An automated method for studying exploratory and stereotyped behaviour in rats

A technique is described for studying exploratory as well as stereotyped behaviour in rats using an automated hole-board. Both visual and automated recordings can be employed using the technique. Hole dipping is monitored automatically using an infra-red detector system. Repetitive patterns of hole-dipping are used as parameters of stereotyped behaviour while the more random patterns of hole-dipping are used as parameters of exploration.There was a high significant correlation between the records of hole-dipping behaviour as recorded visually and automatically. There was also a high significant correlation between the measures of repetitiveness/randomness of hole-dipping behaviour from automatic and visual recordings. The pattern and levels of hole-dipping conformed with expectations both as regards changes with time and with increasing doses of dl-amphetamine.     

An analysis of stereotyped behaviour in Mastomys natalensis

Summary The stereotyped behaviour was analysed in Mastomys natalensis, a species of desert rat recently introduced in laboratory practice. The components of stereotyped behaviour were similar to rat characterised by repetitive sniffing, rearing, licking, head movements and biting. Apomorphine (0.5–2.0 mg/kg), amphetamine (2.5–10 mg/kg), methylphenidate (10 – 30 mg/kg) and adamantanamine (10 – 50 mg/kg) administered intraperitoneally, induced stereotyped behaviour in dose-dependent manner. Positive response was also obtained by other drugs acting on dopamine receptors like 1-dopa, GBR 12909, piribedil, tyramine, BS 9648, BS 9641 and BS 8824. Yohimbine (2 mg/kg) failed to produce any response. Apomorphine (2 mg/kg), amphetamine (10 mg/kg), methylphenidate (30 mg/kg) and piribedil (12 mg/kg) induced stereotypy which could be blocked by dopamine receptor blockers haloperidol (1 mg/kg) or pimozide (1 mg/kg) but yohimbine (2 mg/kg) an alpha adrenoceptor blocker was ineffective. Adamantanamine, piribedil and GBR 12909 enhanced the stereotypy induced by low doses of apomorphine, amphetamine and methylphenidate. The data shows that the stereotyped behaviour in Mastomys natalensis is mediated through dopaminergic mechanisms. It appears that both excitatory and inhibitory types of dopamine receptors are involved. Send offprint requests to A. Gulati     

Modulation of the behavioral effects of amphetamine in rats by clonidine

Clonidine (0.01, 0.05, 0.5 mg/kg) dramatically reduced the locomotor response to amphetamine (2 mg/kg) in a dose related fashion. In contrast, the same doses of clonidine had no effect on locomotions produced by a higher dose of amphetamine (6 mg/kg). Clonidine also had no effect on stereotyped head movements or the duration of the behavioral response to amphetamine. The lower dose of clonidine reduced amphetamine induced licking/biting while the two higher doses potentiated amphetamine induced licking/biting. Thus the behavioral effects of clonidine vary depending upon the dose of amphetamine and the particular behavior selected for study. The known neurochemical effects of clonidine do not account for this phenomenon.     

Effects of dopaminergic stimulants on cyclic nucleotide levels in mouse brain in vivo

Summary Dopaminergic stimulants (amantadine, amphetamine, apomorphine, nomifensine and L-dopa plus benserazide) increased cyclic GMP levels in the medial forebrain and cerebellum of mice. Cyclic AMP levels were not significantly altered under these conditions. Drug-induced stereotyped behaviour correlated in intensity and duration to the changes in cyclic GMP levels in the medial forebrain.Amantadine, apomorphine and nomifensine showed a linear dose response relationship, but differed as to the extent and time course of the increase in cyclic GMP. Amantadine and apomorphine were more effective in elevating cyclic GMP in the medial forebrain than in the cerebellum. Amphetamine produced an exponential dose-related elevation of cyclic GMP in both parts of the brain, being more effective in the cerebellum than in the medial forebrain at high doses, thus indicating a complex mechanism of action. L-Dopa (50 mg/kg) and benserazide (40 mg/kg) alone did neither significantly increase cyclic GMP levels nor induce stereotyped behaviour. However, in animals pretreated with benserazide (15 min prior to L-dopa) L-dopa produced a significant elevation of cyclic GMP and stereotyped behaviour.     

Buprenorphine-cocaine Interactions in Mice: Effect on Locomotor Activity and Hole-dipping Behaviour

Abstract— The effect of cocaine and the mixed μ-opioid partial agonist/κ-antagonist buprenorphine on locomotor activity and hole-dipping behaviour was investigated in mice. The drugs were given alone and in combination. Cocaine (7·5, 15, 30 mg kg^?1, i.p.) significantly increased locomotion in a dose-related manner in the hour following injection. The two highest doses also increased hole-dipping although this response was not consistently seen. Buprenorphine (0·5, 5 mg kg^?1, i.p.) produced an increase in locomotion which occurred 30–60 min after injection but did not alter hole-dipping behaviour. A lower dose (0·05 mg kg^?1) had no effect on either parameter. The locomotion induced by cocaine (15 mg kg^?1, i.p.) was not modified by buprenorphine (0·05, 0·5, 1, 5 mg kg^?1, i.p.; 5 min pretreatment). However, hole-dipping was almost completely abolished in animals given combinations of cocaine and buprenorphine (0·05–5 mg kg^?1, i.p.), although neither drug decreased hole-dipping when given alone. This observation, which was not simply due to the emergence of stereotyped behaviour, suggests an interaction between buprenorphine and cocaine.     

Gonadectomy and sex differences in the behavioral responses to amphetamine and apomorphine of rats

Following treatment with 5 mg/kg d-amphetamine sulfate or 2 mg/kg apomorphine hydrochloride female rats displayed more intense and longer lasting stereotyped behavior than males. Gonadectomy did not affect the display of stereotyped behavior induced by either drug in either sex. A lower dose of amphetamine (1 mg/kg) caused greater stimulation of locomotor activity in females than in males. Castration of males had no effect, but ovariectomy blocked the stimulating effect of amphetamine on activity. By contrast, low doses of apomorphine depressed activity in a dose-dependent manner that was somewhat greater in ovariectomized females than in the other groups. These data add to the growing body of literature demonstrating that gonadal hormones modulate the activity of brain dopamine systems.     

Some effects of chlordiazepoxide and d-amphetamine on response force during punished responding in rats

Rats were reinforced with water on a continuous reinforcement schedule and were also punished with electric shock for every fifth response applied to a silent, isometric, force-sensing manipulandum. Oral doses of chlordiazepoxide (3.0, 9.0, 27.0 mg/kg) increased both conventional rate and force of punished responding. In contrast, d-amphetamine (0.8, 1.6, 3.2 mg/kg, by gavage) further decreased conventional rate and force of response, but this latter drug increased the rate of recorded responses that were lower than the 15-g force criterion for response consequences. The results for chlordiazepoxide are viewed in terms of its anxiolytic properties, while the d-amphetamine data appear to support a theory of amphetamine effects based on the concept of stereotyped behaviors.     

Feeding stimulated by very low doses of d-amphetamine administered systemically or by microinjection into the striatum

The effects of d-amphetamine over a wide range of doses (0.125–4.0 mg/kg IP) on rat unconditioned behaviour were examined in the presence of food and water (experiment 1), in their absence (experiment 2) and after microinjection (2.0 g in 0.5 l) directly into the striatum (experiment 3). In experiment 1 very low doses (0.125 and 0.25 mg/kg) stimulated the intake of food, but not water, and higher doses produced locomotor hyperactivity, rearing, stereotyped sniffing and anorexia. In experiment 2 all doses, including very low doses (0.125 and 0.25 mg/kg), significantly potentiated locomotor activity. In experiment 3, microinjection into the corpus striatum elicited substantial feeding, but not drinking, locomotor activity or stereotyped behaviour. The results suggest that a single graded facilitative mechanism underlies the effects on food intake and other behavioural effects of amphetamine, as implied by a general hypothesis of amphetamine action proposed in the literature, and that these effects may to a large extent by mediated by forebrain dopamine systems.     

Influence of phenoxybenzamine on the stereotyped behaviour induced by fencamfamine in rats: evidence for a qualitative alteration

The interactions between norepinephrine (NE) and dopamine (DA) systems in mediating stereotyped behaviour induced by different doses of fencamfamine (1-30 mg/kg) were studied in male rats. Pretreatment with phenoxybenzamine (5.0 mg/kg) resulted in a significant leftward shift of the control curve for stereotypy. The qualitative analysis of the stereotyped behaviour parameters when compared to controls showed: higher rearing frequency at a dose of 3.0 mg/kg; lower locomotor activity at a dose of 6.0 mg/kg; higher licking and gnawing frequencies at a dose of 10.0 mg/kg. These findings indicate that the role of DA systems on the stereotyped behaviour induced by fencamfamine is dependent on the degree of NE transmission in the CNS.     

Behavioural studies on the effects of d-amphetamine and estradiol benzoate alone and in combination

The effects of d-amphetamine sulphate on grooming, rearing, and ambulatory behaviour in the T-maze was studied in rats. Low doses (0.25–2.0 mg/kg) produced a dose-dependent change in behaviour; ambulatory behaviour was increased while grooming and rearing behaviour was decreased. The results suggest that the behavioural changes are a direct effect of amphetamine rather than a secondary consequence of a competition between different types of behaviour.The effects of d-amphetamine sulphate and/or estradiol benzoate on grooming, rearing, and ambulatory behaviours in the T-maze and open field were also studied. Rats chronically treated with estradiol or oil were injected with amphetamine or saline just prior to evaluation in the maze or open field. Amphetamine treatment, irrespective of environment or hormone treatment, stimulated ambulatory behaviour while inhibiting grooming behaviour. Estradiol specifically antagonized the amphetamine induced reduction of grooming in the maze only. The results suggest that amphetamine has an independent action on T-maze behaviour whereas estradiol has an effect that depends on the environment for its manifestation.     

Atypical antipsychotic drugs block selective components of amphetamine-induced stereotypy

Individual items of behavior produced by 1.0 or 5.0 mg/kg d-amphetamine were monitored in rats pretreated 15 minutes earlier with vehicle or with behaviorally relevant doses of haloperidol (0.1 or 0.25 mg/kg), clozapine (1.0 or 5.0 mg/kg), or thioridazine (1.0 or 5.0 mg/kg). Unlike haloperidol, the atypical antipsychotics failed to block all components of either the low- or high-dose response to amphetamine. These drugs, however, did block selective items of amphetamine-induced stereotyped behavior. Clozapine significantly attenuated the sniffing produced by 1.0 mg/kg d-amphetamine as well as the oral behavior (licking and/or biting) produced by 5.0 mg/kg d-amphetamine. Thioridazine, at a dose of 5.0 mg/kg, also reduced oral behavior and selectively blocked repetitive head bobbing. Taken together, these results suggest that although atypical antipsychotic drugs exert some common effects on the amphetamine behavioral response, these drugs do not influence all amphetamine-induced behaviors equally.     

Importance of environmental context in the development of amphetamine- or apomorphine-induced stereotyped behavior after single and multiple doses

The present study was designed to determine whether single and repeated pretreatment regimens with amphetamine or apomorphine differ in the context-dependency of sensitization of stereotyped behavior. Male CF-1 mice that were pretreated with a single high dose of amphetamine (14 mg/kg intraperitoneally [IP]) or apomorphine (40 mg/kg subcutaneously [SC]) only became sensitized to a lower test dose of amphetamine (7 mg/kg IP) or apomorphine (3 mg/kg SC) when placed in an environment that was the same as the pretreatment environment. However, animals pretreated with 3 high doses (24-h apart) of amphetamine (14 mg/kg IP) or apomorphine (40 mg/kg SC) did demonstrate sensitization to a lower test dose of amphetamine (7 mg/kg IP) or apomorphine (3 mg/kg SC) when placed in an environment that was different from the pretreatment environment. Context-dependent sensitization, but not context-independent sensitization, was extinguished by pairing the test environment with saline injections instead of drug injections. In addition, it was determined that neither sensitization model could be related to pharmacokinetic factors. Therefore, the results indicate that repeated exposure to amphetamine or apomorphine overcomes the context-dependent component of sensitization of amphetamine- or apomorphine-induced stereotyped behavior.     

Importance of environmental context in the development of amphetamine- or apomorphine-induced stereotyped behavior after single and multiple doses

The present study was designed to determine whether single and repeated pretreatment regimens with amphetamine or apomorphine differ in the context dependency of sensitization of stereotyped behavior. Male CF-1 mice that were pretreated with a single high dose of amphetamine (14 mg/kg, IP) or apomorphine (40 mg/kg, SC) only became sensitized to a lower test dose of amphetamine (7 mg/kg, IP) or apomorphine (3 mg/kg, SC) when placed in an environment that was the same as the pretreatment environment. However, animals pretreated with three high doses (24 h apart) of amphetamine (14 mg/kg, IP) or apomorphine (40 mg/kg, SC) did demonstrate sensitization to a lower test dose of amphetamine (7 mg/kg, IP) or apomorphine (3 mg/kg, SC) when placed in an environment that was different from the pretreatment environment. Context-dependent sensitization, but not context-independent sensitization, was extinguished by pairing the test environment with saline injections instead of drug injections. In addition, it was determined that neither sensitization model could be related to pharmacokinetic factors. Therefore, the results indicate that repeated exposure to amphetamine or apomorphine overcomes the context-dependent component of sensitization of amphetamine- or apomorphine-induced stereotyped behavior.     

Untersuchungen über die Stereotypien nach Amphetamin und Apomorphin sowie deren pharmakologische Beeinflussung

The behaviour of mice after various doses of amphetamine or apomorphine which induce stereotypies is described in details. The induced stereotyped behaviour in mice appears more differentiated than that in rats. The amphetamine-syndrome in rats consists of an excitement phase followed by the stereotypy, whereas apomorphine elicits stereotyped behaviour directly after administration. Amphetamine-induced stereotyped behaviour is different from the apomorphine-induced stereotypy in several respects.Neuroleptics inhibit the amphetamine (12.5 mg/kg s.c.) and apomorphine-(10 mg/kg s.c.) syndrome, while thymoleptics potentiate subeffective doses of amphetamine (5 mg/kg s.c.) and apomorphine (2 mg/kg s.c.). This is demonstrated with some neuroleptics of the phenothiazine-type, haloperidol, reserpine, and a group of thymoleptics. The method opens the possibility of differentiating within several groups of neuroleptics and within several groups of thymoleptics.

Wir danken Fräulein Christine Mosimann für die sorgfältige Durchführung der Tierexperimente.     

Sensitization of stereotyped behavior to amphetamine is context and response dependent.

The present study was designed to determine whether the environmental context in which amphetamine is administered plays a role in the development of sensitization to the stereotyped behavioral effects of amphetamine in mice. In male CF-1 mice, the dose-response curve for stereotyped behavior elicited by amphetamine was shifted 1.9-fold to the left 48 h after pretreatment with 14 mg/kg amphetamine. Behavioral sensitization only developed in mice that were pretreated in the same or a similar environment as that of the test environment. In addition, when mice were placed in an environment that attenuated the acute expression of stereotyped behavior elicited by the pretreatment dose of amphetamine, sensitization never developed. A further experiment showed that 96% of the mice that expressed stereotypy after the ED50 pretreatment dose of 10 mg/kg amphetamine showed a stereotyped behavioral response to the lesser dose of 7 mg/kg 48 h later, indicating sensitization. In contrast, mice that did not express stereotypy after the ED50 dose of amphetamine failed to show a significant stereotyped behavioral response to amphetamine challenge compared to vehicle-pretreated controls. Therefore, the results indicate that preexposure to a single high dose of amphetamine produces context- and response-dependent sensitization to amphetamine-induced stereotyped behavior.     

d-Amphetamine in squirrel monkeys of different social status: Effects on social and agonistic behavior,locomotion, and stereotypies

The influences of social status on amphetamine-induced behavioral effects in squirrel monkeys were investigated. Social status was determined by constructing a sociogram. d-Amphetamine (0.3–1.0 mg/kg orally, 0.3 and 0.6 mg/kg IM) increased stereotyped head movements and reduced the time spent in the sitting posture in all monkeys (N=25) regardless of sex, age, or social status. The high levels of locomotor activity in dominant and juvenile monkeys were decreased at higher amphetamine doses (0.6 mg/kg IM, 0.6 and 1.0 mg/kg orally), whereas the same doses increased locomotion in otherwise less active subdominant and submissive animals. Low doses of amphetamine (0.1, 0.3 mg/kg) decreased the incidence of agonistic behavior initiated by dominant monkeys, and higher doses (0.6, 1.0 mg/kg) caused these monkeys to change from predominant initiators of agonistic behavior into recipients. At 2 h after amphetamine administration (0.3 mg/kg IM), the high levels of locomotor behavior had returned to baseline, the social isolation began to disappear, and the disrupted agonistic behavior of dominant monkeys returned to control levels, yet the stereotyped head movements continued to occur with high frequency. In half of the monkeys, amphetamine produced a large increase in distress-like vocalizations. Amphetamine-mediated motor stereotypies may be mediated by mechanisms different than those responsible for agonistic behavior. The selective changes in agonistic behavior by dominant monkeys when challenged with amphetamine may reflect a status-related functional alteration of catecholaminergic processes upon which the drug acts.     

Interpretation of changes in apomorphine-induced stereotyped behaviour in rats receiving continuous administration of trifluoperazine for 15 months

Rats treated continuously with trifluoperazine dihydrochloride (4.4–4.9 mg/kg per day) for 15 months showed an exaggerated stereotyped response to large doses of apomorphine (1.0 mg/kg, s.c.), but inhibition of stereotyped behaviour by a small dose of apomorphine (0.125 mg/kg, s.c.) as compared to responses obtained in age-matched control animals. Apomorphine (0.03–1.0 mg/kg, s.c.) produced more hyperactivity in trifluoperazine-treated rats than in control animals. After withdrawal of the drug for a period of 2 weeks or more. the stereotyped responses to all doses of apomorphine (0.0625–0.5 mg/kg, s.c.) were exaggerated in animals treated with trifluoperazine compared with age-matched control rats. Acute administration of trifluoperazine (4.5 mg/kg. p.o., 3 hr previously) to animals withdrawn from trifluoperazine abolished the stereotyped behaviour induced by a small dose of apomorphine (0.125 mg/kg) but a maximal response still was obtained with large doses (1.0 mg/kg). In contrast, acute challenge with trifluoperazine (4.5 mg/kg, p.o.) in control animals inhibited the stereotyped behaviour at virtually all doses of apomorphine, as compared with the responses to apomorphine in both animals withdrawn from trifluoperazine, given the same treatment, and naive control rats.Administration of trifluoperazine (0.28 and 0.56 mg/kg, p.o.) inhibited stereotypy induced by small doses of apomorphine (0.125 mg/kg, s.c.) in control animals but the response in animals withdrawn from trifluoperazine was exaggerated. Larger doses of trifluoperazine (1.125–4.5 mg/kg) totally inhibited apomorphine-induced (0.125 mg/kg, s.c.) stereotypy in both groups.These findings do not support the concept of separate mechanisms controlling low grade and high grade stereotyped behaviour during chronic treatment with neuroleptics.     

Similarities between the stimulus properties of phenylpropanolamine and amphetamine

Rats at 80% body weight were trained to discriminate 1.0 mg/kg d-amphetamine versus saline in a two-lever, discrete trial drug discrimination task to obtain food pellets. After reliable discriminative control of lever choice was established, various doses of d,l-phenylpropanolamine (PPA, i.e., d,l-norephedrine) were substituted for the amphetamine training dose in non-reinforced test trials. Test doses of 10, 20, and 40 mg/kg PPA resulted in over 90% responses on the amphetamine-appropriate lever. Lower doses (1.25, 2.5, and 5.0 mg/kg) resulted in predominantly saline-appropriate responses. The generalization seen after the 20 mg/kg dose of phenylpropanolamine was blocked by pretreatment with 0.5 mg/kg haloperidol, suggesting that the generalization from amphetamine to PPA was mediated by a dopaminergic mechanism.     

A novel procedure for dissociating the anatomical bases of the behavioral effects of amphetamine

A novel operative procedure is described in which the same cannula may be used to administer drugs either to the caudate nucleus (CN) or to the nucleus accumbens (NAcc) of the rat. Microinjections of amphetamine (10 or 20 micrograms) into the CN produced a reliable and robust stereotyped response; when administered to the NAcc of the same animal the higher dose increased locomotor activity. The stereotypy following peripheral administration of amphetamine (5 mg/kg) was antagonised by infusions of haloperidol (30 micrograms) into the CN but not into the NAcc. Conversely, the locomotor activity following a lower dose of amphetamine (1 mg/kg) was antagonised by infusions of haloperidol (5 micrograms) into the NAcc but not into the CN. The results confirm earlier reports that different anatomical structures mediate the behavioral effects of low and high doses of amphetamine.     

Effects of methamphetamine on novelty-seeking behaviour by mice

The effects of several doses from 0.125–3 mg/kg of methamphetamine on the novelty-seeking behaviour of male Swiss albino mice were studied. Methamphetamine induced a dose-dependent inhibition of novelty preference. Furthermore, a dose of methamphetamine (1 mg/kg) which strongly decreased novelty preference in naive mice induced a significantly lower decrease in exploration of subjects previously exposed to novelty. These data provide some support for Berlyne's (1967) suggestion that amphetamine has a disruptive effect on exploration by producing over-arousal.