Biomedical subjects

T W Robbins

Publications and source records attributed to T W Robbins.

At least 163 records · Page 9Linked to original sources

PubMed1997

Central 5-HT depletion enhances impulsive responding without affecting the accuracy of attentional performance: interactions with dopaminergic mechanisms.

A series of ten experiments examined the effects of profound central 5-HT depletion on attentional performance in the rat in the five-choice serial reaction time task, and also determined the effects of such depletion on responding affected by d-amphetamine and by selective dopamine receptor antagonists. Rats were trained to detect and locate brief visual stimuli randomly presented in one of five spatial locations. When performance had stabilised (> 80% correct, < 20% omissions), selective central 5-HT depletion was induced by intracerebroventricular administration of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) following pretreatment with both a noradrenergic and a dopaminergic re-uptake inhibitor. The lesioned animals performed the five-choice serial reaction time task with the same degree of accuracy as the sham-operated controls. However, 5-HT depletion reduced the percentage of omitted trials and increased the number of premature/anticipatory responses. This pattern of behaviour following 5-HT depletion could not be attributed to enhanced primary motivation as demonstrated by measures of food intake and latencies to collect food reinforcement. The lesion attenuated the increase of premature responding induced by high doses of systemically administered d-amphetamine. 5-HT depletion also attenuated the dose-dependent decrease in accuracy induced by (-)-sulpiride, a D2 receptor antagonist, although the effects of this drug on response latencies and premature responding were similar in both groups. However, the systemic administration of the D1 receptor antagonist, SCH 23390, blocked the impulsive responding produced by the lesion as indicated by a lack of lesion effects on the percentage of omitted trials and premature responding. The results suggest that central 5-HT depletion results in impulsive, fast responding, which nevertheless does not impair accuracy of visual discrimination performance. The increased impulsivity may be mediated by altered 5-HT-dopamine interactions, with the lesion removing an inhibitory influence over dopamine neurotransmission.

5,7-Dihydroxytryptamine↗

PubMed1997

Effects of scopolamine on delayed-matching-to-sample and paired associates tests of visual memory and learning in human subjects: comparison with diazepam and implications for dementia.

Two experiments examined dose-related effects of 200, 400 and 600 micrograms scopolamine (n = 24, s.c.) and 5 and 10 mg diazepam (n = 6, PO) on parallel tests of visual memory and learning taken from the CANTAB battery. Scopolamine significantly impaired accuracy of performance on a delayed matching to sample test of visual recognition memory in a dose- and delay-dependent manner, but had only marginal decremental effects on a test of visuospatial paired associates learning. Scopolamine significantly lengthened decision times in a visual search matching to sample task at the 400 and 600 micrograms doses, without significantly affecting accuracy. The drug also impaired performance on tests of spatial (on accuracy and response time measures) and pattern (on response time only) memory. Most of the deleterious effects on scopolamine were removed by covariance analyses with indices of subjective sedation, but the effects of delayed matching accuracy and latency remained. By contrast, diazepam significantly impaired paired associates learning but affected delayed matching to sample in a delay-independent manner. These results suggest that scopolamine can produce selective deficits in tests of short-term visual recognition memory which do not depend on overall impairments in arousal and which contrast with deficits in visual associative learning produced by diazepam. They have implications for the pharmacological modelling of dementia and memory disorders in man and for the neurochemical substrates of the short-term recognition memory and associative learning for visual stimuli.

Adult↗

PubMed1997

Effects of medial prefrontal or anterior cingulate cortex lesions on responding for cocaine under fixed-ratio and second-order schedules of reinforcement in rats.

Four experiments examined the effects of excitotoxic, axon-sparing lesions of the medial prefrontal cortex or anterior cingulate cortex in rats on responding under different schedules of intravenous cocaine self-administration and on the locomotor stimulant effects of cocaine. Experiment 1 tested the acquisition and maintenance of cocaine self-administration under a fixed ratio schedule. Rats with medial prefrontal cortex lesions showed facilitated acquisition and enhanced responding for low doses of the drug when lesions were induced before self-administration behaviour was established. Lesions of the anterior cingulate cortex did not affect cocaine self-administration. In experiment 2, rats were trained to respond under a second-order schedule of cocaine reinforcement, where responding during the fixed interval was reinforced by presentation of a cocaine-associated visual stimulus under fixed-ratio contingencies. In control rats, these schedule conditions were found to maintain high rates of responding and a scalloped pattern of responding over time. Omission of conditioned stimulus presentation during the fixed interval significantly disrupted response patterns, confirming that the stimulus served to maintain responding during the fixed interval. By contrast, rats with medial prefrontal cortex lesions showed higher rates and disrupted patterns of responding that were unchanged by stimulus omission. Rats with lesions of the anterior cingulate cortex responded at high rates throughout the fixed interval under all test conditions, indicating that the cocaine-associated stimulus did not serve to maintain temporal patterns of responding in these rats. Experiment 3 demonstrated the lack of effect of either lesion on the acquisition of responding for a non-drug reinforcer, sucrose. In experiment 4, measures of spontaneous and cocaine-induced locomotor activity revealed that rats in both lesion groups were significantly more active than controls regardless of test conditions. These data indicate that facilitated acquisition of cocaine self-administration and disrupted response patterns under second-order schedule contingencies may result from deficits in behavioural inhibition induced by medial prefrontal cortical lesions that contrast with deficits following damage to other limbic cortical regions, such as the basolateral amygdala or anterior cingulate cortex.

Animals↗

PubMed1997

Spatial and non-spatial working memory at different stages of Parkinson's disease.

Groups of patients with Parkinson's disease, either medicated or unmedicated, were compared with a matched group of normal control subjects on a computerized battery of tests designed to assess spatial, verbal and visual working memory. In the spatial working memory task, subjects were required to search systematically through a number of boxes to find 'tokens' whilst avoiding those boxes in which tokens had previously been found. In the visual and verbal conditions, the subjects were required to search in exactly the same manner, but through a number of abstract designs or surnames, respectively, avoiding designs or names in which a token had previously been found. Medicated Parkinson's disease patients with severe clinical symptoms were impaired on all three tests of working memory. In contrast, medicated patients with mild clinical symptoms were impaired on the test of spatial working memory, but not on the verbal or visual working memory tasks. Non-medicated patients with mild clinical symptoms were unimpaired on all three tasks. These data are compared with the results of a previous study comparing groups of neurosurgical patients with frontal, temporal or amygdalo-hippocampectomy excisions on the same three tests of working memory. Taken together, the findings suggest that working memory deficits in Parkinson's disease emerge, and subsequently progress, according to a defined sequence, the evolution of which may be linked to the likely spatiotemporal progression of dopamine depletion within the striatum, in relation to the terminal distribution of its cortical afferents.

Antiparkinson Agents↗

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 systemic and intracerebral infusions of the 5-HT1A receptor agonist 8-OH-DPAT on spatial short-term working memory in rats.

The present study compared the effects of systemic 8-OH-DPAT (0.05, 0.1 and 1.0 mg/kg) with intra-raphe and intra-hippocampal infusions of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (10, 30 100 ng) on delayed non-matching-to-position (DNMP) performance in rats. The highest dose of 8-OH-DPAT administered systemically impaired DNMP performance in a delay-independent manner, increased premature responding and increased response bias. Infusions of 8-OH-DPAT (100 ng) into the median raphe nucleus improved performance accuracy, independent of delay whilst having no effect on any other response measure. Infusions of 8-OH-DPAT into the dorsal raphe nucleus had no effect on performance at any dose tested. Infusions of 8-OH-DPAT into the dorsal hippocampus produced a small impairment in performance which was also independent of delay. However, this decrement in performance accuracy was not accompanied by any changes in other response measures. These findings demonstrate a dissociation between the effects of stimulation of pre- and post-synaptic 5-HT1A receptors on performance of a DNMP task although the changes in performance cannot be accounted for by changes in mnemonic function.

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

PubMed1997

Doubly dissociable effects of median- and dorsal-raphé lesions on the performance of the five-choice serial reaction time test of attention in rats.

Six experiments examined the effects of selective median (MRN)- and dorsal (DRN)-raphé nucleus lesions on the performance of the five-choice serial reaction time task. In this test rats are required to localize brief visual stimuli presented randomly in one of five locations in approximately 30 min sessions of 100 trials. Both accuracy and latency to respond are measured, as well as the incidence of premature and perseverative responding. Selective 5-HT lesions were induced by intra-raphé infusions of 5,7-dihydroxytryptamine following pretreatment with both a noradrenergic and a dopaminergic re-uptake inhibitor. Analysis of tissue monoamine content demonstrated that the MRN lesion profoundly depleted hippocampal 5-HT (by about 90%) without affecting noradrenaline and dopamine, whereas the DRN lesion primarily depleted (by about 80%) nucleus accumbens and caudate-putamen 5-HT. Rats with 5-HT lesions of the MRN performed the task with a similar degree of accuracy to that exhibited by sham-operated controls. Although the MRN lesion did not affect the latency to respond correctly to the visual targets the lesioned animals collected the food reward significantly faster than the controls. A transient increase in the number of premature responses also resulted from this lesion. In contrast the DRN lesion produced a transient but significant increase in the accuracy of performance, and increased both the speed and the probability of responding. The similarity of the effects following global forebrain 5-HT depletion and the selective DRN lesion suggests that the 5-HT projections of the DRN rather than the MRN may play an important role in impulsive behaviour following 5-HT depletion.

5,7-Dihydroxytryptamine↗

PubMed1997

Cognitive enhancers in theory and practice: studies of the cholinergic hypothesis of cognitive deficits in Alzheimer's disease.

The current status of the cholinergic hypothesis of cognitive dysfunction in Alzheimer's disease is reviewed in the context of recent attempts to alleviate specific cognitive impairments produced in rats by excitotoxic lesions of basal forebrain neurons by treatment with cholinergic agents. AMPA-induced lesions of the nucleus basalis region in rats produce profound and relatively specific reductions in neocortical markers of cholinergic function but fail to affect performance in many tests of memory and learning in rats. However, such lesions produce specific deficits in responding accurately in a test of visual attentional performance, which are reversed dose-dependently by treatment with systemic physostigmine or nicotine. Analogous improvements have been reported in a clinical trial of the anticholinesterase tacrine in patients with Alzheimer's disease. By contrast, AMPA-induced lesions of the medial septum produce profound reductions in hippocampal acetylcholine and accompanying delay-dependent deficits in a delayed non-matching-to-position procedure which measures spatial working memory in rats. This impairment is shown to be reversed to some extent by treatment with low doses of physostigmine. The results are discussed in terms of the multivariate nature of the neurochemical pathology of Alzheimer's disease and attendant limitations in the use of the cholinergic strategy. The cognitive costs, as well as benefits, of cognitive enhancers are discussed, as well as the need to broaden our therapeutic approach to other neurotransmitter systems and other neurodegenerative disorders.

Alzheimer Disease↗

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

Dissociable effects of cingulate and medial frontal cortex lesions on stimulus-reward learning using a novel Pavlovian autoshaping procedure for the rat: implications for the neurobiology of emotion.

The effects of quinolinic acid-induced lesions of the anterior cingulate, posterior cingulate, and medial frontal cortices on stimulus-reward learning were investigated with a novel Pavlovian autoshaping procedure in an apparatus allowing the automated presentation of computer-graphic stimuli to rats (T. J. Bussey, J. L. Muir, & T. W. Robbins, 1994). White vertical rectangles were presented on the left or the right of a computer screen. One of these conditioned stimuli (the CS+) was always followed by the presentation of a sucrose pellet; the other, the CS-, was never followed by reward. With training, rats came to approach the CS+ more often than the CS-. Anterior cingulate cortex-lesioned rats failed to demonstrate normal discriminated approach, making significantly more approaches to the CS- than did sham-operated controls. Medial frontal cortex-lesioned rats acquired the task normally but had longer overall approach latencies. Posterior cingulate cortex lesions did not affect acquisition.

Animals↗

PubMed1997

Triple dissociation of anterior cingulate, posterior cingulate, and medial frontal cortices on visual discrimination tasks using a touchscreen testing procedure for the rat.

Four experiments examined effects of quinolinic acid-induced lesions of the anterior cingulate, posterior cingulate, and medial frontal cortices on tests of visual discrimination learning, using a new "touchscreen" testing method for rats. Anterior cingulate cortex lesions impaired acquisition of an 8-pair concurrent discrimination task, whereas posterior cingulate cortex lesions facilitated learning but selectively impaired the late stages of acquisition of a visuospatial conditional discrimination. Medial frontal cortex lesions selectively impaired reversal learning when stimuli were difficult to discriminate; lesions of anterior and posterior cingulate cortex had no effect. These results suggest roles for the anterior cingulate, posterior cingulate, and medial frontal cortex in stimulus-reward learning, stimulus-response learning or response generation, and attention during learning, respectively.

Animals↗

PubMed1997

Frontal-striatal cognitive deficits in patients with chronic schizophrenia.

Spatial working memory and planning abilities were assessed in 36 hospitalized patients with chronic schizophrenia, using the computerized Cambridge Neuropsychological Test Automated Battery (CANTAB), and compared with those of normal subjects and patients with neurological disorders (frontal lobe lesions; temporal lobe and amygdalohippocampal lesions; Parkinson's disease), matched for age, sex and National Adult Reading Test IQ. The patients in the group with temporal lobe lesions were unimpaired in their performance on these tasks. Patients with schizophrenia were impaired on visuo-spatial memory span compared with all the other groups, while severity of Parkinson's disease was correlated with the degree of impairment on this task. The patients with schizophrenia and those with frontal lobe lesions were impaired on a 'spatial working memory' task, with increased 'between-search errors'. Patients with Parkinson's disease performed this task poorly compared with the younger control subjects. Patients with schizophrenia were unable to develop a systematic strategy to complete this task, relying instead on a limited visuo-spatial memory span. Higher level planning ability was investigated using the CANTAB 'Tower of London'. All groups were equally able to complete the task. However, the groups of patients with schizophrenia and frontal lobe lesions made fewer perfect solutions and required more moves for completion. Movement times were significantly slower in the schizophrenia group, suggesting impairment in the sensorimotor requirements of the task. The patients with schizophrenia were not impaired in their 'initial thinking' (planning) latencies, but had significantly prolonged 'subsequent thinking' (execution) latencies. This pattern resembled that of the group with frontal lobe lesions and contrasted with the prolonged 'initial thinking' time seen in Parkinson's disease. The results of this study are indicative of an overall deficit of executive functioning in schizophrenia, even greater than that seen in patients with frontal lobe lesions. However, the pattern of results in schizophrenia resembled that seen in patients with lesions of the frontal lobe or with basal ganglia dysfunction, providing support for the notion of a disturbance of frontostriatal circuits in schizophrenia. Our findings also indicate that there is a loss of the normal relationships between different domains of executive function in schizophrenia, with implications for impaired functional connectivity between different regions of the neocortex.

Adolescent↗

PubMed1997

Bilateral lesions of the subthalamic nucleus induce multiple deficits in an attentional task in rats.

Lesioning the subthalamic nucleus (STN) has been suggested as possible therapy for the treatment of parkinsonism. Previous experiments investigating this hypothesis in rats confirmed that excitotoxic STN lesions alleviate the motor impairment induced by striatal dopamine depletion, which reproduced the degeneration observed in parkinsonism, but elicited presumed non-motor deficits such as premature responding, suggesting that the STN could be involved in other aspects of response control. The aim of the present study was to extend this analysis to choice paradigms. We thus investigated the behavioural effects of bilateral excitotoxic lesions of the STN in rats performing a five-choice test of divided and sustained visual attention, modelled on the human continuous performance task. This task required the animals to detect a brief visual stimulus presented in one of five possible locations and respond by a nose-poke in this illuminated hole within a fixed delay, for food reinforcement. Bilateral lesions of the STN severely impaired several aspects of performance, including discriminative accuracy, but also increased premature, anticipatory responding as well as perseverative panel pushes and nose-poke responses. While increasing the stimulus duration and reducing the waiting period for the stimulus partially alleviated the accuracy deficit and the premature responding deficit respectively, other deficits, such as perseverative panel pushes and nose-poke responses, were sustained under these conditions. Systemic injection of the mixed dopaminergic D1/D2 receptor antagonist, alpha-flupenthixol (0.03-0.18 mg/kg), reduced premature responses and perseverative panel pushing without affecting the perseverative nose-poke responses, suggesting that some of the deficits were independent of striatal dopaminergic transmission. These results suggest that STN lesions have multiple, dissociable effects on attentional performance, including discriminative deficits, impulsivity and perseverative behaviour. They are consistent in part with a hypothesized role of the STN in recent models of basal ganglia function in action selection and inhibition. The results also show that other aspects of behaviour should be monitored when examining the capacity of STN lesions to reverse the parkinsonian deficit induced by striatal dopamine depletion.

Analysis of Variance↗

PubMed1997

Abnormal response to negative feedback in unipolar depression: evidence for a diagnosis specific impairment.

OBJECTIVES: To assess in further detail the specific form of motivational impairment influencing neuropsychological performance in depression-oversensitivity to perceived failure. The present study considers two questions: firstly whether this is specific to depression and secondly how the effect relates to clinical features. METHODS: Unipolar depressed patients and matched controls were assessed on two neuropsychological tests giving explicit performance feedback. The data were analysed in two separate studies to consider the questions above. The first study considered the specificity of the effect to depressed patients, using data on the same tests collected from other patient groups. The second study was a longitudinal assessment of the depressed patients on clinical recovery to determine whether the effect is specific to the depressed state. RESULTS: The effect was not seen in non-depressed patient groups, either neurological or psychiatric groups. The longitudinal study showed a residual abnormal response to negative feedback on clinical recovery. CONCLUSIONS: Abnormal response to negative feedback is specific to a primary diagnosis of depression and may be a trait rather than a state factor of the disorder. These results are discussed in relation to the putative neuropathology of depression and also to cognitive and behavioural accounts of the disorder. The findings presented here have important implications for establishing a link between mood and cognition in unipolar depression.

Adult↗

PubMed1997

Central cholinergic systems and cognition.

The organization and possible functions of basal forebrain and pontine cholinergic systems are reviewed. Whereas the basal forebrain cholinergic neuronal projections likely subserve a common electrophysiological function, e.g. to boost signal-to-noise ratios in cortical target areas, this function has different effects on psychological processes dependent upon the neural network operations within these various cortical domains. Evidence is presented that (a) the nucleus basalis-neocortical cholinergic system contributes greatly to visual attentional function, but not to mnemonic processes per se; (b) the septohippocampal projection is involved in the modulation of short-term spatial (working) memory processes, perhaps by prolonging the neural representation of external stimuli within the hippocampus; and (c) the diagonal band-cingulate cortex cholinergic projection impacts on the ability to utilize response rules through conditional discrimination. We also suggest that nucleus basalis-amygdala cholinergic projections have a role in the retention of affective conditioning while brainstem cholinergic projections to the thalamus and midbrain dopamine neurons affect basic arousal processes (e.g. sleep-wake cycle) and behavioral activation, respectively. The possibilities and limitations of therapeutic interventions with procholinergic drugs in patients with Alzheimer's disease and other neurodegenerative disorders in which basal forebrain cholinergic neurons degenerate are also discussed.

Animals↗

PubMed1996

Dissociating executive functions of the prefrontal cortex.

An analysis is provided of three distinct paradigms that have been used to study executive functions of the prefrontal cortex involving planning, self-ordered memory or attentional set-shifting. Psychological and anatomical dissociations are sought from the perspective of studies of patients with frontal lobe lesions, functional neuroimaging, psychometric studies in normal volunteers and experimental studies in non-human primates. Particular attention is paid to attempts to dissociate mnemonic from other executive capacities. Thus, patients with frontal damage are shown to have deficits in their (1) use of strategies to improve performance in a spatial working memory task and (2) capacity to make an extra-dimensional shift due to a high-order failure of inhibition in an attentional set-shifting paradigm. These results are discussed in terms of anatomical and neuropharmacological dissociations of different aspects of executive function within the prefrontal cortex shown in monkeys.

Animals↗