Biomedical subjects

L S Wilkinson

Publications and source records attributed to L S Wilkinson.

At least 19 recordsLinked to original sources

PubMed1999

Maternal deprivation of neonatal rats produces enduring changes in dopamine function.

Isolation-rearing of weanling rats produces a syndrome of behavioral and neurochemical effects that are indicative of enhanced ventrostriatal dopamine function observed in adulthood. By contrast, maternal deprivation of neonatal rats decreases behavioral responses to dopamine agonists when tested in adults, which may indicate the opposite situation. However, in the present study it is reported that in vivo microdialysis of the nucleus accumbens (NAC) revealed enhanced release of dopamine (DA) in response to both d-amphetamine and high K+ perfusate in maternally deprived subjects. Thus, behavioral responses to d-amphetamine are diminished in maternally deprived rats despite apparent increases in presynaptic dopaminergic function in the NAC.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1999

Forebrain serotonin depletion facilitates the acquisition and performance of a conditional visual discrimination task in rats.

Three experiments examined the effects of depleting forebrain 5-hydroxytryptamine (5-HT) on the acquisition and performance of an operant conditional discrimination in the visual modality. In the first experiment, rats with 5-HT lesions induced by infusing the neurotoxin 5,7-dihydroxytryptamine intracerebroventricularly acquired the conditional visual discrimination more rapidly than the sham-operated controls. Following acquisition, a series of manipulations of the task parameters tested the effects of the lesion on cognitive, sensory and motivational aspects of performance. In experiment two, the performance of rats that had acquired the task to asymptote before receiving lesions was assessed. The performance of this second group of serotonin-lesioned rats was similar to that of the pre-acquisition lesioned group following all but one manipulation of the task parameters. When the rate of stimulus presentations was increased, rats with forebrain 5-HT depletions were protected from the disruptive effects on performance seen in the sham-operated controls. This latter finding was also observed in a third experiment, in which the infusion of the 5-HT1A receptor partial agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT), directly into the dorsal raphe nucleus improved the performance of unlesioned rats following an increase in the rate of stimulus presentations. The results are discussed in terms of the behavioural, neurochemical and neuroanatomical specificity of serotonin function in appetitive learning and the implications for general theories of the function of serotoninergic processes in cognition.

Animals↗

PubMed1998

Isolation rearing in rats: pre- and postsynaptic changes in striatal dopaminergic systems.

Isolation rearing of rats produces a behavioral syndrome indicative of altered dopamine (DA) function in the nucleus accumbens (NAC). The present experiments extend these findings by investigating: (a) interactions between isolation rearing and repeated handling/testing on presynaptic DA function in the NAC using in vivo microdialysis: (b) the dose-response curve for the effects of d-amphetamine, and the responses elicited by high potassium, using in vivo microdialysis, and (c) postsynaptic function in isolates as indexed by DA receptor-linked cAMP production. Experiment 1 showed that both isolation rearing and repeated handling/testing had effects on monoamine function in the NAC. However, while both manipulations enhanced DA release evoked by d-amphetamine, only isolated rats had elevated basal DA levels. Opposite neurochemical changes were observed with respect to the serotonin metabolite 5-HIAA, isolates having lower, and repeatedly handled/tested animals having higher, extracellular levels. Experiment 2 provided evidence for enhanced d-amphetamine-evoked DA release in isolated animals, while potassium-evoked DA release was reduced. Experiment 3 provided evidence that the isolation rearing induced changes in presynaptic DA function were accompanied by postsynaptic changes. Specifically, the inhibitory influence of the D2 receptor on D1 receptor-stimulated cAMP production was attenuated in ventral striatal slices taken from isolates, suggesting a functional downregulation of D2 receptors.

Animals↗

PubMed1998

Dissociations in dopamine release in medial prefrontal cortex and ventral striatum during the acquisition and extinction of classical aversive conditioning in the rat.

Dual perfusion in vivo brain microdialysis was used to monitor extracellular levels of dopamine in the medial prefrontal cortex and ventral striatum during the acquisition and extinction of a classical aversive conditioning paradigm in rats. The main finding was a dissociation in the pattern of release in the two brain areas. The first stimulus-footshock pairing elicited large increases in cortical dopamine over baseline levels that were much greater than the increases elicited by different stimuli of equivalent salience that were unpaired with footshock. In contrast, dopamine levels in ventral striatum were unchanged under these conditions. Over the next two pairings, there was a decline in the cortical response and an increase in the response in ventral striatum. The first presentation of the aversive conditioned stimulus in a separate context elicited the largest response in ventral striatum. Post-conditioning, the cortical response to the conditioned stimulus was smaller than that elicited by the initial stimulus-footshock pairing and was equivalent in magnitude to that elicited by stimuli unpaired with footshock. Over the final two conditioned stimuli presentations, in the absence of the footshock reinforcer (extinction), responses declined in both brain areas. Simultaneous monitoring of behaviour indicated that the neurochemical events were accompanied by effective aversive learning, as indexed by conditioned freezing responses. The data are discussed in terms of the hypothesis that medial prefrontal cortex is especially engaged during novel circumstances which may, potentially, require new learning, whilst ventral striatal dopamine more closely follows the expression of conditioned responding during learning and extinction.

Animals↗

PubMed1997

Defining the use of gadolinium enhanced MRI in the assessment of the postoperative lumbar spine.

A retrospective study of case notes and magnetic resonance imaging (MRI) examinations was performed to assess the value of gadolinium enhanced MRI in the investigation of persistent back pain following lumbar spine surgery in patients who have not had a discectomy for disc herniation. Gadolinium enhancement is commonly used during MRI of patients with persistent back pain following surgery and epidural scar is frequently identified in patients who have had a previous discectomy. However the value of gadolinium enhancement in patients without previous discectomy had not been addressed. One hundred sets of case notes were examined and 24 patients with an accurate history of previous lumbar spine surgery without discectomy were identified. The nature of surgery and the MRI findings were correlated in these patients. Epidural enhancement was identified at seven sites in six patients (engorged epidural venous plexus, three; enhancement adjacent to degenerate discs, two; enhancement adjacent to facets, two). In no case was epidural scarring involving nerve roots identified. We conclude that routine gadolinium enhancement is unnecessary in patients without a history of discectomy for disc herniation.

Aged↗

PubMed1997

The effects of isolation-rearing of rats on behavioural responses to food and environmental novelty.

Isolation-reared rats exhibited enhanced behavioural responses to novelty, but only some aspects of such behavior was affected. In Experiment 1, environmental neophobia was enhanced but food neophobia was diminished in isolation-reared rats compared to socially reared rats. However, in Experiment 2, when subjects were not handled extensively prior to testing, no differences in behavioural responses to environmental or food novelty in an open-field were observed between rearing groups. The difference between these experiments was hypothesized to be the result of ceiling effects produced by increased anxiety or arousal in experiment 2 in which the animals had not been extensively handled. In summary, in these experiments anticipatory responses to novelty were alterred by isolation-rearing but the behavioural expression of this increased sensitivity was determined by intrinsic aversive/rewarding or arousing qualities of novel environments and novel foods.

Animals↗

PubMed1997

The effects of isolation-rearing on sucrose consumption in rats.

Three experiments examined the hypothesis that social isolation of weanling rats potentiates hedonic processes by examining the consumption of sucrose solutions. In the first experiment no differences in consumption were found between socially reared rats and isolation-reared rats allowed to consume sucrose in a familiar test apparatus. In a second experiment socially-reared rats and isolation-reared rats were food and water deprived. Again, no differences in consumption were found. In a third experiment socially reared and isolation-reared rats were allowed to consume sucrose presented in either an ascending or descending order of concentration. When given sucrose in an ascending order of presentation isolation-reared rats consumed significantly more sucrose than socially reared rats. This suggests that isolation-rearing increased the effects of positive contrast, and is consistent with other observations of increased incentive motivation in isolates.

Animals↗

PubMed1997

The effects of isolation-rearing on preference by rats for a novel environment.

In the previous paper isolation-reared rats exhibited enhanced environmental neophobia under some conditions in an open-field. However, previous work has shown that isolation-reared rats have greater preferences for a novel environment in a dimly lit enclosed box. The hypothesis examined in the present experiments was that manipulation of the intrinsic aversive qualities of such an environment, by altering lighting conditions, could reverse the preference which isolation-reared rats exhibit for a novel chamber. When preference for a novel chamber was examined in a non-aversive environment in Experiment 1, isolation-reared rats exhibited a preference for a novel environment which was enhanced compared to social controls. When tested under more aversive white light conditions in Experiment 2, no differences in novelty preference were observed between isolation-reared and socially reared rats. Thus, the increased sensitivity to novel environments by isolation-reared rats appears to be critically dependent on the arousing or aversive properties of the testing conditions.

Animals↗

PubMed1997

Contrasting effects of excitotoxic lesions of the prefrontal cortex on the behavioural response to D-amphetamine and presynaptic and postsynaptic measures of striatal dopamine function in monkeys.

The effects of excitotoxic lesions of the prefrontal cortex on behavioural, neurochemical and molecular indices of dopamine function in the caudate nucleus were studied in the marmoset. The lesion, which encompassed both the lateral and orbital regions of prefrontal cortex, made the animals more sensitive to the performance disrupting effects of the dopamine releasing drug, D-amphetamine, in a variation of the object retrieval task. Specifically, following drug administration, the lesioned marmosets were less able to gain access to food reward in the minimum number of responses. Analysis of the nature of the errors suggested that the deficit was not due to inhibition of a prepotent response as the lesioned monkeys were just as likely to make a detour reach to the unopened side of the box as a direct "line-of-sight" reach into the unopened front of the box. Rather, the data indicated a general disorganization of behaviour. The enhanced behavioural responsiveness to manipulations increasing presynaptic dopamine function was accompanied by neurochemical changes indicating a reduced responsiveness, as revealed by in vivo microdialysis. Thus, in lesioned animals, whilst there were no effects on baseline levels of extracellular dopamine in dorsolateral caudate, evoked release, both to systemic D-amphetamine and to a local depolarizing pulse of potassium ions, was attenuated. These opposite effects of the prefrontal cortex lesion on behavioural and neurochemical indices of striatal dopamine function occurred in the absence of any changes in striatal dopamine receptors of the D1 and D2 subtype, as determined both by radioligand binding assays and measurements of messenger RNA using in situ hydridization techniques. These data provide further insight into the interactions between prefrontal cortex and striatal dopamine function in the non-human primate. In particular, when taken in the light of our previous studies they indicate that following prefrontal manipulations, concurrence between behavioural and neurochemical indices of striatal dopamine function depends, critically, on the behavioural task. These findings are discussed with respect to the growing body of evidence implicating abnormalities in frontostriatal neurotransmission in complex disorders such as schizophrenia.

Analysis of Variance↗

PubMed1997

The nature of interactions involving prefrontal and striatal dopamine systems.

A number of converging lines of evidence from work in rodents suggest that dopamine (DA) function in the prefrontal cortex (PFC) and striatal terminal fields may be linked, possibly in an 'inverse' manner, whereby a change in prefrontal dopamine transmission in one direction occasions an opposite change in dopamine function in striatal territories. The present article considers the possible functional importance of this concept in the light of recent neuroanatomical data and new data from our own laboratory indicating that, at the neurochemical level, the basic finding of an inverse relationship between dopamine function in prefrontal and striatal regions also holds good in the non-human primate. The main conclusion is that the simple idea of an inverse relationship between prefrontal and striatal dopamine systems emphasizing presynaptic release mechanisms is unlikely to underlie, solely, the full repertoire of functional interactions. Whilst there is evidence consistent with dynamic interactions between prefrontal and striatal dopamine release under some circumstances, specifically, during the early phases of aversive learning, a complete account of possible interactions between prefrontal and striatal dopamine systems requires consideration of additional factors. Such factors include: (1) the precise nature of the psychological function investigated, (2) the possibility of acute, localized changes in striatal postsynaptic function secondary to changes in presynaptic function and (3) the possibility of manipulations of prefrontal cortex leading to adaptive changes in striatal function, at a diffuse, neural systems level.

Animals↗

PubMed1996

Prepulses inhibit startle-induced reductions of extracellular dopamine in the nucleus accumbens of rat.

In vivo brain microdialysis was used to monitor extracellular levels of dopamine (DA) in the nucleus accumbens (NAc) of rats during exposure to startling acoustic stimuli. Ten rats were prepared with guide cannulae into which dialysis probes were inserted 1 d before testing. Two to three hours after the start of perfusion, rats were placed into the startle chamber and exposed to a continuous 70 dB(A) background noise. Dialysis samples (2.0 microliter/min) were collected at 6 min intervals. Startle pulses (120 dB[A] noise) were presented in 20-trial blocks lasting 5 min. In some blocks, an 86 dB[A] prepulse preceded each of the 20 pulses by 100 msec, with the order of presentation of pulse-alone or prepulse + pulse blocks being counterbalanced between animals. Three to six sample periods intervened between stimulus-containing blocks. Monoamine and metabolite levels were measured using HPLC with electro-chemical detection. During the presentations of startling stimuli, DA levels in the NAc decreased relative to the immediately preceding 12 min baseline. This decrease in DA was maintained for only one additional sample period. By contrast, the presentation of prepulse + pulse trials failed to affect dialysate levels of NAc DA during or immediately after the stimulation. Thus, startling acoustic stimuli produce significant and transient decreases in dialysate levels of DA in the NAc. Furthermore, prepulse stimuli effectively inhibit these neurochemical effects of starting stimuli, in parallel with their establish ability to inhibit the amplitude the behavioral startle response.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1996

Retarded acquisition and reduced expression of conditioned locomotor activity in adult rats following repeated early maternal separation: effects of prefeeding, d-amphetamine, dopamine antagonists and clonidine.

Adult hooded rats exposed to a repeated maternal separation procedure during the neonatal period showed a blunted expression of locomotor hyperactivity conditioned to the presentation of the daily food ration. We have demonstrated that the expression of food-conditioned anticipatory hyperactivity is sensitive to the response-enhancing effects of systemic d-amphetamine (0.5; 1.0 mg/kg) and to the response-attenuating effects of the selective dopamine D2 antagonist sulpiride (8; 20 mg/kg), the selective dopamine D1 antagonist SCH 23390 (0.01; 0.022 mg/kg) and the mixed alpha 1/alpha 2 adrenoceptor agonist clonidine (5; 15 micrograms/kg) in a dose dependent manner. Animals from the early separation groups showed a reduced enhancement of activity in response to 0.5 mg/kg d-amphetamine and a greater attenuation of activity in response to 8 mg/kg sulpiride and 5 micrograms/kg clonidine. Female separated rats also exhibited an attenuated locomotor response to the unconditioned stimulant effects of 0.5 mg/kg systemic d-amphetamine. The experiments confirm that early maternal separation attenuates the response to conditioned appetitive cues in adult rats and implicate altered dopaminergic and noradrenergic function in the changes. It is possible that early maternal separation in the rat may offer a useful preparation for investigation of the neural substrates mediating affective development and affective psychopathology.

Adrenergic alpha-Agonists↗

PubMed1996

Repeated maternal separation of preweanling rats attenuates behavioral responses to primary and conditioned incentives in adulthood.

Early social experience has profound effects on a wide spectrum of behaviors and neurochemical correlates in the rat. Repeated separation of rat pups from their dam during the early neonatal period causes acute perturbation of neuroendocrine and physiological status. The chronic sequelae of repeated separations have not been studied as extensively as the acute responses. Altered social experience at a later developmental stage, postweaning isolation rearing, is known to induce enduring changes in the behavioral responses to reward and reward-related stimuli in maturity. We have evaluated the influence of repeated early maternal separation on the responses to both primary and conditioned incentives in mature rats. Separated animals showed enhanced weight gain, a blunted locomotor response to a novel environment and a blunting of the response to both negative and positive contrast effects. Female separated animals, but not males, exhibited a profound attenuation of the acquisition of a conditioned anticipatory locomotor response to the presentation of food. These data are discussed with respect to the putative involvement of ventral striatal dopamine systems in reward mechanisms and the potential utility of early maternal separation as an animal model of depression.

Animals↗

PubMed1996

Biliary sludge: can ultrasound reliably detect the presence of crystals in bile?

OBJECTIVE: To determine the accuracy of routine gallbladder ultrasound in the detection of crystals in bile. METHODS: Preoperative ultrasonography was performed in 40 patients undergoing elective cholecystectomy. Bile was aspirated at operation and examined microscopically for the presence and quantity of crystals. RESULTS: Six patients had echogenic bile, five of whom had large numbers of crystals at microscopy, and one only a few crystals. Thirty-four patients had hypoechoic bile, nine had large numbers of crystals and 25 of these had few or no crystals at microscopy. For those patients with echogenic bile (hyper- or isoechoic) the sensitivity for detection of large numbers of crystals was 5/14 (35.7%) with a specificity of 25/26 (96%). However, if the bile was hypoechoic the sensitivity was 9/14 (65%). CONCLUSION: For those patients with echogenic bile, ultrasound is highly specific for the detection of crystals, although the sensitivity is low. By contrast, those patients with hypoechoic bile at ultrasound would need a further investigation to exclude the presence of crystals.

Adolescent↗

PubMed1996

Dissociations in hippocampal 5-hydroxytryptamine release in the rat following Pavlovian aversive conditioning to discrete and contextual stimuli.

The experiments examined the release of 5-hydroxytryptamine using in vivo microdialysis methods in the hippocampus of freely moving rats following Pavlovian aversive conditioning to discrete and contextual stimuli. Differential conditioning was achieved by manipulating the interval between the offset of a discrete auditory 'clicker' stimulus and the onset of a mild foot-shock reinforcer (0.5 mA, 0.5 s). Foot-shock occurred either simultaneously with the last second of the discrete auditory stimulus (in short-trace subjects) or 60 s later (long-trace subjects). In this way, subjects were preferentially conditioned to the discrete stimulus and background 'contextual' stimuli respectively. During conditioning subjects also received two identical unpaired visual stimuli. At test, dialysates were collected and behavioural measures taken as all animals experienced (i) the aversive and two other 'neutral' environments, and (ii) the discrete unconditioned and conditioned stimuli presented in both aversive and neutral environments. Exposure to the aversive environment, but not to either of the two neutral environments, was associated with significantly increased hippocampal 5-hydroxytryptamine release in long-trace subjects. There was also a small but non-significant increase in 5-hydroxytryptamine release in short-trace animals. In contrast, hippocampal 5-hydroxytryptamine release was unaffected by presentation of either of the discrete stimuli under all conditions. The last result was obtained despite robust behavioural responses (freezing) to the discrete conditioned stimulus. These data do not agree with the hypothesis that aversive cues generally activate 5-hydroxytryptamine function in the hippocampus. Rather, they suggest a degree of specificity whereby 5-hydroxytryptamine release in the hippocampus was determined primarily by other qualitative properties of the conditioned aversive stimulus, namely whether the aversive cue was discrete or contextual, as well as by the magnitude of conditioning.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1996

Matrix metalloproteinases in the formation of human synovial joint cavities.

Matrix metalloproteinases (MMPs) have been implicated in tissue remodelling in growth and development. A histochemical study of human fetal limbs was undertaken to assess the presence, and consequently the possible role, of MMPs and their inhibitor TIMP-1 (tissue inhibitor of metalloproteinases-1) in synovial joint cavity formation. Cryostat sections of fetal limbs from 7 to 14 wk gestation were stained with specific antibodies to collagenase (MMP-1), gelantinases A (MMP-2) and B (MMP-9), stromelysin (MMP-3) and TIMP-1. Immunoreactive (IR) MMP-1, MMP-2 and MMP-3 were seen chiefly in chondrocytes, but in all cases in zones distant from the joint line before cavity formation. IR-MMP-1 and MMP-2 were also localised both in synovium and on the articular surfaces of joints after cavity formation. In addition IR-MMP-2 was seen in a "collar' of perichondrium alongside the hypertrophic zone of chondrocytes and weakly in bone marrow spaces. IR-MMP-9 was seen in neutrophil leucocytes and in bone marrow spaces. IR-TIMP-1 was generally distributed in connective tissue cells. No IR-MMP (1, 2,3 or 9) was seen along potential joint lines before or at the time of cavity formation, nor was there aspecific decrease in IR-TIMP-1 at this site. These findings confirm a role for metalloproteinases in developmental processes such as cartilage remodelling and bone marrow space formation. MMP-1 and MMP-2 may be involved in the remodelling of developing synovial tissue and the articular surfaces subsequent to cavity formation. However, we have failed to find evidence to indicate that the loss of tissue strength at the joint line which allows synovial joint cavity formation relates to high local levels of MMPS.

Cartilage, Articular↗

PubMed1996

Distribution in human tissues of the synovial lining-associated epitope recognised by monoclonal antibody 67.

Murine monoclonal antibody Mab 67 was originally shown on histochemical screening to bind to synovial intimal fibroblasts (SIF), cells in lymphoid follicles and elastic fibres. As part of a programme to isolate the antigen recognised by Mab 67 and determine its function, a wider histochemical study was performed. Cryostat sections were prepared from normal human adult synovium, skin, placenta, amnion, kidney, tonsil, breast, thyroid, colon and pericardium, fetal limb tissues and rheumatoid arthritic synovium. Sections were stained with Mab 67, anti-CD3, as isotype matched control, and anti-VCAM-1 using alkaline phosphatase -anti-alkaline phosphatase. Selected sections were double labelled for nonspecific esterase activity. Staining by Mab 67 of SIF, identified as NSE-negative intimal cells, and follicle centre cells was confirmed. Staining with Mab 67 was also seen on Bowman's capsule and juxtaglomerular apparatus, stratum granulosum of skin, pulmonary alveolar cells, amniotic epithelium, chorionic villi, fetal synovium, bone marrow stromal cells and epidermis, and interstitial elastic fibres in most tissues, but not at other sites in these tissues or in pericardium, muscle, colon, breast, thyroid, salivary gland or vein. The staining pattern with Mab 67 suggests that the antigen is pericellular. Its distribution does not match any molecule known to us but overlaps at several sites with VCAM-1 (SIF, follicle centres, Bowman's capsule and bone marrow stroma). We suggest that the antigen involved may possible by similarly involved in cell-matrix interaction.

Adult↗

PubMed1995

Differential effects of forebrain 5-hydroxytryptamine depletions on Pavlovian aversive conditioning to discrete and contextual stimuli in the rat.

The experiments examined the effects of depleting forebrain 5-hydroxytryptamine (5HT) on Pavlovian aversive conditioning to discrete and contextual stimuli. Rats were lesioned with intracerebroventricular injections of the neurotoxin 5,7-dihydroxytryptamine and then conditioned in a distinctive environment (termed the context) to a 30 s auditory stimulus. In 50% of animals the interval between the offset of the discrete auditory stimulus and the reinforcer, a mild foot-shock (0.5 mA, 0.5 s), was 5 s (the short-trace group) and in the other 50%, 30 s (the long-trace group). Theory predicts that animals in the short-trace condition will learn more about the discrete stimulus as a predictor of shock and become strongly conditioned, while those in the long-trace condition learn relatively more about the context. The extent of conditioning to the discrete and contextual stimuli was assessed separately, in extinction, using lick-suppression and place-preference measures respectively. Under these conditions sham subjects exhibited the expected dissociation with respect to trace interval. However, lesioned animals exhibited a specific impairment in contextual conditioning. The results are discussed in terms of the behavioural, neurochemical and neuroanatomical specificity of 5HT function in aversive conditioning and the implications for general theories of the role of 5HT in aversive processes.

Animals↗