raclopride and Cognition-Disorders

Individuals differ in how they perceive, remember, and think. There is evidence for the existence of distinct subgroups that differ in cognitive performance within the older population. However, it is less clear how individual differences in cognition in old age are linked to differences in brain-based measures. We used latent-profile analysis on n-back working-memory (WM) performance to identify subgroups in a large sample of older adults (n = 181; age = 64-68 years). Our analysis identified one larger normal subgroup with higher performance (n = 113; 63%), and a second smaller subgroup (n = 55; 31%) with lower performance. The low-performing subgroup showed weaker load-dependent BOLD modulation and lower connectivity within the fronto-parietal network (FPN) as well as between FPN and striatum during n-back, along with lower FPN connectivity at rest. This group also exhibited lower FPN structural integrity, lower frontal dopamine D2 binding potential, inferior performance on offline WM tests, and a trend-level genetic predisposition for lower dopamine-system efficiency. By contrast, this group exhibited relatively intact episodic memory and associated brain measures (i.e., hippocampal volume, structural, and functional connectivity within the default-mode network). Collectively, these data provide converging evidence for the existence of a group of older adults with impaired WM functioning characterized by reduced cortico-striatal coupling and aberrant cortico-cortical integrity within FPN.

Topics: Aged; Aging; Blood Pressure; Brain; Cognition Disorders; Dopamine and cAMP-Regulated Phosphoprotein 32; Female; Humans; Image Processing, Computer-Assisted; Imaging, Three-Dimensional; Male; Memory Disorders; Memory, Short-Term; Mental Recall; Middle Aged; Mutation; Neuropsychological Tests; Oxygen; Raclopride; Receptors, Dopamine D2; Time Perception; Verbal Learning

Self-injurious behavior (SIB) is a common comorbidity of psychiatric disorders but there is a dearth of information about neurological mechanisms underlying the behavior, and few animal models exist. SIB in humans is characterized by any intentional self-directed behavior that leads to wounds, whereas in macaques it is not always accompanied by wounds. We describe a cohort of rhesus macaques displaying SIB as adults, in which changes within the central nervous system were associated with the SIB. In these macaques, increases in central nervous system striatal dopamine (DA) receptor binding (BPND) measured by positron emission tomography (PET) [11C]raclopride imaging correlated with severity of wounding (rs=0.662, P=0.014). Furthermore, utilizing standardized cognitive function tests, we showed that impulsivity (stop signal reaction time, SSRT) and deficits in attentional set shifting (intra-/extradimensional shift) were correlated with increased severity of SIB (rs=0.563, P=0.045 and rs=0.692, P=0.009, respectively). We also tested the efficacy of guanfacine, an α2A adrenergic agonist that acts to improve postsynaptic transmission of neuronal impulses, in reducing SIB. A subset of these animals were enrolled in a randomized experimenter-blinded study that demonstrated guanfacine decreased the severity of wounding in treated animals compared with vehicle-only-treated controls (P=0.043), with residual beneficial effects seen for several weeks after cessation of therapy. Animals with the highest severity of SIB that received guanfacine also showed the most significant improvement (rs=-0.761, P=0.009). The elevated PET BPND was likely due to low intrasynaptic DA, which in turn may have been improved by guanfacine. With underlying physiology potentially representative of the human condition and the ability to affect outcome measures of disease using pharmacotherapy, this model represents a unique opportunity to further our understanding of the biology and treatment of SIB in both animals and humans.

Topics: Adrenergic alpha-2 Receptor Agonists; Animals; Attention; Behavior, Animal; Carbon Radioisotopes; Cognition; Cognition Disorders; Disease Models, Animal; Dopamine Antagonists; Guanfacine; Impulsive Behavior; Macaca mulatta; Male; Neostriatum; Neuropsychological Tests; Positron-Emission Tomography; Raclopride; Random Allocation; Reaction Time; Receptors, Dopamine; Self-Injurious Behavior; Severity of Illness Index

A crucial role of corticostriatal dopaminergic networks in cognitive and motor processes has been well established but largely unexplored in Alzheimer's disease (AD). The study investigated the relationship between striatal DA (D(2)) receptor availability and specific aspects of cognitive (sustained visual attention, spatial planning, word recognition) and motor (speed and dexterity) function in 24 people with mild to moderate AD. In vivo dopamine DA (D(2)) receptor availability was determined with [(11)C] raclopride (RAC) positron emission tomography (PET). Imaging data were analysed using both region of interest (ROI) and voxel-based approaches. Higher [(11)C] RAC binding was associated with increased motor speed and, paradoxically, poorer attentional performance. These findings are broadly consistent with previously conducted studies in healthy older adults and would suggest that the use of DA (D(2)) receptor agonists as an adjunctive treatment strategy in AD may have dissociable effects upon cognitive function.

Topics: Alzheimer Disease; Attention; Binding, Competitive; Brain Chemistry; Brain Mapping; Cognition; Cognition Disorders; Corpus Striatum; Disability Evaluation; Dopamine; Dopamine Agonists; Dopamine Antagonists; Movement; Movement Disorders; Neuropsychological Tests; Positron-Emission Tomography; Raclopride; Receptors, Dopamine D2

Sleep deprivation interferes with cognitive performance but the mechanisms are poorly understood. We recently reported that one night of sleep deprivation increased dopamine in striatum (measured with [(11)C]raclopride, a PET radiotracer that competes with endogenous dopamine for binding to D2 receptors) and that these increases were associated with impaired performance in a visual attention task. To better understand this association here we evaluate the relationship between changes in striatal dopamine (measured as changes in D2 receptor availability using PET and [(11)C]raclopride) and changes in brain activation to a visual attention task (measured with BOLD and fMRI) when performed during sleep deprivation versus during rested wakefulness. We find that sleep induced changes in striatal dopamine were associated with changes in cortical brain regions modulated by dopamine (attenuated deactivation of anterior cingulate gyrus and insula) but also in regions that are not recognized targets of dopaminergic modulation (attenuated activation of inferior occipital cortex and cerebellum). Moreover, the increases in striatal dopamine as well as its associated regional activation and deactivation patterns correlated negatively with performance accuracy. These findings therefore suggest that hyperstimulation of D2 receptors in striatum may contribute to the impairment in visual attention during sleep deprivation. Thus, while dopamine increases in prefrontal regions (including stimulation of D1 receptors) may facilitate attention our findings suggest that hyperstimulation of D2 receptors in striatum may impair it. Alternatively, these associations may reflect a compensatory striatal dopamine response (to maintain arousal) that is superimposed on a larger response to sleep deprivation.

Topics: Adult; Cognition Disorders; Corpus Striatum; Humans; Male; Positron-Emission Tomography; Raclopride; Radiopharmaceuticals; Receptors, Dopamine D2; Sleep Deprivation

Sleep deprivation did not affect dopamine transporters (target for most wake-promoting medications) and thus dopamine increases are likely to reflect increases in dopamine cell firing and/or release rather than decreases in dopamine reuptake. Because dopamine-enhancing drugs increase wakefulness, we postulate that dopamine increases after sleep deprivation is a mechanism by which the brain maintains arousal as the drive to sleep increases but one that is insufficient to counteract behavioral and cognitive impairment. Sleep deprivation can markedly impair human performance contributing to accidents and poor productivity. The mechanisms underlying this impairment are not well understood, but brain dopamine systems have been implicated. Here, we test whether one night of sleep deprivation changes dopamine brain activity. We studied 15 healthy subjects using positron emission tomography and [11C]raclopride (dopamine D2/D3 receptor radioligand) and [11C]cocaine (dopamine transporter radioligand). Subjects were tested twice: after one night of rested sleep and after one night of sleep deprivation. The specific binding of [11C]raclopride in the striatum and thalamus were significantly reduced after sleep deprivation and the magnitude of this reduction correlated with increases in fatigue (tiredness and sleepiness) and with deterioration in cognitive performance (visual attention and working memory). In contrast, sleep deprivation did not affect the specific binding of [11C]cocaine in the striatum. Because [11C]raclopride competes with endogenous dopamine for binding to D2/D3 receptors, we interpret the decreases in binding to reflect dopamine increases with sleep deprivation. However, we cannot rule out the possibility that decreased [11C]raclopride binding reflects decreases in receptor levels or affinity. Sleep deprivation did not affect dopamine transporters (target for most wake-promoting medications) and thus dopamine increases are likely to reflect increases in dopamine cell firing and/or release rather than decreases in dopamine reuptake. Because dopamine-enhancing drugs increase wakefulness, we postulate that dopamine increases after sleep deprivation is a mechanism by which the brain maintains arousal as the drive to sleep increases but one that is insufficient to counteract behavioral and cognitive impairment.

Topics: Adult; Arousal; Brain; Cocaine; Cognition Disorders; Corpus Striatum; Dopamine; Dopamine Antagonists; Dopamine Uptake Inhibitors; Fatigue; Humans; Male; Positron-Emission Tomography; Raclopride; Receptors, Dopamine D2; Receptors, Dopamine D3; Sleep Deprivation; Thalamus

Idiopathic Parkinson's disease (PD) is often accompanied by a pattern of executive deficits similar to those found in patients with frontal lobe lesions. We investigated whether such cognitive deficits are attributable to frontal lobe dysfunction as a direct consequence of impaired mesocortical dopaminergic transmission or an indirect consequence of impaired nigrostriatal dopaminergic function. For this purpose, changes in synaptic dopamine levels during task performance were monitored using a marker of dopamine D2-receptor availability (11)C-raclopride (RAC) PET. During RAC PET, seven patients with early symptomatic PD and seven age-matched healthy controls performed two types of behavioural task, a spatial working memory task (SWT) and a visuomotor control task (VMT). The SWT involves an executive process which is known to be impaired by both frontal lobe lesions and PD while the VMT is a control test for the visuomotor component of the SWT. Parametric images of RAC binding potential during performance of each task were generated, and compared between the tasks using voxel-based statistical parametric mapping as well as region of interest analysis. In controls, RAC binding was reduced in the dorsal caudate during performance of the SWT compared with the VMT, compatible with increased levels of endogenous dopamine release due to the executive process. In PD patients, this RAC binding reduction was not observed. In contrast, RAC binding in the anterior cingulate cortex within the medial prefrontal cortex was reduced by a comparable level during the SWT both in controls and PD patients. Statistical comparisons between controls and PD patients confirmed significantly attenuated dopamine release in the dorsal caudate in PD, but preserved levels of medial prefrontal dopamine release. Our data suggest that executive deficits in early patients with PD are associated with impaired nigrostriatal dopaminergic function resulting in abnormal processing in the cortico-basal ganglia circuit. In contrast, mesocortical dopaminergic transmission appears well preserved in early PD patients.

Topics: Adult; Cognition Disorders; Corpus Striatum; Dopamine; Dopamine Antagonists; Female; Frontal Lobe; Humans; Image Interpretation, Computer-Assisted; Male; Middle Aged; Neuropsychological Tests; Parkinson Disease; Positron-Emission Tomography; Raclopride; Receptors, Dopamine D2

Schizophrenia has a heritability of about 80%, but the detailed molecular genetic basis of the disorder has remained elusive. Relative hyperfunction of the subcortical dopamine system has been previously suggested to be one of the key pathophysiologic mechanisms in schizophrenic psychosis.. To examine the contributions of genetic vulnerability for schizophrenia to the dopamine system in the human brain.. Population-based twin cohort study.. Finland.. Six monozygotic and 5 dizygotic unaffected co-twins of patients with schizophrenia were ascertained, along with 4 monozygotic and 3 dizygotic healthy control twins with no family history of psychotic disorders.. Striatal dopamine D(2) receptor availability estimated with positron emission tomographic imaging and carbon 11 ((11)C)-labeled raclopride, and performance on neuropsychological tests sensitive to frontal lobe functioning and to schizophrenia vulnerability.. Unaffected monozygotic co-twins had increased caudate D(2) density compared with unaffected dizygotic co-twins and healthy control twins. Higher D(2) receptor binding in caudate was associated with a poor performance on cognitive tasks related to schizophrenia vulnerability in the whole sample.. The caudate dopamine D(2) receptor up-regulation is related to genetic risk for schizophrenia. Higher dopamine D(2) receptor density in caudate is also associated with poorer performance on cognitive tasks involving corticostriatal pathways. This finding suggests that caudate dopamine dysregulation is also a trait phenomenon related to psychosis vulnerability. This pattern of results provides a theoretical rationale for early pharmacologic intervention approaches using dopamine D(2) receptor blocking drugs.

Topics: Carbon Radioisotopes; Caudate Nucleus; Cognition Disorders; Cohort Studies; Diseases in Twins; Dopamine; Female; Finland; Genetic Markers; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Raclopride; Receptors, Dopamine D2; Schizophrenia; Twins, Dizygotic; Twins, Monozygotic

The alpha(2) adrenoceptor antagonist idazoxan enhances antipsychotic efficacy of classical dopamine D(2) antagonists in treatment-resistant schizophrenia. The mechanisms are not fully understood, but we have previously shown that the combination of idazoxan with the D(2/3) receptor antagonist raclopride, similarly to clozapine but not classical antipsychotic drugs, augments dopamine efflux in the prefrontal cortex, and also generates an enhanced suppression of the conditioned avoidance response. We have now investigated the effects of clozapine, raclopride, idazoxan and the combination of raclopride and idazoxan on (i) electrically evoked excitatory post-synaptic potentials and currents in pyramidal cells of the rat medial prefrontal cortex, using intracellular electrophysiological recording in vitro, (ii) the impaired cognitive function induced by the selective N-methyl-D-aspartate (NMDA) receptor antagonist MK-801, using the 8-arm radial maze test, (iii) the in-vivo D2, alpha(2A) and alpha(2C) receptor occupancies of these pharmacological treatments, using ex-vivo autoradiography. Whereas neither idazoxan nor raclopride alone had any effect, the combination exerted the same facilitation of glutamatergic transmission in rat prefrontal pyramidal neurons as clozapine, and this effect was found to be mediated by dopamine acting at D(1) receptors. Similarly to clozapine, the combination of idazoxan and raclopride also completely reversed the working-memory impairment in rats induced by MK-801. Moreover, these effects of the two treatment regimes were obtained at similar occupancies at D(2), alpha(2A) and alpha(2C) receptors respectively. Our results provide novel neurobiological and behavioural support for a pro-cognitive effect of adjunctive use of idazoxan with antipsychotic drugs that lack appreciable alpha(2) adrenoceptor-blocking properties, and define presynaptic alpha(2) adrenoceptors as major targets in antipsychotic drug development.

Topics: Adrenergic alpha-Antagonists; Animals; Behavior, Animal; Cerebral Cortex; Clozapine; Cognition Disorders; Disease Models, Animal; Dizocilpine Maleate; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Drug Interactions; Electric Stimulation; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Glutamic Acid; Idazoxan; In Vitro Techniques; Male; Maze Learning; Raclopride; Radioligand Assay; Rats; Rats, Sprague-Dawley; Rats, Wistar; Synaptic Transmission

Although it is documented that brain dopamine activity declines with age, the functional significance of this is not known. This study assessed the relation between measures of brain dopamine activity and indexes of motor and cognitive function in healthy individuals.. Thirty healthy volunteers aged 24-86 years were studied with positron emission tomography and [11C]raclopride to assess dopamine D2 receptors. All subjects underwent a neuropsychological test battery that included tasks found to be sensitive to dopamine alterations in patients with neurodegenerative disease and control tasks.. Transfer of [11C]raclopride from plasma to brain in the striatum and cerebellum was not affected by age. In contrast, D2 receptor availability in the caudate and putamen declined with age. Correlations between D2 receptors and neuropsychological test performance were strongest for the motor task (Finger Tapping Test) and were also significant for most tasks involving frontal brain regions, including measures of abstraction and mental flexibility (Wisconsin Card Sorting Test) and attention and response inhibition (Stroop Color-Word Test, interference score). These relationships remained significant after control for age effects.. Age-related decreases in brain dopamine activity are associated with a decline in motor function and may also contribute to impaired performance on tasks that involve frontal brain regions. Interventions that enhance dopamine activity may improve performance and quality of life for the elderly. The fact that correlations remained significant after age effects were partialed out suggests that dopamine activity may influence motor and cognitive performance irrespective of age.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Aging; Brain; Brain Chemistry; Cerebellum; Cognition Disorders; Corpus Striatum; Dopamine; Geriatric Assessment; Humans; Middle Aged; Motor Skills; Motor Skills Disorders; Neuropsychological Tests; Quality of Life; Raclopride; Receptors, Dopamine D2; Salicylamides; Tomography, Emission-Computed

The main aim of this study was to investigate the relationship between dopaminergic markers and brain volumes for striatal and cortical structures, and cognitive performance in patients with Huntington's disease and control subjects. We used PET and MRI data as predictors of performance in tasks assessing executive function, visuospatial ability, episodic memory, verbal fluency, perceptual speed and reasoning. The dopamine neurotransmission parameters (D1 and D2 receptor density and dopamine transporter density) and the volumetric measurements for caudate and putamen accounted for substantial portions of the variance across the majority of cognitive tasks. In addition, frontal volume showed a strong relationship with all cognitive tasks. D1 binding and volume measurements for the temporal cortex and thalamic volume showed associations with a select number of cognitive tasks. The overall data pattern is consistent with the view that Huntington's disease may be characterized as a frontostriatal dementia, in which cognitive deficits may result from pathological changes at multiple sites in the frontostriatal circuitry.

Topics: Benzazepines; Biomarkers; Brain; Carbon Radioisotopes; Carrier Proteins; Cocaine; Cognition Disorders; Dopamine; Dopamine Plasma Membrane Transport Proteins; Female; Humans; Huntington Disease; Magnetic Resonance Imaging; Male; Membrane Glycoproteins; Membrane Transport Proteins; Memory; Middle Aged; Nerve Tissue Proteins; Organ Specificity; Perception; Predictive Value of Tests; Raclopride; Radiography; Receptors, Dopamine D1; Receptors, Dopamine D2; Reference Values; Salicylamides; Speech; Thinking; Tomography, Emission-Computed