Effects of a piperazine derivative piribedil, on exploration, locomotor activity and social behaviour in the rat.
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Biomedical subjects
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Intraperitoneal injection of Org 2766 (0.01-0.4 microgram/kg) produced a dose-related increase in the number of social contacts and in the time spent in active social interaction by pairs of male rats tested in arenas with which they were familiar, but had little effect when the rats were tested in unfamiliar arenas. The increased social interaction was not accompanied by any change in motor activity. In contrast, alpha-MSH (20-200 microgram/kg) decreased the time spent in active social dose-related. Both peptides reduced exploratory head-dipping only at high doses (4-8 microgram/kg for Org 2766 and 200 microgram/kg for alpha-MSH); this change was not accompanied by a reduction in motor activity.
Kainic acid lesions of the infundibulum resulted in a significant decrease in infundibular ACTH concentrations. However, the lesioned rats did not differ from the vehicle-injected controls in a social interaction test, in their latency to start drinking in a novel environment, or in their aggressive behaviour in home-cage intruder tests. It can therefore be concluded that endogenous infundibular ACTH does not play a significant role in these behaviours. This can be contrasted with the effects of exogenously administered ACTH which has previously been shown to reduce social interaction and increase aggression. Both the lesioned rats and the controls showed decreased social interaction after ACTH administration, and therefore the infundibulum can be excluded as a critical site of action of exogenous ACTH in mediating this behavioural change.
1 The sedative and antiulcer effects of chlordiazepoxide (5 to 50 mg/kg) and lorazepam (0.25 to 2.5 mg/kg) were investigated in the rat. 2 Sedation was measured by recording locomotor activity in a holeboard. Ulceration of the glandular stomach was induced by a 2 h period of restrain at 4 degrees C. 3 Acutely, both drugs produced significant sedation at all doses; high doses only (chlordiazepoxide 10 and 50 mg/kg; lorazepam 2.5 mg/kg) produced a significant reduction in ulcer formation. 4 With chronic treatment, after 5 and 10 days administration of chlordiazepoxide (50 mg/kg), tolerance to sedation was observed without a similar change in antiulcer action. 5 Cimetidine (20 mg/kg) and atropine (0.2 mg/kg) decreased ulcer formation without causing sedation. 6 The antisecretory profile of chlordiazepoxide (2 x 10(-4) M), in the rat isolated gastric mucosa, resembled that of atropine (10(-7) M) rather than cimetidine (10(-5) M). 7 These observations suggest that the antiulcer effect of benzodiazepines probably results from a combination of sedative, anxiolytic and antisecretory actions.
Naloxone (1,2, and 4 mg/kg) produced a dose-related decrease in exploratory head-dipping in rats placed singly in a holeboard for 10 min, without a concomitant reduction in locomotor activity. Naloxone (2 mg/kg) reduced the time spent in active social interaction by pairs of rats tested in an unfamiliar or in a familiar test arena, and also reduced the amount of motor activity shown by the pairs of rats. The results are consistent with proposed roles for opiate peptides in behavioural responses to novel environments and in mediating social contact.
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Intraventricular ACTH (1.25 microgram), ACTH (1.6 microgram) and ACTH:D-Phe (1.6 microgram) resulted in significant reductions in the time that pairs of male rats spent in active social interaction. This decrease in social behaviour was not accompanied by a decrease in motor activity. The results are similar to those previously found with peripheral administration of ACTH and suggest that these behavioural effects of ACTH are centrally mediated. None of the ACTH fragments had a significant effect on the latency with which thirsty rats started drinking in an unfamiliar environment. The results are discussed in relation to a possible anxiogenic action of ACTH.
Microinjections of 5,7-dihydroxytryptamine into both the dorsal and median raphe nuclei resulted in 90% depletions of striatal and hippocampal 5-HT concentrations. Compared with vehicle-injected controls the lesioned rats showed reduced active social interaction scores in all four of the test conditions and also reduced levels of locomotor activity. The lesioned rats did not differ from the controls in their latency to start drinking in a novel environment; or in their response to intruder rats placed in their home cages, or in their behaviour as intruders when they were placed in the home-cages of unoperated rats. The difficulties of interpreting the behavioural effects of a lesion when the lesion produces hypoactivity, and the differences between the effects of these joint lesions of both dorsal and median raphe nuclei amd the effects of separate lesions of each nucleus are discussed.
The social interaction test in rats provides a method for detecting anxiolytic activity that does not use food or water deprivation, or electric shock, and therefore obviates difficulties of interpretation that might arise from drug-induced changes in motivation. Since social interaction is measured under more than one test condition any overall increase or decrease in social behaviour can be detected independently from the drug x test condition interaction that characterizes an anxiolytic drug. The Geller-Seifter conflict test was designed with two schedules of reinforcement for the same reasons. Any candidate test for anxiolytic action that examines drug effects under only one experimental condition is open to misinterpretation and may also prove unreliable if the critical experimental factors ( e.g. the level of food deprivation or the shock intensity) are changed. The testing procedure in the social interaction test is relatively time consuming in terms of observer-hours, but no lengthy pretraining of the animals is required. There is no way of fully automating the scoring and therefore it is important that the observers do not know the experimental group of the rats that they are scoring, and that tape recordings are made so that the scores can be checked. It has not so far been fruitful to analyze drug effects on every individual social behaviour, but this method does allow changes in individual behaviours to be detected. By entering the data directly into a computer we are now able to store the frequency and duration of each behaviour as well as the sequence of behaviours. It will then be possible to determine whether a detailed analysis of drug effects on the patterning of social behaviours will prove a useful addition to the social interaction test
The effects on active social interaction of acute and chronic dosage with diazepam (1 mg/kg), desmethyldiazepam (2 mg/kg), and chlor-desmethyl-diazepam (0.125 mg/kg) were studied in pairs of mice. The mice were tested under either high or low levels of illumination. In all cases acute drug treatment significantly reduced social interaction, but this was not seen with chronic treatment (9 days). Two of the drugs, diazepam and desmethyldiazepam, showed an anxiolytic action, i.e., these drugs resulted in significantly less variation in social interaction with the change in light levels, compared with vehicle-injected controls.
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The biochemical and behavioural effects of acute, 5, 15 and 25 days treatment with chlordiazepoxide (CDP, 5 mg/kg) were examined in the rat. After 5 days of drug treatment, 5-hydroxytryptamine (5HT) levels in the midbrain, hypothalamus and cortex were significantly higher than those of the corresponding controls, and the level of 5-hydroxyindoleacetic acid (5HIAA) was significantly lower, indicating reduced turnover. After 15 days of drug treatment, 5HIAA levels were significantly elevated, compared with the controls, possibly indicating that CDP was blocking the transport of 5HIAA from the brain. This effect appears to be independent of the reduced turnover. After 25 days of drug treatment there were no significant differences compared with the controls. There were no marked changes in noradrenaline and dopamine in any of the areas investigated. It appears that the reduction in 5HT turnover is linked to the anxiolytic effects of CDP; the latter were found after 5 days of drug treatment, but not after 15 or 25 days, using the social interaction test of anxiety.
In a double-blind cross-over study using normal student volunteers, the effects of 1 and 2.5 mg lorazepam on self-rated mood and bodily symptoms, as well as performance in a number of tests were assessed. Both doses significantly increased self ratings of physical and mental sedation, the effects being more marked 4 h after drug administration than after 1 h. Lorazepam impaired simple reaction time, verbal learning, number cancellation, symbol copying and performance in the digit-symbol substitution test. The impairments were greater with the 2.5 mg dose and were more marked 4 h after drug administration than after 1 h.
The effects of Piracetam (100 mg/kg) on passive avoidance learning was investigated in a situation in which rats received multiple conditioning trials. The test was based on the untrained preference of rats for a dark, rather than a brightly lit compartment. After the initial black-white preference was tested, rats were restricted to the black compartment for conditioning. Different groups received different percentages of tone-shock pairings. After the conditioning trials the black-white preference was again tested. The saline-injected rats showed overshadowing of the background stimulus by the tone, in the group that had received 100% tone-shock pairings; and an acquired aversion to the background stimuli in the group that had received 0% tone-shock pairings. In the rats injected with 100 mg/kg Piracetam associative strength was partitioned indiscriminately between the tone and the background stimuli, regardless of the tone-shock pairings that had been received during conditioning.
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Rats were bilaterally implanted with guide cannulae aimed at the central or medial nucleus of the amygdala. Microinjections of morphine (10 microgram) at both sites significantly elevated the threshold of response in the flinch-jump test; but only at medial sites did naloxone (1 microgram) antagonise this effect. However, in the hole-board test, an opposite pattern of results emerged. Morphine injections into the central nucleus produced naloxone-reversible reductions in both exploration and activity whilst, in the medial nucleus, the morphine-induced decrease in exploration was not reversed by naloxone. It is concluded that (1) the presence or absence of naloxone-sensitive opiate receptors cannot always be deduced on the basis of a single behavioural test and (2) within the amygdaloid complex, two distinct naloxone-sensitive opiate systems appear to be involved in the modulation of behavioural responses to different forms of stimulation.
In the social interaction test of anxiety, bilateral microinjections of morphine sulphate (10 microgram) into the central nucleus of the amygdala counteracted the reduction in social interaction normally seen when the test arena is unfamiliar to rats. However, these injections did not counteract the decrease in social interaction that is observed as illuminance of the arena is increased. Morphine injections into the medial site depressed social interaction below the levels shown by control animals. In the open field test, morphine produced a facilitation of peripheral activity when injected into the central nucleus whilst a decrease in rearing was observed following similar injections into the medial nucleus. Overall, these data indicate a partial anxiolytic action of morphine in the central amygdaloid nucleus. Results are discussed in relation to possible differences in opioid peptide innervation of these two amygdaloid nuclei.