Effects of prenatal ethanol exposure in C57BL mice on locomotor activity and passive avoidance behavior

The purpose of this study was to examine the long-term behavioral effects of prenatal ethanol exposure in C57BL mice. Pregnant mice received free access to a liquid diet containing 25% ethanol-derived calories (EDC) from gestation days 6 to 18. Control animals were pair-fed an isocaloric 0% EDC diet during the same period of time. An additional control group was included that was maintained on standard lab chow and water throughout pregnancy. At 30 days of age, female offspring were tested for spontaneous locomotor activity in an open field under two lighting conditions (dim or bright illumination). Male off-spring were tested in a passive avoidance task at 25 days of age. The activity results demonstrated that the 25% EDC female progeny were more active than controls. This hyperactivity was observed under both lighting conditions, despite the fact that all groups evidenced suppressed activity when tested under bright lights. With regard to passive avoidance behavior, male EtOH-exposed offspring required a greater number of trials to reach criterion than controls. Additionally, they exhibited shorter latencies to enter the shock-associated chamber after receiving a single shock. Taken together, these results confirm our previous findings and demonstrate that C57BL mice are sensitive to both the deleterious behavioral and morphological consequences of prenatal ethanol exposure.     

Prolongation of latencies for passive avoidance responses in rats treated with aniracetam or piracetam

Effects of aniracetam (1-anysoyl-2-pyrrolodone) and piracetam (1-acetamido-2-pyrrolidone) on passive avoidance behavior were studied in 2 and 18 months old rats using a step-down passive avoidance task. Repeated administration of aniracetam (30 and 50 mg/kg, IP X 5 days) or piracetam (100 mg/kg, IP X 5 days) significantly prolonged step-down latencies for a passive avoidance task in 2 months old rats. Administration of aniracetam (50 mg/kg, IP) or piracetam (100 mg/kg, IP), however, did not affect locomotor activity. This prolongation of latencies was also seen with oral administration of aniracetam (50 mg/kg X 5 days). Similar prolongation of latencies also occurred in 18 months old rat treated with aniracetam (50 mg/kg, IP X 5 days). The results imply that aniracetam may improve learning and/or memory in 2 and 18 months old rats.     

Sensitive and rapid behavioral differentiation ofN-methyl-d-aspartate receptor antagonists

Behavioral effects of PCP-type noncompetitive antagonists ofN-methyl-d-aspartate (NMDA) receptors overlap with those of a host of other centrally acting compounds. In the present experiment, locomotor activity and performance on an inverted screen test in untrained mice were used to differentiate PCP-type non-competitive NMDA antagonists from other drug classes. These uncompetitive NMDA antagonists [PCP, dizocilpine, (–)-MK-801, TCP, (+)-SKF 10,047, dextrorphan, ketamine] produced dose-related increases in locomotor activity and the percentage of mice falling off an inverted, elevated wire mesh screen. Both effects demonstrated stereoselectivity, occurred at comparable dose levels, and were within the range of doses producing other biological effects (e.g., anticonvulsant). The potencies of these drugs for producing behavioral effects were positively correlated with affinities for PCP ([³H]MK-801) but not ([³H]SKF 10,047) receptors. Although muscarinic antagonists (benactyzine, atropine) produced effects in the same direction, locomotor stimulation was small and occurred at lower doses than those inducing screen failures. Competitive NMDA antagonists (LY 274614, LY 233536, CPP, NPC 12626), receptor ligands (DTG, dextromethorphan), postsynaptic dopamine agonists (quinpirole, SKF 38393) and antagonists (haloperidol, SCH 39166), and some depressant compounds (morphine, diazepam) increased failures on the screen test but decreased locomotor activity. Ligands of the polyamine regulatory site of the NMDA receptor (ifenprodil, SL 82.0715-10) and the AMPA receptor antagonist NBQX decreased locomotor activity without increasing screen failures. An antagonist of the strychnine-insensitive glycine receptor (7-chlorokynurenic acid) did not affect performance on either test. Psychomotor stimulants (cocaine and methamphetamine) stimulated locomotor activity without affecting screen performance. The only false positives occurred with barbiturates (pentobarbital, phenobarbital). Nonetheless, the present procedure demonstrates excellent sensitivity and power for rapid discrimination of uncompetitive NMDA antagonists.     

Effects of second-generation histamine H1 receptor antagonists on the active avoidance response in rats

1. The aim of the present study was to establish a new schedule of active avoidance response in rats to estimate the central effects of second-generation histamine H1 receptor antagonists. 2. With the new schedule, a rat was placed into a dark room. A sliding door was opened after a delay of 5 s and, unless the animal moved into the lit room, an electric shock was delivered for 3 s. With the conventional schedule, the sliding door was opened immediately after the rat was placed into the dark room. 3. Ketotifen, at a dose of 50 mg/kg, showed no significant effect on the retrieval of active avoidance response with the conventional schedule. However, with the new schedule, the drug caused significant inhibition of retrieval of the response, even at a dose of 10 mg/kg. 4. Epinastine showed no significant effect on retrieval of the active avoidance response, even at a dose of 50 mg/kg with the new schedule. 5. Cetirizine, at a dose of 50 mg/kg, caused a significant effect, indicating that cetirizine, at this dose, markedly inhibits memory retrieval. 6. Both olopatadine and loratadine had potent effects; at doses of 20 and 50 mg/kg, respectively, these agents showed significant inhibitory effects on retrieval of the response. 7. In conclusion, we have developed a new schedule of active avoidance response that can be used to estimate the central effects of second-generation histamine H1 receptor antagonists.     

Serotonin-mimetic and antidepressant drugs on passive avoidance learning by olfactory bulbectomised rats

Olfactory bulbectomised rats were treated with drugs and their rate of acquisition of a passive avoidance task was measured. The acquisition-rate, which is disturbed by the bilateral ablations, was completely restored by acute administration of fenfluramine or fluoxetine. Partial restoration was found with quipazine. Clonodine was without effect. Repeated treatments with impramine and mianserine improved passive avoidance of bulbectomised rats. Metergoline blocked these effects of imipramine and mianserin. These results indicate a serotonergic mechanism in the effect of antidepressants on olfactory bulbectomised rats.     

NMDA receptor antagonists impair motor performance in immature rats

RATIONALE: Antagonists of NMDA receptors are excellent anticonvulsants in adult animals but serious side effects prevent their clinical use. The effects of two antagonists on motor performance were studied to find out if they develop in parallel with previously described anticonvulsant action. METHODS: Motor performance of 12-, 18- and 25-day-old rats was studied using a battery of tests (surface righting, negative geotaxis, bar holding and wire mesh ascending and three age-specific tests). A competitive NMDA antagonist CGP 40116 (0.1, 0.5 and/or 1 mg/kg IP) and a noncompetitive one dizocilpine (0.1, 0.5 and/or 1 mg/kg IP) were tested. RESULTS: Ten minutes after CGP 40116, the performance was compromised in all tests but there was negative geotaxis in all age groups. A decrease in efficacy with age was clearly demonstrated. Righting ability remained untouched in 25-day-old animals. Dizocilpine also influenced the performance in all tests but righting (compromised only in the youngest group) when studied 10 min after the injection. The relation to age was not so marked as with CGP 40116. When the tests were applied 4 h after dizocilpine administration the results were similar to those at 10-min interval. Twenty-four hours after dizocilpine only cliff avoidance exhibited prolonged latencies in 12-day-old rats but significant effects were observed in 18-day-old (negative geotaxis, bar holding and wire mesh ascending) as well as 25-day-old animals (bar holding, jumping down with choice). CONCLUSIONS: The acute effects of both NMDA antagonists studied decreased with age; this age-related change was more marked with CGP 40116 than with dizocilpine. In contrast, duration of dizocilpine effects did not exhibit a clear developmental tendency.     

Effects of histamine and opioid systems on memory retention of passive avoidance learning in rats

The present study investigated the effect of interactions between histamine receptor agents and the opioid peptidergic system on memory retention of passive avoidance learning in rats. Post-training intracerebroventricular (i.c.v.) injections were carried out in all the experiments. Administration of histamine (20 micro g/rat) reduced, but the histamine H(1) receptor antagonist, pyrilamine (20 and 50 micro g/rat), and the histamine H(2) receptor antagonist, cimetidine (10 and 50 micro g/rat), increased memory retention in rats. The histamine receptor antagonists decreased the response induced by histamine. Morphine (1-10 micro g/rat) reduced, while pentazocine (5 and 10 micro g/rat) or the opioid receptor antagonist, naloxone (5 and 15 micro g/rat), increased memory retention. The combination of histamine with morphine showed potentiation. Effects of pyrilamine and cimetidine were attenuated by morphine. The responses to pentazocine and naloxone also were decreased by histamine. It is concluded that the histaminergic system has an interaction with opioidergic system that is involved in the memory retention process.     

Effects of different doses of glucose and insulin on morphine state-dependent memory of passive avoidance in mice

Rationale Behavioral effects of morphine, including its effect on memory, have been demonstrated to be influenced by glucose pretreatment. The measurement of step-down latency in passive avoidance has been used to study memory in laboratory animals. The pre-training injection of 5 mg/kg morphine impaired memory, which was restored when 24 h later the same dose of the drug was administered.Objectives To investigate the effects of glucose and insulin alone or in combination with morphine, on pre-test day, on memory recall in mice.Methods The effects of different doses of glucose (50, 100, and 200 mg/kg, IP) and insulin (5, 10, and 20 IU/kg, IP) alone or in combination with morphine, have been studied in mice. The blood glucose level and locomotor activity of the animals were also measured.Results Although the administration of glucose alone showed no effect on morphine-induced memory impairment, its co-administration with morphine resulted in a significant and dose-dependent memory enhancement compared with the effects of morphine administration alone. Like glucose, the administration of different doses of insulin alone produced no change in the memory, but when the drug was co-administered with morphine, it significantly reduced morphine-induced memory retrieval. The effect of insulin was the opposite of glucose. None of the animals subjected to insulin treatment showed convulsions.Conclusions Glucose is suggested to increase, on the test day, the morphine-induced memory enhancement by three different mechanisms: cholinergic or opioidergic modulations, or regulation of the ATP-dependent potassium channels.     

The effect of NMDA receptor antagonists on the neuroleptics-induced catalepsy in mice

The effect of non-competitive (MK-801:/+/-5-methy-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine hydrogen maleate) and competitive (CGP 37849: DL-/E/-2-amino-4-methyl-5-phosphono-3-pentenoic acid) NMDA receptor antagonists on the catalepsy induced by neuroleptics in mice was studied. MK-801 and CGP 37849 antagonized the catalepsy induced by haloperidol, spiperone and fluphenazine. (+)-Cycloserine, a partial glycine agonist, reversed the anticataleptic effect of CGP 37849, but not that of MK-801. The above results indicate that the anticataleptic activity of both these NMDA receptor antagonists is induced by an indirect activation of the dopamine system. The results provide further evidence that competitive NMDA receptor antagonists may be a new class of antiparkinsonian drugs.     

Effects of developmental lead exposure on inhibitory avoidance learning and glutamate receptors in rats

Chronic lead (Pb) exposure during development is known to produce learning deficits. AMPA and NMDA receptors have been shown to participate in the synaptic mechanisms involved in certain forms of learning and memory. We investigated whether the effects of Pb on AMPA and NMDA receptors are associated with Pb-induced impairment in learning and memory. Rats were exposed to 0.2% lead acetate at different developmental stages including a maternally exposed group (including gestation and lactation period), a postweaning exposed group, and a continuously exposed group. Lead treatment impaired learning acquisition, but not memory retention in step-down avoidance learning task in all treatment groups. In parallel with the behavioral data, autoradiographic analyses of brain sections indicated that the [³H]AMPA binding was decreased in the CA1 and dentate gyrus of the hippocampus and entorhinal cortex in all three Pb-exposed groups. However, an increase in [³H]MK801 binding was only observed in CA1 of the hippocampus in the continuously Pb-exposed rats. The findings suggest that alterations in AMPA receptor may contribute to the Pb-induced deficits in learning acquisition of inhibitory avoidance.     

6-Hydroxydopamine induced catecholamine depletion and passive avoidance learning in rats

Rats were injected with 6-hydroxydopamine either intracisternally, intraperitoneally, or both, in order to examine the effects of central vs. peripheral catecholamine depletion on a step-down passive avoidance task. All rats acquired the response at the end of the five asquisition trials but the rates of acquisition of the drug-treated groups were siginificantly different from the control group. No significant difference in the performance results were observed between groups during the extinction period. These findings failed to confirm the hypothesis that an intact central and/or peripheral catecholaminergic systems may be necessary for the acquisition and extinction of a step-down passive avoidance response. In addition, this study also showed that plasma corticosterone levels in the rats depleted of central or peripheral catecholamine did not differ significantly from each other after passive avoidance training.     

选择性N-甲基-D-天门冬氨酸受体NR2B亚型阻滞剂的研究进展

选择性N-甲基-D-天门冬氨酸受体NR2B亚型阻滞剂近年来受到了越来越多的关注。目前，已报道的NR2B亚型阻滞剂的结构类型绝大多数仍为艾芬地尔发展而来的哌啶衍生物，另外还有酰胺、脒、氨基喹啉等结构类型；NR2B亚型阻滞剂在神经元保护、镇痛、抗药物依赖、抗帕金森病等方面表现了潜力。现根据不同结构类型综述NR2B亚型阻滞剂的结构及药理活性，并探讨其毒副作用较低的可能原因和临床应用潜力。     

An analysis of some effects of ethanol on performance in a passive avoidance task

In a one-trial step-through passive avoidance task, pretraining administration of ethanol was shown to decrease the latencies to step through at both training (day 1) and testing (day 2) for both rats and mice. A detailed analysis of these effects showed that they differed from those reported previously by others. The mechanisms underlying these effects of ethanol were also examined. The decreased day 1 latency to step through seen in rats may have been caused by an ethanol-induced hypermotility. However, ethanol did not increase the locomotor activity of mice, although it also reduced the day 1 latency to step through of this species. In addition, it was found that the ethanol-induced impairment of passive avoidance responding (i.e. the decreased day 2 latency to step through) was not state-dependent and that it was unlikely that it could be explained by a drug-induced impairment of task acquisition, long-term memory formation or memory recall. It also seemed unlikely that the impairment could be explained by an ethanol-induced decrease in shock sensitivity. Other mechanisms which may be involved are discussed.     

Passive avoidance in rats: Disruption by dopamine applied to the nucleus accumbens

The acquisition of a one-trial step-through passive avoidance task was examined in rats following the administration of nialamide IP and dopamine (DA) or saline into the nucleus accumbens. DA-treated rats displayed impaired learning of the task as evidenced by their lower step-through latencies on a retest trial 7 days later. The specificity of this impairment was studied in a 2×2 design involving intracerebral injections prior to both training and testing trials. It was found that DA treatment prior to the training trial disrupted learning or memorization of the task but that DA did not affect performance or retrieval and did not induce state-dependent learning. These findings suggest that DA applied to the nucleus accumbens does not facilitate learning per se.     

Functional interaction of NMDA and group I metabotropic glutamate receptors in negatively reinforced learning in rats

Rationale The role of glutamatergic system in learning and memory has been extensively studied, and especially N-methyl-d-aspartate (NMDA) receptors have been implicated in different learning and memory processes. Less is known, however, about group I metabotropic glutamate (mGlu) receptors in this field. Recent studies indicated that the coactivation of both NMDA and group I mGlu receptors is required for the induction of long-term potentiation (LTP) and learning. Objective The purpose of the study is to evaluate if there is a functional interaction between NMDA and group I mGlu receptors in two different models of aversive learning. Methods Effects of NMDA, mGlu1, and mGlu5 receptor antagonists on acquisition were tested after systemic coadministration of selected ineffective doses in passive avoidance (PA) and fear-potentiated startle (FPS). Results Interaction in aversive learning was investigated using selective antagonists: (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate (EMQMCM) for mGlu1, [(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) for mGlu5, and (+)-5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine maleate [(+)MK-801] for NMDA receptors. In PA, the coapplication of MTEP at a dose of 5 mg/kg and (+)MK-801 at a dose of 0.1 mg/kg 30 min before training impaired the acquisition tested 24 h later. Similarly, EMQMCM (2.5 mg/kg) plus (+)MK-801 (0.1 mg/kg), given during the acquisition phase, blocked the acquisition of the PA response. In contrast, neither the combination of MTEP (1.25 mg/kg) nor EMQMCM (5 mg/kg) plus (+)MK-801 (0.05 mg/kg) was effective on the acquisition assessed in the FPS paradigm. Conclusion The findings suggest differences in the interaction of the NMDA and mGlu group I receptor types in aversive instrumental conditioning vs conditioning to a discrete light cue.     

Impairment by apomorphine of one-trial passive avoidance learning in mice: The opposing roles of the dopamine and noradrenaline systems

Pretraining administration of the dopaminergic stimulant apomorphine (0.25–16 mg/kg) impaired retention performance of mice on a one-trial passive avoidance task. Only with a very high dose (16 mg/kg) of this drug did the effect seem related to an interference with memory formation processes. Of the dopamine receptor-blocking agents used, haloperidol (0.125–1 mg/kg), but not chlorpromazine or clozapine (0.25–4 mg/kg), prevented the apomorphine effect. Phenoxybenzamine (8 mg/kg), a noradrenaline receptor-blocker, antagonized the haloperidol effect and, when combined with a subeffective dose of apomorphine, impaired passive avoidance learning. The results obtained are interpreted in terms of the proposed inhibitory actions exerted by central noradrenaline on dopamine systems of the brain.     

Genetic differences in the effects of competitive and non-competitive NMDA receptor antagonists on locomotor activity in mice

The effects of non-competitive (MK-801, phencyclidine, and ketamine) and competitive (CGP 39551, CGS 19755, and NPC 12626) N-methyl-d-aspartate (NMDA) receptor antagonists on locomotor activity in inbred CBA and C57, and in outbred NMRI mice were examined. Administration of the non-competitive NMDA antagonists produced a dose-dependent increase in well-coordinated locomotor activity at lower doses, followed by a bizarre behavioral syndrome (head weaving, body rolling, rotations, ataxia) after higher doses. The pharmacological profile of the competitive antagonists CGP 39551, CGS 19755, and NPC 12626 was more complex. CGP 39551 dose-dependently inhibited locomotor activity, whereas CGS 19755 and NPC 12626 displayed a biphasic action, that is low doses inhibited locomotor activity, whereas higher doses produced mild behavioral stimulation. The behavioral effects of NMDA antagonists appear to be genetically determined, since CBA animals were most sensitive to both noncompetitive and competitive antagonists, followed by NMRI and C57 animals. The differential effects of NMDA antagonists in various strains of mice suggest that the observed behavioral differences may be due to genetic differences in the NMDA/glutamate receptor channel complex.     

Systemic injection of pirenzepine induces a deficit in passive avoidance learning in rats

When injected IP, the M1 muscarinic receptor antagonist pirenzepine dose-dependently induced a deficit in passive avoidance learning in rats. This activity was optimal at 75 mg/kg injected 1 h before the acquisition session. The deficit induced by pirenzepine was antagonized by oxotremorine (0.03–0.3 mg/kg SC) and physostigmine (0.1 mg/kg SC), but not neostigmine. By comparison, under the same experimental conditions, physostigmine and oxotremorine also antagonized the deficit induced by an equipotent dose of scopolamine (0.5 mg/kg IP), although the activity of physostigmine appeared stronger against scopolamine than against pirenzepine. These results suggest that pirenzepine could produce a centrally-mediated behavioural disruption when injected systemically.     

Dose-response effects of d-amphetamine on passive avoidance learning in the rat

Trials and errors to learning a passive avoidance response were assessed in 63 albino rats injected subcutaneously with d-amphetamine, in amounts ranging from 0–7 mg/kg body weight. Both measures indicated dose-response effects on responding; animals under either low or high doses of d-amphetamine made significantly less errors and took significantly fewer trials to learn the response than did middle dosage animals. The scores of the lower and higher dosage animals did not differ from the nondrug control group. Results are discussed in terms of amphetamine stereotypy.     

Effects of high-affinity GABAB receptor antagonists on active and passive avoidance responding in rodents with gamma-hydroxybutyrolactone-induced absence syndrome

RATIONALE: Absence seizures in man are behaviourally manifested as arrest and mild jerks mainly of facial muscles, associated in the electroencephalogram with synchronous spike and wave discharges. Gamma-hydroxybutyrolactone (GHBL) administration is currently used as an experimental model of absence seizures in rats and mice. OBJECTIVE: The aim of the present study was to examine the effects of three potent gamma-aminobutyric acid (GABA)B receptor antagonists CGP55845A, CGP62349 and CGP71982 (0.01 mg/kg) on the development of GHBL-induced absence epilepsy and in learning paradigms of active and passive avoidance tests in GHBL-treated mice and rats. METHODS: After 4 weeks of development of the absence syndrome, active and passive avoidance tests with negative reinforcement were performed. In both animal species, the absence syndrome was observed after 3 weeks of treatment in the saline group. RESULTS: The GABAB receptor antagonists CGP55845A and CGP62349 appeared to suppress the development of the absence syndrome to a greater degree in mice than in rats. CGP71982 suppressed it later than the other two antagonists (fifth week). In an active avoidance test in GHBL-treated mice, the GABAB antagonists had different effects - CGP62349 improved learning and memory retention to a greater extent than CGP55845A, whilst CGP71982 had no influence on it. In a passive avoidance test in GHBL-treated mice, the GABAB antagonists also had different effects - CGP71982 improved both learning and memory retrieval, whereas CGP55845A and CGP62349 had no effect. In the active avoidance test in GHBL-treated rats, the GABAB antagonist CGP55845A improved learning, whereas the other two, CGP62349 and CGP71982, had no effect. In the passive avoidance test the GHBL-treated rats showed an improvement in short memory retrieval. CGP55845A and CGP71982 improved this further, whilst CGP62349 had no effect. CONCLUSIONS: GHBL appeared to influence mice and rats in a different manner - rats learned the active avoidance task better than the GHBL-treated mice. The present study confirms previous data that GABAB antagonists suppress absence behaviour.