive days and zopiclone or zolpidem on day 10; (2) subchronic treatment: each animal received a daily injection of zopiclone or zolpidem for 10 consecutive days, and (3) vehicle: each animal received a daily injection of vehicle for 10 consecutive days (control group). Drugs Zopiclone and zolpidem (Sigma Laboratories) were diluted in physiological saline to provide appropriate doses for injections. Zopiclone was administered either acutely or subchronically (for 10 days) in three doses: 1.5, 3, and 6 mg/kg. Zolpidem was also administered either acute or subchronically (for 10 days) in three doses: 0.75, 1.5, and 3 mg/ kg. The control groups received physiological saline. Drugs and vehicles were injected intraperitoneally in a volume of 10 mL/kg. The doses used in both experiments were chosen on the basis of a pilot study carried out previously in our laboratory. Procedure and Behavioral Analysis Thirty minutes after the last injection, an isolated animal and a ‘‘standard opponent’’ (marked with fur dye for identification) were confronted in a neutral area for 10 min. This neutral cage consisted of an all-glass area, measuring 50 26 30 cm, with a fresh sawdust substrate. Before the encounter, the animals were allowed 1 min of adaptation to the neutral cage, remaining separated by means of a plastic barrier throughout this time. The social encounters were videotaped using a Sony-V8 camera. All tests were conducted under white light between the second and seventh hours of the dark phase of the artificial cycle of the animals. After each encounter, the neutral cage was washed out and the sawdust bedding was replaced.
Zolpidem, Zopiclone, and Aggression in Mice 419 The tapes were analyzed using a microprocessor and a custom-developed program [Brain et al., 1989], which facilitated estimation of time allocated to 10 broad behavioral categories. The names of the categories and their constituent elements are as follows: 1. Body care (abbreviated groom, self-groom, wash, shake, scratch). 2. Digging (dig, kick dig, push dig). 3. Non-social exploration (explore, rear, supported rear, scan). 4. Exploration from a distance (approach, attend, circle, head orient, stretched attention). 5. Social investigation (crawl over, crawl under, follow, groom, head groom, investigate, nose sniff, sniff, push past, walk around). 6. Threat (aggressive groom, sideways offensive, upright offensive, tail rattle). 7. Attack (charge, lunge, attack, chase). 8. Avoidance/flee (evade, flinch, retreat, ricochet, wheel, startle, jump, leave, wall, clutch). 9. Defense/submission (upright defensive, upright submissive, sideways defensive). 10. Immobility (squat, cringe). A detailed description of all elements can be found in Brain et al. [1989]. This ethoexperimental procedure allows a complete quantification of the behavioral elements shown by the subject during the agonistic encounters. Only the behavior of the isolated animal was assessed. The analysis was carried out by a trained experimenter, unaware of the treatment of the groups. Statistical Analysis Nonparametric Kruskal-Wallis tests were used to assess the variance of the behavioral measures over different treatment groups. Subsequently, appropriate paired comparisons were carried out using Mann-Whitney U-tests. The analyses were performed using nonparametric statistics since the criteria for parametric statistics were not met by the data. The criterion for statistical significance for all the tests was Po.05. RESULTS The effects of acute and subchronic administration of different doses of zopiclone and zolpidem are shown in Tables I and II, respectively. Kruskal-Wallis analysis showed that zopiclone administration had significant effects on non-social exploration (Po.05), threat (Po.05), and attack (Po.02). Post-hoc Mann-Whitney U-tests revealed that, after acute treatment, zopiclone significantly reduced the time spent in threat and attack behaviors in comparison with the control group (1.5 and 3 mg/kg, Po.02; 6 mg/kg, Po.001). Non-social exploration was significantly increased with the highest dose used (Po.001). After subchronic treatment, zopiclone (1.5 and 6 mg/kg) produced a significant reduction of threat (Po.02) and attack (3 and 6 mg/kg, Po.02) compared with the control group. Kruskal-Wallis analysis revealed significant treatment effects in mice treated with zolpidem on exploration from a distance, threat, attack, and immobility (Po.05). Further statistical analysis with Mann-Whitney U-tests showed that acute treatment with zolpidem produced a significant increase in exploration from a distance (0.75, 1.5, and 3 mg/kg, Po.02) and immobility (3 mg/kg, Po.02), as well as a significant decrease in threat (1.5 and 3 mg/kg,
420
TABLE 1. Median Values (With Ranges) for Times (In Seconds) Allocated to Broad Behavioral Categories in Animals Receiving Acute and Subchronic
Treatment With Zopiclone
Dose of zopiclone, mg/kg
Acute treatment Subchronic treatment
Behavioral categories Vehicle 1.5 3 6 1.5 3 6
Body care 8.11 3.33 8.63 9.92 4.83 7.22 3.76
(2.4–16.1) (0–19.9) (5.2–14.5) (0–20.1) (0–15.9) (1.7–17.1) (0–10.7)
Digging 14.38 8.34 11.41 3.58 3.68 13.54 2.48
(0–49.5) (0–60.7) (0–40.8) (0–24.1) (0–19.4) (0–33.2) (0–2.5)
Martı´n-López and Navarro
Non–social explorationn 313.13 339.13 312.6 378nnn 291 319.2 310.8
(246–350) (250–442) (184–413) (300–400) (145–368) (257–389) (241–425)
Explore from a distance 34.33 28.24 17.88 52.02 15.83 29.51 40.19
(10–310) (14–107) (5.5–127) (12.4–429) (3.4–111) (14–91) (2.9–105)
Social investigation 91.05 112.05 123.93 115.29 163.6 119.91 141.31
(29–203) (30–212) (31–332) (39–198) (57–440) (55–317) (47–236)
Threatn 109.4 39.7nnnn 69.81nnnn 0nnn 52nnnn 84.16 38.79nnnn
(61–168) (0–147) (0–112) (0–108) (0–115) (0–168) (0–156)
Attacknn 40.23 10.03nnnn 20.4nnnn 0nnn 29.67 18.12**** 3.25nnnn
(20–60) (0–54) (0–61) (0–42) (0–85) (0–51) (0–71)
Avoidance/flee 0 0 0 0 0 0 0
(0–0.33) (0–1.06) (0–2.3) (0–4.43) (0–1.29) (0–0.23) (0–0.55)
Defense/submission 0 0 0 1.1 0 0 0.68
(0–0.31) (0–17.5) (0–27.8) (0–21) (0–56) (0–4.5) (0–21.5)
Immobility 0 0 0 0 0 0 0
(0–0) (0–0) (0–0) (0–0) (0–0) (0–0) (0–0)
nn
Kruskal–Wallis test showed significant variance: nPo.05; Po.02TABLE 2. Median Values (With Ranges) For Times (in Seconds) Allocated to Broad Behavioral Categories in Animals Receiving Acute and
Subchronic Treatment With Zolpidem
Dose of zolpidem, mg/kg
Acute treatment Subchronic treatment
Behavioral categories Vehicle 0.75 1.5 3 0.75 1.5 3
Body care 10.45 6.4 12.5 8.12 7.42 7.23 6.9
(1.3–19) (0.5–30) (1.2–23.4) (0–20) (0.2–24) (1–13.1) (0.7–24.6)
Digging 16.3 7.15 8.68 0.91 13 2.66 4.5
(0–44) (0–27) (0–67) (0–25.5) (0–8.37) (0–34) (0–17)
Non–social exploration 335.2 351.5 353.5 382.6 356.8 340.8 353
(260–381) (227–418) (271–449) (259–428) (267–409) (247–387) (235–424)
Explore from a distancen 24.12 48.41nn 37.28nn 63.58nn 26 43.8nn 47.91nn
(14–34) (15–108) (18–128) (35–121) (10–70) (18–150) (21.5–85)
Social investigation 24.53 33.9 33.49 35.21 43.9 57.6 62.11
(42–139) (3.7–118) (5.4–199) (3.3–151) (6.7–200) (17.3–182) (11–287)
Threatn 132 80.33; 81.59nn 50.69nnn 85.96 104.59nnnn 63.72nnnn;
(32–191) (1.2–234) (0–149) (0–134) (0–201) (0.8–217) (0–156)
Attackn 52.8 26.1 17.64nn 7.72nn 18.85 14.49nn 14.34nn
(13–97) (0.2–84) (0–59) (0–94) (0–99) (0–53) (0–116)
Avoidance/flee 0 0 0 0 0 0 0
(0–0.3) (0–3.8) (0–4) (0–2.13) (0–0.5) (0–0.94) (0–1.33)
Defense/submission 0 0 0 0 0 0.48 0.13
(0–19.2) (0–16.5) (0.68–4) (0–15.5) (0–10.4) (0–14.5) (0–7.41)
Zolpidem, Zopiclone, and Aggression in Mice
Immobilityn 0 0 0 1.9nn 0 0 0nnnnn
(0–0) (0–7.3) (0–4.7) (0–117.3) (0–0) (0–0) (0–0)
nnnn nn nnn
421
Kruskal–Wallis test showed significant variance: nPo.05. Differs from controls on Mann–Whitney U–tests: Po.05; Po.02; Po.001. Differs from acute
treatment on Mann–Whitney U–test: nnnnn Po.02.422 Martı´n-López and Navarro Po.02 and Po.001, respectively) and attack (1.5 and 3 mg/kg, Po.02) behaviors, in comparison with the control group. Furthermore, after subchronic treatment with the drug, exploration from a distance was significantly increased (1.5 and 3 mg/kg; Po.02) whereas threat (1.5 and 3 mg/kg; Po.05) and attack (1.5 and 3 mg/kg; Po.02) behaviors were significantly decreased, as compared with the control group. DISCUSSION The results obtained in the present study indicate that zopiclone (a non-selective omega 1 and 2 ligand) and zolpidem (a selective omega 1 ligand) exhibit an antiaggressive activity in isolated male mice. As Table I shows, acute treatment with zopiclone produced a marked antiaggressive effect, reducing offensive behaviors (threat and attack) at all doses used (1.5, 3, and 6 mg/kg) without affecting immobility. Our findings are in concordance with others studies using this drug [Julou et al., 1983; Martı́n-López et al., 1994; Ueki, 1987]. Thus, in an experiment in which the same animal model of aggression was employed, it was found that a low dose of zopiclone (1 mg/kg) did not modify aggression in mice, whereas a high dose of the drug (8 mg/kg) provoked a significant reduction of aggressive behaviors, without altering immobility [Martı́n-López et al., 1994]. These findings suggest that 1.5 mg/kg might be the minimal effective dose to produce an antiaggressive action, at least when an animal model of isolation-induced aggression is used. In addition, the failure of zopiclone to produce motor impairment agrees with several studies in which are required higher doses of zopiclone to reduce spontaneous locomotor activity (11.5 mg/kg, intraperitoneally) [Perrault et al., 1990] and to produce ataxia in the rotarod test (25 mg/kg, intraperitoneally) in mice [Sanger and Zivkovic, 1992]. On the other hand, our results are similar to those described with benzodiazepines. However, whereas 1 to 4 benzodiazepines usually reduced aggression only at doses that produced pronounced muscle relaxation and sedation [Martı́n-López and Navarro, 1997], zopiclone decreased aggressive behavior selectively, without affecting immobility. In sum, the results of this experiment indicate that zopiclone exhibits an ethopharmacological profile characterized by specific suppression of aggression and no evident impairment of motor activity. In different animal models of anxiety, zopiclone has been demonstrated to possess an anxiolytic-like activity [Carlson et al., 2001; Griebel et al., 1998; Ueki, 1987]. In our study, although zopiclone increased the time spent in social investigation behaviors, a parameter commonly used to assess the anxiety-changing properties of drugs [Brain et al., 1991; Maldonado and Navarro, 2001], no significant differences were reached. This lack of action of the drug on social investigation behaviors may be related to a possible ‘‘ceiling’’ effect (91.05 sec in controls). On the other hand, a significant increase in the behavioral category of non-social exploration was observed with the highest dose used. A possible explanation for this effect might be that animals devote more time to these exploratory behaviors to compensate for the reduction in the offensive behaviors (threat and attack) (see Table I). With repeated treatment, no tolerance to the antiaggressive effects of zopiclone was developed. This finding is in concordance with that of Julou et al. [1983], who also found a lack of tolerance to this action of the drug using a shock-induced aggression model in mice. Repeated administration of various benzodiazepines has been demonstrated to produce sensitivity changes in the efficacy spectrum of compounds acting at the GABAA receptor, and
Zolpidem, Zopiclone, and Aggression in Mice 423 it has been suggested that these changes may be underlying the development of tolerance or dependence. Zopiclone has been shown to possess a limited ability to produce receptor sensitivity changes [Piot et al., 1990]. Perhaps this fact is related to the capacity of zopiclone to bind to a site close to, but probably distinct from, that of the benzodiazepine hypnotics and that zopiclone, whose binding is not sensitive to GABA, may not able to induce the conformational state from which receptor sensitivity changes are triggered [Doble et al., 1995]. After acute treatment with zolpidem, a clear dose-dependent reduction of aggression was observed (see Table II). While the lowest dose used (0.75 mg/kg) reduced the time spent in offensive behaviors (threat and attack), no significant differences were found. The intermediate dose (1.5 mg/kg) significantly decreased aggression in a specific manner, without altering immobility, whereas the highest dose (3 mg/kg) provoked a reduction in aggression accompanied by a weak (but significant) increase in immobility. This slight motor impairment is in agreement with the generalized observation that this compound has a sedative activity [Holm and Goa, 2000; Sanger and Depoortere, 1998]. To our knowledge, this is the first report in which an antiaggressive action of zolpidem is described. Therefore, the lack of experimental studies about the antiaggressive action of zolpidem in animals does not permit us to compare our results with other works. The antiaggressive activity of this substance is foreseeable since other omega receptor agonists (benzodiazepine and non-benzodiazepine compounds) also display remarkable antiaggressive properties in several animal models. Zolpidem, in contrast with other omega ligands, shows a different pattern of behavioral actions in rodents, and these differences have been explained by the selectivity of zolpidem for the omega 1 receptor subtype. This aspect seems to be of particular importance in mediating the sedative/hypnotic effects of this drug [Sanger 1997; Sanger and Depoortere, 1998]. Our results indicate that the antiaggressive action of zolpidem is selective only at 1.5 mg/kg, since with a slightly higher dose (3 mg/kg) a weak sedative action is evident. On the other hand, with repeated treatment, no tolerance to the antiaggressive effects of zolpidem was developed. As Table II shows, no significant differences in the offensive behaviors were found when subchronically and acutely treated groups were compared. A similar absence of tolerance to antiaggressive action has also been described with other omega agonists such as clobazam [Martı́n-López and Navarro, 1996], bentazepam [Martı́n- López and Navarro, 1998], and midazolam [Martı́n-López and Navarro, 1999]. In contrast, after repeated treatment with zolpidem for 10 consecutive days, a significant decrease in immobility was observed, and, consequently, tolerance to the motor effects of the drug was developed. This divergence in the temporal course of tolerance to antiaggressive and motor effects of zolpidem has been also reported with neuroleptic drugs, such as haloperidol [Navarro et al., 1993; Puigcerver et al., 1996] and tiapride [Navarro and Manzaneque, 1997], suggesting that these actions are mediated through different neurophysiological mechanisms. Likewise, animals chronically treated with classical benzodiazepines, such as diazepam or lorazepam, show changes in GABAA receptor subunit genes [Heninger et al., 1990; Impagnatiello et al., 1996], several of these changes being region specific [Galpern et al., 1990; Kang and Miller, 1991]. In this context, recently it has been described as a significant decrease in the level of a1 subunit mRNA in the rat cortex after 14 days of treatment with zolpidem [Holt et al., 1997]. In sum, the development of tolerance may depend not only on pharmacokinetic and pharmacological factors but also on the manner in which different drugs interact with GABAA receptors.
424 Martı´n-López and Navarro
REFERENCES
Bell R, Hobson H. 1994. 5-HT1A receptor influences on Julou L, Bardone MC, Blanchard JC, Garret C,
rodent social and agonistic behaviour: a review and Stutzmann JM. 1983. Pharmacological studies on
empirical study. Neurosci Biobehav Rev 18:325–338. zopiclone. Pharmacology 27:46–58.
Brain PF, Benton D, Childs G, Parmigiani S. 1981. The Kang I, Miller LG. 1991. Decreased GABAA receptor
effect of the opponent in tests of murine aggression. subunit mRNA concentrations following chronic
Behav Processes 6:319–328. lorazepam administration. Br J Pharmacol
Brain PF, McAllister KH, Walmsley S. 1989. Drug 103:1285–1287.
effects on social behavior: methods in ethopharma- Langer SZ, Arbilla S. 1988. Imidazopyridines as a tool
cology. In: Boulton AA, Baker GB, Greenshaw AJ, for the characterization of benzodiazepine receptors:
editors. Neuromethods. Vol. 13, Psychopharmacol- a proposal for a pharmacological classification as
ogy. Clifton, NJ: Humana Press. p 687–739. omega receptor subtypes. Pharmacol Biochem
Brain PF, Kuumorini N, Benton D. 1991. ‘‘Anxiety’’ in Behav 29:763–766.
laboratory rodents: a brief review of some recent Maldonado E, Navarro JF. 2001. MDMA (‘‘ecstasy’’)
behavioural development. Behav Processes 25:71–80. exhibits an anxiogenic-like activity in social encoun-
Carlson JF, Haskew R, Wacker J, Maisonneuve IM, ters between male mice. Pharmacol Res 44:27–31.
Glick SD, Jerussi TP. 2001. Sedative and anxiolytic Manzaneque JM, Navarro JF. 1999. Behavioral profile
effects of zopiclone’s enantiomers and metabolite. of amisulpride in agonistic encounters between male
Eur J Pharmacol 415:181–189. mice. Aggr Behav 25:225–232.
Doble A, Canton T, Malgouris C, Stutzmann JM, Piot Martı́n-López M, Navarro JF. 1996. Behavioural profile
O, Bardone MC, Pauchet C, Blanchard JC. 1995. of clobazam in agonistic encounters betwen male
The mechanism of action of zopiclone. Eur Psychia- mice. Med Sci Res 24: 89–91.
try 10:117–128. Martı́n-López M, Navarro JF. 1997. Acute and sub-
Espert R, Navarro JF, Salvador A, Simón VM. 1993. chronic effects of diazepam on agonistic encounters
Effects of morphine hydrochloride on social en- between male mice. Med Sci Res 25:667–669.
counters between male mice. Aggr Behav Martı́n-López M, Navarro JF. 1998. Behavioral profile
19:377–383. of bentazepam, an anxiolytic benzodiazepine, in
Galpern WR, Miller LG. Greenblatt DJ, Dhader RI. agonistic encounters between male mice. Med Sci
1990. Differential effects of chronic lorazepam and Res 25:335–337.
alprazolam on benzodiazepine binding and GABAA- Martı́n-López M, Navarro JF. 1999. Efectos de la
receptor function. Br J Pharmacol 101:839–842. administración de midazolam sobre la conducta
Goa KL, Heel RC. 1986. Zopiclone: a review of its agonı́stica en ratones machos. Psicothema 11:367–
pharmacodynamic and pharmacokinetic properties 374.
and therapeutic efficacy as a hypnotic. Drugs 32:48– Martı́n-López M, Caño A, Navarro JF. 1994. Effects of
65. zopiclone on social encounters between male mice.
Griebel G, Perrault G, Sanger D. 1998. Limited Med Sci Res 22:729–730.
anxiolytic-like effects of non-benzodiazepine hypno- McKernan RM, Whiting PJ. 1996. Which GABAA-
tics in rodents. J Psychopharmacol 101:839–842. receptor subtypes really occur in the brain? Trends
Heninger C, Saito N, Tallman JF, Garret KM, Vitek Neurosci 19:139–143.
MP, Duman RS, Gallager DW. 1990. Effects of Miczek KA, Weerts E, Haney M, Tidey J. 1994.
continuous diazepam administration on GABAA Neurobiological mechanisms controlling aggression:
subunit mRNA in rat brain. J Mol Neurosci preclinical developments for pharmacotherapeutic
2:101–107. interventions. Neurosci Biobehav Rev 18:97–110.
Holm KJ, Goa KL. 2000. Zolpidem: an update of its Navarro JF. 1997. An ethoexperimental analysis of the
pharmacology, therapeutic efficacy and tolerability agonistic interactions in isolated male mice: compar-
in the treatment of insomnia. Drugs 59:865–889. ison between OF.1 and NMRI strains. Psicothema
Holt RA, Bateson AN, Martin IL. 1997. Chronic 9:333–336.
zolpidem treatment alters GABAA receptor mRNA Navarro JF, Dávila G. 1997. An ethopharmacological
levels in the rat cortex. Eur J Pharmacol assessment of the effects of methadone on agonistic
329:129–132. interactions in male mice. Med Sci Res 25:835–837.
Impagnatiello F, Pesold C, Longone P, Caruncho H, Navarro JF, Maldonado E. 1999. Behavioral profile
Fritschy JM, Costa E, Guidotti A. 1996. Modifica- of 3,4-methylenedioxy-methamphetamine (MDMA)
tions of GABAA receptor subunit expression in rat in agonistic encounters between male mice.
neocortex during tolerance to diazepam. Mol Phar- Prog Neuropsychopharmacol Biol Psychiatry
macol 49:822–831. 23:327–334.Zolpidem, Zopiclone, and Aggression in Mice 425 Navarro JF, Manzaneque JM. 1997. Acute and sub- treatment with the novel hypnotic zolpidem. J chronic effects of tiapride on isolation-induced Pharmacol Exp Ther 263:298–303. aggression in male mice. Pharmacol Biochem Behav Piot O, Betschart J, Stutzmann JM, Blanchard JC. 1990. 58:255–259. Cyclopyrrolones, unlike some benzodiazepines, do Navarro JF, Miñarro J, Simón VM. 1993. Antiaggres- not induce physical dependence in mice. Neurosci sive and motor effects of haloperidol show different Lett 117:140–143. temporal patterns in the development of tolerance. Puigcerver A, Navarro JF, Simón VM. 1996. Sorting out Physiol Behav 53:1055–1059. antiaggressive and motor effects of haloperidol by Navarro JF, Manzaneque JM, Martı́n-López M, Vera means of tolerance development. Med Sci Res F. 1997. Effects of L-NOARG, a nitric oxide 24:343–345. synthase inhibitor, on agonistic interactions between Sánchez C, Arnt J, Hyttel J, Moltzen EK. 1993. The male mice. Med Sci Res 25:495–496. role of serotonergic mechanisms in inhibition of Navarro JF, Velasco R, Manzaneque JM. 2000. Acute isolation-induced aggression in male mice. Psycho- and subchronic effects of pimozide on isolation- pharmacology 110:53–59. induced aggression in male mice. Prog Neuropsy- Sanger DJ. 1997. The effects of new hypnotic drugs in chopharmacol Biol Psychiatry 24:131–142. rats trained to discriminate ethanol. Behav Pharma- Nelson GE, Demas PL, Huang MC, Fishman VL, col 8:287–292. Dawson TM, Snyder SH. 1995. Behavioural ab- Sanger DJ, Depoortere H. 1998. The pharmacology and normalities in male mice lacking neuronal nitric mechanism of action of zolpidem. CNS Drug Rev oxide synthase. Nature 378:383–386. 4:323–340. Olivier B, Mos J, Miczek KA. 1991. Ethopharmacolo- Sanger DJ, Zivkovic B. 1992. Differential development gical studies of anxiolytics and aggression. Eur of tolerance to the depressant effects of benzodiaze- Neuropsychopharmacol 1:97–100. pine and non-benzodiazepine agonists at the omega Perrault G, Morel E, Sanger DJ, Zivkovic B. 1990. (BD) modulatory sites of GABAA receptors. Neu- Differences in pharmacological profiles of a ropharmacology 31:693–700. new generation of benzodiazepine and Ueki S. 1987. Behavioral pharmacology of zopiclone. non-benzodiazepine hypnotics. Eur J Pharmacol Sleep 10:1–6. 187:487–494. Valzelli L. 1969. Aggressive behavior induced by Perrault G, Morel E, Sanger DJ, Zivkovic B. 1992. Lack isolation. In: Gaffattini S, editor. Aggressive beha- of tolerance and physical dependence upon repeated vior. Amsterdam: Excerpta Medica. p 70–76.
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