There is clear evidence that the prefrontal cortex is strongly involved in executive processes and that dopamine can influence performance on working memory tasks. Although, some studies have emphasized the role of striatal dopamine in executive functions, the role played by prefrontal dopamine during executive tasks is unknown. In order to investigate cortical dopamine transmission during executive function, we used D2-dopamine receptor ligand [11C]FLB 457 PET in healthy subjects while performing the Montreal Card Sorting Task (MCST). During the retrieval with shift task of the MCST, the subjects had to match each test card to one of the reference cards based on a classification rule (color, shape or number) determined by comparing the previously viewed cue card and the current test card. A reduction in [11C]FLB 457 binding potential in the right dorsal anterior cingulate cortex (ACC) was observed when subjects performed the active task compared to the control task. These findings may suggest that right dorsal ACC dopamine neurotransmission increases significantly during the performance of certain executive processes, e.g., conflict monitoring, in keeping with previous evidence from fMRI studies showing ACC activation during similar tasks. These results may provide some insights on the origin of cognitive deficits underlying certain neurological disorders associated with dopamine dysfunction, such as Parkinson’s disease and schizophrenia.
PMID: 19264140 CAMSID: cams1532
FLB 457; Positron emission tomography; Executive function; Anterior cingulate cortex; Dopamine; Conflict monitoring
The prefrontostriatal network is considered to play a key role in executive functions. Previous neuroimaging studies have shown that executive processes tested with card-sorting tasks requiring planning and set-shifting [e.g. Montreal-card-sorting-task (MCST)] may engage the dorsolateral prefrontal cortex (DLPFC) while inducing dopamine release in the striatum. However, functional imaging studies can only provide neuronal correlates of cognitive performance and cannot establish a causal relation between observed brain activity and task performance. In order to investigate the contribution of the DLPFC during set-shifting and its effect on the striatal dopaminergic system, we applied continuous theta burst stimulation (cTBS) to left and right DLPFC. Our aim was to transiently disrupt its function and to measure MCST performance and striatal dopamine release during [11C]raclopride PET. A significant hemispheric asymmetry was observed. cTBS of the left DLPFC impaired MCST performance and dopamine release in the ipsilateral caudate–anterior putamen and contralateral caudate nucleus, as compared to cTBS of the vertex (control). These effects appeared to be limited only to left DLPFC stimulation while right DLPFC stimulation did not influence task performance or [11C]raclopride binding potential in the striatum. This is the first study showing that cTBS, by disrupting left prefrontal function, may indirectly affect striatal dopamine neurotransmission during performance of executive tasks. This cTBS-induced regional prefrontal effect and modulation of the frontostriatal network may be important for understanding the contribution of hemisphere laterality and its neural bases with regard to executive functions, as well as for revealing the neurochemical substrate underlying cognitive deficits.
PMID: 19046396 CAMSID: cams1540
basal ganglia; executive function; positron emission tomography; transcranial magnetic stimulation
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 [11C] 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 [11C]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.
Dopamine D2 receptors; Raclopride; Visual attention; PET; fMRI; Default network; Thalamus
Dopaminergic medication for motor symptoms in Parkinson’s disease (PD) recently has been linked with impulse control disorders, including pathological gambling (PG), which affects up to 8% of patients. PG often is considered a behavioral addiction associated with disinhibition, risky decision-making, and altered striatal dopaminergic neurotransmission. Using [11C]raclopride with positron emission tomography, we assessed dopaminergic neurotransmission during Iowa Gambling Task performance. Here we present data from a single patient with PD and concomitant PG. We noted a marked decrease in [11C]raclopride binding in the left ventral striatum upon gambling, indicating a gambling-induced dopamine release. The results imply that PG in PD is associated with a high dose of dopaminergic medication, pronounced motor symptomatology, young age at disease onset, high propensity for sensation seeking, and risky decision-making. Overall, the findings are consistent with the hypothesis of medication-related PG in PD and underscore the importance of taking clinical variables, such as age and personality, into account when patients with PD are medicated, to reduce the risk of PG.
Parkinson’s disease; pathological gambling; impulse control disorders; decision-making; dopamine
Sequential learning is an important aspect of cognitive processing. Neuropharmacological evidence acquired in laboratory animals suggests that striatal dopaminergic mechanisms may be important for processing of this form of learning. However, because experiments conducted on dopamine deficient patients have reported contradictory evidence, the role of dopamine and the striatum remains unclear in human sequential learning. We used a newly developed dynamic molecular imaging technique to determine whether striatal dopamine is released during performance of a sequential learning task. In this study we localized striatal regions where dopamine receptor ligand (11C-raclopride) was displaced from receptor sites, during performance of a motor sequence learning (serial reaction time) task. The results suggest that the task induces release of endogenous dopamine in the posterior two-third of dorsomedial aspect of left putamen and the anterior part of the body of caudate bilaterally. The activations of the left putamen and the right caudate coincided with the activations observed earlier during performance of a motor planning task. Since these activations are associated with the selection and execution of a response, the activation in the left caudate, which was not observed in motor planning, is probably associated with the detection of a change in the ‘context’, and in the formulation of a new ‘rule’. Thus, the results suggest that sequential learning involves two striatal dopaminergic mechanisms, one for the detection of a change in context, and the other for selection and execution of the response.
Inhibition of unwanted response is an important function of the executive system. Since the inhibitory system is impaired in patients with dysregulated dopamine system, we examined dopamine neurotransmission in the human brain during processing of a task of executive inhibition. The experiment used a recently developed dynamic molecular imaging technique to detect and map dopamine released during performance of a modified Eriksen's flanker task. In this study, young healthy volunteers received an intravenous injection of a dopamine receptor ligand (11C-raclopride) after they were positioned in the PET camera. After the injection, volunteers performed the flanker task under Congruent and Incongruent conditions in a single scan session. They were required to inhibit competing options to select an appropriate response in the Incongruent but not in the Congruent condition. The PET data were dynamically acquired during the experiment and analyzed using two variants of the simplified reference region model. The analysis included estimation of a number of receptor kinetic parameters before and after initiation of the Incongruent condition. We found increase in the rate of ligand displacement (from receptor sites) and decrease in the ligand binding potential in the Incongruent condition, suggesting dopamine release during task performance. These changes were observed in small areas of the putamen and caudate bilaterally but were most significant on the dorsal aspect of the body of left caudate. The results provide evidence of dopaminergic processing of executive inhibition and demonstrate that neurochemical changes associated with cognitive processing can be detected and mapped in a single scan session using dynamic molecular imaging.
Electrophysiological studies showed that mesostriatal dopamine (DA) neurons increase activity in response to unpredicted rewards. With respect to other functions of the mesostriatal dopaminergic system, dopamine’s actions show prominent laterality effects. Whether changes in DA transmission elicited by rewards also are lateralized, however, has not been investigated. Using [11C]raclopride-PET to assess the striatal DA response to unpredictable monetary rewards, we hypothesized that such rewards would induce an asymmetric reduction of [11C]raclopride binding in the ventral striatum, reflecting lateralization of endogenous dopamine release. In 24 healthy volunteers, differences in the regional D2/3 receptor binding potential (ΔBP) between an unpredictable reward condition and a sensorimotor control condition were measured using the bolus-plus-constant-infusion [11C]raclopride method. During the reward condition subjects randomly received monetary awards while performing a “slot-machine” task. The ΔBP between conditions was assessed in striatal regions-of-interest and compared between left and right sides. We found a significant condition × lateralization interaction in the ventral striatum. A significant reduction in binding potential (BPND) in the reward condition versus the control condition was found only in the right ventral striatum, and the ΔBP was greater in the right than the left ventral striatum. Unexpectedly, these laterality effects appeared to be partly accounted for by sex differences, as our data showed a significant bilateral BPND reduction in women, while in men the reduction reached significance only in the right ventral striatum. These data suggest that DA release in response to unpredictable reward is lateralized in the human ventral striatum, particularly in males.
positron emission tomography; dopamine; hemispheric; motivation
We used a Positron Emission Tomography (PET) paradigm with the D2/3 radiotracer [11C]raclopride and an alcohol challenge to examine the magnitude of alcohol induced dopamine release and compare it between young men and women.
Twenty-one non-alcohol dependent young social drinkers completed two PET scans on separate days following ingestion of a juice mix containing either ethanol (0.75 mg/kg body water) or trace ethanol only.
The extent of dopamine released after alcohol was estimated by the percent difference in [11C]raclopride binding potential (ΔBPND) between days.
Alcohol administration significantly displaced [11C]raclopride in all striatal subregions indicating dopamine release, with the largest effect observed in the ventral striatum. Linear mixed model analysis across all striatal subregions of regional ΔBPND with region of interest as repeated measure showed a highly significant effect of sex (p < 0.001). Ventrostriatal dopamine release in men, but not in women, showed a significant positive correlation to alcohol-induced measures of subjective activation. Furthermore, we found a significant negative correlation between the frequency of maximum alcohol consumption per 24 hours and ventrostriatal ΔBPND (r=0.739, p=0.009) in men.
This study provides definitive evidence that oral alcohol induces dopamine release in non-alcoholic human subjects, and shows sex differences in the magnitude of this effect. The ability of alcohol to stimulate dopamine release may contribute to its rewarding effects and, thereby, to its abuse liability in humans. Our report further suggests several biological mechanisms that may mediate the difference in vulnerability for alcoholism between men and women.
Despite evidence that dopamine neurotransmission in the striatum is critical for learning as well as for movement control, little is yet known about how the learning-related dynamics of striatal activity are affected by dopamine depletion, a condition faced in Parkinson’s disease. We made localized intrastriatal 6-hydroxydopamine lesions in rats and recorded within the dopamine-depleted sensorimotor striatal zone and its contralateral correspondent as the animals learned a conditional maze task. Rather than producing global, non-specific elevations in firing rate across the task, the dopamine depletion altered striatal projection neuron activity and fast-spiking interneuron activity selectively, with sharply task-specific and cell-type specific effects, and often, with learning-stage selective effects as well. Striatal projection neurons with strong responses during the maze runs had especially elevated responsiveness during the maze runs. Projection neurons that, instead, fired most strongly prior to maze running showed elevated pre-start firing rates, but not during maze running, as learning progressed. The intrastriatal dopamine depletion severely affected the learning-related patterning of fast-spiking interneuron ensembles, especially during maze running and after extended training. Remarkably, L-DOPA treatment almost entirely reversed the depletion-induced elevations in pre-run firing of the projection neurons, and elevated their responses around start and end of maze runs. By contrast, L-DOPA failed to normalize fast-spiking interneuron activity. Thus the effects of striatal dopamine depletion and restoration on striatal activity are highly dependent not only on cell type, as previously shown, but also on the behavioral activity called for and the state of behavioral learning achieved.
Normal aging is associated with a decrease in dopaminergic function and a reduced ability to form new motor memories with training. This study examined the link between both phenomena. We hypothesized that levodopa would (a) ameliorate aging-dependent deficits in motor memory formation, and (b) increase dopamine availability at the dopamine type 2-like (D2) receptor during training in task-relevant brain structures. The effects of training plus levodopa (100mg, plus 25 mg carbidopa) on motor memory formation and striatal dopamine availability were measured with [11C] raclopride (RAC) positron emission tomography (PET). We found that levodopa did not alter RAC-binding potential at rest but it enhanced training effects on motor memory formation as well as dopamine release in the dorsal caudate nucleus. Motor memory formation during training correlated with the increase of dopamine release in the caudate nucleus. These results demonstrate that levodopa may ameliorate dopamine deficiencies in the elderly by replenishing dopaminergic presynaptic stores, actively engaged in phasic dopamine release during motor training.
aging; motor; memory formation; positron emission tomography; neuropharmacology; neurotransmitter; neurorehabilitation
Positron Emission tomography (PET) imaging studies have shown that addiction to a number of substances of abuse is associated with a decrease in dopamine D2/3 receptor binding and decreased pre-synaptic dopamine release in the striatum. Some studies have also shown that these reductions are associated with the severity of addiction. For example, in cocaine dependence, low dopamine release is associated with the choice to self-administer cocaine. The goal of the present study was to investigate these parameters of striatal dopamine transmission in heroin dependence and their association with drug seeking behavior.
Heroin dependent and healthy control subjects were scanned with [11C]raclopride before and after stimulant administration (methylphenidate) to measure striatal D2/3 receptor binding and pre-synaptic dopamine release. Following the PET scans, the heroin dependent subjects performed heroin self-administration sessions.
Both striatal D2/3 receptor binding and dopamine release were reduced in the heroin dependent subjects compared to healthy controls. However, neither PET measure of dopamine transmission predicted the choice to self-administer heroin.
These findings show that heroin addiction, like addiction to other drugs of abuse, is associated with low D2/3 receptor binding and low pre-synaptic dopamine. However, neither of these outcome measures were associated with the choice to self-administer heroin.
PET imaging; dopamine; dopamine receptors; addiction; heroin dependence; drug self-administration
Since the role of dopamine in human emotional processing is unclear, we used a dynamic molecular imaging technique to examine whether striatal dopamine is released during processing of negative emotions in healthy volunteers. After volunteers have received an intravenous injection of a dopamine receptor ligand 11C-raclopride, they were asked to perform a task that elicited negative emotions. During task performance the ligand concentration was measured dynamically using a positron emission tomography camera. Analysis of the data indicated that the task performance is associated with dopamine release in the head of caudate and in the dorsal putamen bilaterally.
emotion; dopamine; striatum; caudate; putamen; raclopride; molecular imaging; PET; negative emotion
Parkinson's disease (PD) disrupts temporal processing, but the neuronal sources of deficits and their response to dopamine (DA) therapy are not understood. Though the striatum and DA transmission are thought to be essential for timekeeping, potential working memory (WM) and executive problems could also disrupt timing.
The present study addressed these issues by testing controls and PD volunteers ‘on’ and ‘off’ DA therapy as they underwent fMRI while performing a time-perception task. To distinguish systems associated with abnormalities in temporal and non-temporal processes, we separated brain activity during encoding and decision-making phases of a trial. Whereas both phases involved timekeeping, the encoding and decision phases emphasized WM and executive processes, respectively. The methods enabled exploration of both the amplitude and temporal dynamics of neural activity. First, we found that time-perception deficits were associated with striatal, cortical, and cerebellar dysfunction. Unlike studies of timed movement, our results could not be attributed to traditional roles of the striatum and cerebellum in movement. Second, for the first time we identified temporal and non-temporal sources of impaired time perception. Striatal dysfunction was found during both phases consistent with its role in timekeeping. Activation was also abnormal in a WM network (middle-frontal and parietal cortex, lateral cerebellum) during encoding and a network that modulates executive and memory functions (parahippocampus, posterior cingulate) during decision making. Third, hypoactivation typified neuronal dysfunction in PD, but was sometimes characterized by abnormal temporal dynamics (e.g., lagged, prolonged) that were not due to longer response times. Finally, DA therapy did not alleviate timing deficits.
Our findings indicate that impaired timing in PD arises from nigrostriatal and mesocortical dysfunction in systems that mediate temporal and non-temporal control-processes. However, time perception impairments were not improved by DA treatment, likely due to inadequate restoration of neuronal activity and perhaps corticostriatal effective-connectivity.
Knowledge of the reproducibility of striatal [11C]raclopride (RAC) binding is important for studies that use RAC PET paradigms to estimate changes in striatal dopamine during pharmacological and cognitive challenges. To our knowledge, no baseline test-retest data exist for nontreatment-seeking alcoholics (NTS). We determined the test-retest reproducibility of baseline RAC binding potential (BPND) in twelve male NTS subjects. Subjects were scanned twice with single-bolus RAC PET on separate days. Striatal RAC binding potential (BPND) for left and right dorsal caudate, dorsal putamen, and ventral striatum was estimated using the Multilinear Reference Tissue Method (MRTM) and Logan Graphical Analysis with a reference region (LGA). Test-retest variability (TRV), % change in BPND between scan days, and the intraclass correlation coefficient (ICC) were used as metrics of reproducibility. For MRTM, TRV for striatal RAC binding in NTS subjects was ± 6.5%, and ± 7.1% for LGA. Average striatal ICCs were 0.94 for both methods (p < 0.0001). Striatal BPND values were similar to those reported previously for detoxified alcoholics. The results demonstrate that baseline striatal RAC binding is highly reproducible in NTS subjects, with a low variance similar to that reported for healthy control subjects.
D2 receptor; positron emission tomography; dopamine; nicotine; craving; striatum
Previous research has shown that dopamine signaling in the limbic striatum is crucial for selecting adaptive, motivated behavior, and that disrupted dopamine transmission is associated with impulsive and maladaptive behavior. In humans, Positron Emission Tomography (PET) imaging studies have shown that cocaine dependence is associated with the dysregulation of striatal dopamine signaling, which is associated with cocaine seeking behavior. The goal of the present study was to investigate whether this association applies to the treatment setting. Our hypothesis was that dopamine signaling in the limbic striatum would be associated with response to a behavioral treatment that uses positive reinforcement to replace impulsive cocaine use with constructive personal goals. Prior to treatment, cocaine dependent subjects underwent two PET scans using [11C]raclopride, before and after the administration of a stimulant (methylphenidate), to measure striatal D2/3 receptor binding and pre-synaptic dopamine release. The results showed that both of these outcome measures were reduced in the volunteers who failed to respond to treatment compared to those who experienced a positive treatment response. These findings provide insight into the neurochemistry of treatment response and show that low dopamine transmission is associated with treatment failure. In addition, these data suggest that the combination of behavioral treatment with methods that increase striatal dopamine signaling might serve as a therapeutic strategy for cocaine dependence.
Microdialysis studies report that systemic alcohol increases extracellular dopamine in the rat striatum. The present study examined whether changes in striatal dopamine could be detected in rats using small animal positron emission tomography (PET). PET images were acquired in 44 alcohol-naïve male Wistar and alcohol-preferring (P) rats. Subjects received up to three [11C]raclopride scans (rest, alcohol, and saline). Animals were anesthetized with isoflurane and secured on a stereotactic-like holder during all scans. Blood samples were collected from the tail or lateral saphenous vein of 12 animals 10 minutes after tracer injection for determination of blood alcohol concentration (BAC). Time activity curves were extracted from the striatum and the cerebellum and binding potential (BPND) was calculated as a measure of D2 receptor availability. Wistars given 1.0g/kg alcohol (20%v/v) I.V. or 3.0g/kg alcohol (20%v/v) I.P showed significant alcohol-induced decreases in BPND. In P rats (given 1.5, 2.25, or 3.0 g/kg alcohol), no individual group showed a statistical effect of alcohol on BPND, but taken together, all P rats receiving I.P. alcohol had significantly lower BPND than rest or saline scans. Large decreases in BPND were primarily observed in rats with BAC above 200 mg%. Also, a significant difference was found between baseline BPND of Wistars who had undergone jugular catheterization surgery for I.V. alcohol administration and those who had not. These preliminary results suggest that alcohol-induced DA release in the rat striatum is detectable using small animal PET given sufficiently large cohorts and adequate blood alcohol levels.
binding potential; P rats; Wistars; striatum; BAC; stress; surgery
Cognitive deficits are very common in Parkinson's disease particularly for ‘executive functions’ associated with frontal cortico-striatal networks. Previous work has identified deficits in tasks that require attentional control like task-switching, and reward-based tasks like gambling or reversal learning. However, there is a complex relationship between the specific cognitive problems faced by an individual patient, their stage of disease and dopaminergic treatment. We used a bimodality continuous performance task during fMRI to examine how patients with Parkinson's disease represent the prospect of reward and switch between competing task rules accordingly. The task-switch was not separately cued but was based on the implicit reward relevance of spatial and verbal dimensions of successive compound stimuli. Nineteen patients were studied in relative ‘on’ and ‘off’ states, induced by dopaminergic medication withdrawal (Hoehn and Yahr stages 1–4). Patients were able to successfully complete the task and establish a bias to one or other dimension in order to gain reward. However the lateral prefrontal cortex and caudate nucleus showed a non-linear U-shape relationship between motor disease severity and regional brain activation. Dopaminergic treatment led to a shift in this U-shape function, supporting the hypothesis of differential neurodegeneration in separate motor and cognitive cortico–striato–thalamo–cortical circuits. In addition, anterior cingulate activation associated with reward expectation declined with more severe disease, whereas activation following actual rewards increased with more severe disease. This may facilitate a change in goal-directed behaviours from deferred predicted rewards to immediate actual rewards, particularly when on dopaminergic treatment. We discuss the implications for investigation and optimal treatment of this common condition at different stages of disease.
Parkinson's disease; reward; task-shift; fMRI; dopamine
Attention system abnormalities represent a significant barrier to scholastic achievement in children with neurofibromatosis-1 (NF1). Using a novel mouse model of NF1-associated attention deficit (ADD), we demonstrate a presynaptic defect in striatal dopaminergic homeostasis and leverage this finding to apply [11C]-raclopride positron-emission tomography (PET) in the intact animal. While methylphenidate and L-Deprenyl correct both striatal dopamine levels on PET imaging and defective attention system function in Nf1 mutant mice, pharmacologic agents that target de-regulated cyclic AMP and RAS signaling in these mice do not. These studies establish a robust preclinical model to evaluate promising agents for NF1-associated ADD.
dopamine; behavior; neurofibromin; cyclic AMP; RAS
Dopamine D2 receptors are involved with wakefulness but their role in the decreased alertness associated with sleep deprivation is unclear. We had shown that sleep deprivation reduced dopamine D2/D3 receptor availability (measured with PET and [11C]raclopride in controls) in striatum, but could not determine if this reflected dopamine increases ([11C]raclopride competes with dopamine for D2/D3 receptor binding) or receptor downregulation. To clarify this, we compared the dopamine increases induced by methylphenidate (drug that increases dopamine by blocking dopamine transporters), during sleep deprivation versus rested-sleep with the assumption that methylphenidate’s effects would be greater, if indeed, dopamine release was increased during sleep deprivation. We scanned 20 controls with [11C]raclopride after rested-sleep and after one night of sleep deprivation; both after placebo and after methylphenidate. We corroborated a decrease in D2/D3 receptor availability in the ventral striatum with sleep deprivation (compared to rested-sleep) that was associated with reduced alertness and increased sleepiness. However, the dopamine increases induced by methylphenidate (measured as decreases in D2/D3 receptor availability compared to placebo) did not differ between rested-sleep and sleep deprivation and were associated with the increased alertness and reduced sleepiness when methylphenidate was administered after sleep deprivation. Similar findings were obtained by microdialysis in rodents subjected to one night of paradoxical sleep deprivation. These findings are consistent with a downregulation of D2/D3 receptors in ventral striatum with sleep deprivation that may contribute to the associated decreased wakefulness and also corroborate an enhancement of D2 receptor signaling in the arousing effects of methylphenidate in humans.
receptor internalization; striatum; stimulants; wakefulness; brain imaging
The acquisition of new motor skills is essential throughout daily life and involves the processes of learning new motor sequence and encoding elementary aspects of new movement. Although previous animal studies have suggested a functional importance for striatal dopamine release in the learning of new motor sequence, its role in encoding elementary aspects of new movement has not yet been investigated. To elucidate this, we investigated changes in striatal dopamine levels during initial skill-training (Day 1) compared with acquired conditions (Day 2) using 11C-raclopride positron-emission tomography. Ten volunteers learned to perform brisk contractions using their non-dominant left thumbs with the aid of visual feedback. On Day 1, the mean acceleration of each session was improved through repeated training sessions until performance neared asymptotic levels, while improved motor performance was retained from the beginning on Day 2. The 11C-raclopride binding potential (BP) in the right putamen was reduced during initial skill-training compared with under acquired conditions. Moreover, voxel-wise analysis revealed that 11C-raclopride BP was particularly reduced in the right antero-dorsal to the lateral part of the putamen. Based on findings from previous fMRI studies that show a gradual shift of activation within the striatum during the initial processing of motor learning, striatal dopamine may play a role in the dynamic cortico-striatal activation during encoding of new motor memory in skill acquisition.
Cools (2006) suggested that prefrontal dopamine levels are related to cognitive stability whereas striatal dopamine levels are related to cognitive plasticity. With such a wide ranging role, almost all cognitive activities should be affected by dopamine levels in the brain. Not surprisingly, factors influencing brain dopamine levels have been shown to improve/worsen performance in many behavioral experiments. On the one hand, Nadler and her colleagues (2010) showed that positive affect (which is thought to increase cortical dopamine levels) improves a type of categorization that depends on explicit reasoning (rule-based) but not a type that depends on procedural learning (information-integration). On the other hand, Parkinson’s disease (which is known to decrease dopamine levels in both the striatum and cortex) produces proactive interference in the odd-man-out task (Flowers & Robertson, 1985) and renders subjects insensitive to negative feedback during reversal learning (Cools et al., 2006). This article uses the COVIS model of categorization to simulate the effects of different dopamine levels in categorization, reversal learning, and the odd-man-out task. The results show a good match between the simulated and human data, which suggests that the role of dopamine in COVIS can account for several cognitive enhancements and deficits related to dopamine levels in healthy and patient populations.
Dopamine; COVIS; Parkinson’s disease; positive affect; computational modeling
The most extensively described pathological abnormality in Parkinson's disease (PD) is loss of dopaminergic neurons in the substantia nigra pars compacta and the ventral tegmental area, with degeneration of their striatal terminals. Because of the intimate connections between the striatum and the frontal lobes, individuals with PD often demonstrate impairments on those tasks relying on the prefrontal cortex (e.g., tests of executive functioning). Source memory, or memory for context, is believed to rely on the prefrontal cortex and has been previously associated with executive functioning performance, although it has received little attention in the PD literature. Executive functioning and source memory were measured in a group of nondemented PD patients and healthy control participants. Within the PD group, an anti-Parkinson's medication withdrawal manipulation was used to examine whether source memory was affected by phasic changes in dopamine levels. Compared to healthy control participants, PD patients were impaired in source memory (both on- and off-medication) and on a composite measure of executive functioning. Within the PD group, medication administration improved motor performance but did not have a significant effect on source memory.
Dopamine; Cognition; Frontal lobe; Neuropsychology; Medication; Executive functioning
In the field of small animal positron emission tomography (PET), the assumptions underlying human and primate kinetic models may not be sustained in rodents. That is, the threshold dose at which a pharmacologic response occurs may be lower in small animals. In order to define this relationship, we combined microPET imaging using 11C-raclopride with microdialysis measures of extracellular fluid (ECF) dopamine (DA). In addition, we performed a series of studies in which a known mass of raclopride was microinfused into one striatum prior to a high specific activity (SA) systemic injection of 11C-raclopride. This single-injection approach provided a high and low SA region of radiotracer binding in the same animal during the same scanning session. Our data demonstrate that the binding potential (BP) declines above 3.5 pmol/ml (0.35 μg), with an ED50 of 8.55 ± 5.62 pmol/ml. These data also provide evidence that BP may be compromised by masses of raclopride below 2.0 pmol/ml (0.326 μg). Increases in ECF DA were produced by mass doses of raclopride over 3.9 pmol/ml (0.329 μg) with an ED50 of 8.53 ± 2.48 pmol/ml. Taken together, it appears that an optimal range of raclopride mass exists between 2.0 and 3.5 pmol/ml, around which the measured BP can be compromised by system sensitivity, endogenous DA, or excessive competition with unlabeled compound.
MicroPET; Rodent; 11C-raclopride; D2 receptors; Microdialysis; Mass effect
The default mode network (DMN) comprises a set of brain regions with “increased” activity during rest relative to cognitive processing. Activity in the DMN is associated with functional connections with the striatum and dopamine (DA) levels in this brain region. A functional single-nucleotide polymorphism within the dopamine D2 receptor gene (DRD2, rs1076560 G > T) shifts splicing of the 2 D2 isoforms, D2 short and D2 long, and has been associated with striatal DA signaling as well as with cognitive processing. However, the effects of this polymorphism on DMN have not been explored. The aim of this study was to evaluate the effects of rs1076560 on DMN and striatal connectivity and on their relationship with striatal DA signaling. Twenty-eight subjects genotyped for rs1076560 underwent functional magnetic resonance imaging during a working memory task and 123 55 I-Fluoropropyl-2-beta-carbomethoxy-3-beta(4-iodophenyl) nortropan Single Photon Emission Computed Tomography ([123I]-FP-CIT SPECT) imaging (a measure of dopamine transporter [DAT] binding). Spatial group-independent component (IC) analysis was used to identify DMN and striatal ICs. Within the anterior DMN IC, GG subjects had relatively greater connectivity in medial prefrontal cortex (MPFC), which was directly correlated with striatal DAT binding. Within the posterior DMN IC, GG subjects had reduced connectivity in posterior cingulate relative to T carriers. Additionally, rs1076560 genotype predicted connectivity differences within a striatal network, and these changes were correlated with connectivity in MPFC and posterior cingulate within the DMN. These results suggest that genetically determined D2 receptor signaling is associated with DMN connectivity and that these changes are correlated with striatal function and presynaptic DA signaling.
DRD2; dopamine; default mode network; functional magnetic resonance imaging; single-photon emission computerized tomography
We have developed a feedback-controlled bolus plus infusion (FC-B/I) method for monitoring the interaction between positron emission tomography (PET) ligands and their specific target molecules with PET. The usefulness of the FC-B/I method was evaluated by the direct interaction between [11C]raclopride, a dopamine D2 receptor (D2R) ligand, and cold raclopride (10 and 100 μg/kg) in the brains of conscious monkeys. The present results demonstrated that the FC-B/I method could achieve the equilibrium state of [11C]raclopride in the striatum of monkey brain, and also that the cold raclopride-induced reduction of [11C]raclopride binding to D2R was observed in a dose-dependent manner. Good correlations of distribution volume ratio of the striatum to cerebellum between the conventional bolus plus infusion (B/I) method and the FC-B/I method as well as between the conventional bolus injection method and the FC-B/I method were observed. These results indicated that the system could be a useful tool for the evaluation of interaction between drug candidates and their target molecules like enzymes, receptors, and transporters by using of their specific PET ligands.
bolus plus infusion; dopamine D2 receptor; feedback control; PET; [11C]raclopride