dizocilpine-maleate and Amnesia

Topics: Alzheimer Disease; Amnesia; Animals; Cognition; Dizocilpine Maleate; Glycogen Synthase Kinase 3 beta; Histamine H3 Antagonists; Mice; Mice, Inbred C57BL; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases

Memory recovery in amnestic animals is one of the most poorly studied processes. In this paper, we examine the role of protein synthesis and a reminder in the mechanisms of amnesia and memory recovery in grape snails trained to conditioned food aversion. Amnesia was induced by the impairment of memory reconsolidation using NMDA (N-methyl d-aspartate) glutamate receptor antagonists. In an early stage of amnesia (day 3), injections of protein synthesis inhibitors into animals combined with a reminder by a conditioned stimulus (CS) led to the recovery of aversive reactions to its presentation. Two types of changes in reactions to CS were revealed. In most animals, a persistent recovery of memory retrieval was found that lasted for at least 10 days. In other snails, aversive responses to CS persisted for 24 h. Isolated injections of inhibitors, injections of inhibitors and a reminder by the learning environment (without presenting a CS), usage of a differentiating stimulus instead of a CS, or inhibitor injections after the reminder did not affect the development of amnesia. The administration of protein synthesis inhibitors and a reminder in the late period after amnesia induction (10 days) did not affect its development or caused a short-term memory recovery. We suggest that amnesia is an active process that develops over time. The reminder induces the reactivation of the amnesia process dependent on protein synthesis, while the administration of protein synthesis inhibitors leads to the impairment of amnesia reactivation and recovery of the state formed before amnesia induction (i.e., recovery of conditioned food aversion memory).

Topics: Amnesia; Animals; Avoidance Learning; Conditioning, Operant; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Helix, Snails; Memory Consolidation; Mental Recall; Protein Synthesis Inhibitors; Valine

Differences in cytoarchitectural organization and connectivity distinguishes granular (or area 29, A29) and dysgranular (or area 30, A30) subdivisions of the retrosplenial cortex (RSC). Although increasing evidence supports the participation of RSC in contextual fear learning and memory, the contribution of each RSC subdivision remains unknown. Here we used orchiectomized rats and intraperitoneal (i.p.) injections of saline (control) or 5 mg/kg MK801, to trigger selective degeneration of pyramidal neurons in layers IV-Va of A29 (A29

Topics: Amnesia; Animals; Dizocilpine Maleate; Fear; Hippocampus; Male; Mental Recall; Motor Activity; Neurons; Proto-Oncogene Proteins c-fos; Rats

We studied the involvement of NMDA glutamate receptors in the mechanisms of anterograde amnesia. It was found that repeated training of amnestic animals treated with D-cycloserine, a potent agonist of the glycine site of NMDA receptors, did not lead to consolidation of long-term memory, while expression of short-term memory was more pronounced in comparison with control animals that received saline before repeated training. It was shown that D-cycloserine in amnestic snails did not affect the food reactions caused by the presentation of a conditioned stimulus during the reminder (without combination with the unconditioned stimulus). It is assumed that NMDA glutamate receptors in amnestic animals are involved in the neural plasticity mechanisms that underlie short-term memory, but their activation does not influence the anterograde amnesia processes and does not lead to the formation or recovery of long-term memory.

Topics: Amnesia; Amnesia, Anterograde; Animals; Avoidance Learning; Conditioning, Classical; Cycloserine; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Glutamic Acid; Glycine; Helix, Snails; Memory; Memory, Long-Term; Memory, Short-Term; Models, Animal; N-Methylaspartate; Neuronal Plasticity; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate; Reproducibility of Results; Synapses

We studied the involvement of protein kinase Mζ (PKMζ) in the mechanisms of amnesia development within 10 days after disruption of conditioned food aversion memory with ZIP (a PKMζ inhibitor). Repeated training performed in 3 days after amnesia induction with ZIP, led to the formation of conditioned food aversion memory, but the number of combined presentations of food and reinforcer stimuli was lower than during the initial training. Repeated training performed in 10 days after amnesia induction also led to memory formation, but the number of combined presentations of the stimuli was similar to that during the initial training. It was hypothesized that at the early stages of ZIP-induced amnesia, residual memory trace can be restored and amplified during repeated training, which led to memory expression at the behavioral level. At the late stages of amnesia, this memory trace was completely erased and repeated training led to the formation of a new memory. Thus, PKMζ inhibition results in the relatively fast impairment of memory retrieval and induces long-term process of memory erasing.

Topics: Amnesia; Animals; Avoidance Learning; Cell-Penetrating Peptides; Conditioning, Classical; Conditioning, Psychological; Dizocilpine Maleate; Feeding Behavior; Helix, Snails; Lipopeptides; Memory Consolidation; Memory, Long-Term; Protein Kinase C; Protein Kinase Inhibitors; Time Factors

Elucidation of amnesia mechanisms is one of the central problems in neuroscience with immense practical application. Previously, we found that conditioned food presentation combined with injection of a neurotransmitter receptor antagonist or protein synthesis inhibitor led to amnesia induction. In the present study, we investigated the time course and features of two amnesias: induced by impairment of memory reconsolidation using an NMDA glutamate receptor antagonist (MK-801) and a serotonin receptor antagonist (methiothepin, MET) on snails trained with food aversion conditioning. During the early period of amnesia (<10th day), the unpaired presentation of conditioned stimuli (CS) or unconditioned stimuli (US) in the same training context did not have an effect on both types of amnesia. Retraining an on 1st or 3rd day of amnesia induction facilitated memory formation, i.e. the number of CS + US pairings was lower than at initial training. On the 10th or 30th day after the MET/reminder, the number of CS + US pairings did not change between initial training and retraining. Retraining on the 10th or 30th day following the MK-801/reminder in the same or a new context of learning resulted in short, but not long-term, memory, and the number of CS + US pairings was higher than at the initial training. This type of amnesia was specific to the CS we used at initial training, since long-term memory for another kind of CS could be formed in the same snails. The attained results suggest that disruption of memory reconsolidation using antagonists of serotonin or NMDA glutamate receptors induced amnesias with different abilities to form long-term memory during the late period of development.

Topics: Amnesia; Animals; Avoidance Learning; Conditioning, Classical; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Feeding Behavior; Helix, Snails; Memory; Methiothepin; Receptors, N-Methyl-D-Aspartate; Serotonin Antagonists; Time Factors

Tramadol, an atypical μ-opioid receptor agonist, as a psychoactive drug, is frequently abused by human beings. Understanding the neurobiological mechanisms of drug-associated learning and memory formation may help prevent drug addiction and relapse. Previous study revealed that dorsal hippocampus (CA1) plays a crucial role in the retrieval of tramadol-associated memory and that its role depends on the expression of CA1 N-methyl-D-aspartate (NMDA) receptors (Jafari-Sabet et al. Can J Physiol Pharmacol 96:45-50, 2018).. To clarify the exact mechanisms involved, the activation of CA1 nitric oxide (NO) signaling pathway by L-arginine (a nitric oxide precursor) on the interaction between tramadol and MK-801 in memory retrieval was examined. The dorsal hippocampal CA1 regions of adult male NMRI mice were bilaterally cannulated and a single-trial step-down inhibitory avoidance apparatus was used for the assessment of memory retrieval.. Post-training and/or pre-test microinjection of tramadol (0.5 and 1 μg/mouse) and/or a non-competitive NMDA receptor antagonist, MK-801 (0.25 and 0.5 μg/mouse), induced amnesia which were reversed when the same doses of the drugs were administered 24 h later in a pre-test session, suggesting tramadol state-dependent learning (SDL) and MK-801 SDL. The amnesia induced by post-training microinjection of tramadol (1 μg/mouse) was reversed by pre-test microinjection of MK-801 (0.25 and 0.5 μg/mouse). Pre-test microinjection of MK-801 (0.125 and 0.25 μg/mouse) with an ineffective dose of tramadol (0.25 μg/mouse) potentiated tramadol SDL. The amnesia induced by post-training microinjection of MK-801 (0.5 μg/mouse) was reversed by pre-test microinjection of tramadol (0.5 and 1 μg/mouse). Pre-test microinjection of tramadol (0.25 and 0.5 μg/mouse) with an ineffective dose of MK-801 (0.125 μg/mouse) potentiated MK-801 SDL. Pre-test microinjection of ineffective doses of L-arginine (0.125, 025, and 0.5 μg/mouse) improved amnesia induced by the co-administration of tramadol and MK-801. Pre-test microinjection of L-arginine (0.125, 025, and 0.5 μg/mouse) could not reverse amnesia induced by post-training microinjection of tramadol while same doses of L-arginine improved MK-801 response on tramadol SDL.. The results strongly propose that activation of CA1 NO signaling pathway has a pivotal role in cross SDL among tramadol and MK-801.

Topics: Amnesia; Analgesics, Opioid; Animals; Arginine; CA1 Region, Hippocampal; Conditioning, Classical; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hippocampus; Learning; Male; Memory; Mice; Microinjections; Nitric Oxide; Receptors, N-Methyl-D-Aspartate; Substance-Related Disorders; Tramadol

AC-3933, a novel benzodiazepine receptor partial inverse agonist, is a drug candidate for cognitive disorders including Alzheimer's disease. We have previously reported that AC-3933 enhances acetylcholine release in the rat hippocampus and ameliorates scopolamine-induced memory impairment and age-related cognitive decline in both rats and mice. In this study, we further evaluated the procognitive effect of AC-3933 on memory impairment induced by MK-801, an N-methyl-d-aspartate receptor antagonist, in mice. Unlike the acetylcholinesterase inhibitor donepezil and the benzodiazepine receptor inverse agonist FG-7142, oral administration of AC-3933 significantly ameliorated MK-801-induced memory impairment in the Y-maze test and in the object location test. Interestingly, the procognitive effects of AC-3933 on MK-801-induced memory impairment were not affected by the benzodiazepine receptor antagonist flumazenil, although this was not the case for the beneficial effects of AC-3933 on scopolamine-induced memory deficit. Moreover, the onset of AC-3933 ameliorating effect on scopolamine- or MK-801-induced memory impairment was different in the Y-maze test. Taken together, these results indicate that AC-3933 improves memory deficits caused by both cholinergic and glutamatergic hypofunction and suggest that the ameliorating effect of AC-3933 on MK-801-induced memory impairment is mediated by a mechanism other than inverse activation of the benzodiazepine receptor.

Topics: Amnesia; Animals; Disease Models, Animal; Dizocilpine Maleate; Male; Maze Learning; Memory; Mice; Naphthyridines; Oxadiazoles; Receptors, GABA-A

The dynamics of amnesia development under conditions of memory reconsolidation disruption by serotonin receptor antagonist methiothepin or NMDA glutamate receptor antagonist MK-801 was studied in snails trained in conventional food aversion. In 2 days after training, injection of methiothepin or MK-801 before reminder induced amnesia development. During repeated training in 3 days after amnesia induction, the skill was formed more rapidly than during the initial training. During repeated training in 10 days after administration of methiothepin and reminder, the dynamics of habit formation was similar to that during initial learning. At the same time, repeated training in 10 days after MK-801 administration and reminder did not result in long-term memory formation. Disruption of reconsolidation of conditioned food aversion memory by antagonists of serotonin or NMDA glutamate receptors led to the development of different types of amnesia that had similar strengthening gradient at the early stages, but differed by the possibility of memory formation during re-training at the late stage.

Topics: Amnesia; Animals; Avoidance Learning; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Helix, Snails; Memory, Long-Term; Methiothepin; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Serotonin Antagonists

Both the acetylcholine esterase (AChE) and the histamine H3 receptor (H3R) are involved in the metabolism and modulation of acetylcholine release and numerous other centrally acting neurotransmitters. Hence, dual-active AChE inhibitors (AChEIs) and H3R antagonists hold potential to treat cognitive disorders like Alzheimer's disease (AD). The novel dual-acting AChEI and H3R antagonist 7-(3-(piperidin-1-yl)propoxy)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one (UW-MD-72) shows excellent selectivity profiles over the AChE's isoenzyme butyrylcholinesterase (BChE) as well as high and balanced in-vitro affinities at both AChE and hH3R with IC50 of 5.4μM on hAChE and hH3R antagonism with Ki of 2.54μM, respectively. In the current study, the effects of UW-MD-72 (1.25, 2.5, and 5mg/kg, i.p.) on memory deficits induced by the muscarinic cholinergic antagonist scopolamine (SCO) and the non-competitive N-methyl-d-aspartate (NMDA) antagonist dizocilpine (DIZ) were investigated in a step-through type passive avoidance paradigm in adult male rats applying donepezil (DOZ) and pitolisant (PIT) as reference drugs. The results observed show that SCO (2mg/kg, i.p.) and DIZ (0.1mg/kg, i.p.) significantly impaired learning and memory in rats. However, acute systemic administration of UW-MD-72 significantly ameliorated the SCO- and DIZ-induced amnesic effects. Furthermore, the ameliorating activity of UW-MD-72 (1.25mg/kg, i.p.) in DIZ-induced amnesia was partly reversed when rats were pretreated with the centrally-acting H2R antagonist zolantidine (ZOL, 10mg/kg, i.p.), but not with the CNS penetrant H1R antagonist pyrilamine (PYR, 10mg/kg, i.p.). Moreover, ameliorative effect of UW-MD-72 (1.25mg/kg, i.p.) in DIZ-induced amnesia was strongly reversed when rats were pretreated with a combination of ZOL (10mg/kg, i.p.) and SCO (1.0mg/kg, i.p.), indicating that these memory enhancing effects were, in addition to other neural circuits, observed through histaminergic H2R as well as muscarinic cholinergic neurotransmission. These results demonstrate the ameliorative effects of UW-MD-72 in two in-vivo memory models and provide evidence for the potential of dual-acting AChEI and H3R antagonists to treat cognitive disorders.

Topics: Amnesia; Analysis of Variance; Animals; Avoidance Learning; Cholinesterase Inhibitors; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Histamine H3 Antagonists; Male; Pyrroles; Pyrrolidines; Quinazolines; Quinazolinones; Rats; Rats, Wistar; Scopolamine

In this study, the effects of 5-HT4 receptors of the CA1 on MK801-induced amnesia and hyperlocomotion were examined. One-trial step-down method was used to assess memory retention and then, the hole-board method to assess exploratory behaviors. The results showed that post-training intra-CA1 administration of RS67333 (62.5 and 625 ng/mouse) and RS23597 (1 and 10 ng/mouse) decreased memory consolidation, but it did not alter head-dip counts, head-dip latency and locomotor activity. Similarly, MK801 (0.5 and 1 μg/mouse) decreased memory consolidation, but had no effect on head-dip counts and head-dip latency. Interestingly, it increased locomotor activity. The results also showed that post-training intra-CA1 injection of a sub-threshold dose of RS67333 (6.25 ng/mouse) or RS23597 (0.1 ng/mouse) could heighten MK801 induced amnesia and decrease locomotor activity, but it did not alter head-dip counts and head-dip latency. In conclusion, our findings suggest that the CA1 5-HT4 receptors are involved in MK801-induced amnesia and hyperlocomotion.

Topics: Amnesia; Aniline Compounds; Animals; CA1 Region, Hippocampal; Dizocilpine Maleate; Drug Partial Agonism; Exploratory Behavior; Male; Memory; Mice; Motor Activity; para-Aminobenzoates; Piperidines; Receptors, N-Methyl-D-Aspartate; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Serotonin 5-HT4 Receptor Antagonists

Non-competitive N-methyl-d-aspartate receptor (NMDA-R) antagonists impair rodent cognition. Specifically, MK-801, the most potent NMDA-R antagonist, induces an amnesic effect on the modified elevated plus maze (mEPM) learning test in rodents, which reflects spatial long-term memory. However, alterations in anxiety-related behaviors could overlap this amnesic effect. Accumulated evidence supports the role of brain-derived neurotrophic factor (BDNF) in learning and memory processes and deficits in hippocampal BDNF function, which underlie cognitive impairments, have been extensively reported. Therefore, we investigated if changes in anxiety-related behaviors and hippocampal BDNF levels are related with the amnesic effect induced by MK-801 in the mEPM.Transfer latency (TL) as an index of spatial memory in the mEPM was used. TL1 was evaluated 30 min after saline/MK-801 injection (day 1, acquisition session) while learning/memory performance was measured 24 h later at TL2 (day 2, retention session). Also at TL2, two other experimental groups were added to measure the anxiety-related behaviors using the classic EPM and BDNF protein levels by ELISA. To evaluate if amnesia endures, an additional session was recorded on day 3 (TL3) and BDNF levels were measured.While TL1 was not significantly modified by MK-801, TL2 was increased compared to the control group indicating an amnesic effect. This effect was not mimicked by anxiety-related behaviors and it was associated to a significant attenuation of BDNF levels. During the third post-training day, the cognitive performance of MK-801-treated animals was improved and an increased BDNF protein expression in the hippocampus accompanied this change

Topics: Amnesia; Analysis of Variance; Animals; Anxiety; Brain-Derived Neurotrophic Factor; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Exploratory Behavior; Hippocampus; Male; Maze Learning; Rats; Rats, Wistar; Reaction Time; Time Factors

We studied the role of DNA methylation in the mechanisms of amnesia in edible snails, which was induced by impairment of conditioned food aversion memory reconsolidation with NMDA glutamate receptor antagonist. The effects of DNA methyltransferase inhibitors were shown to depend on the stage of amnesia. At the early stage of amnesia (day 3 after induction), injections of methyltransferase inhibitors in combination with conditioned food stimulus (reminder) were followed by memory recovery. Application of inhibitors in the absence of the reminder was ineffective. Methyltransferase inhibitors were ineffective at the late stage of amnesia (day 10). Our results suggest that the presentation of reminding conditioned stimuli is followed by reactivation of amnesia. Methylation or demethylation of DNA in nerve cells serves as one of the key mechanisms for amnesia.

Topics: Amnesia; Animals; Conditioning, Psychological; Cytidine; Dizocilpine Maleate; DNA Methylation; DNA-Cytosine Methylases; Helix, Snails; Learning; Phthalimides; Receptors, N-Methyl-D-Aspartate; Tryptophan

The specific features of memory reconsolidation in edible snails were studied over 30 days after learning of conditioned food aversion. Injections of a NMDA glutamate receptor antagonist MK-801 or protein synthesis inhibitor cycloheximide in combination with the conditioned food stimulus (reminder) on day 2 after learning were followed by the development of amnesia. Repeated training on day 10 after the induction of amnesia did not result in skill formation. Injections of MK-801 or cycloheximide and reminder by the 10th day after training had no effect on memory retention. Injections of MK-801 or cycloheximide and reminder by the 30th day after training were followed by the development of amnesia. In these experiments, memory was recovered after repeated training. Our results indicate that a complex phase reorganization of memory occurs over 30 days after learning. This process includes memory consolidation over the first days after training, stabilization and resistance to adverse factors after 10 days, and newly acquired ability for reconsolidation by the 30th day after training.

Topics: Amnesia; Animals; Conditioning, Classical; Cycloheximide; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Feeding Behavior; Food; Helix, Snails; Learning; Memory, Long-Term; Protein Synthesis Inhibitors; Receptors, N-Methyl-D-Aspartate; Reinforcement, Psychology; Time Factors

Accumulating evidence indicates that the brain-gut peptide ghrelin which is expressed in hippocampus improves memory and learning processes. The MK-801, a noncompetitive NMDA receptor antagonist, has also shown amnesic properties in animal model. The current study was to find out whether intracerebroventricular administration of ghrelin can prevent amnesia induced by MK-801 in rats. A week after the surgery, during which cannuals were implanted in the lateral ventricular, the animals were trained and tested in a step-through type passive avoidance task. Memory retrieval was measured by step-through latency (STL) and total time in dark compartments (TDC). In the first series of experiments, we established a dose-response relationship for ghrelin on the passive avoidance paradigm. In the second set of experiments, animals were divided to two groups. In the first group, MK-801 (0.075, 0.15 and 0.3mg/kg) was injected intraperitoneally (i.p.) immediately after the acquisition session and in the second group MK-801 (same doses) was injected (i.p.) 30 min before the retention session. Analysis of data showed that in both groups, MK-801 impaired learning and memory. In the third set of experiments, administration of ghrelin (200 ng/rat) right after the acquisition session (i.e. before MK-801 injection) improved the MK-801 induced memory impairment, but administration of ghrelin before retrieval session did not affect the MK-801 induced memory impairment. These results show an interaction between ghrelin and glutamatergic system. A novel finding in this study is that ghrelin can prevent amnesia produced by NMDA antagonist in rats when injected in post-training phase.

Topics: Amnesia; Animals; Avoidance Learning; Dizocilpine Maleate; Dose-Response Relationship, Drug; Ghrelin; Injections, Intraventricular; Male; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Retention, Psychology

Involvement of neurotransmitter receptors and translation and transcription processes in reconsolidation of conditioned food aversion memory was investigated in experiments on edible snails. Injections of neurotransmitter receptor antagonists and protein synthesis inhibitors before the reminder session were found to induce amnesia that was characterized by the possibility of memory recovery in repeated training and under the effect of mnemotropic agent D-cycloserine (early stage of amnesia) or by resistance to the mentioned actions (late stage). It has been shown that amnesia induction by memory reconsolidation impairment by neurotransmitter receptor antagonists depends on synthesis of specific proteins and mRNA, similar to the cases of induction of other adaptive brain modifications.

Topics: Amnesia; Analysis of Variance; Animals; Avoidance Learning; Conditioning, Psychological; Cycloserine; Dizocilpine Maleate; Memory, Long-Term; Methiothepin; Protein Synthesis Inhibitors; Serotonin Antagonists; Snails

The effect of MK-801, an antagonist to NMDA-glutamate receptors, on reconsolidation of olfactory discrimination task in rats and taste discrimination in edible snails was examined. Twenty-four hours after conditioning, the animals received a single systemic injection of MK-801 followed by a reminding conditional stimulus. Disturbances in retrieval of the acquired task were observed 10 days after injection followed by a reminding procedure. Repeated conditioning of these animals did not restore the task. Injection of MK-801 without reminding stimulation had no effect on task retention. Thus, disturbances of NMDA-dependent reconsolidation of the associative memory in animals of different taxonomic groups irreversibly eliminated long-term memory.

Topics: Amnesia; Animals; Association; Conditioning, Psychological; Discrimination Learning; Dizocilpine Maleate; Male; Memory, Long-Term; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Smell; Snails; Statistics, Nonparametric; Taste

In this study, we investigated the effects of both N-methyl D-aspartate (NMDA) and MK-801 on WIN55,212-2(WIN)-induced amnesia in rats. Step-through inhibitory avoidance of memory was used to examine the retrieval of memory, 24 h after training. All drugs were injected bilaterally into the dorsal hippocampus (intra-CA1) of rats. Pretraining and posttraining or pretesting administration of the nonselective CB1/CB2 receptor agonist, WIN (0.5 µg/rat), decreased the step-through latency. However, amnesia induced by pretraining or posttraining injections of WIN was reversed by a pretest administration of WIN (0.25 and 0.5 µg/rat). Pretest microinjections of different doses of NMDA (0.1, 0.5, and 1 µg/rat) elicited no response, but NMDA (0.5 and 1 µg/rat) did induce full recovery from amnesia induced by WIN (0.5 µg/rat). The posttraining and pretest injection of a higher dose of the NMDA receptor antagonist, MK801 (MK; 4 µg/rat), caused an impairment in the memory retrieval. However, amnesia induced by posttraining injections of MK (4 µg/rat) was reversed by a pretest administration of MK (4 µg/rat). In addition, pretest administration of different doses of the antagonist (2 and 4 µg/rat) induced full recovery of WIN-induced amnesia, but did not influence memory recovery in the subjects, which had received posttraining (0.5 µg/rat) and pretest WIN (0.25 and 0.5 µg/rat). Pretesting coadministration of ineffective doses of WIN (0.1 µg/rat) with NMDA (0.1 µg/rat), but not with MK (1 µg/rat), restored WIN-induced (0.5 µg/rat) amnesia. It can be concluded that the NMDA receptor mechanism located in the dorsal hippocampus may be involved in WIN-induced amnesia.

Topics: Amnesia; Animals; Avoidance Learning; Behavior, Animal; Benzoxazines; Cannabinoid Receptor Agonists; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Interactions; Hippocampus; Injections, Intraventricular; Male; Maze Learning; Memory; Memory, Short-Term; Morpholines; Naphthalenes; Neuroprotective Agents; Random Allocation; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate

Growing evidence indicates that antagonists of the 5-hydroxytryptamine (serotonin) receptor(6) (5-HT(6)) improve memory and reverse amnesia although the mechanisms involved are poorly understood. Hence, in this paper RT-PCR was used to evaluate changes in mRNA expression of 5-HT(6) receptor in trained and untrained rats treated with the 5-HT(6) receptor antagonist SB-399885 and amnesic drugs scopolamine or dizocilpine. Changes in mRNA expression of 5-HT(6) receptor were investigated at different times in prefrontal cortex, hippocampus and striatum. Data indicated that memory in the Pavlovian/instrumental autoshaping task was a progressive process associated to reduced mRNA expression of 5-HT(6) receptor in the three structures examined. SB-399885 improved long-term memory at 48h, while the muscarinic receptor antagonist scopolamine or the non-competitive NMDA receptor antagonist dizocilpine impaired it at 24h. Autoshaping training and treatment with SB-399885 increased 5-HT(6) receptor mRNA expression in (maximum increase) prefrontal cortex and striatum, 24 or 48h. The scopolamine-induced amnesia suppressed 5-HT(6) receptor mRNA expression while the dizocilpine-induced amnesia did not modify 5-HT(6) receptor mRNA expression. SB-399885 and scopolamine or dizocilpine were able to reestablish memory and 5-HT(6) receptor mRNA expression. These data confirmed previous memory evidence and of more interest is the observation that training, SB-399885 and amnesic drugs modulated 5-HT(6) receptor mRNA expression in prefrontal cortex, hippocampus and striatum. Further investigation in different memory tasks, times and amnesia models together with more complex control groups might provide further clues.

Topics: Amnesia; Animals; Brain; Conditioning, Classical; Corpus Striatum; Dizocilpine Maleate; Hippocampus; Male; Memory; Piperazines; Prefrontal Cortex; Psychotropic Drugs; Random Allocation; Rats; Rats, Wistar; Receptors, Serotonin; RNA, Messenger; Scopolamine; Serotonin Antagonists; Sulfonamides; Time Factors

The NMDA glutamate receptor antagonists (MK-801 or APV) as well as protein synthesis inhibitors (cycloheximide or anisomycine) affect reactivation processes of long-term memory as studied in snail Helix lucorum with food aversion conditioning. It was found that, 24 hours after training, injection of each of the above mentioned substances initiated amnesia with duration more than 3 weeks. Repeated aversion conditioning with the same food (as at initial one) produced no memory restoration. However, amnesia was not observed in snails after simultaneous injection of protein synthesis inhibitor and NMDA glutamate receptor antagonists (MK-801 + cycloheximide or APV + anisomycin) before reminding procedure. In next experiments, cycloheximide was injected 3-9 hours after MK-801/reminding procedure. We have found development of incomplete amnesia in snails with cycloheximide injection 3 or 6 hours after MK-801/reminding procedure and, at repeated aversion conditioning with the same food, memory was quickly restored. Cycloheximide injection 9 hours after MK-801/reminding procedure led to development ofa steady-state amnesia with disruption of aversion conditioning with the same food as at repeated training. We suggest that mechanisms of "MK-801-induced amnesia" (as well as other mechanisms of long-term adaptive processes in the brain) depend on novel protein synthesis and become suppressed after inhibitors of protein synthesis application. "Time window" of amnesia induction process dependence on protein molecules synthesis remains during 6-9 hours after MK-801/reminding procedure.

Topics: Amnesia; Animals; Anisomycin; Cycloheximide; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Helix, Snails; Memory; Protein Biosynthesis; Protein Synthesis Inhibitors; Receptors, N-Methyl-D-Aspartate; Time Factors; Valine

We have previously found two stages of amnesia evoked by disruption of memory reconsolidation with MK-801 (NMDA glutamate receptors antagonists) application in food aversion conditioned snails. Repeated conditioning restored the food aversion at early stage of amnesia development (<10 days), whereas repeated conditioning 10 days after MK-801 application did not restore the food aversion. In present work, amnesia was induced with MK-801/reminding 24 hours after food aversion conditioning, and antiamnestic effects of NMDA receptor glycine site agonist d-cycloserine were studied at early (3rd day) or late (12th day) stages of amnesia development. D-cycloserine injection and reminding restored memory only 3 days after amnesia induction whereas d-cycloserine injection without reminding was ineffective. D-cycloserine injection and reminding as well as repeated learning 12 days after amnesia induction were also ineffective in memory restoration. Thus, for the first time, it is revealed that NMDA receptor agonist d-cycloserine influences the memory restoration processes only at early but not the later stages of amnesia development.

Topics: Amnesia; Animals; Antimetabolites; Cycloserine; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Helix, Snails; Memory; Protein Synthesis Inhibitors; Receptors, N-Methyl-D-Aspartate; Receptors, Serotonin; Serotonin Antagonists

Traditional remedies prepared from Ptychopetalum olacoides (PO) are used throughout the Amazon to alleviate age-related conditions. These formulas are mainly used by elders, and alleged effects may be related to the anticholinesterase properties identified in a standardized ethanol extract of this species [P. olacoides standardized ethanol extract (POEE)].. To further characterize the potential of this extract for developing drugs useful to treat cognitive deficits, the effects of POEE on scopolamine (scop)- and MK801-induced amnesias (acquisition, consolidation, and retrieval) in mice were investigated.. Scop (3.0 mg/kg, ip) significantly impaired memory (all three phases) in the step-down inhibitory avoidance protocol. As expected, MK801 (0.1 mg/kg, ip) was amnesic regarding acquisition and consolidation, but not retrieval. POEE (100 mg/kg, ip) reversed the scop-induced impairment in all three phases of long-term and short memories, whereas only the memory consolidation deficit was reversed with MK801-induced amnesia.. This study complements previously reported promnesic properties of this plant extract and suggests that POEE may be further developed for treating conditions associated with cognitive deficits, especially those linked with cholinergic malfunction.

Topics: Amnesia; Animals; Avoidance Learning; Brazil; Dizocilpine Maleate; Electroshock; Excitatory Amino Acid Antagonists; Injections, Intraperitoneal; Male; Memory; Memory, Short-Term; Mice; Muscarinic Antagonists; Olacaceae; Plant Extracts; Plant Roots; Scopolamine

N-methyl-D-aspartate (NMDA) receptor and nitricoxide syntheses are the emerging target sites for development of novel drug molecules because their modulation affects the long term potentiation (LTP) process. NMDA receptor antagonists and nitric oxide synthase inhibitors induce amnesia in animals and therefore have been employed for evaluation of efficacy of several novel antiamnesic agents.Bacopa monniera Linn (syn. Brahmi) is commonly used in the ancient Indian medical system for improvement of memory deficit.We have earlier described the involvement of GABAergic and cholinergic system to account for the antiamnesic effects of B. monniera on diazepam- and scopolamine-induced amnesia.In extension to our previous study this study was designed to investigate the downstream mechanism of B. monniera by evaluation of its effect on MK-801 (an NMDA receptor antagonist) and N(w)-nitro-L-arginine (L-NNA) (a nitric oxide inhibitor)induced memory deficit. We used a Morris water maze scale and compared the degree of reversal of amnesia induced by the two agents. Male Swiss albino mice were subjected to a Rotarod muscle incoordination test followed by water maze tasks.Our data revealed that L-NNA and MK-801 produced anterograde and retrograde amnesia and B. monniera significantly attenuated the L-NNA-induced anterograde amnesia, partially reversing L-NNA-induced retrograde amnesia. On the other hand, B. monniera neither attenuated the MK-801-induced anterograde amnesia nor improved retrograde amnesia caused by it.

Topics: Amnesia; Amnesia, Anterograde; Amnesia, Retrograde; Analysis of Variance; Animals; Bacopa; Dizocilpine Maleate; Excipients; Male; Maze Learning; Memory; Mice; Motor Activity; Nitroarginine; Phytotherapy; Plant Preparations; Polysorbates

Previously acquired aversive and appetitive memories are not stable and permanent. The reactivation of such memories by re-exposure to training stimuli renders them vulnerable to disruption by amnestic agents such as the noncompetitive N-methyl-D-aspartate receptor antagonist (+)-5-methyl-10,11-dihydro-SH-dibenzo{a,d}cyclohepten-5,10-imine maleate (MK-801). However, relatively little is known about the parameters that influence the reactivation process. Here, we show that the method of stimulus presentation during memory reactivation is of great importance. Male Lister Hooded rats were trained to acquire a lever press response that delivered a sucrose reward paired with a light conditioned stimulus (CS). The CS-sucrose association was then reactivated through re-exposure to the CS, either contingently upon the lever press response, or noncontingently in the absence of instrumental responding. Systemic administration of MK-801 (0.1 mg/kg) at the time of memory reactivation resulted in amnesia, and hence a reduction in subsequent sucrose seeking induced by, and dependent upon, presentation of the CS, only when the memory was reactivated contingently. Therefore, stimuli may have to be presented in the same manner at memory reactivation as during learning in order to render a previously acquired memory vulnerable to disruption. These results have important implications for the potential translational use of glutamatergic treatments in conjunction with targeted memory reactivation.

Topics: Amnesia; Animals; Appetitive Behavior; Conditioning, Operant; Cues; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Male; Memory; Mental Recall; Photic Stimulation; Rats; Receptors, N-Methyl-D-Aspartate; Sucrose

The theory of memory reconsolidation relates to the hypothesized restabilisation process that occurs following the reactivation of a memory through retrieval. Thus the demonstration of reactivation-dependent amnesia for a previously acquired memory is a prerequisite for showing that such a memory undergoes reconsolidation. Here we show that the appetitive Pavlovian representations that underlie Pavlovian approach and Pavlovian-instrumental transfer are destabilized following their retrieval. This reactivation-dependent amnesia demonstrates that the general motivational or incentive properties of appetitive conditioned stimuli, as well as their conditioned reinforcing properties, can be reduced by blocking memory reconsolidation.

Topics: Adrenergic beta-Antagonists; Amnesia; Animals; Appetitive Behavior; Brain; Conditioning, Classical; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Male; Memory; Propranolol; Rats

The cyclic adenosine monophosphate (cAMP) is a second messenger and a central component of intracellular signaling pathways that regulate a wide range of biological functions, including memory. Hence, in this work, firstly the time-course of memory formation was determined in an autoshaping learning task, which had allowed the identification of testing times for increases or decreases in performance. Next, untrained, trained and overtrained groups were compared in cAMP production. Moreover, selective stimulation and antagonism of 5-HT(1A) and 5-HT(7) receptors during memory formation and cAMP production were determined. Finally, since there is scarce information about how pharmacological models of amnesia affect cAMP production, the cholinergic or glutamatergic antagonists, scopolamine and dizocilpine, were tested. The major findings of this work showed that when the time-course was determined inasmuch as training and testing sessions occurred, memory performance was graduate and progressive. Notably, for the fourth to seventh (i.e., 48-120 h following autoshaping training session) testing session performance was significantly higher from the previous ones. When animals received 5-HT(1A) and 5-HT(7) receptor agonists and antagonists or amnesic drugs significant increases or decrements in memory performance were observed at 24 and 48 h. Moreover, when ex vivo cAMP production from trained and overtrained groups were compared to untrained ones, significant differences were observed among groups and brain areas. Trained animals treated with 8-OHDPAT, AS19, 8-OHDPAT plus AS19, WAY100635, SB-269970, scopolamine or dizocilpine were compared to similar untrained groups, and eightfold-reduced cAMP production was evident, showing the importance of cAMP production in the signaling case in mammalian memory formation.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Amnesia; Animals; Behavior, Animal; Cholinergic Antagonists; Cyclic AMP; Dizocilpine Maleate; Enzyme-Linked Immunosorbent Assay; Excitatory Amino Acid Antagonists; Hippocampus; Learning; Male; Memory; Phenols; Piperazines; Pyrazoles; Pyridines; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT1A; Receptors, Serotonin; Scopolamine; Serotonin Antagonists; Serotonin Receptor Agonists; Sulfonamides; Tetrahydronaphthalenes

We studied the effect of activation (N-methyl-D-aspartic acid and D-cycloserine) and blockade (dizocilpine and 7-chlorokynurenic acid) of N-methyl-D-aspartate receptors on the development of amnesia in intact and depressive mice under conditions of conditioned passive avoidance response. Agonists and antagonists of N-methyl-D-aspartate receptors produce a strong antiamnesic effect in mice with behavioral despair. In intact animals, only N-methyl-D-aspartic acid and D-cycloserine improved passive avoidance performance.

Topics: Amnesia; Analysis of Variance; Animals; Avoidance Learning; Behavior, Animal; Cycloserine; Depression; Dizocilpine Maleate; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Kynurenic Acid; Male; Mice; Mice, Inbred C57BL; N-Methylaspartate; Receptors, Amino Acid

Traditionally, the search for memory circuits has been centered on examinations of amnesic and AD patients, cerebral lesions and, neuroimaging. A complementary alternative might be the use of autoradiography with radioligands. Indeed, ex vivo autoradiographic studies offer the advantage to detect functionally active receptors altered by pharmacological tools and memory formation. Hence, herein the 5-HT(6) receptor antagonist SB-399885 and the amnesic drugs scopolamine or dizocilpine were used to manipulate memory consolidation and 5-HT(6) receptors expression was determined by using [(3)H]-SB-258585. Thus, memory consolidation was impaired in scopolamine and dizocilpine treated groups relative to control vehicle but improved it in SB-399885-treated animals. SB-399885 improved memory consolidation seems to be associated with decreased 5-HT(6) receptors expression in 15 out 17 brain areas. Scopolamine or dizocilpine decreased 5-HT(6) receptors expression in nine different brain areas and increased it in CA3 hippocampus or other eight areas, respectively. In brain areas thought to be in charge of procedural memory such basal ganglia (i.e., nucleus accumbens, caudate putamen, and fundus striate) data showed that relative to control animals amnesic groups showed diminished (scopolamine) or augmented (dizocilpine) 5-HT(6) receptor expression. SB-399885 showing improved memory displayed an intermediate expression in these same brain regions. A similar intermediate expression occurs with regard to amygdala, septum, and some cortical areas in charge of explicit memory storage. However, relative to control group amnesic and SB-399885 rats in the hippocampus, region where explicit memory is formed, showed a complex 5-HT(6) receptors expression. In conclusion, these results indicate neural circuits underlying the effects of 5-HT(6) receptor antagonists in autoshaping task and offer some general clues about cognitive processes in general.

Topics: Amnesia; Amygdala; Analysis of Variance; Animals; Autoradiography; Brain; Dizocilpine Maleate; Hippocampus; Male; Memory; Neural Pathways; Piperazines; Rats; Rats, Inbred WF; Receptors, Serotonin; Scopolamine; Septum of Brain; Serotonin Agents; Sulfonamides

Effects of serotonin or glutamate receptors antagonists on reactivation of food aversion conditioning were studied in snail Helix lucorum. Metiotepin (nonselective serotonin receptor antagonist, 0.1 mg/snail) or MK-801 (NMDA glutamate receptor antagonist, 0.005 mg/snail) were injected 24 hours after 3 days of food aversion conditioning, then reminding stimulus (banana, "conditioned" food) was presented and food aversion conditioning was tested. Long-term impairing (more then 2 weeks) of food aversion conditioning was found 3 hours after concurrent reminding and inhibitors injection. Injection of receptor antagonists without reminding stimulus did not influence on food aversion conditioning retrieval. Besides, in snails with amnesia after metiotepin/reminder, facilitation of repeated elaboration aversion conditioning on banana is revealed. The repeated training of snails with amnesia caused by MK-801/reminder did not result in food aversion conditioning. It is was suggested that 5-HT5,6,7 serotonin receptors are involved in mechanisms of memory "trace" extraction of food aversion conditioning, whereas NMDA glutamate receptor - in processes of its storage in snail.

Topics: Amnesia; Animals; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Helix, Snails; Memory; Methiothepin; Receptors, N-Methyl-D-Aspartate; Serotonin Antagonists

The effect of a sulbutiamine chronic treatment on memory was studied in rats with a spatial delayed-non-match-to-sample (DNMTS) task in a radial maze and a two trial object recognition task. After completion of training in the DNMTS task, animals were subjected for 9 weeks to daily injections of either saline or sulbutiamine (12.5 or 25 mg/kg). Sulbutiamine did not modify memory in the DNMTS task but improved it in the object recognition task. Dizocilpine, impaired both acquisition and retention of the DNMTS task in the saline-treated group, but not in the two sulbutiamine-treated groups, suggesting that sulbutiamine may counteract the amnesia induced by a blockade of the N-methyl-D-aspartate glutamate receptors. Taken together, these results are in favor of a beneficial effect of sulbutiamine on working and episodic memory.

Topics: Amnesia; Analysis of Variance; Animals; Behavior, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Maze Learning; Memory, Short-Term; Psychomotor Performance; Rats; Rats, Sprague-Dawley; Reaction Time; Recognition, Psychology; Space Perception; Thiamine; Time Factors

In the literature, there is some evidence indicating that H3 histamine receptor antagonists, in particular thioperamide, can facilitate learning and memory retrieval in laboratory rodents. The present study aimed at verifying whether this also holds for memory consolidation, a phase of memory for which there is scarcity of convincing data on the effects of H3 receptor antagonists given systemically. To that end, memory consolidation was assessed in C57BL/6J mice using the one-trial step-through inhibitory avoidance task, the compounds being injected immediately after training (foot-shock) and performance measured 24 h later. More specifically, the following effects of thioperamide (1.25-20 mg/kg) were dose-dependently analysed: (1) its potential direct effects on memory consolidation; (2) its potential reversing effects on retrograde amnesia induced by the NMDA antagonist dizocilpine (MK-801, 0.5 mg/kg) and (3) its potential reversing effects on the well-known amnesia induced by the muscarinic antagonist scopolamine (0.25 mg/kg). We found that thioperamide exerted a dose-dependent facilitative effect on memory consolidation. Furthermore, the H3 receptor antagonist reversed scopolamine- and especially dizocilpine-induced amnesia. The results strongly support the view that the brain mechanisms of memory consolidation involve a functional interaction between the NMDA and the H3 sites.

Topics: Amnesia; Analysis of Variance; Animals; Avoidance Learning; Dizocilpine Maleate; Dose-Response Relationship, Drug; Histamine Antagonists; Male; Memory; Mice; Mice, Inbred C57BL; Piperidines; Reaction Time; Scopolamine

The study was to investigate the ameliorating effects of three Chinese herbs--Achyranthes bidentata (AB), Ophiopogon japonicus (OJ) and Cnidium monnieri (CM) on scopolamine (SCOP)- and MK-801-induced amnesia by using a passive avoidance task in rats. AB, OJ and CM at 0.1 and 0.3 g/kg prolonged the step-through latency (STL) of the retention trial. In addition, AB, OJ and CM reversed the STL shortened by MK-801, but only AB reversed the STL shortened by SCOP. In conclusion, these Chinese herbs possess cognition-enhancing activities and anti-amnestic effects, but the mechanism of the effect of AB was different from those of OJ and CM.

Topics: Achyranthes; Amnesia; Animals; Avoidance Learning; Cnidium; Dizocilpine Maleate; Male; Muscarinic Antagonists; Ophiopogon; Phytotherapy; Plant Extracts; Plants, Medicinal; Rats; Rats, Sprague-Dawley; Scopolamine

Experiments with invertebrates support the view that intracellular events subserving the consolidation phase of memory are preserved across evolution. Here, we investigate whether such evolutionary persistence extends to reconsolidation mechanisms, which have recently received special attention in vertebrate studies. For this purpose, the memory model of the crab Chasmagnathus is used. A visual danger stimulus (VDS) elicits crab escaping, which declines after a few stimulus presentations. The long-lasting retention of this decrement, called context-signal memory (CSM), is mediated by an association between contextual cues of the training site and the VDS. The present results show amnesia for CSM in crabs re-exposed at 24 hr (day 2) for 5 min to the learning context, 24 hr after training, and injected with one of two amnesic agents, then tested 24 hr later. Agents and timing were either 15 microg of cycloheximide given between 1 hr before and 4 hr after re-exposure or 1 microg/gm (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine given between 1 hr before and 2 hr after re-exposure. The amnesic effects are specific to behavior that occurs a long time after reactivation but not a short time after. No CSM deficit is produced by such agents when crabs are exposed to a context different from that of training. Findings are consistent with those reported for vertebrates, with both showing that reactivation induces a recapitulation of the postacquisition cascade of intracellular events. The agreement between results from such phylogenetically disparate animals suggests that evolution may have adopted a given molecular cascade as the preferred means of encoding experiences in the nervous system.

Topics: Amnesia; Animals; Behavior, Animal; Brachyura; Cycloheximide; Dizocilpine Maleate; Drug Administration Schedule; Escape Reaction; Excitatory Amino Acid Antagonists; Glutamic Acid; Male; Memory; Photic Stimulation; Protein Biosynthesis; Protein Synthesis Inhibitors; Receptors, N-Methyl-D-Aspartate; Retention, Psychology; Time Factors

Puerarin at 10-50 mg/kg attenuated the mecamylamine- but not scopolamine-induced acquisition impairment of inhibitory avoidance performance in an inverse U-shape manner. p-Chloroamphetamine- and dizocilpine-induced acquisition impairment were reversed by puerarin at 25-50 mg/kg. Both piracetam, and tacrine attenuated impairment of inhibitory avoidance performance induced by all used drugs. Furthermore, puerarin, piracetam and tacrine alone did not alter step-through latency in the training trail but puerarin at 50 mg/kg and tacrine plus mecamylamine prolonged it in comparison with mecamylamine alone. From these results, we suggest that puerarin attenuated the deficits of inhibitory avoidance performance induced by mecamylamine, p-chloroamphetamine, and dizocilpine, the effects were related to increasing cholinergic activity via nicotinic but not muscarinic receptors, activating NMDA receptors, and decreasing serotonergic neuronal activity.

Topics: Amnesia; Animals; Avoidance Learning; Behavior, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Isoflavones; Male; Mecamylamine; p-Chloroamphetamine; Phytotherapy; Pueraria; Random Allocation; Rats; Rats, Sprague-Dawley; Scopolamine

MK-801, a non-competitive NMDA receptor antagonist, has been shown to have amnesic properties in animal models. The purpose of the present study was to examine potential amnesic effects of MK-801 in mice using the modified elevated plus-maze paradigm. An animal was placed on the distal end of an open arm, and the transfer latency, i.e. the time in which it moves to the enclosed arm, was measured. Four different experimental schedules (i.e. the combination of the treatment and the testing) were used: MK-801 (0.075, 0.15, 0.25 and 0.4 mg/kg or saline) were given (a) 30 min before the acquisition session, (b) immediately after the acquisition session, (c) 60 min after the acquisition session, and (d) 30 min before the retention session. The retention session always followed 24 h after the acquisition session. Analysis of data showed a significant shortening of the transfer latency in saline-treated animals during the retention session. Further, MK-801 (at the dose range of 0.15--0.4 mg/kg) administered before and immediately after the acquisition session as well as before the retention session prolonged the transfer latency during the retention session. In fact, transfer latencies in MK-801 treated mice did not differ from those measured during the acquisition session. Thus, prolongation of the transfer latency in MK-801-treated mice indicates deficits in 'memorization' processes. On the contrary, MK-801 given 60 min after the acquisition session failed to increase the transfer latency, which suggests that the memory trace was sufficiently consolidated at this time. Based on the present results, the glutamatergic NMDA receptor mechanisms play an important role in a spatial orientation of mice placed on the elevated plus-maze.

Topics: Amnesia; Animals; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Maze Learning; Mice; Time Factors; Transfer, Psychology

The sigma1 (sigma1) receptor cDNA was recently cloned in several animal species, including the mouse. In order to firmly establish the implication of sigma1 receptors in memory, a phosphorothioate-modified antisense oligodeoxynucleotide (aODN) targeting the sigma1 receptor mRNA and a mismatched analog (mODN) were administered intracerebroventricularly for 3 days in mice. Scatchard analyses of in vitro (+)-[3H]SKF-10,047 binding to sigma1 sites showed that Bmax values were significantly decreased in the hippocampus (-58.5%) and cortex (-38.1%), but not in the cerebellum, of aODN treated mice, as compared to saline- or mODN-treated animals. In vivo binding levels were also significantly decreased after aODN treatment in the hippocampus and cortex but not in the cerebellum. The anti-amnesic effects of the selective sigma1 agonists PRE-084 or SA4503 were evaluated against the learning impairments induced by dizocilpine or scopolamine, respectively, using spontaneous alternation behavior and passive avoidance task. The anti-amnesic effects of PRE-084 or SA4503, observed after saline- or mODN-treatment, were blocked after aODN administration. These observations bring a molecular basis to the modulatory role of sigma1 receptors in memory processes.

Topics: Amnesia; Animals; Brain; Dizocilpine Maleate; Excitatory Amino Acid Agonists; In Vitro Techniques; Learning Disabilities; Male; Maze Learning; Mice; Morpholines; Nootropic Agents; Oligonucleotides, Antisense; Phenazocine; Piperazines; Receptors, sigma

1. The sigma(1) (sigma(1)) receptor cDNA was cloned in several animal species. Molecular tools are now available to identify its endogenous effectors, such as neuroactive steroids, and to establish its precise physiological role. In particular, the sigma(1) receptor is involved in memory processes, as observed in pharmacological and pathological rodent models of amnesia. 2. In order to establish the involvement of sigma(1) receptors in memory, a 16-mer oligodeoxynucleotide antisense to the sigma(1) receptor cDNA (aODN), and its mismatched control (mODN) were prepared and centrally administered into the mouse brain. The anti-amnesic effects induced by the selective sigma(1) agonist PRE-084 and the steroid dehydroepiandrosterone (DHEA) sulphate or pregnenolone sulphate were examined in ODN-treated animals. 3. The aODN treatment failed to affect the dissociation constant (K(d)) but significantly decreased the number of sigma(1) sites (B(max)) labelled with [(3)H]-(+)-SKF-10,047 in the hippocampus and cortex. In these structures, the in vivo binding levels were also diminished, according to the dose and number of injections, as compared with control animals injected with saline or mODN. 4. Cannulation and injections failed to affect the open-field behaviour of the animals. However, the anti-amnesic effects of PRE-084 and DHEA sulphate against the dizocilpine-induced impairments were blocked after aODN treatment in the short- and long-term memory tests. The anti-amnesic effects of pregnenolone sulphate remained unchanged. 5. These observations bring a molecular basis to the modulatory role of sigma(1) receptors in memory, and reveal that the anti-amnesic action of neuroactive steroids may not similarly involve an interaction with sigma(1) receptors.

Topics: Amnesia; Animals; Avoidance Learning; Behavior, Animal; Binding Sites; Blotting, Western; Brain; Cerebral Cortex; Dehydroepiandrosterone; Dizocilpine Maleate; Dose-Response Relationship, Drug; Hippocampus; In Vitro Techniques; Learning Disabilities; Male; Maze Learning; Memory; Mice; Morpholines; Oligonucleotides, Antisense; Phenazocine; Pregnenolone; Receptors, sigma; Sigma-1 Receptor

Operant delayed non-matching-to-position (delayed non-matching-to-position) tasks have been widely used as tests of working memory in rats, but have suffered some loss in sensitivity to differentiating selective mnemonic from non-mnemonic deficits due to floor and ceiling effects. To circumvent this problem, a novel delayed non-matching-to-position was developed in which the retention interval was adjusted on a trial-by-trial basis to hold performance accuracy at an intermediate value. The present study assessed the effects of three amnestic drugs in this delayed non-matching-to-position. Rats were administered (i.p.) NMDA receptor antagonist ((5R,10S)-(+)-5-Methyl-10, 11-dihydro-5H-dibenzo[a,d,] cyclohepten-5,10-imine (Dizocilpine or MK-801), muscarinic receptor antagonist (-)-scopolamine hydrobromide (scopolamine), or cannabinoid receptor agonist ((R)-(+)-[2, 3-Dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1, 4-benzoxazin-6-yl]-1-naphthalenylmethanone) (WIN 55, 212-2). At high doses, both MK-801 (0.12-0.25 mg/kg) and scopolamine (0.25 mg/kg) produced deficits not selective to working memory. At low doses, scopolamine (0.06-0.12 mg/kg) and MK-801 (0.06 mg/kg) produced no deficits in any mnemonic or secondary measures. WIN 55, 212-2 produced deficits at 2.0 mg/kg that were consistent with a specific impairment of working memory. Using this particular delayed non-matching-to-position revealed that consistent changes in performance accuracy at the short retention interval were evident for scopolamine and MK-801, at times in the absence of changes in response tendency, which are consistent with an interpretation that these drugs produce general deficits in reference or procedural memory. In contrast, cannabinoid-induced deficits in choice accuracy support previous reports of delay-dependent deficits. Together, these data suggest that this delayed non-matching-to-position task is able to differentiate deficit patterns of amnestic drugs, and isolate the effects of motivational side effects of drugs from working memory measurement.

Topics: Amnesia; Animals; Behavior, Animal; Benzoxazines; Dizocilpine Maleate; Dose-Response Relationship, Drug; Male; Memory; Morpholines; Naphthalenes; Psychomotor Performance; Rats; Rats, Sprague-Dawley; Retention, Psychology; Scopolamine

We investigated the effect of the nootropic substance oxiracetam on the impairment of memory induced in mice by the non-competitive NMDA antagonist MK-801. Memory capacities of animals having different experience were evaluated using the elevated plus-maze test. Oxiracetam was injected immediately after the acquisition session(s), MK-801 was given 30 min before the retention session which followed 24 h after the acquisition session(s). In slightly experienced animals (Section 3.1), oxiracetam (3 and 30 mg/kg, s.c.) prevented MK-801 (0.15 mg/kg, i.p.) induced memory deficits characterized by a prolongation of the transfer latency. In well-trained animals (Section 3.2), oxiracetam (30 mg/kg, s.c.) attenuated MK-801 (0.15,0. 25 and 0.4 mg/kg, i.p.) induced amnesia for a spatial orientation in the elevated plus-maze. These results show that oxiracetam interacted with the glutamatergic NMDA receptor system and forestalled the impairment of retrieval of long-term memory. The results also justify the usage of the elevated plus-maze method in the evaluation of potential anti-amnesic or nootropic drugs.

Topics: Amnesia; Analysis of Variance; Animals; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Maze Learning; Memory; Mice; Nootropic Agents; Pyrrolidines; Random Allocation; Receptors, N-Methyl-D-Aspartate

Sigma (sigma) receptors have generated a great deal of interest on the basis of their possible role in psychosis, neuroprotection and various other behaviors including learning processes. The existence of at least two classes of sigma receptor binding sites (sigma(1) and sigma(2)) is now well established. The recent cloning of the mouse, guinea pig and human sigma(1) receptors has allowed the study of the discrete distribution of the sigma(1) receptor mRNA in rodent and human brain tissues using in situ hybridization. Overall, the sites of expression of specific sigma(1) receptor mRNA signals were in accordance to the anatomical distribution of sigma(1) receptor protein first established by quantitative receptor autoradiography. Specific sigma(1) receptor hybridization signals were found to be widely, but discretely distributed, in mouse and guinea pig brain tissues. The highest levels of transcripts were seen in various cranial nerve nuclei. Lower, but still high hybridization signals were observed in mesencephalic structures such as the red nucleus, periaqueductal gray matter and substantia nigra, as well as in some diencephalic structures including such as the habenula and the arcuate, paraventricular and ventromedial hypothalamic nuclei. Superficial (I-II) and deeper (IV-VI) cortical laminae were moderately labeled in the mouse brain. Moderate levels of sigma(1) receptor mRNA were also found in the pyramidal cell layer and the dentate gyrus of the hippocampal formation. Other structures such as the thalamus and amygdaloid body also expressed the sigma(1) receptor mRNA although to a lesser extent. In murine peripheral tissues, strong hybridization signals were observed in the liver, white pulp of the spleen and the adrenal gland. In the postmortem human brain, moderate levels of sigma(1) receptor mRNA, distributed in a laminar fashion, were detected in the temporal cortex with the deeper laminae (IV-VI) being particularly enriched. In the hippocampal formation, the strongest hybridization signals were observed in the dentate gyrus while all other subfields of the human hippocampal formation expressed lower levels of the sigma(1) receptor mRNA. Antisense oligodeoxynucleotides against the purported sigma(1) receptor were used next to investigate the possible role of this receptor in dizocilpine (MK-801)/NMDA receptor blockade-induced amnesia. Following a continuous intracerebroventricular infusion of a specific sigma(1) receptor antisense into the third

Topics: Amnesia; Analgesics, Opioid; Animals; Antisense Elements (Genetics); Autoradiography; Brain Chemistry; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Gene Expression; Guinea Pigs; Humans; In Situ Hybridization; Male; Mammals; Mice; Mice, Inbred Strains; Pentazocine; Receptors, N-Methyl-D-Aspartate; Receptors, sigma; RNA, Messenger; Tritium

Pyrithiamine-induced thiamine deficiency (PTD), which has been used as a model of Wernicke-Korsakoff syndrome (WKS), produces a range of neuropathological and behavioral abnormalities in rodents. The extent of the diencephalic damage produced by this treatment varies from moderate to extreme cell loss. The magnitude of working memory impairment tends to correlate with the degree of neuropathology. In this study a PTD protocol that produces moderate thalamic pathology was used to gain further insight into the neurobehavioral consequences of thiamine deficiency. Towards this end, two distinct manipulations were conducted. First, the differential outcomes procedure (DOP), which correlates specific reinforcers with specific to-be-remembered events, was applied to an operant version of matching-to-position (MTP). This behavioral manipulation was conducted to determine if the DOP would improve memory performance in PTD-treated rats, demonstrating some intact cognitive functions. Additionally, to assess the functional integrity of the cholinergic and glutamatergic systems, normal and PTD-treated rats were administered i.p. injections of scopolamine and MK-801. It was found that the DOP enhanced memory, but not acquisition performance, in both normal and PTD-treated rats. Furthermore, when administered scopolamine, but not MK-801, rats trained with the DOP continued to outperform rats trained with a non-differential outcomes procedure (NOP). However, PTD-treated rats, regardless of training procedure (DOP, NOP), were more disrupted by the 'amnestic' effects of both scopolamine and MK-801. The differential sensitivity of treatment groups to the amnestic effects of scopolamine and MK-801 reveals insights into the neurochemical correlates of memory processes and WKS.

Topics: Acute Disease; Amnesia; Analysis of Variance; Animals; Behavior, Animal; Conditioning, Operant; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Korsakoff Syndrome; Male; Memory, Short-Term; Pyrithiamine; Rats; Rats, Sprague-Dawley; Reaction Time; Scopolamine; Thalamus; Thiamine Deficiency

Amnesic properties of scopolamine, a muscarinic receptor antagonist, and MK-801, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, were evaluated in mice by means of the elevated plus-maze test. In this test, transfer latency, the time mice took to move from the open arm to the enclosed arm, was used as an index of learning and memory. The 3-day pretreatment training dramatically decreased transfer latencies. On the 4th day, the retention trial was performed 30 min after the intraperitoneal injection of scopolamine (Experiment 1) or MK-801 (Experiment 2). The doses of 0.25 and 0.5 mg/kg of scopolamine as well as the doses of 0.1, 0.15, 0.2 and 0.4 mg/kg of MK-801 significantly prolonged the transfer latency as compared with both that in the saline-treated group and that measured on the 3rd day. In Experiment 3, subthreshold doses of these two drugs given in combination (which were ineffective when given alone: scopolamine 0.25 mg/kg, MK-801 0.075 mg/kg) significantly prolonged the transfer latency on the fourth day. However, an amnesic effect of scopolamine plus MK-801 was transient. On the 5th day, no differences in the transfer latency were found. This finding clearly indicates that there is a close relationship between cholinergic and glutamatergic systems and that both systems play an important role in a spatial orientation of mice on the elevated plus-maze.

Topics: Amnesia; Animals; Dizocilpine Maleate; Drug Synergism; Female; GABA Antagonists; Maze Learning; Mice; Muscarinic Antagonists; Receptors, N-Methyl-D-Aspartate; Scopolamine

The ability of the nitric oxide (NO) synthase inhibitor, NG-nitro-l-arginine methyl ester (L-NAME), to modulate the attenuating effects of neurosteroids on the aging- and NMDA receptor antagonist dizocilpine-induced learning impairment, was tested in mice using two different behavioral models of long-term memory. The performance of aged mice (16 months old) in step-down type of passive-avoidance and elevated plus-maze paradigms was significantly impaired compared to that of young mice (3 months old). Neurosteroids pregnenolone sulfate (PS) and dehydroepiandrosterone sulfate (DHEAS), at 1-20 mg/kg, s.c., significantly improved the passive-avoidance and plus-maze performances in aged mice. Neurosteroids PS and DHEAS, at doses 1-20 mg/kg, s.c., significantly attenuated dizocilpine (0.1 mg/kg, i.p.)-induced amnesia, without producing any promnestic effects alone in adult mice. In both cognitive tasks, the effects exhibited by the neurosteroids tested had a bell-shaped curve. Preadministration of L-NAME (10 and 20 mg/kg, i.p.), at doses that did not disrupt cognition alone in either young or aged mice, significantly blocked the beneficial and antiamnesic effects of neurosteroids PS (5 mg/kg) and DHEAS (10 mg/kg). A selective action of L-NAME on the effects of neurosteroids was indicated, since the effects of L-NAME were completely reversed by L-arginine (300 mg/kg, i.p.), a competitive substrate for NO synthase. Neither L-NAME nor L-arginine alone affected the antinociception, locomotor activity or rota-rod performance of young or aged mice. These observations suggest that a NO-dependent mechanism may be involved in the beneficial and antiamnesic effects of neurosteroids PS and DHEAS on the aging- and dizocilpine-induced impairment of learning and memory processes.

Topics: Aging; Amnesia; Animals; Avoidance Learning; Dehydroepiandrosterone Sulfate; Dizocilpine Maleate; Enzyme Inhibitors; Learning Disabilities; Male; Maze Learning; Memory; Mice; Mice, Inbred Strains; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Nootropic Agents; Pregnenolone

Investigations indicate that the induction of long-term potentiation (LTP) may be mediated by postsynaptic N-methyl-D-aspartate (NMDA) receptors and that the maintenance of LTP may be initiated by nitric oxide (NO), a retrograde messenger carrying signals backward from the postsynaptic to the presynaptic neuron. The present study compared amnestic effects of dizocilpine maleate (MK-801), an NMDA receptor antagonist, and nitro-L-arginine-methyl-ester (L-NAME) and N-nitro-L-arginine (L-NOARG), nitric oxide (NO) inhibitors, in goldfish, using active-avoidance conditioning as the learning paradigm. The results showed that MK-801 and NO inhibitors produced anterograde amnesia at doses that did not impair performance processes necessary for learning to occur. Furthermore, MK-801 did not produce retrograde amnesia, whereas L-NAME did, suggesting that MK-801 impaired learning whereas NO inhibitors impaired memory consolidation and possibly also learning.

Topics: Amnesia; Analysis of Variance; Animals; Avoidance Learning; Dizocilpine Maleate; Electroshock; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Goldfish; Long-Term Potentiation; Memory; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitroarginine; Receptors, N-Methyl-D-Aspartate; Time Factors

The effects of dynorphin A (1-13) on carbon monoxide (CO)-induced amnesia in mice were investigated. Memory deficiency was apparent during Y-maze testing 5 days after CO exposure (delayed amnesia). Percent alternation in the CO-exposed group was significantly lower than that in the control group. Administration of dynorphin A (1-13) (1.5 nmol, i.c.v.) 15 min before the Y-maze test session reversed the impairment of spontaneous alternation performance in the CO-exposed group. To determine whether this effect was mediated via kappa opioid receptors, we attempted to block the effect of dynorphin A using the kappa opioid receptor antagonist nor-binaltorphimine. Nor-binaltorphimine (5.44 nmol, i.c.v.) blocked the effect of dynorphin A (1-13) on delayed amnesia. Dynorphin A (1-13) did not affect the impairment of alternation induced by the blockade of NMDA-receptors by dizocilpine (MK-801), but significantly prevented the impairment induced by mecamylamine. These results suggest that dynorphin A (1-13) modulates the kappa receptor-mediated opioid neuronal system, and reverses the impairment of spontaneous alternation performance induced by CO exposure.

Topics: Amnesia; Animals; Carbon Monoxide Poisoning; Dizocilpine Maleate; Dynorphins; Excitatory Amino Acid Antagonists; Injections, Intraventricular; Male; Maze Learning; Mecamylamine; Mice; Mice, Inbred Strains; Naltrexone; Narcotic Antagonists; Narcotics; Nicotinic Antagonists; Peptide Fragments; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid, kappa

The effects of N-methyl-D-aspartate NMDA receptor antagonists on scopolamine-induced amnesia and on delay-interposed short-term memory performance were investigated using an 8-arm radial maze in rats. Scopolamine, a muscarinic antagonist, deteriorated the radial maze performance, while MK-801, an NMDA receptor channel blocker and CGS-19755, a competitive NMDA receptor antagonist, showed no obstruction to the spatial cognition in the non-delayed maze task. MK-801 (0.01-0.03 mg/kg, i.v.) and CGS-19755 (1-10 mg/kg, i.v.) significantly augmented scopolamine-induced deficit in the non-delayed maze task and impaired the short-term memory in the 5-min delay-interposed task. These results suggest that NMDA antagonists have a negative action on short-term memory and that the interaction between the NMDA and the central muscarinic system plays a role in modulating the cognitive function.

Topics: Amnesia; Animals; Cholinergic Antagonists; Dizocilpine Maleate; Drug Synergism; Excitatory Amino Acid Antagonists; Learning Disabilities; Male; Maze Learning; Memory, Short-Term; N-Methylaspartate; Pipecolic Acids; Rats; Rats, Wistar; Scopolamine

We report here data suggesting that reactivation of a well-established memory by a retention test triggers cellular events which depend upon N-methyl-D-aspartate (NMDA) receptors for up to 2 h after reactivation. Rats were overtrained on a maze task requiring integration of distal spatial information contained in cues strategically placed around the maze. Previous experiments showed that pretrial injection of the noncompetitive NMDA receptor antagonist, MK-801, at a dose which had no effect on overt behavior (0.05 mg/kg), markedly disrupted the well-trained performance of the task. Surprisingly, the behavioral deficit persisted on subsequent, drug-free trials, 24 h later. The present experiments showed that post-trial injections produced the same effects on performance on one or two subsequent daily trials. A temporal gradient for this amnestic effect of the drug treatment was established by injecting rats at 5, 30, 60, 90, 120 or 180 min after the performance trial. Only those rats whose MK-801 treatment was delayed for 120 min or more after the trial were able to perform the task normally 24 h later. All other treatment times induced significant amnesia for the task, when the rats were tested 24 h later. A subsequent experiment, using a more difficult version of the task, showed a longer amnesia gradient, but the predrug performance level could be reinstated within one multiple trial test session. Thus, it appears that activation of a well-established memory circuit renders the trace labile, requiring its reconsolidation. To what extent the entire post-acquisition cascade of NMDA receptor-dependent intracellular events is recapitulated each time a memory is activated and reorganised is probably a function of the age and complexity of the memory and the amount of new information to be integrated into the circuit. These results provide physiological evidence for the notion that memory is a dynamic process undergoing continual reorganization as a function of the ongoing experience of the organism.

Topics: Amnesia; Animals; Cues; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Memory; Rats; Rats, Sprague-Dawley; Time Factors

The selective sigma1 receptor agonist 1-(3,4-dimethoxyphenethyl)-4-(3-phenyl propyl)piperazine dihydrochloride (SA4503) was reported to reverse the amnesia induced by the muscarinic receptor antagonist scopolamine at sub-mg/kg doses. We examined its effect on the learning impairment induced in mice by the non-competitive NMDA receptor antagonist dizocilpine. Learning capacities were evaluated using spontaneous alternation in the Y-maze for spatial working memory, and step-down type passive avoidance. SA4503 (0.03-1 mg/kg s.c.) attenuated the dizocilpine (0.15 mg/kg i.p.)-induced memory deficits following a bell-shaped curve in both tests. These effects of SA4503 were blocked by haloperidol (0.05 mg/kg i.p.), implicating sigma1 receptors. SA4503 also reversed the alternation deficit induced by N(omega)-nitro-L-arginine methyl ester (L-NAME, 100 mg/kg i.p.) at the same dosage, indicating that it acted on working memory through the nitric oxide (NO)-mediated signalling pathway. Furthermore, progesterone (2 mg/kg s.c.) blocked the SA4503 effects in the dizocilpine- and L-NAME-amnesia models, in accordance with the purported neurosteroids/sigma1 receptors interaction. These results demonstrate a promising neurobehavioural profile of SA4503, a ligand equally efficient to reverse the deficit in the glutamatergic as well as in the cholinergic amnesia model. Pertinent informations on the potential mechanism of the anti-amnesic effects of sigma1 receptor ligands were also obtained.

Topics: Amnesia; Analysis of Variance; Animals; Avoidance Learning; Cognition; Disease Models, Animal; Dizocilpine Maleate; Dopamine Antagonists; Drug Interactions; Excitatory Amino Acid Antagonists; Haloperidol; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Maze Learning; Mice; NG-Nitroarginine Methyl Ester; Nitric Oxide; Piperazines; Progesterone; Receptors, N-Methyl-D-Aspartate; Receptors, sigma; Spatial Behavior

Training chicks on a one-trial passive avoidance task results in transient up-regulation of the N-methyl-D-aspartate (NMDA) receptor in the left intermediate medial hyperstriatum ventrale (IMHV) of the forebrain 30 min post-training. Injection of the non-competitive NMDA receptor inhibitor, (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)-cyclohepten 5,10-imine maleate (MK-801), around the time of training renders chicks amnesic for the task. Training also results in enhanced expression of the immediate early gene (IEG) c-fos in the IMHV. To determine the relationship between NMDA receptor up-regulation and IEG induction during memory formation we have examined the expression of Fos, Jun and their related proteins 2 h following training in the presence/absence of the putative amnestic agent MK-801. Western blotting of IMHV samples revealed two protein bands with immunoreactivity to the Fos antibody at 47 and 54 kDa. Using an antibody to Jun, two immunoreactive bands were revealed at 39 and 54 kDa. All bands were enhanced in the left IMHV following passive avoidance training. Post-training intraperitoneal injections of MK-801 (75 mM) produced amnesia in approximately 50% of the birds when tested 1 h after training. Injection of MK-801 significantly attenuated expression of these proteins in birds rendered amnesic, but not in those that recalled the task. We conclude that NMDA receptor activation precedes immediate early gene expression in the memory formation cascade.

Topics: Amnesia; Animals; Autoradiography; Avoidance Learning; Cerebral Ventricles; Chickens; Dizocilpine Maleate; Electrophoresis, Polyacrylamide Gel; Female; Gene Expression; Genes, fos; Genes, jun; Immunoblotting; Male; Up-Regulation

The anterograde amnestic effects of non-competitive NMDA antagonists MK-801 and HA-966 on classic fear conditioning in goldfish (Carassius auratus) were examined in a series of experiments. Experiments 1 and 2 contrasted the anterograde amnestic effects of MK-801, (+)HA-966, and (-)HA-966. Experiment 3 examined the effects of MK-801 and (+)HA-966 on the expression of conditioned responses. Experiments 4 and 5 investigated whether the potency of MK-801, (+)HA-966 or (-)HA-966 in blocking NMDA-induced convulsions paralleled their potency in producing amnesia. The results showed that MK-801 was more potent than (+)HA-966 in producing anterograde amnesia and impairing expression, while (-)HA-966 did not produce anterograde amnesia. The anticonvulsant potency of MK-801, (+)HA-966, and (-)HA-966 paralleled their amnestic potency. These findings suggested that MK-801 and (+)HA-966 produced anterograde amnesia by their specific antagonism of the NMDA receptor complex.

Topics: Amnesia; Animals; Anticonvulsants; Conditioning, Classical; Dizocilpine Maleate; Fear; Goldfish; N-Methylaspartate; Pyrrolidinones; Receptors, N-Methyl-D-Aspartate

Topics: Amnesia; Animals; Brain Injuries; Dizocilpine Maleate; Rats; Reaction Time

Pregnenolone (PREG) is metabolized in brain to progesterone (PROG), 5 alpha-dihydroprogesterone (5 alpha-DHP) and allopregnanolone (ALLO). Infusion of adrenalectomized/castrated rats with PREG sulfate prevented the cognition deficit elicited by the ionotropic glutamate receptor antagonists, dizocilpine and CPPene. Using a new gas chromatographic/mass-spectrometric method, we demonstrated that PREG sulfate infusion markedly increased the PREG, PROG, 5 alpha-DHP and ALLO brain content. The increase in 5 alpha-DHP and ALLO, but not PREG or PROG content and the antagonism of dizocilpine amnesia observed by injecting rats with PREG sulfate was reversed by inhibiting the conversion of PROG to 5 alpha-DHP with the 5 alpha-reductase blocker SKF 105111. We and others have shown that ALLO potently modulate GABAA receptor function whereas 5 alpha-DHP fails to induce rapid changes in neurotransmitter receptor function. Thus it is possible to suggest that the increase in the brain content of ALLO, rather than 5 alpha-DHP, mediates the effect of PREG sulfate on dizocilpine- or CPPene-induced cognition deficit.

Topics: Amnesia; Animals; Anti-Anxiety Agents; Brain; Cognition; Dizocilpine Maleate; Dose-Response Relationship, Drug; Pregnanolone; Pregnenolone; Rats; Rats, Sprague-Dawley; Reaction Time

Cell death, neuronal dysfunction and deterioration of memory function can be produced after carbon monoxide exposure in mice as in human. These deficiencies are developed in a delayed manner (delayed amnesia). The neurotoxicity of excitatory amino acids may be involved in this model, since dizocilpine (MK-801) fully protects against carbon monoxide-induced cell death, learning impairment and delayed amnesia. In the present paper, we described the method of carbon monoxide exposure and the characteristic of behavioral and biochemical changes after carbon monoxide exposure. These data indicate that carbon monoxide can provide an amnesic model for the investigation of memory deterioration and the development of new anti-amnesic drugs.

Topics: Amnesia; Animals; Avoidance Learning; Brain; Carbon Monoxide; Catecholamines; Disease Models, Animal; Dizocilpine Maleate; Drug Design; Drug Evaluation, Preclinical; Excitatory Amino Acids; Mice

We investigated the effect of the sigma selective PCP derivative PRE-084 on the impairment of learning induced in mice by the noncompetitive NMDA antagonist MK-801. Learning capacities were evaluated using the spontaneous alternation in a Y-maze test for spatial working memory, the step-down passive avoidance and the elevated plus-maze test for long-term memory. At doses about 1 mg/kg IP, PRE-084 significantly attenuated MK-801 (0.2 mg/kg IP) induced impairment of learning. The dose-response curve was bell-shaped which is typical for cognition enhancers. The effect of PRE-084 was antagonized by BMY-14802 (10 mg/kg IP) and suppressed by a chronic treatment with haloperidol (4 mg/kg/day SC for 7 days). Furthermore, PRE-084 did not affect scopolamine (1 mg/kg SC) induced amnesia but significantly attenuated mecamylamine (10 mg/kg IP) induced amnesia. These results show that sigma sites mediate a modulation of the NMDA receptor complex-dependent learning processes and may similarly affect the cholinergic nicotinic memory processes. Moreover, the PCP derivative PRE-084, acting selectively at sigma sites, reverses the amnesia induced by a drug acting at the PCP site.

Topics: Amnesia; Animals; Anti-Anxiety Agents; Avoidance Learning; Cholinergic Agents; Dizocilpine Maleate; Dose-Response Relationship, Drug; Haloperidol; Learning; Male; Maze Learning; Memory; Memory, Short-Term; Mice; Morpholines; Phencyclidine; Pyrimidines; Rats; Rats, Wistar; Receptors, sigma

1. The effects of several drugs on the habituation of exploratory activity in mice were investigated by using animal movement analyzing systems which could detect horizontal and vertical activities. 2. Habituation was regarded as the difference between exploratory activity measured first (session 1) and that measured second (session 2). 3. Scopolamine (1, 3 and/or 6 mg/kg), pirenzepine (20 and 40 micrograms) injected immediately after session 1, cycloheximide (30 mg/kg), diazepam (1, 2 and/or 4 mg/kg) and dizocilpine (0.05, 0.1 and/or 0.2 mg/kg), unlike butylscopolamine (1, 3 and 6 mg/kg) or haloperidol (0.2 and 0.4 mg/kg), significantly increased horizontal activity but not always vertical activity in session 2. 4. From the results obtained, it appears that the increase in horizontal activity in session 2 is more appropriate as an indicator of the impairments of memory processes than that in vertical activity.

Topics: Amnesia; Animals; Behavior, Animal; Butylscopolammonium Bromide; Cycloheximide; Diazepam; Dizocilpine Maleate; Exploratory Behavior; Habituation, Psychophysiologic; Haloperidol; Male; Memory; Mice; Mice, Inbred Strains; Pirenzepine; Scopolamine

The authors have examined the effect of experimental traumatic brain injury on the amnesia produced by the N-methyl-D-aspartate (NMDA) antagonist MK-801. Rats were either subjected to a moderate level of fluid-percussion injury or prepared for injury but not injured ("sham injury"). Nine days following injury or sham injury, the rats were injected either with saline (sham/saline group, nine rats; injured/saline group, nine rats) or with 0.1 mg/kg of MK-801 (sham/MK-801 group, nine rats; injured/MK-801 group, eight rats) 30 minutes before being trained on a passive-avoidance task. Twenty-four hours later, the rats were tested for retention of the passive-avoidance task. Results revealed that the low dose of MK-801 did not significantly affect retention of the passive-avoidance task in the sham-injured group. In injured animals, administration of MK-801 produced a profound amnesia in contrast to the sham-injured animals treated with MK-801 and the injured animals treated with saline. To further investigate this enhanced sensitivity to the amnesic effects of MK-801 exhibited by the injured animals, nine injured and eight sham-injured rats were injected with 0.3 mg/kg of MK-801 15 minutes before injury. Results indicated that the animals treated with MK-801 before injury did not significantly differ from the sham-injured animals in retention of the passive-avoidance task. In addition, test results in the animals treated with MK-801 before injury and reinjected with MK-801 before passive-avoidance testing did not differ from those in untreated injured animals reinjected with saline before passive-avoidance testing. These findings indicate that MK-801 treatment before injury prevented the enhanced sensitivity to MK-801-induced amnesia that follows traumatic brain injury.

Topics: Amnesia; Animals; Avoidance Learning; Brain Concussion; Brain Injuries; Dizocilpine Maleate; Male; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, N-Methyl-D-Aspartate

In rats trained to retain a passive avoidance response or to retrieve a learned task in the radial and water maze tests, a pretreatment with 2-hexyl-3-indoleacetamide (FGIN-1-27) (IC50 57 mumol/kg p.o.) or 4' chlorodiazepam (4'CD) (15 mumol/kg i.p.), two steroidogenic ligands at the mitochondria diazepam-binding inhibitor receptor complex (MDRC), antagonized the performance deficit elicited by dizocilpine (0.3 mumol/kg i.p.), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. The 1-(2-chlorophenyl)-N-methyl-N-(-1-methyl-propyl)-3-isoquinoline carboxamide (PK-11195), an antagonist at MDRC in vivo, failed to modify the disruptive effect of dizocilpine in the passive avoidance response but reversed the FGIN-1-27- or 4' CD-induced antagonism of dizocilpine behavioral actions. Pretreatment with pregnenolone sulfate (48 mumol/kg i.p.), 3 alpha, 21-dihydroxy-5 alpha-pregnan-20-one (THDOC) (15 mumol/kg i.v.) and 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone) (15 mumol/kg i.v.) also reduced the passive avoidance retention deficit elicited by dizocilpine. The (17-beta)-17-[[bis(1-methylethyl)amino[carbonyl]androstane-3,5-diene-3- carboxylic acid (SKF-105111), a 5 alpha-reductase inhibitor, blocked the antagonism of dizocilpine behavioral actions by pregnenolone sulfate or by FGIN-1-27 but not those caused by THDOC or allopregnanolone either in normal or adrenalectomized-castrated rats. Thus, it is inferred that the amnesic effect of dizocilpine is counteracted by FGIN-1-27, 4'CD and pregnenolone sulfate because of their ability to increase brain accumulation of allopregnanolone.

Topics: Amnesia; Animals; Avoidance Learning; Cognition; Cognition Disorders; Dizocilpine Maleate; Indoleacetic Acids; Male; Mitochondria; Pregnanolone; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; Scopolamine; Steroids; Tritium

The potentiating effect of low doses of sigma ligands on the N-methyl-D-aspartate (NMDA)-induced excitation of pyramidal CA3 dorsal hippocampal neurons has recently been reported. In the present study, we investigated behavioral effects relevant to these findings in the experimental amnesia induced by the non-competitive NMDA antagonist, dizocilpine (MK-801), in mice. At doses below 1 mg/kg s.c., the sigma ligands, 1,3-di-(2-tolyl)guanidine (DTG), (+)-SKF 10,047, and (+)-pentazocine, but not their (-)-isomers, significantly decreased MK-801 (100 microgram/kg s.c.)-induced impairment of spontaneous alternation performances in 8-min sessions of a Y-maze exploration, an index of spatial working memory, without affecting the concomitant hyperlocomotion. The effect of DTG (100 micrograms/kg s.c.) was completely antagonized by the simultaneous administration of BMY 14802 (10 mg/kg i.p.) and NE-100 (1 mg/kg i.p.), two putative sigma antagonists, which had no effect by themselves. In long-term memory tests (step-down and step-through types of passive avoidance, elevated plus-maze), DTG exhibited a significant attenuation of MK-801-induced amnesia, at doses of 10 and 100 micrograms/kg s.c. In all tests of short- and long-term memory, the effects exhibited by the sigma ligands tested had a bell-shaped curve; no effect was seen at 1 mg/kg. DTG did not affect the impairment of alternation induced by CPP (5 mg/kg i.p.): the modulation may selectively target the blockade of NMDA receptor-associated ion channels. Moreover, DTG (1-1000 micrograms/kg) did not affect the impairment induced by scopolamine (1 mg/kg i.p.) or diazepam (4 mg/kg i.p.), but significantly prevented the impairment induced by mecamylamine (10 mg/kg i.p.). These results suggest that the potentiating effect of sigma ligands on NMDA receptor-mediated glutamatergic neurotransmission, already demonstrated electrophysiologically, may have some relevance to learning and memory processes in the hippocampus. A similar modulation may also affect cholinergic nicotinic systems.

Topics: Amnesia; Animals; Behavior, Animal; Dizocilpine Maleate; Guanidines; Ligands; Male; Memory; Mice; Receptors, sigma

Two antagonists of metabotropic glutamate receptors, L-AP4 and MCPG, were tested in a one-trial passive avoidance task in the chick to investigate whether these receptor subtypes play a role in learning and memory. Drugs were injected i.c. L-AP4 produced amnestic effects when injected pre- or post-training. When injected pretraining, amnesia onset was observed after 1 h post-training. D-AP4 had no effect on memory formation. MCPG in comparison had no effect when injected post-training. When injected pretraining, the onset of amnesia was dose-dependent, ranging from 2 to 1 h post-training. When injecting MCPG along with the mGluR agonist ACPD, no amnestic effect was visible. ACPD on its own had no effect at the dose used.

Topics: Aminobutyrates; Amnesia; Animals; Avoidance Learning; Benzoates; Chickens; Cycloleucine; Cyclopropanes; Dizocilpine Maleate; Dose-Response Relationship, Drug; Female; Glycine; Injections, Intraperitoneal; Injections, Intraventricular; Male; Motor Activity; Phosphoserine; Receptors, Metabotropic Glutamate

This study examined the involvement of amygdala N-methyl-D-aspartate (NMDA) receptors in long-term retention of an inhibitory avoidance response. Rats bearing chronic cannulae implanted into the basolateral amygdala were trained on a one-trial inhibitory avoidance task and tested for retention 21 days later. They received intra-amygdala injections of vehicle (Veh) or 0.25, 1.25 or 5.0 micrograms of a competitive NMDA antagonist-2-amino-5-phosphonopentoic acid (AP5) either 5 min before training, immediately after training or 5 min before testing. Results indicated that pretraining intra-amygdala injections of AP5 at all doses impaired retention performance profoundly. Intra-amygdala injections of AP5 immediately after training caused a dose-dependent retention deficit: 0.25 microgram induced no deficit and 5.0 micrograms induced a great deficit. Immediate posttraining intra-amygdala injections of a non-competitive NMDA antagonist MK-801, also impaired retention but MK-801 given 2 hrs after training had no significant effect. In contrast to the marked amnestic effect produced by pre- or posttraining intra-amygdala injections of AP5, intra-amygdala injections of AP5 given just before retention tests had no discernible effect on retention performance. The retention deficit induced by pretraining intra-amygdala injections of 1.25 micrograms AP5 was ameliorated completely by N-methyl-DL-aspartate (0.25 microgram), but also partially by norepinephrine (0.2 microgram) infused into the amygdala immediately after training. However, posttraining infusion 0.2 microgram norepinephrine failed to attenuate significantly the amnestic effect induced by 5.0 micrograms AP5. These findings, taken together, suggest that NMDA receptors in the amygdala are normally involved in memory formation processing of affective experience.

Topics: 2-Amino-5-phosphonovalerate; Amnesia; Amygdala; Animals; Avoidance Learning; Dizocilpine Maleate; Long-Term Potentiation; Male; N-Methylaspartate; Norepinephrine; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Retention, Psychology

Learning and memory were previously evaluated by using the elevated plus-maze test in mice. We investigated whether this method could be used for the evaluation of amnesic properties of drugs, including those which alter behavior on the first (training) trial. Six drugs of different types, scopolamine, MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate), diazepam, butylscopolamine, methamphetamine and haloperidol were administered before training. The transfer latency of vehicle-treated mice on retention testing was significantly shorter than that on training. The transfer latencies in mice given scopolamine (1 and 3 mg/kg s.c.), butylscopolamine (6 mg/kg s.c.), methamphetamine (2 and 4 mg/kg i.p.), or haloperidol (0.4 mg/kg i.p.) were significantly prolonged on training compared with those of the corresponding vehicle groups. However, significant prolongation of the transfer latency in the retention test, compared to the vehicle groups, was observed only in mice given scopolamine (3 mg/kg s.c.), MK-801 (0.1 and 0.15 mg/kg i.v.), diazepam (4 mg/kg i.p.), or methamphetamine (4 mg/kg i.p.). These results suggested that the prolongation of the transfer latency on retention testing in the plus-maze method might be used as an indicator for impairment of learning and memory induced by the drugs which have amnesic properties, and is not related to the change in transfer latency on training.

Topics: Amnesia; Animals; Behavior, Animal; Butylscopolammonium Bromide; Diazepam; Dizocilpine Maleate; Haloperidol; Male; Methamphetamine; Mice; Mice, Inbred Strains; Psychopharmacology; Scopolamine

The effects of non-competitive N-methyl-D-aspartate receptor antagonists on amnesia induced by carbon monoxide (CO) were investigated, since they have neuroprotective effects on delayed degeneration induced by ischemia. In the mice exposed to CO, acute and delayed amnesia were induced. (+)-MK-801 and (-)-MK-801 improved the delayed amnesia, but the effects of phencyclidine (PCP) were weak. (+)-MK-801 and PCP potentiated the acute amnesia. From these results, it is suggested that there is a stereoselectivity in the effects of MK-801 on CO-induced amnesia and that CO-induced delayed amnesia animals could be used as an ischemic amnesia model.

Topics: Amnesia; Animals; Avoidance Learning; Carbon Monoxide; Dibenzocycloheptenes; Dizocilpine Maleate; Hypoxia, Brain; Male; Mice; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter