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The role of the pedunculopontine tegmental nucleus (PPTg) in stimulus-reward learning was assessed by testing the effects of PPTg lesions on performance in visual autoshaping and conditioned reinforcement (CRf) paradigms. Rats with PPTg lesions were unable to learn an association between a conditioned stimulus (CS) and a primary reward in either paradigm. In the autoshaping experiment, PPTg-lesioned rats approached the CS+ and CS- with equal frequency, and the latencies to respond to the two stimuli did not differ. PPTg lesions also disrupted discriminated approaches to an appetitive CS in the CRf paradigm and completely abolished the acquisition of responding with CRf. These data are discussed in the context of a possible cognitive function of the PPTg, particularly in terms of lesion-induced disruptions of attentional processes that are mediated by the thalamus.

This study examined the effects of depletion of dopamine from the caudate nucleus of the common marmoset (Callithrix jacchus), on tasks sensitive to prefrontal damage (attentional set-shifting and spatial delayed response). There was a marked impairment in performance on the spatial delayed response task, but performance on the attentional set-shifting task was relatively preserved except for an impairment in re-engagement of a previously relevant perceptual dimension. This pattern of impairment is distinct from that seen after excitotoxic lesions of the prefrontal cortex and in patients with Parkinson's disease. Though it is not possible to identify specific cognitive functions that are independent of dopaminergic modulation of the caudate nucleus, due to the partial nature of the lesion, the results do provide insight into those cognitive processes that appear most dependent on caudate dopamine.

Human decision-making arises from both reflective and reflexive mechanisms, which underpin goal-directed and habitual behavioural control. Computationally, these two systems of behavioural control have been described by different learning algorithms, model-based and model-free learning, respectively. Here, we investigated the effect of diminished serotonin (5-hydroxytryptamine) neurotransmission using dietary tryptophan depletion (TD) in healthy volunteers on the performance of a two-stage decision-making task, which allows discrimination between model-free and model-based behavioural strategies. A novel version of the task was used, which not only examined choice balance for monetary reward but also for punishment (monetary loss). TD impaired goal-directed (model-based) behaviour in the reward condition, but promoted it under punishment. This effect on appetitive and aversive goal-directed behaviour is likely mediated by alteration of the average reward representation produced by TD, which is consistent with previous studies. Overall, the major implication of this study is that serotonin differentially affects goal-directed learning as a function of affective valence. These findings are relevant for a further understanding of psychiatric disorders associated with breakdown of goal-directed behavioural control such as obsessive-compulsive disorders or addictions.

Impulsivity is an endophenotype of vulnerability for compulsive behaviors. However, the neural mechanisms whereby impulsivity facilitates the development of compulsive disorders, such as addiction or obsessive compulsive disorder, remain unknown. We first investigated, in rats, anatomical and functional correlates of impulsivity in the anterior insular (AI) cortex by measuring both the thickness of, and cellular plasticity markers in, the AI with magnetic resonance imaging and in situhybridization of the immediate early gene zif268, respectively. We then investigated the influence of bilateral AI cortex lesions on the high impulsivity trait, as measured in the five-choice serial reaction time task (5-CSRTT), and the associated propensity to develop compulsivity as measured by high drinking levels in a schedule-induced polydipsia procedure (SIP). We demonstrate that the AI cortex causally contributes to individual vulnerability to impulsive–compulsive behavior in rats. Motor impulsivity, as measured by premature responses in the 5-CSRTT, was shown to correlate with the thinness of the anterior region of the insular cortex, in which highly impulsive (HI) rats expressed lower zif268 mRNA levels. Lesions of AI reduced impulsive behavior in HI rats, which were also highly susceptible to develop compulsive behavior as measured in a SIP procedure. AI lesions also attenuated both the development and the expression of SIP. This study thus identifies the AI as a novel neural substrate of maladaptive impulse control mechanisms that may facilitate the development of compulsive disorders.

Masked prime tasks have shown that sensory information that has not been consciously perceived can nevertheless trigger the preactivation of a motor response. Automatic inhibitory control processes prevent such response tendencies from interfering with behaviour. The present study investigated the possibility that these inhibitory control processes are mediated by a cortico-striatal-pallidal-thalamic pathway by using a masked prime task with Huntington's disease patients (Experiment 1) and with healthy volunteers in a functional MRI (fMRI) study (Experiment 2). In the masked prime task, clearly visible left- or right-pointing target arrows are preceded by briefly presented and subsequently masked prime arrows. Participants respond quickly with a left or right key-press to each target. Trials are either compatible (prime and target pointing in the same direction) or incompatible (prime and target pointing in different directions). Prior behavioural and electrophysiological results show that automatic inhibition of the initially primed response tendency is reflected in a 'negative compatibility effect' (faster reaction times for incompatible trials than for compatible trials), and is shown to consist of three distinct processes (prime activation, response inhibition and response conflict) occurring within 300 ms. Experiment 1 tested the hypothesis that lesions of the striatum would interrupt automatic inhibitory control by studying early-stage Huntington's disease patients. Findings supported the hypothesis: there was a bimodal distribution for patients, with one-third (choreic) showing disinhibition, manifested as an absent negative compatibility effect, and two-thirds (non-choreic) showing excessive inhibition, manifested as a significantly greater negative compatibility effect than that in controls. Experiment 2 used fMRI and a region of interest (ROI) template-based method to further test the hypothesis that structures of the striatal-pallidal-thalamic pathway mediate one or more of the processes of automatic inhibitory control. Neither prime activation nor response conflict significantly engaged any ROIs, but the response inhibition process led to significant modulation of both the caudate and thalamus. Taken together, these experiments indicate a causal role for the caudate nucleus and thalamus in automatic inhibitory motor control, and the results are consistent with performance of the task requiring both direct and indirect striatal-pallidal-thalamic pathways. The finding that Huntington's disease patients with greater chorea were disinhibited is consistent with the theory that chorea arises from selective degeneration of striatal projections to the lateral globus pallidus, while the exaggerated inhibitory effect for patients with little or no chorea may be due to additional degeneration of projections to the medial globus pallidus.

Previous research on cognitive set shifting in patients with Parkinson's disease has often been confounded by concept formation, rule learning, working memory and/or general slowing of cognitive processes. To circumvent this problem, the present study used the task-set switching procedure in which good performance was independent of rule learning, and in which working memory load was reduced by explicitly cueing the task switches. Our results provide strong evidence for a specific cognitive set shifting deficit in patients with mild Parkinson's disease in a non-learning context, which also cannot be explained by general slowing of cognitive processes. Moreover, the deficit was robust in a small sample of patients at the earliest stages of the disease. Finally, the impairment in task-set switching was only apparent when competing information was present, i.e. when the load on selection mechanisms was increased.

Poor decision-making is often observed clinically in the manic syndrome. In normal volunteers, decision-making has been associated with activation in the ventral prefrontal cortex and the anterior cingulate gyrus. The aim of this study was to evaluate task-related activation in bipolar manic patients in these regions of the prefrontal cortex using PET. Six subjects with mania, 10 controls and six subjects with unipolar depression (an affective patient control group) were scanned using the bolus H(2)(15)O method while they were performing a decision-making task. Activations associated with the decision-making task were observed at two levels of difficulty. Task-related activation was increased in the manic patients compared with the control patients in the left dorsal anterior cingulate [Brodmann area (BA) 32] but decreased in the right frontal polar region (BA 10). In addition, controls showed greater task-related activation in the inferior frontal gyrus (BA 47) than manic patients. A positive correlation (r(s) = 0.88) between task-related activation in the anterior cingulate and increasing severity of manic symptoms was found. Depressed patients did not show significant task-related differences in activation compared with control subjects in the regions of interest. In conclusion, these patterns of activation point to abnormal task-related responses in specific frontal regions in manic patients. Moreover, they are consistent with neuropsychological observations in patients with lesions in the ventromedial prefrontal cortex, who show similar difficulties with decision-making and provide early evidence for context-specific neural correlates of mania.

Groups of subjects whose primary drug of abuse was amphetamine or heroin were compared, together with age- and IQ-matched control subjects. The study consisted of a neuropsychological test battery which included both conventional tests and also computerised tests of recognition memory, spatial working memory, planning, sequence generation, visual discrimination learning, and attentional set-shifting. Many of these tests have previously been shown to be sensitive to cortical damage (including selective lesions of the temporal or frontal lobes) and to cognitive deficits in dementia, basal ganglia disease, and neuropsychiatric disorder. Qualitative differences, as well as some commonalities, were found in the profile of cognitive impairment between the two groups. The chronic amphetamine abusers were significantly impaired in performance on the extra-dimensional shift task (a core component of the Wisconsin Card Sort Test) whereas in contrast, the heroin abusers were impaired in learning the normally easier intra-dimensional shift component. Both groups were impaired in some of tests of spatial working memory. However, the amphetamine group, unlike the heroin group, were not deficient in an index of strategic performance on this test. The heroin group failed to show significant improvement between two blocks of a sequence generation task after training and additionally exhibited more perseverative behavior on this task. The two groups were profoundly, but equivalently impaired on a test of pattern recognition memory sensitive to temporal lobe dysfunction. These results indicate that chronic drug use may lead to distinct patterns of cognitive impairment that may be associated with dysfunction of different components of cortico-striatal circuitry.

We used a novel computerized decision-making task to compare the decision-making behavior of chronic amphetamine abusers, chronic opiate abusers, and patients with focal lesions of orbital prefrontal cortex (PFC) or dorsolateral/medial PFC. We also assessed the effects of reducing central 5-hydroxytryptamine (5-HT) activity using a tryptophan-depleting amino acid drink in normal volunteers. Chronic amphetamine abusers showed sub-optimal decisions (correlated with years of abuse), and deliberated for significantly longer before making their choices. The opiate abusers exhibited only the second of these behavioral changes. Importantly, both sub-optimal choices and increased deliberation times were evident in the patients with damage to orbitofrontal PFC but not other sectors of PFC. Qualitatively, the performance of the subjects with lowered plasma tryptophan was similar to that associated with amphetamine abuse, consistent with recent reports of depleted 5-HT in the orbital regions of PFC of methamphetamine abusers. Overall, these data suggest that chronic amphetamine abusers show similar decision-making deficits to those seen after focal damage to orbitofrontal PFC. These deficits may reflect altered neuromodulation of the orbitofrontal PFC and interconnected limbic-striatal systems by both the ascending 5-HT and mesocortical dopamine (DA) projections.Neuropsychopharmacology (1999) 20 322–339.10.1016/S0893-133X(98)00091-8

Although Parkinson's disease has traditionally been considered as a motor disorder1,2, there has been much recent interest in the nature and the neural substrates of parkinsonian dementia3,4and cognitive dysfunction4. These disabilities, which can induce visuospatial impairment5and visual ‘neglect’6, may also have a bearing on the controversy about the normal functions of the nigrostriatal dopamine (DA) projection and the basal ganglia2,7–9. The observations that neurones in both substantia nigra and striatum respond to sensory events in terms of neuronal firing10,11or DA release12,13, also suggest a role for striatum in sensorimotor integration. An important behavioural correlate of this integration is the ‘sensorimotor neglect’ syndrome14in animals with unilateral lesions of the nigrostriatal projection who fail to orient to contralateral sensory events. However, this neglect may arise not from contralateral sensory inattention14,15, but from an inability to express this sensory selection via motor output. We present here two lines of evidence that unilateral striatal DA depletion in the rat does not affect sensory attention to visual signals of reward, but rather impairs the initiation (though not the completion) of contralateral motor acts. These results not only help to clarify the function of the nigrostriatal DA projection, but also show that depletion in this system is linked specifically to a process of response initiation, which may be the fundamental impairment in Parkinson's disease.

Degeneration of the cholinergic magnocellular neurons in the basal forebrain and their cortical projections is a major feature of the neuropathology of Alzheimer's disease. In the present study, two experiments examined the disruptive effects on visual attentional performance of two different manipulations that reduce central cholinergic function. In Expt. I, pharmacological manipulation of the cholinergic system was investigated using icv administration of hemicholinium (HC-3), a 9high affinity choline uptake blocker, administered either alone or in conjunction with the anticholinesterase, physostigmine. The results revealed impairments in the ability of the rats to localize brief visual targets in a serial reaction time task, as shown in particular by a reduction in choice accuracy and lengthening of the latency to respond correctly to the visual stimulus. Cholinergic specificity was supported by the reversal of these behavioural impairments by pre-treatment with the anticholinesterase, physostigmine. In Expt. II, quisqualateinduced lesions of the basal forebrain produced behavioural deficits at 3 weeks post-lesion surgery similar to those observed following icv infusion of HC-3. In an attempt to restore the extrinsic cortical cholinergic innervation by reinnervation of the deafferented cortex, embryonic basal forebrain cholinergic cells were transplanted into the cortex of lesioned animals. After three months recovery, impairments in performance on the baseline schedule of the task were no longer apparent in lesioned animals. However, behavioural deficits, observed predominantly as a lengthening of correct response latency, could be reinstated in the lesioned animals by interpolation of distracting bursts of white noise during each trial, and this deficit was ameliorated by the cholinergic grafts. Furthermore, a non-specific effect of both cholinergic and non-cholinergic grafts in controlling the increase in perseverative time-out responses which occurred as a result of the basal forebrain lesion was consistently observed. These results suggest that cholinergic dysfunction can produce deficits in visual attention which can be ameliorated by cholinergic treatments such as physostigmine or cholinergic-rich cortical grafts. These data provide support for a role for the basal forebrain-neocortical cholinergic projection in attentional function.

Human subjects and non-human primates (the common marmoset) were trained on a series of reversals of both a simple (stimuli varying along one dimension) and compound (stimuli varying along two different dimensions) visual discrimination, using computer-generated stimuli. They were then shifted to a third series of reversals using completely novel compound stimuli. Those humans and marmosets for which the previously relevant dimension remained relevant, following the shift (shapes to shapes or lines to lines; intradimensional shift) made fewer errors than those for which the previously irrelevant dimension became relevant (shapes to lines or lines to shapes; extradimensional shift). These findings suggest that both humans and marmosets can learn to attend to the specific attributes or dimensions of a stimulus and use this information in visual discrimination learning.

Holding, D. H. The psychology of ches skill. Hillsdale, N. J.: Lawrence Erlbaum Associates. 1985. Pp. 271. ISBN 0-89859-575-4. £28.95.Brown, Fredick M. and Greaber, . Curtis (Eds.). Rhythmic aspects of behaviour. Hillsdale, N. J.: Lawence Erlbaum Associates. 1982. Pp. xvii + 483. ISBN 0-89859-168-6 £30.00.Harris, J. E. and Morris, P. E. (Eds.). Everyday memory, actins and absent-mindedness. London: Academic Press. 1984. Pp. 253. ISBN 0-12-32764-3. £27.50.Graesser, A. C. and Black, J. B. (Eds.). The psychology of questins. Hillsdale, N. J.: Lawrence Erlbaum associates. 1985. Pp. 383. ISBN 0-89859-444-8 $45.00, £36.00.Donchin, E. (Ed.). Congnitive psychophysiology : Event-related potentials and the study of cognition. Hillside, N. J.: Lawrence Erlbaum Associates. 1984. Pp. 428. ISBN 0-89859-150-3 £44.00.Oyama, S. The ontogeny of information : Development systems and evolution. Cambridge: Cambridge University Press. Pp. 206. Hardback : ISBN 0-521-32098-4. £22.50. Paperback: ISBN 0-521-31257-4. £8.95.Benser, D., Waller, T. G. and MacKinnon, G. E. (Eds.). Reading research: Advances in theory and practice, Vl. 5. Orlando, Fla.: Academic Press Inc. 1985. Pp. 356. ISBN 0-12-572305-9.Barr, A. and Feigenbaum, E. A. (Eds., Vols. 1 and 2). Cohen, P. R. and figenbaum, E. A. (Eds., Vol. 3). The handbook of atificial intelligence. Los Altos, Calif.: William Kaufmann, Inc. 1986. Paperback set: ISBN 0-86576-088-8. Pp. xiv + 409, xiii + 428, xviii+ 640. £69.00.Arnheim, R. New essays on the psychology of art. Berkeley: University of California Press, 1986. Pp. 331. ISBN 0-530-05553-5. £21.25.Ottoson, D. and Zeki, S. (Eds.). Central and perpheral mechanisms of colour vision. London: Macmillan. 1985. Pp. x +239. ISBN 0-333-39321-X. £60.00.Totman, R. Social and biological roles of language : The psychology of justification. London: Academic Press. 1985. Pp. 190. £39.50.Lynch, G., McGaugh, J. L. and Weinberger, N. M. (Eds.). Neurobiology of learining and memoryNew York: guilford. 1984. Pp. xiii + 528. ISBN 0-89862-645-5. £70.85.Weinberger, N. M., McGaugh, J. L. and Lynch, G. (Eds.). Memory systems of the brain. New York: Guilfrd. 1985. Pp. xiii + 514 ISBN 0-89862-666-8. £57.00.King, M. (Ed.). Parsing natural language. London: Academic Press. 1983. Pp. 308. ISBN 0-12-408280-7. $21.00.Cracco, R. Q. and Bodis-Wollner, I. (Eds.). Evoked potentials (Frontiers of clinical neuroscience, Vol, 3). New York: Alan R. Liss. 1986. Pp. xiv +551. ISBN 0-8451-4502-9. £98.05.Freeman, N. H. and Cox, M. V. Visual order : The nature and development of pictorial representation. Cambridge: Cambridge Unversity Press. 1985. Pp. 395. ISBN 0-521-26668-8. £27.50.Sndgrass, J. G., Levy-Berger, G. and Matin Haydon. Human experimental psychology. New York: Oxford University Press. 1985. Pp. 484. ISBN 0-19-503574-7. £30.00.Bradshaw, J. Basic experiments in neuropsychology. Amsterdam: Elsevier Science Publishers. 1986. Pp. 206. ISBN 0-444-80803-5. $42.25.Halpern, J. Y. (Ed.). Theoretical aspects of reasoning about knowledge: Proceedings of the 1986 Conference. Los Altos, CA: Morgan Kaufman. 1986. Pp. vii + 407. ISBN 0-934613-04-4. Paperback £ 18.95.Moore, B. C. J. (Ed.). Frequency selectivity in hearing. London: Academic Press. 1986. Pp. xv + 492. ISBN 0-12-505625-7. £49.50.Kandel, E. R. and Schwatz, J. H. (Eds.). Principles of neural science(Second Edition). New York: Elsevier. 1985. Pp. 979. ISBN 0-444-00944-2. £39.00.D. Frank Bensn and Eran Zaidel (Eds). The dual brain : Hemispheric specialization in humans. New York: Guilford Press. 1985. Pp. xviii +430. ISBN 0-89862-643-9. $49.95. £34.00.Posner, M. I. Chronometric explorations of mind: The third Paul M. Fitts lectures. Oxford: Oxford University Press. 1986. Pp. 271. ISBN 0-19-503999-8. £16.00.

This article summarizes the main discussions at a meeting on the biological, social and clinical bases of drug addiction focused on contemporary topics in drug dependence. Four main domains are surveyed, reflecting the structure of the meeting: psychological and pharmacological factors; neurobiological substrates; risk factors (including a consideration of vulnerability from an environmental and genetic perspective); and clinical treatment. Among the topics discussed were tolerance, sensitization, withdrawal, craving and relapse; mechanisms of reinforcing actions of drugs at the behavioural, cognitive and neural levels; the role of subjective factors in drug dependence; approaches to the behavioural and molecular genetics of drug dependence; the use of functional neuroimaging; pharmaceutical and psychosocial strategies for treatment; epidemiological and sociological aspects of drug dependence. The survey takes into account the considerable disagreements and controversies arising from the discussions, but also reaches a degree of consensus in certain areas.

A series of experiments examined the effects of lesions of the dorsal noradrenergic bundle (DNAB), induced by 6-hydroxydopamine (6-OHDA), on the behavioural response to systemic and intra-accumbens amphetamine, using a rat analogue of Leonard's 5-choice serial reaction time task for humans. Although the 6-OHDA DNAB lesion produced a profound depletion of cortical noradrenaline (NA) (to around 5% of control levels) it did not impair any aspect of performance on this task. Both systemic and intra-accumbens amphetamine increased behavioural measures of impulsivity of responding, but neither impaired discriminative accuracy in the sham-operated control rats. However, the DNAB lesioned rats did show a discriminative impairment following both low doses of systemic amphetamine, and intra-accumbens amphetamine. The latter effect was antagonised by systemic administration of the specific dopaminergic (DA) antagonist alpha-flupenthixol. The DNAB lesion did not alter the effect of amphetamine on any other behavioural measure, including speed and impulsivity of responding. These results suggest that although DA and NA participate in qualitatively different behavioural processes, the effects of DNAB lesions on attentional processes depend on the level of DA activity within the nucleus accumbens.

The effects of various psychomotor stimulant drugs and drugs outside this class were examined on the efficacy of stimuli previously paired with reinforcement or reward (conditioned reinforcers, CR) in controlling responding. Pipradrol (5–45 µmol/kg), d-amphetamine (1.25–15.0 µmol/kg), and the cocaine analogues WIN 35,428 (0.1–30.0 µmol/kg) and in one of two determinations WIN 35,065-2 (0.1–29.0 µmol/kg) all generally increased responding on a lever providing CR, but did not change or decreased responding on a lever providing no CR (NCR). Cocaine (5–125 µmol/kg) and chlordiazepoxide (3.75–60.0 µmol/kg) had no significant effects. Morphine (3.2–32.0 µmol/kg) and a-flupenthixol (0.02–2.0 µmol/kg) generally reduced responding on both levers. Apomorphine (0.1–1.0 µmol/kg) generally increased responding on both levers. Neurochemical data showed that d-amphetamine was generally more potent than pipradrol in its effects on in vitro monoamine uptake and release.

Four experiments examined the effects of d-amphetamine on response switching and perseveration in apparatus allowing a choice of response location. The relative ‘cost’ of a switch between two response locations and repetitive responding at a single location by rats was manipulated in the various test settings to provide baseline probabilities of switching. d-Amphetamine (0.2–2.3 mg/kg) increased response switching. This effect did not depend on switching being necessary to produce reinforcement and was not explained by increases in locomotor activity, motivational change or randomisation of responding. Further evidence was provided in support of a ‘probability-dependency’ hypothesis, that the effect of the drug depends in part upon the baseline probability of a response. A measure of perseveration independent of response switching (extra responses made prior to the collection of food) showed that increased switching and increased perseveration occurred in the same situation at the same doses, although perseveration generally occurred at higher doses than increased switching. Therefore the effect of amphetamine on response switching or repetition depends on the dose of drug, the context of the response and its probability of occurrence under control conditions.

The role of reinforcers in influencing choice was studied by use of a schedule that included a random intermixing of reinforced and explicitly non-reinforced components. The just-reinforced response had a high likelihood of being repeated (win-stay), although there was no differential reinforcement for doing so, whereas responses just followed by explicit non-reinforcement had a very low probability of repetition (lose-stay). Non-parametric indices based on the theory of signal detection were used to derive a choice measure of reinforcement which was independent of alterations in average response rate. Treatments with d-amphetamine (0.2–4.5 mg/kg), chlordiazepoxide (0.25–16 mg/kg) and a-flupenthixol (0.03–0.6 mg/kg) showed that changes in the choice measure could be dissociated from changes in the response rate. These findings were supported by extinction and satiation tests.

The effects of d-amphetamine on temporal discrimination in the rat were studied. Rats were trained on a two-manipulandum task involving the discrimination between two tones differing only in duration. d-Amphetamine (0.1–1.6 mg/kg) disrupted performance on this task, although not in an obvious dose-related manner.

ABSTRACT: The monoaminergic and cholinergic systems are implicated in different forms of behavioral arousal that can be dissected in terms of their forebrain targets and the nature of the behavioral processes they modulate in distinct regions. Thus, evidence in rats with selective neurochemical manipulations tested behaviorally using an analog of an attentional task developed for human subjects indicates that the coeruleo‐cortical noradrenergic system is implicated in divided and selective attention, the basal forebrain cholinergic system in stimulus detection, the mesostriatal and mesolimbic dopaminergic systems in response speed and vigor, and the mesencephalic serotoninergic or 5‐HT systems in response inhibition. Our recent studies have focused on fractionating, in the same task, the differential contributions of the dorsal and median raphé 5‐HT systems as well as elucidating the functions of the mesocortical dopaminergic system, each of which may be relevant to understanding the behavioral and cognitive sequelae of cocaine administration in human subjects as well as in experimental animals.

The most extensive development during primate brain evolution involves the cortex of the frontal lobe, especially its prefrontal region. The distribution of neurotransmitter receptors is unknown in this part of the cortex of New World monkeys. The respective distributions of eight different receptors for the transmitters l-glutamate (l-glu and NMDA), ?-amino-butyric acid (GABAA), noradrenaline (a1), acetylcholine (M1 and M2) and serotonin (5-HT1 and 5-HT2) were therefore studied in cortical areas of the frontal lobe of the lissencephalic New World monkey, Callithrix jacchus. The results are compared to earlier data on Old World monkeys in order to obtain insight into evolutionary trends at the level of chemical neuroanatomy. Our results indicate that the density and laminar pattern of some receptors change precisely at the cytoarchitectonic boundaries between different cortical areas, while some other receptors do not exhibit measurable changes. For example, the premotor area 6 can be distinguished from prefrontal areas by its high concentration of adrenergic a1 receptors as labelled with [3H] prazosin, with only the cingulate area 24 showing higher values. In other cases, the receptor distribution changes within a cytoarchitectonically homogeneous area. Thus, area 8 can be subdivided into dorsal and ventral regions on the basis of the distribution of GABAA, muscarinic and serotonin receptors. Comparison of these results in a New World monkey with receptor distributions in other primate species reveals much larger interspecies differences in the areas of the frontal lobe than e.g. in the primary visual cortex. This is interpreted as an indication of extensive changes in the neuro-chemical organisation of this part of the brain during primate brain evolution.

The regional and laminar distributions of eight different transmitter-binding sites were measured in the marmoset hippocampus by means of quantitative in vitro receptor autoradiography. Receptors for 5-HT1, l-glutamate, N-methyl-d-aspartate (NMDA) and GABAA were similarly distributed. The highest concentrations of these receptors were found in the pyramidal layer of CA1 and the molecular layer of the dentate gyrus. The 5-HT2 receptors showed the highest concentrations in the oriens layer of CA2. The highest concentrations of muscarinic M1 receptors were seen in the pyramidal layer of CA1. Muscarinic M2 receptors were most densely concentrated in the pyramidal layers of CA1, CA2 and CA3. The noradrenergic a1 receptors were most densely packed in the radiatum-lacunosum-molecular layer of CA2 and the molecular layer of the dentate gyrus. Statistically significant co-distributions of serotoninergic, glutamatergic and GABAergic receptors point to possible interactions between these receptor systems in the same hippocampal regions and layers. Comparisons of marmoset distribution patterns for GABAA, NMDA, l-glutamate and 5-HT1 receptors with those in human hippocampi and those of other primates showed similarities between them. Clear differences in the patterns of a1, M1, M2 and 5-HT2 receptors could be seen between marmoset and human hippocampi, indicating a high degree of species specificity in a presumably “conservative” brain region. More similarities, however, could be found between marmoset and human hippocampi than between those of rat and human brains, especially in relation to 5-HT1 and GABAA receptors and l-glutamate-binding sites. In addition to the functional significance of receptor distribution patterns, such studies represent a valuable tool for the analysis of neurochemical aspects of brain evolution.

Dissociable effects of bilateral excitotoxic lesions of different regions of the rat neocortex, including medial prefrontal and anterior cingulate cortices, were investigated in a five-choice serial reaction time task that provides several indices of the accuracy and speed of attentional function. Whereas medial prefrontal cortical lesions impaired performance of the task as revealed by a reduction in choice accuracy, an increase in the latency to respond correctly to the visual target and enhanced perseverative responding, lesions of the anterior cingulate cortex specifically increased premature responding. By contrast, lateral frontal cortical lesions did not significantly disrupt baseline performance of the task, but rather increased the latency to respond correctly to the visual target during various behavioral manipulations, for example, when the length of the intertrial interval was varied unpredictably and during interpolation of distracting bursts of white noise. Lesions of the parietal cortex failed to disrupt any aspect of task performance investigated. These behavioral effects in the five-choice task were compared with the effect of these same lesions on acquisition and retention of a one-trial passive avoidance task. The main finding from this paradigm was that lesions of the lateral frontal cortex produced a significant disruption to the retention of passive avoidance, which stands in marked contrast to the successful retention observed by animals of the other lesion groups. In addition, this pattern of results reveals that the 'disinhibitory' effect of cingulate cortex lesions are relatively specific to the five-choice attentional task. Finally, the results of the present study are compared with the findings of previous experiments using the five-choice task, which have examined the effect of selective manipulations of the ascending noradrenergic, cholinergic, dopaminergic, and serotonergic projections. In particular, the deficits in attentional function observed following cholinergic lesions of the nucleus basalis magnocellularis appear to be attributable to cholinergic denervation of the medial frontal cortex. These results are discussed in terms of the role of parallel distributed neural systems within the neocortex that mediate continuous attentional performance in the rat.

After training under a fixed-interval 60 sec schedule of food presentation in the presence of a water tube (to permit schedule-induced licking), groups of rats received either 6-hydroxy-dopamine (6-OHDA)(8 micrograms base/2 microliters) or 0.2% ascorbate-0.9% saline vehicle bilaterally into the nucleus accumbens. 6-OHDA produced greater than 80% depletion of the catecholamines dopamine and norepinephrine and the dopamine metabolite dihydroxyphenylacetic acid in the nucleus accumbens and olfactory tubercle, but nonsignificant depletions in the corpus striatum. The behavior of the groups treated with 6-OHDA ("lesion") and vehicle ("sham") was assessed for up to 58 days postoperatively. In the first few days after 6-OHDA, the lesion group showed reductions in high rates of responding toward the end and in high rates of licking at the beginning of the fixed-interval. However, licking was increased during later portions of the fixed interval in the lesion group. d-Amphetamine (0.25-2.0 mg/kg) increased low rates but decreased high rates of schedule-controlled responding, while generally reducing licking. The lesion group showed attenuated rate-reducing effects of d-amphetamine. In contrast, the lesion group showed enhanced rate-reducing effects of apomorphine (0.025-0.1 mg/kg) on both schedule-controlled responding and schedule-induced licking. In a second determination of the effect of d-amphetamine (0.25-2.0 mg/kg), schedule-induced locomotor activity was recorded and the water tube was removed. The lesion group showed attenuated rate-increasing and rate-decreasing effects of d-amphetamine upon schedule-controlled responding and reductions in the drug-induced increases in locomotor activity. The results are discussed in terms of the functions of dopamine in the control of behavior and in the mediation of the response to d-amphetamine and apomorphine.

Although benzodiazepine agonists and inverse agonists have opposite effects on drinking elicited by water deprivation, there is much less information about the effects of these drugs on nonhomeostatic drinking. In this experiment the effects of diazepam (0.3–5.0 mg/kg), a benzodiazepine receptor agonist, and FG 7142 (1.0–9.0 mg/kg), an inverse agonist, were determined on drinking elicited by a FT-60 schedule of food delivery (SIP). Both diazepam and FG 7142 dose-dependently reduced SIP, measured as either licking or volume consumed. In addition, diazepam reduced panel pressing for food, decreased locomotor activity, and changed the time course of each behavior. In contrast, FG 7142 reduced schedule-induced drinking without significantly altering other behaviors. The antagonist RO 15-1788, when given in combination with these drugs, only partially restored the reductions in licking produced by diazepam, but was much more effective in reversing the effects of FG 7142 at doses of the antagonist that failed by themselves to affect responding. The opposite pattern of effects was seen on the volume of water consumed. These effects are discussed in terms of the behavioral and pharmacological specificity of these drugs.

A test of attentional switching was devised for the rat in which it obtained sucrose reinforcement by an appropriate nose-poke response that discriminated which of two visual events terminated first, in a specially designed chamber. The effect of mesolimbic dopamine depletion (to 20% of control values) produced by infusions of 6-hydroxy-dopamine (6-OHDA) into the nucleus accumbens (N. Acc) on stable discrimination was measured alone and in the presence of a range of doses of d-amphetamine (0.4–2.3 mg/kg IP). The 6-OHDA lesion of the N. Acc impaired post-operative performance transiently by reducing choice accuracy and slowing response latency. By post-operative days 12–16, however, performance recovered to control levels and was not differentially affected by a mainpulation of task difficulty. d-Amphetamine produced dose-dependent performance impairments, which were antagonised by the 6-OHDA treatment. In a second group of N. Acc lesioned rats, the neuroleptic alpha-flupenthixol (0.1–1.0 mg/kg) led to fewer trials being completed and longer latencies than in the sham-operated control group. The results are discussed in terms of the possible attentional mechanisms underlying the d-amphetamine-induced disruption of performance mediated by the N. Acc and of the implications for psychopathology resulting from possible dysfunction of this region.

Rats were trained to respond to one of two levers under a random ratio schedule of food reinforcement. Which of the levers was correct was redetermined before each response and signalled by a light. The effects of d-amphetamine (0.2–3.2 mg/kg), chlordiazepoxide (1–8 mg/kg), and the neuroleptic alpha-flupenthixol (0.03–0.33 mg/kg) on the efficiency of rats tracking this visual cue were examined. d-Amphetamine increased the proportion of responses made on the correct lever at low and intermediate doses, but reduced the proportion at 3.2 mg/kg. At the highest dose, chlordiazepoxide produced a small increase in this measure, together with a reduction in response rate, but alpha-flupenthixol had no effect, even at a dose reducing response rate. Low doses of amphetamine also increased switching between the levers, producing a proportionately greater increase in switching from the correct lever to the incorrect lever than vice versa. The results are interpreted as showing that d-amphetamine facilitates tracking performance as a result of its action of enhancing response switching, and supporting the hypothesis that facilitation of performance by amphetamine-like drugs depends on the effect of the drug on response output coinciding with task requirements.

The neuropsychology of dementia and depression is surveyed with a focus on dementia of Alzheimer type (DAT) and depression in old age. Some of the main cognitive deficits in DAT are identified as loss of memory for events and attentional or executive deficit. The course of deterioration across various cognitive domains in DAT is consistent with a posterior-to-anterior spread of pathology in the cerebral cortex. Depressed, elderly patients exhibit a generalised profile of deficits, with impairments in tests shown to be sensitive to temporal or frontal cortex dysfunction. The depressed also exhibit a specific deficit in response to negative feedback (failure) which may contribute to different forms of cognitive dysfunctioning. Gross similarities in the deficits presented by subjects in depression or DAT necessitate a search for qualitative differences between the two, in order to facilitate their differential diagnosis: one such difference is the reversibility of certain of the cognitive deficits following recovery from depression.

The Law of Effect dictates that animals will repeat the just-reinforced response “win-stay”, and yet there have been apparent violations of this by rats running for food in mazes, in the form of “win-shift” behaviour. Four experiments analysed the conditions determining win-stay and win-shift behaviour. All the experiments employed a schedule in which reinforcement was distributed across two choices, and in which the probability of reinforcement for the first response after previous reinforcement was equivalent for the two options. Despite this lack of programmed differential reinforcement, rats showed a significant win-stay tendency in Experiment 1, with no spatial bias. Experiments 2 and 3 used respectively a Y-maze and an operant chamber in which responding required a return to a central choice point. In both situations, significant win-shift behaviour resulted initially, at relatively high frequencies of reinforcement, but this win-shift changed to significant win-stay over many sessions, and with intermittent reinforcement. Experiment 4 introduced explicitly non-reinforced trials and demonstrated a “lose-shift” tendency, parallel to win-stay. Possible artefacts underlying win-stay and win-shift behaviour are rejected, and various mechanisms for these effects, including theories of optimal choice and associative learning, are discussed.