The exploratory behaviour in normal and aggressive mice

Summary The emotional level can deeply change the exploratory behaviour in mice measured in the hole-board test.Psychoactive drugs in small amount influence this behavioural parameter differently in normal or in aggressive mice.This work was supported by U.S. Army Contract N DAJA 37-68 C-1076.     

Behavioral and neurochemical effects of caffeine in normal and aggressive mice

Caffeine is known to exert psychostimulant effects both in man and in animals and it has been shown to modify the levels of brain neurotransmitters. In normal and isolated-aggressive mice, caffeine induces modifications of both the level and the turnover of brain serotonin. Such modifications are however more evident in normal than in aggressive mice. Moreover, caffeine shows an antiaggressive effect and increases the exploratory activity of aggressive mice, without altering the performance of normal animals. It seems possible to conclude that the biochemical and behavioral effects of this drug differ in extent and intensity depending upon the emotional baseline on which it acts.     

Effects of N-(ethyl-2 pyrrolidinyl-methyl)-2-methoxy-5-sulfamoil-benzamide (sulpyrid) on the central nervous system in rats and mice

Sulpyrid is a new psychoactive drug and several clinical studies indicate a series of polymorphic therapeutic indications.Experimentally, sulpyrid blocks muricide reactions by isolation in rats but it is not active on aggressiveness in mice. Sulpyrid also modifies the exploratory activity in mice in which it decreases the brain 5-hydroxytryptamine turnover, as well as in rats.     

The effects of benzodiazepines on the behaviour of mice on a hole-board

The effect of exposing mice to a hole-board in reducing the number of head dips made on a subsequent exposure was studied. The period of first exposure that was effective in causing this reduction, the interval between exposure that must elapse before this effect appears and the duration of the effect were also determined. Chlordiazepoxide and other benzodiazepine tranquillizers, given before initial exposure, increased activity in small doses but had little effect upon subsequent activity. They did not affect characteristics of familiarization beyond possibly a slight shortening of the latent period.     

Effect of pyrithioxine (Encephabol) on growth and exploratory behaviour of rats malnourished in early life

Effects of pyrithioxine (Encephabol Merck) on growth, mortality and exploratory activity were studied in groups of rats kept on a low protein (LP) diet from birth to day 42 of life. In the first experiment pyrithioxine (40 mg/kg b.w.) was administered i.p. from day 35 to day 48, in the second experiment from day 100 to day 115.Pyrithioxine given to young rats by injection reduced mortality during protein deprivation and during the first weeks of nutritional rehabilitation as compared with malnourished rats injected with NaCl solution. Between days 90 and 140 better growth was recorded in the LP group treated with pyrithioxine. Pyrithioxine normalized behavioral symptoms of early malnutrition both during the period of deprivation and after realimentation. On day 150 of life these rats did not differ behaviorally from the well nourished group.Pyrithioxine injected in adult age did not affect the body weight of the LP group, and its the favorable effect on exploratory activity was transient. In normal rats pyrithioxine did not influence growth or behavior either in the first or in the second experiment.Presented in part at the annual Psychopharmacological meeting, Jeseník Spa, January 1971 (Fraková and Beneová, 1971).     

The action of the drug prenylamine (Segontin) on exploratory activity in strains of rats selectively bred for differences in emotionality

Summary The action of 20 mg/kg, i.p. of the drug prenylamine (Segontin) upon two forms of exploratory activity was examined in strains of rats selectively bred for differences in emotionality. The drug significantly depressed ambulation in an Open Field arena compared to placebo and although not apparently related to a strain specific action of the drug, this depression was greater in the more emotional Reactive strain. On the rearing frequency the depressive effect was not statistically significant and, further, no strain differences were revealed in this situation.     

Habituation of exploratory activity in mice: A screening test for memory enhancing drugs

The habituation of exploratory activity was investigated as an experimental model of memory processes. Mice were given two sessions in a simple photo-cell activity cage and the decrease in activity at the second session (habituation) served as an index of retention. Retention decreased as the interval between sessions increased from 1 to 7 days. Retention was facilitated or impaired by post-session IP injections of several drugs known respectively to improve [(+)-amphetamine, nicotine, physostigmine, strychnine] or impair (chlordiazepoxide, chlorpromazine, scopolamine) memory in other animal models. Memory facilitation or impairment only occurred if administration of the enhancing or impairing agent closely followed the first session, suggesting that the consolidation period was of limited duration. Post-session administration of presumably rewarding or noxious stimuli did not affect retention. Finally, retention was enhanced by several drugs which are used clinically for the treatment of memory disorders (bromocriptine, dihydroergotoxine, meclofenoxate, naftidrofuryl and piracetam). These results, consistent with classical learning data, suggest that habituation of exploratory activity in mice provides a simple but valid model of memory processes suitable for the screening of memory enhancing drugs.     

Time sampling of rat exploratory behaviour: A reliable screening test for the C.N.S. effects of anorexic agents

A series of eight experiments were conducted on the acute effects of a number of anorexic agents on rat exploratory behaviour, as assessed by a time sampling procedure of behavioural categorisation. Compounds studied were of three types. Firstly, some well known anorexiants (Amphetamine, Diethylpropion, Fenfluramine); secondly, a series of fenfluramine derivatives (Norfenfluramine, SE 780, SE 1513 and SKF 1-39728); and thirdly, an indole derivative (U 22-394A). All the compounds except the latter are based upon a phenylethylamine configuration. The results indicate that amphetamine and diethylpropion are stimulants whilst fenfluramine is a sedative, in accord with the clinical reports of the effects of acute administration of these compounds. All the other phenylethylamines and U 22-394A were found to be sedatives. The technique of activity analysis described here is a useful screening test for psychotropic agents which affect C.N.S. excitability in humans, which is probably superior to other measures of activity in its predictive value. However, it is noted that the effects of acute administration do not always provide a reliable index of chronic effects. The compounds SE 780 and SKF 1-39728 would seem to merit further study. It is suggested that all the fenfluramine derivatives, except SKF 1-39728, have a similar mode of anorexic action to U 22-394A.     

Effect of ketamine on exploratory behaviour in BALB/C and C57BL/6 mice

In this study, we evaluated the effect of ketamine on exploratory locomotion behaviours in the Balb/c and C57BL/6 strains of mice, which differ in their locomotion behaviours.Intraperitoneal administration of ketamine at three different doses (1, 5 or 10 mg/kg, 0.1 ml/10 gr body weight) was performed on adult male Balb/c and C57BL/6 mice. The same volume of saline was applied to the control group. The open-field and elevated plus maze apparatus were used to evaluate exploratory locomotion.In the open-field test, Balb/c mice less spend time in the centre of the field and was decreased locomotor activity compared to C57BL/6 mice (p < 0.01). Ketamine treatment of Balb/c mice at 10 mg/kg dose caused an increase in locomotor activity and an increase in the amount of time spent in the centre in the open-field test, compared to the control group (p < 0.05). In C57BL/6 mice, ketamine treatment (1 and 10 mg/kg) decreased locomotor activity (p < 0.05). In C57BL/6 mice, the three different doses of ketamine application each caused a decrease in the frequency of centre crossing (p < 0.001) and the spent time in the centre (p < 0.05).In the elevated plus maze, the number of open-arm entries, the percentage of open-arm time and total arm entries were decreased in Balb/c mice compared to C57BL/6 mice (p < 0.001). Ketamine treatment of Balb/c mice at 10 mg/kg dose caused an increase in the open-arm activity (p < 0.001). Ketamine application (10 mg/kg) decreased the open-arm activity in C57BL/6 mice (p < 0.05).A subanaesthetic dose of ketamine increased exploratory locomotion in Balb/c mice. In contrast, a subanaesthetic dose of ketamine decreased exploratory locomotion in C57BL/6 mice. In conclusion, hereditary factors may play an important role in ketamine-induced responses.     

Alteration of the neurochemical effects of fenfluramine by previous treatment with d-amphetamine

It was found in an earlier study that a 15-day IP subacute d-amphetamine treatment rendered an apparent "tolerance" to the food intake suppressant effects of fenfluramine. The purpose of the present study was to determine if the neuronal substrate on which fenfluramine supposedly acts to produce a decrement in food consumption was altered by the previous treatment with d-amphetamine. The time course effects (0-90 min) of a single IP injection of 10 mg/kg fenfluramine on brain monoamines in saline-treated rats included a significant lowering of serotonin in all brain regions examined. Although the serotonin depleting actions of fenfluramine in the d-amphetamine-treated rats generally paralleled those seen in the saline group (i.e., as in the hypothalamus), no such effects were noted in regions where baseline values (see below) were already lowered by d-amphetamine treatment (i.e., pons-medulla, thalamus, and substantia nigra). Norepinephrine and dopamine depletions were observed in the pons-medulla and hypothalamic areas after fenfluramine administration in the saline-treated rats, but fenfluramine caused no decreases in hypothalamic dopamine or in pons-medulla and hypothalamic norepinephrine content in rats previously treated with d-amphetamine. Analysis of the baseline amine levels (i.e., values in the d-amphetamine and saline-treated rats before fenfluramine was given) indicated that the repeated d-amphetamine treatment generally lowered norepinephrine in most brain regions, serotonin in the pons-medulla, substantia nigra and thalamus, and dopamine in the striatum.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of heroin,alone or in combination with other drugs,on the locomotor activity in two inbred strains of mice

The locomotor activity of C57B1/6J and DBA/2J mice was studied, under the influences of heroin, amphetamine, strychnine, or ethanol, and of combinations of the opiate with each one of the other drugs. Heroin treatment was followed by the typical running fit in the C57 mice, while the DBA strain was unaffected. Amphetamine enhanced the activity in the C57 strain only. The combination of heroin with amphetamine or ethanol increased the locomotor activity only in the DBA strain, while heroin + strychnine exerted a clear stimulating effect on the activity of the C57 mice. The strychnine + heroin mixture was more toxic than heroin alone when the lethal doses (LD50) were determined in the 2 strains.     

The effects of fenfluramine and fluoxetine on the acquisition of a conditioned avoidance response in rats

This study tested a behavior-suppressing punishment system and how its activity may be altered by agents known to interrupt or enhance serotonergic (5-HT) transmission. Holtzman male albino rats were tested for shuttle box avoidance acquisition and intertrial responding either 1 or 8 h following daily injections of fenfluramine (FEN) or fluoxetine (FXT). When the drug-test interval was 1 h, a time when both drugs are presumably potentiating 5-HT activity, avoidance acquisition and intertrial responding were impaired. When testing occurred 8 h after drug treatment, a time when 5-HT levels are unaltered by FXT and are maximally reduced by FEN, these drugs had no effect on avoidance acquisition, but FEN produced an increase in intertrial responses whereas FXT did not. These results support the proposal of an inhibitory 5-HT system. Furthermore, these data demonstrate that FEN is capable of exerting a biphasic action on intertrial responding and suggest that the time interval between drug administration and behavioural testing is a crucial variable when investigating FEN.     

Chronic anorexic and behavioural effects of the fenfluramine metabolite,norfenfluramine: An evaluation of its role in the actions of fenfluramine

The anorexic and behavioural effects of Norfenfluramine were studied in rats. Two separate experiments were conducted involving administration by intra-peritoneal and sub-cutaneous routes respectively. Behavioural effects were assessed by time sampling categorisation on Days 1 and 14 of a 20 day chronic study and anorexic effects by daily weighing. Norfenfluramine was found to be a potent anorexiant, to which tolerance is established fairly quickly. It was also found to possess sedative properties after acute administration, but marked stimulant properties after 14 days chronic administration. These results are similar to those previously reported in a study of Fenfluramine, although the behavioural effects of Norfenfluramine are more marked. The results implicate Norfenfluramine in the anorexic and behavioural effects of Fenfluramine, and provide indirect confirmation of the suggestion made in an earlier paper that Fenfluramine may have chronic stimulant properties.The work reported here forms part of an M.Sc. thesis to be submitted to the Department of Psychology, U.C.N.W. Bangor.     

Characterisation of adjustments to the structure of feeding behaviour following pharmacological treatment: Effects of amphetamine and fenfluramine and the antagonism produced by pimozide and methergoline

An observational procedure for examining the micro-structure of eating has been employed to establish the characteristic behaviour patterns displayed after various pharmacological manipulations. Using a double dissociation design it was shown that amphetamine and fenfluramine gave rise to quite distinctive readjustment to the structure of feeding behaviour. Amphetamine anorexia was characterized by a long initial delay, following which feeding was typified by infrequent short bursts of rapid eating. These effects were antagonised by the dopamine receptor blocking agent, pimozide. Fenfluramine exerted a more restricted pattern of action characterised by a marked slowing of the rate of eating. This effect was countered by the serotonin receptor blocking agent methergoline. These data throw light on the way in which pharmacological agents may impede food consumption and upon the neurochemical systems believed to be involved in the expression of feeding behaviour.     

Sleep-waking patterns in cats after administration of fenfluramine and other monoaminergic modulating drugs

Fenfluramine produced a dose-dependent, biphasic effect on sleep-waking patterns in cats. At low doses (0.4 mg/kg) fenfluramine elicited an increase in total waking time and a marked reduction in REM sleep, similar to that seen after administration of amphetamine, without affecting SWS. At anorectic doses (5.0 mg/kg) fenfluramine almost completely suppressed REM sleep, reduced waking time and increased SWS, an effect similar to that seen after administration of 5-HTP, the precursor of serotonin. The fenfluramine-induced increase in SWS was facilitated by 5-HTP and blocked by LSD, a serotonin antagonist. Serotonin was significantly reduced in the neocortex, pyriform lobe, cerebellum and hindbrain at the time of the drug's peak effect on SWS suggesting that the fenfluramine-induced increase in SWS is mediated via serotonin dependent mechanisms.     

Dissociation of multiple effects of acute LSD on exploratory behavior in rats by ritanserin and propranolol

Rats tested for 1 h in the Behavioral Pattern Monitor (BPM) after injection of the mixed serotonergic agonistd-lysergic acid diethylamide (LSD) exhibit a behavioral profile similar to that produced by various hallucinogenic 5HT-2 agonists. The characteristic effects of the hallucinogens include suppression of locomotor and exploratory behavior and a preferential decrease in entries into the center of the BPM during the initial half of the test session. After LSD, the initial suppression of responding is followed by a subsequent increase in locomotor activity that is not observed with other serotonergic agonists. In the present studies, the 5HT-1 andβ-adrenergic antagonistd,1-propranolol and the 5HT-2 antagonist ritanserin were administered individually or in combination prior to the acute administration of LSD to test for the involvement of these receptor subtypes in the mediation of the effects of LSD in the BPM paradigm. Propranolol (20 mg/kg) abolished the initial suppression of activity induced by 60 μg/kg LSD without affecting the subsequent increase in locomotion. Conversely, 2.0 mg/kg ritanserin failed to block the initial suppressive effects of 60 or 120 μg/kg LSD, but attenuated the LSD-induced increases in activity during the second half of the session. The combination of propranolol and ritanserin prevented both these effects of LSD. By contrast, the more selective 5HT-2 agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) (0.27 mg/kg) produced an initial suppression of activity in the BPM that was blocked by 2.0 mg/kg ritanserin and was not followed by a subsequent increase in activity. These findings suggest that the initial suppressive effects of LSD in the BPM paradigm are dissociable from the subsequent increases in locomotion and that the two effects are mediated via different serotonergic orβ-adrenergic receptors.     

Anxiolytic effects of nitrous oxide in mice in the light-dark and holeboard exploratory tests

To investigate anxiolytic effects of nitrous oxide (N₂O), male mice were tested in two exploratory models — a two-chambered light-dark (L-D) unit and a holeboard. Tests were conducted inside a glovebag through which one of three mixtures of N₂O and oxygen (25, 50 and 75% N₂O) or room air (RA) was circulated at a flow rate of 101/min. The principal findings in the L-D unit were a concentration-related increase in number of interdepartmental transitions and a generalized increase in time spent on the light side. Nitrous oxide effectively elevated transitions in the L-D unit at a lower concentration (25% N₂O) than was required to increase locomotor activity in an open field (50% N₂O), suggesting that these two measures are at least partially independent; transitions might reflect a specific exploratory component of locomotor behavior. In the holeboard test, a concentration-related increase in number of head dips was observed. Pretreatment with naltrexone-HCl or saline vehicle revealed a contribution by an endogenous opioid-linked locomotor stimulant effect in some measures. A dose-related reversal by flumazenil of 50% N₂O-induced shifts in number of head dips and time spent head-dipping implicates a benzodiazepine receptor. Both paradigms, in particular the holeboard, should prove useful in future N₂O research.     

The action of the drug prenylamine (Segontin) on exploratory activity and aversive learning in a selected strain of rats

Summary Sixteen rats of both sexes of a strain selectively bred for high performance levels in an aversive learning task, were examined for differences in rearing frequency and escape/avoidance performance under various doses of the drugs reserpine and prenylamine. At the highest dosages employed 4.0 mg/kg of reserpine and 40.0 mg/kg of prenylamine, activity and conditioned avoidance performance was depressed. These findings seem to suggest that the depletion of the catecholamine levels of the organism may be responsible for these effects and that disruption of aversive learning is due to the action of the drugs in depressing activity, rather than some more direct action on the learning process itself.     

Aggressive behaviour elicited in rats by Cannabis sativa: effects of p-chlorophenylalanine and DOPA

The influence of p-chlorophenylalanine (PCPA) and dihydroxyphenylalanine (DOPA) on aggressiveness elicited by marihuana in starved rats was studied. PCPA and DOPA potentiated several-fold this behavioural manifestation; the potentiation was still greater when the animals received both drugs. On the other hand, PCPA and DOPA alone or in combination, but without marihuana, failed to elicit aggressive behaviour in starved rats. Aggressiveness did not appear when rats fed ad libitum were treated with PCPA, DOPA and marihuana. The role played by starvation, PCPA and DOPA on the capability of marihuana to induce aggressive behaviour in rats is discussed.