Interaction of amisulpride with GLUT1 at the blood-brain barrier. Relevance to Alzheimer's disease.

Blood-brain barrier (BBB) dysfunction may be involved in the increased sensitivity of Alzheimer's disease (AD) patients to antipsychotics, including amisulpride. Studies indicate that antipsychotics interact with facilitated glucose transporters (GLUT), including GLUT1, and that GLUT1 BBB expression decreases in AD. We tested the hypotheses that amisulpride (charge: +1) interacts with GLUT1, and that BBB transport of amisulpride is compromised in AD. GLUT1 substrates, GLUT1 inhibitors and GLUT-interacting antipsychotics were identified by literature review and their physicochemical characteristics summarised. Interactions between amisulpride and GLUT1 were studied using in silico approaches and the human cerebral endothelial cell line, hCMEC/D3. Brain distribution of [3H]amisulpride was determined using in situ perfusion in wild type (WT) and 5xFamilial AD (5xFAD) mice. With transmission electron microscopy (TEM) we investigated brain capillary degeneration in WT mice, 5xFAD mice and human samples. Western blots determined BBB transporter expression in mouse and human. Literature review revealed that, although D-glucose has no charge, charged molecules can interact with GLUT1. GLUT1 substrates are smaller (184.95±6.45g/mol) than inhibitors (325.50±14.40g/mol) and GLUT-interacting antipsychotics (369.38±16.04). Molecular docking showed beta-D-glucose (free energy binding: -15.39kcal/mol) and amisulpride (-29.04kcal/mol) interact with GLUT1. Amisulpride did not affect [14C]D-glucose hCMEC/D3 accumulation. [3H]amisulpride uptake into the brain (except supernatant) of 5xFAD mice compared to WT remained unchanged. TEM revealed brain capillary degeneration in human AD. There was no difference in GLUT1 or P-glycoprotein BBB expression between WT and 5xFAD mice. In contrast, caudate P-glycoprotein, but not GLUT1, expression was decreased in human AD capillaries versus controls. This study provides new details about the BBB transport of amisulpride, evidence that amisulpride interacts with GLUT1 and that BBB transporter expression is altered in AD. This suggests that antipsychotics could potentially exacerbate the cerebral hypometabolism in AD. Further research into the mechanism of amisulpride transport by GLUT1 is important for improving antipsychotics safety.

Endocannabinoid system alterations in Alzheimer's disease: A systematic review of human studies.

Studies investigating alterations of the endocannabinoid system (ECS) in Alzheimer's disease (AD) in humans have reported inconsistent findings so far. We performed a systematic review of studies examining alterations of the ECS specifically within humans with AD or mild cognitive impairment (MCI), including neuroimaging studies, studies of serum and cerebrospinal fluid biomarkers, and post-mortem studies. We attempted to identify reported changes in the expression and activity of: cannabinoid receptors 1 and 2; anandamide (AEA); 2-arachidonoylglycerol (2-AG); monoacylglycerol lipase (MAGL); fatty acid amide hydrolase (FAAH); and transient receptor potential cation channel V1 (TRPV1). Twenty-two studies were identified for inclusion. Mixed findings were reported for most aspects of the ECS in AD, making it difficult to identify a particular profile of ECS alterations characterising AD. The included studies tended to be small, methodologically heterogeneous, and frequently did not control for important potential confounders, such as pathological progression of AD. Eight studies correlated ECS alterations with neuropsychometric performance measures, though studies infrequently examined behavioural and neuropsychiatric correlates. PROSPERO database identifier: CRD42018096249.

The neurochemistry of agitation in Alzheimer's disease: a systematic review.

OBJECTIVE: To provide an up-to-date systematic review of the characteristics, methodology and findings of studies that have investigated the neurochemistry of agitation in Alzheimer's disease (AD). METHODS: Electronic databases were searched for published peer-reviewed articles which provided data on any neurotransmitter system in relation to agitation in AD. Screening of titles and abstracts and data extraction from full texts were conducted in duplicate. RESULTS: Forty-five studies were included. Monoamines (serotonin, dopamine and noradrenaline) were most commonly investigated. A variety of methods were used to investigate the neurochemistry underlying agitation in AD and, although there were several conflicting findings, there was evidence of serotonergic deficit, relatively preserved dopaminergic function and compensatory overactivity of postsynaptic noradrenergic neurons in agitation in AD. CONCLUSIONS: Disruption of the dynamic balance between multiple neurotransmitter systems could impair functional neural networks involved in affective regulation and executive function. Differences in study design and methodology may have contributed to conflicting findings. Future studies that overcome these limitations (e.g. using standardized criteria to define agitation) and employ neuroimaging methods such as MRI/PET to investigate specific neural networks are needed to clarify the role of neurotransmitter alterations in these patients.

Service and treatment engagement of people with very late-onset schizophrenia-like psychosis.

Aims and method Electronic patient records were used to investigate the level of engagement and treatment that patients with very late-onset schizophrenia-like psychosis (VLOSLP) had with mental health services. Results Of 131 patients assessed and diagnosed, 63 (48%) were taking antipsychotic treatment at 3 months, 46 (35%) at 6 months and 36 (27%) at 12 months. At discharge from mental health services, 54% of patients had failed to engage with services or became lost to follow-up, 18% had engaged with services but were not taking antipsychotic medication and only 28% were taking treatment. Clinical implications Results showed that less than half of the patients with VLOSLP were commenced on antipsychotic treatment and less than a third remained on treatment at 1 year or at point of discharge. This highlights the need for services to consider being more assertive in taking potentially effective treatment to this patient group.

Cognitive phenotype of psychotic symptoms in Alzheimer's disease: evidence for impaired visuoperceptual function in the misidentification subtype.

BACKGROUND: Establishing the cognitive phenotype of psychotic symptoms in Alzheimer's disease (AD) could localise discrete pathology and target symptomatic treatment. This study aimed to establish whether psychotic symptoms would be associated with poorer performance on neuropsychological tests known to correlate with striatal dopaminergic function and to investigate whether these differences would be attributed to the paranoid (persecutory delusions) or misidentification (misidentification phenomena +/- hallucinations) subtype. METHODS: Seventy patients with probable AD (34 psychotic and 36 nonpsychotic) were recruited to the study. Analysis of covariance was used to compare motor speed and the rapid visual processing test of sustained visual attention, after adjusting for potential confounding factors. Multivariate analyses were used to compare performance across other cognitive domains. Significant findings were explored by separating patients on the basis of subtype. RESULTS: Rapid visual processing performance accuracy was reduced in patients with psychotic symptoms (F1,58 = 5.94, p = 0.02) and differed significantly across subtypes (F2,51 = 3.94, p = 0.03), largely because of poorer performance in the misidentification compared with nonpsychotic group. Multivariate analyses (corrected for multiple comparisons) showed poorer performance on the incomplete letters task in psychotic patients (F1,63 = 8.77, p = 0.004) and across subtypes (F2,55 = 10.90, p < 0.001), similarly attributed to the misidentification subtype. CONCLUSIONS: These findings provide further support of the involvement of dopaminergic networks in the psychosis endophenotype in AD and, in addition, implicate the ventral (temporo-occipital) pathway in the misidentification subtype. Future studies should investigate the early trajectory of neuropathological change in vivo across psychosis subtypes.

Does human presynaptic striatal dopamine function predict social conformity?

Socially desirable responding (SDR) is a personality trait which reflects either a tendency to present oneself in an overly positive manner to others, consistent with social conformity (impression management (IM)), or the tendency to view one's own behaviour in an overly positive light (self-deceptive enhancement (SDE)). Neurochemical imaging studies report an inverse relationship between SDR and dorsal striatal dopamine D2/3 receptor availability. This may reflect an association between SDR and D2/3 receptor expression, synaptic dopamine levels or a combination of the two. In this study, we used a [¹8F]-DOPA positron emission tomography (PET) image database to investigate whether SDR is associated with presynaptic dopamine function. Striatal [¹8F]-DOPA uptake, (k(i)(cer), min⁻¹), was determined in two independent healthy participant cohorts (n=27 and 19), by Patlak analysis using a cerebellar reference region. SDR was assessed using the revised Eysenck Personality Questionnaire (EPQ-R) Lie scale, and IM and SDE were measured using the Paulhus Deception Scales. No significant associations were detected between Lie, SDE or IM scores and striatal [¹8F]-DOPA k(i)(cer). These results indicate that presynaptic striatal dopamine function is not associated with social conformity and suggests that social conformity may be associated with striatal D2/3 receptor expression rather than with synaptic dopamine levels.

Establishing test-retest reliability of an adapted [(18)F]fallypride imaging protocol in older people.

[(18)F]fallypride is a high-affinity dopamine D2/3 receptor tracer with the ability to reliably quantify D2/3 receptor sites in both striatal and corticolimbic regions. The translational potential of [(18)F]fallypride imaging is, however, limited by the lengthy scanning sessions (60-80 minutes duration over a total of 3-4 hours) required by current protocols. The aims of our study were to adapt [(18)F]fallypride imaging for use in clinical populations with neurological and neuropsychiatric disorders, by reducing the duration of individual scanning sessions; and to establish the reproducibility and reliability of our adapted protocol in healthy older people. Eight participants (five male and three female; mean age=75.87±4.39 years) were scanned twice, 4-6 weeks apart. [(18)F]fallypride binding potential was determined from image data collected during three sampling times: 0-30; 60-90; and 210-240 minutes post injection. High reproducibility and reliability (test-retest variability <8%; intraclass correlation coefficient >0.8) were observed in all but the prefrontal regions, and remained so when sampling times were reduced to 20 minutes (0-20; 70-90; 220-240 minutes). The adapted protocol is feasible for use across neuropsychiatric disorders in which dopamine has been implicated and is sufficiently sensitive to detect within-subject changes between 2.7% and 5.5% in striatal and limbic regions.

Origins of delusions in Alzheimer's disease.

Research over the past two decades supports a shared aetiology for delusions in Alzheimer's disease (AD) and schizophrenia. Functional networks involved in salience attribution and belief evaluation have been implicated in the two conditions, and striatal D2/3 receptors are increased to a comparable extent. Executive/frontal deficits are common to both disorders and predict emergent symptoms. Putative risk genes for schizophrenia, which may modify the AD process, have been more strongly implicated in delusions than those directly linked with late-onset AD. Phenotypic correlates of delusions in AD may be dependent upon delusional subtype. Persecutory delusions occur early in the disease and are associated with neurochemical and neuropathological changes in frontostriatal circuits. In contrast, misidentification delusions are associated with greater global cognitive deficits and advanced limbic pathology. It is unclear whether the two subtypes are phenomenologically and biologically distinct or are part of a continuum, in which misidentification delusions manifest increasingly as the pathological process extends. This has treatment implications, particularly if they are found to have discrete chemical and/or pathological markers.

Limbic striatal dopamine D2/3 receptor availability is associated with non-planning impulsivity in healthy adults after exclusion of potential dissimulators.

Positron emission tomography (PET) studies have reported an association between reduced striatal dopamine D2/3 receptor availability and higher scores on self-report measures of trait impulsivity in healthy adults. However, impulsivity is a multi-faceted construct, and it is unclear which aspect(s) of impulsivity might be driving these associations. The current study aimed to investigate the relationship between limbic (ventral) striatal D2/3 receptor availability and individual components of impulsivity (attentional, motor and non-planning) using the Barratt Impulsiveness Scale (BIS-11) and [(11)C]raclopride PET in 23 healthy volunteers. A partial correlational analysis showed a significant association between non-planning impulsiveness (lack of forethought or 'futuring') and limbic D2/3 receptor availability, which was only apparent after the exclusion of potential dissimulators (indexed by high scores on impression management). Our findings suggest that non-planning impulsiveness is associated with individual variation in limbic striatal D2/3 receptor availability and that different facets of impulsivity may have specific neurochemical correlates. Future studies that combine D2/3 receptor imaging with behavioral measures of impulsivity are required to further elucidate the precise relationship between individual components of trait impulsivity and brain dopaminergic function.

Association of serotonin and dopamine gene pathways with behavioral subphenotypes in dementia.

Genetic association studies investigating the association between genes of serotonergic and dopaminergic systems and behavioral and psychological symptoms in dementia (BPSD) are contradictory. We have utilized 1008 probable Alzheimer's disease (AD) patients from the UK and used the 12-item Neuropsychiatric Inventory. We applied a multiple indicators-multiple causes (MIMIC) approach to investigate the effect of 11 polymorphisms on the 4 behavioral subphenotypes "psychosis", "moods", "agitation", and "behavioural dyscontrol". Significant associations were observed between the serotonin transporter gene (SERT) polymorphism STin2 and "psychosis"; the dopamine transporter gene (DAT) 3' variable number tandem repeats (VNTR) and "agitation"; and the dopamine receptor 4 (DRD4) VNTR and "moods" factors. Direct associations were identified between the dopamine receptor 3 (DRD3) BalI polymorphism and depression; the dopamine receptor 1 (DRD1) and dopamine transporter gene 3' VNTR polymorphisms and aberrant motor behavior; the DRD4 VNTR and sleep disturbances; and the SERT gene VNTR 5HTTLPR and apathy items. Significant interactions observed between polymorphisms suggested epistatic effects and interactions between polymorphisms and medications highlighted potential treatment response. This multiple indicators multiple causes (MIMIC) model efficiently captured the complexity of the interrelations between genetic variation, behavioral symptoms, and clinical variables.

Truth, lies or self-deception? Striatal D(2/3) receptor availability predicts individual differences in social conformity.

Previous positron emission tomography (PET) studies have consistently shown a negative association between striatal D(2/3) receptor availability and socially desirable responding (SDR). However, as SDR is a complex personality trait, the functional significance of this relationship is unclear. The aim of the present study was to determine whether the relationship between D(2/3) receptor availability and SDR reflects a tendency to present oneself positively to others, consistent with social conformity (impression management, IM), or the tendency to view one's own behavior positively (self-deceptive enhancement, SDE). Striatal D(2/3) receptor availability was assessed in 23 healthy volunteers using [(11)C]raclopride PET. SDR was assessed using the Lie scale of the revised Eysenck Personality Questionnaire, and IM and SDE were measured using the Paulhus Deception Scales. Analysis of personality variables revealed a positive relationship between Lie and log IM (r=0.64, p=0.01) but not Lie and SDE (r=-0.36, ns). Consistent with previous findings, Lie was negatively associated with D(2/3) receptor availability in the sensorimotor striatum (r=- 0.55, p=0.05), and a similar trend-level relationship was observed for log IM (r=-0.54 p=0.06) but not SDE (r=0.23, ns). Whilst these associations are modest, results suggest that striatal D(2/3) receptor availability may be particularly associated with social conformity, rather than self-deception.

Acute effect of the anti-addiction drug bupropion on extracellular dopamine concentrations in the human striatum: an [11C]raclopride PET study.

Bupropion is an effective medication in treating addiction and is widely used as an aid to smoking cessation. Bupropion inhibits striatal dopamine reuptake via dopamine transporter blockade, but it is unknown whether this leads to increased extracellular dopamine levels at clinical doses in man. The effects of bupropion on extracellular dopamine levels in the striatum were investigated using [(11)C]raclopride positron emission tomography (PET) imaging in rats administered saline, 11 or 25 mg/kg bupropion i.p. and in healthy human volunteers administered either placebo or 150 mg bupropion (Zyban Sustained-Release). A cognitive task was used to stimulate dopamine release in the human study. In rats, bupropion significantly decreased [(11)C]raclopride specific binding in the striatum, consistent with increases in extracellular dopamine concentrations. In man, no significant decreases in striatal [(11)C]raclopride specific binding were observed. Levels of dopamine transporter occupancy in the rat at 11 and 25 mg/kg bupropion i.p. were higher than predicted to occur in man at the dose used. Thus, these data indicate that, at the low levels of dopamine transporter occupancy achieved in man at clinical doses, bupropion does not increase extracellular dopamine levels. These findings have important implications for understanding the mechanism of action underlying bupropions' therapeutic efficacy and for the development of novel treatments for addiction and depression.

The dopaminergic basis of human behaviors: A review of molecular imaging studies.

This systematic review describes human molecular imaging studies which have investigated alterations in extracellular DA levels during performance of behavioral tasks. Whilst heterogeneity in experimental methods limits meta-analysis, we describe the advantages and limitations of different methodological approaches. Interpretation of experimental results may be limited by regional cerebral blood flow (rCBF) changes, head movement and choice of control conditions. We revisit our original study of striatal DA release during video-game playing [Koepp, M.J., Gunn, R.N., Lawrence, A.D., Cunningham, V.J., Dagher, A., Jones, T., Brooks, D.J., Bench, C.J., Grasby, P.M., 1998. Evidence for striatal dopamine release during a video game. Nature 393, 266-268] to illustrate the potentially confounding influences of head movement and alterations in rCBF. Changes in [(11)C]raclopride binding may be detected in extrastriatal as well as striatal brain regions-however we review evidence which suggests that extrastriatal changes may not be clearly interpreted in terms of DA release. Whilst several investigations have detected increases in striatal extracellular DA concentrations during task components such as motor learning and execution, reward-related processes, stress and cognitive performance, the presence of potentially biasing factors should be carefully considered (and, where possible, accounted for) when designing and interpreting future studies.

Dopamine release in the human striatum: motor and cognitive tasks revisited.

Striatal dopamine (DA) release has been shown during behavioural tasks, but the relative contribution of motor, reward, and cognitive components is unclear. Dopamine release was quantified using [(11)C]-raclopride in two studies using a triple-scan approach, comprising active task, motor control, and rest. In the first, bolus radiotracer was delivered during a sequential motor learning paradigm; in the second, a spatial planning task, bolus plus constant infusion was applied. [(11)C]-raclopride binding potentials (BP(ND)s) in striatal functional subdivisions were compared across conditions. [(11)C]-raclopride BP(ND) was significantly reduced in active task compared with rest in both the sensorimotor and associative striatum in both studies, because of differences between rest and motor control conditions. In both regions, the motor control BP(ND) fell between the rest and active task in the planning study, but the difference between motor control and active task conditions was not significant. No such changes were observed in the limbic striatum. Using rigorous methodology, this study validates earlier evidence that striatal DA release occurs during behavioural challenges. Increased DA release during movement was reliably detected in the sensorimotor and associative striatum, supporting use of the functional subdivision model in humans. No additional DA release was observed specific to the cognitive component of either task.

Premorbid personality and behavioral and psychological symptoms in probable Alzheimer disease.

OBJECTIVES: Previous research investigating the influence of premorbid personality on behavioral and psychological symptoms in dementia (BPSD) has produced mixed findings. Addressing some limitations of previous studies, the authors aimed to investigate whether some of the common individual symptoms of BPSD (depression, anxiety, irritability, and aggression) were associated with key aspects of previous personality (neuroticism and agreeableness); and also to perform an exploratory investigation into the broader influence of personality factors on behavioral and psychological syndromes. METHODS: Two hundred eight patients with a diagnosis of probable Alzheimer disease were assessed for the presence of BPSD over the disease course using the caregiver-rated Neuropsychiatric Inventory (NPI). One or two knowledgeable informants rated patients' midlife personalities using a retrospective version of the NEO-FFI questionnaire. RESULTS: Premorbid neuroticism was correlated with anxiety and total NPI score, although not with depression. Premorbid agreeableness was negatively correlated with agitation and irritability. Principal components analysis of the 10 NPI behavioral domains identified three syndromes: "agitation/apathy," "psychosis," and "affect." In stepwise linear regression analyses, including personality domains from the Five-Factor Model and a range of potential confounders as independent variables; the only significant personality predictor of a behavioral syndrome was "agitation/apathy," predicted by lower premorbid agreeableness. CONCLUSION: Lower premorbid agreeableness is associated with agitation and irritability symptoms in Alzheimer disease and also predicts an "agitation/apathy" syndrome. The relationship between premorbid neuroticism and BPSD is less straightforward, and premorbid neuroticism does not appear to be associated with depression in Alzheimer disease or predict an "affect" syndrome.

Striatal dopamine (D2) receptor availability predicts socially desirable responding.

Research in non-human primates has implicated striatal dopamine (D2) receptor function in the expression of social dominance--a fundamental component of social extraversion. We predicted that trait extraversion - indexed by the revised Eysenck Personality Questionnaire (EPQ-R) - would correlate with striatal DA (D2) receptor measures - indexed by [(11)C]-Raclopride binding potential (BP) - in 28 healthy post-menopausal females (mean age=75 years; range=58-91 years). Region of interest (ROI) and voxel-based statistical parametric mapping (SPM) analyses were performed, using a reference tissue model for [(11)C]-Raclopride. ROI analysis showed moderately significant negative correlations between extraversion and BP measures in the left caudate and between psychoticism scores and BP in the right putamen. Unexpectedly, scores on the Lie scale, a measure of socially desirable responding, were significantly and negatively correlated with BP measures in the putamen and survived Bonferroni correction on the right side. After controlling for the potential confounding of self-report bias in high Lie scorers, only the correlation between Lie scores and BP measures in the right putamen remained significant. Voxel-based analysis showed only Lie scores to be significantly and negatively correlated with BP measures in the right putamen. We explored this association further by applying an ROI-based approach to data on a previously scanned sample of young adults (n=13) and found a similar pattern of association, which achieved trend level significance in the right putamen. Although unanticipated, the relationship observed between BP measures in the right putamen and Lie scores is consistent with dopaminergic involvement in socially rewarding behaviour. How this relates to dopaminergic tone will need to be further explored.

Age effects on diffusion tensor magnetic resonance imaging tractography measures of frontal cortex connections in schizophrenia.

Diffusion tensor magnetic resonance imaging (DT-MRI) has previously been used to investigate white matter tracts in schizophrenia, with inconsistent results. The aim of the study was to use a novel method for tract-specific measurements of fronto-temporal fasciculi in early-onset schizophrenia. We hypothesized that by making tract-specific measurements, clear diffusion abnormalities would be revealed in specific fasciculi in schizophrenia. Measurements of diffusion anisotropy and mean diffusivity were localized within fronto-temporal fasciculi by forming 3-D reconstructions of the cingulum, uncinate, superior longitudinal, and inferior fronto-occipital fasciculi using diffusion tensor tractography. We were limited in our ability to test our hypothesis by the important and surprising finding that age affected DT-MRI-based measures in schizophrenia patients in a different way from comparison subjects, most notably in the left superior longitudinal fasciculus. The youngest schizophrenia patients that we studied had lower diffusion anisotropy than age-matched comparison subjects, but this difference diminished with increasing age. The main conclusion of this study was that direct comparisons of absolute DT-MRI-based measures between individuals with schizophrenia and comparison subjects may be problematic and misleading because of underlying age-related differences in brain maturation between groups.

A diffusion tensor magnetic resonance imaging study of frontal cortex connections in very-late-onset schizophrenia-like psychosis.

OBJECTIVE: Onset of psychosis after the age of 60 may be associated with structural abnormalities within cerebral white matter. The authors looked within white-matter tracts, which mediate connectivity of the frontal lobes, in psychotic patients for evidence of loss of fiber integrity consistent with degenerative damage. METHODS: Fourteen patients with very-late-onset schizophrenia-like psychosis and an age-matched control group underwent diffusion tensor magnetic resonance imaging. Tract maps were constructed for each subject from the imaging data, and measurements of fractional anisotropy and mean diffusivity were made within the uncinate, superior longitudinal, and inferior occipito-frontal fasciculi, and the cingulum. RESULTS: There were no significant differences in fractional anisotropy, a measure of the ordering of axons within fiber tracts, nor in mean diffusivity, an orientationally-averaged measure of the bulk diffusivity within each voxel, between patients and control subjects. CONCLUSION: The lack of difference in fractional anisotropy and mean diffusivity measures between patients and controls argues against the presence of structural abnormalities within these tracts and the notion that a focal white-matter abnormality within the tracts investigated underpins the onset of psychosis.

A positron emission tomography (PET) investigation of the role of striatal dopamine (D2) receptor availability in spatial cognition.

The functional significance of age-related changes in regional brain dopamine (DA) function is poorly understood in health. Two recent studies have reported positive linear associations between measures of striatal DA (D2) receptor availability (binding potential) and specific aspects of motor and cognitive performance, after controlling for the effects of age [(Volkow, N.D., Gur, R.C., Wang, G.-J., Fowler, J.S., Moberg, P.J., Ding, Y.-S., Hitzemann, R., Smith, G., Logan, J., 1998. Association between decline in brain dopamine activity with age and cognitive and motor impairment in healthy individuals. Am. J. Psychiatry 155 (3), 344-349; Backman, L., Ginovart, N., Dixon, R.A., Wahlin, T.-B.R., Wahlin, A., Halldin, C., Farde, L., 2000. Age-related cognitive deficits mediated by changes in the striatal dopamine system. Am. J. Psychiatry 157 (4), 635-637)]. We investigated the relationship between measures of striatal DA (D2) receptor availability and visuo-spatial cognitive performance in thirty healthy post-menopausal women aged 58-90 years. [(11)C] Raclopride (RAC) positron emission tomography (PET) was used to assess dopamine (D2) receptor availability. The CANTAB neuropsychological test battery was used to assess spatial span, spatial working memory (SWM) and planning ability. Age showed significant linear correlations with several of the CANTAB performance measures. After controlling for age effects, DA (D2) receptor measures in left-sided striatal regions (caudate and putamen) were significantly and positively correlated with 'perfect solution' scores--the measure of performance accuracy--on the Tower of London (TOL) test of spatial planning. When this relationship was examined in relation to task difficulty, only perfect scores for the most 'difficult' (4-move) problems were significantly correlated with BP measures in all striatal regions, most notably the right and left caudate nuclei. Paradoxically, individuals with higher DA (D2) receptor measures in the right caudate performed less accurately on the SWM task, exhibiting a higher number of errors within each search sequence. The relative contribution of striatal DA (D2) receptor availability to specific aspects of cognitive performance needs to be evaluated in larger mixed-sex samples to facilitate the meaningful investigation of the potential therapeutic benefits of DA (D2) agonists in later life.