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PubMed2003

Prenatal administration of morphine decreases CREBSerine-133 phosphorylation and synaptic plasticity range mediated by glutamatergic transmission in the hippocampal CA1 area of cognitive-deficient rat offspring.

The central nervous system (CNS) exhibits remarkable plasticity in early life and can be altered significantly by various prenatal influences. We previously showed that prenatal exposure to morphine altered kinetic properties of N-methyl-D-aspartate (NMDA) receptor-mediated synaptic currents in the hippocampus of young rat offspring at the age of 14 days (P14). The present study further investigates whether NMDA receptor-mediated synaptic plasticity and/or cyclic adenosine monophosphate-responsive element-binding protein (CREBSerine-133), an important transcription factor underlying learning and memory, can be altered by prenatal morphine exposure in these offspring. Subsequently, the Morris water maze task was performed at the older ages (P28-P31). The magnitude of long-term depression (LTD) generated by a low-frequency stimulation (LFS, 1 Hz for 15 min) in hippocampal slices from the vehicle-control offspring (P14) was significantly larger than that in slices from the morphine-treated offspring, although there was no such difference in the magnitude of long-term potentiation (LTP) elicited by a high-frequency stimulation (100 Hz for 1 s) between the two groups. Comparison of the expression range of glutamatergic synaptic plasticity in slices from the vehicle-control and morphine-treated offspring, calculated as the difference in the maximal magnitude between LTP and LTD, demonstrated a remarkably smaller range in the slices from the morphine-treated offspring. In addition, the decreased phosphorylation of CREBSerine-133 and the impaired ability of spatial learning were also seen in the morphine-treated offspring, as compared with the vehicle-control offspring. Collectively, the study suggests that maternal exposure to morphine reduces the range of synaptic plasticity by decreasing the expression of LTD, but not of LTP, in CA1 pyramidal neurons of the hippocampus from rat offspring. More importantly, decreased phosphorylation of CREBSerine-133 may play a role for the impaired spatial learning and memory in rat offspring exposure to prenatal morphine. Thus, the findings here may provide important insights into cellular/molecular mechanisms underlying pathophysiological changes in the CNS of young offspring from morphine-addicted mothers and serve as a basis for possible therapeutic intervention.

Animals↗
PubMed1996

Cognitive effects of neonatal hippocampal lesions in a rat model of schizophrenia.

Lesioning the ventral hippocampus of neonatal rats has been proposed as an experimental model of schizophrenia. This lesion causes a syndrome of hyperresponsivity to the stimulant effects of amphetamine, impaired grooming and disrupted social interactions, effects that emerge during adolescence, much like schizophrenia. Persisting cognitive effects of neonatal ventral hippocampal lesions were assessed in the current study, because the hippocampus is critically important for a variety of cognitive functions and cognitive impairment and because it is an important feature of schizophrenia. Spatial learning and working memory were assessed in the radial-arm maze, which is sensitive to the adverse effects of hippocampal lesions made in adults. Lesioned rats showed pronounced deficits in radial-arm maze choice accuracy that persisted throughout training. Deficits were seen during the prepubertal period as well as in adulthood. Even though the lesioned rats performed more poorly, they were significantly less sensitive to the amnestic effects of the nicotinic antagonist mecamylamine and the muscarinic antagonist scopolamine. No significant effects of nicotine or amphetamine were seen in either the lesioned or control groups. The long-lasting deficits in spatial learning and working memory resulting from neonatal ventral hippocampal lesions show that, unlike frontal cortical lesions during the same age, the effects of hippocampal lesions are not overcome during development. The resistance to the amnestic effects of nicotinic and muscarinic acetylcholine (ACh) antagonists suggests that the hippocampus is a critical site for the action of these drugs. Neonatal hippocampal lesions may provide a good model of the cognitive impairments of schizophrenia and may be useful to assess novel drug effects to counteract the cognitive deficits in schizophrenia.

Amphetamine↗
PubMedDate not supplied

Training in the Morris water maze occludes the synergism between ACPD and arachidonic acid on glutamate release in synaptosomes prepared from rat hippocampus.

We report here that release of glutamate, inositol phospholipid metabolism, and protein kinase C (PKC) activity are increased in synaptosomes prepared from hippocampi of rats that had been trained in a spatial learning task. In hippocampi obtained from animals that were untrained, activation of the metabotropic glutamate receptor by the specific agonist trans-1-amino-cyclopentyl-1,3-dicarboxylate (ACPD) increased release of glutamate but only in the presence of a low concentration of arachidonic acid. A similar interaction between arachidonic acid and ACPD was observed on inositol phospholipid turnover and on PKC activity. However, the synergistic effect of arachidonic acid and ACPD on glutamate release was occluded in hippocampal synaptosomes prepared from trained rats. Occlusion of the effect on inositol phospholipid turnover and PKC activation was also observed. These data suggest that the molecular changes that underlie spatial learning may include activation of metabotropic glutamate receptors in the presence of arachidonic acid and that the interaction between arachidonic acid and ACPD triggers the presynaptic changes that accompany learning.

Animals↗
PubMed2003

Neurobehavioral changes resulting from recombinase activation gene 1 deletion.

Recombinase activation gene 1 (RAG-1) function is essential for V(D)J recombination in T-cell-receptor and immunoglobulin rearrangements whereby the immune system may encode memories of a vast array of antigens. The RAG-1 gene is also localized to neurons in the hippocampal formation and related limbic regions that are involved in spatial learning and memory as well as other parameters of neurobehavioral performance. Since the unique ability to encode memory is shared by the immune system and the brain, we tested the hypothesis that loss of the RAG-1 gene in the brain would influence learning and memory performance and examined several different domains of behavior in RAG-1-knockout and control mice. Compared to control mice, RAG-1-knockout mice exhibited increased locomotor activity in an open field under both dim and bright lighting conditions and decreased habituation (reduction in the expected decline in locomotor activity with increasing familiarity with the novel environment in a 1-h test session) in bright lighting. RAG-1-knockout mice also showed reduced levels of fearfulness for some measures of fear-motivated behavior in both the open-field behavior test and elevated-plus maze test. Contrary to our hypothesis, no differences in spatial learning and memory were found between the groups, although modest differences were observed visible-platform testing in the Morris water maze. Neither prepulse inhibition, a measure of sensorimotor gating, nor reflexive acoustic startle responses differed between the RAG-1-knockout and control mice. It remains to be determined if these changes are due to the loss of RAG-1 gene expression in the brain, are due to the absence of the gene in the immune system (e.g., the loss of cytokines with neuromodulatory activities), or are due to some combination of both effects. Study of the neurobiological actions of RAG-1 in the brain may provide new insights into important processes involved in normal brain function and disease.

Animals↗
PubMedDate not supplied

Behavioral activity of angiotensin II after stimulation of L-arginine/nitric oxide pathway in rats.

This study was conducted to determine what, if any, role L-arginine [an endogenous donor of nitric oxide (NO)] plays in the behavioral changes induced by angiotensin II (AII) in rats. The motility, stereotypy, spatial learning performance, learning of conditioned avoidance response and retention of passive avoidance behavior allowing to avoid aversive stimulation were investigated. Saline (0.9% NaCl), AII, L-arginine and AII combined with L-arginine were injected 15 min before the experiment into lateral cerebral ventricles (icv). L-arginine significantly enhanced locomotor activity while the treatment with AIIplus L-arginine reduced number of bar approaches in the open field test. AII, L-arginine and AII combined with L-arginine (but not with D-arginine) significantly accelerated acquisition of conditioned avoidance responses and not significantly improved recall of the passive avoidance. Only L-arginine displayed a tendency to inhibit acquisition of spatial learning on the second day of investigation in the Morris water maze. AII, L-arginine and AII with L-arginine applied immediately before the experiment intensified stereotypy evoked by apomorphine at a dose of 1 mg/kg and amphetamine at a dose of 7.5 mg/kg given intraperitoneally. These results showed that: 1) L-arginine as a donor of NO might be involved in memory and learning processes, 2) overproduction of NO did not change behavioral effects of AII in these experiments.

Amphetamine↗
PubMed1996

Radial maze performance, open-field and elevated plus-maze behaviors in Fyn-kinase deficient mice: further evidence for increased fearfulness.

Fyn-deficient mice produced by inserting the beta-galactosidase gene (lacZ) into the fyn gene locus were tested in a radial maze, an open field and an elevated plus-maze. In the radial maze, the homozygous Fyn-deficient (fynz/fynz) mice showed no impairment in spatial learning, although they showed a stronger avoidance tendency for those arms located closer to the experimenter during pretraining (adaptation). In the open-field test, the fynz/fynz mice defecated more frequently in the bright condition than did the +/fynz mice, and they were less active during the first 10-min test period than the +/fynz mice. In addition, the temporal pattern of locomotor activity for fynz/fynz mice was altered by changing the illumination while the pattern for +/fynz mice remained relatively unchanged. Scores reflecting the fear-response in the elevated plus-maze were higher in the fynz/fynz mice. These results indicate that Fyn deficiency increased fear-response, but did not impair spatial learning in the radial maze. It is suggested that we should take account of effects of emotional factors in the learning experiment using mutant mice.

Animals↗
PubMed2003

Hilar neuropeptide Y interneuron loss in the aged rat hippocampal formation.

Neuropeptide Y-immunoreactive (NPY-I) interneurons in the dentate gyrus are vulnerable to various insults, including septohippocampal cholinergic deafferentation. The present study examined whether a loss of NPY-I neurons occurs during aging, when the functional integrity of the septohippocampal pathway is thought to be compromised. Sets of male Long Evans rats (consisting of young and aged rats, with and without spatial learning impairments assessed by the Morris water maze) were examined. Light microscopic analysis revealed that hilar NPY-I neuronal number in matched dorsal sections was significantly decreased in aged compared to young rats. Ultrastructural analysis disclosed that the microenvironment (the types of processes apposed to the plasmalemmal surface) of NPY-I neurons also differed significantly between young and aged rats. In particular, a subgroup of NPY-I neurons, distinguished by a higher percentage of unmyelinated axon coverage of the plasmalemmal surface, was present in young, but not aged, rats. Neither the number nor the microenvironment of NPY-I neurons significantly differed between aged animals that were impaired versus unimpaired in spatial learning performance. To our knowledge these findings represent the first report of an age-associated decline in the number of a specific, neurochemically identified neuronal subpopulation within the hippocampal formation. Additionally, they closely parallel observations in 192 IgG-saporin-lesioned animals, suggesting that a distinct subgroup of NPY-I interneurons is particularly dependent on the viability of septohippocampal cholinergic innervation for its survival. Since neuronal loss was not correlated with performance, this alteration by itself does not appear to be sufficient to produce learning impairment.

Age Factors↗
PubMed1997

SDZ ENA 713 facilitates central cholinergic function and ameliorates spatial memory impairment in rats.

We have clarified the effects of SDZ ENA 713 (ENA), a new phenyl-carbamate derivative, on the spatial learning impairment and neurochemical indices of central cholinergic neurons in rats. Basal forebrain (BF) lesioning with ibotenic acid markedly impaired acquisition ability in the water maze task without changing swimming rates and decreased choline acetyltransferase (ChAT) activity in the frontal cortex of rats. ENA (0.1, 0.2 mg/kg, p.o.) significantly ameliorated the impairment in acquisition ability in a dose-dependent manner. At 0.2 mg/kg, ENA prevented the reduction in ChAT activity. In normal rats, ENA (1 mg/kg, p.o.) increased extracellular ACh concentration of the prefrontal cortex. On the other hand, tissue concentrations of norepinephrine, serotonin, dopamine and their metabolites were not changed in the frontal cortex, hippocampus and striatum of normal rats. These results suggest that ENA ameliorates spatial learning disability by not only facilitating the cholinergic transmission, but normalizing impaired ChAT activity in the learning-impaired rat model.

Animals↗
PubMed1998

Aging of glutamate receptors: correlations between binding and spatial memory performance in mice.

C57B1/6 mice aged 3, 10, and 26 months were tested for spatial learning in the Morris water maze. Ten and 26 month old mice were ad libitum-fed or diet restricted (60% of ad libitum-fed calories). Diet restriction significantly improved memory performance among the 10 and 26 month olds. In age/diet group comparisons, aged ad libitum-fed mice had significantly higher average proximity scores, indicating poorer performance, in probe trials for place learning than the 3 month olds and diet restricted 10 month olds. Diet restricted 26 month olds did not differ significantly from 3 month olds or any other groups in probe trial measures. The group means for average proximity scores were significantly correlated with binding densities for the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors in the frontal cortex and CA1 region of the hippocampus. Alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate (AMPA) binding correlated with group proximity scores in frontal and parietal cortices and within the CA1 and CA3 regions of the hippocampus. Kainate and metabotropic binding sites showed no significant correlations with behavior. These results suggest that there is a sparing of spatial memory with diet restriction in aging C57B1/6 mice and that the effects of aging on NMDA and AMPA receptors may be associated with age-related declines in spatial learning.

Aging↗
PubMed2003

Effects of early training and nicotine treatment on the performance of male NMRI mice in the water maze.

This research aimed to evaluate the effect of nicotine treatment and prior training on a spatial learning task in differently aged NMRI male mice. In a longitudinal study, mice were randomly assigned to one of 14 experimental groups receiving different combinations of chronically injected nicotine (0.35 mg/kg) administered for 10 days (5 days before and during 5 days acquisition of task) or control treatments and training in the water maze at different ages. The mice displayed shorter escape latencies when evaluated at 6 and 10 months than when tested in this task at 2 months for the first time, demonstrating that early training preserves performance in the water maze up to 8 months after the initial experience. Nicotine treatment did not significantly change performance in the water maze at any age tested. Early practice in a spatial reference memory task appears to have lasting consequences and can potentially contribute to preventing some age-related spatial learning deficits.

Aging↗
PubMed2002

Effect of naloxone on cognitive function in vascular dementia in rats.

BACKGROUND & OBJECTIVES: The endogenous opioid system plays an important role in cognitive functions and may also contribute to the progression of some kind of dementia. Naloxone has been shown to exert beneficial effects on memory deficits in patients with senile dementia and reverse some of the effects induced by endogeneous opioids. We therefore investigated the effects of naloxone on cognitive function in rats with vascular dementia (VD). METHODS: Vascular dementia was established by permanent occlusion of the common carotid arteries. Rats were divided into three groups viz., sham-operated controls, naloxone treated VD rats (naloxone 0.8 mg/kg, i.p. daily for 7 days), and nontreated VD rats. The Morris water maze test was performed to study spatial learning and memory. The extracellular recording technique was used to record long-term potentiation (LTP) of the Schaffer collateral-CA1 synapse in the rat hippocampal slices. RESULTS: In the hidden platform trials, escape latencies of the naloxone treated VD rats were significantly shorter than that of the nontreated VD rats (P < 0.001). In the probe trials, the number of enteries in the target area of the naloxone treated VD rats (8.36 +/- 1.38 times/min) were more than that of the nontreated VD rats (4.64 +/- 1.73 times/min) (P < 0.01). The magnitudes of LTP recorded in the CA1 pyramidal neurons of the naloxone treated VD rats were significantly augmented when compared to the nontreated VD rats (P < 0.05). INTERPRETATION & CONCLUSION: Naloxone could facilitate spatial learning and memory and enhance LTP in the CA1 region of hippocampus in rats with VD. It is postulated that naloxone might exert beneficial effects on cognitive function in VD in rats by modulating the synaptic plasticity in the hippocampal neuronal network.

Animals↗
PubMed2005

Correlation of hippocampal morphological changes and morris water maze performance after cortical contusion injury in rats.

OBJECTIVE: The hippocampus is essential to the processing and formation of memory. This study analyzed the relationship among memory dysfunction as revealed by Morris water maze (MWM) trial, cortical lesion volume, and regional hippocampal morphological changes after controlled cortical contusion (CCC). We also analyzed the influence of pretreatment with the nitrone radical scavenger alpha-phenyl-N-tert-butyl-nitrone (PBN). METHODS: Rats were subjected to CCC. We used two levels of CCC (mild, 1.5 mm and severe, 2.5 mm) and pretreated some severely injured animals with PBN. The animals were killed 15 days postinjury. We evaluated morphological changes to the hippocampus semiquantitatively by scoring sections immunohistochemically stained for microtubule-associated protein 2 with a four-point scale for the cornu ammonis (CA) 1, CA2, CA3, and hilus of the dentate gyrus (HDG). The cortical lesion volume was quantified. RESULTS: Rats subjected to severe, but not mild, CCC demonstrated impaired spatial learning ability in the MWM, but this impairment was attenuated with pretreatment with the radical scavenger PBN. We documented bilateral morphological changes in CA1, CA3, and HDG and an ipsilateral neocortical cavitation in severely injured rats. PBN treatment attenuated (P < 0.05) the morphological characteristics of abnormality in the ipsilateral CA1, CA2, HDG, and the contralateral HDG and reduced the cortical lesion volume. Mild injury led to minor ipsilateral hippocampal and cortical damage but no MWM deficiency. Hippocampal morphological scores and total mean latencies in the MWM task were strongly correlated (r = 0.69; P < 0.001). The correlation between the cortical lesion volume and MWM latency was weaker (r = 0.48; P = 0.02). CONCLUSION: Severe CCC causes bilateral morphological changes in the hippocampus and ipsilateral neocortical cavitation, which correlate to impairment in a spatial learning task (MWM). PBN protected the structure of the CA2 ipsilaterally and HDG bilaterally and reduced the cortical lesion volume, correlating to improved functional outcome.

Animals↗
PubMedDate not supplied

[Spatial memory in bank voles (Clethrionomys glareolus Schreb) assessed in the cue-controlled open field with the place of refuge].

The capacity of bank voles (Clethrionomys glareolus Schreb) for rapid spatial learning was assessed in cue-controlled open field using their species-specific habits (high fear). Animals were tested in open field after 3 days of pretraining. During testing, novel stimuli (black-and-white geometric figures arranged in symmetric or asymmetric modes for different vole groups) were attached to a curtain surrounding the open field, and a shelter (a familiar box from the home cage) was introduced into the field. Testing consisted of four 10-min trials, the last (probe) trial was performed without the shelter. Time spent in different fielld areas was recorded. The voles remembered previous location of the shelter and preferred to visit this area. It was possible only in the condition with asymmetric arrangement of visual stimuli when animals could use them for navigation. The findings conclude that bank vole have a good capacity for rapid spatial learning.

Animals↗
PubMed1995

The selective 5-HT3 receptor antagonist, WAY100289, enhances spatial memory in rats with ibotenate lesions of the forebrain cholinergic projection system.

The effects of three doses (0.003, 0.03 and 1.0 mg/kg sc) of the 5-HT3 receptor antagonist, WAY 100289, on spatial learning and memory in the water maze were examined in rats before and after ibotenate lesions to the nucleus basalis and medial septal brain regions at the source of cholinergic projections to cortex and hippocampus. The representative cholinergic nicotinic and muscarinic receptor agonists nicotine (0.1 mg/kg) and arecoline (1.0 mg/kg) were also tested for comparison. Both arecoline and nicotine improved initial acquisition in rats before lesioning, in terms of latency to find a hidden platform and accuracy of search strategy. WAY100289 did not affect the performance of normal rats significantly, apart from some non-significant trends towards improvement with the highest dose. However, in animals showing transient navigational deficits in retention and relearning after lesioning, WAY100289 improved performance at all three doses, though ameliorative effects of nicotine and arecoline were more marked also in lesioned rats. These results show that WAY100289 improved spatial learning in animals impaired after lesions to cholinergic projection nuclei, which may reflect an interaction with cholinergic transmission to enhance cognitive function. However, in the present study, WAY100289 appeared to be less effective than direct cholinergic agonists.

Animals↗
PubMed1990

Tetrahydroaminoacridine improves the spatial acquisition deficit produced by nucleus basalis lesions in rats.

We administered tetrahydroaminoacridine (THA), a cholinesterase inhibitor, to rats with bilateral nucleus basalis magnocellularis lesions and measured their performance in a spatial learning task. The subjects, 34 male Fischer-344 rats, received bilateral excitotoxic NBM lesions; 10 other rats served as unlesioned controls. Two weeks later the animals were tested in a circular water maze for time and distance swum to find a submerged platform. We tested three different doses (5.0, 2.5, and 1.25 mg/kg) of daily subcutaneous THA against a lesioned control group receiving saline and a fifth group of untreated unlesioned controls. The saline-treated lesioned group showed a significant impairment of acquisition. The 1.25 mg/kg group performed significantly better than the lesioned controls with respect to latency. Analysis of swim speed data showed slowing in the 2.5 and 5.0 mg/kg groups. Analysis of the distance swum to find the platform, an untimed task that corrects for the difference in swim speeds, showed statistically significant improvement in all three treated groups. Additionally, spatial memory for the platform location was improved by two of the three doses of THA tested. Passive avoidance retention was not impaired by our lesion. All lesioned groups had comparable reductions of cortical choline acetyltransferase. Our data show significantly improved spatial learning with THA. These data provide an additional rationale for further clinical testing of THA and other centrally active cholinergic agents in diseases with cholinergic loss.

Acetylcholinesterase↗
PubMed1996

Spatial and nonspatial learning in mice: effects of S100 beta overexpression and age.

S100 beta, a Ca2+ binding astrocytic brain protein implicated in brain development and neurophysiology, has elevated levels in progressive neurodegenerative diseases, Down's Syndrome, and Alzheimer Disease. Transgenic mice carrying multiple S100 beta gene copies exhibited abnormal exploratory behaviors and synaptic processes suggesting hippocampal dysfunction. Here we analyze learning in a hippocampal-dependent (spatial) as well as a non-hippocampal-dependent (nonspatial) version of the Morris water maze and compare CD1 control and CD1-derived S100 beta transgenic mice. We also investigate possible progressive age-dependent effects of S100 beta overexpression by comparing two age groups of the above mice: 3- and 16-month-old. We show that 3-month-old S100 beta transgenic mice have a spatial task-specific impairment confirming a hippocampal dysfunction. However, we found the 16-month-old transgenic mice statistically indistinguishable from their normal counterparts, a result that does not confirm progressive S100 beta transgene effects. We also show that age, independently of the transgene, impairs spatial learning, spares nonspatial learning and reference memory, but leads to behavioral rigidity.

Age Factors↗
PubMed2001

Effects of binge ethanol administration on the behavioral outcome of rats after lateral fluid percussion brain injury.

This study examined the effects of 4 weeks of binge ethanol administration (BEAn) on the behavioral outcome in rats after lateral fluid percussion (FP) brain injury. Rats were intragastrically given 7.5 mL/kg of either 40% ethanol in 5% glucose solution (3 g ethanol/kg; binge ethanol group), or 5% glucose solution (vehicle group), twice on Thursday and Friday of 3 consecutive weeks. Then rats from both groups were subjected to either lateral FP brain injury of moderate severity (1.8 atm) or to sham operation. Postinjury behavioral measurements revealed that brain injury caused significant spatial learning disability in both groups. There were no significant differences in mean search latencies in the sham animals between the vehicle and binge ethanol groups. On the other hand, the mean search latency of the binge ethanol group was significantly higher than that of the vehicle group in trial blocks 2 and 4. There were no significant differences in the target visits (expressed as mean zone difference [MZD]) during the probe trial between the injured animals of binge ethanol and vehicle groups. However, there was only a minor trend towards worsened MZD score in the binge-injured animals. Histologic analysis of injured animals from both injured ethanol and vehicle groups revealed similar extents of ipsilateral cortical and observable hippocampal damage. These results suggest that 4 weeks of binge ethanol treatment followed by ethanol intoxication at the time of injury worsens some aspects of the spatial learning ability of rats. This worsening is probably caused by subtle, undetectable morphologic damage by binge ethanol administration.

Animals↗
PubMed2001

Long-term behavioral and neurodegenerative effects of perinatal phencyclidine administration: implications for schizophrenia.

Both acute and chronic administration of N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine and dizocilpine have been proposed to mimic some of the symptoms of schizophrenia. The purposes of the present study were first, to characterize the long-term behavioral and neurodegenerative effects of subchronic administration of phencyclidine to perinatal rats and second, to determine whether pretreatment with olanzapine could attenuate these effects. On postnatal days 7, 9 and 11 rat pups were pretreated with either vehicle or olanzapine prior to administration of either saline or phencyclidine (10 mg/kg). Some pups were killed on postnatal day 12 for biochemical determinations and others were tested on postnatal days 24-28 for prepulse inhibition of acoustic startle, on postnatal day 42 for phencyclidine-induced locomotor activity and between postnatal days 33 and 70 for acquisition of a delayed spatial learning task. Phencyclidine treatment resulted in a substantial increase in fragmented DNA in the frontal and olfactory cortices consistent with neurodegeneration by an apoptotic mechanism. An increase in the NMDA receptor NR1 subunit mRNA was also observed in the cortex. Gel shift assays showed that phencyclidine also increased the nuclear translocation of nuclear factor-kappaB proteins in the prefrontal cortex. In tissue from the frontal cortex, western blot analysis revealed that phencyclidine treatment increased Bax and decreased Bcl-X(L) proteins. Later in development, it was observed that perinatal phencyclidine treatment significantly retarded baseline prepulse inhibition of acoustic startle measured shortly after weaning. In 42-day-old rats, it was found that challenge with 2 mg/kg phencyclidine increased locomotor activity to a significantly greater extent in the rats that had been pretreated with phencyclidine. Similarly, perinatal phencyclidine treatment significantly delayed the acquisition of a delayed spatial alternation task. Each of the aforementioned changes (except for the spatial learning task, which was not tested) was significantly inhibited by olanzapine pretreatment, an antipsychotic drug known to be effective against both positive and negative symptoms of schizophrenia. Further, olanzapine treatment for 12 days following the administration of phencyclidine was also able to reverse the phencyclidine-induced deficit in baseline prepulse inhibition. Together these data suggest that perinatal administration of phencyclidine results in long-term behavioral changes that may be mechanistically related to the apoptotic neurodegeneration observed in the frontal cortex. It is postulated that these deficits may model the hypofrontality observed in schizophrenia and that this model may be helpful in designing appropriate pharmacotherapy.

Animals↗