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Glucose was tested alone or in combination with two stimulant drugs, amphetamine and nicotine, in mice of the CD-1 strain subjected to five daily shuttle-box training sessions. Pretraining intraperitoneal administration of glucose (50 or 100 mg/kg) had no effect, while amphetamine and nicotine, given alone, significantly improved avoidance acquisition at a dose of 0.5 mg/kg, but not 0.025 mg/kg. Significant improvement of avoidance learning was also produced by a combination of glucose with the lower dose of amphetamine or nicotine. This enhancing action, produced by a combination of glucose and stimulant drugs, at doses ineffective by themselves, might be due to a concomitant cholinergic and dopaminergic activation, induced by glucose and stimulant drugs, respectively., (Copyright 2000 Academic Press.)

Five experiments were carried out to investigate opioid and NMDA receptor-mediated responses to one-trial inhibitory avoidance training in CD1 mice. In the first experiment immediate posttraining intraperitoneal administration of the noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 impaired the performance of mice. The effects of MK-801 were time-dependent (they were absent in mice injected with the drug starting 120 min after training). No effect was evident in no-foot-shock groups, showing lack of proactive influence of the treatment on performance. In the second experiment preexposure of the mice to the testing apparatus decreased the effects of MK-801. In the the third experiment naltrexone antagonized the effects of MK-801, suggesting an involvement of opioid neurons. In the fourth experiment immediate posttraining immobilization stress exerted a potentiating effect on the performance of MK-801-injected animals. In the fifth experiment the potentiation of the impairing effect of MK-801 induced by immobilization stress was antagonized by naltrexone., (Copyright 1999 Academic Press.)

The acetylcholinesterase reversible inhibitor N-octyl-1,2,3, 4-tetrahydro-9-aminoacridine (THA-C8) is a new synthesized derivative of tacrine (THA) characterized by an alkyl chain in the molecular structure which ameliorates the penetrability of the compound into the central nervous system. THA-C8 (0.1-5 mg/kg) significantly reduced spontaneous locomotor activity in CD1 mice at a dose of 3 mg/kg. Moreover, THA-C8 (0.2-2 mg/kg) significantly improved shuttle-box avoidance acquisition at doses (0.25, 0.3, 1 mg/kg) not affecting locomotion and that are much lower than the doses reported to be effective for THA in animal models. From the data reported it seems that the new compound could be interesting for therapeutic purposes., (Copyright 1999 Academic Press.)

The effects of the dihydropyridine calcium channel blocker nimodipine on avoidance impairment induced by the tricyclic antidepressant amitriptyline were assessed during shuttle-box training and in previously trained mice of the DBA/2 strain. Nimodipine (0, 0.5, 1, 2.5, or 5 mg/kg) had no effect alone, but attenuated the avoidance impairment induced by 5 mg/kg amitriptyline on avoidance acquisition, as well as on a previously learned avoidance response. The avoidance improving action of the calcium channel blocker was less evident in mice receiving a larger dose (7.5 mg/kg) of the antidepressant drug. The effect of nimodipine did not appear to be specifically related to the avoidance impairment induced by amitriptyline, because the calcium antagonist also attenuated the avoidance impairing action of the neuroleptic chlorpromazine. The avoidance impairment induced by amitriptyline and chlorpromazine, and the related ameliorating action of nimodipine, seem imputable to drug effects on the performance of the avoidance response, rather than to interferences with learning processes. The results suggest that, in the case of concomitant administration, nimodipine could alleviate adverse side effects of tricyclic antidepressant, i.e., psychomotor disturbances.

Glucose and the acetylcholinesterase inhibitor tacrine were tested, alone and in combination, in mice of the CD-1 strain subjected to five daily shuttle-box training sessions. Pretraining intraperitoneal administration of glucose alone (50-400 mg/kg) had no significant effect, while tacrine alone (0.5-3 mg/kg) improved avoidance acquisition at the dose of 2 mg/kg only. Significant avoidance learning improvements were instead produced by 50 or 100 mg/kg glucose combined with 0.5 or 1 mg/kg tacrine. The effects on shuttle-box avoidance acquisition produced by glucose combined with a cholinomimetic agent support the hypothesis that cholinergic mechanisms may be involved in the action of glucose on learning and memory. However, the main finding of the present study is related to the enhancement by glucose of the learning improving action of a drug clinically used as cognitive enhancer.

The effects of two cognition enhancers on avoidance impairment induced by the tricyclic antidepressant amitriptyline were assessed during shuttle-box avoidance acquisition and in previously trained mice of the DBA/2 strain. The nootropic agent piracetam (50, 100 or 200 mg/kg, i.p.) had slight or no effect in mice receiving amitriptyline (5 or 10 mg/kg, i.p.). Conversely, the acetylcholinesterase inhibitor tacrine (0.5, 1, 2 or 3 mg/kg, i.p.) prevented the avoidance impairment induced by 5 mg/kg amitriptyline on shuttle-box avoidance acquisition as well as on a previously learned avoidance response. The avoidance disrupting action produced by 10 mg/kg of the antidepressant drug was not affected by the anticholinesterase drug. The preventing action of tacrine seems specifically related to the avoidance impairment induced by amitriptyline, since the acetylcholinesterase inhibitor did not reduce, but enhanced the avoidance impairing action of the neuroleptic chlorpromazine. Taken together, the results indicate that amitriptyline-induced avoidance impairment, and the related preventing action of tacrine, may be ascribed to drug effects on the performance of the avoidance response, rather than to interferences with learning processes.

The effects of the cholinergic muscarinic agonist, oxotremorine (0.005, 0.01, 0.02 and 0.04 mg/kg), the serotonergic agonist, 5-methoxy-NN-dimethyltriptamine (5-MeODMT) (0.5, 1 and 2 mg/kg), and their combination, were investigated in C57BL/6 and DBA/2 mice using a one-trial inhibitory avoidance task, drug treatment being given immediately after the acquisition trial. Post-trial administration of oxotremorine facilitated, while post-trial administration of 5-MeODMT inhibited memory retention of both strains in a dose-dependent fashion. The DBA/2 strain was more affected by oxotremorine than the C57BL/6 mice; no strain-dependent sensitivity to serotonergic agonist administration was observed. In both strains, the combination of oxotremorine plus 5-MeODMT inhibited the performance improvement shown by the administration of the cholinergic agonist alone. The facilitatory role of cholinergic stimulation on retention performance was confirmed and an inhibitory action of the serotonergic system on memory processes was suggested. Moreover, the present results support a functional interaction between cholinergic and serotonergic systems on memory consolidation.

The effects of the selective opiate kappa-receptor agonist tifluadom on memory were investigated in a passive avoidance task in 3 sets of experiments carried out with DBA/2 (DBA) mice both familiarized and unfamiliarized with the apparatus. In a first set of experiments, tifluadom (1.0 or 2.5, but not 0.5 mg/kg) administration immediately after training impaired retention performance of non-familiarized mice. This impairment was still evident when the drug was injected 15 or 30, but not 60 min after training. A second set of experiments was carried out with mice familiarized with the apparatus. Tifluadom was less effective in impairing memory in this group of animals, as compared with non-familiarized mice. Finally, in a third set of experiments, carried out with non-familiarized mice, a 15 min immobilization stress, which was ineffective when administered alone, enhanced the effects of tifluadom (1.0 mg/kg). The results are discussed in terms of attenuation of emotionality, resulting in impaired retention, following post-training opiate administration.

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.

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 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.

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.

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 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.