Effects of apomorphine and amphetamine on patterns of locomotor and investigatory behavior in rats

Rats were tested in a Behavioral Pattern Monitor after various doses of either amphetamine or apomorphine in order to characterize their behavioral profiles, including patterns and sequences of holepokes, rearings and locomotor movements. To enable direct comparisons between the behavioral effects of the two stimulants, doses and times for each drug were selected with which locomotor hyperactivity was the predominant behavioral response. Although both drugs increased the total amount of locomotor activity, amphetamine induced a relatively varied behavioral profile while apomorphine induced repetitive behavior with a restricted range of responses. These contrasting effects of the stimulants were interpreted as reflective of their differing modes of action with regard to central dopaminergic systems. It is suggested that, in the dose range used, the release of dopamine by amphetamine is coupled to neuronal firing and therefore this release increases behavioral activity without altering the normal response repertoire of the animal. Conversely, the direct agonist action of apomorphine results in a restricted and perseverative behavioral pattern because its activation of forebrain dopamine receptors is independent of the normal physiological pattern of dopaminergic neuronal firing.     

Dose-dependent changes in the locomotor responses to methamphetamine in BALB/c mice: Low doses induce hypolocomotion

The overall goal of the present study was to determine the effects of different doses of (+)-methamphetamine (meth) on locomotor activity of Balb/C mice. Four experiments were designed to test a wide range of meth doses in BALB/c female mice. In Experiment 1, we examined locomotor activity induced by an acute administration of low doses of meth (0.01 and 0.03 mg/kg) in a 90-min session. Experiment 2 was conducted to test higher meth doses (0.3-10 mg/kg). In Experiment 3, separate sets of mice were pre-treated with various meth doses once or twice (one injection/week) prior to a locomotor challenge with a low meth dose. Finally, in Experiment 4, we tested whether locomotor activation would be affected by pretreatment with a low or moderate dose of meth one month prior to the low meth dose challenge. Results show that low doses of meth induce hypolocomotion whereas moderate to high doses induce hyperlocomotion. Prior exposure to either one moderate or high dose of meth or to two, low doses of meth attenuated the hypolocomotor effect of a low meth dose one week later. This effect was also attenuated in mice tested one month after administration of a moderate meth dose. These results show that low and high doses of meth can have opposing effects on locomotor activity. Further, prior exposure to the drug leads to tolerance, rather than sensitization, of the hypolocomotor response to low meth doses.     

Acute nicotine and phencyclidine increase locomotor activity of the guinea pig with attenuated potencies relative to their effects on rat or mouse

Behavioral assays of the responses to psychomotor stimulants can be used to model certain aspects of CNS pathologies such as psychosis and addiction. However, species-dependent differences in the effects of neuromodulators in these assays can confound the interpretation of the results. The goal of this study was to determine the utility of the guinea pig as a model for assessing the behavioral actions of nicotinic receptor agonists and NMDA receptor antagonists. In the present study, the locomotor activity of adult male guinea pigs was measured, prior to and following an acute injection of nicotine, MK-801 or phencyclidine. Each animal received a single dose of the drug.Nicotine produced a dose-dependent increase in activity with an ED₅₀ of 1.5 mg/kg. Phencyclidine also increased activity, with an ED₅₀ of 3.4 mg/kg. Nicotine produced increases in locomotion in all individual subjects tested, whereas at the maximally-effective dose of phencyclidine, only a fraction of the animals had locomotor activation. There was no change in activity in response to a single dose of MK-801 (0.5 mg/kg). Haloperidol had a significant inhibitory effect on locomotor activity independent of the stimulant administered. Thus, both phencyclidine and nicotine are psychomotor stimulants when given to guinea pigs, although the intensity of the response and the potencies of these drugs are lower than in mice or rats under otherwise similar conditions.     

Inherent differences in sensitivity to methylxanthines among inbred mice

The behavioral effects of caffeine, theophylline, paraxanthine, and theobromine on locomotor activity were analyzed in four strains of inbred mice that were previously shown to differ in their acute toxic responses to caffeine administered at high dosages. Dose response curves for the effects of caffeine, theophylline, paraxanthine and theobromine on locomotor activity were established in CBA/J, C57BL/6J, DBA/2J and SWR/J strains of inbred mice. Paraxanthine was the maximally effective methylxanthine in the CBA/J, DBA/2J and SWR/J strains, while in the C57BL/6J strain, caffeine was the maximally effective methylxanthine. Theophylline failed to stimulate locomotor activity in the C57BL/6J strain and theobromine failed to stimulate activity in all of the strains tested. Decreases in locomotor activity were seen at the 100 mg/kg dose of caffeine in the C57BL/6J mice and at the 100 mg/kg dose of theophylline in the C57BL/6J, DBA/2J and SWR/J strains. Theobromine produced decreases in locomotor activity in the C57BL/6J, DBA/2J and SWR/J strains of mice. In contrast to the other methylxanthines, paraxanthine failed to decrease activity across the range of doses tested (1.0-150 mg/kg). These data suggest that the methylxanthines have genetically specified multiple modes of action upon locomotor activity and that the use of genetically distinct strains of mice may have important value in the neurochemical and pharmacological dissection of methylxanthine-induced behavioral effects.     

Centrally administered neurotensin suppresses locomotor hyperactivity induced by d-amphetamine but not by scopolamine or caffeine

The effects of intracisternally (i.c.) administered neurotensin (NT) on locomotor responses to scopolamine and caffeine, two psychomotor stimulants which do not depend on an intact mesolimbic dopamine (DA) system, were compared with the effects of the peptide on locomotion induced by d-amphetamine, which does depend on this DA system. Adult rats were injected intracisternally with 30 micrograms of neurotensin or vehicle. Immediately following these injections, the rats received intraperitoneal injections of either d-amphetamine (1, 2 or 3 mg/kg), scopolamine (0.25, 0.5, 1.0 or 2.0 mg/kg), caffeine (5, 15, 30 or 50 mg/kg) or the appropriate vehicle. After a 10 min recovery period, interruptions of photocells by ambulatory and non-ambulatory behavior were recorded every 30 min for 2 hr. Analyses of variance indicate that d-amphetamine and caffeine significantly elevated locomotor and non-locomotor activity at every dose tested. Scopolamine elevated locomotor activity at every dose and non-locomotor activity at 0.5, 1.0 and 2.0 mg/kg. Statistical analysis revealed that neurotensin significantly suppressed the locomotor response to 2 and 3 mg/kg of d-amphetamine but did not suppress the locomotor responses to any dose of scopolamine or caffeine or the non-locomotor responses to any of the three stimulants tested. Behavioral ratings of stereotyped responses indicated that neurotensin altered none of these responses to any stimulant tested. These findings are consistent with previous behavioral and biochemical data which indicate that neurotensin modulates the activity of the mesolimbic, but not nigroneostriatal, DA system and moreover, demonstrate that neurotensin does not simply induce a non-specific impairment of locomotor activity.     

On the possible involvement of glutamate receptors in conditioning of behavioural effects of apomorphine

It was shown previously that behavioural effects of apomorphine (locomotor activation and stereotyped behaviour) can be conditioned when they are associated with well-defined environmental stimuli. In the present study, the hypothesis was tested that glutamatergic mechanisms play an important role either in formation of conditioned responses to apomorphine or in the expression of previously established conditioned responses. For this purpose, two blockers of glutamate receptors were applied, either MK-801 (dizocilpine), a non-competitive, but selective blocker of NMDA-type receptors or MLV-6976, a non-selective blocker of glutamate receptors. MK-801 produced some locomotor activation by itself in a dose-dependent way (0.125–0.50 mg/kg ip). The locomotor activation produced by 0.25 mg/kg could not be conditioned. When rats were conditioned 9 times with 2 mg/kg apomorphine after pretreatment with 0,25 mg/kg of MK-801, this pretreatment did not prevent the development of apomorphine-conditioned locomotor activity or stereotypies which appeared when the rats were treated with saline in presence of the conditioned stimuli. Similar results were obtained when rats were conditioned 7 times with the same dose of apomorphine after pretreatment with 20 mg/kg ip MLV-6976, which drug did not induce any visible alterations in motility by itself. When rats were conditioned 7 times with 2 mg/kg apomorphine alone and tested with MK-801 (0.25 mg/kg) in the presence of the conditioned stimuli, neither locomotor activity nor stereotypies appeared as conditioned responses. When rats were conditioned with the same dose of apomorphine alone and tested with MLV-6976 (20 mg/kg ip), stereotypies did not appear as conditioned responses, but some locomotor activity occurred. The results suggest that glutamatergic mechanisms are not relevant for the development of conditioned responses to apomorphine, but might be of some relevance for the expression of previously established conditioned responses.     

Effects of combined treatment with nortriptiline and lorazepam on conflict behavior and motility of rats

Lorazepam attenuated the suppressant effects of punishment on the response rate of rats in the multiple schedule of reinforcement devised by Geller and Seifter (1960). Nortriptiline alone was ineffective on punished responses. Both drugs, at certain dose levels, inhibited the nonpunished response. Combined treatment with the two drugs in a dose ratio of 1:20 attenuated the effects of punishment at all dose levels tested. The effects of the combination upon both punished and nonpunished responding was greater than might be accounted for by a simple additive effect of the individual treatments. Lorazepam and nortriptiline both induced a dose-related decrease in the locomotor activity of rats; when given together the 2 drugs antagonized each other.The results give an experimental support to the clinical observations about the usefulness of the benzodiazepine-antidepressant combination in certain depressive illnesses.     

A comparison of motor behaviours in groups of rats distinguished by their climbing response to apomorphine

Administration of apomorphine hydrochloride (0.5 mg kg-1 s.c.) to adult male or female Wistar rats previously acclimatized to the test environment induced climbing behaviour in approximately 50% of animals examined. The proportion of animals climbing was related to age, being maximal at 8-9 weeks. Those animals showing an initial climbing response to apomorphine (0.5 mg kg-1 s.c.), climbed when challenged with this dose of apomorphine on subsequent occasions. In 'climbing' animals the intensity of response was related to the dose of apomorphine administered; no dose-response relationship was observed in 'non-climbing' animals. No overall differences in the spontaneous motor behaviour of 'climbing' and 'non-climbing' animals were apparent as assessed by measurement of spontaneous climbing behaviour, by holeboard activity, and by locomotor activity measured in either photocell cages or in a treadwheel. There was no overall difference in the ability of apomorphine to induce locomotor activity or stereotyped behaviour in 'climbing' and 'non-climbing' animals. However, the administration of apomorphine induced rearing and treadwheel activity only in those animals classified as 'climbers'. There was no difference between the number (Bmax) of specific [3H]-spiperone binding sites or the dissociation constant (KD) in striatal or mesolimbic tissue preparations for 'climbing' and 'non-climbing' rats. The ability of an animal to climb in response to apomorphine appears to be dependent on an ability to orient vertically, since this is a component of behaviour common to climbing, rearing, and treadwheel activity. The ability to climb does not appear to be related to differences in dopamine receptor numbers in brain or to the penetration of apomorphine into brain.     

Complex genetic determinants of susceptibility to methylxanthine-induced locomotor activity changes

The intent of this study was to investigate the role of inheritance in the determination of susceptibility to methylxanthine-induced behavioral changes. Two strains of inbred mice, SWR and CBA, which differ significantly in their response to caffeine- and theophylline-induced stimulation of locomotor activity, were used in classical genetic crosses to produce reciprocal F1 hybrids, reciprocal backcross progeny F2 progeny. Theophylline dose response curves in the reciprocal F1 hybrid strains were identical to each other and to their methylxanthine-responsive (CBA) parent. These results indicated that theophylline responsiveness behaved as a simple autosomal dominant trait. Behavioral responses of these F1 hybrid strains to caffeine showed the same maximal enhancement of locomotor activity as their CBA progenitor at a dose 10 mg/kg IP, but locomotor activity stimulation also occurred at 32 mg/kg IP, a dose which inhibited their CBA parent. These data suggest that the genes specifying caffeine responsiveness differ from those encoding theophylline responsiveness. For both caffeine and theophylline, behavioral phenotypes and their expected frequencies of occurrence among backcross and F2 progeny differed significantly from the segregation ratios expected for a trait determined by a single gene. These non-Mendelian segregation ratios suggest that locomotor activity stimulation by both of these methylxanthines is polygenically determined. It was anticipated that the same genetically encoded neurochemical mechanism would underlie the difference in behavioral response to the two methylxanthines. However, no significant correlation between caffeine-induced and theophylline-induced stimulation of locomotor activity was observed among progeny derived from backcrosses of F1 self-crosses.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of 5,7-dihydroxytryptamine lesions of extrapyramidal and mesolimbic sites on spontaneous motor behaviour,and amphetamine-induced stereotypy

Summary 5,7-Dihydroxytryptamine lesions of the nucleus accumbens septi, or substantia nigra, resulted in a twofold increase in spontaneous locomotor activity. Striatal 5HT depletion also raised basal activity levels, as well as increasing rearing behaviour in an open field. The stereotyped responses to all doses of amphetamine tested (2.5–10 mg/kg, i.p.) were enhanced by lesions of the nucleus accumbens or substantia nigra. Striatal lesions only affected the response to the lowest dose of amphetamine. Lesions of the tuberculum olfactorium were without effect on spontaneous or amphetamine induced responses. The results support the concept of a modulatory 5HT influence on nigro-striatal function, and suggest that 5HT in the nucleus accumbens has an antagonistic role with respect to dopamine function in this site.     

Investigation into stereoselective pharmacological activity of phenotropil

Phenotropil [N-carbamoylmethyl-4-aryl-2-pyrrolidone (2-(2-oxo-4-phenyl-pyrrolidin-1-yl) acetamide; carphedon)] is clinically used in its racemic form as a nootropic drug that improves physical condition and cognition. The aim of this study was to compare the stereoselective pharmacological activity of R- and S-enantiomers of phenotropil in different behavioural tests. Racemic phenotropil and its enantiomers were tested for locomotor, antidepressant and memory-improving activity and influence on the central nervous system (CNS) using general pharmacological tests in mice. After a single administration, the amount of compound in brain tissue extracts was determined using an ultra performance liquid chromatography-tandem mass spectrometry (UPLC/MS/MS) method in a positive ion electrospray mode. In the open-field test, a significant increase in locomotor activity was observed after a single administration of R-phenotropil at doses of 10 and 50 mg/kg and S-phenotropil at a dose of 50 mg/kg. In the forced swim test, R-phenotropil induced an antidepressant effect at doses of 100 and 50 mg/kg, and S-phenotropil was active at a dose of 100 mg/kg. R-phenotropil significantly enhanced memory function in a passive avoidance response test at a dose of 1 mg/kg; the S-enantiomer did not show any activity in this test. However, the concentrations of R- and S-phenotropils in brain tissue were similar. In conclusion, the antidepressant and increased locomotor activity relies on both R- and S-phenotropils, but the memory-improving activity is only characteristic of R-phenotropil. These results may be important for the clinical use of optically pure isomers of phenotropil.     

Cognitive enhancers prevent the hypoxia-induced disruption of conditioned avoidance response

Six cognitive enhancer compounds, the new class of central nervous system (CNS)-active drugs (vinpocetine, vincamine, dihydroergotoxine, nicergoline, piracetam, and meclofenoxate) were tested before acquired two-way active avoidance response of spontaneously hypertensive (SH) rats had been disrupted by lowered environmental oxygen concentration (6% oxygen). Exposure to normobaric hypoxia reduced the number of conditioned avoidance responses (CAR) by 44%; at the same time the spontaneous locomotor activity of the animals (measured by the alteration in the number of intertrial crossings) was not considerably decreased, and latency times of conditioned responses were not lengthened significantly. The compounds tested showed protective effect against hypoxia-induced performance deficit without stimulating spontaneous activity. Vinpocetine antagonized nearly completely CAR blockade in the 1.25-5.0 mg/kg p.o. dose range, restoring the ratio of avoidance responses to normal level. Vincamine exerted activity at a dose of 20 mg/kg p.o. Dihydroergotoxine and nicergoline were effective at 10 mg/kg p.o., Piracetam and meclofenoxate showed moderate protective activity at 2,000 and 500 mg/kg p.o., respectively. For comparison, the effect of dopaminergic drugs of a different mechanism of action (amphetamine, apomorphine, bromocriptine, and methylphenidate) was also tested in a similar situation. Only amphetamine (at 1.0 mg/kg i.p.) and low doses of apomorphine (0.1 and 1.0 mg/kg) had a favorable effect against hypoxia-induced CAR blockade; this effect was accompanied by an increase in locomotor activity. On the basis of these data, the relatively simple behavioral method applied by us, protection of acquired conditioned response against the disruptive effect of hypoxia in SH rats, seems suitable to detect nootropic activity.     

Does locomotor response to novelty in rats predict susceptibility to develop sensitization to cocaine and PHNO?

It has been suggested that the locomotor response of rats to novelty is positively correlated with motor stimulant effects of acute injections with psychomotor stimulants, and liability to self-administer these drugs. In addition, response to novelty appears to be inversely correlated with an individual's susceptibility to develop behavioural sensitization (an increase in the behavioural response to a given dose of stimulant after repeated treatments). To test some of these putative relationships, 96 rats were allocated to one of two subgroups based on a median split of locomotor responses to novelty. Animals then received 10 successive injections of either vehicle, cocaine (10 mg/kg), or the direct D2 agonist, (+)-4-propyl-9-hydroxynaphthoxazine (PHNO: 15 microg/kg), and locomotor activity was monitored. Conditioning tests and additional sensitization and cross-sensitization tests were conducted. Results showed that locomotor responses to novelty are not significantly correlated with locomotor effects of either acute injection with cocaine or PHNO, or rate of development of behavioural sensitization to these drugs. However, locomotor responses to novelty did predict level of locomotor and stereotypy responses to cocaine, and to a lessor extent to PHNO. Cocaine-treated, but not PHNO-treated, rats exhibited drug-conditioned-like effects. Cross-sensitization between cocaine and PHNO was not observed, indicating independent mechanisms for sensitization. It is concluded that the locomotor response to novelty can predict level of locomotion and stereotypy produced by cocaine and PHNO, but does not predict the degree or rate of behavioural sensitization to either of these drugs.     

Cocaine produces locomotor stimulation in SS but not LS mice: Relationship to dopaminergic function

Cocaine produces several behavioral effects, most notably locomotor stimulation. While low doses of cocaine have been shown to decrease locomotor activity, moderate to high doses in the range of 5–50 mg/kg usually produce a marked increase in locomotor activity in rodents. This study examined the effects of a range of cocaine doses, 1–75 mg/kg, on locomotor activity in LS/Ibg (LS) and SS/Ibg (SS) mice. At the lowest doses, activity was depressed in both lines, but to a greater extent in LS mice. As the dose of cocaine was increased, activity returned to baseline, and at the highest doses, increases in locomotor activity were found, but only in SS mice. In LS mice, cocaine was ineffective in increasing locomotor activity at any of the doses tested. Since striatal dopaminergic neurons influence locomotor activity, we also assessed ligand affinity and receptor density of dopamine transporters and dopaminergic D₁ and D₂ receptors in striatal tissue obtained from these two selected lines. No differences in these receptor binding parameters were found. However, because of their anomalous locomotor response to cocaine, LS mice may prove to be a valuable tool in increasing our understanding of those sites which mediate specific effects of cocaine.     

Individual differences in initial low-dose cocaine-induced locomotor activity and locomotor sensitization in adult outbred female Sprague-Dawley rats

Sex and individual differences are important considerations when studying cocaine responsiveness. We have previously shown that male Sprague-Dawley (S-D) rats can be classified as low or high cocaine responders (LCRs or HCRs, respectively) based on their locomotor activity following a single dose of cocaine (10 mg/kg, i.p.). Further, this distinction was found to predict dopamine transporter function, cocaine-induced locomotor sensitization, cocaine conditioned place preference and motivation to self-administer cocaine. Here we investigated whether or not individual differences in cocaine-induced locomotor activity and locomotor sensitization exist in female S-D rats. Female rats exhibited a broad range of locomotor activation following either a 5 or 10 mg/kg cocaine injection, allowing for classification as LCRs or HCRs. When administered over 7 days, both doses induced locomotor sensitization in female LCRs/HCRs. However, the magnitude of effects produced by 5 mg/kg cocaine in female LCRs/HCRs was more comparable to that produced by 10 mg/kg in male LCRs/HCRs, both of which, interestingly, developed sensitization in this study. These findings suggest that female S-D rats, like male S-D rats, can be classified as LCRs/HCRs and highlight the importance of accounting for dose when studying sex and individual differences to the effects of cocaine.     

Kainic acid injections in the striatum alter the cataleptic and locomotor effects of drugs influencing dopaminerig and cholinergic systems

Rats with bilateral injections of kainic acid into the striatum were tested for their motor responsiveness to drugs influencing dopaminergic and cholinergic systems. The kainic acid-induced lesions potentiated the locomotor response to both the dopaminergic agonist, d-amphetamine, and the cholinergic antagonist, scopolamine, attenuated the cataleptic response to the dopaminergic antagonist, haloperidol, and potentiated the cataleptic and convulsive responses to the cholinergic agonist, pilocarpine. The analogy of these pharmacological effects with those induced by similar drugs in patients with Huntington's disease supports the view that this animal preparation is a useful model of Huntington's disease. The opposite effects of haloperidol and pilocarpine on catalepsy in kainic acid-lesioned rats suggest that more work should be done to elucidate the mechanism behind this conflict before full support can be given to its use as a model system for evaluating possible pharmacotherapy in Huntington's disease.     

丁螺环酮对小鼠主动和被动回避反应的影响

应用小鼠一次性被动回避和穿箱主动回避行为法 ,观察抗焦虑剂丁螺环酮 (Bus)对学习获得和记忆保持的影响 .结果发现 ,训练前 ip Bus0 .3- 1 0mg·kg-1不影响小鼠一次性被动回避反应的获得 ,但训练后立即 ip Bus 0 .3- 1 mg· kg-1时损害其保持 ,缩短小鼠进入暗室的潜伏期 .每天训练前 ipBus 0 .3- 1 0 mg· kg-1时 ,小鼠 d 1穿箱主动回避反应率显著提高 ,但随后的 d2 - 4,1 ,3,1 0 mg·kg-1组小鼠主动回避反应率显著降低 .Bus 0 .3-3.0 mg· kg-1不影响小鼠自发活动 ,1 0 mg· kg-1使小鼠活动性降低 ,这些结果表明 Bus不影响或促进学习获得 ,对记忆的保持具有损害作用     

The effects of flumazenil on two way active avoidance and locomotor activity in diazepam-treated rats.

The present study was undertaken to determine the effects of chronic flumazenil treatment alone and simultaneously with diazepam on acquisition performance in an active-avoidance task and on locomotor activity in rats. Flumazenil (5, 10 and 20 mg/kg) and diazepam (0,5, 1.0 and 2.0 mg/kg) were administered intraperitoneally to rats before each daily training session for 5 days. The baseline of avoidance performance was set to approximately 50% and responses were expressed as acquisition rate. Locomotor activity of the rats was simultaneously recorded but only following the first training session. Diazepam decreased acquisition rate between the dose range used. Flumazenil had no effect on the acquisition rate of naive rats but reversed low dose diazepam-induced learning and memory impairment. Diazepam induced locomotor depression within the same dose range that decreased acquisition rate. Flumazenil had no effect on locomotor activity, but reversed the locomotor depressant effect of diazepam. The striking contradiction with previous data that flumazenil has no effect on learning-memory processing is discussed.     

Tolerance and withdrawal after chronic lorazepam treatment in rats

The purpose of the study was to develop an animal model for benzodiazepine tolerance and dependence on the basis of oral administration, using lorazepam as the test drug. We have used the continuous measurement of locomotor activity in home cages to obtain a narrow estimation of the time course of withdrawal related hyperactivity as an observer-independent symptom.

Acute administration of lorazepam (9.5–37.5 mg/kg body weight/day) resulted in the first week in a dose-dependent muscle relaxation on the accelerod and sedation in the open field. The most striking manifestation of sedation, however, was the decrease of nocturnal locomotor activity in home cages. After 5 weeks of administration tolerance to the sedative effect had developed. In a second study , using a lower dose range (2.5–9.5 mg/kg body weight/day), a decrease of nocturnal locomotor activity was also observed as was the development of tolerance. The latter can be partly explained by dispositional tolerance, i.e., decreased serum concentrations after administration of lorazepam for more than 2- weeks. Withdrawal of lorazepam in the experiment using high doses led to three symptoms, i.e., a decrease in food intake, loss of body weight and an increase in daytime locomotor activity. The decrease in food intake and the loss of body weight were maximal on the first day of withdrawal. The increase in the daytime locomotor activity was present in the high dose experiment only, with a maximum on days 2–3 and a duration of at least 1 week. The increase however, was not dependent on the dose previously administered.

The symptoms ‘loss of body weight’ and ‘decrease in food intake’ appeared to be more sensitive in benzodiazepine withdrawal: they were dose dependently present over the whole dosage range (2.5–37.5 mg/kg body weight/day).

It is concluded that the model represents a sensitive model to measure lorazepam tolerance and dependence in animals. Comparative studies with other benzodiazepines are in progress.