Biomedical subjects

J Feldon

Publications and source records attributed to J Feldon.

At least 91 records · Page 5Linked to original sources

PubMed1999

Dopamine and serotonin imbalances in the left anterior cingulate and pyriform cortices following the repeated intermittent administration of cocaine.

Studies on the neurobiology of cocaine abuse suggest that cocaine directly modifies the activity of dopamine neurons projecting from the dopamine-synthesizing cells of the ventral tegmental area to the nucleus accumbens. The repeated use of cocaine produces persistent adaptations within the mesocorticolimbic system and the resulting changes in monoamine neurotransmission may lead to behavioral sensitization. The present series of experiments sought to determine the effects of the repeated, intermittent challenge that took place two days after discontinuation of the pretreatment regimen; (ii) the ex vivo levels of biogenic monoamines, choline and acetylcholine in the nucleus accumbens, the dorsolateral caudate nucleus, as well as the anterior cingulate, frontal motor, frontal somatosensory and pyriform cortices; and (iii) the degree of neurochemical relationship between the left and right hemispheres. The repeated administration of cocaine produced sensitized behavioral responses to a subsequent challenge. Neurochemical correlates of repeated cocaine administration were observed at the cortical level and included a significant decrease in serotonin levels in the left anterior cingulate and pyriform cortices and an increase in dopamine metabolism in the left pyriform cortex. Furthermore, a shift in the interhemispheric coupling coefficient matrix for dopamine neurotransmission was observed in both the pyriform cortex and nucleus accumbens of cocaine-sensitized animals suggesting that, in these structures, the two hemispheres are operating independently. These results demonstrate that cocaine produces alterations in specific dopaminergic and serotonergic pathways that arise from the mesencephalon and project towards both the anterior cingulate and pyriform cortices.

Acetylcholine↗

PubMed1999

The effects of radiofrequency lesion or transection of the fimbria-fornix on latent inhibition in the rat.

Latent inhibition consists of a decrement in conditioning to a stimulus as a result of its prior non-reinforced pre-exposure. Based on evidence pointing to the involvement of the hippocampus and the nucleus accumbens in latent inhibition disruption, it has been proposed that latent inhibition depends on the integrity of the subicular input to the nucleus accumbens. Since fibers originating in the subiculum and destined for the nucleus accumbens run through the fimbria-fornix, we assessed the effects of radiofrequency lesion or transection of the fimbria-fornix, on latent inhibition. The effectiveness of both lesions was demonstrated by the total disappearance of acetylcholinesterase staining in the hippocampus and of retrogradely labeled cells in the hippocampus/subiculum following the injection of the retrograde tracer biotin-dextran amine into the shell subregion of the nucleus accumbens. Likewise, in accord with previously documented behavioral effects of lesions to the hippocampus and related structures, both lesions increased spontaneous activity and disrupted performance in Morris water maze, and the radiofrequency lesion facilitated the acquisition of two-way active avoidance. In spite of the above, latent inhibition remained unaffected by both fimbria-fornix lesions, indicating that the critical projections subserving latent inhibition are not those traversing the fimbria-fornix from the hippocampus/subiculum to the nucleus accumbens. The implications of these results for the neural circuitry of latent inhibition and the latent inhibition model of schizophrenia are discussed.

Animals↗

PubMed1999

Dissociative effects of apomorphine infusions into the medial prefrontal cortex of rats on latent inhibition, prepulse inhibition and amphetamine-induced locomotion.

Impaired ability to "gate out" sensory and cognitive information is considered to be a central feature of schizophrenia and is manifested, among others, in disrupted prepulse inhibition and latent inhibition. The present study investigated, in rats, the effects of increasing dopamine receptor activation within the medial prefrontal cortex by local administration of the dopamine receptor agonist apomorphine (9 microg/side) on prepulse inhibition and latent inhibition, as well as on spontaneous and amphetamine-induced activity. Apomorphine infusions decreased spontaneous locomotor activity and blocked amphetamine-induced increase in locomotor activity in the open field, which is in line with the suggestion that dopamine receptor activation in the medial prefrontal cortex inhibits mesolimbic dopamine activity. However, apomorphine infusions induced a disruption of prepulse inhibition, an effect associated with increased dopaminergic activity in the nucleus accumbens, and left the latent inhibition effect intact. While these results support previous evidence that the medial prefrontal cortex is a component of the neural circuitry mediating prepulse inhibition but plays no role in latent inhibition, they show that dopamine receptor activation in the medial prefrontal cortex of the rat produces behavioural outcomes that cannot be explained by postulating a simple reciprocal relationship between the mesocortical and mesolimbic dopamine systems.

Amphetamine↗

PubMed1999

The effects of hippocampal and fimbria-fornix lesions on prepulse inhibition.

The present experiments tested the effects of conventional (dorsal aspiration and electrolytic) and excitotoxic (N-methyl-D-aspartate [NMDA]) hippocampal lesions and fimbria-fornix (FF) transection on prepulse inhibition (PPI) of startle response and on open-field activity. Activity was increased by FF transection and by conventional but not excitotoxic hippocampal lesions; complete NMDA lesion increased amphetamine-induced activity. Whereas dorsal hippocampal aspiration lesion disrupted PPI, the phenomenon was not affected by dorsal hippocampal electrolytic lesion, partial or complete excitotoxic (NMDA) hippocampal lesions, or complete FF transection, which interrupted the cholinergic input to the hippocampus as well as the hippocampal-subicular input to the nucleus accumbens. Systemic apomorphine disrupted PPI in both FF-transected rats and their controls. It is suggested that the hippocampus is essential for PPI disruption rather than for PPI expression.

Acoustic Stimulation↗

PubMed1999

Dissociating context and space within the hippocampus: effects of complete, dorsal, and ventral excitotoxic hippocampal lesions on conditioned freezing and spatial learning.

Rats with complete excitotoxic hippocampal lesions or selective damage to the dorsal or ventral hippocampus were compared with controls on measures of contextually conditioned freezing in a signaled shock procedure and on a spatial water-maze task. Complete and ventral lesions produced equivalent, significant anterograde deficits in conditioned freezing relative to both dorsal lesions and controls. Complete hippocampal lesions impaired water-maze performance; in contrast, ventral lesions improved performance relative to the dorsal group, which was itself unexpectedly unimpaired relative to controls. Thus, the partial lesion effects seen in the 2 tasks never resembled each other. Anterograde impairments in contextual freezing and spatial learning do not share a common underlying neural basis; complete and ventral lesions may induce anterograde contextual freezing impairments by enhancing locomotor activity under conditions of mild stress.

Analysis of Variance↗

PubMed1999

The effects of NMDA-induced retrohippocampal lesions on performance of four spatial memory tasks known to be sensitive to hippocampal damage in the rat.

Four separate cohorts of rats were employed to examine the effects of cytotoxic retrohippocampal lesions in four spatial memory tasks which are known to be sensitive to direct hippocampal damage and/or fornix-fimbria lesions in the rat. Selective retrohippocampal lesions were made by means of multiple intracerebral infusions of NMDA centred on the entorhinal cortex bilaterally. Cell damage typically extended from the lateral entorhinal area to the distal ventral subiculum. Experiment 1 demonstrated that retrohippocampal lesions spared the acquisition of a reference memory task in the Morris water maze, in which the animals learned to escape from the water by swimming to a submerged platform in a fixed location. In the subsequent transfer test, when the escape platform was removed, rats with retrohippocampal lesions tended to spend less time searching in the appropriate quadrant compared to controls. Experiment 2 demonstrated that the lesions also spared the acquisition of a working memory version of the water maze task in which the location of the escape platform was varied between days. In experiment 3, both reference and working memory were assessed using an eight-arm radial maze in which the same four arms were constantly baited between trials. In the initial acquisition, reference memory but not working memory was affected by the lesions. During subsequent reversal learning in which previously baited arms were now no longer baited and vice versa, lesioned animals made significantly more reference memory errors as well as working memory errors. In experiment 4, spatial working memory was assessed in a delayed matching-to-position task conducted in a two-lever operant chamber. There was no evidence for any impairment in rats with retrohippocampal lesions in this task. The present study demonstrated that unlike direct hippocampal damage, retrohippocampal cell loss did not lead to a general impairment in spatial learning, implying that the integrity of the retrohippocampus and/or its interconnection with the hippocampal formation is not critical for normal hippocampal-dependent spatial learning and memory. This outcome is surprising for a number of current hippocampal theories, and suggests that other cortical as well as subcortical inputs to the hippocampus might be of more importance, and further raises the question regarding the functional significance of the retrohippocampal region.

Animals↗

PubMed1999

Isolation rearing-induced disruption of prepulse inhibition: further evidence for fragility of the response.

The present study investigated isolation-induced disruptions of prepulse inhibition (PPI), and effects on locomotor activity as a function of home caging condition (sawdust vs grid-floor) in the Wistar rat. Isolates reared in grid-floor cages did not show a disruption of PPI. However, when isolates were reared in sawdust cages, a PPI deficit was evident. In an open field environment, isolates demonstrated significantly increased spontaneous locomotor activity compared to their group-housed counterparts, irrespective of the caging condition employed. Grouped animals reared in grid-floor cages, however, showed reduced activity compared to grouped animals reared in sawdust cages. Although d-amphetamine treatment appeared to enhance locomotor activity selectively in isolates, particularly in those reared in grid-floor cages, this result could be explained by the existing pre-drug activity levels. With respect to PPI, not only were isolation-induced deficits in the Wistar rat difficult to detect in a variable prepulse intensity PPI procedure, but when apparent, the deficits were of a fragile nature. The findings suggest that caging condition may be a critical methodological factor in experiments investigating isolation-induced PPI deficits. Indeed, our results may indicate that rearing animals in grid-floor cages represents a form of chronic mild stress, which can interfere with normal sensorimotor gating mechanisms, in addition to other behaviours.

Acoustic Stimulation↗

PubMed1999

Effects of smoking status and schizotypy on latent inhibition.

Two experiments investigated the effects of smoking status and schizotypy on the ability to gate out irrelevant information as assessed in auditory and visual latent inhibition (LI), Stroop effect and negative priming. The two experiments used 10 or 30 pre-exposures for auditory LI and a long or short interstimulus interval for the Stroop task, respectively, which included negative priming and served as masking task for the visual LI. Smoking status did not affect performance on any of the tasks, except for auditory LI after 30 pre-exposures, which was enhanced. The relationship between schizotypy and cognitive performance was complex. In Experiment 1, high schizotypals had smaller visual LI and negative priming than low schizotypals, whereas in Experiment 2 the reverse was observed, namely, larger LI and negative priming in high schizotypals.

Acoustic Stimulation↗

PubMed1998

A computer controlled analysis of freezing behaviour.

The conditioned freezing response in rats has been much used both by psychologists and neuroscientists to investigate the behavioural effects of brain lesions and of changes in motivational state. The primary advantage of the freezing response is that it can be used without motivational manipulations such as food or water deprivation. Previously, freezing has been measured by a human observer either from video recordings or during the test sessions themselves. But these methods of data collection have potential disadvantages. In the present paper, we describe a new, computer controlled, automated procedure for assessing conditioned freezing. Each conditioning chamber contains a mini-video camera. Behaviour is analysed on-line by means of a programme which compares every two adjacent seconds of video tape to generate a screen representing the percentage difference between them. A difference of <0.05% (50 pixels) is classified as a freezing response. Experiments are described in which we measure conditioned freezing and its development over time, in response to contextual cues and to a discrete tone which had been paired with foot shock. We demonstrate our apparatus and methods of data analysis to be sensitive to: number of tone-shock pairings, rat strain and tone pre-exposure.

Animals↗

PubMed1998

Reevaluation of the striatal role in the expression of turning behavior in the rat model of Parkinson's disease.

A traditional view holds the belief that the behavioral effects of l-dihydroxyphenilalanine (l-DOPA) in Parkinsonian patients are achieved through the action of the newly produced dopamine (DA) on striatal DA receptors. In contrast to this view, recent studies in the rat model of Parkinson's disease point to the substantia nigra pars reticulata as an important target for the behavioral effects of l-DOPA. In the present study, we tested the contribution of the substantia nigra vs. that of the striatum, in the expression of contralateral turning induced by l-DOPA in rats with unilateral dopaminergic depletion. Rats turned contralaterally to the lesion in response to either intrastriatal or systemic l-DOPA administration. Injections of lidocaine into the denervated striatum substantially decreased, and occasionally completely abolished, the contralateral turning after systemic l-DOPA. These findings indicate that activation of the DA depleted striatum is both sufficient and essential for the expression of behavioral response after systemic administration of l-DOPA. The contribution of the substantia nigra to this behavioral response seems to depend to a great extent on an active striatal outflow.

Animals↗

PubMed1998

Electrolytic lesion of globus pallidus ameliorates the behavioral and neurodegenerative effects of quinolinic acid lesion of the striatum: a potential novel treatment in a rat model of Huntington's disease.

Bilateral electrolytic pallidal lesion ameliorated the deleterious effects of bilateral quinolinic acid (QA) lesion to the striatum on post-surgery weight, activity level, and performance in a water maze task, and reduced the extent of striatal damage. Given that the neurodegenerative and behavioral effects of QA striatal lesion are thought to mimic those seen in Huntington's disease, these results may point to a potential novel treatment for this disease.

Animals↗

PubMed1998

Amphetamine-induced neurochemical and locomotor responses are expressed differentially across the anteroposterior axis of the core and shell subterritories of the nucleus accumbens.

The administration of psychostimulants increases dopamine (DA) release within the nucleus accumbens (NAC), a terminal projection site of mesolimbic DA neurons, originating in the ventral tegmental area (VTA). Recent evidence demonstrates that two subdivisions of the NAC, the dorsolateral core and the ventromedial shell, can be distinguished by morphological and immunohistochemical differences, as well as by their distinct anatomical connections. It has been suggested that these two subregions subserve different functions that are related to goal-directed behaviors, stimulus-reward associations, and reinforcement induced by addictive drugs. The shell region, in particular, modulates inputs from the limbic system, whereas the core is preferentially innervated by nuclei that process motor information. In the present study, we sought to investigate if (1) the direct infusion of d-amphetamine (AMPH) by reverse microdialysis into either the core or shell of the NAC across its anteroposterior axis differentially affects dialysate DA and 5-HT levels, and (2) these subterritories also subserve different behavioral functions. Following the determination of basal DA and 5-HT levels, four increasing concentrations of AMPH (0.05, 0.10, 0.50, 1.00 microM) were substituted for the dialysis perfusate for 60 min each. Movement units were detected by an infrared sensor and were transmitted through a motion interface to an activity monitor analyzer. AMPH produced a dose-dependent increase in locomotor activity after microinfusion into either the rostral shell, caudal shell or core of the NAC. The potency of the AMPH-induced locomotor activating effect was significantly higher in the rostral shell of the NAC compared with the caudal shell and the core. The lowest concentrations of AMPH (0.05, 0.1 microM) produced an equipotent decrease in dialysate DA in either the rostral shell, caudal shell, or core. At 1.0 microM, however, AMPH selectively increased DA in the rostral shell, whereas DA reached baseline values both in the caudal shell and core. Basal dialysate DA levels were significantly higher in the core relative to both the rostral and caudal parts of the shell. The highest dose of AMPH significantly increased dialysate 5-HT levels over baseline only in the caudal shell of the NAC. The basal dialysate 5-HT levels did not significantly differ between the three subterritories of the NAC. These results emphasize the heterogeneity and functional compartmentalization within the NAC, the differential regulation of neurochemical and motor responses across the anteroposterior axis of the NAC, and the preferential effect of AMPH in the rostral shell subterritory of the NAC.

Amphetamine↗

PubMed1998

The effects of smoking on acoustic prepulse inhibition in healthy men and women.

Acoustic prepulse inhibition (PPI) refers to the reduction of the startle reflex to an intense stimulus if it is preceded by a weak stimulus. Nicotine and smoking have been reported to enhance PPI in rats and in healthy men, respectively. We studied the influence of smoking on PPI in healthy men and women, comparing non-smokers, deprived smokers, and smokers smoking during the test session after deprivation or after ad libitum smoking. Smoking during the session enhanced PPI, without affecting startle reaction or habituation over time. In addition, the effect of smoking on PPI was gender dependent. In men, ad libitum smoking enhanced PPI compared with non-smokers, while, in women, deprivation reduced PPI and smoking restored PPI to the level of non-smokers.

Acoustic Stimulation↗

PubMed1998

Long-term effects of repeated maternal separation on three different latent inhibition paradigms.

In the present study we investigated the effect of repeated maternal separation on postnatal days 12, 14, 16, and 18 for 6 h/day on Wistar rats on three latent inhibition (LI) paradigms: two-way active avoidance, conditioned emotional response (CER), and conditioned taste aversion (CTA). In addition, hyperactivity induced by d-amphetamine and stereotypies induced by apomorphine were evaluated. In all three LI experiments, the control animals showed only marginal LI, whereas the maternally separated animals showed enhanced LI (only males in CTA). In two-way active avoidance within the nonpreexposed condition maternally separated animals showed improved acquisition of avoidance learning compared with the control animals. Sensitivity in response to amphetamine and apomorphine was not altered by the maternal separation procedure. Thus, maternal separation in this study, contrary to previous reports, but in line with results obtained following early handling before weaning, led to enhancement of the LI phenomenon as assessed in each of the three procedures. As our maternal separation procedure (6 h on days 12, 14, 16, and 18) led to behavioral outcomes that differed from those reported by Ellenbroek and Cools (24 h on day 10), it is suggested that maternal separation regimens that are dissimilar may lead to different and sometimes opposite behavioral effects.

Amphetamine↗

PubMed1998

The disruption of prepulse inhibition by social isolation in the Wistar rat: how robust is the effect?

Postweaning isolation rearing in rats is shown to have consequences for the expression of numerous behaviors. The present studies investigated isolation-induced disruptions of the prepulse inhibition (PPI) response in the Wistar rat strain, as a function of exposure of the animals to locomotor activity testing. Further, repeated testing of PPI was investigated to examine the robustness of the isolation-induced disruptions. The results indicate that experimentally naive isolation-reared animals exhibit disruptions in the PPI response that are retained in a second test 7 days later. The disruptions obtained are shown to be consistent across all pulse frequencies examined and independent of effects on startle. Exposure to activity testing, however, either before or after the measurement of PPI, abolished the isolation-induced disruption of PPI in a subsequent test. In contrast, locomotor activity testing consistently revealed a hyperactivity response in isolation-reared animals that was not influenced by the temporal occurrence of the testing. The findings are discussed relative to the interpretation of data emerging from studies where both activity testing and PPI are performed in the same animals, and in the relation to the use of PPI in isolation-reared animals as representing a nonpharmacological animal model of schizophrenia.

Acoustic Stimulation↗

PubMed1998

Differential effects of prenatal stress in two inbred strains of rats.

The long-term effects of prenatal stress (three times daily restraint stress during the last week of gestation) on the behavioral response to stress, as assessed by novelty-induced locomotion, performance in the forced swim test, and the acquisition of a two-way active avoidance, were investigated in two inbred strains of rats, Fischer 344 (F344/NHsd/Zur) and Lewis (LEW/SsNHsd/Zur). Additional measures included birth weights, pain threshold on the hot plate, and basal and stress-induced corticosterone secretion. In all of the behavioral paradigms strain differences were found: LEW rats showed poorer acquisition of avoidance conditioning, displayed higher levels of activity on the open plate, less immobility time in the forced swim test, and lower pain thresholds in the hot-plate test compared with F344 rats. LEW rats had higher birth weights after prenatal stress, whereas F344 rats were lighter. Following prenatal stress the pattern of behavioral effects obtained in LEW rats in stress-related tests could be interpreted as improved coping abilities with stress, i.e., improved acquisition of active avoidance, less immobility in the forced swim test, and reduced novelty-induced locomotion. Prenatal stress was much less effective in inducing long-term behavioral changes in F344 rats, yielding only one effect, namely, enhanced novelty-induced locomotion in female F344 rats. Pain thresholds were increased as a consequence of prenatal stress, irrespective of strain and gender. Basal and stress-induced corticosterone release differed in the two strains, with LEW rats showing less stress-induced corticosterone release. Prenatal stress did not, however, affect basal or stress-induced corticosterone release. The results suggest that prenatal stress exerts long-term effects on behavior, which depend on the genetic background.

Animals↗

PubMed1998

Rat strain differences in open-field behavior and the locomotor stimulating and rewarding effects of amphetamine.

Fischer 344 (F344) and Lewis (LEW) rats show considerable neuroanatomical and neurophysiological differences within the mesolimbic dopamine system. The aim of our experiments was to study the functional correlates of such differences by examining open-field behavior and the sensitivity towards the psychostimulant and rewarding effects of amphetamine in male and female, F344 and LEW rats. In addition, the consequences of short versus extended habituation to open-field testing on amphetamine locomotion in these two rat strains was assessed. LEW but not F344 rats irrespective of gender showed between-session habituation of open-field activity. Amphetamine-induced locomotion was higher in F344 compared to LEW rats and in females compared to male rats. In addition, extended habituation increased the locomotor effects of amphetamine. The rewarding effects of amphetamine as measured by the conditioned place preference test were more pronounced in F344 than in LEW rats. Our results suggest that the two rat strains differed in their behavioral response to mild stress and to amphetamine and that these differences may depend upon differences within the mesolimbic dopamine system.

Amphetamine↗

PubMed1998

Fimbria-fornix cut affects spontaneous activity, two-way avoidance and delayed non matching to sample, but not latent inhibition.

Latent inhibition (LI) consists of a decrement in conditioning to a stimulus as a result of its prior nonreinforced preexposure. Based on evidence pointing to the involvement of the hippocampus and the nucleus accumbens (NAC) in LI disruption, it has been proposed that LI depends on the integrity of the subicular input to the NAC. Since fibers originating in the subiculum and destined for the NAC run through the fimbria-fornix, we assessed the effects of fimbria-fornix lesion, made using a knife cut, on LI. In addition, we assessed the effects of the fimbria-fornix cut in three tests known to be sensitive to lesions to the hippocampal region, namely, spontaneous activity, two-way active avoidance and delayed-non-matching-to-sample. In accord with previously documented effects of lesions to the hippocampus and related structures, the fimbria-fornix cut increased spontaneous activity (Experiment 1), facilitated the acquisition of two-way active avoidance (Experiment 3), and produced a delay-dependent deficit in the delayed-non-match-to-sample task (Experiment 4), demonstrating that it disrupted hippocampal functioning. In contrast, LI remained unaffected by the fimbria-fornix cut (Experiment 2), indicating that disruption of subicular input to the NAC is not responsible for the attenuation of LI following non-selective hippocampal lesions. The implications of these results for the neural circuitry of LI are discussed.

Adaptation, Psychological↗