M. Votava · M. Krsˇiak · J. Podhorná · K.A. Miczek
Alprazolam withdrawal and tolerance measured in the social conflict test in mice Abstract Rationale: It is difficult to assess withdrawal
locomotion while aggression tended to be increased.
from benzodiazepines, and preclinical assessment of be- Conclusions: Tolerance to the alprazolam effects on ag- haviour during social conflict offers the opportunity to gressive and social behaviour developed at different quantify tolerance and withdrawal by measuring aggres- rates suggesting that they are differentially regulated.
sive, defensive and social behaviour. The relationship Furthermore, the evidence of withdrawal responses ap- between benzodiazepine withdrawal symptoms and the pearing in a behaviour to which tolerance had not devel- development of tolerance is not well understood. Are oped does suggest that tolerance and withdrawal phe- withdrawal symptoms dependent on the development of nomena are dissociated in benzodiazepines.
tolerance? Objective: The aim of the present study wasto compare the development of tolerance to alprazolam Keywords Benzodiazepine · Withdrawal · Tolerance ·
effects on the behavioural repertoire during the social conflict test in mice, and to determine whether or not be-havioural changes during alprazolam withdrawal are cor-related with the development of tolerance. Methods: An experimental model consisting of interactions of pairs ofsingly housed male mice with non-aggressive group- Benzodiazepines are widely used therapeutic agents with housed male mice was used. Alprazolam (1 mg/kg) was sedative, anxiolytic, anticonvulsant and muscle relaxant given orally once or repeatedly (twice daily) for 8 or effects in humans and animals. The use of these agents is21 days. Behaviour was measured, based on videoanaly- limited by the development of tolerance to their effects sis, in aggressive mice before treatment, 30 min or 3 and the risk of developing dependence (File and days after the last dose, respectively. Results: A single Andrews 1993; File 1985b, 1990; Olivieri et al. 1986; administration of alprazolam significantly reduced ag- Dorow and Duka 1986). Dependence to benzodiazepines gressive activities and increased social investigation can be also manifested by a withdrawal syndrome which without changing locomotion or other behaviour. Toler- may include symptoms such as tremors, sweating, sleep ance developed to the inhibitory effects of alprazolam on disturbance, lowered seizure threshold, increased tension aggressive behaviour but not to the effects of alprazolam and anxiety, irritability, difficulty in concentration etc.
to increase social investigation. When withdrawn from (Petursson 1994; Woods et al. 1987; Schweizer and alprazolam, mice exhibited less social investigation and Behavioural studies of benzodiazepine withdrawal in animal models have been mostly focused on detection ofsigns of increased anxiety. For example, reduced explo-ration of open arms in the elevated plus maze, reducedsocial behaviour in the social interaction test or in-creased ultrasonic “distress” vocalizations were reportedin rats or mice after withdrawal from benzodiazepines(File et al. 1987, 1991; Kulkarni and Sharma 1993; Miczek and Vivian 1993; Vivian et al. 1994; Andrews etal. 1997; Ward and Stephens 1998). However, it is possi-ble that behavioural changes after benzodiazepine with-drawal are more diverse and that the expression of anxi-ety is not the only and predominant behavioural response to benzodiazepine withdrawal. To test this possibility, a behavioural model engendering a broad spectrum of be-havioural measures was employed in the present study.
The ethologically oriented model is based on the analy-sis of offensive, defensive-escape, social, locomotor and Male albino random-bred mice derived from ICR strain (Velaz, other behavioural acts and postures occurring during so- Prague, Czech Republic) weighing 18–20 g at the beginning of theexperiment were used. They were housed singly in self-cleaning cial conflict in mice. Anxiolytic-like, anxiogenic-like, cages or in groups of ten. The self-cleaning cages used for the in- anti-aggressive, aggressogenic, sedative and other be- dividual housing were made of solid metal walls 13 cm high with havioural changes are readily detected in this model after wire-mesh floors (8×17 cm) which were placed 3 cm above trays acute administration of agonists or inverse agonists at with wood shavings. This wire-mesh floor ensured that the iso-lates were not handled throughout the period of single housing.
benzodiazepine receptors (Krsˇiak 1975, 1979; Krsˇiak et The group-housed mice were housed in large standard plastic cag- al. 1984; Krsˇiak and Sulcova 1990; Sulcova et al. 1992).
es (26×42×15 cm) with floors covered with wood shavings. All In a preliminary study (Krsˇiak et al. 1998), withdrawal mice were housed under room lighting (with lights on from 6 a.m.
from relatively short (8 days) treatment with alprazolam to 6 p.m.) and under temperature ranging from 22 to 24°C. Foodand water were available ad libitum.
reduced social investigation, moderately increased ag- The mice were observed in transparent cages (20×30×20 cm) gression but did not produce marked signs of anxiety in with wood shavings on the floor and tops covered with transparent the present model of social conflict in mice. The first covers with apertures for air. The observations were performed aim of the present study was to explore whether with- under room lighting from 8 a.m. to 1 p.m.
drawal from longer (21 days) alprazolam treatment pro- Experiments were approved by the Expert Committee for Pro- tection of Experimental Animals of the 3rd Faculty of Medicine duces more marked increase of aggression and other ac- and were performed in accordance with the Animal Protection Act tivities, particularly increased defensive-escape behav- of the Czech Republic (No. 246/1992 Sb).
iour as a putative measure of increased anxiety.
The development of tolerance to several benzodiaze- pine effects has been studied extensively in various ex-perimental models (e.g. File 1985a, 1990; Shumsky and Social interactions always involved one singly-housed and one Lucki 1994; Fernandes et al. 1999). It has been shown group-housed mouse, being placed as pairs in the observationalcages. Each isolate was paired with the same group-housed part- that tolerance develops at different rates to diverse be- ner throughout the experiment. The isolates were allowed 30-min havioural effects of benzodiazepines (File 1985a). For adaptation in the observational cages before the group-housed example, tolerance to the sedative effects develops rapid- partners were introduced; the interaction ended after 4 min. This ly (Fernandes et al. 1996) while tolerance to the anxio- procedure, which suppresses aggression in group-housed miceand reduces their social behaviour, facilitates active social behav- lytic effects is slow or absent (File 1985a; Fernandes et iour in isolates. The observational cages were cleaned and their al. 1999). However, the development of tolerance has floors were covered with new wood shavings after each interac- been mostly measured in different tests and animals, which could influence the rate of development of toler- Three experiments were performed and all of them consisted ance. Therefore, the second aim of the present paper was of three phases. In the first phase, mice were housed singly or ingroups for 3 weeks. In the second phase, singly housed mice (iso- to compare the development of tolerance to alprazolam lates, the test mice) were given drugs daily for a specific time (1, 8 effects on different behaviours occurring during the same or 21 days). Group-housed mice (the stimulus animals) remained untreated. The third phase consisted of withdrawal from alprazo- The relationship between benzodiazepine withdrawal In the first experiment, alprazolam (1 mg/kg) or the vehicle symptoms and the development of tolerance is not well were administered orally only once (n=16 each). In the second ex- understood. Are withdrawal symptoms dependent on the periment, alprazolam (1 mg/kg) or the vehicle were administered development of tolerance? Are they a mirror image of twice daily for 8 days and on day 9 an additional dose of alprazo- acute effects of benzodiazepines? Several benzodiaze- lam (1 mg/kg) (n=19) or the vehicle (n=18) were given. In thethird experiment, alprazolam (1 mg/kg) or a vehicle were adminis- pine studies reported withdrawal responses in a behav- tered twice daily for 21 days and on day 22 an additional dose of iour to which tolerance had not developed (File and alprazolam (1 mg/kg) or the vehicle was given (n=16 or 17, re- Wilks 1990; van der Laan et al. 1993; Shumsky and Lucki 1994; Andrews et al. 1997) but these phenomena Altogether, three social interactions were performed in each have been mostly measured in separate tests and ani- experiment. The first interaction was performed 1 day before thealprazolam treatment started (pretreatment interaction) and served mals. Thus, the third purpose of the present study was to for classification of animals. The second interaction was conduct- determine in the same test and animals whether behav- ed 30 min after the last dose of alprazolam (treatment interaction) ioural changes during alprazolam withdrawal are corre- and the third interaction was performed 72 h after the last dose of lated with, or independent of, the development of toler- alprazolam (the withdrawal interaction). According to our pilotexperiments and published findings (Lopez et al. 1990), an inter- val of 48–96 h after discontinuation of alprazolam administrationappears to be most appropriate for ascertainment of behaviouraland receptor changes produced by the withdrawal.
The behaviour of animals during the interaction was recorded on videotape. Next, the tapes were analyzed by an observer withno knowledge of the drug treatment. This was done with a key-board that was connected to a standard PC and software for behav-ioural analysis (Donat 1991).
rare frequency in aggressive mice and we present this data for in-tegrity. The behavioural categories were evaluated by a three-way The frequency, total duration and latency of a number of aggres- repeated measures ANOVA (Wilks Lambda) with the factors treat- sive, defensive-escape (timid), social and locomotor activities de- ment (control and alprazolam), duration of treatment (1, 8 and rived from the ethogram of mice (Grant and Mackintosh 1963) 21 days) and observation period (pretreatment, last day of treat- and described in detail previously (Krsˇiak 1975; Krsˇiak et al.
ment and withdrawal). Subsequent analysis was performed using 1984) were recorded. In short, the acts and postures evaluated in Bonferroni t-test to reveal significant differences between the con- the present paper were defined as follows: trol and the alprazolam treated group of mice. All statistical testsused two-tailed criteria, with an alpha level of P<0.05.
Sociable activities (social investigation) Social sniff (Sn) – also referred to as naso-nasal and ano-genitalcontacts, sniffing the partner's head, body, genitals or tail; climb(Cl) – the mouse places its forepaws on the partner's back, mostly in the shoulder region, and usually sniffs this area at the same time(Grant and Mackintosh called this Attempted Mount); follow (Fo) A three-way repeated measures ANOVA showed a sig- – following the partner by quiet walking.
nificant effect of treatment [F(2,97)=7.652, P<0.001],duration of treatment [F(4,194)=5.109, P=0.001] and ob- servation period [F(2,97)=6.522, P=0.002] in the num-ber of aggressive acts (attacks, threats, tail rattles). Next, Attack (At) – a fierce lunging at the partner often associated withbiting; threat (Th) – a sideways or an upright stance with head and a three-way repeated measures ANOVA showed a signif- forebody movements toward the partner, and trying to bite the icant effect of observation period [F(2,196)=4.920, partner (offensive sideways or upright posture); tail rattle (Tr) – P=0.008] in the time spent in aggressive acts and a sig- nificant effect of treatment [F(2,196)=10.225, P<0.001],duration of treatment [F(4,196)=24.064, P<0.001] and observation period [F(2,196)=12.829, P<0.001] for la-tencies to aggressive acts.
Defense (De) – the mouse responds to the partner's social behav-iour by raising forepaws, hunching the back (defensive uprightposture) or by some rotation of the body bringing the legs closestto the other animal off the ground (defensive sideways posture); escape (Es) – a rapid running or jumping away from the partner;alert posture (Al) – a sudden interruption of all movements with A three-way repeated measures ANOVA showed a sig- eyes and ears being directed toward the partner.
nificant effect of treatment [F(2,97)=26.321, P<0.001],duration of treatment [F(4,194)=8.916, P<0.001] and ob- servation period [F(2,97)=20.466, P<0.001] in the num-ber of sociable acts (social sniffs, climbs, follows). Next, Walk (Wa) – any walking across the cage which is not apparently a three-way repeated measures ANOVA showed a signif- related to the partner; and rear (Re) – the mouse stands only on icant effect of treatment [F(2,196)=19.679, P<0.001], his hind legs and usually sniffs air or walls at the same time.
Duration was not measured for escapes and attacks because of duration of treatment [F(4,196)=13.725, P<0.001] and momentary character of these acts (i.e. measurement of duration observation period [F(2,196)=36.964, P<0.001] in the was not considered accurate enough and meaningful in these acts).
time spent in sociable acts and a significant effect of The inter-observer reliability of the recorded items was satis- treatment [F(2,196)=8.039, P<0.001], duration of treat- factory as determined by several observers independently scoring ment [F(4,196)=7.609, P<0.001] and observation period a videotaped record of behaviour of 70 mice in interactions lasting4 min each. The correlation ranged from r=0.83 to 0.97.
[F(2,196)=8.205, P<0.001] for latencies to sociable acts.
Alprazolam (Lécˇiva, Prague) was dissolved in distilled water withtwo drops of Tween 80 and administered orally in a volume A three-way repeated measures ANOVA showed a sig- 0.1 ml/10 g body weight. After administration, isolated mice were nificant effect of treatment [F(2,97)=7.084, P=0.001] always returned to their home cages (except for the last adminis- and observation period [F(2,97)=28.168, P<0.001] in the tration when they were placed into the observational cage).
number of locomotor acts (walks, rears), effect of treat-ment [F(2,196)=13.580, P<0.001] and observation peri- od [F(2,196)=14.668, P<0.001] in the time spent in loco-motor acts and a significant effect of observation period Mice exhibiting attacks (aggressive mice) in the pretreatment in- [F(2,196)=4.786, P=0.009] for latencies to locomotor teraction were selected for the analysis (the number of non-aggres- sive mice was too small for evaluation).
Behavioural elements, their frequency, duration and latency were summed in four behavioural categories (sociable, aggressive,locomotor and timid) for the statistical analysis. Statistical evalua-tion and interpretation of timid activities is limited due to their Table 1 Mean number of fre-
quency, duration and latency
(±SEM) of behavioural catego-ries after acute, 8 days and 21 Sociable acts (social sniff, climb, follow)Number of acts (±SEM)Control Aggressive acts (attack, threat, tail rattle)Number of acts (±SEM)Control Locomotor acts (rear, walk)Number of acts (±SEM)Control Timid acts (defence, escape, alert)Number of acts (±SEM)Mean parison with Bonferroni t-test,*P<0.05, **P<0.01, sive activities after a single administration of alprazolam(1 mg/kg PO) (t=4.105, df=92, P<0.001) compared to Behaviour after alprazolam administration the control group of mice (Table 1, Fig. 1). The acutetreatment with alprazolam also shortened the total dura- Aggressive activities. Subsequent Bonferroni tion of aggressive activities (t=3.134, df=96, P=0.002) showed a significant reduction of the number of aggres- and prolonged the latency to aggressive activities Fig. 1 Changes in aggression and social investigation after alpra-
Fig. 2 Changes of aggression and social investigation after alpra-
zolam administration. Alprazolam or the vehicle was given once zolam withdrawal. Alprazolam or the vehicle was given once (acute treatment 1 mg/kg), for 8 or 21 days (1 mg/kg b.i.d.). Be- (acute treatment 1 mg/kg), for 8 or 21 days (1 mg/kg b.i.d.). Be- haviour was measured 30 min. after the last dose of alprazolam.
haviour was measured 72 h after the last dose of alprazolam.
Changes are expressed as the percent difference between the num- Changes are expressed as the percent difference between the num- ber of aggressive and sociable acts in the alprazolam treated and ber of aggressive and sociable acts in the alprazolam treated and control groups. *P<0.05, **P<0.01, ***P<0.001 for the difference control group. *P<0.05, **P<0.01 for the difference between the between the control and the alprazolam-treated group of mice, a control and the alprazolam-treated group of mice, a three-way re- three-way repeated measures ANOVA with the subsequent Bon- peated measures ANOVA with the subsequent Bonferroni t-test (t=5.548, df=96, P<0.001). After the 8-day and the Behaviour after alprazolam withdrawal21-day treatment, the number and the duration of aggres-sive activities was reduced and the latency was length- Social investigation was reduced while aggression tend- ened to a lesser degree and these changes were not sig- ed to be increased after withdrawal from alprazolam (Ta- nificantly different from the control values (Table 1, Fig. 1). There was a large decline in the number of ag-gressive acts (but not in the duration of these acts) and a Sociable activities. The number and the duration of so- marked prolongation of the latency to their first occur- ciable activities was decreased significantly (t=2.390, rence in the control mice given vehicle for 8 or 21 days, df=92, P<0.019, t=2.383, df=92, P<0.019, respectively) which was probably due to adaptation to handling of the already after withdrawal from 8 days treatment with al- animals during the repeated administrations of the vehi- prazolam. This decrease was still more pronounced after 21 days of treatment (t=2.731, df=92, P=0.008 for thenumber and t=2.895, df=92, P=0.005 for the duration, Sociable activities. When alprazolam was administered once, the number and duration of sociable activitieswas increased significantly (t=2.416, df=92, P=0.018 Aggressive activities. Although aggressive activities ap- and t=3.766, df=92, P<0.001, respectively) and the peared to be increased directly in proportion to thelatency to their first occurrence was shortened (t=2.879, length of previous alprazolam treatment, only the total df=92, P=0.005, Table 1, Fig. 1). Similarly, the number duration after withdrawal from 21 days of alprazolam of sociable activities was increased after 8 days treat- treatment was significantly increased (t=2.128, df=92, ment with alprazolam (t=3.083, df=92, P<0.003) and the latency to their first occurrence was shortened(t=2.145, df=92, P=0.036). Also, after 21 days of al- Timid and locomotor activities. No significant changes prazolam treatment, the number and duration of socia- were found in any measure of timidity after alprazolam ble activities were increased significantly (t=2.782, withdrawal. The number but not the duration of locomo- df=92, P=0.007 and t=3.116, df=92, P=0.002, Table 1, tor activities tended to be reduced directly to the length of the alprazolam treatment. When compared to the con-trol group of mice, the number and the duration of loco- Locomotion and timid activities. No significant changes motion activities was reduced significantly in mice with- were found in any of the measures of timid and loco- drawn from alprazolam given for 21 days (t=3.133, motion activities except of the mean number and total df=92, P=0.002, t=2.808, df=92, P=0.006, respectively, duration of locomotion activities which was decreased after the 21 days of alprazolam treatment (t=2.257,df=92, P=0.026, t=4.191, df=92, P<0.001, respective-ly).
Table 2 Mean number of fre-
quency, duration and latency
(±SEM) of behavioural catego-ries after 72 h withdrawal from Sociable acts (social sniff, climb, follow)Number of acts (±SEM)Control Aggressive acts (attack, threat, tail rattle)Number of acts (±SEM)Control Locomotor acts (rear, walk)Number of acts (±SEM)Control Timid acts (defence, escape, alert)Number of acts (±SEM)Control ANOVA with subsequent com-parison with Bonferroni t-test, *P<0.05, **P<0.01, when of social investigation appears to be in agreement withinhibition of social interaction in the social interaction In the present study, social investigation was reduced test as an index of increased anxiety reported after with- while aggression tended to be increased after withdrawal drawal from benzodiazepines (File et al. 1991; Andrews from alprazolam. These behavioural changes correlated et al. 1997). However, the reduction of “sociable” behav- with the length of alprazolam treatment. The reduction iour in terms of components of social investigation such as social sniffing, climbing and following partners found diazepines than to their disinhibitory or stimulating ef- in the present study does not seem to reflect anxiety. In fects. Different rates of development of tolerance to be- the present model, anxiogenic activity is manifested by havioural effects of benzodiazepines suggest that they increased defensive-escape behaviour, which can be ac- are differentially regulated. The decrement of antiaggres- companied (in aggressive animals), with reduced aggres- sive activity of alprazolam after 8 and 21 days of treat- sion. Such behavioural changes were produced by anxio- ment does not seem to be due to the decrease of control genic drugs such as inverse agonists at benzodiazepine (basal) level of aggressivity because it occurred also in a receptors (beta-CCE and FG 7142; Sulcova et al. 1992).
parameter (the time spent in aggressive acts) where con- In the present study, however, no significant increase of trol values remained comparable. The rapid development defensive and escape behaviour on alprazolam with- of tolerance to the inhibitory effects of alprazolam on ag- drawal was found even after 21 days of treatment with gressive behaviour is in agreement with a study using lo- the drug. Thus, no evidence of increased anxiety during razepam, where tolerance to anti-aggressive effects had withdrawal from alprazolam was found in aggressive developed after 7 days of admininstration of the drug Although aggression during alprazolam withdrawal In contrast to the marked and rapid tolerance to the appeared to be increased directly in proportion to the inhibitory effects of alprazolam on aggressive behaviour, length of alprazolam treatment, only the increase in total only moderate increases of aggression were detected af- duration of aggressive behaviour was significant on al- ter withdrawal of alprazolam treatment. Social investiga- prazolam withdrawal after 21 days of treatment with the tion was reduced upon alprazolam withdrawal, although drug. Only a few reports deal with changes in aggressive tolerance had not developed to this behavioural effect.
behaviour during benzodiazepine withdrawal. Increased Reduction of social investigation appears to be a consis- frequency of threats was observed in a few monkeys fol- tent consequence of withdrawal from benzodiazepines lowing withdrawal from diazepam precipitated with flu- during social conflict in mice. It was found also after mazenil (Grant et al. 1985). On the other hand, no withdrawal from lorazepam (File and Wilks 1990), diaz- changes in aggressive behaviour were found during so- epam (Podhorná and Krsˇiak 1995; Andrews et al. 1997) cial conflict in mice after withdrawal from 21 days of lo- and chlordiazepoxide (Baldwin and File 1989). Reduc- tion of locomotion represents another behavioural The increase in social investigation and reduction of change occurring upon withdrawal from alprazolam to aggressive behaviour found after alprazolam treatment in which tolerance had not developed. Locomotion was re- the present study is in good agreement with a number of duced after withdrawal after 21 days alprazolam treat- previous studies using this behavioural model (Krsˇiak ment, while acute and 8 days of treatment did not change 1975, 1979; Krsˇiak and Sulcova 1990). In general, ben- locomotion. Alternatively, no changes in locomotion zodiazepines have a biphasic effect on aggressive behav- were observed after withdrawal of low doses of loraze- iour; low doses enhance this behaviour and higher doses pam although tolerance developed to the inhibitory ef- decrease it (Miczek 1974, 1987; Miczek and Krsˇiak fect of the drug on locomotion (van der Laan et al.
1979; Olivier et al. 1991; Ferrari et al. 1997). However, 1993). The evidence of withdrawal responses appearing evidence for this effect with alprazolam is scarce (Mos for a behaviour to which tolerance had not developed does suggest that benzodiazepine tolerance and with- Tolerance developed to the inhibitory effects of alpra- drawal phenomena can be dissociated.
zolam on aggressive behaviour but it had not developedto the stimulatory effects of alprazolam on social investi- Acknowledgements This work was supported by research grants
gation. Tolerance did not develop to the slight inhibitory GACR No. 305/99/1481, GAUK 193/98, IGA NF 5513-3 ofCzech Ministry of Health with contributions from MSMT effect of alprazolam on locomotion either. In fact, loco- VS96129 and VZ J13/98: 111200005. We wish to thank Mrs. M.
motion was reduced only after 21 days of treatment with Likovská and Mrs. L. Bartosˇová for their excellent laboratory as- alprazolam. Tolerance developed at different rates to di- sistance and Dr. Malý for his great advice with statistical evalua- verse actions of benzodiazepines in separate tests. For example, tolerance developed rapidly to the anticonvul-sant effects (File and Wilks 1990; Byrnes et al. 1993), tomotor-impairing effects in the rotarod test (Shumsky and Lucki 1994) or to sedative effects measured in the hole-board test (File 1981; Lister et al. 1983; Fernandes et al.
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What can be done to improve Irritable Bowel Syndrome (IBS)? Last updated: August 2002 Traditionally, physicians have had a great deal of difficulty coming up with adequate medical treatments for IBS. Medications used to treat the disorder have generally been aimed at treating single symptoms (such as pain or diarrhea) of this complex syndrome, and have often proven limited in effectiveness e

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*Antidepressant trial of adequate dose/duration is 4-6 weeks at FDA approved maximum dosage or maximum tolerated dose with minimum 80% Meets DSM-IV criteria for Major Depressive Disorder or severe DysthymiaPsychotherapy should be the initial treatment of choice and should be continued throughout treatment even if drug therapy is started. Fluoxetine 20 – 60 mg/day for 4-6 weeks*Switch to al

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