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Biomedical subjects

J A Gray

Publications and source records attributed to J A Gray.

At least 19 recordsLinked to original sources
PubMed1992

Classical conditioning after temporal lobe lesions in man: sparing of simple discrimination and extinction.

Recent reports of impaired conditional discrimination learning in temporal lobectomy subjects have raised the question of response inhibition deficits in these patients. In the present study, left and right temporal lobectomy subjects and healthy controls completed an eyelid conditioning task, which required simple two-tone discrimination learning, followed by extinction. There were no group differences with regard to discrimination learning or extinction. General deficits in response inhibition are therefore not likely to account for the impairment in conditional discrimination observed in temporal lobectomy patients.

Acoustic Stimulation↗
PubMed1992

Loss of the Kamin blocking effect in acute but not chronic schizophrenics.

Differences between research diagnostic criteria (RDC)-diagnosed acute and chronic schizophrenics and normal controls were studied using a Kamin blocking procedure. Blocking is an established animal learning procedure, thought by some researchers to reflect selective attention; decreased blocking indicates increased processing of irrelevant stimuli. It was predicted that this pattern would be obtained in acute schizophrenics, tested soon after admission, for two reasons: (1) evidence from previous clinical studies indicates that acute schizophrenics are more aware of nonsalient aspects of their environment than controls; and (2) blocking is disrupted in animals in a hyperdopaminergic state and restored by neuroleptic medication. This was the case: acute, but not chronic, schizophrenics showed disrupted blocking. This disruption was especially clear in those acute schizophrenics tested within 2 weeks of hospital admission. By the second test session (in a cross-over design), there was some evidence of normalization in performance in the acute schizophrenics. These findings are considered with regard to the dopamine hypothesis of schizophrenia.

Acute Disease↗
PubMed1992

Analysis of relative mRNA levels and protein patterns in brains of rat strains bred for differing levels of emotionality.

mRNA and protein populations were studied in the brains of Maudsley reactive (MR) and Maudsley nonreactive (MNR) rat strains, which exhibit differing levels of emotionality. Translational analysis of forebrain mRNA indicated that the relative levels of two translation products (42 kDA, pI 5.0; 30 kDa, pI 5.8) were increased in the MR compared to the MNR strain. In addition, a charge-shift variant of a 36 kDa protein was present in the MR strain. Analysis of brain protein patterns indicated that a protein of 39 kDa, pI 5.0, was found to be more abundant in MR compared with MNR strains in both frontal cortex and hippocampus and the relative level of one protein (40 kDa, pI 5.8) was decreased in the frontal cortex.

Animals↗
PubMed1992

Abolition of latent inhibition by a single 5 mg dose of d-amphetamine in man.

The performance of healthy volunteer subjects on an auditory latent inhibition (LI) paradigm was assessed following administration of a single oral dose of d-amphetamine or placebo. It was predicted that a low (5 mg), but not a high (10 mg), dose of d-amphetamine would disrupt LI. The prediction was supported with left ear presentation of the preexposed stimulus only. When the preexposed stimulus was presented to the right ear the predicted pattern of findings was not obtained. It is concluded that the dopaminergic system is involved in the mediation of LI in man and it is speculated that the interaction between amphetamine dose and ear of presentation of the preexposed stimulus may reflect normally occurring dopaminergic hemisphere asymmetry.

Acoustic Stimulation↗
PubMed1992

Effects of acute subcutaneous nicotine on attention, information processing and short-term memory in Alzheimer's disease.

This single-blind, placebo controlled study reports on the effects of administering three acute doses of nicotine (0.4, 0.6 and 0.8 mg) subcutaneously to a group of Alzheimer's disease (DAT) patients (n = 22), young adult controls (n = 24), and normal aged controls (n = 24). The study extends our previous findings obtained using smaller groups of subjects. Drug effects were examined on three computerised tests: the first measuring rapid visual information processing, sustained visual attention and reaction time (RVIP task); a delayed response matching to location-order task measuring sustained visual attention and visual short-term memory (DRMLO task); and a finger tapping test measuring simple reaction time (FT task). The critical flicker fusion test (CFF) was used as a measure of perception and the WAIS digit span forwards (DS), of auditory short-term memory. Tests were graded in difficulty, titrated to avoid floor and ceiling effects so that meaningful, direct comparisons between groups could be made. Nicotine significantly improved sustained visual attention (in both RVIP and DRMLO tasks), reaction time (in both FT and RVIP tasks), and perception (CFF task--both ascending and descending thresholds). Nicotine administration did not improve auditory and visual short-term memory. There were no consistent, overall patterns of difference in performance between smokers and non-smokers in the control groups, or between males and females in any group. Despite the absence of change in memory functioning, these results demonstrate that DAT patients have significant perceptual and visual attentional deficits which are improved by nicotine administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Increased dopamine release in vivo in nucleus accumbens and caudate nucleus of the rat during drinking: a microdialysis study.

Changes in dopamine release and metabolism during drinking in thirsty rats were studied using in vivo microdialysis. Animals were maintained on controlled water (1 h per day) and trained to lick for water in a behavioural box. Microdialysis probes were then inserted into the left nucleus accumbens and right caudate nucleus through previously implanted guide cannulae, and the following day animals were connected for dialysis perfusion, during which they were allowed 1 h free access to water. Dopamine, and its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, increased in both nucleus accumbens and caudate nucleus in association with drinking, but the 5-hydroxytryptamine metabolite, 5-hydroxyindoleacetic acid, only increased in the caudate nucleus. There was a direct correlation between the maximum dopamine release in nucleus accumbens and the maximum licking rate per 10-min period, but the maximum increase in dopamine did not occur until after the period of maximum licking. Increases in 3,4-dihydroxyphenylacetic acid and homovanillic acid were further delayed (by 20 and 30 min, respectively). In the caudate, changes in 5-hydroxyindoleacetic acid showed a very similar time-course to those of 3,4-dihydroxyphenylacetic acid. These data show that dopamine systems in both nucleus accumbens and caudate nucleus are activated in relation to drinking in thirsty rats. In addition, they indicate that 5-hydroxytryptamine systems in the caudate nucleus, but not in nucleus accumbens, may also be involved. The support that the results provide for the hypothesized connection between reward and limbic dopamine is discussed.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Fetal dexamethasone exposure accelerates development of renal function: relationship to dose, cell differentiation and growth inhibition.

Fetal exposure to high doses of glucocorticoids slows cellular development and impairs organ performance, in association with growth retardation. Nevertheless, low doses of glucocorticoids may enhance cell differentiation and accelerate specific functions. The current study examined this apparent paradox in the developing rat kidney, using doses of dexamethasone that span the threshold for growth impairment: 0.05 or 0.2 mg/kg given on gestational days 17, 18 and 19. At the lower dose, which did not significantly retard body growth, the postnatal development of tubular reabsorptive capabilities for sodium, potassium, osmotic particles, water and urea was accelerated. These effects were less notable at the higher dose, which caused initial body growth impairment. The selectivity toward promotion of tubular function was evidenced by the absence of effect of either dose of dexamethasone on development of glomerular filtration rate. Because of the wide spectrum of dexamethasone's effects on tubular function, we also assessed fetal kidney adenylate cyclase as a means of detecting altered cell differentiation in the prenatal period during which dexamethasone was given. Either glucocorticoid dose increased the total adenylate cyclase catalytic activity (assessed with forskolin). Thus, the net effect of fetal dexamethasone exposure on development of renal excretory capabilities probably represents the summation of promoted cell differentiation and slowed development consequent to growth retardation. At low dose levels, the former effect predominates, leading to enhanced functional development, whereas higher doses that interfere with general growth and development can offset the direct promotional effect.

Adenylyl Cyclases↗
PubMed1991

The effects of cholinergic drugs and cholinergic-rich foetal neural transplants on alcohol-induced deficits in radial maze performance in rats.

Chronic alcohol (20% v/v in drinking water for 28 weeks) impaired acquisition of radial maze spatial and associative tasks by increasing both within-trial working and long-term reference memory errors; animals with high (above the median of 100 mg/100 ml) blood alcohol concentrations (BACs) during treatment were significantly more impaired than those with BACs below the median. Alcohol-treated rats showed improvements in radial maze performance after treatment with cholinergic agonists (arecoline and nicotine) and disruption with antagonists (scopolamine and mecamylamine) at low doses which did not affect controls. These effects were more pronounced for working than reference memory, and not manifest with the peripherally acting antagonists hexamethonium and N-methylscopolamine. Transplants into cortex and hippocampus of cholinergic-rich basal forebrain (BF) and ventral mesencephalon (VM) foetal neural tissue improved radial maze performance of alcohol-treated rats to control level over a period of 9-12 weeks after grafting. Cholinergic-poor foetal hippocampal (HC) grafts were without effect. BF and VM, but not HC, grafts showed dense acetylcholinesterase (AChE) staining, tyrosine-hydroxylase staining was most pronounced in VM sections and dopamine-beta-hydroxylase staining was minimal in all grafts. Choline acetyltransferase (ChAT) activity was significantly reduced in cortex and hippocampus of alcohol-treated rats, except those given cholinergic-rich transplants. Alcohol treatment also significantly reduced AChE-positive cell counts in the nucleus basalis, medial septal and diagonal band brain areas, at the sources of the forebrain cholinergic projection system (FCPS). Cortical levels of noradrenaline were significantly reduced in all alcohol-treated rats, regardless of transplant, whereas cortical dopamine content was significantly elevated in all rats receiving transplants, regardless of behavioural effect, but not in alcohol-treated controls. Forebrain serotonin levels were not significantly altered by grafting or alcohol treatment. These results suggest that damage to the FCPS, as shown by reduced ChAT activity in target areas, and reduced AChE cell counts in projection areas, played an important part in the radial maze deficits displayed by alcohol-treated rats, since these animals were sensitive to cholinergic drug challenge, and cholinergic-rich transplants from two different sites in foetal brain elevated ChAT activity and restored cognitive function. In contrast alcohol- or graft-induced alterations in other transmitter systems did not correlate with the pattern of behavioural deficit and recovery.

Acetylcholine↗
PubMed1991

Effect of acute administration of nicotine on in vivo release of noradrenaline in the hippocampus of freely moving rats: a dose-response and antagonist study.

The effect of systemic administration of (-)-nicotine on release of noradrenaline in the hippocampus was studied by in vivo microdialysis in freely moving rats, using dialysate containing nomifensine (5 microM). (-)-Nicotine, at both 0.4 and 0.8 mg/kg but not 0.2 mg/kg, rapidly and significantly increased extracellular levels of noradrenaline. Extracellular levels of dopamine were also increased, but this was only significant after the larger dose. Both 0.4 and 0.8 mg/kg also produced a significant increase in extracellular levels of the metabolites of dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid. Extracellular levels of the metabolite of 5-hydroxytryptamine, 5-hydroxyindoleacetic acid, increased after 0.8 mg/kg but this effect was only apparent much later. Injection of a second 0.8 mg/kg challenge of (-)-nicotine, 150 min after the first, produced similar increases in extracellular levels of noradrenaline, dopamine, 3-4-dihydroxyphenylacetic acid and homovanillic acid. Over the experimental period, there was no further increase in extracellular levels of 5-hydroxyindoleacetic acid. Increases in extracellular levels of noradrenaline, dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid, in response to 0.8 mg/kg (-)-nicotine, were prevented by the systemic administration of mecamylamine, but not hexamethonium (both at 5 mg/kg). Mecamylamine also inhibited the delayed increase in extracellular levels of 5-hydroxyindoleacetic acid, produced by the first injection of (-)-nicotine. These results suggest that (-)-nicotine, dose-dependently stimulated the release and metabolism of amine transmitters by an action at central nicotinic receptors. However, the precise site of action, i.e. at nerve terminals, cell bodies or both, requires further elucidation.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Effects of cholinergic-rich neural grafts on radial maze performance of rats after excitotoxic lesions of the forebrain cholinergic projection system--I. Amelioration of cognitive deficits by transplants into cortex and hippocampus but not into basal forebrain.

After ibotenate (10.0 mg/ml) lesions to the nucleus basalis and medial septal regions, at the source of the cortical and hippocampal branches of the forebrain cholinergic projection system, rats displayed long-lasting stable impairment in reference and working memory in both spatial (place) and associative (cue) radial maze tasks. Cell suspension transplants of cholinergic-rich fetal basal forebrain tissue dissected at embryonic day 15 substantially improved all aspects of radial maze performance to a comparable degree whether sited in cortex, hippocampus, or both regions of the host brain. No additive effects were obtained with grafts in both terminal regions, but total graft volume, assessed stereologically, showed a significant negative correlation with error scores. Rats with behaviourally effective grafts, like controls, were disrupted in the place task when tested in dim light which obscured extra-maze spatial cues. Lesioned rats were not affected by change in lighting. Grafts of cholinergic-poor fetal hippocampal tissue did not improve radial maze performance; neither did grafts of cholinergic-rich tissue placed within the host basal forebrain lesion sites. In rats with cholinergic-rich terminal grafts, cortical and hippocampal choline acetyltransferase activity was restored to control level, commensurate with site of transplant, whereas it was significantly reduced in lesioned animals and those with functionally ineffective grafts. The indiscriminate error pattern and insensitivity to changes in lighting shown by lesioned rats suggested that lesioning primarily disrupted attention rather than short- or long-term spatial or associative memory processes. Since rats with cholinergic-rich grafts showed both reduced errors and recovery of stimulus control, the data indicated that grafts affected information processing, rather than changes in motor or motivational processes. Changes in choline acetyltransferase activity and the behavioural efficacy of cholinergic-rich grafts are consistent with the involvement of acetylcholine in the behavioural deficits and recovery displayed by lesioned and grafted groups, but do not rule out contributions from other factors. The equipotency of grafts within each terminal region suggests also that there may be a considerable degree of functional cooperation between the two branches of the forebrain cholinergic projection system. Functional recovery may involve local, nonspecific synaptic or paracrine mechanisms within the target regions, since grafts were efficacious only when placed in the terminal areas, but not when sited homotopically in the basal forebrain, indicating that they did not achieve any functionally significant structural repair to the host brain at that site.

Acetylcholine↗
PubMed1991

Effects of cholinergic-rich neural grafts on radial maze performance of rats after excitotoxic lesions of the forebrain cholinergic projection system--II. Cholinergic drugs as probes to investigate lesion-induced deficits and transplant-induced functional recovery.

The effects of two doses of muscarinic (arecoline and scopolamine) and nicotinic (nicotine and mecamylamine) cholinergic receptor agonists and antagonists on the radial maze errors of rats, performing poorly after ibotenate lesions to the nucleus basalis and medial septal brain regions, were assessed before and after transplantation of cholinergic-rich and -poor fetal grafts, using tasks which measured short- (working) and long-term (reference) spatial and associative memory. Lesioned rats showed improvement with the agonists, and impairment with the antagonists, at low doses which did not affect the performance of controls; these effects were more marked for working than reference memory, especially in the spatial task. The peripherally acting antagonists N-methylscopolamine and hexamethonium did not affect the performance of control or lesioned rats. Effects of the cholinergic probes were re-examined 16 weeks after grafting, in groups with cholinergic-rich grafts to cortex and/or hippocampus which showed functional recovery, and groups with cholinergic-rich grafts to basal forebrain, or cholinergic-poor grafts to basal forebrain, cortex, and hippocampus, which showed no improvement. All lesioned rats, regardless of site, type, or efficacy of transplant, continued to show marked impairment with the antagonists. Poorly performing grafted animals also showed improvement with the agonists. In rats with behaviourally effective cholinergic-rich grafts, arecoline had no effect, but nicotine substantially increased working and reference memory errors, particularly spatial working memory errors. Rats with grafts in both cortex and hippocampus showed the largest increases in errors after nicotine. These results show that lesioned rats were more sensitive to the bi-directional effects of cholinergic receptor ligands than controls, consistent with a role for acetylcholine in the lesion-induced deficits. The predominant effect of drugs on working memory may also be consistent with disruption of acquisition rather than of storage or retrieval processes in memory, and may be related to impairment of attention. The results further show that, despite behavioural recovery, supersensitive responses to cholinergic drugs were not normalized in rats with cholinergic-rich grafts, and that an additive interaction between graft and host may have occurred in response to nicotine.

Acetylcholine↗
PubMed1991

T-maze discrimination and reversal learning after unilateral temporal or frontal lobe lesions in man.

The interpretation of conditional discrimination and reversal learning as acquisition of declarative knowledge suggests that subjects with temporal lobe/hippocampal lesions are likely to be impaired on such tasks. Patients with unilateral left or right temporal lobectomy (and small hippocampal excisions) and patients with unilateral frontal lobe resections were compared with healthy controls on a discrimination reversal task, embedded in a computer game modelled on T-maze tasks traditionally used in animal experiments. The right temporal group showed a deficit in acquiring an initial conditional discrimination, and the frontal group tended to display a marginal impairment in discrimination reversal. These findings are compared with results from animal studies in terms of the mechanisms underlying reversal learning.

Adult↗
PubMed1991

Classical conditioning after temporal lobe lesions in man: impairment in conditional discrimination.

Left and right temporal lobectomy patients, patients with frontal lobe lesions, and healthy control subjects participated in an eyelid conditioning study based on conditional discrimination learning. All groups acquired the first conditioned response at a similar time during learning, but both temporal lobectomy groups showed poorer discrimination than control subjects. The results support models that relate hippocampal function to operation of if-then rules.

Adult↗
PubMed1991

The RhsD-E subfamily of Escherichia coli K-12.

The Escherichia coli K-12 chromosome contains a family of five large, unlinked sequences known as the Rhs elements. They share several complex homologies, the most prominent being a 3.7 kb Rhs core. The elements are divided into two subfamilies, RhsA-B-C and RhsD-E, according to the sequence similarities of the cores. The RhsD core is 3747 bp long compared to 3714 bp for RhsA. Despite a 22% sequence divergence, the RhsD core conserves features previously noted for RhsA. Similar to RhsA, the RhsD core maintains a single ORF, the start codon coinciding with the first nucleotide of the homology. The RhsD core-ORF continues 177 codons beyond the homology, resulting in a carboxy terminal extension unrelated to that of RhsA. The RhsD core retains all 28 copies of the repeated motif GxxxRYxYDxxGRL(I/T) seen in RhsA. The other member of the RhsD-E subfamily, RhsE, has been mapped to minute 32 of the E. coli map. It appears defective in that it contains only the last 1550 bp of the 3.7 kb core. Its sequence is more closely related to that of RhsD than RhsA. In addition, RhsE and RhsB share a 1.3 kb homology, known as the H-repeat. The H-repeats from RhsE and RhsB are more closely related than their cores, showing only 1% nucleotide divergence.

Amino Acid Sequence↗
PubMed1991

Section 47--assault on or protection of the freedom of the individual? A short response to Greaves.

Section 47 of the 1948 National Assistance Act allows incompetent people, usually old people, to be removed from their homes. It can be considered as a repressive tool, designed to infringe personal liberty, but in this article it is argued that it can also be considered as being legislation which governs and controls professional practice and protects the old person from public prejudice.

Aged↗
PubMed1991

Contextual effects on choice reaction time and accuracy in acute and chronic schizophrenics. Impairment in selective attention or in the influence of prior learning?

Two hypotheses were tested concerning the nature of the cognitive dysfunction in schizophrenia: (a) that there is a broadening of selective attention; and (b) that there is an impairment in associational learning. RDC-diagnosed acute and chronic schizophrenics and normal controls carried out a choice reaction time (RT) task in which conflict between the correct response to a target (a letter in the centre of a computer screen) and that cued by simultaneously presented flankers (two letters either side of the target) increased RT. For 80 ('valid') trials, flankers and targets were consistent in the response cued (pressing a button with either left or right hand); on 8 ('invalid') trials they conflicted. On invalid trials there was a slowing of RT, and an increase of errors for left-hand responses. Chronic schizophrenics showed the same reactions to cue validity as normal controls, both groups differing significantly from acute schizophrenics. For the latter, the RT data supported hypothesis (b), but the error rates appeared to support hypothesis (a).

Acute Disease↗