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Effects of acute and subchronic administration of propranolol on the social behaviour of mice; an ethopharmacological study.

The effects of dl-propranolol on the behaviour of adult male CD1 mice were examined after acute intraperitoneal injection (1.5 and 6 mg/kg) and after administration for 10-13 days in the drinking fluid at 12.4 mg/l (1.9 mg/kg daily) and 24.9 mg/l (4.6 mg/kg daily). The behaviour of each mouse was examined by ethological procedures during 5 min social encounters with an untreated partner in an aversive and a less aversive situation, an unfamiliar neutral cage and the animals' home cage. The behaviour of each mouse also was monitored for 5 min in the light-dark box. In the acute studies, behavioural observations commenced at 30 min after the injection. In the light-dark box, propranolol, after acute administration, increased the number of transitions between the light and dark compartments and increased scanning in the light area but propranolol had no significant effect after subchronic administration. In the home cage, propranolol significantly increased social investigation during social encounters and reduced exploratory activity at all doses tested, after both acute and subchronic administration. In the neutral cage, propranolol, after acute administration, increased digging of the sawdust and decreased exploratory activity at both dose levels, while at the largest dose it also increased social investigation. In the neutral cage, propranolol, given by subchronic administration, increased aggressive behaviour as well as social investigation and digging of the sawdust at both dose levels, while reducing non-social exploratory activity. The largest dose of propranolol also increased investigation of the substrate. These results indicate that propranolol increased reactivity to normal environmental and social stimuli, in addition to its anxiolytic profile of behavioural effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Aggression↗

Reduction of NMDA-induced behaviour after acute and chronic administration of desipramine in mice.

The mechanisms of the antinociceptive effect of desipramine (DMI) are only partly known. It is generally accepted that excitatory amino acids act as neurotransmitters in primary nociceptive fibres and recent in vitro studies have shown an interaction between tricyclic antidepressants and the N-methyl-D-aspartic acid (NMDA) receptor complex. In this study, the modulatory effect of DMI on the biting and scratching behaviour induced by intrathecal (i.th.) administration of NMDA (0.25 nmol) was investigated. Desipramine was administered acutely, either intrathecally (0.7-35 micrograms) or intraperitoneally (i.p., 10 mg/kg), or chronically in the drinking water (0.15 g/l) for 3 weeks. The NMDA-induced behaviour was significantly reduced both after acute and chronic administration of DMI. Several studies have shown a functional upregulation of the 5-HT1A receptor after chronic treatment with DMI. The activation of this receptor using the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT), leads to a reduction in NMDA-induced behaviour. Using the 5-HT1A antagonist NAN-190 (10 micrograms, i.th.), the effect of chronic administration of DMI on the NMDA-induced behaviour was reversed. However, NAN-190 also increased NMDA-induced behaviour in the control group, suggesting that a tonic inhibition of this behaviour, mediated by the 5-HT1A receptor, may exist. These findings indicate that DMI may reduce glutaminergic transmission at the spinal NMDA receptor. As this receptor is central in spinal nociceptive transmission, this could be one mechanism for the antinociceptive effect of DMI.

Animals↗

Effects of chlordiazepoxide, buspirone and the 5-HT3 receptor antagonist, BRL 46470, on the behaviour of oestrous and dioestrous female mice when encountering male partners.

Ethological procedures were employed to examine the differences in behaviour between oestrous and dioestrous control mice, and to investigate the changes to behavioural responsiveness in oestrous and dioestrous mice induced by treatment with the anxiolytic compounds, chlordiazepoxide (CDP, 21.5 mg/l), buspirone (12.8 mg/l) and the 5-HT3 receptor antagonist, BRL 46470 (40 micrograms/l). Compounds were given in drinking fluid for 6-8 days prior to behavioural observations (average daily intake: CDP--5 mg/kg; buspirone--2.5 mg/kg; BRL 46470--10 micrograms/kg). Behaviour of the females was examined in the "approach-avoidance" situation of 5 min encounters with an unfamiliar male in a neutral cage. Oestrous controls spent more time in social investigation, sniffing of the substrate and scanning than dioestrous controls and spent less time in digging and exploration. Each of the anxiolytic compounds, CDP, buspirone and BRL 46470, significantly raised the duration of social investigation both in oestrous and dioestrous females. Each of these compounds also increased the duration of "digging" by oestrous females, and duration of the social element "investigate" in dioestrous females. Effects on the occurrence of other individual elements within each behavioural category depended on the anxiolytic compound administered and the stage of the ovarian cycle at the time of testing. There were few significant differences between the behaviour of the male partners in each group. It is concluded that in this paradigm both oestrous and dioestrous females are sensitive to the enhancement of social investigation by anxiolytic compounds and that the use of female mice in this test situation may provide a potentially useful method in drug screening.

Animals↗

Sexual behaviour of male rats injected with the anti-oestrogen MER-25 during infancy.

Newborn male rats were injected SC with 50, 100 or 200 micrograms MER-25 or 0.05 ml oil daily for the first 10 days of life. As adults, they were tested for male sexual behaviour both before and after castration and replacement with testosterone propionate, and for female sexual behaviour after injections of oestradiol benzoate followed by progesterone. Injections of 100 and 200 micrograms MER-25/day during infancy caused significantly fewer rats to ejaculate than 0.05 ml oil/day in both series of tests for male sexual behaviour. The reduced occurrence of ejaculation could not be related to defective penile development as there was no significant difference in penis weights or the numbers of penile spines between the MER-25 and oil-injected rats. All doses of MER-25 caused significantly more lordosis behaviour after oestrogen and progesterone than did injections of oil. These results provide further evidence that neonatal testicular androgens must be converted to oestrogen in the brain in order to organise male sexual behaviour patterns, including the neural substrate for ejaculation, as well as to suppress female sexual behaviour.

Animals↗

Effects of lysine-vasopressin in an exploratory behaviour test situation.

Changes in the exploratory behaviour pattern in rats were studied over a period of eight weeks. Certain characteristics emerged during repeated exposure to the same environment. The activity of "investigating" behaviour increased, while rearing activity decreased. We suggest that these changes reflect habituation by the animal to the test situation. Administration of lysine-vasopressin (LVP; 5.0 micrograms/kg SC) resulted in some alterations of the exploratory behaviour pattern, but no other behaviours than those observed without drug treatment were seen. The administration of LVP resulted in a higher performance of "investigating" behaviour. Since the change in the exploratory behaviour pattern after LVP administration was similar to that during repeated exposure to the test situation, we conclude that the LVP treatment influenced processes of habituation.

Animals↗

Inescapable footshocks induce progressive and long-lasting behavioural changes in male rats.

Long-term behavioural consequences of exposure to a brief (15 min) session of inescapable footshocks (10 x 6 s, 1 mA) were investigated in male rats. The time course of the effects of inescapable footshocks was assessed by studying the behaviour of groups of rats at different post-stress intervals. Footshocked rats (S) did not differ from control (C) rats (exposed to the shock box for 15 min) in their behavioural response to an open field whether tested 1 h or 4 h post-stress. However, one day after shocks, S rats showed less locomotion and rearing, and more immobility and attention as compared to C rats. At 7 days or 14 days post-stress, S rats exhibited decreased locomotion, rearing, sniffing, and grooming, and increased immobility, attention, and defecation relative to C rats. In a second experiment, we investigated whether footshocks affect the behavioural response to a sudden drop in background noise during exposure to a novel environment. At 21 days post-stress, S rats showed a markedly enhanced immobility response to this stimulus as compared to C rats. In order to investigate whether rats could be exposed repeatedly to the open field without affecting the differences in behaviour between the two treatment groups, C and S rats were tested in an open field for the first time at 7 days post-stress, which yielded the typical effects of footshocks. When these rats were exposed to a second open-field test one week later, the behavioural responses of C and S rats were not different.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Characterization of stress-induced long-term behavioural changes in rats: evidence in favor of anxiety.

Recently, we reported that rats exposed to one brief session of inescapable footshocks showed a gradually developing and long-lasting decrease in behavioural activity and an increase in defecation in an open field. The aim of the present study was to further characterize the long-lasting changes in behavioural responsiveness to environmental stimuli. For this purpose, behavioural paradigms validated as tools in the preclinical study of the psychobiology of depression were used. Footshocked rats (S) showed a decreased response latency in an one-way avoidance-escape task and decreased immobility in a forced swim test as compared to nonshocked control rats (C) 14 days after shock exposure. These S rats showed decreased behavioural activity and increased defecation as compared to the C rats in an open field test carried out 28 days after footshock exposure. In addition, footshock exposure did not affect the preference for or consumption of a 0.05% saccharin solution on a long-term basis, although a decreased consumption of this solution was evident in S rats on day 1 postshock. These S rats showed an exaggerated immobility response to a sudden reduction in background noise level compared to C rats while placed in a novel environment on day 11 postshock. We conclude that the long-term effects of one short session of inescapable footshocks are not compatible with what is supposed to represent behavioural manifestations of depression in animals. It is argued that the common denominator of shock-induced long-lasting changes is increased behavioural defensiveness, which is more likely related to increased fear and/or anxiety.

Animals↗

Prevention of stereotypy in laboratory mice: effects on stress physiology and behaviour.

According to the coping hypothesis, the adaptive significance of stereotypies in barren housing conditions may lie in their potency to attenuate the deleterious consequences of chronic stress. Present evidence from experimental studies is ambiguous. When Zur:ICR mice were selectively prevented from stereotypic wire gnawing at the cage lid, the previous amount of stereotyped behaviour after a short-term decrease in activity was compensated by variable active behaviour on the cage floor. This change in behaviour was associated with a short-term elevation of serum corticosterone concentrations 24 h after stereotypy prevention. However, 3 days later corticosterone levels were back at pretreatment base levels. Both behavioural and physiological short-term effects were caused by the impact of prevention on behavioural organization. They disappeared as soon as new habits were established, even though they were not stereotyped. In contrast to the predictions of the coping hypothesis, prevention of stereotypy had no significant effects on chronic measures of both the sympathetic-adrenal-medullary system and the hypothalamus-pituitary-adrenal system. Thus, there is no evidence that stereotypic wire gnawing reduces chronic stress in Zur:ICR mice. This implies that coping with stress is not a general aspect of cage-induced stereotypic behaviour.

Adrenal Medulla↗

The 5-HT1B receptor agonist CP-94,253 reduces food intake and preserves the behavioural satiety sequence.

The 5-HT1B receptor has been proposed as a link in the relationship between serotonin and satiety. However, the anorexia induced by RU-24969, a 5-HT1A/1B agonist, has been shown to delay behaviours associated with the onset of satiety, increase the frequency of intake and increase some nonfeeding activities. CP-94,253 is a highly selective agonist at the 5-HT1B receptor site with less affinity for other receptor sites, and has been used in this study to determine if agonism of 5-HT1B receptor sites adjust the behavioural satiety sequence in a way consistent with satiety. The effects of an ED50 of dose of CP-94,253 (5.0 mg/kg, IP) on eating behaviour of the fasted rat were monitored. Temporal profiles of behaviour duration and frequency were generated. Food intake was reduced 57% by CP-94,253 (p < 0.0005). Analysis confirmed that CP-94,253 reduced rearing (p < 0.05) and increased resting (p < 0.05) but preserved the overall pattern of the satiety sequence. Increased locomotion was not significant and caused no gross disruption of the behavioural repertoire. Such changes are also produced by prefeeding. In a second experiment, RU-24969 (1.0 mg/kg, IP) reduced food intake by only 30% (p < 0.05) However, RU-24969 markedly disrupted the satiety sequence profile, which did not resemble the profile produced by prefeeding. RU-24969 presumably induces this disruption via a mechanism other than 5-HT1B activation. The use of CP-95,253 demonstrates that selective activation of 5-HT1B receptor sites is sufficient to reduce food intake and enhance satiety as represented by the behavioural satiety sequence.

Animals↗

Reliability of two activity boxes commonly used to assess drug induced behavioural changes.

Rats were given different drug treatments known to affect central catecholamine neurotransmission and to induce different types of behavioural changes which were recorded simultaneously by two different types of conventional activity boxes: an Animex activity meter and a photocell cage. All animals were also visually observed simultaneously with the automatic recordings. It was found that the two activity boxes reflected the behavioural changes differently and that the results from the two boxes were not correlated. When comparing the observations with the automatic recordings it was found that some clearly observable changes in behaviour were not reflected as changes in the automatic recordings and conversely that increases or decreases in the recorded motor activity were not always related to any particular changes in behaviour. The results show that motor activity can not be regarded as a simple or homogeneous behaviour that is reliably measured in conventional activity boxes. It is an undescriptive measure consisting of an artificial summation of those components of behaviour that affect the movement-detecting device in the particular box which is used. Practical and theoretical implications of this are discussed.

Animals↗

Anti-aggressive effect of a new phenylpiperazine compound (DU27716) on hypothalamically induced behavioural activities.

Using the same hypothalamic electrodes, the following behaviour was evoked in male rats by electrical stimulation at roughly equal current intensities: attacks on a partner, teeth-chattering, switch-off behaviour and locomotion. Current thresholds were determined for each behaviour following the intraperitoneal administration of saline or DU27716, a new phenylpiperazine compound with interesting inhibitory effects on territorial and intermale aggression. DU27716 raised current thresholds for attack and teeth-chattering beginning at the lowest dose (4 mg/kg), whereas there was no effect on switch-off behaviour, and only a slight but significant effect on locomotion thresholds at the highest dose (8 mg/kg). The results provide support for the hypothesis that DU27716 possesses behaviourally selective, anti-aggressive properties, and illustrate the usefulness of hypothalamically induced behaviours as a pharmacological model.

Aggression↗

On the mechanism by which methylxanthines enhance apomorphine-induced rotation behaviour in the rat.

Methylxanthines, such as caffeine and theophylline, potentiate the rotation behaviour induced by dopamine receptor agonists in rats with unilateral lesions of the nigro-striatal pathway. In the present study we have examined the possibility that interaction with central adenosine mechanisms could influence rotation behaviour. Under in vitro conditions adenosine and N6-phenylisopropyl-adenosine (PIA) stimulate cyclic AMP accumulation. This effect was enhanced by the phosphodiesterase inhibitor rolipram, but blocked by alkylxanthines such as caffeine, theophylline and, particularly, 8-phenyl-theophylline. Rotation behaviour induced by apomorphine (0.05 mg/kg), was inhibited by PIA and rolipram and by a low dose of the adenosine deaminase inhibitor EHNA (2 mg/kg). By contrast, theophylline and 8-phenyl-theophylline caused a potentiation. The former drug stimulated rotation behaviour per se, while the latter did not. 8-Phenyl-theophylline entered the brain poorly and its concentration in brain it was less than 1/10 of theophylline. It is concluded that theophylline does not potentiate rotation behaviour secondarily to inhibition of phosphodiesterase. Antagonism of endogenous adenosine may partly explain the effect of methylxanthines. Possibly, some as yet unknown mechanism may also contribute to the effects of xanthine-derivatives on rotation behaviour.

Adenosine↗

Effects of neuroleptic drugs on the inhibition of exploratory behaviour induced by a low dose of apomorphine: implications for the identity of dopamine receptors.

Apomorphine in low doses inhibits spontaneous exploratory behaviour in rats. This effect is commonly referred to as an expression of selective stimulation of dopaminergic autoreceptors. The aim of the present study was to investigate the influence of neuroleptic drugs with different pharmacological profiles on this apomorphine induced inhibition of exploration using techniques for detailed recording of behaviour and multivariate statistical analysis of the results. By comparison with dose response analyses of apomorphine it was possible to determine whether a neuroleptic specifically antagonised the apomorphine effect or if the pattern of behaviour was qualitatively changed in some way. Apomorphine (0.05 mg/kg) was tested against cis-flupenthixol (0.01-0.5 mg/kg), haloperidol (0.01-0.1 mg/kg), metoclopramide (0.2-5 mg-kg), sulpiride (0.5-50 mg/kg) and SCH 23390 (0.005-0.05 mg/kg). Metoclopramide and haloperidol had weak antagonising effects against apomorphine while cis-flupenthixol and SCH 23390 was completely inefficient in this respect. The multivariate analysis indicated that the effects of haloperidol was restricted to only some aspects of the behavioural effects of apomorphine. Only sulpiride did selectively and dose-dependently antagonise the apomorphine induced behavioural suppression. The data provide evidence for a functional subdivision of dopamine receptors at the behavioural level.

Animals↗

Behavioural effects in adulthood of neonatal manipulation of brain serotonin levels in normal and androgenized females.

5HT concentrations in the hypothalamus are higher in females than males over the second week of life and this differentiation is testosterone-dependent. We have investigated the possible influence of 5HT over this period on the development of systems that control adult behaviour, in particular those influenced by neonatal testosterone. Neonatal androgenization (250 micrograms/pup testosterone propionate; TP; on day 1 postpartum) induced a masculine pattern of behaviour in females ovariectomised in adulthood and bearing a TP implant. The neonatal treatment reduced exploration, motor activity and female sexual behaviour and increased anxiety, orientation toward the incentive female and male sexual behaviour. Depletion of 5HT by pCPA (100 mg/kg days 8-16 postpartum) enhanced the TP-induced increment in locomotion and female sexual behaviour and increased sexual orientation toward the incentive female, while 5HTP (20 mg/kg days 8-16 postpartum) antagonised the reduction in exploration by TP. Thus 5HT may normally exert an inhibitory control on the action of neonatal testosterone on exploration, motor activity and sexual behaviour. Neonatal PCPA treatment also had a marked anxiolytic effect which was independent of the presence of T as it was noted in normal and androgenized females and previously has been observed in intact males. This might indicate a primary control by a serotonergic system on the development of the systems controlling anxiety.

5-Hydroxytryptophan↗

6-Hydroxydopamine-induced turning behaviour in the rat: the significance of acetylcholinesterase in cerebrospinal fluid.

In the substantia nigra, acetylcholinesterase may have a novel function related not to cholinergic transmission, but to the homeostasis of dopaminergic nigrostriatal neurones. The initial aim of this study was thus to see whether, in the rat, release of the enzyme into cerebrospinal fluid would reflect turning behaviour following unilateral 6-hydroxydopamine lesions of varying severity. It was found that acetylcholinesterase levels, lower than those in the cerebrospinal fluid of control rats, were accompanied by marginal circling behaviour and a small loss of striatal dopamine: on the other hand, elevated acetylcholinesterase activity was observed in the cerebrospinal fluid of rats displaying vigorous turning behaviour and with large depletion of striatal dopamine. It has already been demonstrated that exogenous acetylcholinesterase, applied locally to nigral neurones, has both electrophysiological and behavioural effects reminiscent of dopamine agonists. Hence it is possible that exogenous acetylcholinesterase could modify turning behaviour resulting from unilateral striatal dopamine depletion. Purified acetylcholinesterase, administered by cisternal puncture, attenuated circling behaviour for up to 7 days. The possible mechanisms are discussed by which endogenous acetylcholinesterase in cerebrospinal fluid could serve as an index of dopamine depletion in the nigrostriatal pathway and how exogenous enzymes might alleviate the accompanying motor dysfunction.

Acetylcholinesterase↗

The effect of archistriatal lesions on 'open field' and fear/avoidance behaviour in the domestic chick.

The chick archistriatum has been implicated in avoidance learning and filial imprinting. However, its role in these learning paradigms may be due to the inhibition of normal avoidance responses, since the avian archistriatum has been shown to play a role in fear/avoidance behaviour. The involvement of the archistriatum in the expression of unlearned fear/avoidance behaviour was therefore investigated in two day-old chicks. Chicks were exposed individually to a novel 'open field' for 5 min. Behaviour was recorded on videotape for analysis. In a separate but concurrent experiment, bilateral archistriatal lesions, sham archistriatal lesions or lateral cerebral lesions were made in day-old chicks which were then exposed to the 'open field' arena. At the end of each exposure a novel object was dropped near the chick. Chicks with archistriatal lesions generally displayed greater movement, more pecking behaviour and spent more time near the centre of the 'open field' than other chicks. There were no differences between the treatment groups in latencies to move or begin peeping. The behaviour of untreated chicks in the 'open field' was similar to that of sham-lesioned chicks and there was no effect of hatch on behaviour. Upon exposure to a novel object, indices of fear and avoidance were not changed in lesioned chicks. These results demonstrate that in the young chick, the archistriatum may be involved in the response to mild or intermediate levels of environment or isolation-related stress, but does not appear to be important for overt fear responses or avoidance of novel objects. Taken together with the results of previous work, the data suggests that the archistriatum may be directly involved in avoidance learning and imprinting.

Animals↗

Effect of the GABA-transaminase inhibitor vigabatrin on exploratory behaviour in socially isolated rats.

Elevation of the brain levels of the major inhibitory neurotransmitter gamma-aminobutyric acid (GABA) by inhibiting the GABA-catabolizing enzyme GABA-transaminase (GABA-T) is known to induce a number of functional effects including changes in behaviour. Vigabatrin (gamma-vinyl GABA, GVG) is an anti-epileptic drug that increases brain GABA levels by an irreversible inhibition of GABA-T. Using the elevated plus-maze model of anxiety and the open-field behaviour test, the effects of GABA-T inhibition and social isolation on rat exploratory behaviour were investigated. Social isolation for 1 week did not induce any change in the exploratory-behaviour of adult rats. However, rats socially isolated for 2 weeks, showed suppressed exploratory behaviour in the elevated plus-maze test. In both groups of differentially housed rats, treatment with vigabatrin at a dose of 250 mg/kg, i.p., significantly reduced the anxiety level in the plus-maze test. In the open-field test, vigabatrin tended to increase the exploratory behaviour only in the group of isolated rats. The results may suggest that vigabatrin has a better anxiolytic-like effect in the isolated rats than that in the socially housed rats.

4-Aminobutyrate Transaminase↗

Social isolation increases aggressive behaviour and alters the effects of diazepam in the rat social interaction test.

Isolation rearing in the early stages of life has been shown to modify a variety of behaviours in many animals and the responsitivity to psychotropic drugs. The aims of the present study were to investigate the effects of isolation rearing on anxiety using the social interaction paradigm and to compare the effects of diazepam on social interaction behaviours in isolation and socially reared rats. Male Lister hooded rats were reared from weaning either alone (isolation reared) or in groups of four (socially reared) for 6 weeks and then were tested for social interaction. Both isolation and socially reared rats were exposed to the social interaction test either without drug treatment or following saline or diazepam (1 and 2.5 mg/kg, i.p., 30 min before testing). The results demonstrate that under high light in an unfamiliar arena, the isolation compared to the socially reared rats showed a significantly (P < 0.01) higher level of social interaction, manifested as increases in aggressive and avoidance behaviours, and that this interaction occur for a greater length of time during the test period (10 min). However, when the light level was decreased or when the arena was familiar, active social interaction of isolation reared rats decreased but increased in the socially reared rats. In both conditions the isolation reared rats displayed more aggressive behaviours, in particular biting and boxing the partners which did not occur with the socially reared rats. Pretreatment of diazepam (1 and 2.5 mg/kg., i.p.) caused a dose-related reduction in aggressive behaviours in rats reared under both conditions but increased passive interactions in the socially reared rats. In contrast diazepam (2.5 mg/kg) reduced active interaction in the isolation reared rats but had no effect on passive interaction. These results indicate that isolation rearing increases aggressive behaviours and alters the effects of diazepam.

Aggression↗