A role for mesencephalic dopamine in activation: commentary on Berridge (2006).
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Animals↗
Biomedical subjects
T W Robbins
Publications and source records attributed to T W Robbins.
Functions of frontostriatal systems in cognition: comparative neuropsychopharmacological studies in rats, monkeys and humans.
A comparative and integrated account is provided of the evidence that implicates frontostriatal systems in neurodegenerative and neuropsychiatric disorders. Specifically, we have made detailed comparisons of performance following basal ganglia disease such as Parkinson's disease, with other informative groups, including Alzheimer's disease, schizophrenia and attention deficit/hyperactivity disorder and structural damage to the frontal lobes themselves. We have reviewed several behavioural paradigms including spatial attention and set-shifting, working memory and decision-making tasks in which optimal performance requires the operation of several cognitive processes that can be successfully dissociated with suitable precision in experimental animals. The role of ascending neurotransmitter systems are analysed from the perspective of different interactions with the prefrontal cortex. In particular, the role of dopamine in attentional control and spatial working memory is surveyed with reference to its deleterious as well as facilitatory effects. Parallels are identified in humans receiving dopaminergic medication, and with monkeys and rats with frontal dopamine manipulations. The effects of serotonergic manipulations are also contrasted with frontal lobe deficits observed in both humans and animals. The main findings are that certain tests of frontal lobe function are very sensitive to several neurocognitive and neuropsychiatric disorders. However, the nature of some of these deficits often differs qualitatively from those produced by frontal lobe lesions, and animal models have been useful in defining various candidate neural systems thus enabling us to translate basic laboratory science to the clinic, as well as in the reverse direction.
Animals↗
Saccadic latency distributions in Parkinson's disease and the effects of L-dopa.
Parkinson's disease (PD) is associated with a loss of central dopaminergic pathways in the brain leading to an abnormality of movement, including saccades. In PD, analysis of saccadic latency distributions, rather than mean latencies, can provide much more information about how the neural decision process that precedes movement is affected by disease or medication. Subject to the constraints of intersubject variation and reproducibility, latency distribution may represent an attractive potential biomarker of PD. Here we report two studies that provide information about these parameters, and demonstrate a novel effect of dopamine on saccadic latency, implying that it influences the neural decision process itself. We performed a detailed cross-sectional study of saccadic latency distributions during a simple step task in 22 medicated patients and 27 age-matched controls. This revealed high intersubject variability and an overlap of PD and control distributions. A second study was undertaken on a different population specifically to investigate the effects of dopamine on saccadic latency distributions in 15 PD patients. L-dopa was found to prolong latency, although the magnitude of the effect varied between subjects. The implications of these observations for the use of saccadic latency distributions as a potential biomarker of PD are discussed, as are the effects of L-dopa on neural decision making, where it is postulated to increase the criterion level of evidence required before the decision to move is made.
Aged↗
Impaired dimensional selection but intact use of reward feedback during visual discrimination learning in Parkinson's disease.
It has been suggested that Parkinson's disease (PD) impairs the ability to learn on the basis of reward or reinforcing feedback i.e., by trial-and-error. In many learning tasks, particular 'dimensions' of stimulus information are relevant whilst others are irrelevant; therefore, efficient performance depends on identifying the dimensions of these 'compound' stimuli and selecting the relevant dimension for further processing. We investigated the ability of patients with PD, as well as patients with Huntington's disease and patients with frontal or temporal lobe lesions, to learn visual discriminations which required either a number of associations to be learned concurrently (the 'eight-pair' task) or the selection of information from compound stimuli (the 'five-dimension' task), both tasks being learned by trial-and-error. None of the basal ganglia disorder patient groups was impaired on the eight-pair task, militating against a crucial role for these brain structures in trial-and-error learning per se. Patients with mild, medicated PD, but not unmedicated PD patients, were impaired at identifying all five feature dimensions in the five-dimension task, implying dopaminergic 'overdosing' of the ability to analyse compound stimuli in terms of their component dimensions. Temporal lobe lesion patients performed similarly, suggesting that the temporal lobe may be the site of the medication overdose effect. Patients with severe, medicated PD were impaired at compound discrimination learning on the five-dimension task in the absence of an underlying impairment in identifying component stimulus dimensions; this pattern resembled that seen in Huntington's disease and frontal lobe lesion patients, implying that fronto-striatal circuitry is involved in the formation of rules based upon selected stimulus dimensions.
Adult↗
Cognitive inflexibility after prefrontal serotonin depletion is behaviorally and neurochemically specific.
We have previously demonstrated that prefrontal serotonin depletion impairs orbitofrontal cortex (OFC)-mediated serial discrimination reversal (SDR) learning but not lateral prefrontal cortex (PFC)-mediated attentional set shifting. To address the neurochemical specificity of this reversal deficit, Experiment 1 compared the effects of selective serotonin and selective dopamine depletions of the OFC on performance of the SDR task. Whereas serotonin depletions markedly impaired performance, OFC dopamine depletions were without effect. The behavioral specificity of this reversal impairment was investigated in Experiment 2 by examining the effect of OFC serotonin depletion on performance of a modified SDR task designed to distinguish between 3 possible causes of the impairment. The results showed that the reversal deficit induced by prefrontal serotonin depletion was not due to a failure to approach a previously unrewarded stimulus (enhanced learned avoidance) or reduced proactive interference. Instead, it was due specifically to a failure to inhibit responding to the previously rewarded stimulus. The neurochemical and behavioral specificity of this particular form of cognitive inflexibility is of particular relevance to our understanding of the aetiology and treatment of inflexible behavior apparent in many neuropsychiatric and neurodegenerative disorders involving the PFC.
5,7-Dihydroxytryptamine↗
Selective prefrontal serotonin depletion impairs acquisition of a detour-reaching task.
We have recently shown that serotonin in the primate orbitofrontal cortex (OFC) contributes to the flexible control of behaviour. 5,7-dihydroxytryptamine-induced 5-HT depletions of OFC impair performance on a serial reversal discrimination task [Clarke et al. (2004)Science, 304, 878-880]. The deficit is characterized by perseverative responding to the previously rewarded stimulus, a deficit similar to that seen following lesions of the intrinsic neurones of the OFC [Dias et al. (1996)Nature, 380, 69-72]. The effect is neurochemically selective as dopaminergic lesions of the OFC, induced by 6-hydroxydopamine, have no effect [Clarke et al. (2006)Cerebral Cortex]. In order to test for the generality of the effect of serotonin on orbitofrontal processing and, in particular, its effects on flexible behaviour, the present study investigated the effects of serotonin depletions of OFC on performance of another task dependent upon an intact OFC, the detour-reaching task [Wallis et al. (2001)European Journal of Neuroscience, 13, 1797-1808]. Successful performance of this task requires inhibition of the animal's prepotent response tendency to reach directly along its line of sight to the reward. Compared with sham-operated controls, we found that lesioned monkeys made significantly more barrier reaches directly along their line of sight to the visible reward during task acquisition. This finding provides further support for the role of prefrontal serotonin in inhibitory control processes specifically in tasks sensitive to OFC dysfunction.
5,7-Dihydroxytryptamine↗
Profile of neurocognitive impairments associated with female in-patients with anorexia nervosa.
BACKGROUND: Although many studies have reported impairments of neurocognitive performance in patients with anorexia nervosa (AN), these have involved a wide range of assessment methods and some findings are inconsistent. METHOD: Twenty-five female in-patients with a DSM-IV diagnosis of AN, identified from three units specializing in the treatment of eating disorders, volunteered for the study. Twenty-five non-clinical control subjects were recruited, matched for age, gender and estimated IQ. Subjects were assessed with a range of computer-administered neurocognitive tasks from the Cambridge Neuropsychological Test Automated Battery (CANTAB), which has been validated in many studies of neuropsychiatric disorders. RESULTS: The patient group showed significant but moderate impairments (i.e. less than one standard deviation below the mean performance of the control group) on tests of spatial recognition memory, a planning task and rapid visual information processing, while a subgroup of patients (n = 14) showed greater degrees of impairments on at least one of these tests. The degrees of impairments did not correlate with body mass index (BMI). No impairments were observed on tests of spatial span, pattern recognition memory, spatial working memory, matching-to-sample, paired associates learning and set-shifting. CONCLUSIONS: The findings, in relation to a mean BMI of 15.3, are compatible with, in general, subtle impairments in neurocognition in AN. However, in those patients with relatively severe degrees of impairments, these may have adverse effects on complex tasks of social and occupational functioning. Further research is needed on the nature of relevant causal mechanisms, including the effects of potentially confounding variables.
Adolescent↗
Stop signal response inhibition is not modulated by tryptophan depletion or the serotonin transporter polymorphism in healthy volunteers: implications for the 5-HT theory of impulsivity.
RATIONALE: Reduced serotonin neurotransmission is implicated in disorders of impulse control, but the involvement of serotonin in inhibitory processes in healthy human subjects remains unclear. OBJECTIVES: To investigate the effects of an acute manipulation of serotonin and genotype at a functional polymorphism in a gene coding for the serotonin transporter (5-HTT) on an established measure of response inhibition. METHODS: Serotonin function was reduced by the acute tryptophan depletion (ATD) procedure in a double-blind, crossover design in 42 healthy subjects. The Stop Signal Task (SST) was administered 5-7 h after drink administration. The influences of 5-HTT polymorphism, gender and trait impulsivity were investigated. RESULTS: ATD was associated with significant depletion of plasma tryptophan levels but did not increase the stop signal reaction time in comparison to the balanced (placebo) amino acid mixture. Subjects possessing the short allele of the 5-HTT polymorphism were not more impulsive on the SST than subjects homozygous for the long allele under placebo conditions and were not disproportionately sensitive to the effects of ATD. There was no effect of gender or trait impulsivity on ATD-induced change. CONCLUSIONS: We find no support for the involvement of brain serotonin neurotransmission in this form of inhibitory control in healthy human subjects.
Adolescent↗
Abnormal frontal activations related to decision-making in current and former amphetamine and opiate dependent individuals.
RATIONALE: There is converging evidence for impairments in decision-making in chronic substance users. In the light of findings that substance abuse is associated with disruptions of the functioning of the striato-thalamo-orbitofrontal circuits, it has been suggested that decision-making impairments are linked to frontal lobe dysfunction. We sought to investigate this possibility using functional neuroimaging. METHODS: Decision-making was investigated using the Cambridge Risk Task during H2(15)O PET scans. A specific feature of the Risk Task is the decisional conflict between an unlikely high reward option and a likely low reward option. Four groups, each consisting of 15 participants, were compared: chronic amphetamine users, chronic opiate users, ex-drug users who had been long-term amphetamine/opiate users but are abstinent from all drugs of abuse for at least 1 year and healthy matched controls without a drug-taking history. RESULTS: During decision-making, control participants showed relatively greater activation in the right dorsolateral prefrontal cortex, whereas participants engaged in current or previous drug use showed relatively greater activation in the left orbitofrontal cortex. CONCLUSION: Our results indicate a disturbance in the mediation by the prefrontal cortex of a risky decision-making task associated with amphetamine and opiate abuse. Moreover, this disturbance was observed in a group of former drug users who had been abstinent for at least 1 year.
Adult↗
Plasma level-dependent effects of methylphenidate on task-related functional magnetic resonance imaging signal changes.
RATIONALE: Methylphenidate (MPH) is a dopamine and noradrenaline enhancing drug used to treat attentional deficits. Understanding of its cognition-enhancing effects and the neurobiological mechanisms involved, especially in elderly people, is currently incomplete. OBJECTIVES: The aim of this study was to investigate the relationship between MPH plasma levels and brain activation during visuospatial attention and movement preparation. METHODS: Twelve healthy elderly volunteers were scanned twice using functional magnetic resonance imaging (fMRI) after oral administration of MPH 20 mg or placebo in a within-subject design. The cognitive paradigm was a four-choice reaction time task presented at two levels of difficulty (with and without spatial cue). Plasma MPH levels were measured at six time points between 30 and 205 min after dosing. FMRI data were analysed using a linear model to estimate physiological response to the task and nonparametric permutation tests for inference. RESULTS: Lateral premotor and medial posterior parietal cortical activation was increased by MPH, on average, over both levels of task difficulty. There was considerable intersubject variability in the pharmacokinetics of MPH. Greater area under the plasma concentration-time curve was positively correlated with strength of activation in motor and premotor cortex, temporoparietal cortex and caudate nucleus during the difficult version of the task. CONCLUSION: This is the first pharmacokinetic/pharmacodynamic study to find an association between plasma levels of MPH and its modulatory effects on brain activation measured using fMRI. The results suggest that catecholaminergic mechanisms may be important in brain adaptivity to task difficulty and in task-specific recruitment of spatial attention systems.
Aged↗
D-Amphetamine remediates attentional performance in rats with dorsal prefrontal lesions.
Although amphetamine treatment has been shown to promote recovery of motor function in animals with cortical ablations, the potential therapeutic effect of amphetamine on processes other than motor control, such as attention and working memory, has been relatively unexplored. Accordingly, we investigated the beneficial effect of D-amphetamine treatment in animals with dorsal prefrontal cortex lesions (dPFC) compared with sham controls on a novel combined attention-memory task (CAM) that simultaneously measures attention to a visual stimulus and memory for that stimulus. The dPFC group was impaired in their ability to correctly detect the visual stimulus. Although this deficit occurred together with increased omissions and slow response latencies, these associated deficits largely recovered within the 10 post-operative baseline sessions revealing a selective attentional deficit in this group of animals. Nonetheless, the dPFC lesion did not substantially affect the working memory component of the task. The systemic administration of d-amphetamine served to ameliorate the attentional deficit in the dPFC group at the low dose only (0.2 mg/kg). By contrast, the dPFC group were less sensitive to the detrimental effects of the high dose (0.8 mg/kg) on any aspect of task performance. However, despite improving attention to the visual stimulus, D-amphetamine did not improve memory for that stimulus which instead appeared to deteriorate. The results provide apparently the first demonstration that low doses of D-amphetamine can ameliorate an attentional deficit in animals with selective dPFC lesions and may be a useful model of cognitive deficit in ADHD, schizophrenia or frontal brain injury.
Animals↗
Prefrontal serotonin depletion affects reversal learning but not attentional set shifting.
Recently, we have shown that serotonin (5-HT) depletion from the prefrontal cortex (PFC) of the marmoset monkey impairs performance on a serial discrimination reversal (SDR) task, resulting in perseverative responding to the previously correct stimulus (Clarke et al., 2004). This pattern of impairment is just one example of inflexible responding seen after damage to the PFC, with performance on the SDR task being dependent on the integrity of the orbitofrontal cortex. However, the contribution of 5-HT to other forms of flexible responding, such as attentional set shifting, an ability dependent on lateral PFC (Dias et al., 1996a), is unknown. The present study addresses this issue by examining the effects of 5,7-dihydroxytryptamine-induced PFC 5-HT depletions on the ability to shift attention between two perceptual dimensions of a compound visual stimulus (extradimensional shift). Monkeys with selective PFC 5-HT lesions, despite being impaired in their ability to reverse a stimulus-reward association, were unimpaired in their ability to make an extradimensional shift when compared with sham-operated controls. These findings suggest that 5-HT is critical for flexible responding at the level of changing stimulus-reward contingencies but is not essential for the higher-order shifting of attentional set. Thus, psychological functions dependent on different loci within the PFC are differentially sensitive to serotonergic modulation, a finding of relevance to our understanding of cognitive inflexibility apparent in disorders such as obsessive-compulsive disorder and schizophrenia.
5,7-Dihydroxytryptamine↗
The neuropsychology of obsessive compulsive disorder: the importance of failures in cognitive and behavioural inhibition as candidate endophenotypic markers.
Obsessive compulsive disorder (OCD) is a highly debilitating neuropsychiatric condition with estimated lifetime prevalence of 2-3%, more than twice that of schizophrenia. However, in contrast to other neuropsychiatric conditions of a comparable or lesser prevalence, relatively little is understood about the aetiology, neural substrates and cognitive profile of OCD. Despite strong evidence for OCD being familial, with risk to first-degree relatives much greater than for the background population, its genetic underpinnings have not yet been adequately delineated. Although cognitive dysfunction is evident in the everyday behaviour of OCD sufferers and is central to contemporary psychological models, theory-based studies of neurocognitive function have yet to reveal a reliable cognitive signature, and interpretation has often been confounded by failures to control for co-morbidities. The neuroimaging findings in OCD are amongst the most robust reported in the psychiatric literature, with structural and functional abnormalities frequently reported in orbitofrontal cortex, anterior cingulate cortex, and caudate nucleus. In spite of this, our relative lack of understanding of OCD neurochemical processes continues to impede progress in the development of novel pharmacological treatment approaches. Integrating the neurobiological, cognitive, and clinical findings, we propose that OCD might usefully be conceptualised in terms of lateral orbitofrontal loop dysfunction, and that failures in cognitive and behavioural inhibitory processes appear to underlie many of the symptoms and neurocognitive findings. We highlight existing limitations in the literature, and the potential utility of endophenotypes in overcoming these limitations. We propose that neurocognitive indices of inhibitory functions may represent a useful heuristic in the search for endophenotypes in OCD. This has direct implications not only for OCD but also for putative obsessive-compulsive spectrum conditions including attention deficit hyperactivity disorder, Tourette's syndrome, and trichotillomania (compulsive hair pulling).
Animals↗
Heterogeneity of Parkinson's disease in the early clinical stages using a data driven approach.
OBJECTIVE: To investigate the heterogeneity of idiopathic Parkinson's disease (PD) in a data driven manner among a cohort of patients in the early clinical stages of the disease meeting established diagnostic criteria. METHODS: Data on demographic, motor, mood, and cognitive measures were collected from 120 consecutive patients in the early stages of PD (Hoehn and Yahr I-III) attending a specialist PD research clinic. Statistical cluster analysis of the data allowed the existence of the patient subgroups generated to be explored. RESULTS: The analysis revealed four main subgroups: (a) patients with a younger disease onset; (b) a tremor dominant subgroup of patients; (c) a non-tremor dominant subgroup with significant levels of cognitive impairment and mild depression; and (d) a subgroup with rapid disease progression but no cognitive impairment. CONCLUSIONS: This study complements and extends previous research by using a data driven approach to define the clinical heterogeneity of early PD. The approach adopted in this study for the identification of subgroups of patients within Parkinson's disease has important implications for generating testable hypotheses on defining the heterogeneity of this common condition and its aetiopathological basis and thus its treatment.
Age of Onset↗
Lateralisation of striatal function: evidence from 18F-dopa PET in Parkinson's disease.
OBJECTIVES: The aetiology of the cognitive changes seen in Parkinson's disease (PD) is multifactorial but it is likely that a significant contribution arises from the disruption of dopaminergic pathways. This study aimed to investigate the contribution of the dopaminergic system to performance on two executive tasks using (18)F-6-fluorodopa positron emission tomography ((18)F-dopa PET) in PD subjects with early cognitive changes. METHODS: 16 non-demented, non-depressed PD subjects were evaluated with the Tower of London (TOL) spatial planning task, a verbal working memory task (VWMT) and (18)F-dopa PET, all known to be affected in early PD. Statistical parametric mapping (SPM) localised brain regions in which (18)F-dopa uptake covaried with performance scores. Frontal cortical resting glucose metabolism was assessed with (18)F-fluoro-2-deoxy-D-glucose ((18)F-FDG) PET. RESULTS: SPM localised significant covariation between right caudate (18)F-dopa uptake (Ki) and TOL scores and between left anterior putamen Ki and VWMT performance. No significant covariation was found between task scores and (18)F-dopa Ki values in either limbic or cortical regions. Frontal cortical glucose metabolism was preserved in all cases. CONCLUSIONS: These findings support a causative role of striatal dopaminergic depletion in the early impairment of executive functions seen in PD. They suggest that spatial and verbal executive tasks require integrity of the right and left striatum, respectively, and imply that the pattern of cognitive changes manifest by a patient with PD may reflect differential dopamine loss in the two striatal complexes.
Aged↗
Cognitive inflexibility after prefrontal serotonin depletion.
Serotonergic dysregulation within the prefrontal cortex (PFC) is implicated in many neuropsychiatric disorders, but the precise role of serotonin within the PFC is poorly understood. Using a serial discrimination reversal paradigm, we showed that upon reversal, selective serotonin depletion of the marmoset PFC produced perseverative responding to the previously rewarded stimulus without any significant effects on either retention of a discrimination learned preoperatively or acquisition of a novel discrimination postoperatively. These results highlight the importance of prefrontal serotonin in behavioral flexibility and are highly relevant to obsessive-compulsive disorder, schizophrenia, and the cognitive sequelae of drug abuse in which perseveration is prominent.
5,7-Dihydroxytryptamine↗
Psychopharmacological approaches to modulating attention in the five-choice serial reaction time task: implications for schizophrenia.
RATIONALE: In schizophrenia, attentional disturbance is a core feature which may not only accompany the disorder, but may precede the onset of psychiatric symptoms. OBJECTIVES: The five-choice serial reaction time task (5CSRTT) is a test of visuo-spatial attention that has been used extensively in rats for measuring the effects of systemic and central neurochemical manipulations on various aspects of attentional performance, including selective attention, vigilance and executive control. These findings are relevant to our understanding of the neural systems that may be compromised in patients with schizophrenia. METHODS: The 5CSRTT is conducted in an operant chamber that has multiple response locations, in which brief visual stimuli can be presented randomly. Performance is maintained using food reinforcers to criterion levels of accuracy. Various aspects of performance are measured, including attentional accuracy and premature responding, especially under different attentional challenges. RESULTS: The effects of systemic and intra-cerebral infusions of selective dopamine, serotonin and cholinergic receptor agents on the 5CSRTT are reviewed with a view to identifying attention-enhancing effects that may be relevant to the treatment of cognitive deficits in schizophrenia. In addition, some novel agents such as modafinil and histamine receptor agents are also considered. Examining the effects of selective neurochemical lesions helped define the neural locus of attentional effects. Similarly, findings from microdialysis studies helped identify the extracellular changes in neurotransmitters and their metabolites in freely moving rats during performance of the 5CSRTT. CONCLUSIONS: The monoaminergic and cholinergic systems have independent but complementary roles in attentional function, as measured by the 5CSRTT. These functions are predominantly under the control of the prefrontal cortex and striatum. These conclusions are considered in the context of their application towards therapeutic approaches for attentional disturbances that are typically observed in schizophrenic patients.
Animals↗
Effects of acute and chronic buspirone on impulsive choice and efflux of 5-HT and dopamine in hippocampus, nucleus accumbens and prefrontal cortex.
RATIONALE: Reduced central serotonin (5-HT) activity has been associated with impulsive choice behaviour, but there is no consensus about the precise nature of these effects. Behavioural and neurochemical effects of 5-HT(1A) agonists such as buspirone depend critically on the dose and the duration of treatment. We thus undertook a parametric study of the effects of acute and chronic buspirone on the performance on a test of delayed gratification, as well as on the efflux of serotonin and dopamine (DA) in cortical and subcortical regions in rats. OBJECTIVES: Three experiments examined (i) the effects of acute buspirone on impulsive choice and how such effects were modified by prior chronic exposure to buspirone; (ii) the effects of chronic buspirone on impulsive choice; (iii) the effects on impulsive choice of a selective 5-HT(1A) antagonist, WAY-100635 tested alone and in combination with buspirone; (iv) the effects of chronic and acute buspirone on 5-HT and DA efflux in anaesthetised rats. METHODS: In experiment 1, rats previously trained on the delayed gratification task were tested with acute buspirone (0.5, 1 and 2 mg/kg). The same rats were then treated with chronic buspirone (1 mg/kg/day) over the next 65 days, and the effects of acute buspirone (1 mg/kg) re-determined at 20, 45 and 65 days of chronic treatment. In experiment 2, two groups of rats trained on the delayed gratification task were treated either with saline or buspirone (1 mg/kg/day) continually for 65 days before being tested with acute buspirone (1 mg/kg), WAY-100635 (0.08 mg/kg), or a combination of the two drugs. In experiment 3, rats received the same regimen of buspirone dosing as in experiment 2, before receiving in-vivo microdialysis for 5-HT and DA in the ventral hippocampus, nucleus accumbens and medial prefrontal cortex. RESULTS: Acute buspirone dose dependently increased the choice for the small, immediate reinforcer (impulsive choice) but the effects of 1 mg/kg were reversed on chronic administration of buspirone. This increased choice of the large, delayed reinforcer, which was not accompanied by any changes in baseline (non-drugged) performance, was blocked by the 5-HT(1A) receptor antagonist WAY-100635. The chronic buspirone regimen did not alter buspirone-evoked reductions in 5-HT efflux in hippocampus but did lead to a differential effect of acute buspirone in medial prefrontal cortex, with the chronic buspirone and saline groups exhibiting decreases and increases in efflux, respectively. There were no systematic changes in DA efflux under any condition. CONCLUSIONS: These findings show that the effects of acute buspirone on impulsive choice are reversed following chronic treatment and are mediated by 5-HT(1A) receptors, and suggest, in addition, that the behavioural effects may involve changes in 5-HT functioning in medial prefrontal cortex.
Analysis of Variance↗