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Biomedical subjects

J Feldon

Publications and source records attributed to J Feldon.

At least 73 records · Page 4Linked to original sources
PubMed2000

Influence of promoter and WHV post-transcriptional regulatory element on AAV-mediated transgene expression in the rat brain.

Recombinant adeno-associated viruses (rAAVs) can transduce several tissues, including the brain. However, in brain the duration of gene expression in different areas is variable, which has been ascribed to viral (CMV) promoter silencing in some regions over time. We have compared expression of enhanced green fluorescent protein (EGFP) in the nigrostriatal pathway of rats mediated by rAAVs containing the CMV or platelet-derived growth factor-beta chain (PDGF-beta) promoter. In addition, we studied the effects of the woodchuck hepatitis virus post-transcriptional regulatory element (WPRE) on transgene expression in vivo. The rAAV vectors containing the neuron-specific PDGF-beta chain promoter transduced significantly more dopaminergic neurons than titer-matched vectors carrying the CMV promoter. Moreover, the WPRE further increased EGFP expression, and a rAAV vector incorporating both the PDGF-beta chain promoter and the WPRE resulted in efficient EGFP expression in dopaminergic neurons and their projections in the striatum for at least 41 weeks after virus injection. Our results emphasize the importance of a strong tissue-specific promoter in achieving optimal transgene expression, not only in long-term but also in short-term studies where viral titers may be limiting. Furthermore, they suggest that incorporation of the WPRE into rAAVs, and possibly other types of vectors, is useful to enhance transgene expression in vivo.

Animals↗
PubMed2000

Low-dose clozapine pretreatment partially prevents haloperidol-induced deficits in conditioned active avoidance.

The effectiveness of neuroleptics in disrupting conditioned active avoidance has led to the widespread use of this test as an index of antipsychotic efficacy, whereas the tendency for these drugs to induce catalepsy is believed to reflect their propensity to cause extrapyramidal motor side-effects. Although the typical neuroleptic haloperidol produces catalepsy as well as profound deficits in conditioned active avoidance, the atypical neuroleptic clozapine does not induce catalepsy and is less effective than haloperidol in disrupting active avoidance. Furthermore, clozapine pretreatment prevents haloperidol-induced catalepsy. We investigated whether clozapine pretreatment might also reduce the disruptive effects of haloperidol on two-way active avoidance. We assessed the avoidance acquisition of the following drug treatment groups in which all animals received two injections prior to testing: vehicle + vehicle, vehicle + haloperidol (0.1 mg/kg, i.p.), clozapine (2.5, 5.0 or 10 mg/kg, i.p.) + haloperidol (0.1 mg/kg, i.p.), or clozapine (2.5, 5.0 or 10 mg/kg, i.p.) + vehicle. Haloperidol-pretreated animals showed markedly impaired active avoidance, deficits which were improved by 2.5 and 5 mg/kg but not by 10 mg/kg clozapine pretreatment. These data suggest that the disruptive effects of haloperidol on conditioned active avoidance partially mirror its capacity to induce catalepsy and extrapyramidal motor symptoms. Furthermore, this study indicates that clozapine may be effective in reducing motor side-effects caused by typical neuroleptics.

Animals↗
PubMed2000

Long-term biobehavioral effects of maternal separation in the rat: consistent or confusing?

Over the last decades of research there has been increasing interest in endocrine and behavioral effects of postnatal environmental manipulations. A manipulation procedure that has been widely used to date is that of maternal separation. Many studies have demonstrated that, in the rat, a single or repeated separation of the pups from the mother leads to acute as well as long-term effects on endocrinology and behavior. However, reviewing the literature shows that contrary findings for almost all parameters investigated can be found. A possible explanation for this inconsistency may be the fact that maternal separation has become a collective term for a variety of extremely different experimental manipulations. Therefore, this review aims at evaluating typical effects of maternal separation in the laboratory rat by categorizing different experimental procedures. We concentrate in particular on longterm behavioral effects, although a brief summary of neuroendocrine effects is also provided. In addition, important methodological issues of maternal separation studies are discussed as a possible source for inconsistent findings.

Adaptation, Physiological↗
PubMed2000

Strain differences in the isolation-induced effects on prepulse inhibition of the acoustic startle response and on locomotor activity.

The authors investigated the effects of isolation rearing on acoustic startle response, prepulse inhibition (PPI), its modification by apomorphine, and locomotor activity in 3 rat strains: Wistar (WS), Sprague-Dawley (SD), and Lister hooded (LH). SD and LH, but not WS, showed isolation-induced PPI deficits. In 2 consecutive PPI tests, only SD isolates showed significant PPI deficits. An isolation rearing effect in LH was significant only in the 1st PPI test. Apomorphine dose-dependently (0.0-0.5 mg/kg) disrupted PPI, but sensitivity to the drug differed, with WS and SD rats being more sensitive to lower doses (0.01-0.05 mg/kg) than LH rats (0.5 mg/kg). Isolates, irrespective of strain, did not differ from grouped rats in their response to the apomorphine challenge. Only WS and LH isolates demonstrated significantly increased locomotor activity. Strain differences in the different parameters measured did not predict isolation-induced effects on PPI.

Animals↗
PubMed1999

Peripheral benzodiazepine receptors in cerebral cortex, but not in internal organs, are increased following inescapable stress and subsequent avoidance/escape shuttle-box testing.

Stress-induced alterations in peripheral benzodiazepine receptor (PBR) density have been reported in humans and in rats. However, the PBR response is highly specific, and its function remains largely unexplained. The aim of the present study was to investigate the relationship between behavior in the two-way active avoidance paradigm (2WAA) and post-test PBR densities in adrenal, testis, kidney, and cerebral cortex. Adult male Wistar rats were tested in the 2WAA either in the naive state (AA) or 24 h following shock preexposure (PE), known to interfere with avoidance/escape response acquisition, and decapitated immediately after testing. Control subjects were decapitated without experimental experience. The stressful characteristic of the experiment was validated by significantly increased post-test corticosterone levels in AA and PE subjects compared with controls, with a trend towards higher corticosterone levels in PE relative to AA rats. Similarly, PE compared with AA subjects tended to show retarded acquisition of the escape/avoidance response. PBR densities in adrenal, kidney, and testis and central benzodiazepine receptors (CBR) in the cerebral cortex remained unaffected by avoidance testing. Cerebral cortex PBR density was significantly increased in PE subjects. These findings suggest that avoidance testing, although stressful to the animals, led to changes confined to cerebral cortex PBR, indicating that the hypothalamic-pituitary-adrenal (HPA) response occurs independently of the PBR response in peripheral organs, and also suggest that the opportunity for coping alters the impact of the stressor on the subject and prevents the expression of PBR response in peripheral organs.

Adrenal Glands↗
PubMed1999

Disruption of prepulse inhibition following N-methyl-D-aspartate infusion into the ventral hippocampus is antagonized by clozapine but not by haloperidol: a possible model for the screening of atypical antipsychotics.

The present study tested the effects of the typical neuroleptic haloperidol and an atypical neuroleptic clozapine on ventral hippocampus stimulation-induced disruption of prepulse inhibition (PPI). Bilateral infusions of 0.7 microg NMDA into the ventral hippocampus disrupted PPI. The impairment of PPI following the infusion was completely normalized 24 h after the infusion. This disruption of PPI was antagonized by clozapine (5.0 mg/kg), but not by haloperidol (0.2 mg/kg). Since disruption of PPI is considered to constitute an animal model of schizophrenia that is related to the deficit of sensorimotor gating observed in schizophrenic patients, these results suggest that PPI disruption induced by intra-ventral hippocampal infusions of NMDA may serve as an animal model for the selective detection of atypical antipsychotics.

Acoustic Stimulation↗
PubMed1999

Effects of cocaine on dopamine in subregions of the rat prefrontal cortex and their efferents to subterritories of the nucleus accumbens.

The present study sought to investigate the contributions of the ventral prelimbic/infralimbic cortices and shell subterritory of the nucleus accumbens as well as the dorsal prelimbic/anterior cingulate cortices and core subregion of the nucleus accumbens to the acute systemic effects of cocaine (20 mg/kg i.p.) on both locomotor activity and simultaneous dialysate dopamine levels using a dual-probe microdialysis design. Basal dopamine levels were significantly higher in the ventral medial prefrontal cortex compared with the dorsal medial prefrontal cortex and higher concentrations of dopamine were also observed in the core of the nucleus accumbens compared with its shell counterpart. Cocaine produced a significant decrease in dopamine levels in both the ventral and dorsal medial prefrontal cortices. In contrast, cocaine significantly increased dialysate dopamine in the shell of the nucleus accumbens, whereas only a slight increase in dopamine was observed in the core subregion of the nucleus accumbens. A significant negative relationship between dopamine levels in the ventral and dorsal medial prefrontal cortices and dialysate dopamine concentrations in the shell and core of the nucleus accumbens was observed. Finally, in both the ventral and dorsal medial prefrontal cortices, the magnitude of the locomotor response to cocaine was inversely related to dialysate dopamine levels. In contrast, the magnitude of the locomotor response to cocaine became progressively larger as dopamine levels increased in the shell of the nucleus accumbens. These results show a dissociation in the pattern of dopamine release in subterritories of both the medial prefrontal cortex and nucleus accumbens in response to the acute systemic administration of cocaine.

Animals↗
PubMed1999

Comparisons of the densities of NADPHd reactive and nNOS immunopositive neurons in the hippocampus of three age groups of young nonhandled and handled rats.

The complete absence of handling of male rats during neonatal development (from birth to postnatal day 21) correlates with an impairment of latent inhibition [J. Feldon, I. Weiner, From an animal model of an attentional deficit towards new insights into the pathophysiology of schizophrenia, J. Psychiatr. Res. 26 (1992) 345-366.]. Such nonhandling of rats reportedly also correlates with a decreased expression of reduced nicotinamide adenine dinucleotide phosphate-diaphorase (NADPHd) reactivity in the hippocampus in adult rats (6 months of age) when compared with rats of the same age that were handled during the same neonatal period [R.R. Vaid, B.K. Yee, U. Shalev, J.N. Rawlins, I. Weiner, J. Feldon, S. Totterdell, Neonatal nonhandling and in utero prenatal stress reduce the density of NADPH-diaphorase-reactive neurons in the fascia dentata and Ammon's horn of rats, J. Neurosci. 17 (1997) 5599-5609.]. The present study investigated whether such a decrease in NADPHd activity would be detectable at earlier ages. Therefore, the present study assessed the density of nitric oxide (NO) producing neurons in the fascia dentata and Ammon's horn in 28-, 54-, and 118-day-old nonhandled and handled male rats using NADPHd histochemistry and immunohistochemical localization of neuronal isoform of nitric oxide synthase (nNOS), a NADPHd. This showed that in these three age groups, the numbers of NADPHd positive neurons per unit area throughout the hippocampus of rats that received no handling during neonatal development did not differ significantly from those of rats that received regular daily handling. In addition, we found in the rats of 118 days of age that the areal density of nNOS immunopositive neurons in the hippocampus also did not differ significantly between nonhandled and handled rats. Nevertheless, in a parallel study, rats from the same experimental group receiving identical treatments showed the expected impairment of latent inhibition at 4 months of age [R. Weizman, J. Lehmann, S. Leschiner, I. Allmann, T. Stoehr, C. Heidbreder, A. Domeney, J. Feldon, M. Gavish, Long-lasting effect of early handling on the peripheral-type benzodiazepine receptor, Pharmacol. Biochem. Behav. in press.]. These results suggest that nonhandling of rats during the early neonatal period, that does result in impairment in latent inhibition, does not affect the numbers of NO producing neurons in the hippocampus in rats of young ages, including the age of observed impairment of latent inhibition.

Aging↗
PubMed1999

Latent inhibition in smokers vs. nonsmokers: interaction with number or intensity of preexposures?

Latent inhibition (LI) refers to the slowing of learning about a stimulus after preexposure, i.e., previous presentation of the stimulus without any consequence. This report summarizes results of four studies investigating the effect of being a smoker or nonsmoker on auditory LI as a function of procedural parameters, namely number (10 vs. 30) and intensity (low vs. high) of preexposed stimuli. In general, the number of preexposures did not affect LI, whereas low-intensity stimuli led to greater LI than high-intensity stimuli. These findings underline the importance of automatic vs. controlled processing of the preexposed stimuli for the development of human LI. Smokers showed increased LI compared to nonsmokers in low-intensity task versions as well as compared to both smokers and nonsmokers in high-intensity versions. These findings may indicate that nicotinic effects on LI depend on the robustness of LI in the control group.

Acoustic Stimulation↗
PubMed1999

Circadian time does not modify the prepulse inhibition response or its attenuation by apomorphine.

The present study investigated the influence of circadian time (experimental testing during the light or dark phase of the light:dark cycle) on the acoustic startle response (ASR), prepulse inhibition (PPI), and apomorphine-induced PPI deficits in Wistar rats housed under a reversed light:dark cycle (lights off at 0700 h and on at 1900 h). There was no significant difference in the startle response amplitude or PPI response of animals tested during the light phase compared with those tested during the dark phase. Similarly, the response to apomorphine (0.01-0.05 mg/kg subcutaneously) was not modulated by circadian time. Thus, under the conditions adopted in the present study, ASR, PPI, and apomorphine-induced PPI deficits remained stable across the circadian cycle. Such findings may be of importance for other investigators using the PPI paradigm to study brain plasticity mechanisms and pharmacological manipulations of apomorphine-induced PPI deficits in rats housed under normal or reversed light:dark cycle conditions.

Acoustic Stimulation↗
PubMed1999

Long-lasting effect of early handling on the peripheral benzodiazepine receptor.

The present study determined the impact of early handling (EH) in rats on behavioral response to environmental stress and on peripheral benzodiazepine receptor (PBR) binding characteristics (Bmax and Kd) in various organs. The behavioral consequences of EH in rats were expressed as increased exploratory activity in an open-field paradigm, when compared with nonhandled control rats. These findings are interpreted in terms of decreased emotionality. The biochemical consequences of EH, in both male and female rats, were expressed as the upregulation of PBR in the adrenal and kidney and the downregulation of gonadal (testis and ovary) PBR. It is possible that the long-lasting adrenal and renal changes in PBR expression in EH rats may enable better regulation of the hypothalamic-pituitary-adrenal axis, renin-angiotensin system, and autonomic nervous system responses to stress in adulthood. The significance of the EH-induced reduction in gonadal PBR for gonadal activity in adulthood is as yet unclear.

Adaptation, Biological↗
PubMed1999

Effect of sex on fear conditioning is similar for context and discrete CS in Wistar, Lewis and Fischer rat strains.

Enhanced fear in males relative to females, both innate and conditioned, is a well-described characteristic of behavior in the laboratory rat. In the case of aversive conditioning to foot shock in Long-Evans rats, it has been described that conditioning to general (nondiscrete) contextual cues is greater in male rats relative to female rats, whereas conditioning to a discrete, predictive stimulis (CS) is not. These findings have been combined with evidence for greater levels of hippocampal LTP in males in Sprague-Dawley rats to derive a model of hippocampal-LTP-mediated contextual and not CS, fear conditioning. The present study reports on an analysis of the effect of sex in contextual and discrete CS conditioning to foot shock, assessed via measurement of freezing behavior in a novel automated paradigm, in three rat strains: Wistar, Fischer, and Lewis. In Wistar rats, there was a consistent but nonsignificant tendency for males to demonstrate both more contextual and more CS conditioning than females; in Fischer rats, males demonstrated both more contextual and more CS conditioning than females; in Lewis rats, a markedly enhanced acquisition of freezing in males did not translate into a sex difference in either context or CS conditioning at expression. Therefore, within each strain the effect of sex was consistent between context and CS conditioning. These findings, taken together with the hippocampal LTP evidence, suggest that the latter mediates both contextual and discrete CS aversive conditioning, and contributes to sex differences in both these forms of conditioning, in those strains where these sex differences exist.

Animals↗
PubMed1999

The maternal separation paradigm and adult emotionality and cognition in male and female Wistar rats.

A single 24-h maternal separation (MS) in the rat during the stress hyporesponsive period alters adult behavior and neuroendocrine stress response. The age of the animal at MS might be a crucial factor for effects in adulthood. We report here on adult behavioral effects of MS performed on postnatal day 4 (MS4), 9 (MS9), or 18 (MS18) in male and female Wistar rats. Unrelated subjects were used to avoid confounding litter effects. Subjects were tested on paradigms of unconditioned fear/anxiety, i.e., open field and elevated plus-maze, and on paradigms involving learning in an aversive situation, i.e., conditioned freezing, active avoidance, and water maze. In line with our predictions we obtained (a) sex differences that were consistent with enhanced fear/anxiety in males relative to females, (b) evidence that MS4 yielded deficits in active avoidance learning and conditioned freezing (trend level), whereas MS9 yielded enhanced active avoidance and water maze learning, (c) evidence (at trend level) that these effects of MS are greater in males than in females. There was no evidence for an effect of MS on paradigms of unconditioned fear/anxiety. We conclude that MS, irrespective of the age at separation, does not provide a robust environmental model of modified behavior in aversive situations.

Analysis of Variance↗
PubMed1999

Behavioural and hormonal differences between two Lewis rat lines.

Lewis (LEW) is an inbred strain of rats frequently used as an animal model of autoimmune diseases. However, there is evidence that some lines of LEW rats develop autoimmune diseases more readily than do other LEW rat lines. Because the hypothalamus-pituitary-adrenal system is involved in the pathophysiology of these diseases, we compared two LEW lines (SsNHsd and HANRijHsd) in their behavioural and neuroendocrine response to stress. In addition, we studied the psychostimulant effects of acute and repeated amphetamine in these two LEW rat lines. HAN rats were less active in the open field test and showed faster habituation of novelty-induced locomotion. The acoustic startle response was lower in HAN than in SSN rats, whereas prepulse inhibition of the startle response was greater in the HAN than in the SSN LEW subline. Moreover, HAN rats showed impaired acquisition of the two-way active avoidance response relative to SSN rats. The psychostimulant effects of acute amphetamine were smaller in HAN rats. Following repeated injections of amphetamine, behavioural sensitization to the psychostimulant effects of amphetamine was more pronounced in HAN than in SSN rats. Basal concentrations of serum corticosterone did not differ between the two rat lines. Following stress, however, HAN rats showed slightly higher corticosterone secretion than SSN rats. Our results show that two sublines of the LEW inbred strain of rats show profound behavioural differences which are only marginally paralleled by differences at the level of the HPA system.

Amphetamine↗
PubMed1999

Sex differences in the acoustic startle response and prepulse inhibition in Wistar rats.

The prepulse inhibition paradigm (PPI) is based on the phenomenon that the acoustic startle response (ASR) to an acoustic stimulus is reduced when the stimulus is preceded by a weak prepulse. It has been shown that PPI is dramatically disrupted in patients with schizotypic disorders. Since PPI can be easily tested in animals as well as in humans it is a widely used model to investigate the neurobiological mechanisms underlying those disorders. In humans it has been demonstrated that men show increased PPI at weak prepulses relative to women. Only very few studies have investigated PPI sex differences in rats and these report negative findings. Studies are reported on here where consistent differences have been found in ASR and PPI between adult male and female Wistar rats. Compilation of data from a series of experiments demonstrates that ASR and PPI are both greater in males than in females in this rat strain, a finding which is largely in line with the human evidence. This study therefore adds weight to the argument that PPI of the ASR provides an animal model with high validity for the study of important human disorders which are characterized by sensorimotor gating deficits.

Acoustic Stimulation↗
PubMed1999

Behavioral neurochemistry reveals a new functional dichotomy in the shell subregion of the nucleus accumbens.

1. The behavioral and neurochemical effects produced by the direct infusion of amphetamine by reverse microdialysis into either the core or shell of the nucleus accumbens were studied across the anteroposterior axis of this nucleus. 2. Amphetamine (0.05; 0.10; 0.50; 1.00 microM) produced a dose-dependent increase in locomotor activity after microinfusion into either the rostral shell, caudal shell or core of the nucleus accumbens. However, the amphetamine-induced locomotor activating effect, was significantly higher in the rostral shell of the nucleus accumbens compared with both the caudal shell and core. 3. The lowest concentrations of amphetamine produced an equipotent decrease in dialysate dopamine in either the rostral shell, caudal shell, or core. At 1.0 microM, however, amphetamine selectively increased dopamine in the rostral shell. In contrast, the highest dose of amphetamine significantly increased dialysate serotonin levels over baseline only in the caudal shell of the nucleus accumbens. 4. These results demonstrate the preferential effect of amphetamine on dopamine in the rostral shell and serotonin in the caudal shell subterritory of the nucleus accumbens.

Amphetamine↗