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J Feldon

Publications and source records attributed to J Feldon.

At least 127 records · Page 7Linked to original sources
PubMed1995

Basolateral amygdala lesions do not disrupt latent inhibition.

Latent inhibition (LI) is a measure of retarded conditioning to a previously presented non-reinforced stimulus that is impaired in schizophrenic patients and in rats treated with amphetamine, and is restored in both by neuroleptic drugs. In terms of neural substrates, LI depends on the integrity of the nucleus accumbens (NAC) and the inputs to this structure from the hippocampal formation and adjacent cortical areas. The present experiments investigated the effects of electrolytic lesions to the basolateral amygdala (BLA), which is another major source of input to the NAC, on the LI effect. LI was assessed in a conditioned emotional response (CER) procedure in rats licking for water, consisting of three stages: pre-exposure, in which the to-be-conditioned stimulus (a tone) was repeatedly presented without being followed by reinforcement; conditioning, in which the pre-exposed stimulus was paired with reinforcement (a foot shock); and test, in which LI was indexed by the animal's degree of suppression of licking during tone presentation. In Expt. 1, which used a lesion at a more posterior location, no effect on either LI or CER conditioning was seen. In Expt. 2, lesion at a more anterior location reduced the magnitude of CER conditioning in both the pre-exposed and the non-pre-exposed animals, but left the LI effect intact. The latter lesion did not affect spontaneous and amphetamine-induced activity (Expt. 3). These results suggest that the development of LI is not dependent on the amygdalar input to the NAC, but that the input from the anterior aspects of BLA to the NAC is involved in the establishment of stimulus-reinforcement associations.

Acoustic Stimulation↗
PubMed1995

Both electrolytic and excitotoxic lesions of nucleus accumbens disrupt latent inhibition of learning in rats.

Evidence indicating a role for the nucleus accumbens in the development of latent inhibition of learning has accumulated. Two experiments were conducted using Wistar rats to investigate this role directly. Experiment 1 used a conditioned emotional response paradigm to assess the effects of discrete electrolytic lesions in the shell region of the nucleus accumbens. Latent inhibition was attenuated by this lesion. In order to determine the contribution made by damage to fibers en passage associated with electrolytic lesions, Experiment 2 assessed the effects of NMDA-induced lesions in the shell of the nucleus accumbens in the same task. Latent inhibition was again significantly attenuated. These findings support the proposition that an intact nucleus accumbens is necessary for the normal development of latent inhibition.

Animals↗
PubMed1995

Potentiation of amphetamine-induced locomotor activity following NMDA-induced retrohippocampal neuronal loss in the rat.

The present experiment assessed the locomotor response to a low dose (1 mg/kg) of systemic D-amphetamine in rats with cytotoxic lesions of the retrohippocampus (entorhinal and extra-subicular cortices), compared with vehicle-operated shams and unoperated controls. Under spontaneous and saline conditions, both the sham and the lesioned animals were more active than unoperated controls, and they did not differ from each other. Systemic D-amphetamine produced increased locomotion in all groups, but this effect was potentiated in animals with retrohippocampal lesions; two control groups did not differ from each other in their response to the drug. The present results are consistent with the suggestion that cell loss within the retrohippocampal region could affect the functional response of nucleus accumbens to amphetamine. The results are discussed in terms of the interaction between the retrohippocampus and nucleus accumbens in the control of mesolimbic dopamine release and the possible implications for schizophrenia.

Animals↗
PubMed1995

Latent inhibition in rats is abolished by NMDA-induced neuronal loss in the retrohippocampal region, but this lesion effect can be prevented by systemic haloperidol treatment.

Latent inhibition (LI) refers to the retardation in learning about the significance of a neutral stimulus that results from its nonreinforced preexposure. There is evidence that electrolytic or aspiration lesions of the hippocampal formation can disrupt LI (see I. Weiner, 1990). It has been suggested that this effect may stem from the interruption of a projection from the retrohippocampal region to the nucleus accumbens (A. J. M. Clark et al., 1992). The present experiment assessed this possibility by comparing LI in rats with retrohippocampal N-methyl-D-aspartate (NMDA) lesions extending from the entorhinal cortex to the ventral subiculum to that seen in vehicle controls and unoperated controls. LI was abolished by the retrohippocampal lesion. The effect of the lesion on LI was prevented by treatment with systemic haloperidol (0.2 mg/kg). The results are discussed with respect to an animal model of schizophrenia.

Animals↗
PubMed1994

Antagonism of amphetamine-induced disruption of latent inhibition in rats by haloperidol and ondansetron: implications for a possible antipsychotic action of ondansetron.

Latent inhibition (LI) is a behavioural phenomenon whereby preexposure to a stimulus without reinforcement interferes with the formation of subsequent associations to that stimulus. Using preexposure to a tone stimulus which subsequently serves as a conditioned stimulus for suppression of licking, we have confirmed that LI is disrupted by a low dose of amphetamine. Haloperidol was able to prevent this effect of amphetamine. Ondansetron, a selective and potent 5HT3 receptor antagonist, was also shown to be effective at blocking the amphetamine-induced disruption of LI at a dose of 0.01 mg/kg, but not at 0.1 mg/kg. In addition, it was demonstrated that ondansetron could enhance LI; using only ten preexposures, no LI was obtained in the saline group, but was apparent in animals given ondansetron, an effect which has been previously shown with haloperidol. Haloperidol, at the higher dose used, reduced suppression of licking, however, ondansetron at the effective dose had no such effect. It is concluded that ondansetron is able to attenuate increases in dopamine activity, produced pharmacologically with amphetamine without affecting baseline dopamine activity. The implications of these findings for a possible antipsychotic action of ondansetron are discussed.

Acoustic Stimulation↗
PubMed1993

Decreased density of forebrain cholinergic neurons and disintegration of the spatial organization of behavior in experimental autoimmune dementia (EAD).

Experimental autoimmune dementia (EAD) is a rat model designed to examine the potential role of anti-cholinergic neurons antibodies (Abs) in the neuropathology of Alzheimer's disease (AD) and dementia. We have previously shown that sera of AD and Down's syndrome patients contain Abs which bind specifically to the high molecular weight neurofilament protein (NF-H) of the purely cholinergic electromotor neurons of Torpedo. Production of such Abs in EAD rats by prolonged immunization with Torpedo cholinergic NF-H results in the accumulation of IgG in the septum and hippocampus of the immunized rats and in memory deficits. In the present study, we examined immunohistochemically whether the anti-cholinergic NF-H immune response of the EAD rats affects their brain cholinergic neurons. In addition, since dementia is associated with severe deterioration in the spatio-temporal organization of behavior, we examined whether EAD rats also mimic this important feature of dementia. The results obtained show that production in EAD rats of anti-cholinergic NF-H Abs similar to those found in AD patients results in a marked decrease in the density of forebrain cholinergic neurons and in derangements in the spatio-temporal organization of their behavior. These findings may replicate pathogenic processes in AD and support a role for anti-cholinergic NF-H Abs in the degeneration of cholinergic neurons in the disease.

Animals↗
PubMed1993

Decreased density of forebrain cholinergic neurons in experimental autoimmune dementia.

Sera of Alzheimer's disease and Down's syndrome patients contain antibodies which bind specifically to the high molecular weight neurofilament protein of Torpedo cholinergic neurons. We have recently shown that prolonged immunization of rats with this antigen results in the accumulation of IgG in neurons in the septum and hippocampus of the immunized rats and in cognitive impairments. This animal model is termed experimental autoimmune dementia. In the present study we examined whether the anti-cholinergic high molecular weight neurofilament subunit immune response of the experimental autoimmune dementia rats affects forebrain cholinergic neurons. This was performed immunohistochemically utilizing a monoclonal antibody to nerve growth factor receptor, a specific marker of cholinergic neurons in the forebrain. The results obtained revealed significant decreases in the density of cholinergic neurons in the medial septal nucleus and diagonal band of the experimental autoimmune dementia rats. These decreases are specific to the anti-cholinergic high molecular weight neurofilament subunit immune response of the experimental autoimmune dementia rats and are not observed in control rats which were immunized with chemically heterogeneous high molecular weight neurofilament subunit. The decrease in density of forebrain cholinergic neurons in experimental autoimmune dementia rats may mimic pathogenic processes in Alzheimer's disease and supports a role for anti-cholinergic high molecular weight neurofilament subunit antibodies in the degeneration of cholinergic neurons in the disease.

Acetylcholine↗
PubMed1993

Disintegration of the spatial organization of behavior in experimental autoimmune dementia.

Experimental autoimmune dementia is a rat model designed to examine the potential role of anti-cholinergic neurons antibodies in neuronal degeneration in dementia and Alzheimer's disease. We have previously shown that sera of patients with Alzheimer's disease contain antibodies which bind specifically to the high molecular weight neurofilament protein of the purely cholinergic electromotor neurons of Torpedo. Production of such antibodies in experimental autoimmune dementia rats by prolonged immunization with the Torpedo cholinergic high molecular weight neurofilament subunit results in accumulation of antibodies in the septum and hippocampus of the immunized rats, in a marked decrease in the density of forebrain cholinergic neurons, and in memory deficits. In the present study we characterized the open-field behavior of experimental autoimmune dementia rats, and examined whether, like in dementia, the spatiotemporal organization of their behavior is impaired. The results obtained revealed that experimental autoimmune dementia rats travel shorter distances; explore a smaller part of the open-field; and perform less round-trips to the key location--the home base--in reference to which their behavior is normally organized. The shrinkage of the explored space and the reduced number of round trips are independent of the amount of locomotion and represent a deterioration in the organization of behavior in time and space. These behavioral changes are specific to the anti-cholinergic immune response of experimental autoimmune dementia rats as they are not observed in rats which were immunized with chemically heterogeneous high molecular weight neurofilament subunit.(ABSTRACT TRUNCATED AT 250 WORDS)

Afferent Pathways↗
PubMed1992

From an animal model of an attentional deficit towards new insights into the pathophysiology of schizophrenia.

The paper presents an animal model of schizophrenic-like attentional deficit, consisting of an inability to ignore irrelevant stimuli. It is based on the paradigm of latent inhibition (LI), in which animals learn to ignore repeatedly presented stimuli not followed by meaningful consequences. In a series of experiments it was demonstrated that the capacity to ignore irrelevant stimuli is lost in rats treated with systemic or intra-accumbens injections of amphetamine, in normal volunteers given amphetamine, in high "psychosis-prone" persons, in acute schizophrenic patients and in untreated male adult rats that were raised until weaning under conditions of extremely restricted stimulation. In addition, LI is lost following the disruption of the hippocampal input to the nucleus accumbens. In all of the above conditions tested for antagonism by anti-psychotic drugs a loss of LI is reversed. On the basis of these results we propose an animal model which accommodates a neurodevelopmental dysfunction, hippocampal pathology, mesolimbic DA overactivity, vulnerability to stress, and gender differences, all of which have been postulated as factors in the pathophysiology of schizophrenia.

Animals↗
PubMed1992

Phencyclidine does not disrupt latent inhibition in rats: implications for animal models of schizophrenia.

Latent inhibition (LI) is a behavioral paradigm in which prior exposure to a stimulus not followed by reinforcement retards subsequent conditioning to that stimulus when it is paired with reinforcement. The development of LI reflects a process of learning to ignore, or tune out, irrelevant stimuli. Three experiments investigated the effects of phencyclidine (PCP) on LI. The investigation was carried out using a conditioned emotional response (CER) procedure consisting of three stages: preexposure, in which the to-be-conditioned stimulus, tone, was repeatedly presented without reinforcement; conditioning, in which the preexposed stimulus was paired with shock; and test, where LI was indexed by animals' suppression of licking during tone presentation. The three stages were conducted 24 h apart. In Experiment 1, 1 mg/kg PCP was administered either in the preexposure or in the conditioning stage or in both. Experiment 2 used 5 mg/kg PCP in the same procedure. In Experiment 3, 5 mg/kg PCP was administered throughout the LI procedure, including the test stage. In all three experiments, PCP did not affect LI. The implications of these findings for the development of animal models of schizophrenia are discussed.

Amphetamine↗
PubMed1992

Amphetamine and the multitrial partial reinforcement extinction effect (PREE) in an operant chamber: procedural modifications that lead to an attenuation of the PREE.

The partial reinforcement extinction effect (PREE) consists of the fact that animals receiving partial reinforcement (PRF) exhibit higher resistance to extinction than animals receiving continuous reinforcement (CRF). In previous studies, we found that amphetamine (AMPH) did not affect resistance to extinction of PRF animals trained with a multitrial procedure, but abolished resistance to extinction of PRF animals trained with a 1 trial/day procedure. Based on theoretical distinctions regarding the processes underlying the development of increased resistance to extinction at short and long intertrial intervals, we suggested that AMPH disrupts the formation of a context-mediated association between stimuli associated with nonreinforcement and subsequent reinforcement. To examine further this possibility, we designed conditions in a multitrial PRF procedure that do not allow a direct association between stimuli associated with nonreinforcement and reinforcement, and thus promote a context-mediated association between them. Two experiments were conducted in an operant chamber. In experiment 1, instead of the conventional 50% schedule of reinforcement throughout PRF training, days of 33% schedule of reinforcement were interspersed with days of continuous reinforcement; in experiment 2, a block (5 days) of 50% PRF schedule was alternated with a block (5 days) of CRF training, given either prior to or following PRF. In experiment 1, interspersing days of CRF training with days of 33% reinforcement schedule led to an attenuation of the PREE in AMPH-treated animals. In experiment 2, control animals that received CRF training either prior to or following PRF training exhibited a PREE similar to animals trained on PRF alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphetamine↗
PubMed1992

A neuroleptic-like effect of ceronapril on latent inhibition.

Three experiments that used a latent inhibition procedure to investigate the effects of ceronapril on attentional processes in the rat are reported. Latent inhibition is a behavioural paradigm in which prior exposure to a stimulus with no significant consequences retards subsequent conditioning to that stimulus when it is paired with reinforcement. Latent inhibition reflects a process of learning to ignore, or tune out, irrelevant stimuli, and has been suggested as an animal model of the attentional processes disrupted in the acute phase of schizophrenia. In animals, latent inhibition is disrupted by the administration of low doses of amphetamine and enhanced by the administration of neuroleptics. Ceronapril is an angiotensin converting enzyme inhibitor that has been shown to retard the breakdown of central cholecystokinin. It has been proposed that elevation of cholecystokinin levels in the brain may possess neuroleptic-like properties. We assessed this possibility by determining the effects of ceronapril on latent inhibition using a conditioned emotional response procedure, consisting of three stages: pre-exposure, in which the to-be-conditioned stimulus, a tone, was repeatedly presented without reinforcement; conditioning, in which the pre-exposed stimulus was paired with shock; and test, where latent inhibition was indexed by animals' suppression of licking during tone presentation. In Experiment 1, 20 tone pre-exposures were given, and conditioning consisted of five tone-shock pairings; we assessed the effects of 0.005 mg/kg, 0.05 mg/kg and 0.5 mg/kg ceronapril, compared with vehicle injections. In Experiment 2, five tone pre-exposures were given, and conditioning consisted of two tone-shock pairings: we assessed the effects of 0.05 mg/kg ceronapril, compared with vehicle injections.(ABSTRACT TRUNCATED AT 250 WORDS)

Acoustic Stimulation↗
PubMed1992

Aspiration lesions of rat ventral hippocampus disinhibit responding in conditioned suppression or extinction, but spare latent inhibition and the partial reinforcement extinction effect.

Latent inhibition refers to a decrement in learning about a stimulus as a result of its prior non-reinforced presentation. There is evidence that lesions of nucleus accumbens and conventional hippocampal lesions both disrupt the development of latent inhibition. The partial reinforcement extinction effect reflects the observation that resistance to extinction is normally greater in animals that have been rewarded on a 50% random proportion of acquisition trials than in those rewarded on every trial. Conventional hippocampal lesions, excitotoxic lesions of hippocampus plus subiculum, or conventional lesions of nucleus accumbens abolish this effect. The present experiments examined the possibility that a projection originating in the ventral [temporal in the nomenclature proposed by Blackstad: (1956) J. comp. Neurol. 105, 417-537] subiculum and terminating in nucleus accumbens underlies the normal development of latent inhibition and the partial reinforcement extinction effect, by evaluating the performance on these two behaviours of rats with aspiration lesions in the ventral hippocampal region. There was equally clear evidence of latent inhibition and of a partial reinforcement extinction effect in controls and in rats with ventral hippocampal damage. However, superimposed on this, the hippocampal lesion induced a loss of behavioural inhibition in both paradigms. Subsequent anatomical analyses indicated that cell bodies in nearby retrohippocampal cortex had maintained intact projections to nucleus accumbens. We suggest that these extra-hippocampal projections may underlie the ability to learn to ignore irrelevant stimuli.

Analysis of Variance↗
PubMed1991

The latent inhibition model of schizophrenic attention disorder. Haloperidol and sulpiride enhance rats' ability to ignore irrelevant stimuli.

Latent inhibition (LI) is a behavioral paradigm in which prior exposure to a stimulus not followed by reinforcement retards subsequent conditioning to that stimulus when it is paired with reinforcement. The development of LI reflects a process of learning to ignore, or tune out, irrelevant stimuli. Two experiments investigated the effects of haloperidol (0.02, 0.1, and 0.5 mg/kg) and sulpiride (100 mg/kg) administration on LI. The investigation was carried out using a conditioned emotional response (CER) procedure consisting of three stages: (1) preexposure, in which the to-be-conditioned stimulus, tone, was repeatedly presented without reinforcement; (2) conditioning, in which the preexposed stimulus was paired with shock; and (3) test, where LI was indexed by animals' suppression of licking during tone presentation. The three stages were conducted 24 hr apart. In the preexposure stage, only ten nonreinforced stimulus preexposures were given, a procedure known to be insufficient to yield LI in normal animals. In both experiments, LI was indeed absent in the placebo animals. In marked contrast, animals treated with haloperidol (experiment 1) as well as with sulpiride (experiment 2) exhibited LI. These results demonstrate that both typical and atypical neuroleptics enhance animals' capacity to ignore irrelevant stimuli. The implications of this finding for an animal model of schizophrenia and for a novel screening test for antipsychotic drugs are discussed.

Animals↗
PubMed1991

Electrolytic lesions of the nucleus accumbens in rats which abolish the PREE enhance the locomotor response to amphetamine.

The partial reinforcement extinction effect (PREE) refers to the increased resistance to extinction observed in animals trained on a partial reinforcement (PR) schedule compared with those trained on a schedule of continuous reinforcement (CR). It has been suggested that the PREE is dependent upon the integrity of the septo-hippocampal system, but recent evidence has indicated that the role originally proposed for the lateral septal nucleus may in fact be subserved by the nucleus accumbens. Experiment I therefore tested the effects of electrolytic lesions of the nucleus accumbens on the PREE. These lesions abolished the PREE, the abolition resulting from a decreased rate of extinction in the lesion CR rats coupled with an increased rate of extinction in the PR rats. These results clearly implicate the nucleus accumbens in the development of the PREE, and suggest that theoretical models of the PREE based simply upon consideration of septohippocampal interactions need radical revision. The lesion also enhanced running speeds in acquisition in both the CR and the PR groups. Experiment II therefore assessed spontaneous locomotor activity and the locomotor response to amphetamine challenge at two doses. The lesion produced no increase in spontaneous locomotion; an enhanced increase in response to 1 mg/kg amphetamine; and no changes in the stereotyped behaviours induced by 10 mg/kg amphetamine.

Amphetamine↗
PubMed1991

Effects of haloperidol on the multitrial partial reinforcement extinction effect (PREE): evidence for neuroleptic drug action on nonreinforcement but not on reinforcement.

Two experiments investigated the effects of haloperidol (0.1 mg/kg) on the partial reinforcement extinction effect (PREE). In experiment 1 two groups of rats were trained to run in a straight alley using six trials/day with an intertrial interval (ITI) of 5-8 min. The continuously reinforced (CRF) group received food reward on every trial. The partially reinforced (PRF) group was rewarded on a quasi-random 50% schedule. All animals were then tested in extinction. Haloperidol was administered in a 2 x 2 design, i.e., drug-no drug in acquisition and drug-no drug in extinction. In experiment 2 two groups of rats were trained to press a lever in an operant chamber using a discrete trial procedure of ten trials/day with an ITI of 60 s. The CRF group was rewarded on each trial and the PRF group was rewarded on a quasi-random 50% schedule. Haloperidol was administered for 22 days prior to the start of the PREE procedure as well as throughout acquisition and extinction. The PREE, i.e., increased resistance to extinction of PRF as compared to CRF animals, was obtained in both experiments in all drug conditions. In both experiments haloperidol increased the rate of extinction. Experiment 1 revealed that this effect was entirely due to the administration of the drug in extinction, independently of the drug condition in acquisition. In contrast to previous results in a one trial/day procedure, the administration of haloperidol to CRF animals did not increase resistance to extinction, failing to support the notion that neuroleptics attenuate the rewarding properties of reinforcement.

Animals↗
PubMed1991

Latent inhibition is unaffected by direct dopamine agonists.

Latent inhibition (LI) refers to the finding that nonreinforced preexposure to a stimulus retards subsequent conditioning to that stimulus when it is paired with reinforcement. The development of LI reflects a process of learning not to attend, or ignore, irrelevant stimuli. Previous experiments showed that LI was disrupted by low but not high doses of amphetamine, and facilitated by neuroleptic drugs. The present experiments sought to investigate the role of dopamine D1 and D2 receptors in LI disruption. Experiments 1 and 2 showed that the selective D1 agonist, SKF-38393 (1, 5, 10 mg/kg) and the selective D2 agonist, quinpirole (0.1, 0.3, 1.0 mg/kg), did not affect LI. Experiment 3 showed that both low (0.3 mg/kg) and high (1.5 mg/kg) doses of the mixed D1-D2 agonist, apomorphine, failed to affect L1. These results show that L1 is not disrupted by direct stimulation of DA receptors and suggest that the differential effect exerted on this phenomenon by apomorphine (and possibly SKF-38393 and quinpirole) and amphetamine is related to the direct versus the indirect agonist action of these drugs. In addition, apomorphine at the dose of 0.03 mg/kg, which is believed to activate preferentially DA autoreceptors, did not produce neuroleptic-like facilitation of LI. The implications of the results of the involvement of DA mechanisms in L1 are discussed.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗