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The effects of bremazocine on memory processes were studied in DBA/2 mice tested in a passive avoidance apparatus. In a first set of experiments, memory impairments following immediately posttraining bremazocine administration (0.025 and 0.05 but not 0.01 mg/kg), and memory improvements following immediately posttraining administration of the kappa-opioid-receptor antagonist MR-1452 (1.0 and 2.0 but not 0.5 mg/kg), were observed. No effect was evident when the drugs were injected starting 120 min after training. In a second set of experiments, the effects of bremazocine (0.05 mg/kg) were antagonized by a per se ineffective dose of MR-1452 (0.5 mg/kg), suggesting involvement of kappa-opioid-receptors. In a third set of experiments, the effects of bremazocine were enhanced by a per se ineffective (15 min) immobilization stress, and were decreased by familiarization with the passive avoidance apparatus. The results are discussed in terms of attenuation of emotionality following bremazocine administration.

A passive avoidance methodology was used to test the effect of ethanol, and its interference with GABAergic mechanisms, on memory in male CD1 mice. Retention performance was reduced in a dose-related manner, by ethanol and by muscimol, a GABA agonist, while it was increased by the GABA antagonists picrotoxin and bicuculline. These effects were evident when treatments were carried out immediately, but not 120 min, after training, suggesting that they were due to a specific action of the drugs on the time-dependent memory consolidation process. The ethanol-induced reduction of retention performance was enhanced by muscimol and decreased by picrotoxin and bicuculline administrations. Taken together the results confirm the involvement of a GABAergic mechanism in memory consolidation and demonstrate that it underlies the negative effect of ethanol on passive avoidance behavior in the mouse.

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.

Dermorphin and [D-Ala2-D-Leu5]enkephalin, administered intracerebroventricularly (icv) immediately after training in a passive avoidance test, exerted dose- and strain-dependent effects in DBA/2 (DBA) and C57BL/6 (C57) mice. In fact, the peptides impaired, at a low dose (5 ng), the retention performances of both strains; a higher dose (50 ng) impaired retention in DBA but improved it in C57 mice. A dose of naloxone (0.3 microgram, icv), which was ineffective when administered alone, antagonized the effects observed. The results are discussed in terms of strain differences in central mechanisms.

In a first set of experiments, immediately post-training morphine (1.0 or 2.5 but not 0.5 mg/kg) treatment, or immobilization stress (30 or 60 but not 15 min) impaired memory processes of non-pretrained DBA/2 mice tested in a passive avoidance box. The effects were naloxone-reversible and time-dependent (they were absent in mice injected with morphine, or immobilized, starting 120 min after training). No effect was evident in no-footshock groups injected with morphine (2.5 mg/kg) or immobilized (60 min), thus showing lack of proactive influence of the treatments on performance. In a second set of experiments, in which pretrained animals were used, both morphine and immobilization stress were less effective in disrupting memory processes of mice. In both sets of experiments a per se ineffective stress enhanced the effects of morphine. A number of possible hypotheses concerning the results obtained are examined. In particular the possible role of emotional factors in the effects of morphine on memory is discussed.

In a first set of experiments the posttrial intraperitoneal acute administration of the GAD-inhibitor DL-allylglycine impaired the memory processes of C57BL/6 (C57) mice tested in a passive avoidance apparatus. Memory improvements were, on the contrary, observed following morphine treatment. These effects were dose- and time-dependent. They were, in particular, evident if mice were injected immediately, or 30 min, but not 60 min, after training in the apparatus, and were absent in the no-footshock groups, suggesting lack of proactive effects of the drugs on performance. In a second set of experiments, the posttraining administration of allylglycine, at a per se ineffective dose (5 mg/kg), antagonized the memory improvement exerted by the administration of morphine (0.5 or 1.0 mg/kg). The results support the hypothesis of an involvement of GABAergic mechanisms in the memory consolidation processes, and suggest the possibility that GABAergic systems play a role in the effects of morphine on memory in C57BL/6 mice.

The nootropic drug oxiracetam and the anticholinergic agent scopolamine were tested, alone or in combination, on shuttle-box avoidance acquisition and locomotor activity in mice of the CD-1 strain. Both drugs, given separately, slightly but significantly enhanced avoidance performance, but only scopolamine increased locomotor activity. Combinations of the 2 drugs, in some instances, enhanced avoidance performance more than drugs given separately, but the disinhibitory property of scopolamine makes it difficult to understand the role played by cholinergic mechanisms in these effects.

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.

Classical conditioning of stress-induced analgesia (SIA) resulted in higher tail flick latencies in BALB/c mice. Transfer of classical conditioning of SIA was evident when the same repetition rate (pulsed light or pulsed tone) characterized stimuli in different sensory modalities. This finding is discussed in terms of opioid production and of generalization of emotional reactions.

Postnatal administration of an aqueous suspension of phosphatidylserine (BC-PS) to C57BL/6 mice resulted in improvement of memory processes in adulthood, as assessed in a passive avoidance task. These findings are discussed in terms of the effects of BC-PS on cholinergic mechanisms and of cholinergic patterns of this inbred strain.

The synthesis of a series of physostigmine analogs, in which the methylcarbamyl group has been substituted with monoalkylcarbamyl, dimethyl- and diethylcarbamyl groups, is reported. These compounds were prepared with the aim of investigating their possible therapeutic effects in the treatment of Alzheimer's type dementia. The new analogs of physostigmine are inhibitors of acetylcholinesterase from Electroforus electricus, with a value of the reactivation constant, k3 smaller than the one of physostigmine. The percentage of anticholinesterase activity in vitro and in vivo, the acute toxicity and some behavioural effects were also evaluated for selected derivatives. The reactivation constant, in vitro, supports the view that the derivatives described would be more suitable for therapeutic use than physostigmine.

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.

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.

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.

The involvement of GABAergic mechanisms in the effects exerted by the opioid antagonists naloxone and naltrexone on memory consolidation was investigated in CD1 mice tested in a one-trial inhibitory avoidance task. In a first group of experiments posttraining administration of naloxone (2.0 and 4.0 but not 1.0 mg/kg) and naltrexone (0.5 and 1.0 but not 0.25 mg/kg), as well as those of the GABA-antagonists picrotoxin (0.5 and 1.0 but not 0.25 mg/kg) and bicuculline (0.25 and 0.5 but not 0.1 mg/kg) enhanced, whereas those of the GABA-agonist muscimol (1.0 and 2.0 but not 0.5 mg/kg) impaired retention on a 24-hr test. In a second group of experiments, picrotoxin, or bicuculline, administration enhanced, while muscimol treatment attenuated the effects of naloxone and naltrexone on retention. The results suggest that naloxone and naltrexone may influence memory consolidation in CD1 mice by interacting with the GABAergic system.

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.

A series of analogues of physostigmine were prepared with the aim of investigating their inhibitory effects on acetylcholinesterase in the treatment of Alzheimer's disease. One of the isomers prepared was evaluated for its anticholinesterase activity in vivo, acute toxicity, and some behavioral effects. This compound was a competitive inhibitor of the enzyme and was found to antagonize the stimulating effect produced by scopolamine on locomotor activity and to facilitate memory consolidation.

The effects of flunitrazepam on passive avoidance behaviour were investigated in DBA/2 mice. In a first set of experiments retention performance impairment was observed in mice injected with the drug immediately but not 120 min after training. In a second set of experiments, immobilization stress enhanced, while familiarization with the apparatus decreased, the effects of flunitrazepam, suggesting involvement of emotional factors. All the effects observed were antagonized by naltrexone, showing involvement of opioid receptors.

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.