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Pharmacological and behavioral studies in mice and rats have shown that the imidazopyridine alpidem possesses anxiolytic activity with a profile which is substantially different from that of benzodiazepines. Thus, in mice, alpidem inhibited marble-burying behavior and enhanced feeding under stressful conditions, as did benzodiazepines; in contrast to these drugs, however, alpidem was inactive against shock-induced fighting and shock-suppressed exploration. In rats, alpidem exerted anticonflict activity in the punished drinking test, but failed to antagonize punishment-induced inhibition of operant behavior. Moreover, in rats trained to discriminate chlordiazepoxide from saline, alpidem did not produce a benzodiazepine-like interoceptive stimulus. Alpidem also produced anticonvulsant effects in a variety of tests sensitive to benzodiazepines. However, the order of potencies against convulsions induced by different convulsive agents was different from that of the benzodiazepines. Alpidem decreased motor performance in the rotarod test and only produced a deficit in muscle strength at doses which were more than 20 times higher than the doses active in anxiolytic tests. Moreover, alpidem did not interfere with the acquisition of conditioned fear, except at very high doses, indicating a weak potential to impair memory. The effects of alpidem were antagonized by flumazenil, indicating that central omega receptors are involved in the action of this drug. The weak sedative effects of alpidem may be attributed to its low intrinsic activity, as demonstrated by its low efficacy in increasing latency to isoniazid-induced convulsions.

Previous studies have shown that, in rodents, chlordiazepoxide and other benzodiazepines can interfere with learning in passive avoidance or conditioned suppression procedures. The most consistent effects are observed when the drugs are administered before the acquisition trial and subjects are re-tested in the non-drugged state. It is not clear, however, whether this effect on learning is associated with the behavioural depressant actions of these drugs. In the present study mice were injected with chloridiazepoxide, diazepam, zopiclone, or CGS 9896 and locomotor activity measured in a two-compartment box. The animals were then enclosed in one of the compartments and received a series of footshocks. On a second trial, 24 h after the first, the mice were returned to the box without injection and locomotion and time spent in each compartment were measured. During trial 1 chlordiazepoxide, diazepam, and zopiclone produced dose-related decreases in locomotor activity. The same doses disrupted fear conditioning. CGS 9896 also interfered with the conditioning of fear but did not reduce exploratory activity during the first trial at any of a wide range of doses, showing that learning can be affected without direct behavioural depressant activity. In a further experiment, chlordiazepoxide and CGS 9896 disrupted fear conditioning when injected before trial 1 but not when injected immediately after this trial. Mice drugged with chlordiazepoxide or CGS 9896 before both trials 1 and 2 also showed disrupted conditioning, demonstrating that the drug effects cannot be interpreted in terms of state dependent learning.

Benzodiazepines and other compounds which act at benzodiazepine binding sites have been shown previously to attenuate the acquisition of conditioned fear in rodents when administered before the acquisition session, an effect which may parallel the disruption of human memory produced by anxiolytics and sedatives. Such an action is usually, but not invariably, produced by doses which have direct behavioural depressant effects. The present study was carried out to extend previous work by investigating the effects of the hypnotic benzodiazepine triazolam and the nonbenzodiazepines zolpidem and CL 218,872 on the acquisition of learned fear in mice. All these drugs reduced locomotor activity shortly after injection. They also produced disruptions of the acquisition of learned fear. Triazolam exerted behavioural effects similar to those found previously with other benzodiazepines, the does which disrupted the acquisition of conditioned fear being similar to, or lower than, the doses which depressed locomotion. In contrast, the results indicated that zolpidem was more potent at reducing locomotion than at interfering with fear conditioning, a result which may reflect the preferential sedative action of zolpidem.

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