Michel Mercier

Anxiolytic potential of sulpiride, clozapine and derivatives in the open-field test

Recently acquired data question the sharp dichotomy between anxiolytics and neuroleptics, since disinhibitory effects have been measured in the rat with very low doses of haloperidol and higher doses of atypical neuroleptics in FI and DRL schedules, but also in the open-field test. That the DA transmission in certain brain regions is involved in some aspects of anxiety has recently been suggested. The present study confirms this hypothesis particularly with high doses of sulpiride (80 mg/kg) and clozapine (24 mg/kg) when tested in the open-field test. Moreover, the results show how a slight chemical modification of clozapine can give a direction to pharmacological activity with one derivative still resembling clozapine and the second one resembling haloperidol. As neuroleptics do not seem to influence the synthesis and utilization of GABA, the higher entry score observed with them would seem to depend above all on DA antagonism in the mesolimbic system.

Effects of specific dopaminergic agonists and antagonists in the open-field test

It has been found that dopaminergic transmission could be involved in some aspects of anxiety. The present study aims to explore this hypothesis further, using specific DA1 (SKF 38393) and DA2 (bromocriptine) agonists or DA1 (SCH 23390), and DA2 (zetidoline) antagonists in the open-field test. The results confirm previous studies indicating that DA1 and DA2 agonists predominantly increase locomotor activity, while DA1 and DA2 antagonists predominantly decrease it. However, at low doses, the four drugs increase the peripheral ambulation score significantly and, with the exception of zetidoline, also increase the central ambulation score. The observations made with zetidoline confirm the hypothesis that a specific presynaptic DA2 antagonism could be determinant for the disinhibitory effects of low doses of neuroleptics. A collateral action on 5HT transmission is also suggested to explain an hypothetic anxiolytic action of DA agonists and SCH 23390 at lower doses.

Comparative study of typical neuroleptics, clozapine and newly synthesized clozapine-analogues: correlations between neurochemistry and behaviour.

While neuroleptic therapy with classical compounds has frequently been associated with extrapyramidal side effects, clozapine has revealed an interesting antipsychotic profile without producing any clearcut motor side effects. However, some adverse reactions remained that stimulated the search for improved antipsychotic agents. The aim of this study was to characterize the behavioural and neurochemical profiles of typical neuroleptics (chlorpromazine, haloperidol), clozapine, and four newly synthesized clozapine-analogues. Affinity for dopaminergic (D1, D2), serotonergic (5-HT2) and cholinergic (muscarinic) receptors were measured and the ratios of these different binding affinities were determined and correlated with the behavioural effects of the drugs in a complex temporal regulation task in the dog. The four clozapine-analogues showed most of the behavioural characteristics previously described for neuroleptics and their neurochemical profile, particularly their 5-HT2/D2 pKi ratio, was compatible with an atypical antipsychotic effect. Among these drugs, JL5 and JL13 showed a high degree of similarity with clozapine. Like clozapine, they did not induce catalepsy and stereotypy/hyperkinesia. Moreover, other motor effects were also reduced (ataxia, akinesia, dystony). and tremor and sialorrhea were completely absent with these two molecules.

Differentiation of haloperidol and clozapine using a complex operant schedule in the dog

This study aimed to differentiate chronically administered typical (haloperidol) and atypical (clozapine) neuroleptics in the dog using a complex temporal regulation schedule combining operant, voluntary, and involuntary motor parameters. Although clozapine and haloperidol showed some characteristics of neuroleptics, justifying their adherence to the same class of compounds, differences have also been highlighted and compared to the clinical observations. Haloperidol induced catalepsy, tremor, dystony, hyperkinesia, and stereotypy. Subjects produced anticipated responses before any stimulus. Incomplete and delayed responses were also produced. An interpretation in terms of akathisia and anhedonia has been suggested. Clozapine induced tremor, exploration, dystony, and hypersalivation. Subjects produced disinhibitory responses to the negative stimulus and incomplete responses but these latter were submitted to tolerance. The simultaneous presence of tranquilizing and disinhibitory effects has been reported on the clinical potential of clozapine both in cases of positive and negative schizophrenic symptomatologies.

Effect of chronic hypoxic treatment on the retention of fixed-interval responding

The present experiments aimed to study the effects of hypoxic treatment (10 min on 3.5% oxygen) on the stabilized performance of rats in a fixed-interval schedule (FI 60 s). The hypoxic treatment was given once a day, for 3 days, immediately after the FI session. The results showed that the operant performance was disturbed from the very first posthypoxia FI session. There was a sharp drop in response rate, and changes in the temporal distribution of responses occurred. The data obtained greatly limit the importance of nonspecific factors in explaining these changes in performance. The results are discussed with reference to the retrieval hypothesis. In particular, it is suggested that the decreases of performance may be due to an effect of hypoxia on the retrieval mechanisms associated with long-term memory.

Stimulant effect of the β-carboline FG 7142 in the open-field test

Abstract The anxiogenic activity of N-methyl-β-carboline-3-carboxamide (FG 7142) is sometimes difficult to observe in rats. As the open field has recently been applied successfully to test the anxiogenic potential of n-butyl-β-carboline-3-carboxylate (β-CCB) in mice, a comparable experiment was performed with FG 7142 (1, 5, 10, 30 mg/kg i.p.) in rats. In contrast to the inhibitory effects measured with β-CCB, FG 7142 significantly increased the ambulation and rearing scores and induced aggressivity in some animals. A differential sensitivity of mice and rats to β-carbolines, predominant analeptic properties of FG 7142, and differences in the types of anxiety induced are proposed to account for this discrepancy.

Amineptine improves the performance of dogs in a complex temporal regulation schedule

Amineptine is a tricyclic antidepressant with activating properties, that stimulates spontaneous locomotor activity in rodents and elevates mood in humans. It mainly inhibits dopamine uptake and weakly increased dopamine release. Formulating the hypothesis that this drug would decrease waiting capacity, we decided to test amineptine in a Differential Reinforcement of Response Duration schedule (DRRD 9 s Limited Hold 1.5 s) in the dog. The drug was administered orally at 2.5, 5.0, 7.5, 10 and 20 mg/kg, 1 h before the experimental session. Between 2.5 and 10 mg/kg, amineptine improved the performance by increasing the response (nonsignificantly) and reinforcement (significantly) rates and by increasing the peak of correct responses (significantly). The inverse effect was measured for the reinforcement rate (nonsignificantly) and for the peak of correct responses (significantly) at the dose of 20 mg/kg. These results were compared to those obtained with other classes of drugs, like neuroleptics, barbiturates or anxiolytics, that disturbed the performance, and particularly with low doses of neuroleptics, which also increase the dopamine release. The positive effects of amineptine on performance (2.5-10 mg/kg) were related to its inhibitory effect on dopamine uptake and discussed in terms of improved vigilance and attention, increase of waiting capacity, improved anticipation, and cognitive enhancement.

Enhanced resistance effect of piracetam upon hypoxia-induced impaired retention of fixed-interval responding in rats

Rats were trained on a fixed-interval schedule of 60 s (FI 60). After stabilization of performance, rats were chronically submitted to hypoxic treatment (3.5% O2, 10 min) once a day, immediately after the daily FI 60 session. Hypoxia disturbed the retention of FI responding. It was mainly characterized by a decrease in response rate and in pause duration, and by changes in the temporal distribution of responses. Animals receiving piracetam (100 mg/kg, IP) 30 min before each FI session followed by hypoxia were significantly less affected than saline-treated animals. Results are discussed with reference to the effects of hypoxia and piracetam on nonspecific factors and on memory function. It is suggested that the effects of piracetam are due to alleviation of hypoxia-induced memory retrieval deficit rather than to a protection against hypoxic brain cell injury.

Effects of low doses of neuroleptics on temporal regulation in a differential reinforcement of response duration (DRRD) schedule in the dog

It has been shown that low doses of neuroleptics could disinhibit behaviour in animals as well as in man. This study aims to measure the effects of low doses of haloperidol (0.01, 0.05, 0.1 mg/kg) and sulpiride (5, 10, 15 mg/kg) in the dog using a differential reinforcement of response duration (DRRD) schedule with positive and negative external stimuli. Together with a decrease in response rate, a leftward shift in the temporal distribution of response duration is measured. These results are discussed in terms of a deregulation of the internal clock, a lessening in the ability to wait for the reward, a reduction in the frustration of not obtaining reinforcements when errors are made and an increase in the sensibility to reinforcement through appetite stimulation or decrease in the satiety level.

Effects of a long-interval retention on the hypoxia-induced impairment of performance in a fixed-interval schedule

Retention of the fixed-interval (FI) responding was studied in rats after a chronic hypoxic treatment. The rats were trained over a 25-day period on a FI 60 s schedule. The rats were then given a normoxic or hypoxic (3.5% O2 for 10 min) treatment once a day for 4 days after which they were maintained in the animal quarters for 6 supplementary days. A retention test consisting of 4 daily FI 60 session followed the 10-day interval. The results showed that the performance during the retention test was very similar for both groups of rats. These data contrast with the deficit of retention observed when the retention FI 60 session were undertaken 24 h after the same hypoxic treatment. It is suggested that the results are due to a recovery from hypoxia-induced retrieval deficits rather than to the progressive attenuation of non-specific effects of hypoxia, such as anhedonia, hypoactivity, motivational changes or structural brain damage.