Biomedical subjects

Joram Feldon

Publications and source records attributed to Joram Feldon.

At least 73 records · Page 4Linked to original sources

PubMed2004

The Effects of dizocilpine and phencyclidine on prepulse inhibition of the acoustic startle reflex and on prepulse-elicited reactivity in C57BL6 mice.

Prepulse inhibition (PPI) of the acoustic startle response refers to the reduction in startle reaction to a startle-eliciting stimulus when it is shortly preceded by a subthreshold prepulse stimulus. Here, we evaluated the possible effects on prepulse-elicited reactivity by dizocilpine (MK-801) and phencyclidine (PCP) in the PPI of acoustic startle paradigm in C57BL6/J mice. The aim was to ascertain whether these two drugs would affect prepulse-elicited reactivity in a manner similar to apomorphine, which enhances prepulse-elicited reactivity at doses that disrupt PPI. In two dose-response studies, we showed that both drugs exhibited a tendency to attenuate prepulse-elicited reaction at higher doses when PPI was severely disrupted. On the other hand, at lower doses when PPI was marginally disrupted, reaction to the prepulse, if anything, tended to increase. It is concluded that PPI disruption induced by noncompetitive NMDA receptor antagonists can be distinguished from apomorphine-induced PPI disruption by their concomitant effects on prepulse-elicited reactivity. Our data support the suggestion that dopamine receptor agonists and NMDA receptor antagonists disrupt PPI via interference with distinct neural pathways or neuronal systems.

Acoustic Stimulation↗

PubMed2004

Expression of the CS- and US-pre-exposure effects in the conditioned taste aversion paradigm and their abolition following systemic amphetamine treatment in C57BL6/J mice.

In classical conditioning, pre-exposures to either the to-be-conditioned stimulus (CS) or unconditioned stimulus (US) can retard subsequent conditioning between the CS and US. The present experiment evaluated the expression of these two pre-exposure effects in mice of the C57BL6/J strain, one of the most common background strains for genetically altered mice. We tested whether their expression would be disrupted by amphetamine treatment (2.5 mg/kg, i.p.) in a conditioned taste aversion paradigm with sucrose as the CS and lithium chloride-induced gastric malaise as the US. We found that one pre-exposure (PE) to either the CS or the US reduced aversion to sucrose solution in the controls following conditioning, but no such tendency was evident in the amphetamine-treated mice. The present study represents the first report of amphetamine-induced disruption of the CS-PE effect (ie latent inhibition) in mice, and the first attempt to compare it directly with the US-PE effect in any species. It extended previous reports in rats and humans, suggesting that the sensitivity of latent inhibition to amphetamine is largely comparable across species, thereby lending credence to the use of the latent inhibition effect as a behavioral assay for psychotic-like phenotype in transgenic mice. The parallel observation in the US-PE effect further indicates that its expression, at least in the present conditioned taste aversion paradigm, may also be under similar influence of the dopaminergic system.

Amphetamine↗

PubMed2004

Dissociation of function between the dorsal and the ventral hippocampus in spatial learning abilities of the rat: a within-subject, within-task comparison of reference and working spatial memory.

Lesions restricted to the dorsal, but not the ventral, hippocampus severely impair the formation of spatial memory. This dissociation was first demonstrated using the water maze task. The present study investigated whether the dorsal and the ventral hippocampus are involved differentially in spatial reference and spatial working memory using a four-baited/four-unbaited version of the eight-arm radial maze task. This test allows the concurrent evaluation of reference and working memory with respect to the same set of spatial cues, and thereby enables a within-subjects within-task comparison between the two forms of memory functions. Rats with N-methyl-d-aspartic acid-induced excitotoxic lesions of the dorsal hippocampus, ventral hippocampus or both were compared with sham and unoperated controls. We showed that dorsal lesions were as effective as complete lesions in severely disrupting both reference and working spatial memory, whereas rats with ventral lesions performed at a level comparable with controls. These results lend further support to the existence of a functional dissociation between the dorsal and the ventral hippocampus, with the former being preferentially involved in spatial learning.

Animals↗

PubMed2004

GABA receptors containing the alpha5 subunit mediate the trace effect in aversive and appetitive conditioning and extinction of conditioned fear.

A reduction in alpha5 subunit-containing gamma-aminobutyric acid (GABA)A receptors has been reported to enhance some forms of learning in mutant mouse models. This effect has been attributed to impaired alpha5 GABAA receptor-mediated inhibitory modulation in the hippocampus. The introduction of a point mutation (H105R) in the alpha5 subunit is associated with a specific reduction of alpha5 subunit-containing GABAA receptors in the hippocampus. The present study examined the modulation of associative learning and the extinction of conditioned response in these animals. The strength of classical conditioning can be weakened when a trace interval is interposed between the conditioned stimulus and unconditioned stimulus. Here we report that this 'trace effect' in classical conditioning was absent in the mutant mice--they were insensitive to the imposition of a 20-s trace interval. This effect of the mutation was most clearly in the female mice using an aversive conditioning paradigm, and in the male mice using an appetitive conditioning paradigm. These gender-specific phenotypes were accompanied by a resistance to extinction of conditioned fear response in the mutant mice that was apparent in both genders. Our results identify neuronal inhibition in the hippocampus mediated via alpha5 GABAA receptors as a critical control element in the regulation of the acquisition and expression of associative memory.

Animals↗

PubMed2004

Genetic ablation of tumor necrosis factor-alpha (TNF-alpha) and pharmacological inhibition of TNF-synthesis attenuates MPTP toxicity in mouse striatum.

The impact of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) in the pathology of Parkinson's disease (PD) and in MPTP neurotoxicity remains unclear. Here, male TNF-alpha (-/-) deficient mice and C57bL/6 mice were treated with MPTP (4 x 15 mg/kg, 24 h intervals) and in one series, thalidomide was administered to inhibit TNF-alpha synthesis. Real-time RT-PCR revealed that the striatal mRNA levels of TNF-alpha, of the astrocytic marker glial fibrillary acidic protein (GFAP) and of the marker for activated microglia, macrophage antigen complex-1 (MAC-1), were significantly enhanced after MPTP administration. Thalidomide (50 mg/kg, p.o.) partly protected against the MPTP-induced dopamine (DA) depletion, and TNF-alpha (-/-) mice showed a significant attenuation of striatal DA and DA metabolite loss as well as striatal tyrosine hydroxylase (TH) fiber density, but no difference in nigral TH and DA transporter immunoreactivity. TNF-alpha deficient mice suffered a lower mortality (10%) compared to the high mortality (75%) seen in wild-type mice after acute MPTP treatment (4 x 20 mg/kg, 2 h interval). HPLC measurement of MPP(+) levels revealed no differences in TNF-alpha (-/-), wild-type and thalidomide treated mice. This study demonstrates that TNF-alpha is involved in MPTP toxicity and that inhibition of TNF-alpha response may be a promising target for extending beyond symptomatic treatment and developing anti-parkinsonian drugs for the treatment of the inflammatory processes in PD.

1-Methyl-4-phenylpyridinium↗

PubMed2004

Transduction profiles of recombinant adeno-associated virus vectors derived from serotypes 2 and 5 in the nigrostriatal system of rats.

We compared the transduction efficiencies and tropisms of titer-matched recombinant adeno-associated viruses (rAAV) derived from serotypes 2 and 5 (rAAV-2 and rAAV-5, respectively) within the rat nigrostriatal system. The two serotypes (expressing enhanced green fluorescent protein [EGFP]) were delivered by stereotaxic surgery into the same animals but different hemispheres of the striatum (STR), the substantia nigra (SN), or the medial forebrain bundle (MFB). While both serotypes transduced neurons effectively within the STR, rAAV-5 resulted in a much larger EGFP-expressing area than did rAAV-2. However, neurons transduced with rAAV-2 vectors expressed higher levels of EGFP. Consistent with this result, EGFP-positive projections emanating from transduced striatal neurons covered a larger area of the SN pars reticulata (SNr) after striatal delivery of rAAV-5, but EGFP levels in fibers of the SNr were higher after striatal injection of rAAV-2. We also compared the potentials of the two vectors for retrograde transduction and found that striatal delivery of rAAV-5 resulted in significantly more transduced dopaminergic cell bodies within the SN pars compacta and ventral tegmental area. Similarly, EGFP-transduced striatal neurons were detected only after nigral delivery of rAAV-5. Furthermore, we demonstrate that after striatal AAV-5 vector delivery, the transduction profiles were stable for as long as 9 months. Finally, although we did not target the hippocampus directly, efficient and widespread transduction of hippocampal neurons was observed after delivery of rAAV-5, but not rAAV-2, into the MFB.

Animals↗

PubMed2004

Evidence for altered monoamine activity and emotional and cognitive disturbance in marmoset monkeys exposed to early life stress.

In common marmoset monkeys (Callithrix jacchus, order Primates), infants aged 2-28 days were deprived of parental care for 30-120 min/day in order to investigate the long-term effects of this neglect-stress model on affect and cognition in a primate species. Basal morning levels of urinary cortisol across the first year of life were unaffected in early deprived marmosets relative to their sibling controls. Basal morning levels of urinary dopamine were chronically increased. This peripheral increase in dopamine activity could represent a marker for central dopamine hyperactivity. Certainly, subadult early deprived marmosets exhibited performance deficits in two dopamine-regulated neuropsychological tasks. They demonstrated: (1) impaired behavioral inhibition in an object reaching with detour task, exhibiting significantly more nonreinforced forward reaches to a reward visible inside a cube that could only be retrieved through an opening to the side of the cube; and (2) impaired reversal learning in a two-way discrimination task based on visual icons presented on a touch-sensitive computer screen. These findings provide further evidence for the relevance of this novel primate model of parent-infant neglect to the environmental causes and mechanisms of human developmental psychopathology.

Affective Symptoms↗

PubMed2003

Rotenone increases glutamate-induced dopamine release but does not affect hydroxyl-free radical formation in rat striatum.

Impairment of the mitochondrial complex I has been found in Parkinson's disease and recently long-term treatment with the complex I inhibitor rotenone led to neurodegeneration and Lewy body-like inclusions in rats. To investigate the relationship of free radical formation, complex I inhibition, and dopamine release, rotenone (15 mg/kg s.c.) was injected in male Sprague Dawley rats. Complex I inhibition was measured in the striatum and substantia nigra using the lactate accumulation assay. Dopamine release and free radical formation was determined using striatal microdialysis in combination with the salicylate hydroxylation assay. In a second experiment, glutamate (10 mM) stimulation via the microdialysis probe was used to provoke hydroxyl radical formation and dopamine release 60 min after rotenone or vehicle pretreatment. Rotenone significantly increased striatal and nigral lactate levels. However, rotenone did not produce a significant increase in hydroxyl radical formation and dopamine release, but led to a pronounced hypokinesia. In contrast, rotenone in comparison to vehicle pretreatment produced a significant augmentation of glutamate-induced dopamine release (67-fold and 31-fold increase, respectively) and did not affect the glutamate-induced hydroxyl free radical formation (23-fold and 21-fold increase, respectively). The present study demonstrates that a single systemic rotenone administration does not lead to neurotoxicity, but rather to enhanced glutamate-induced dopamine release with no further increase of hydroxyl free radical formation. Thus, acute complex I inhibition in the presence or absence of high extracellular dopamine and glutamate levels is not critically involved in the formation of hydroxyl free radicals.

Amphetamine↗

PubMed2003

Dopamine-dependent neurodegeneration in rats induced by viral vector-mediated overexpression of the parkin target protein, CDCrel-1.

Mutations in the parkin gene are linked to autosomal-recessive juvenile parkinsonism (AR-JP). Parkin functions as a ubiquitin protein ligase in the degradation of several proteins, including the neuron-specific septin CDCrel-1. AR-JP-associated parkin mutations inhibit ubiquitination and degradation of CDCrel-1 and other parkin target proteins. Here we show that recombinant adeno-associated virus-mediated CDCrel-1 gene transfer to the substantia nigra of rats results in a rapid onset (6-10 days) of nigral and striatal CDCrel-1 expression that is followed by a progressive loss of nigral dopaminergic neurons and a decline of the striatal dopamine levels. In contrast, neurons of the globus pallidus are spared from CDCrel-1 toxicity. Furthermore, CDCrel-1 inhibits the release of dopamine from stably-transfected PC12 cells, and pharmacological inhibition of tyrosine hydroxylase and dopamine synthesis in rats prevents CDCrel-1-induced nigral neurodegeneration. These results show that CDCrel-1 overexpression exerts dopamine-dependent neurotoxicity and suggest that inhibition of dopamine secretion by CDCrel-1 may contribute to the development of AR-JP.

Animals↗

PubMed2003

Attenuation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity by the novel selective dopamine D3-receptor partial agonist FAUC 329 predominantly in the nucleus accumbens of mice.

We previously synthesised a novel dopamine (DA) partial agonist FAUC 329 with high affinity and selectivity for the DA D(3) receptor. This is the first in vivo study to investigate the protective effects of FAUC 329 in a MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model of Parkinson's disease. Adult male C57bl/6 mice were injected with FAUC 329 (0, 0.1, 0.5, 0.75, or 1 mg/kg) 30 min before MPTP (2 x 30 mg/kg, 4 hr apart). One week later, accumbal and striatal tissue was processed for DA and metabolite HPLC determination as well as immunohistochemical analysis of DA transporter positive neurons in the substantia nigra pars compacta and ventral tegmental area was carried out. FAUC 329 showed a significant attenuation of MPTP-induced DA reduction in the nucleus accumbens (0.5, 0.75 and 1 mg/kg) in a dose-dependent manner. FAUC 329 (0.75 mg/kg) partly protected against DA depletion in the dorsal striatum as well as protected against loss of DA transporter immunoreactivity in the substantia nigra pars compacta. The highest dose of FAUC 329 (1 mg/kg), however, showed a non-significant tendency to augment the MPTP-induced striatal DA reduction. The protective effect of FAUC 329 against MPTP-induced DA depletion was most pronounced in the nucleus accumbens and appears to be linked to the preferential abundance of D(3) receptors in this region. Targeting the mesolimbic DA system may have implications for improvement of impaired motor behaviour and particularly non-motor functions related to the nucleus accumbens.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2003

Haloperidol and clozapine antagonise amphetamine-induced disruption of latent inhibition of conditioned taste aversion.

RATIONALE: Latent inhibition (LI) describes a process by which repeated pre-exposure of a stimulus without any consequence retards the learning of subsequent conditioned associations with that stimulus. It is well established that LI is impaired in rats and in humans by injections of the indirect dopamine agonist amphetamine (AMPH), and that this disruption can be prevented by co-administration of either the typical neuroleptic haloperidol (HAL) or the atypical neuroleptic clozapine (CLZ). OBJECTIVES: Most of what is known of the pharmacology of LI is derived from studies using either the conditioned emotional response or the conditioned active avoidance paradigm. The goal of the present study was to determine whether these results would generalize to the conditioned taste aversion assay. METHODS: We tested whether AMPH (0.5 mg/kg) pretreatment would disrupt LI of a conditioned aversion to sucrose, and if so, which stage of the procedure is critical for mediating the disruption; in addition, we tested whether HAL (0.2 mg/kg) or CLZ (5.0 mg/kg) could restore such an expected LI disruption. RESULTS: We determined that AMPH disrupted LI when it was injected before pre-exposure and prior to conditioning, but not if the rats were injected before either stage alone. When HAL or CLZ was given 40 min before AMPH (before both pre-exposure and conditioning), it blocked LI disruption. CONCLUSION: These results are in line with the pharmacology of LI as derived from other conditioning paradigms. We conclude that the pharmacological regulation of LI in the CTA paradigm is similar to what has been observed previously in the conditioned emotional response and the conditioned active avoidance paradigms.

Adrenergic Agents↗

PubMed2003

Dorsal hippocampus and classical fear conditioning to tone and context in rats: effects of local NMDA-receptor blockade and stimulation.

Consistent with the importance of the hippocampus in learning more complex stimulus relations, but not in simple associative learning, the dorsal hippocampus has commonly been implicated in classical fear conditioning to context, but not to discrete stimuli, such as a tone. In particular, a specific and central role in contextual fear conditioning has been attributed to mechanisms mediated by dorsal hippocampal N-methyl-D-aspartate (NMDA)-type glutamate receptors. The present study characterized the effects of blockade or tonic stimulation of dorsal hippocampal NMDA receptors by bilateral local infusion of the noncompetitive NMDA receptor antagonist MK-801 (dizocilpine maleate; 6.25 microg/side) or of NMDA (0.7 microg/side), respectively, on classical fear conditioning to tone and context in Wistar rats. Freezing was used to measure conditioned fear. Regardless of whether conditioning was conducted with tone-shock pairings or unsignaled footshocks (background or foreground contextual conditioning), both NMDA and MK-801 infusion before conditioning resulted in reduced freezing during subsequent exposure to the conditioning context. Freezing during subsequent tone presentation in a new context, normally resulting from conditioning with tone-shock pairings, was not impaired by MK-801 but was strongly reduced by NMDA infusion before conditioning; this freezing was also reduced by NMDA infusion before tone presentation (in an experiment involving NMDA infusions before conditioning and subsequent tone presentation to assess the role of state-dependent learning). It was assessed whether unspecific infusion effects (altered sensorimotor functions, state dependency) or infusion-induced dorsal hippocampal damage contributed to the observed reductions in conditioned freezing. Our data suggest that formation of fear conditioning to context, but not tone, requires NMDA receptor-mediated mechanisms in the dorsal hippocampus. As indicated by the effects of NMDA, some dorsal hippocampal processes may also contribute to fear conditioning to tone. The role of the dorsal hippocampus and local NMDA receptor-mediated processes in fear conditioning to tone and context is discussed in comparison with ventral hippocampal processes.

Acoustic Stimulation↗

PubMed2003

Spatial learning in rats is impaired after degeneration of the nigrostriatal dopaminergic system.

We investigated spatial learning in rats with unilateral and bilateral lesions of the nigrostriatal dopaminergic system. We used the Morris water maze paradigm, which tests spatial forms of learning and memory and allows discrimination between sensory-motor and learning disabilities. Animals were trained preoperatively to learn the location of a spatially fixed hidden platform to escape from the swimming pool (acquisition training). A visual and a probe test were used before and after the acquisition training, respectively. Our results show that animals with unilateral lesions, although displaying longer escape latencies, have normal spatial memory abilities. Animals with bilateral lesions were able to swim as fast or even faster than animals with unilateral lesion. Despite the fact that these animals had learned the spatial navigation tasks preoperatively, bilateral dopaminergic lesions led to a profound deficit in ability to find a hidden platform during an acquisition task. In general, animals with bilateral lesions persisted in swimming along the pool walls and their spatial navigation performance during a probe test was very poor. These results suggest that deficit of the nigrostriatal dopaminergic system can affect the selection and maintenance of behavioral strategies in spatial navigation.

Animals↗

PubMed2003

Amphetamine withdrawal modulates FosB expression in mesolimbic dopaminergic target nuclei: effects of different schedules of administration.

Different patterns of psychostimulant intake can elicit widely varying behavioral and neurochemical consequences. Accordingly, rats were studied during withdrawal from either of two schedules of amphetamine administration, one consisting of 6 days of low-dose (1.5 mg/kg, i.p.) daily intermittent (INT) amphetamine (AMPH) injections, and the other of 6 days of moderately high-dose (1-5 mg/kg, i.p.) escalating (ESC) AMPH injections, for the effects of these treatments on numbers of FosB-positive nuclei and monoamine utilization in dopaminergic target areas. Withdrawal from AMPH pretreatment according to the ESC schedule markedly increased FosB expression in the nucleus accumbens shell and basolateral amygdala. In contrast, withdrawal from INT-AMPH administration did not increase FosB expression in any of the regions examined. Post-mortem neurochemical analyses of these same brain regions did not reveal effects of withdrawal from either INT or ESC administration of AMPH. These results suggest that withdrawal from a moderately high-dose AMPH regimen modifies patterns of gene expression in mesocorticolimbic dopaminergic target nuclei without significantly affecting basal monoamine levels. The strength of these effects in the nucleus accumbens shell and basolateral nucleus of the amygdala are consistent with behavioral and clinical data indicating the importance of these areas in the neuroadaptive changes which characterize addiction and withdrawal states.

Amygdala↗

PubMed2003

Effect of the 5-HT6 receptor antagonists Ro04-6790 and Ro65-7199 on latent inhibition and prepulse inhibition in the rat: comparison to clozapine.

In the present study, we have investigated the effects of two selective 5-HT6 receptor antagonists, Ro04-6790 and Ro65-7199, in three drug-induced models of PPI disruption and on latent inhibition (LI) utilizing a conditioned lick suppression (CLS) procedure. Clozapine was included in each experiment for comparison. Neither Ro04-6790 nor Ro65-7199 (both 30 mg/kg) affected the PPI disruption produced by PCP (1.5 mg/kg s.c.), apomorphine (0.1 mg/kg s.c.), or LSD (0.1 mg/kg s.c.). There was also no interaction between each drug and CS preexposure in the CLS test indicating a failure of each drug to facilitate LI. In contrast, clozapine (12 mg/kg) attenuated an apomorphine and PCP-induced PPI deficit, although the PPI disruption produced by LSD was not significantly affected. At a lower dose of 5 mg/kg, clozapine also facilitated LI. Since each of these tests bear some predictive validity for the detection of antipsychotic drugs, the present studies do not support a therapeutic potential of 5-HT6 receptor antagonists in this regard.

Acetylcholine↗

PubMed2003

Hippocampal modulation of sensorimotor processes.

While the hippocampus makes unique contributions to memory, it has also long been associated with sensorimotor processes, i.e. innate processes involving control of motor responses to sensory stimuli. Moreover, hippocampal dysfunction has been implicated in neuropsychiatric diseases, such as schizophrenia and anxiety disorders, primarily characterized by non-mnemonic deficits in the processing of and responding to sensory information. This review is concerned with the hippocampal modulation of three sensorimotor processes in rats-locomotor activity, prepulse inhibition (PPI) of the startle reflex, and the startle reflex itself-whose alterations are related to human psychosis or anxiety disorders. Its main purpose is to present and discuss the picture emerging from studies examining the effects of pharmacological manipulations of the dorsal and ventral hippocampus by local drug microinfusions. While a role of the hippocampus in regulating locomotor activity, PPI, and startle reactivity has also been suggested based on the effects of hippocampal lesions, the microinfusion studies have revealed additional important details of this role and suggest modifications of notions based on lesion studies. In summary, the microinfusion studies corroborate that hippocampal mechanisms can directly influence locomotor activity, PPI, and startle reactivity, and that aberrant hippocampal function may contribute to neuropsychiatric diseases, in particular psychosis. The relation between different sensorimotor processes and hippocampal neurotransmission, the role of ventral and dorsal hippocampus, and the extrahippocampal mechanisms mediating the hippocampal modulation of different sensorimotor processes can partly be dissociated. Thus, the hippocampal modulation of these sensorimotor processes appears to reflect multiple operations, rather than one unitary operation.

Animals↗

PubMed2003

ApoE4 impairs hippocampal plasticity isoform-specifically and blocks the environmental stimulation of synaptogenesis and memory.

Alzheimer's disease (AD) is associated with genetic risk factors, of which the allele E4 of apolipoprotein E (apoE4) is the most prevalent, and is affected by environmental factors that include education early in life and socioeconomic background. The extent to which environmental factors affect the phenotypic expression of the AD genetic risk factors is not known. Here we show that the neuronal and cognitive stimulations, which are elicited by environmental enrichment at a young age, are markedly affected by the apoE genotype. Accordingly, exposure to an enriched environment of young mice transgenic for human apoE3, which is the benign AD apoE allele, resulted in improved learning and memory, whereas mice transgenic for human apoE4 were unaffected by the enriched environment and their learning and memory were similar to those of the nonenriched apoE3 transgenic mice. These cognitive effects were associated with higher hippocampal levels of the presynaptic protein synaptophysin and of NGF in apoE3 but not apoE4 transgenic mice. In contrast, cortical synaptophysin and NGF levels of the apoE3 and apoE4 transgenic mice were similarly elevated by environmental enrichment. These findings show that apoE4 impairs hippocampal plasticity and isoform-specifically blocks the environmental stimulation of synaptogenesis and memory. This provides a novel mechanism by which environmental factors can modulate the function and phenotypic expression of the apoE genotype.

Alzheimer Disease↗

PubMed2003

A differential involvement of the shell and core subterritories of the nucleus accumbens of rats in memory processes.

The role of the core and the shell subterritories of the nucleus accumbens in conditioned freezing and spatial learning was investigated by means of selective N-methyl-D-aspartate lesions. Shell-lesioned rats showed reduced conditioned freezing to context and a tendency toward reduced freezing to the discrete stimulus compared with controls. However, lesions of the core did not modify the freezing response either to the context or to the discrete stimuli. Although spatial memory, as assessed by a water-maze paradigm, was not disrupted by the lesions, in a 4-arm baited, 4-arm unbaited radial-arm maze paradigm, the shell-lesioned rats showed selective deficits in working memory, but not in reference memory. In contrast, core-lesioned rats showed no memory deficits.

Animals↗