Suppression of nitric oxide synthesis by L-NAME reverses the beneficial effects of pioglitazone on scopolamine-induced memory impairment in mice

Pioglitazone, an agonist of peroxisome proliferator-activated receptor gamma (PPARγ), which is widely used in treatment of type 2 diabetes, has shown some therapeutic effect in Alzheimer's disease. In this study, effects of acute pioglitazone on acquisition, consolidation and retrieval of memory, and also the involvement of nitric oxide (NO) in the effects of pioglitazone on spatial recognition memory has been investigated in a two-trial recognition Y-maze test and passive avoidance in mice. Memory impairment was induced by scopolamine (1 mg/kg, i.p.). Pioglitazone (10 and 20 mg/kg, p.o.) was administrated prior to either acquisition, consolidation or retention trials, while L-NAME (N-nitro-l-arginine methyl ester), a non-specific NO synthase inhibitor, was administered (10 mg/kg, i.p.) 30 min before each trial. Results: 1) pioglitazone improved the acquisition of recognition spatial memory-impaired by scopolamine; L-NAME dramatically reversed improving effects of pioglitazone on memory acquisition; 2) pioglitazone did not change the consolidation of spatial memory, impaired by scopolamine; 3) pioglitazone improved the retrieval of spatial memory and L-NAME did not alter the beneficial effect of pioglitazone; 4) pioglitazone did not affect scopolamine-induced cognitive impairments in the passive avoidance test.The present study demonstrates the beneficial effect of acute pioglitazone administration on acquisition and retrieval of scopolamine-induced cognitive deficits. This effect was reversed only in acquisition phase by nitric oxide synthase inhibitor, L-NAME, therefore, it could be concluded that NO might be involved in the pioglitazone beneficial effect of spatial memory acquisition.     

Molsidomine attenuates N(omega)-nitro-L-argininemethylester-induced deficits in a memory task in the rat

The present study was designed to investigate the role of nitric oxide (NO) on recognition memory in the rat. For this purpose, the effects on memory exerted by post-training administration of the NO synthase (NOS) inhibitor N(omega)-nitro-L-argininemethylester (L-NAME) and the NO donor molsidomine were assessed by using the object recognition task. In a first dose-response study, L-NAME, at 30 but not at 10 mg/kg impaired the animals' performance, whereas at 60 mg/kg, it induced side-effects. Molsidomine, 4 mg/kg, antagonized the L-NAME-induced performance deficits. These results indicate that NO is involved in post-training memory processes.     

Enhancement of place and object recognition memory in young adult and old rats by RS 67333, a partial agonist of 5-HT4 receptors.

There is recent evidence that activation of central 5-hydroxytryptamine (5-HT)4 receptors enhances cognitive processes such as learning and memory. In the present study, we assessed the effects of a selective 5-HT4 receptors agonist, RS 67333 [1(4-amino-5-chloro-2-methoxyphenyl)-3-(1-n-butyl-4-piperidinyl)-1-propanone], in a two-trial recognition task designed to test place or object recognition memory.RS 67333 was injected in young adult (0.0001, 0.01, 1 mg/kg, i.p.) and old (0.0001, 0.01, 1, 10 mg/kg, i.p.) rats before the acquisition phase, immediately after it, or before the retrieval phase, to determine the stage of information processing affected by the compound.When injected before the acquisition phase, RS 67333 (1 mg/kg) enhanced place and object recognition in young adult rats. In old rats, RS 67333 (10 mg/kg) improved place recognition when injected before the acquisition phase, and object recognition when injected before the acquisition or in the consolidation phase of information processing. The beneficial effects of RS 67333 were abolished by prior treatment with a selective 5-HT4 receptors antagonist, GR 125487 [(1-[2-[methyl sulphonyl)-amino]ethyl]-4-piperidinyl-methyl 5-fluoro-2-methoxy-1H-indole-3-carboxylate); 10 mg/kg, i.p.].These results support the view that selective 5-HT4 receptors agonists may be of value in the treatment of cognitive disorders related to normal aging or neurodegenerative conditions such as Alzheimer's disease.     

Effects of molsidomine on scopolamine-induced amnesia and hypermotility in the rat

Nitric oxide (NO) is hypothesized to be a novel intracellular messenger in the central nervous system. Recently, NO involvement in learning and memory processes has been proposed. Compounds that inhibit nitric oxide synthase, the key synthesizing enzyme, may block cognition, while NO donors may facilitate it. The aim of this study was to assess in the rat the effects of the NO donor molsidomine (2 and 4 mg/kg, i.p.) on memory deficits caused by scopolamine. For this purpose, the object recognition task and the step-through passive avoidance procedure were chosen. In addition, the effects of molsidomine in antagonizing the scopolamine-induced hypermotility were also examined. Scopolamine at 0.2 mg/kg (object recognition) and 0.75 mg/kg (passive avoidance) disrupted acquisition in both the tasks and induced locomotor hyperactivity at the dose of 0.2 mg/kg. Molsidomine at either dose reversed the scopolamine-induced deficits in the object recognition paradigm but did not counteract the hypermotility and the deficits occurred in the passive avoidance test. These results suggest that to some extent, the NO donor molsidomine is involved in memory processing.     

Involvement of nitric oxide in pioglitazone memory improvement in morphine-induced memory impaired mice

Introduction

Pioglitazone, a PPAR‐γ agonist, which is clinically used in treating diabetic patients, has been recently reported to have crucial roles in improving cognition and memory performance. Since the mechanisms involved in the neuroprotective effect of pioglitazone are not entirely understood, the current study was designed to investigate the possible interaction of pioglitazone with morphine in memory-impaired mice and the probable role of nitric oxide (NO) in this effect.

Materials and methods

All the experiments were performed in passive avoidance and Y-maze paradigms. To induce memory impairment, mice were administered morphine (1, 3 and 10 mg/kg, s.c.) immediately before the training trial. Pioglitazone (20, 40 and 80 mg/kg, p.o.) was gavaged 2 h prior to the training trial. Further, an NO synthase inhibitor, L-NAME (10 mg/kg, i.p.), or an inducible NO synthase inhibitor, aminoguanidine (100 mg/kg, i.p.) was administered 30 min before the training trial to determine the possible involvement of NO in the restorative effect of pioglitazone.

Results

1) Morphine dose dependently impaired the acquisition of spatial memory and passive avoidance task. 2) Treatment with pioglitazone significantly improved the memory performance in morphine-treated mice in both tests. 3) In the passive avoidance task, L-NAME, but not aminoguanidine, altered the effect of pioglitazone on morphine-induced memory impairment. 4) In Y-maze discrimination, the memory improving effect of pioglitazone was reversed by both NO synthase inhibitors, L-NAME and aminoguanidine.

Discussion

Our results demonstrate that the pioglitazone improving effect on the morphine-induced impairment of memory acquisition is at least in part through the NO pathway. It is suggested that in short term spatial recognition memory, both inducible and constitutive NO synthases are involved, but in the long term fear memory, only the constitutive NO synthases indicated a prominent role in the anti‐amnestic effect of pioglitazone on morphine-induced memory impairment.     

Nitric oxide involvement in consolidation, but not retrieval phase of cognitive performance enhanced by atorvastatin in mice

Atorvastatin, a widely-used medication in treatment of hypercholesterolemia, has shown some benefits in treating cognition impairment in Alzheimer's disease. In this study, effects of atorvastatin on spatial recognition memory and the involvement of nitric oxide (NO) has been determined on consolidation and retrieval of memory in a two-trial recognition Y-maze test. Memory was impaired using scopolamine (1mg/kg, i.p.); atorvastatin (1, 5mg/kg, p.o.) was administered, either in presence or in absence of a non-specific NO synthase inhibitor, L-NAME (3, 10mg/kg, i.p.); a specific inducible NO synthase inhibitor, aminoguanidine (100mg/kg, i.p.); and a NO precursor, L-arginine (750 mg/kg, i.p.). Results: 1) atorvastatin (5mg/kg) significantly improved memory performance in a dose-dependent manner on consolidation and retrieval stage of memory in scopolamine-treated mice; 2) the beneficial effects of atorvastatin on memory consolidation was significantly reversed by L-NAME (10mg/kg) and aminoguanidine; 3) L-arginine slightly potentiated the effects of sub-effective dose of atorvastatin (1mg/kg) on memory consolidation; 4) either L-NAME (up to 10mg/kg), or aminoguanidine did not affect the memory improvement by atorvastatin on retrieval stage; 5) the effects of sub-effective dose of atorvastatin (1mg/kg) on retrieval of memory were not potentiated by L-arginine. The present study demonstrates that atorvastatin improves both consolidation and retrieval phases of memory. This effect is affected by NO synthase inhibitors and NO precursor, L-arginine, only in memory consolidation phase, but not in retrieval phase. It is concluded that NO might be involved in consolidation of spatial memory improvement by atorvastatin.     

Anxiolytic effects of acute morphine can be modulated by nitric oxide systems

This study was performed to investigate whether nitric oxide (NO) precursor (L-arginine), NO donor (S-nitroso-N-acetylpenicillamine, SNAP) and NO synthase inhibitors [N(G)-nitro-L-arginine-methylester (L-NAME) and N(G)-nitro-L-arginine (L-NOARG)] modulate morphine-induced anxiolytic effects in the plus-maze. L-Arginine (100, 200 and 300 mg kg(-1), i.p.) and SNAP (4, 8 and 10 mg kg(-1), i.p.) reduced the anxiolytic effect of morphine (20 mg kg(-1), s.c.). L-NAME (10, 20 and 40 mg/kg, i.p.) and L-NOARG (10, 15 and 20 mg kg(-1), i.p.) enhanced the anxiolytic effects of morphine (20 mg kg(-1), s.c.). On the other hand, L-arginine and SNAP increased the morphine-induced locomotor activity. L-NAME decreased the morphine-induced locomotor activity, but L-NOARG did not modify the morphine-induced locomotor activity. Therefore, these results suggest that the anxiolytic effects of morphine can be modulated by NO systems.     

Effects of the nitric oxide donor molsidomine on different memory components as assessed in the object-recognition task in the rat

RATIONALE: Nitric oxide (NO) is sought to be a novel intracellular messenger in the central nervous system. Recently, NO involvement in learning and memory processes has been proposed. Compounds that inhibit NO synthase, the key synthesizing enzyme, may block cognition, while NO donors may facilitate it. OBJECTIVES: The present study was designed to further investigate in the rat the effects on distinct memory processes exerted by the NO donor molsidomine. For this aim, the object-recognition task was chosen. This test is based on the differential exploration of a new and familiar object.METHODS. Object recognition was evaluated in a two-trial nonrewarded paradigm. In a first study, the influence of the retention time (the delay between the two trials) on the performance of 3-month-old male rats was assessed. Subsequently, the effects of molsidomine (2 mg/kg and 4 mg/kg), injected i.p., on acquisition, storage, and retrieval of information were evaluated. For the latter experiments, the delay condition at which recognition memory was extinguished in the normal rat was used (24 h). RESULTS: Under our experimental conditions, object recognition was extinguished in the rat when an intertrial interval (ITI) of 24 h was utilized. Using this ITI, molsidomine at 4 mg/kg but not at 2 mg/kg improved the animal's performance in the object-recognition task, suggesting that molsidomine affected acquisition, storage, and retrieval of information. CONCLUSIONS: These results indicate that the NO donor molsidomine may modulate different aspects of memory.     

Nitric oxide modulates state dependency induced by lithium in an inhibitory avoidance task in mice

The effect of intracerebroventricular (i.c.v.) injections of L-arginine, a nitric oxide (NO) precursor and L-NAME, an inhibitor of NO synthase, on retrieval of state-dependent memory induced by LiCl (lithium) was investigated. A one-trial step-down inhibitory avoidance task was used for memory assessment in adult male NMRI mice. Intraperitoneal administration of lithium (10 mg/kg), immediately after training, impaired memory on the test day. Pretest administration of different doses of lithium (5, 10 and 20 mg/kg) reversed the impairment of memory caused by posttraining lithium (10 mg/kg). In addition, pretest administration of L-arginine (0.001, 0.01 and 0.1 microg/mouse, i.c.v.) or L-NAME (0.001, 0.01 and 0.1 microg/mouse, i.c.v.) also reversed amnesia induced by posttraining lithium. Furthermore, pretest coadministration with lithium of a dose of L-arginine (0.0001 microg/mouse, i.c.v.) or L-NAME (0.0001 microg/mouse, i.c.v.) that had no effects when administered alone, increased the effect of lithium on retrieval of inhibitory avoidance memory. The results suggest that NO may have a modulatory role on state-dependent retrieval of inhibitory avoidance memory induced by lithium.     

Dual effect of nitric oxide in articular inflammatory pain in zymosan-induced arthritis in rats

The contribution of nitric oxide (NO) to articular pain in arthritis induced by zymosan (1 mg, intra articular) in rats was assessed by measuring articular incapacitation (AI). Systemic treatment with the non-selective NO synthase (NOS) inhibitor L-NAME (10 - 100 mg kg(-1) i.p.) or with the selective iNOS inhibitors aminoguanidine (AG; 10 - 100 mg kg(-1) i.p.) or 1400W (0.5 - 1 mg kg(-1) s.c.) inhibited the AI induced by injection of zymosan 30 min later. Local (intra articular) treatment with the NOS inhibitors (L-NAME or AG, 0.1 - 1 micromol; 1400W, 0.01 (micromol) 30 min before zymosan also inhibited the AI. Systemic or local treatment with the NOS inhibitors (L-NAME; AG, 100 mg kg(-1) i.p. or 0.1 micromol joint(-1); 1400W, 1 mg kg(-1) s.c. or 0.01 micromol joint(-1)), 2 h after zymosan did not affect the subsequent AI. Local treatment with the NO donors SNP or SIN-1, 2 h after zymosan did inhibit AI. L-NAME and AG, given i.p. inhibited nitrite but not prostaglandin E(2) (PGE(2)) levels in the joints. L-NAME (100 mg kg(-1)) but not AG (100 mg kg(-1)) increased mean arterial blood pressure. Neither L-NAME, AG nor the NO donor SIN-1 altered articular oedema induced by zymosan. In conclusion, inhibitors of iNOS decrease pain in zymosan arthritis only when given before the zymosan. This was not due to inhibition of articular PGE(2) release or oedema. NO donors also promoted antinociception in zymosan arthritis without affecting oedema.     

The effects of nitric oxide on the acquisition and expression of nicotine-induced conditioned place preference in mice

In the present study, the possible role of nitric oxide on the conditioned place preference (CPP) induced by nicotine in mice was investigated. Intraperitoneal (i.p.) injections of nicotine (1 mg/kg) and the nitric oxide (NO) precursor, L-arginine (200 and 500 mg/kg), produced significant place preference. However, injection of mecamylamine (0.05 and 0.1 mg/kg; i.p.) or the NO synthase (NOS) inhibitor, L-Nitro-amino-methyl-ester, L-NAME (5-20 mg/kg; i.p.), had no effect. Ineffective doses of nicotine in combination with ineffective doses of L-arginine produced significant place preference. Administration of L-arginine (50, 100 and 150 mg/kg; i.p.) on the test day reduced the expression of nicotine-induced place preference. Nicotine injection (0.25, 0.5 and 0.75 mg/kg) on the test day reduced the expression of place preference induced by L-arginine, while both mecamylamine (0.05 and 0.1 mg/kg) and L-NAME (5, 10 and 20 mg/kg) inhibited the acquisition of place preference induced by nicotine (1 mg/kg) and L-arginine (200 mg/kg). Moreover, neither of the antagonists reduced the expression of nicotine- or L-arginine-induced place preference. It is suggested that nitric oxide may play an important role in nicotine-induced place preference.     

Characteristics of learning and memory impairment induced by delta9-tetrahydrocannabinol in rats

We investigated the characteristics of delta9-tetrahydrocannabinol (THC)-induced impairment of learning and memory using an 8-arm radial maze task, a water maze, a visual discrimination task with 2 figures and a passive avoidance test in rats. THC (6 mg/kg, i.p.) impaired spatial memory in the standard task of the 8-arm radial maze. THC (4-6 mg/kg, i.p.) selectively impaired working memory in a reference and working memory task of the 8-arm radial maze. Even at a dose of 10 mg/kg, THC did not impair spatial memory in the water maze. In addition, THC at a dose of 6 mg/kg, which had inhibitory effects in the 8-arm radial maze, did not affect performance in the visual discrimination task. These results indicate that at low doses (2-6 mg/kg), THC may not produce visual function abnormalities. THC impaired retrieval (6 mg/kg, i.p.) as well as acquisition (10 mg/kg, i.p.) in the passive avoidance test. The consolidation process was also impaired by i.c.v. injection (100 microg), but not i.p. injection (6-10 mg/kg) of THC. These results suggest that THC-induced impairment of spatial memory is based on the selective impairment of working memory through its effects on acquisition and retrieval processes.     

BGC20-761, a novel tryptamine analog, enhances memory consolidation and reverses scopolamine-induced memory deficit in social and visuospatial memory tasks through a 5-HT6 receptor-mediated mechanism

Inhibition of 5-HT(6) receptors has been shown to improve memory consolidation, thus we tested whether a novel tryptamine analog with high affinity for 5-HT(6) receptors, BGC20-761 (5-methoxy-2-phenyl-N,N-dimethyltryptamine, PMDT), can enhance long-term memory. BGC20-761 (10 mg/kg i.p.) alone had no effect on social recognition in young rats, however, at doses of 5 mg/kg and 10 mg/kg i.p, BGC20-761 dose-dependently reversed a deficit of social recognition induced by scopolamine (0.4 mg/kg i.p.), an anticholinergic drug that impairs memory. BGC20-761 (10 mg/kg i.p.), scopolamine (0.2 mg/kg i.p.) or BGC20-761 + scopolamine had no effects on novel object discrimination in young rats (2 months). In mature rats (6 months), recognition of the novel object was improved following administration of BGC20-761. Scopolamine had no effect in object recognition. However, the addition of scopolamine disrupted the memory-enhancing effect of BGC20-761. Based on the high affinity of BGC20-761 for 5-HT(6) receptors, these cognitive enhancing effects are most likely mediated by 5-HT(6) receptor inhibition. The difference in effects of BGC20-761 in young vs. mature rats may reflect the status of memory consolidation in these different age ranges.     

Time-dependent involvement of cAMP and cGMP in consolidation of object memory: studies using selective phosphodiesterase type 2, 4 and 5 inhibitors

The present study investigated the time-dependent memory enhancing properties of three selective phosphodiesterase inhibitors (PDE-I) vardenafil (PDE5-I), rolipram (PDE4-I) and BAY 60-7550 (PDE2-I) in the object recognition task. In particular, the time-dependent involvement of cAMP and cGMP in memory consolidation was assessed by altering the time points of drug administration. Vardenafil (1 mg/kg, p.o.), rolipram (0.03 mg/kg, i.p.), and BAY 60-7550 (3 mg/kg, p.o.) were tested in rats with a 24 h delay between the learning and the test trial. The PDE-Is were administered at different time points, i.e. directly after, 1 h, 3 h and 6 h after the first trial. Using a 24 h interval, vardenafil only showed an effect on object memory when injected directly after trial 1, rolipram only showed an improvement when injected 3 h after trial 1 and BAY 60-7550 improved memory when injected either directly after or 3 h after trial 1. No treatment effects were found when the compounds were administered 1 h or 6 h after the first trial. Our results extend our previous data that different types of PDE-Is affect different stages of memory consolidation. Moreover, the present study provides further support that selective PDE-Is can influence memory consolidation in a time-dependent manner, assumingly by elevating central cAMP and cGMP levels.     

The timing of endothelin and nitric oxide inhibition affects survival in a mice model of septic shock

The effect of endothelin and nitric oxide (NO) inhibition on survival from septic shock was investigated in male Swiss albino mice (20-40 g), with particular emphasis on the timing of the administration of their blockers after Escherichia coli endotoxin (lipopolysaccharide, O55:B5, 60 mg kg(-1), i.p.) challenge. Mice were injected with the endothelin receptor antagonist bosentan (30 mg kg(-1), i.p., either 2 or 12 h after endotoxin) alone or in addition to the NO synthase blockers L-canavanine (100 mg kg(-1), i.p.), N(G)-nitro-L-arginine methyl ester (L-NAME, 3 mg kg(-1), i.p.) or aminoguanidine (15 mg kg(-1), i.p.), which were also given twice at 2 and 6 h after endotoxin. Control animals received saline, and survival rates in each group (n=10) were recorded over 24 h at 6-h intervals. At 24 h, the survival rate was 10% in controls, but 30% (n.s.) and 70% (P<0.05) in animals that received only bosentan at 2 and 12 h, respectively, indicating a relatively late involvement of endothelin in comparison to NO. In contrast, these figures were 70% (P<0.05) and 80% (P<0.05) at 12 h for L-NAME and L-canavanine, respectively, and 10% (n.s.) at 24 h, implying a relatively early involvement of NO compared to endothelin. Interestingly, survival in the aminoguanidine group (75% at 24 h, P<0.05 vs. controls) was markedly higher than that in the L-NAME and L-canavanine groups, an effect that was attributed to mechanisms other than NO inhibition. Survival was better (60%, P<0.05 vs. endotoxin alone) when bosentan was given at 2 h in combination with L-NAME, but the best outcome (90% survival, P<0.05) was observed in animals when bosentan was given at 12 h and L-NAME was injected twice at 2 and 6 h. However, the statistical analysis revealed no significant additional beneficial effect of L-NAME coadministered with bosentan. Therefore, we conclude that NO is involved during the earlier phases of septic shock in comparison to a relatively late involvement of endothelin peptides, and that bosentan alone appears to be beneficial when administered at least 12 h after the endotoxin challenge in our mice model of septic shock.     

Morphine state-dependent learning sensitization and interaction with nitric oxide

In the present study, the effects of nitric oxide (NO) precursor L-arginine and L-NAME, a potent inhibitor of NO synthase (NOS), on the expression of sensitization of morphine were investigated. Pre-training administration of morphine (5 mg/kg) impaired memory retrieval compared to pre-training saline-treated animals. Amnesia due to pre-training morphine (5 mg/kg) was restored by pre-test morphine (5 mg/kg).The retrieval impairment was also inhibited in mice which had received once-daily injections of morphine (20 and 30 mg/kg, s.c.) for 3 days, followed by 5 days of no drug treatment before training (in order to induce morphine sensitization). Administration of L-arginine (60 mg/kg/day - 3 days) or L-NAME (20 mg/kg/day - 3 days) before training did not alter morphine state dependency. During acquisition of sensitization, administration of L-arginine (60 mg/kg) 20 min before morphine (10 mg/kg/day, for 3 days) increased, while injection of L-NAME (20 mg/kg) 20 min before morphine (30 mg/kg/day, for 3 days) decreased morphine state dependency. It is concluded that NO is involved in the morphine-induced sensitization.     

Nitric oxide synthase mediates delta opioid receptor-induced hypothermia in rats

The role of nitric oxide (NO) production in delta opioid receptor-induced hypothermia has not been reported. The present study investigated the effect of nitric oxide synthase (NOS) inhibitors on the hypothermic effect of (+)-4-[(aR)-a-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC-80), a nonpeptide delta opioid agonist. SNC-80 (35 mg/kg, i.p.) administered to rats caused a significant hypothermia. N-nitro-L-arginine methyl ester (L-NAME) (10, 25 and 50 mg/kg, i.p.), a NOS inhibitor, and 7-nitroindazole (7-NI) (5 and 10 mg/kg, i.p.), a neuronal NOS inhibitor, were ineffective. For combined administration, L-NAME (50 mg/kg, i.p.) or 7-NI (10 mg/kg, i.p.) attenuated SNC-80-evoked hypothermia. To determine the involvement of central NOS, L-NAME (0.25, 0.5 and 1 mg/rat) was administered i.c.v. 30 min prior to SNC-80 (35 mg/kg, i.p.). Experiments revealed that L-NAME (1 mg/rat, i.c.v.) attenuated SNC-80-induced hypothermia. The present data demonstrate that central NO production is necessary for delta opioid receptor-induced hypothermia.     

5-HT6 receptor antagonists reverse delay-dependent deficits in novel object discrimination by enhancing consolidation--an effect sensitive to NMDA receptor antagonism

5-HT(6) receptors are expressed in brain regions associated with learning and memory, and blockade of their function increases central cholinergic and glutamatergic neurotransmission and enhances cognitive processes. This study examined the effects of acute systemic administration of two selective 5-HT(6) receptor antagonists Ro 04-6790 and SB-271046 (10 mg kg(-1) i.p.) on acquisition, consolidation, and retrieval in the novel object discrimination (NOD) task, a two-trial test of recognition memory in which rats exposed to two identical objects during a familiarisation trial can discriminate a novel from a familiar object during the subsequent choice trial, following inter-trial delays of up to 3 h. 5-HT(6) receptor antagonist administration 20 min prior to or immediately after the familiarisation trial, but not 20 min prior to the choice trial reversed the deficit in object discrimination produced by a 4 h inter-trial interval. The nootropic effects of the 5-HT(6) receptor antagonists in this task thus appear to involve enhanced consolidation. Pre-treatment with the non-competitive NMDA receptor antagonist MK-801 (0.05 mg kg(-1) i.p.) prevented the effect of Ro 04-6790 on delay-induced deficits in object discrimination. This suggests that the 5-HT(6) receptor antagonist-induced enhancement of consolidation involves increased central glutamatergic neurotransmission.     

Beneficial effects of galantamine on performance in the object recognition task in Swiss mice: deficits induced by scopolamine and by prolonging the retention interval

Episodic memory has been found to be impaired in several neuropsychiatric disorders. The object recognition task (ORT), introduced by Ennaceur and Delacour [Ennaceur A., Delacour J. A new one-trial test for neurobiological studies of memory in rats: 1. Behavioral data. Behav Brain Res 1988; 31: 47-59.], is a method to measure a specific form of episodic memory in rats and mice. It is based on the spontaneous behavior of rodents and can be considered as a retention test completely free of reference memory components. Therefore, the ORT has been increasingly used as an experimental tool in assessing drug effects on memory and investigating the neural mechanisms underlying learning and memory. In the present study, the main goal was to evaluate the effects of galantamine in Swiss mice in the ORT on scopolamine-induced deficits and with different retention intervals. Mice had a good object recognition memory at the 15 min retention intertrial interval (ITI). Object discrimination was absent at the longer intervals (1 h, 4 h and 24 h). Galantamine (10 mg/kg, administered s.c., 30 min prior to acquisition) partially reversed effects of scopolamine (0.63 mg/kg, administered s.c., 30 min prior to acquisition) and normalized performance to control levels. A lower dose of galantamine (0.63 mg/kg) was also investigated when two different retention intervals (15 min and 1 h) were used. Galantamine (0.63 mg/kg) had no adverse effects. Solvent-treated mice in the 1 h ITI condition did not discriminate between the novel and the familiar object (discrimination index was equal to zero), while galantamine (0.63 mg/kg)-treated mice attained a good object recognition memory performance. In conclusion, galantamine was shown to possess memory-enhancing effects in two conditions that reduced object discrimination: scopolamine-induced deficits and when a longer retention interval was used.     

Effects of haloperidol, sulpiride and SCH 23390 on passive avoidance learning in mice

The main purpose of the present study was to examine the effect of dopamine blockers on memory processes by means of a one-trial passive avoidance (PA) task with ddY mice. Haloperidol (0.025-0.4 mg/kg i.p.) did not affect the PA response when it was given before the training or retention test. Sulpiride (10-80 mg/kg i.p.) had different effects, depending on the doses employed: A lower dose (20 mg/kg) of sulpiride, which is thought to block presynaptic receptors, impaired the PA response but higher doses (40 and 80 mg/kg i.p.) did not affect it when sulpiride was given before the training or retention test. SCH 23390 (0.025-0.1 mg/kg i.p.) impaired the PA response only when it was given before the training. These results suggest that blocking of postsynaptic D-2 receptors does not impair memory processes but blocking of presynaptic D-2 receptors impairs both acquisition and retrieval stages of memory processes following an increase in dopamine release. The involvement of D-1 receptors in memory processes involved in the PA response may be essentially different from that of D-2 receptors, since the blocking of D1 receptors impaired only memory acquisition.