Neurocognitive Profiles of Older Adults with Working-Memory Dysfunction.

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.

Affinity States of Striatal Dopamine D2 Receptors in Antipsychotic-Free Patients with Schizophrenia.

Background: Dopamine D2 receptors are reported to have high-affinity (D2High) and low-affinity (D2Low) states. Although an increased proportion of D2High has been demonstrated in animal models of schizophrenia, few clinical studies have investigated this alteration of D2High in schizophrenia in vivo. Methods: Eleven patients with schizophrenia, including 10 antipsychotic-naive and 1 antipsychotic-free individuals, and 17 healthy controls were investigated. Psychopathology was assessed by Positive and Negative Syndrome Scale, and a 5-factor model was used. Two radioligands, [11C]raclopride and [11C]MNPA, were employed to quantify total dopamine D2 receptor and D2High, respectively, in the striatum by measuring their binding potentials. Binding potential values of [11C]raclopride and [11C]MNPA and the binding potential ratio of [11C]MNPA to [11C]raclopride in the striatal subregions were statistically compared between the 2 diagnostic groups using multivariate analysis of covariance controlling for age, gender, and smoking. Correlations between binding potential and Positive and Negative Syndrome Scale scores were also examined. Results: Multivariate analysis of covariance demonstrated a significant effect of diagnosis (schizophrenia and control) on the binding potential ratio (P=.018), although the effects of diagnosis on binding potential values obtained with either [11C]raclopride or [11C]MNPA were nonsignificant. Posthoc test showed that the binding potential ratio was significantly higher in the putamen of patients (P=.017). The Positive and Negative Syndrome Scale "depressed" factor in patients was positively correlated with binding potential values of both ligands in the caudate. Conclusions: The present study indicates the possibilities of: (1) a higher proportion of D2High in the putamen despite unaltered amounts of total dopamine D2 receptors; and (2) associations between depressive symptoms and amounts of caudate dopamine D2 receptors in patients with schizophrenia.

The Differential Binding of Antipsychotic Drugs to the ABC Transporter P-Glycoprotein Predicts Cannabinoid-Antipsychotic Drug Interactions.

Cannabis use increases rates of psychotic relapse and treatment failure in schizophrenia patients. Clinical studies suggest that cannabis use reduces the efficacy of antipsychotic drugs, but there has been no direct demonstration of this in a controlled study. The present study demonstrates that exposure to the principal phytocannabinoid, Δ9-tetrahydrocannabinol (THC), reverses the neurobehavioral effects of the antipsychotic drug risperidone in mice. THC exposure did not influence D2 and 5-HT2A receptor binding, the major targets of antipsychotic action, but it lowered the brain concentrations of risperidone and its active metabolite, 9-hydroxy risperidone. As risperidone and its active metabolite are excellent substrates of the ABC transporter P-glycoprotein (P-gp), we hypothesized that THC might increase P-gp expression at the blood-brain barrier (BBB) and thus enhance efflux of risperidone and its metabolite from brain tissue. We confirmed that the brain disposition of risperidone and 9-hydroxy risperidone is strongly influenced by P-gp, as P-gp knockout mice displayed greater brain concentrations of these drugs than wild-type mice. Furthermore, we demonstrated that THC exposure increased P-gp expression in various brain regions important to risperidone's antipsychotic action. We then showed that THC exposure did not influence the neurobehavioral effects of clozapine. Clozapine shares a very similar antipsychotic mode of action to risperidone, but unlike risperidone is not a P-gp substrate. Our results imply that clozapine or non-P-gp substrate antipsychotic drugs may be better first-line treatments for schizophrenia patients with a history of cannabis use.

Negative association of pretreatment cigarette use with smoking-induced striatal dopamine release in smokers receiving bupropion treatment.

BACKGROUND AND OBJECTIVES: In an effort to help identify factors that maintain heavy smoking, this study tested the association of pretreatment cigarette use (cigarettes per day) with striatal dopamine release during smoking-cessation treatment. METHODS: Thirteen regular smokers (≥10 cigarettes per day) were evaluated on parameters of smoking behavior, and they entered a smoking cessation treatment protocol, including bupropion administration and individual counseling for 2 months. On week 7 of treatment, 10 of the participants underwent brain scans using [(11) C]raclopride with positron emission tomography to assess smoking-induced dopamine release in the caudate nucleus and putamen, inferred from changes in dopamine D2 -type receptor availability. RESULTS: Receptor availability, measured as binding potential referred to non-displaceable uptake (BPND ) in both striatal regions re-demonstrated a significant decrease after smoking a cigarette; and pre-treatment cigarette use significantly negatively correlated with smoking-induced dopamine release in the caudate. CONCLUSIONS AND SIGNIFICANCE: The negative association of cigarette use with dopamine release suggests tolerance or down-regulation of the dopamine system by chronic smoking, or a pre-existing condition that promotes more frequent smoking. This association should be regarded as preliminary evidence that warrants verification. (Am J Addict 2016;25:486-492).

Relation of dopamine receptor 2 binding to pain perception in female fibromyalgia patients with and without depression--A [¹¹C] raclopride PET-study.

Dopamine D2/D3 receptor availability at rest and its association with individual pain perception was investigated using the [(11)C] raclopride PET-method in 24 female Fibromyalgia (FMS) participants with (FMS+, N=11) and without (FMS-, N=13) comorbid depression and in 17 healthy women. Thermal pain thresholds (TPT) and pain responses were assessed outside the scanner. We compared the discriminative capacity, i.e. the individual׳s capacity to discriminate between lower and higher pain intensities and the response criterion, i.e. the subject׳s tendency to report pain during noxious stimulation due to psychological factors. [(11)C] raclopride binding potential (BP), defined as the ratio of specifically bound non-displaceable radioligand at equilibrium (BP(ND)) was used as measure of D2/D3 receptor availability. We found significant group effects of BP(ND) in striatal regions (left ventral striatum, left caudate nucleus and left nucleus accumbens) between FMS+ and FMS- compared to healthy subjects. Correlational analysis showed negative associations between TPT and D2/D3 receptor availability in the left caudate nucleus in FMS-, between TPT and D2/D3 receptor availability in the right caudate nucleus in FMS + and positive associations between TPT and D2/D3 receptor availability in the left putamen and right caudate nucleus in healthy controls. The response criterion was positively associated with D2/D3 receptor availability in the right nucleus accumbens in FMS - and negatively with D2/D3 receptor availability in the left caudate nucleus in healthy controls. Finally, no significant associations between D2/D3 receptor availability and discriminative capacity in any of the groups or regions were determined. These findings provide further support for a disruption of dopaminergic neurotransmission in FMS and implicate DA as important neurochemical moderator of differences in pain perception in FMS patients with and without co-morbid depression.

Lesson From a Case of Cervical Meningioma Misdiagnosed as Parkinsonism.

INTRODUCTION: Lesion localization based on patient's manifestation is a fundamental step in making a neurological diagnosis. However, it has been reported that diagnosticians are vulnerable to the effects of various cognitive biases during diagnostic processes. CASE REPORT: A 69-year-old man with right-hand stiffness visited the Movement Disorder Clinic with the history of periodic limb movement syndrome and restless leg syndrome. His sensory and deep tendon reflex examination results were normal. Brain magnetic resonance imaging was normal. Corticobasal degeneration was considered as a possibility, but functional imaging studies including FP-CIT positron emission tomography were all normal. Later, cervical spine magnetic resonance imaging revealed a cervical meningioma at the C2-C3 levels and he showed tingling senses in his right ulnar 3 fingers and a hyperactive knee jerk on his right side, which were absent on the first examinations. CONCLUSIONS: Insufficient clinical information (declarative shortcoming) and inherent heuristic pitfalls (procedural shortcoming) were 2 major causes of the diagnostic error. Especially, in the present case, cognitive biases from framing effects and anchoring heuristics misled the clinical reasoning during the process of localization.

Single versus multiple impulse control disorders in Parkinson's disease: an ¹¹C-raclopride positron emission tomography study of reward cue-evoked striatal dopamine release.

Impulse control disorders (ICDs) are reported in Parkinson's disease (PD) in association with dopaminergic treatment. Approximately 25 % of patients with ICDs have multiple co-occurring ICDs (i.e. more than one diagnosed ICD). The extent to which dopaminergic neurotransmission in PD patients with multiple ICDs differs from those with only one diagnosed ICD is unknown. The aims of this study are: (1) to investigate dopamine neurotransmission in PD patients diagnosed with multiple ICDs, single ICDs and non-ICD controls in response to reward-related visual cues using positron emission tomography with (11)C-raclopride. (2) to compare clinical features of the above three groups. PD individuals with mulitple ICDs (n = 10), single ICD (n = 7) and no ICDs (n = 9) were recruited and underwent two positron emission tomography (PET) scans with (11)C-raclopride: one where they viewed neutral visual cues and the other where they viewed a range of visual cues related to different rewards. Individuals with both multiple ICDs and single ICDs showed significantly greater ventral striatal dopamine release compared to non-ICD PD individuals in response to reward cues, but the two ICD groups did not differ from each other in the extent of dopamine release. Subjects with multiple ICDs were, however, significantly more depressed, and had higher levels of impulsive sensation-seeking compared to subjects with single ICDs and without ICDs. This is the first study to compare dopamine neurotransmission using PET neuroimaging in PD subjects with multiple vs. single ICDs. Our results suggest that striatal dopamine neurotransmission is not directly related to the co-occurrence of ICDs in PD, potentially implicating non-dopaminergic mechanisms linked to depression; and suggest that physicians should be vigilant in managing depression in PD patients with ICDs.

Imaging nicotine- and amphetamine-induced dopamine release in rhesus monkeys with [(11)C]PHNO vs [(11)C]raclopride PET.

The radiotracer [(11)C]PHNO may have advantages over other dopamine (DA) D2/D3 receptor ligands because, as an agonist, it measures high-affinity, functionally active D2/D3 receptors, whereas the traditionally used radiotracer [(11)C]raclopride measures both high- and low-affinity receptors. Our aim was to take advantage of the strength of [(11)C]PHNO for measuring the small DA signal induced by nicotine, which has been difficult to measure in preclinical and clinical neuroimaging studies. Nicotine- and amphetamine-induced DA release in non-human primates was measured with [(11)C]PHNO and [(11)C]raclopride positron emission tomography (PET) imaging. Seven adult rhesus monkeys were imaged on a FOCUS 220 PET scanner after injection of a bolus of [(11)C]PHNO or [(11)C]raclopride in three conditions: baseline; preinjection of nicotine (0.1 mg/kg bolus+0.08 mg/kg infusion over 30 min); preinjection of amphetamine (0.4 mg/kg, 5 min before radiotracer injection). DA release was measured as change in binding potential (BPND). Nicotine significantly decreased BPND in the caudate (7 ± 8%), the nucleus accumbens (10 ± 7%), and in the globus pallidus (13 ± 15%) measured with [(11)C]PHNO, but did not significantly decrease BPND in the putamen or the substantia nigra or in any region when measured with [(11)C]raclopride. Amphetamine significantly reduced BPND in all regions with both radiotracers. In the striatum, larger amphetamine-induced changes were detected with [(11)C]PHNO compared with [(11)C]raclopride (52-64% vs 33-35%, respectively). We confirmed that [(11)C]PHNO is more sensitive than [(11)C]raclopride to nicotine- and amphetamine-induced DA release. [(11)C]PHNO PET may be more sensitive to measuring tobacco smoking-induced DA release in human tobacco smokers.

Creating dynamic images of short-lived dopamine fluctuations with lp-ntPET: dopamine movies of cigarette smoking.

We describe experimental and statistical steps for creating dopamine movies of the brain from dynamic PET data. The movies represent minute-to-minute fluctuations of dopamine induced by smoking a cigarette. The smoker is imaged during a natural smoking experience while other possible confounding effects (such as head motion, expectation, novelty, or aversion to smoking repeatedly) are minimized. We present the details of our unique analysis. Conventional methods for PET analysis estimate time-invariant kinetic model parameters which cannot capture short-term fluctuations in neurotransmitter release. Our analysis--yielding a dopamine movie--is based on our work with kinetic models and other decomposition techniques that allow for time-varying parameters. This aspect of the analysis--temporal-variation--is key to our work. Because our model is also linear in parameters, it is practical, computationally, to apply at the voxel level. The analysis technique is comprised of five main steps: pre-processing, modeling, statistical comparison, masking and visualization. Preprocessing is applied to the PET data with a unique 'HYPR' spatial filter that reduces spatial noise but preserves critical temporal information. Modeling identifies the time-varying function that best describes the dopamine effect on 11C-raclopride uptake. The statistical step compares the fit of our (lp-ntPET) model to a conventional model. Masking restricts treatment to those voxels best described by the new model. Visualization maps the dopamine function at each voxel to a color scale and produces a dopamine movie. Interim results and sample dopamine movies of cigarette smoking are presented.

Imaging of alcohol-induced dopamine release in rats:preliminary findings with [(11) C]raclopride PET.

Microdialysis studies report that systemic alcohol increases extracellular dopamine (DA) in the rat striatum. The present study examined whether changes in striatal DA 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 [(11) C]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 min after tracer injection for determination of blood alcohol concentration (BAC). Time activity curves were extracted from the striatum and the cerebellum and binding potential (BP(ND) ) was calculated as a measure of D(2) receptor availability. Wistars given 1.0 g kg(-1) alcohol (20%v/v) i.v. or 3.0 g kg(-1) alcohol (20%v/v) i.p. showed significant alcohol-induced decreases in BP(ND) . In P rats (given 1.5, 2.25, or 3.0 g kg(-1) alcohol), no individual group showed a statistical effect of alcohol on BP(ND) , but taken together, all P rats receiving i.p. alcohol had significantly lower BP(ND) than rest or saline scans. Large decreases in BP(ND) were primarily observed in rats with BAC above 200 mg%. Also, a significant difference was found between baseline BP(ND) of Wistars who had undergone jugular catheterization surgery for i.v. alcohol administration and those who had not. 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.

Smoking-induced change in intrasynaptic dopamine concentration: effect of treatment for Tobacco Dependence.

The aim of this study was to determine whether standard treatments for Tobacco Dependence affect smoking-induced changes in intrasynaptic dopamine (DA) concentration. Forty-three otherwise healthy adult cigarette smokers (10 to 40 cigarettes per day) were treated with either practical group counseling (PGC) psychotherapy (n=14), bupropion HCl (n=14), or matching pill placebo (n=15) (random assignment) for 8 weeks. Before and after treatment, each subject underwent a bolus-plus-continuous-infusion (11)C-raclopride positron emission tomography (PET) scanning session, during which he or she smoked a regular cigarette. The PET scanning outcome measure of interest was percent change in smoking-induced (11)C-raclopride binding potential (BP(ND)) in the ventral caudate/nucleus accumbens (VCD/NAc), as an indirect measure of DA release. Although the entire study sample had a smaller mean smoking-induced reduction in VCD/NAc BP(ND) after treatment (compared to before treatment), this change was highly correlated with smaller total cigarette puff volumes (and not other treatment variables). These data indicate that smoking-induced DA release is dose-dependent, and is not significantly affected by reductions in daily smoking levels or treatment type.

Quinolinic acid induced neurodegeneration in the striatum: a combined in vivo and in vitro analysis of receptor changes and microglia activation.

PURPOSE: Huntington's disease (HD) is a progressive neurodegenerative disorder, which is characterised by prominent neuronal cell loss in the basal ganglia with motor and cognitive disturbances. One of the most well-studied pharmacological models of HD is produced by local injection in the rat brain striatum of the excitotoxin quinolinic acid (QA), which produces many of the distinctive features of this human neurodegenerative disorder. Here, we report a detailed analysis, obtained both in vivo and in vitro of this pharmacological model of HD. MATERIALS AND METHODS: By combining emission tomography (PET) with autoradiographic and immunocytochemical confocal laser techniques, we quantified in the QA-injected striatum the temporal behavior (from 1 to 60 days from the excitotoxic insult) of neuronal cell density and receptor availability (adenosine A(2A) and dopamine D(2) receptors) together with the degree of microglia activation. RESULTS: Both approaches showed a loss of adenosine A(2A) and dopamine D(2) receptors paralleled by an increase of microglial activation. CONCLUSION: This combined longitudinal analysis of the disease progression, which suggested an impairment of neurotransmission, neuronal integrity and a reversible activation of brain inflammatory processes, might represent a more quantitative approach to compare the differential effects of treatments in slowing down or reversing HD in rodent models with potential applications to human patients.

Increased binding potential of [(11)C]raclopride during unilateral continuous microinjection of nicotine in rat striatum observed by positron emission tomography.

Nicotine injections and nicotine skin patches significantly improve attention, memory, and learning in Alzheimer's disease. In animal studies, nicotine improves the performance of various memory-related tasks, an effect that is thought to be mediated by the neuronal dopaminergic system as systemic administration of nicotine decreased [(11)C]raclopride binding in the anesthetized state. Since high doses of systemically administered nicotine are harmful, we administrated it directly into the rat striatum via microdialysis. We then examined the acute effects of continuous central administration of high doses of nicotine on striatal dopamine concentrations by measuring [(11)C]raclopride binding by positron emission tomography. The concentration of dopamine in the dialysates was significantly increased from basal levels when microdialysis with 100 mM nicotine was initiated. However, contrary to expectations, the binding potential (BP) of [(11)C]raclopride in the nicotine-perfused striatum was significantly higher than that in control striatum. Preinjection of mecamylamine (3 mg/kg), a nicotinic antagonist, had no effect on either extracellular dopamine levels or on the BP of [(11)C]raclopride. These findings suggest that the high dose of local nicotine administration induced mecamylamine-insensitive local increases in extracellular dopamine, but might have decreased the total amount of extracellular dopamine in the striatum.

Fibromyalgia patients show an abnormal dopamine response to pain.

Fibromyalgia is characterized by chronic widespread pain and bodily tenderness and is often accompanied by affective disturbances. Accumulating evidence indicates that fibromyalgia may involve a dysfunction of modulatory systems in the brain. While brain dopamine is best known for its role in pleasure, motivation and motor control, recent evidence suggests that it is also involved in pain modulation. Because dopamine is implicated in both pain modulation and affective processing, we hypothesized that fibromyalgia may involve a disturbance of dopaminergic neurotransmission. Fibromyalgia patients and matched healthy control subjects were subjected to deep muscle pain produced by injection of hypertonic saline into the anterior tibialis muscle. In order to determine the endogenous release of dopamine in response to painful stimulation, we used positron emission tomography to examine binding of [(11)C]-raclopride (D2/D3 ligand) in the brain during injection of painful hypertonic saline and nonpainful normal saline. Fibromyalgia patients experienced the hypertonic saline as more painful than healthy control subjects. Control subjects released dopamine in the basal ganglia during the painful stimulation, whereas fibromyalgia patients did not. In control subjects, the amount of dopamine release correlated with the amount of perceived pain but in fibromyalgia patients no such correlation was observed. These findings provide the first direct evidence that fibromyalgia patients have an abnormal dopamine response to pain. The disrupted dopaminergic reactivity in fibromyalgia patients could be a critical factor underlying the widespread pain and discomfort in fibromyalgia and suggests that the therapeutic effects of dopaminergic treatments for this intractable disorder should be explored.

Effects of intravenous glucose on dopaminergic function in the human brain in vivo.

Dopamine is known to regulate food intake by modulating food reward via the mesolimbic circuitry of the brain. The objective of this study was to compare the effects of high energy input (i.v. glucose) on striatal and thalamic dopamine release in overweight and lean individuals. We hypothesized that glucose would induce dopamine release and positive ratings (e.g., satiety) in Behavioral Analog Scales, particularly in food-deprived lean subjects. [(11)C]raclopride PET was performed for 12 lean (mean BMI = 22 kg/m(2)) and 12 overweight (mean BMI = 33 kg/m(2)) healthy subjects. Each subject was imaged twice in a blinded counter-balanced setting, after 300 mg/kg i.v. glucose and after i.v. placebo. Dopamine D2 receptor binding potentials (BPs) were estimated. The voxel-based analysis of the baseline scans indicated lower striatal BPs in the overweight group and a negative correlation between BMIs and BPs. Intravenous glucose did not have a significant effect on BPs in overweight or lean subjects (male and female groups combined). However, BP changes were opposite in the two gender groups. In male subjects, significant BP reductions after glucose were seen in the right and left caudate nucleus, left putamen, and right thalamus. In female subjects, increases in BP secondary to glucose were seen in the right caudate nucleus and right and left putamen. The sexually dimorphic effect of glucose was seen in both overweight and lean subjects. Although gender differences were not among the a priori hypotheses of the present study and, therefore, they must be considered to be preliminary findings, we postulate that this observation is a reflection of an interaction between glucose, sex steroids (estrogen), leptin, and dopamine.

Increase in A2A receptors in the nucleus accumbens after extended cocaine self-administration and its disappearance after cocaine withdrawal.

Effects of extended cocaine self-administration and its withdrawal have been studied on A(2A) and D(2) receptor binding characteristics and expression in the nucleus accumbens and the anterior and posterior dorsal striatum of the rat (Rattus norvegicus). Biochemical binding techniques have been used with the D(2)-like receptor antagonist radioligand [(3)H]-Raclopride and the A(2A) receptor antagonist radioligand [(3)H]-ZM 241385 and immunoblots to study their expression. A substantial and significant increase in functional A(2A), but not in functional D(2) receptors, was observed in the nucleus accumbens immediately following 10 days of cocaine self-administration which returned to normal levels after 7 days of drug withdrawal. In contrast, in the posterior dorsal striatum significant reductions in A(2A) expression were observed immediately after cocaine self-administration which was associated with a trend for a reduction of the A(2A) receptor antagonist binding sites. In cocaine withdrawal groups, significant increases in the density and K(d) value of D(2)-like antagonist binding sites were observed in the nucleus accumbens in the absence of changes in D(2) expression, suggesting an up-regulation of D(3) receptors in this region after cocaine withdrawal. A(2A) receptor increases in the nucleus accumbens induced by cocaine may represent a compensatory up-regulation to counteract cocaine-induced increases in D(2) signaling and D(3) signaling which is in line with its disappearance in the 7-day withdrawal group displaying increased reinforcing efficacy of cocaine. A(2A) agonists may therefore represent cocaine antagonist drugs to be used in treatment of cocaine addiction acting inter alia by antagonizing signaling in accumbens A(2A)/D(2) and A(2A)/D(3) heteromers.

Cocaine cues and dopamine in dorsal striatum: mechanism of craving in cocaine addiction.

The ability of drugs of abuse to increase dopamine in nucleus accumbens underlies their reinforcing effects. However, preclinical studies have shown that with repeated drug exposure neutral stimuli paired with the drug (conditioned stimuli) start to increase dopamine by themselves, which is an effect that could underlie drug-seeking behavior. Here we test whether dopamine increases occur to conditioned stimuli in human subjects addicted to cocaine and whether this is associated with drug craving. We tested eighteen cocaine-addicted subjects using positron emission tomography and [11C]raclopride (dopamine D2 receptor radioligand sensitive to competition with endogenous dopamine). We measured changes in dopamine by comparing the specific binding of [11C]raclopride when subjects watched a neutral video (nature scenes) versus when they watched a cocaine-cue video (scenes of subjects smoking cocaine). The specific binding of [11C]raclopride in dorsal (caudate and putamen) but not in ventral striatum (in which nucleus accumbens is located) was significantly reduced in the cocaine-cue condition and the magnitude of this reduction correlated with self-reports of craving. Moreover, subjects with the highest scores on measures of withdrawal symptoms and of addiction severity that have been shown to predict treatment outcomes, had the largest dopamine changes in dorsal striatum. This provides evidence that dopamine in the dorsal striatum (region implicated in habit learning and in action initiation) is involved with craving and is a fundamental component of addiction. Because craving is a key contributor to relapse, strategies aimed at inhibiting dopamine increases from conditioned responses are likely to be therapeutically beneficial in cocaine addiction.

Serial microPET measures of the metabolic reaction to a microdialysis probe implant.

Despite the widespread use of chronic brain implants in experimental and clinical settings, the effects of these long-term procedures on brain metabolism and receptor expression remain largely unknown. Under the hypothesis that intracerebral microdialysis transiently alters tissue metabolism, we performed a series of 18FDG microPET scans prior to and following surgical implantation of microdialysis cannulae. Parallel microPET measures using the competitive dopamine (DA) D2 receptor antagonist, 11C-raclopride, provided an assay of DA stability in these same animals. 18FDG scans were performed prior to microdialysis cannulation and again at 2, 12, 24, 48, 120, 168, 360 and 500 h (0.2, 0.5, 1, 2, 5, 7, 15 and 25 days). Separate animals received a sham surgery and the control group had no surgical intervention. For the first 24 h (scans at 2, 12 and 24 h post-surgery) uptake was reduced in both hemispheres. However, by 48 h, contralateral uptake had returned to pre-surgical levels. The striking finding was that from 48 to 500 h, the microdialysis cannulation produced widespread ipsilateral reductions in 18FDG uptake that encompassed the entire hemisphere. Despite the extent and persistence of these reductions, 11C-raclopride binding and ECF DA concentrations remained stable.

Biodistribution and radiation dosimetry of the dopamine D2 ligand 11C-raclopride determined from human whole-body PET.

UNLABELLED: Whole-body radiation dosimetry of 11C-raclopride was performed in healthy human volunteers. METHODS: Subjects (n = 6) were scanned with PET. Subjects received single-bolus injections of 11C-raclopride (S-(-)-3,5-dichloro-N-[(1-ethyl-2-pyrrolidinyl)]methyl-2-hydroxy-6-methoxybenzamide) (533 +/- 104 MBq) and were scanned for approximately 110 min with a 2-dimensional whole-body protocol. Regions of interest were placed over all visually identifiable organs and time-activity curves were generated. Residence times were computed as the area under the curve of the time-activity curves, normalized to injected activities and standard values of organ volumes. Absorbed doses were computed according to the MIRD schema with MIRDOSE3.1 software. RESULTS: Organs with the highest radiation burden were gallbladder wall, small intestine, liver, and urinary bladder wall. CONCLUSION: On the basis of the estimated absorbed dose, the maximum allowable single study dose under U.S. federal regulations for studies performed under Radiation Drug Research Committee is 1.58 GBq (42.8 mCi). This is still considerably higher than the doses of 11C-raclopride commonly used in research PET (370-555 MBq).