Biomedical subjects

D P Cain

Publications and source records attributed to D P Cain.

At least 19 recordsLinked to original sources

PubMed2003

Partial reversal of the effect of maternal care on cognitive function through environmental enrichment.

Maternal care influences hippocampal development in the rat. The offspring of mothers that exhibit increased levels of pup licking/grooming and arched-back nursing (High LG-ABN mothers) show increased hippocampal N-methyl-D-aspartate (NMDA) receptor binding and enhanced hippocampal-dependent spatial learning. In these studies we examined whether environmental enrichment from days 22-70 of life might reverse the effects of low maternal care. Environmental enrichment eliminated the differences between the offspring of High and Low LG-ABN mothers in both Morris water maze learning and object recognition. However, enrichment did not reverse the effect of maternal care on long-term potentiation in the dentate gyrus or on hippocampal NMDA receptor binding. In contrast, peripubertal enrichment did reverse the effects of maternal care on hippocampal alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor binding. These findings provide evidence for the reversal of the effects of reduced maternal investment in early life on cognitive function in adulthood. Such effects might involve compensatory changes associated with peripubertal enrichment.

Animals↗

PubMed2002

Ethanol impairs behavioral strategy use in naive rats but does not prevent spatial learning in the water maze in pretrained rats.

RATIONALE: Ethanol impairs performance in the water maze in rats. A detailed behavioral analysis is required to fully evaluate the nature of the impairment. OBJECTIVES: A detailed behavioral analysis was carried out to evaluate the effect of ethanol on performance in the water maze task in male hooded rats given 2.0 or 6.0 g/kg ethanol by gavage. Multiple measures of water maze strategies learning and spatial learning were studied. METHODS: Water maze trials were recorded on videotape and digitized for offline analysis. Some rats were naive at the start of spatial training, whereas other rats received water maze strategies pretraining prior to spatial training to familiarize them with the general behavioral strategies required in the task. RESULTS: Naive ethanol-treated rats exhibited both spatial learning and water maze behavioral strategies impairments. There was no evidence of a spatial learning impairment that was independent of an associated behavioral strategies impairment. Further, ethanol impaired the ability of naive rats to swim to a stable visible platform. Pretrained ethanol-treated rats performed significantly better than naive ethanol-treated rats on almost all measures, and were indistinguishable from controls on most measures. CONCLUSIONS: These results suggest that ethanol may impair water maze performance in naive rats by interfering with their ability to acquire and use required water maze behavioral strategies and generate adaptive swim paths. Ethanol does not prevent robust spatial learning in rats that are familiar with required water maze behavioral strategies.

Animals↗

PubMed2000

Individual and combined manipulation of muscarinic, NMDA, and benzodiazepine receptor activity in the water maze task: implications for a rat model of Alzheimer dementia.

Recent evidence indicates that Alzheimer disease typically involves different degrees of impairment in a variety of neurotransmitter systems, behaviors, and cognitive abilities in different patients. To investigate the relations between neurotransmitter system, behavioral, and cognitive impairments in an animal model of Alzheimer disease we studied spatial learning in a Morris water maze in male Long-Evans rats given neurochemical agents that targeted muscarinic cholinergic, NMDA, or benzodiazepine systems. Naive rats given a single agent or a combination of agents were severely impaired in place responding and had behavioral strategy impairments. Rats made familiar with the required water maze behavioral strategies by non-spatial pretraining performed as well as controls if given a single agent. Non-spatially pretrained rats with manipulation of both muscarinic cholinergic and NMDA or muscarinic cholinergic and benzodiazepine systems had a specific place response impairment but no behavioral strategy impairments. The results suggest that impairment of both muscarinic cholinergic and NMDA, or muscarinic cholinergic and benzodiazepine systems may model some aspects of human Alzheimer disease (impairments in navigation in familiar environments), but not other aspects of this disorder (global dementia leading to general loss of adaptive behavior). Previous research suggests that impairment of both muscarinic cholinergic and serotonergic systems may provide a better model of global dementia. The water maze testing and detailed behavioral analysis techniques used here appear to provide a means of investigating the contributions of various combinations of neurotransmitter system impairments to an animal model of Alzheimer disease.

Alzheimer Disease↗

PubMed1999

Behavioral effects of anti-muscarinic, anti-serotonergic, and anti-NMDA treatments: hippocampal and neocortical slow wave electrophysiology predict the effects on grooming in the rat.

Previous research has shown that hippocampal and neocortical activation accompanies the postural changes occurring during self-grooming in rats but is absent or reduced during the stereotyped components of grooming, including head-washing and licking or biting. Since electrocortical activation is dependent on ascending cholinergic and serotonergic projections, we hypothesized that central muscarinic and serotonergic blockade would disrupt grooming by degrading cerebral control of changes in posture. Consistent with this, we find that systemic injections of scopolamine: (a) markedly reduce the occurrence of adaptive changes in posture during grooming; (b) reduce the probability of transitions from head-washing to body grooming; (c) reduce both the probability and duration of sequences of body grooming; and (d) do not affect the duration of head-washing or the probability of transitions from washing the snout to washing over the top of the head. Destruction of central serotonergic neurons with intracerebral injections of 5,7-dihydroxytryptamine increases the tendency of scopolamine to shorten the duration and increase the number of separate sequences of grooming. Systemic injections of a NMDA antagonist (CGS 19755) also impair grooming behavior. The data show that blockade of muscarinic and glutamatergic transmission impairs instinctive behavior as well as learned behavior and that the behavioral effects of muscarinic and serotonergic blockade are consistent with data obtained from the study of cortical slow wave electrophysiology.

5,7-Dihydroxytryptamine↗

PubMed1999

Complex behavioral strategy and reversal learning in the water maze without NMDA receptor-dependent long-term potentiation.

Successful performance of the water maze task requires that rats learn complex behavioral strategies for swimming in a pool of water, searching for and interacting with a hidden platform before its spatial location can be learned. To evaluate whether NMDA receptor-dependent long-term potentiation (NMDA-LTP) is required for learning the required behavioral strategies, rats with NMDA-LTP blocked by systemic pharmacological treatment were trained in the behavioral strategies using simplified and stepwise training methods. Despite the blockade of NMDA-LTP in the dentate gyrus and hippocampal area CA1, rats learned the required behavioral strategies and used them to learn both initial and reversed platform locations. This is the first evaluation of the role of NMDA-LTP specifically in behavioral strategy learning. Although hippocampal NMDA-LTP might contribute to the water maze task, this form of LTP is not essential for learning complex behavioral strategies or multiple hidden platform locations.

Animals↗

PubMed1998

Testing the NMDA, long-term potentiation, and cholinergic hypotheses of spatial learning.

The problems and issues associated with the use of pharmacological antagonists in studies on learning and memory are considered in a review of the role of N-methyl-D-aspartate (NMDA) receptors, NMDA receptor-mediated long-term potentiation (LTP), and muscarinic receptors in spatial learning in the water maze. The evidence indicates that neither NMDA nor muscarinic receptors, nor NMDA receptor-mediated LTP, are required for spatial learning, although they might normally contribute to it. Detailed behavioral analyses have indicated that the water maze task is more complex than generally has been appreciated, and has a number of dissociable components. Naive rats trained under NMDA or muscarinic antagonism display sensorimotor disturbances that interfere with their ability to acquire the task. Rats made familiar with the general requirements of the task can learn the location of a hidden platform readily under NMDA or muscarinic antagonism. The ability of a rat to acquire the water maze task depends on its ability to apply instinctive behaviors to performance of the task in an adaptive manner. The instinctive behaviors undergo modification as the rat learns the general strategies required in the task. The evidence suggests that at least some of the plastic changes involved in acquiring the task occur in existing neural circuits situated in widespread areas of the brain, including sensory and motor structures in the cortex and elsewhere, and are therefore difficult to distinguish from existing sensorimotor mechanisms. More generally, the findings indicate the difficulty of inferring the occurrence or nonoccurrence of learning from behavior, and the difficulty of causally linking the action of particular receptor populations with the formation of specific memories.

Animals↗

PubMed1998

Behavioural, physiological and morphological analysis of a line of apolipoprotein E knockout mouse.

Using apolipoprotein E knockout mice derived from the Maeda source [Piedrahita J. A. et al. (1992) Proc. natn. Acad Sci. US.A. 89, 4471 4475], we have studied the influence of apolipoprotein E gene deletion on normal CNS function by neurological tests and water maze learning, hippocampal ultrastructure assessed by quantitative immunocytochemistry and electron microscopy, CNS plasticity, i.e. hippocampal long-term potentiation and amygdaloid kindling, and CNS repair, i.e. synaptic recovery in the hippocampus following deafferentation. In each study there was little difference between the apolipoprotein E knockout mice and wild-type controls of similar age and genetic background. Apolipoprotein E knockout mice aged eight months demonstrated accurate spatial learning and normal neurological function. Synaptophysin and microtubule-associated protein 2 immunohistochemistry and electron microscopic analysis of these animals revealed that the hippocampal synaptic and dendritic densities were similar between genotypes. The induction and maintenance of kindled seizures and hippocampal long-term potentiation were indistinguishable between groups. Finally, unilateral entorhinal cortex lesions produced a marked loss of hippocampal synaptophysin immunoreactivity in both groups and a marked up-regulation of apolipoprotein E in the wild-type group. Both apolipoprotein E knockout and wild-type groups showed immunohistochemical evidence of reactive synaptogenesis, although the apolipoprotein E knockout group may have initially shown greater synaptic loss. It is suggested that either apolipoprotein E is of no importance in the maintenance of synaptic integrity and in processes of CNS plasticity and repair, or more likely, alternative (apolipo)proteins may compensate for the loss of apolipoprotein E in the knockout animals.

Animals↗

PubMed1997

Prior non-spatial pretraining eliminates sensorimotor disturbances and impairments in water maze learning caused by diazepam.

Diazepam has been reported to impair spatial learning in the water maze. This experiment reexamined this topic using control groups that had first been non-spatially pretrained to familiarize them with the general behavioral strategies required in the water maze task. Naive rats given diazepam (0.5, 3.0, 6.0 mg/kg, IP) displayed dose-related maze acquisition impairments and sensorimotor disturbances (swimming in the periphery of the pool, deflecting off or swimming over the hidden platform, jumping off the platform when placed there after a trial, ataxia on a narrow wooden beam). The sensorimotor disturbances interfered with the acquisition of information about the spatial location of the platform, occurred in the absence of impairments in a subsequent visible platform task or swim speed, and correlated strongly with measures of acquisition. In contrast, the non-spatially pretrained groups did not exhibit sensorimotor disturbances in the water maze and acquired the maze task as rapidly under diazepam as control rats. The non-spatially pretrained groups continued to display diazepam-induced sensorimotor disturbances (ataxia) in a novel beam walking task. CGS8216 (10.0 or 20.0 mg/kg), a benzodiazepine receptor antagonist, attenuated the effect of 3.0 or 6.0 mg/kg diazepam in naive rats, suggesting that the effects of diazepam were mediated by benzodiazepine receptors. Occupancy of benzodiazepine receptors by diazepam does not prevent robust spatial learning in the water maze.

Animals↗

PubMed1997

Testing hypotheses of spatial learning: the role of NMDA receptors and NMDA-mediated long-term potentiation.

The role of NMDA receptors and NMDA-mediated hippocampal long-term potentiation (LTP) in spatial learning was studied in rats using the competitive, systemically administered NMDA receptor antagonists CGS19755 ((+/-)-cis-4-phosphonomethyl-2-piperidine carboxylic acid) and NPC17742 (2R,4R,5S-2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid). CGS19755 caused sensorimotor disturbances and disrupted acquisition of the water maze in naive rats. The sensorimotor disturbances were greatly reduced and maze learning was normal in spite of the blockade of dentate gyrus LTP by CGS19755 in rats that had first been familiarized with the general task requirements by non-spatial pretraining. In a second experiment, antagonism of NMDA receptors caused small, but reliable, impairments in Y-maze and visible platform visual discrimination tasks. The results indicate that NMDA receptors are not crucial for water maze acquisition using a spatial learning strategy, and that NMDA antagonists cause visual and other sensorimotor disturbances in naive rats that could help account for their poor performance in this task.

Amino Acids↗

PubMed1997

The effect of nonspatial water maze pretraining in rats subjected to serotonin depletion and muscarinic receptor antagonism: a detailed behavioural assessment of spatial performance.

A detailed behavioural analysis of water maze spatial performance in the rat was utilized to determine the effect of single and combined administration of p-chlorophenylalanine (PCPA; 1000 mg/kg, i.p.), an inhibitor of serotonin biosynthesis, and scopolamine hydrobromide (SCO; 1.0 mg/kg, i.p.), a muscarinic receptor antagonist. In some groups a water maze pretraining regimen known as non-spatial pretraining (NSP) was used to familiarize the animals with the general requirements of the task before spatial training was begun. The results showed that: (a) depletion of serotonin with PCPA had no effect on water maze performance and produced no sensorimotor disturbances; (b) antagonism of muscarinic receptors produced impairments in spatial and sensorimotor function in naive rats but neither effect was observed in rats first given NSP; (c) combined disruption of muscarinic and serotonergic function produced a severe deficit in spatial performance that was only partially alleviated by NSP; and (d) there was an association between poor maze acquisition scores and a high incidence of sensorimotor dysfunction. In addition to the water maze task the rats were also assessed for motoric performance on a beam walking test. The role of cholinergic and serotonergic systems in learning and memory is discussed.

Animals↗

PubMed1997

LTP, NMDA, genes and learning.

In the past year, several tests of the hypothesis that NMDA-dependent hippocampal long-term potentiation (LTP) underlies learning have been reported. Data from mutant mice point to a potential role for NMDA-dependent LTP in hippocampal place cell function and spatial learning, but evidence for a causal relation is not yet available. Other studies have shown that robust spatial learning is possible without NMDA-dependent hippocampal LTP. Although the current evidence for the role of LTP in learning is mixed, LTP remains the most promising neural mechanism for associative learning. Several new experimental approaches are now available for future research.

Animals↗

PubMed1997

Fractionating the nonspatial pretraining effect in the water maze task.

Nonspatial pretraining (NSP) enables rats to learn the general strategies of the water maze task (WMT; e.g., learning to swim away from the wall and to climb onto the hidden platform), reduces sensorimotor disturbances, and eliminates acquisition impairments caused by scopolamine hydrobromide, a muscarinic antagonist. To evaluate the contributions of the components of NSP to these effects, NSP was fractionated so that different groups of male rats swam, were placed onto the hidden platform, climbed onto the hidden platform, or were placed into an empty maze before spatial training under scopolamine. No single component of the NSP procedure was sufficient to produce its full effects on sensorimotor disturbances and WMT acquisition. Experience with most or perhaps all of the specific behaviors required in the WMT appears to be important for NSP to produce its full effects.

Animals↗

PubMed1996

The effects of a single neonatally induced convulsion on spatial navigation, locomotor activity and convulsion susceptibility in the adult rat.

The effect of a single neonatal convulsion on subsequent behaviour was investigated in the male rat. Convulsions were induced by heat or pentylenetetrazol on days 1, 10 or 21. As adults, locomotor activity, spatial ability and convulsion susceptibility were measured. Significant differences were seen in some measures and some groups but a single neonatal convulsion did not induce a consistent and significant pattern of behavioural change, despite the persistent change in hippocampal physiology shown in a previous study.

Aging↗

PubMed1996

Competitive NMDA receptor antagonists do not block cholinergic kindling with carbachol.

The role of NMDA receptor activity in kindling was examined in rats pretreated with the competitive NMDA receptor antagonists aminophosphonovaleric acid (APV) or NPC17742 (2R,4R,2S-(2-amino-4,5(cyclohexyl)-7-phosphonoheptanoic acid). After pretreatment, the rats received an infusion of carbachol, a muscarinic agonist, into the amygdala or hippocampus. Kindling sessions with carbachol occurred once every 48 h until a stage 5 convulsion was displayed. Electrical kindling of the amygdala after pretreatment with NPC17742 was also examined. Both APV and NPC17742 retarded the rate of carbachol kindling in its early stages, but all rats displayed kindled stage 5 convulsions under APV or NPC17742 in fewer than 10 sessions. Convulsion development was accompanied by growth in the duration and strength of the accompanying epileptiform activity. All rats exhibited a stage 5 convulsion on the first or second session after cross-over to vehicle pretreatment, confirming the development of kindled convulsions under pretreatment with NMDA antagonists. NPC17742 retarded electrical kindling, but after cross-over to vehicle there was savings in the rate of kindling to stage 5 convulsions. These findings indicate that carbachol kindling of the amygdala or hippocampus readily occurs under NMDA antagonism. They are consistent with the view that NMDA receptor activity may contribute to, but is not required for, the kindling of seizures.

2-Amino-5-phosphonovalerate↗

PubMed1996

Detailed behavioral analysis of water maze acquisition under APV or CNQX: contribution of sensorimotor disturbances to drug-induced acquisition deficits.

N-methyl-D-aspartate (NMDA) receptor antagonists disrupt acquisition of the water maze and cause sensorimotor disturbances. In a detailed behavioral analysis in male rats, it was found that the NMDA antagonist DL-2-aminophosphonovaleric acid (APV) caused sensorimotor disturbances in behaviors required for maze performance and that these correlated with acquisition impairments in both hidden and visible platform versions of the maze. Behavioral disturbances included thigmotaxic swimming, swimming over and deflecting off the platform, abnormal swim behavior, and hyperactivity. Rats familiar with the behavioral strategies involved in the task performed normally under APV. The results are consistent with the known role of NMDA receptors in sensorimotor mechanisms and suggest that drug-induced sensorimotor disturbances contributed to poor acquisition scores in naive rats. NMDA may contribute to but does not appear to be essential for spatial learning in the water maze.

2-Amino-5-phosphonovalerate↗

PubMed1996

Detailed behavioral analysis of water maze acquisition under systemic NMDA or muscarinic antagonism: nonspatial pretraining eliminates spatial learning deficits.

A detailed behavioral analysis of water-maze acquisition showed that the N-methyl-D-aspartate (NMDA) antagonist NPC17742 and the muscarinic antagonist scopolamine caused sensorimotor disturbances in behaviors required for maze performances and that these correlated with acquisition impairments in both hidden and visible platform versions of the maze in male rats. Behavioral disturbances included thigmotaxic swimming, swimming over and deflecting off the platform, abnormal swim behavior, and hyperactivity. Rats familiar with the behavioral strategies involved in the task performed normally under NPC17742 or scopolamine. The results indicated that drug-induced sensorimotor disturbances contributed to poor acquisition scores in naive rats. NMDA or muscarinic activity may contribute to but do not appear to be essential for spatial learning in the water maze.

Amino Acids↗

PubMed1995

Spatial learning without NMDA receptor-dependent long-term potentiation.

Hippocampal lesions impair spatial learning in the watermaze. Drugs that antagonize N-methyl-D-aspartate (NMDA)-receptor activity, which is required for long-term potentiation (LTP) at various hippocampal synapses, block LTP and impair watermaze learning. This has led to the hypothesis that NMDA receptors, through their involvement in LTP, may be necessary for spatial and other forms of learning. We examined this hypothesis using NPC17742 (2R,4R,5S-2-amino-4,5-(1,2-cyclo hexyl)-7-phosphonoheptano acid), a potent and specific antagonist of NMDA receptors. Here we report that NPC17742 completely blocked dentate gyrus LTP but did not prevent normal spatial learning in rats that had been made familiar with the general task requirements by non-spatial pretraining. Although these results do not rule out a contribution of NMDA-mediated dentate LTP to spatial learning, they indicate that this form of LTP is not required for normal spatial learning in the watermaze.

Amino Acids↗

PubMed1995

MK801-induced hyperactivity: duration of effects in rats.

MK801, a noncompetitive NMDA antagonist, induces hyperactivity, the duration of which is unknown. Thus, the hyperactivity induced by three different doses of MK801 was measured for 4 h using an automated open-field system. Adult male rats were habituated to the monitors for 1 h immediately prior to data collection. Rats were then administered one of three doses (0.05 mg/kg, n = 15; 0.1 mg/kg, n = 14; 0.5 mg/kg, n = 11) of MK801 or equivalent volumes of saline (n = 14). Upon injection, individual monitors were activated, and 48 consecutive 5-min samples were collected. Results indicated that MK801 induced hyperactivity in a dose-dependent fashion, with the two lower doses being significantly different from saline controls, but not from each other. The 0.5 mg/kg dose indicated that the peak behavioral activation occurred approximately 30 min after administration. This was followed by either a slow decline or a plateau phase, dependent upon the measure examined. By approximately 3 h after administration all measures had returned to the level of saline controls.

Animals↗