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The effect of the administration of the muscarinic cholinergic agonist oxotremorine on locomotor activity was investigated in DBA/2 mice subjected to chronic restraint stress of different durations (120 min daily for 10, 14 or 18 days). Oxotremorine induced a depressant effect on locomotion, which was reduced after 10 and 14 days of restraint, but not after a 18-day restraint stress. Acetylcholine (ACh) content was significantly reduced in prefrontal cortex after 10 and 14 days of stress but returned to control values after 18 days of restraint. No changes in ACh content were observed in nucleus accumbens and striatum. These results are discussed in terms of possible changes in muscarinic receptor sensitivity.

The effect of diazepam on locomotor activity was tested by measuring the number of crossings between two compartments of a toggle-floor box, in control mice (water drinking) and in mice receiving caffeine solution (0.5 g/I) instead of drinking water. In control mice, diazepam did not produce any significant change in total activity measured on the whole 60-min test, but animals showed phases of increased activity broken by periods of immobility. After chronic ingestion (18 days) of caffeine, doses of 0.5, 1 and 2 mg/kg ip diazepam significantly increased total locomotor activity. Caffeine slightly reduced diazepam-induced immobility and increased the frequency of crossings in active periods. Taken together, these two effects may explain the significant increase in total activity induced by diazepam in caffeine-treated mice. Mixed stimulatory-depressant action was also produced by 3 mg/kg diazepam, a dose that slightly decreased the total activity.

The dihydropyridine calcium channel blocker nifedipine did not affect spontaneous locomotor activity in mice when given alone but enhanced the depressant effects of the muscarinic receptor agonist oxotremorine and of the acetylcholinesterase inhibitor physostigmine. Such a behavioral depression might be due to neuronal changes induced by central calcium channel blockade combined with cholinergic activation. However, an involvement of hemodynamic factors, related to peripheral vasodilatation, cannot be excluded as locomotor depressant effects were also exerted by combinations of the two cholinomimetic agents with hydralazine, a non-calcium antagonist vasodilator.

Nociception and locomotor activity were tested in mice (C57BL/6 and DBA/2 strains), receiving the dihydropyridine calcium-channel blocker nifedipine, alone or combined with morphine. The calcium antagonist did not change the reaction time to thermal stimulation (tail-flick test), when administered alone, but combinations of nifedipine and morphine prolonged tail-flick latencies less than did the opiate alone. Nifedipine decreased locomotion in both strains, reduced the hypermotility induced by morphine in C57 mice, and enhanced the locomotor depression induced by the opiate in DBA mice. A comparison of the effects of nifedipine with those of the non-calcium antagonist vasodilator, hydralazine, suggests that the interactions with morphine were not exclusively related to neuronal changes produced by calcium channel blockade, but also to haemodynamic factors. In fact, except for the lack of interference with morphine-induced hypermotility in C57 mice, hydralazine, given alone or in combination with morphine, produced effects similar to those of nifedipine.

Nifedipine, a dihydropyridine calcium channel blocker, and hydralazine, a non-calcium channel antagonist vasodilatator, enhanced pentobarbitone-induced sleeping time and reversed locomotor hyperactivity induced by a subhypnotic dose of the barbiturate in mice. The similarity of the behavioural effects, exerted by nifedipine and hydralazine, suggest that haemodynamic factors may play an important role in the interaction of calcium channel antagonists with barbiturates.

The effects of the benzomorphan analogue bremazocine on locomotor activity were studied in DBA/2 (DBA) and C57BL/6 (C57) mice. Three sets of experiments were carried out. In a first set, bremazocine depressed activity in both strains, but DBA mice were more sensitive to the effects of the drug. In a second set of experiments the effects of bremazocine were antagonized by a per se ineffective dose (0.5 mg/kg) of the selective kappa-opioid receptor antagonist MR 1452, showing that they were mediated through an interaction with this sub-population of opioid receptors. In a third set of experiments the effects of bremazocine were enhanced by the administration of a per se ineffective dose (0.025 mg/kg) of haloperidol, showing the involvement of dopaminergic mechanisms.

In C57BL/6 mice caffeine antagonized morphine-induced hyperactivity. This effect was most evident when caffeine was used in doses that slightly increased locomotor activity. Given at the same dose caffeine did not affect morphine-induced analgesia. Two possibilities of explanation of this effect are discussed: action of caffeine on dopaminergic mechanisms responsible for morphine-induced running fit through its effect on cyclic AMP level, and a direct action of caffeine on delta opiate receptors involved in the stimulatory effect of morphine.

The effects of the kappa-opioid receptor agonists tifluadom, bremazocine and U-50,488 on locomotor activity (test: toggle-floor box) and memory (test: passive avoidance) were assessed in C57BL/6 (C57) and DB/2 (DBA) mice. The drugs administration resulted in activity depression in both strains, the effect was higher in DBA mice and was enhanced by pretreatment with haloperidol and with muscimol. Memory impairment was observed in DBA mice following posttraining administration of all drugs. This effect was enhanced by immobilization stress and decreased by familiarization with the apparatus. Memory improvement was evident in C57 mice (U-50,488 experiments). In a research carried out with CD1 mice, amygdaloid lesions decreased the memory impairing effect of U-50,488. The results are compared with those previously obtained with mu agonists and, as concerns memory, are discussed in terms of the involvement of emotional factors in mice responses to kappa agonists administration.

Locomotor activity of CD-1 mice, tested in an unfamiliar environment (toggle-floor box), was increased either by a subhypnotic dose (20 mg kg-1) of pentobarbitone or after recovery from pentobarbitone-induced (50 mg kg-1) anaesthesia. On the contrary, when mice were tested 6 h after a single exposure to the apparatus, pentobarbitone in either case failed to produce hyperactivity. The results demonstrate that mice recovering from barbiturate anaesthesia maintain susceptibility to the exteroceptive stimuli provided by a novel environment and knowledge of the environment acquired during past experience.

Some behavioural effects of flunitrazepam were investigated in two sets of experiments in C57BL/6 mice. In the first set, flunitrazepam administration (0.025 or 0.05 mg/kg) enhanced the locomotor activity of mice. In the second set, memory impairments were observed following posttraining (immediately or 30 min, but not 60 min) treatment with the drug (0.05 mg/kg). All effects were antagonized by a per se ineffective dose of naltrexone (0.5 mg/kg for the activity, 0.1 mg/kg for the memory experiments), suggesting the involvement of opioid receptors. The results are discussed on the basis of recent evidence suggesting a link between benzodiazepine and opiate mechanisms of action.

Several doses of tifluadom, an opioid benzodiazepine with affinity for opioid kappa receptors, were tested on analgesia and locomotor activity in two strains of mice, the C57BL/6 and the DBA/2. The analgesic properties of the compound were confirmed in both strains by a tail flick test. As concerns locomotor activity both strains, that in previous researches showed opposite responses to opiates, were depressed by tifluadom, suggesting the involvement of kappa receptors in this effect.

Some behavioural effects of the kappa-opioid receptor agonist U-50,488 were investigated in DBA/2 (DBA) and C57BL/6 (C57) mice. In a first set of experiments, which was carried out with the toggle-floor box, U-50,488 depressed locomotor activity in both strains. Moreover, this activity depression was enhanced in both strains by the administration of haloperidol and muscimol, showing the involvement of dopaminergic and gabaergic mechanisms. In a second set of experiments, which were carried out with a passive avoidance apparatus, memory impairments, in DBA mice, and improvements, in C57 mice, were observed following immediately posttraining U-50,488 administrations. The results are compared with those of previous researches carried out, in the same strains of mice, with mu-opioid receptor agonists.

The opioid benzodiazepine, tifluadom, and the benzodiazepine tranquilizer, diazepam, were compared for their influence on morphine and scopolamine-induced locomotor stimulation in mice. Diazepam enhanced drug-induced hyperactivity, while tifluadom had no effect or reduced locomotor activity. The results demonstrate that tifluadom, a benzodiazepine compound possessing opiate-like analgesic properties, is devoid of either benzodiazepine or morphine-like effects in activity tests.

Subhypnotic doses (10 and 20 mg/kg) of pentobarbital significantly elevated locomotor activity measured for 30 min in CD-1 mice. The hyperactivity was also observed in mice recovering from pentobarbital-induced (50 mg/kg) sleep (measurements starting 15 min after recovery of righting reflex). Naloxone in doses up to 4 mg/kg did not affect significantly the pentobarbital-induced hyperactivity in any experiment; a dose of 8 mg/kg only partially attenuated the hyperactivity induced by a dose of 20 mg/kg of pentobarbital, but did not affect significantly either the stimulatory effect of a low subhypnotic dose (10 mg/kg) or the posthypnotic hyperactivity. This suggests a negligible involvement of opioid mechanisms in the hyperactivity induced by pentobarbital.