René Misslin

5-HT1B receptor knock out — behavioral consequences

Serotonin is a neuromodulator that is involved in a number of mood disorders such as depression, anxiety and impulsive violence. In an attempt to dissect the contribution of individual 5-HT receptor subtypes to behavior, we have generated by homologous recombination, mutant mice lacking the 5-HT1B receptor. These mice did not exhibit any obvious developmental or behavioral defect. However, the hyperlocomotor effect of the 5-HT1A/1B agonist, RU 24969 was completely absent in mutant mice, indicating that this effect is mediated by 5-HT1B receptors. Moreover, when confronted with an intruder, isolated mutant mice attacked the intruder faster and more intensely than wild-type mice, suggesting an involvement of 5-HT1B receptors in the modulation of aggressive behavior. These data might be related to the fact that a class of 5-HT1 agonists, termed serenics, have anti-aggressive properties, and with the findings that certain impulsive aggressive behaviors are associated with deficits in central serotonin.

Anxiogenic effects of methyl-β-carboline-3-carboxylate in a light/dark choice situation

Doses of benzodiazepine, clorazepate, and also of the inverse agonist of the benzodiazepine receptor, beta-CCM, which failed to present sedative or postictal depressive effects, were at first determined in a free exploratory situation. Then, the effects of clorazepate dosed at 1.0, 2.0 and 4.0 mg/kg and beta-CCM dosed at 1.0 and 2.5 mg/kg were studied in the light/dark box choice procedure. Clorazepate tended to produce an increase of the time spent by mice in the lit box as well as of the number of transitions between the two boxes, whereas the dose of 1.0 mg/kg of beta-CCM had opposite effects. The benzodiazepine antagonist RO 15-1788 completely counteracted the anxiolytic effects of clorazepate dosed at 2.0 mg/kg and the anxiogenic effects of beta-CCM.

Some critical determinants of the behaviour of rats in the elevated plus-maze

The effects of daytime testing periods, repeated test exposures, and level of illumination were tested on the behavior of rats in an elevated plus-maze consisting of two open and two enclosed arms. Rats made significantly more entries into the open arms and spent significantly more time in the open arms when testing was carried out between 8 h and 12 h than when performed between 14 h and 17 h. Repeated exposure to the test apparatus tended to reduce time spent by rats in the open arms, number of entries into the open arms and total locomotor activity. Finally, it was found that an increase of the level of illuminance was followed by a decrease of all behavioural parameters. Since conflicting results have been reported for drug treatments evaluated in the elevated plus-maze (e.g., for compounds acting at the 5-HT1A receptor), the present results, based on the experimental conditions used, provide one possible explanation for these discrepancies.

Effects of isolation, handling and novelty on the pituitary-adrenal response in the mouse

Male Swiss strain mice were individually- or group-housed for four weeks. Basal corticosterone levels did not differ with the type of housing, providing no support for the suggestion that the condition of the individually-housed mouse is stressful. Plasma corticosterone levels also were determined for mice which had been either left undisturbed or exposed to new cages which differed from their home cages by varying degrees. There were elevations in mean plasma corticosterone levels corresponding to the degree of difference between the home cage and the new cage. This finding supports the suggestion that changes in 11-OHCS levels are sensitive measures of environmental changes. Mice forced to remain in novel places exhibited higher plasma corticoid concentrations than animals which were given the opportunity to move freely between familiar and novel places. Corticoid values, as well as neurophysiological and behavioral responses, suggested that the stress induced by forced exploration might be due to the fact that animals are prevented from freely regulating their exposure to novel places rather than to novelty per se.

Acute and chronic treatment with 5-HT reuptake inhibitors differentially modulate emotional responses in anxiety models in rodents

This study investigated behavioural effects of very potent 5-HT reuptake inhibitors after acute treatment (cianopramine and citalopram), as well as after chronic treatment (cianopramine), in two behavioural models of anxiety: 1) the light/dark choice procedure in mice and 2) the elevated plus-maze test in rats. In addition, the responses of mice to novelty in a free exploration paradigm were assessed after acute administration of both drugs. A single injection of cianopramine or citalopram increased neophobic reactions in the free exploration test. Furthermore, these drugs increased the avoidance reaction to a brightly illuminated chamber in the light/dark choice procedure as well as to open arms in the elevated plus-maze test. In contrast, after chronic treatment (10 mg/kg IP, once daily for 21 days) of cianopramine, anxiogenic-like effects were no longer produced in the light/dark choice paradigm whereas in the elevated plus-maze test, anxiolytic-like effects appeared. These results shed more light on the 5-HT hypothesis of anxiety, insofar as the increased availability of 5-HT resulting here from reuptake inhibition seems to initially result in an increased emotional reactivity which, however, subsequently disappears during chronic treatment.

Does neophobia necessarily imply fear or anxiety

Mice which had the opportunity to move around freely in simultaneously presented novel and familiar environments, did not display significant changes in plasma corticosterone levels nor in autonomic responses. In contrast, the signs of anxiety only appeared when mice were unable to regulate their own approach towards novelty, by preventing them from returning to their familiar compartment once they had freely entered the unfamiliar one, or by placing them physically into the novel compartment. These results demonstrate that contrary to the view generally encountered in the literature, anxiety, or fear, is not induced by novelty per se but when animals are artificially confronted novel stimuli and prevented from displaying normal neophobic responses.

Influence of dystrophin-gene mutation on mdx mouse behavior. I. Retention deficits at long delays in spontaneous alternation and bar-pressing tasks.

X-linked Duchenne muscular dystrophy (DMD) is frequently associated with a nonprogressive, cognitive defect attributed to the absence of dystrophin in the brain of DMD patients. The mutantmdx mouse, lacking in 427-kDa dystrophin in both muscle and brain tissues, is considered to be a valuable model of human DMD. In the present study, we comparedmdx and C57BL/10 control mice and showed thatmdx mice had impaired retention in a T-maze, delayed spontaneous alternation task 24 h, but not 6 h, after acquisition.mdx mice were not impaired in acquisition of a bar-pressing task on 4 consecutive days but showed poor retention 22 days after the last training session. Mutants and controls showed similar behavioral responses in free exploration and light/dark choice situations and did not differ in spontaneous locomotor activity or motor coordination. Retention impairments at long delays inmdx mice suggest a role of dystrophin in long-term consolidation processes.

Comparison of the behavioural effects of an adenosine A1/A2-receptor antagonist, CGS 15943A, and an A1-selective antagonist, DPCPX.

CGS 15943A is the first reported nonxanthine adenosine antagonist and it shows high affinity towards A1 and A2 receptors. The present data show that CGS 15943A increased in a dose-dependent manner locomotor activity of mice confronted with a free exploratory test without markedly modifying rears or, at low or medium doses, novelty seeking responses. In the light/dark choice procedure, which is especially appropriate for revealing anxiolytic and anxiogenic drug-effects, CGS 15943A decreased the time spent by mice in the lit box and increased the number of transitions. By contrast, the highly selective adenosine A1 receptor, DPCPX, did not significantly modify the behavior of mice except at high doses, which decreased it in the free exploratory test. It is suggested that the present findings confirm the hypothesis that the behavioral effects of adenosine antagonists are linked to their actions at adenosine A2 receptors.

Interaction of RO 15-4513 and ethanol on the behaviour of mice: antagonistic or additive effects?

Opposite effects were observed of ethanol on the behaviour of mice in the two chambered light/dark test. At a low dose, it had anxiogenic effects, while it produced anxiolytic effects at a higher dose. Selective antagonistic actions of RO 15-4513 against the behavioural effects of ethanol have been reported by others without intrinsic actions. In contrast, we found intrinsic depressive properties of RO 15-4513. This drug reduced locomotion in a running wheel test. We suggest that RO 15-4513 reversed certain effects of ethanol in an additive, rather than interactive, manner. In addition, RO 15-4513 did not block the sedation produced by a high dose of ethanol. Since RO 15-4513 revealed proconvulsant properties, it is proposed that the depressive effects of this drug could be related to its proconvulsive activity.

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 Berlynes (1967) suggestion that amphetamine has a disruptive effect on exploration by producing over-arousal.