Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002622 (amnesia)
 5,520 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of aniracetam, a nootropic drug, and midazolam, which produces amnesia, on the long-term potentiation (LTP) of population spikes was investigated using hippocampal slices (CA3 area) from the guinea pig. Aniracetam at concentrations of 10(-7) and 10(-8) M, but not at 10(-6) M, significantly augmented LTP. On the other hand, midazolam (10(-9) M) significantly suppressed LTP. The suppressive effect was antagonized by Ro 15-1788 (10(-8) M). Both drugs did not affect the population spikes in the absence of tetanic stimulation at those concentrations. It was suggested that in vitro application of LTP is a feasible model system for evaluating the nootropic activity of drugs.
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PMID:Aniracetam augments, and midazolam inhibits, the long-term potentiation in guinea-pig hippocampal slices. 301 33

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.
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PMID:Behavioral evidence for a modulating role of sigma ligands in memory processes. I. Attenuation of dizocilpine (MK-801)-induced amnesia. 806 4

Amnesia is one of the most common consequences of seizures. We modelled this phenomenon in the in vitro hippocampal slice preparation by examining effects of seizure-like activity on long-term potentiation (LTP). LTP is an expression of neuronal plasticity which has been correlated with learning. Electrographic seizures (EGSs) were induced in area CA1 by electrical stimulation of CA3. Trains of tetanic stimuli were then immediately delivered to the Schaffer collateral-CA1 pathway in order to induce LTP. The subsequent LTP in these test slices was significantly lower in magnitude compared to LTP in control slices (with no EGSs). LTP could be successfully induced in test slices 1 h after the EGS. EGSs alone produced no long-lasting effect on baseline responses. These results indicate that the hippocampal slice preparation may serve as a model system in which to study the mechanisms by which seizures can disrupt neuronal plasticity.
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PMID:Seizure-like activity disrupts LTP in vitro. 829 25

Our previous studies have demonstrated that FK960 (FR59960; N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate), a novel antidementia piperazine derivative, exerts beneficial effects on memory deficits in various animal models of amnesia in rats [M. Yamazaki, N. Matsuoka, N. Maeda, Y. Ohkubo, I. Yamaguchi, FK960 N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate ameliorates the memory deficits in rats through a novel mechanism of action, J. Pharmacol. Exp. Ther., 279 (1996) 1157-1173.] and in rhesus monkeys [N. Matsuoka, T.G. Aigner, FK960 [N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate], a novel potential antidementia drug, improves visual recognition memory in rhesus monkeys: comparison with physostigmine, J. Pharmacol. Exp. Ther., 280 (1997) 1201-1209]. To clarify the synaptic mechanisms of its antiamnesic action, FK960 was investigated for its effects on the development of long-term potentiation (LTP) in guinea-pig hippocampal slices. The magnitude of LTP of population spike recorded in CA3 pyramidal neurons was significantly augmented by perfusing FK960 (10-9-10-6 M) for 25 min before and during tetanic stimulation of the mossy fibers, whereas the basal amplitude of population spikes before tetanus was hardly affected by the drug. The dose-response curve was bell-shaped with a maximal augmentation at 10-7 M. Scopolamine (10-6 M) per se had little effect on the magnitude of LTP in the mossy fiber-CA3 pathway, but significantly attenuated its enhancement by FK960 (10-7 M). In hippocampal slices from animals treated with cysteamine (200 mg/kg, s.c.), which was shown to deplete the hippocampal somatostatin, FK960 (10-7 M) hardly affected the LTP. These results suggest that FK960 enhances the magnitude of LTP in the mossy fiber-CA3 pathway through an activation of the cholinergic-somatostatinergic link in the hippocampal formation. Furthermore, it can be postulated that the drug regulates the cognitive function by modulating directly synaptic plasticity in the hippocampal neuronal network.
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PMID:FK960, a novel potential anti-dementia drug, augments long-term potentiation in mossy fiber-CA3 pathway of guinea-pig hippocampal slices. 962 44

We previously reported that dehydroevodiamine.HCl (DHED) has anticholinesterase and antiamnesic activities. To verify the effects of DHED on cognitive deficits further, we tested it on the scopolamine-induced amnesia model of the rat using the passive avoidance and eight-arm radial maze tests. A single (20 mg/kg p.o.) and repeated (10 mg/kg p.o.) administrations of DHED could significantly reverse the latency time shortened by scopolamine (1 mg/kg i.p.) to control level. The impaired spatial working memory induced by scopolamine (1 mg/kg i.p.) was also improved significantly by a single injection (6.25 mg/kg i.p.) and repeated administrations of DHED (10 mg/kg p.o.) in the eight-arm radial maze test. In addition, we examined the effects of DHED on the memory impairment and the histological changes of the brain after unilateral electrolytic lesion of the entorhinal cortex (EC) and middle cerebral artery occlusion in rats. The cognitive deficits caused by EC lesion and middle cerebral artery occlusion were improved significantly by repeated administrations of DHED (6.25 mg/kg i.p.) after EC lesion or ischemic insult once a day for 7 days in the passive avoidance test. Histological analysis showed that the neuronal loss in the DHED-treated group was notably reduced in the hippocampal area (CA1) of ischemic rats and in the dentate gyrus and hippocampal area (CA1 and CA3) of EC-lesioned rats compared with the nontreated group. The infarction area was decreased significantly by a single administration of DHED (6.25 mg/kg i.p.) 30 min before ischemic insult for 6 h. These results suggest that DHED might be an effective drug for not only the Alzheimer's disease type, but also the vascular type of dementia.
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PMID:Dehydroevodiamine.HCl prevents impairment of learning and memory and neuronal loss in rat models of cognitive disturbance. 1061 26

There is accumulating evidence suggesting that synapse formation in the adult brain is dynamically regulated, and that this regulation plays a role in cognitive function. A decrease in synaptic density is reportedly related to memory deficits in aged animals as well as in Alzheimer's patients. FK960 [N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate], a novel anti-dementia drug, has been shown to ameliorate experimental amnesia in rats and monkeys through activation of the somatostatinergic nervous system in the hippocampus. Furthermore, FK960 has been shown to be considerably more effective in a model of spontaneous amnesia in aged rats than cholinesterase inhibitors. In the present electron microscopy study, we demonstrated that the density of axodendritic and axosomatic synapses in the hippocampal CA3 region of aged rats was reduced compared to young rats, and that repeated treatment with FK960 for either 3 or 21 days dose-dependently reversed these deficits in aged rats. This FK960-induced increase in synaptic density was transient and density returned to basal levels at 8 days after the final dose. In contrast, FK960 did not alter synaptic density in the cingulate cortex or hippocampal CA1 region in aged rats, nor the CA3 region of young rats. Collectively, these results suggest that FK960 can selectively and reversibly increase synaptic density in the hippocampal CA3 region of aged rats, and that this activity may play a role in its cognitive-enhancing action.
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PMID:FK960, a potential anti-dementia drug, increases synaptic density in the hippocampal CA3 region of aged rats. 1247 Aug 74

Central administration of angiotensin IV (Ang IV) and its analogues facilitates memory retention and retrieval in normal animals and reverses amnesia induced by scopolamine or by bilateral perforant pathway lesions. Ang IV binds with high affinity and specificity to a novel binding site designated the AT(4) receptor. AT(4) receptors are abundant in the medial septum and hippocampus, a cholinergic pathway associated with memory processing. The aim of this study was to determine whether AT(4) receptors in the guinea pig hippocampus were associated with the neural input from the basal forebrain. The fimbria-fornix was lesioned by a unilateral-knife cut and the brain was processed for 125I-Ang IV binding, acetylcholinesterase, and cresyl violet staining. Unilateral lesions of the fimbria-fornix significantly reduced acetylcholinesterase staining in the ipsilateral hippocampus. The loss in cholinergic input to the hippocampus was associated with a small, but significant, reduction in 125I-Ang IV binding in the CA2 (-9%; P=0.001), and CA3 (-5%; P=0.003) of the rostral hippocampus. No other changes in 125I-Ang IV binding were observed. These results provide evidence that the majority of AT(4) receptor binding occurs in a post-synaptic locus in the guinea pig hippocampus.
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PMID:Effect of fimbria-fornix lesion on 125I-angiotensin IV (Ang IV) binding in the guinea pig hippocampus. 1285 May 65

Herpes simplex virus-derived amplicon vectors simultaneously expressing the open reading frame encoding NR1 subunit of the NMDA receptor, either in sense or antisense orientation, as well as the open reading frame encoding the green fluorescent protein (GFP), as distinct transcription units, were constructed. Vector expression in cells was demonstrated by GFP-fluorescence, immunofluorescence, Western blots and RT-PCR. The vectors were inoculated into the dorsal hippocampus of adult male rats, which were then trained for habituation to an open field and for inhibitory avoidance to a foot-shock. Those animals injected with vectors expressing NR1 protein showed habituation to a new environment, and achieved the criteria for a step-down inhibitory avoidance to a foot-shock. In contrast, animals injected with vectors carrying the NR1 open reading frame in antisense position, showed neither habituation nor appropriate performance in the inhibitory avoidance task. There was no evidence for motor impairment or motivational disturbance, since all the animals exhibit similar behavior and performance in the training sessions. Hence, the impaired performance might be due to either amnesia or disability to record events. Transgene expression in brain, as revealed by GFP fluorescence, was mainly observed in pyramidal cells of CA1, but also in CA3. Therefore, our results strongly support the participation of hippocampal NR1 subunit in habituation to a new environment, but also in recording events for the inhibitory avoidance task. Hence, amplicon vectors appear to be useful tools to modify endogenous gene expression at a defined period, in restricted brain regions, and should allow investigating in vivo functions of genes.
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PMID:Hippocampal infection with HSV-1-derived vectors expressing an NMDAR1 antisense modifies behavior. 1288 67

Amyloid beta-peptide (Abeta) plays an important role in the pathophysiology of Alzheimer's disease. The relationship between amnesia induced by central administration of aggregated Abeta(25-35) and neurodegeneration in the hippocampus was investigated. One month after a single intracerebroventricular injection of Abeta(25-35) (15 nmol), male Wistar rats were tested in an eight-arm radial maze. A quantitative evaluation of cell number in hippocampal regions was carried out on H&E-stained brain sections of rats used in the behavioral study. Indices of free radical-mediated processes in the hippocampus were evaluated in additional groups of animals 1, 3, 5, and 30 days after surgery. Abeta(25-35) induced impairments of working and reference memory (RM) as well as neurodegeneration in the CA1 but not in the CA3 field of the hippocampus. A significant correlation between both reference and working memory (WM) impairments and the neuronal cell loss in the hippocampal CA1 region was demonstrated. A gradually developing oxidative stress was evident in the hippocampus of rats treated with Abeta(25-35) as indicated by the increase in 2-thiobarbituric acid (TBARS) reactive substances and superoxide generation. These data suggest the involvement of oxidative stress in Abeta(25-35)-induced neurodegeneration and a relation between memory impairment and neurodegeneration in the CA1 subfield of the hippocampus.
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PMID:Amyloid-beta(25-35)-induced memory impairments correlate with cell loss in rat hippocampus. 1498 98

A neural model is described of how adaptively timed reinforcement learning occurs. The adaptive timing circuit is suggested to exist in the hippocampus, and to involve convergence of dentate granule cells on CA3 pyramidal cells, and N-methyl-D-aspartate (NMDA) receptors. This circuit forms part of a model neural system for the coordinated control of recognition learning, reinforcement learning, and motor learning, whose properties clarify how an animal can learn to acquire a delayed reward. Behavioral and neural data are summarized in support of each processing stage of the system. The relevant anatomical sites are in thalamus, neocortex, hippocampus, hypothalamus, amygdala and cerebellum. Cerebellar influences on motor learning are distinguished from hippocampal influences on adaptive timing of reinforcement learning. The model simulates how damage to the hippocampal formation disrupts adaptive timing, eliminates attentional blocking and causes symptoms of medial temporal amnesia. Properties of learned expectations, attentional focussing, memory search and orienting reactions to novel events are used to analyze the blocking and amnesia data. The model also suggests how normal acquisition of subcortical emotional conditioning can occur after cortical ablation, even though extinction of emotional conditioning is retarded by cortical ablation. The model simulates how increasing the duration of an unconditioned stimulus increases the amplitude of emotional conditioning, but does not change adaptive timing; and how an increase in the intensity of a conditioned stimulus 'speeds up the clock', but an increase in the intensity of an unconditioned stimulus does not. Computer simulations of the model fit parametric conditioning data, including a Weber law property and an inverted U property. Both primary and secondary adaptively timed conditionings are simulated, as are data concerning conditioning using multiple interstimulus intervals (ISIs), gradually or abruptly changing ISIs, partial reinforcement and multiple stimuli that lead to time-averaging of responses. Neurobiologically testable predictions are made to facilitate further tests of the model.
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PMID:A neural network model of adaptively timed reinforcement learning and hippocampal dynamics. 1549 33


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