Nigrostriatal and Mesolimbic D2/3 Receptor Expression in Parkinson's Disease Patients with Compulsive Reward-Driven Behaviors.

The nigrostriatal and mesocorticolimbic dopamine networks regulate reward-driven behavior. Regional alterations to mesolimbic dopamine D2/3 receptor expression are described in drug-seeking and addiction disorders. Parkinson's disease (PD) patients are frequently prescribed D2-like dopamine agonist (DAgonist) therapy for motor symptoms, yet a proportion develop clinically significant behavioral addictions characterized by impulsive and compulsive behaviors (ICBs). Until now, changes in D2/3 receptor binding in both striatal and extrastriatal regions have not been concurrently quantified in this population. We identified 35 human PD patients (both male and female) receiving DAgonist therapy, with (n = 17) and without (n = 18) ICBs, matched for age, disease duration, disease severity, and dose of dopamine therapy. In the off-dopamine state, all completed PET imaging with [18F]fallypride, a high affinity D2-like receptor ligand that can measure striatal and extrastriatal D2/3 nondisplaceable binding potential (BPND). Striatal differences between ICB+/ICB- patients localized to the ventral striatum and putamen, where ICB+ subjects had reduced BPND In this group, self-reported severity of ICB symptoms positively correlated with midbrain D2/3 receptor BPND Group differences in regional D2/3 BPND relationships were also notable: ICB+ (but not ICB-) patients expressed positive correlations between midbrain and caudate, putamen, globus pallidus, and amygdala BPNDs. These findings support the hypothesis that compulsive behaviors in PD are associated with reduced ventral and dorsal striatal D2/3 expression, similar to changes in comparable behavioral disorders. The data also suggest that relatively preserved ventral midbrain dopaminergic projections throughout nigrostriatal and mesolimbic networks are characteristic of ICB+ patients, and may account for differential DAgonist therapeutic response.SIGNIFICANCE STATEMENT The biologic determinants of compulsive reward-based behaviors have broad clinical relevance, from addiction to neurodegenerative disorders. Here, we address biomolecular distinctions in Parkinson's disease patients with impulsive compulsive behaviors (ICBs). This is the first study to image a large cohort of ICB+ patients using positron emission tomography with [18F]fallypride, allowing quantification of D2/3 receptors throughout the mesocorticolimbic network. We demonstrate widespread differences in dopaminergic networks, including (1) D2-like receptor distinctions in the ventral striatum and putamen, and (2) a preservation of widespread dopaminergic projections emerging from the midbrain, which is associated with the severity of compulsive behaviors. This clearly illustrates the roles of D2/3 receptors and medication effects in maladaptive behaviors, and localizes them specifically to nigrostriatal and extrastriatal regions.

Mesocorticolimbic hemodynamic response in Parkinson's disease patients with compulsive behaviors.

BACKGROUND: PD patients treated with dopamine therapy can develop maladaptive impulsive and compulsive behaviors, manifesting as repetitive participation in reward-driven activities. This behavioral phenotype implicates aberrant mesocorticolimbic network function, a concept supported by past literature. However, no study has investigated the acute hemodynamic response to dopamine agonists in this subpopulation. OBJECTIVES: We tested the hypothesis that dopamine agonists differentially alter mesocortical and mesolimbic network activity in patients with impulsive-compulsive behaviors. METHODS: Dopamine agonist effects on neuronal metabolism were quantified using arterial-spin-labeling MRI measures of cerebral blood flow in the on-dopamine agonist and off-dopamine states. The within-subject design included 34 PD patients, 17 with active impulsive compulsive behavior symptoms, matched for age, sex, disease duration, and PD severity. RESULTS: Patients with impulsive-compulsive behaviors have a significant increase in ventral striatal cerebral blood flow in response to dopamine agonists. Across all patients, ventral striatal cerebral blood flow on-dopamine agonist is significantly correlated with impulsive-compulsive behavior severity (Questionnaire for Impulsive Compulsive Disorders in Parkinson's Disease- Rating Scale). Voxel-wise analysis of dopamine agonist-induced cerebral blood flow revealed group differences in mesocortical (ventromedial prefrontal cortex; insular cortex), mesolimbic (ventral striatum), and midbrain (SN; periaqueductal gray) regions. CONCLUSIONS: These results indicate that dopamine agonist therapy can augment mesocorticolimbic and striato-nigro-striatal network activity in patients susceptible to impulsive-compulsive behaviors. Our findings reinforce a wider literature linking studies of maladaptive behaviors to mesocorticolimbic networks and extend our understanding of biological mechanisms of impulsive compulsive behaviors in PD. © 2017 International Parkinson and Movement Disorder Society.

Dopaminergic mechanisms of individual differences in human effort-based decision-making.

Preferences for different combinations of costs and benefits are a key source of variability in economic decision-making. However, the neurochemical basis of individual differences in these preferences is poorly understood. Studies in both animals and humans have demonstrated that direct manipulation of the neurotransmitter dopamine (DA) significantly impacts cost/benefit decision-making, but less is known about how naturally occurring variation in DA systems may relate to individual differences in economic behavior. In the present study, 25 healthy volunteers completed a dual-scan PET imaging protocol with [(18)F]fallypride and d-amphetamine to measure DA responsivity and separately completed the effort expenditure for rewards task, a behavioral measure of cost/benefit decision-making in humans. We found that individual differences in DA function in the left striatum and ventromedial prefrontal cortex were correlated with a willingness to expend greater effort for larger rewards, particularly when probability of reward receipt was low. Additionally, variability in DA responses in the bilateral insula was negatively correlated with willingness to expend effort for rewards, consistent with evidence implicating this region in the processing of response costs. These findings highlight the role of DA signaling in striatal, prefrontal, and insular regions as key neurochemical mechanisms underlying individual differences in cost/benefit decision-making.

Impact of isoflurane anesthesia on D2 receptor occupancy by [18F]fallypride measured by microPET with a modified Logan plot.

UNLABELLED: In the previous work, we reported a method that utilized imaging data collected from 60 to 120 min following [(18) F]fallypride administration to estimate the distribution volume ratio DVR' (DVR' ∝ DVR; DVR = 1 + BP(ND) , where BP(ND) is a measure of receptor density, DA D2 in this case). In this work, we use this method to assess the effects of isoflurane anesthesia on [(18) F]fallypride DVR'. METHODS: Rats were injected with [(18) F]fallypride either unconsciously under ∼1.5% isoflurane via the tail vein (Group 1) or consciously via a catheter inserted either in the jugular vein (Group 2) or the tail vein (Group 3). After about 1 h of free access to food and water the rats were anesthetized with 1.5% isoflurane and imaged in a microPET for 60 min. The rats that were injected consciously (Groups 2 and 3) were placed in a rat restrainer during [(18) F]fallypride injection. They were habituated in that restrainer for 3 days prior to the experiment day to minimize restraint-related stress. For comparison, a control group of rats was imaged for 120 min simultaneously with the administration of [(18) F]fallypride i.v. while under 1.5% isoflurane. The DVR' estimates from the 60 min acquisitions were compared with the DVR' from the last 60 min of the 120 min acquisitions (after neglecting the first 60 min). In addition, the striatal time-activity curves were fit with a 2-tissue + plasma compartment model using an arbitrary simulated plasma input function to obtain k(3) /k(4) (≈ BP(ND) ) for the 60 and 120 min acquisitions. RESULTS: Isoflurane anesthesia caused a significant reduction, up to 22%, in the DVR' estimates, which were 15.7 ± 0.3 (mean ± SE) for the controls, 17.7 ± 0.3 for Group 1, 19.2 ± 0.4 for Group 2, and 18.8 ± 0.7 for Group 3. The compartmental model fit produced similar results, ∼30% reduction in k(3) /k(4) for the 120-min acquisitions compared with the 60-min acquisitions (initial conscious uptake of the radiotracer). CONCLUSION: The results of this study demonstrate that isoflurane anesthesia significantly decreases striatal [(18) F]fallypride BP(ND) in rats. Of similar importance, this work demonstrates the effectiveness of delayed scans following radiotracer injection and the implication that different types of studies can be conducted simultaneously with this method, including studies of behavioral and environmental impact on brain receptors.

Time series fMRI measures detect changes in pontine raphé following acute tryptophan depletion.

Serotonin is synthesized from its precursor, tryptophan, by brainstem raphé neurons and their synaptic terminals in limbic regions. The omission of tryptophan from an Acute Tryptophan Depletion (ATD) diet transiently diminishes serotonin synthesis, alters raphé activity, and mimics symptoms of depression. Raphé functional magnetic resonance imaging (fMRI) poses challenges using signal-averaging analyses. Time-series properties of fMRI blood oxygenation level dependent (BOLD) signals may hold promise, so we analyzed raphé signals for changes with the ATD diet. Eleven remitted (previously depressed) patients were awake with eyes-closed during seven-minute resting scans with 0.5s(-1) sampling. BOLD signal time-series data were frequency-filtered using wavelet transforms, yielding three octave-width frequency bands from 0.25 to 0.03s(-1) and an unbounded band below 0.03s(-1). Spectral power, reflecting signal information, increased in pontine raphé at high frequencies (0.25 to 0.125s(-1)) during ATD (compared to control, balanced, diet, P<0.004) but was unchanged at other frequencies. Functional connectivity, the correlation between time-series data from pairs of regions, weakened between pontine raphé and anterior thalamus at low frequencies during ATD (P<0.05). This preliminarily supports using fMRI time-series features to assess pontine raphé function. Whether, and how, high frequency activity oscillations interfere with low frequency signaling requires further study.

The interrelationship of dopamine D2-like receptor availability in striatal and extrastriatal brain regions in healthy humans: a principal component analysis of [18F]fallypride binding.

Individual differences in dopamine D2-like receptor availability arise across all brain regions expressing D2-like receptors. However, the interrelationships in receptor availability across brain regions are poorly understood. To address this issue, we examined the relationship between D2-like binding potential (BPND) across striatal and extrastriatal regions in a sample of healthy participants. PET imaging was performed with the high affinity D2/D3 ligand [18F]fallypride in 45 participants. BPND images were submitted to voxel-wise principal component analysis to determine the pattern of associations across brain regions. Individual differences in D2-like BPND were explained by three distinguishable components. A single component explained almost all of the variance within the striatum, indicating that individual differences in receptor availability vary in a homogenous manner across the caudate, putamen, and ventral striatum. Cortical BPND was only modestly related to striatal BPND and mostly loaded on a distinct component. After controlling for the general level of cortical D2-like BPND, an inverse relationship emerged between receptor availability in the striatum and the ventral temporal and ventromedial frontal cortices, suggesting possible cross-regulation of D2-like receptors in these regions. The analysis additionally revealed evidence of: (1) a distinct component involving the midbrain and limbic areas; (2) a dissociation between BPND in the medial and lateral temporal regions; and (3) a dissociation between BPND in the medial/midline and lateral thalamus. In summary, individual differences in D2-like receptor availability reflect several distinct patterns. This conclusion has significant implications for neuropsychiatric models that posit global or regionally specific relationships between dopaminergic tone and behavior.

Midbrain dopamine receptor availability is inversely associated with novelty-seeking traits in humans.

Novelty-seeking personality traits are a major risk factor for the development of drug abuse and other unsafe behaviors. Rodent models of temperament indicate that high novelty responding is associated with decreased inhibitory autoreceptor control of midbrain dopamine neurons. It has been speculated that individual differences in dopamine functioning also underlie the personality trait of novelty seeking in humans. However, differences in the dopamine system of rodents and humans, as well as the methods for assessing novelty responding/seeking across species leave unclear to what extent the animal models inform our understanding of human personality. In the present study we examined the correlation between novelty-seeking traits in humans and D(2)-like (D(2)/D(3)) receptor availability in the substantia nigra/ventral tegmental area. Based on the rodent literature we predicted that novelty seeking would be characterized by lowered levels of D(2)-like (auto)receptor availability in the midbrain. Thirty-four healthy adults (18 men, 16 women) completed the Tridimensional Personality Questionnaire-Novelty-Seeking Scale and PET scanning with the D(2)/D(3) ligand [(18)F]fallypride. Novelty-Seeking personality traits were inversely associated with D(2)-like receptor availability in the ventral midbrain, an effect that remained significant after controlling for age. We speculate that the lower midbrain (auto)receptor availability seen in high novelty seekers leads to accentuated dopaminergic responses to novelty and other conditions that induce dopamine release.

Novel selective allosteric activator of the M1 muscarinic acetylcholine receptor regulates amyloid processing and produces antipsychotic-like activity in rats.

Recent studies suggest that subtype-selective activators of M(1)/M(4) muscarinic acetylcholine receptors (mAChRs) may offer a novel approach for the treatment of psychotic symptoms associated with schizophrenia and Alzheimer's disease. Previously developed muscarinic agonists have provided clinical data in support of this hypothesis, but failed in clinical development because of a lack of true subtype specificity and adverse effects associated with activation of other mAChR subtypes. We now report characterization of a novel highly selective agonist for the M(1) receptor with no agonist activity at any of the other mAChR subtypes, termed TBPB [1-(1'-2-methylbenzyl)-1,4'-bipiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one]. Mutagenesis and molecular pharmacology studies revealed that TBPB activates M(1) through an allosteric site rather than the orthosteric acetylcholine binding site, which is likely critical for its unprecedented selectivity. Whole-cell patch-clamp recordings demonstrated that activation of M(1) by TBPB potentiates NMDA receptor currents in hippocampal pyramidal cells but does not alter excitatory or inhibitory synaptic transmission, responses thought to be mediated by M(2) and M(4). TBPB was efficacious in models predictive of antipsychotic-like activity in rats at doses that did not produce catalepsy or peripheral adverse effects of other mAChR agonists. Finally, TBPB had effects on the processing of the amyloid precursor protein toward the non-amyloidogenic pathway and decreased Abeta production in vitro. Together, these data suggest that selective activation of M(1) may provide a novel approach for the treatment of symptoms associated with schizophrenia and Alzheimer's disease.

Cerebral morphology and dopamine D2/D3 receptor distribution in humans: a combined [18F]fallypride and voxel-based morphometry study.

The relationship between cerebral morphology and the expression of dopamine receptors has not been extensively studied in humans. Elucidation of such relationships may have important methodological implications for clinical studies of dopamine receptor ligand binding differences between control and patient groups. The association between cerebral morphology and dopamine receptor distribution was examined in 45 healthy subjects who completed T1-weighted structural MRI and PET scanning with the D(2)/D(3) ligand [(18)F]fallypride. Optimized voxel-based morphometry was used to create grey matter volume and density images. Grey matter volume and density images were correlated with binding potential (BP(ND)) images on a voxel-by-voxel basis using the Biological Parametric Mapping toolbox. Associations between cerebral morphology and BP(ND) were also examined for selected regions-of-interest (ROIs) after spatial normalization. Voxel-wise analyses indicated that grey matter volume and density positively correlated with BP(ND) throughout the midbrain, including the substantia nigra. Positive correlations were observed in medial cortical areas, including anterior cingulate and medial prefrontal cortex, and circumscribed regions of the temporal, frontal, and parietal lobes. ROI analyses revealed significant positive correlations between BP(ND) and cerebral morphology in the caudate, thalamus, and amygdala. Few negative correlations between morphology and BP(ND) were observed. Overall, grey matter density appeared more strongly correlated with BP(ND) than grey matter volume. Cerebral morphology, particularly grey matter density, correlates with [(18)F]fallypride BP(ND) in a regionally specific manner. Clinical studies comparing dopamine receptor availability between clinical and control groups may benefit by accounting for potential differences in cerebral morphology that exist even after spatial normalization.

Brief communication: ß-cell function influences dopamine receptor availability.

We aim to identify physiologic regulators of dopamine (DA) signaling in obesity but previously did not find a compelling relationship with insulin sensitivity measured by oral-minimal model (OMM) and DA subtype 2 and 3 receptor (D2/3R) binding potential (BPND). Reduced disposition index (DI), a ß-cell function metric that can also be calculated by OMM, was shown to predict a negative reward behavior that occurs in states of lower endogenous DA. We hypothesized that reduced DI would occur with higher D2/3R BPND, reflecting lower endogenous DA. Participants completed PET scanning, with a displaceable radioligand to measure D2/3R BPND, and a 5-hour oral glucose tolerance test to measure DI by OMM. We studied 26 age-similar females without (n = 8) and with obesity (n = 18) (22 vs 39 kg/m2). Reduced DI predicted increased striatal D2/3R BPND independent of BMI. By accounting for ß-cell function, we were able to determine that the state of insulin and glucose metabolism is pertinent to striatal D2/3R BPND in obesity. Clinical Trial Registration Number: NCT00802204.

Lack of consistent sex differences in D-amphetamine-induced dopamine release measured with [18F]fallypride PET.

RATIONALE: Sex differences in the dopaminergic response to psychostimulants could have implications for drug abuse risk and other psychopathology involving the dopamine system, but human data are limited and mixed. OBJECTIVES: Here, we sought to investigate sex differences in dopamine release after oral D-amphetamine administration. METHODS: We used [18F]fallypride positron emission tomography (PET) to measure the change in dopamine D2/3 receptor availability (%ΔBPND, an index of dopamine release) between placebo and D-amphetamine sessions in two independent datasets containing a total of 39 females (on either hormonal birth control n = 18, postmenopausal n = 10, or studied in the first 10 days of their menstrual cycle n = 11) and 37 males. RESULTS: Using both a priori anatomical regions of interest based on previous findings and voxelwise analyses, we failed to consistently detect broad sex differences in D-amphetamine-induced dopamine release. Nevertheless, there was limited evidence for greater right ventral striatal dopamine release in young adult males relative to similarly aged females, but this was not consistently observed across samples. Plasma estradiol did not correlate with dopamine release and this measure did not differ in females on and off hormonal birth control. CONCLUSIONS: While our finding in young adults from one dataset of greater %ΔBPND in males is partially consistent with a previously published study on sex differences in D-amphetamine-induced dopamine release, our data do not support the presence of consistent widespread sex differences in this measure of dopamine release.

[18F]fallypride characterization of striatal and extrastriatal D2/3 receptors in Parkinson's disease.

Parkinson's disease (PD) is characterized by widespread degeneration of monoaminergic (especially dopaminergic) networks, manifesting with a number of both motor and non-motor symptoms. Regional alterations to dopamine D2/3 receptors in PD patients are documented in striatal and some extrastriatal areas, and medications that target D2/3 receptors can improve motor and non-motor symptoms. However, data regarding the combined pattern of D2/3 receptor binding in both striatal and extrastriatal regions in PD are limited. We studied 35 PD patients off-medication and 31 age- and sex-matched healthy controls (HCs) using PET imaging with [18F]fallypride, a high affinity D2/3 receptor ligand, to measure striatal and extrastriatal D2/3 nondisplaceable binding potential (BPND). PD patients completed PET imaging in the off medication state, and motor severity was concurrently assessed. Voxel-wise evaluation between groups revealed significant BPND reductions in PD patients in striatal and several extrastriatal regions, including the locus coeruleus and mesotemporal cortex. A region-of-interest (ROI) based approach quantified differences in dopamine D2/3 receptors, where reduced BPND was noted in the globus pallidus, caudate, amygdala, hippocampus, ventral midbrain, and thalamus of PD patients relative to HC subjects. Motor severity positively correlated with D2/3 receptor density in the putamen and globus pallidus. These findings support the hypothesis that abnormal D2/3 expression occurs in regions related to both the motor and non-motor symptoms of PD, including areas richly invested with noradrenergic neurons.

Caloric Restriction-Induced Decreases in Dopamine Receptor Availability are Associated with Leptin Concentration.

OBJECTIVE: It has been previously reported that early after Roux-en-Y-gastric bypass, dopamine (DA) type 2 and 3 receptor (D2/3R) binding potential (BPND ) was decreased from preoperative levels. The current study aimed to determine whether calorie restriction without weight loss modifies D2/3R BPND and whether such changes are explained by neuroendocrine regulation. METHODS: Fifteen females with obesity (BMI = 39 ± 6 kg/m2 ) were studied before and after ∼10 days of a very-low-calorie-diet (VLCD). Outcome measures included fasting insulin, leptin, acyl ghrelin, and glucose, and insulin sensitivity and disposition index were estimated using the oral-minimal model (OMM) method. Participants underwent positron emission tomography scanning with the displaceable radioligand [18 F]fallypride to estimate available regional D2/3R levels. Regions of interest included the caudate, putamen, ventral striatum, hypothalamus, and substantia nigra (SN). RESULTS: With the VLCD, weight decreased slightly (-3 kg). Insulin, glucose, and leptin decreased significantly, but there was no change in acyl ghrelin or measures from OMM. SN D2/3R BPND decreased significantly, with trends toward decreased levels in the remaining regions. The decrease in leptin concentration strongly predicted the change in D2/3R BPND in all regions (all P ≤ 0.004). CONCLUSIONS: In obesity, reductions in regional D2/3R availability after VLCD are suggestive of increased endogenous DA competing with the radioligand. Changes in regional D2/3R availability were associated with decreases in leptin concentrations that occurred before clinically significant weight loss.

Occupancy of striatal and extrastriatal dopamine D2 receptors by clozapine and quetiapine.

Clozapine and quetiapine have a low incidence of extrapyramidal side effects at clinically effective doses, which appears to be related to their significantly lower occupancy of striatal dopamine D2 receptors (DA D2r) compared to typical antipsychotic drugs (APDs). Animal studies have indicated that clozapine and quetiapine produce selective effects on cortical and limbic regions of the brain and in particular on dopaminergic neurotransmission in these regions. Previous PET and SPECT studies have reported conflicting results regarding whether clozapine produces preferential occupancy of cortical DA D2r. To examine whether clozapine and/or quetiapine produce preferential occupancy of DA D2r in cortex and limbic regions, we studied the occupancy of putamenal, ventral striatal, thalamic, amygdala, substantia nigra, and temporal cortical DA D2r using PET with [18F]fallypride in six schizophrenic subjects receiving clozapine monotherapy and in seven schizophrenic subjects receiving quetiapine monotherapy. Doses were chosen clinically to minimize psychopathology at tolerable levels of side effects such as drowsiness. All had minimal positive symptoms at the time of the study. Regional receptor occupancies were estimated using mean regional DA D2r levels calculated for 10 off-medication schizophrenic subjects. Both clozapine and quetiapine produced lower levels of putamenal DA D2r occupancy than those reported for typical APDs, 47.8 and 33.5%, respectively. Clozapine produced preferential occupancy of temporal cortical vs putamenal DA D2r, 59.8% (p=0.05, corrected for multiple comparisons), and significantly lower levels of occupancy in the substantia nigra, 18.4% (p=0.0015, corrected for multiple comparisons). Quetiapine also produced preferential occupancy of temporal cortical DA D2r, 46.9% (p=0.03, corrected for multiple comparisons), but did not spare occupancy of substantia nigra DA D2r. The therapeutic effects of clozapine and quetiapine appear to be achieved at less than the 65% threshold for occupancy seen with typical APDs, consistent with the involvement of non-DA D2r mechanisms in at least partially mediating the therapeutic effects of these drugs. Preferential occupancy of cortical DA D2r, sparing occupancy of substantia nigra receptors, and non-DA D2r-mediated actions may contribute to the antipsychotic actions of these and other atypical APDs.

The neurobiological basis of binge-eating disorder.

Relatively little is known about the neuropathophysiology of binge-eating disorder (BED). Here, the evidence from neuroimaging, neurocognitive, genetics, and animal studies are reviewed to synthesize our current understanding of the pathophysiology of BED. Binge-eating disorder may be conceptualized as an impulsive/compulsive disorder, with altered reward sensitivity and food-related attentional biases. Neuroimaging studies suggest there are corticostriatal circuitry alterations in BED similar to those observed in substance abuse, including altered function of prefrontal, insular, and orbitofrontal cortices and the striatum. Human genetics and animal studies suggest that there are changes in neurotransmitter networks, including dopaminergic and opioidergic systems, associated with binge-eating behaviors. Overall, the current evidence suggests that BED may be related to maladaptation of the corticostriatal circuitry regulating motivation and impulse control similar to that found in other impulsive/compulsive disorders. Further studies are needed to understand the genetics of BED and how neurotransmitter activity and neurocircuitry function are altered in BED and how pharmacotherapies may influence these systems to reduce BED symptoms.

Variability in paralimbic dopamine signaling correlates with subjective responses to d-amphetamine.

Subjective responses to psychostimulants vary, the basis of which is poorly understood, especially in relation to possible cortical contributions. Here, we tested for relationships between participants' positive subjective responses to oral d-amphetamine (dAMPH) versus placebo and variability in striatal and extrastriatal dopamine (DA) receptor availability and release, measured via positron emission tomography (PET) with the radiotracer (18)F-fallypride. Analyses focused on 35 healthy adult participants showing positive subjective effects to dAMPH measured via the Drug Effects Questionnaire (DEQ) Feel, Like, High, and Want More subscales (Responders), and were repeated after inclusion of 11 subjects who lacked subjective responses. Associations between peak DEQ subscale ratings and both baseline (18)F-fallypride binding potential (BPnd; an index of D2/D3 receptor availability) and the percentage change in BPnd post dAMPH (%ΔBPnd; a measure of DA release) were assessed. Baseline BPnd in ventromedial prefrontal cortex (vmPFC) predicted the peak level of High reported following dAMPH. Furthermore, %ΔBPnd in vmPFC positively correlated with DEQ Want More ratings. DEQ Want More was also positively correlated with %ΔBPnd in right ventral striatum and left insula. This work indicates that characteristics of DA functioning in vmPFC, a cortical area implicated in subjective valuation, are associated with both subjective high and incentive (wanting) responses. The observation that insula %ΔBPnd was associated with drug wanting converges with evidence suggesting its role in drug craving. These findings highlight the importance of variability in DA signaling in specific paralimbic cortical regions in dAMPH's subjective response, which may confer risk for abusing psychostimulants.

Individual differences in timing of peak positive subjective responses to d-amphetamine: Relationship to pharmacokinetics and physiology.

Rate of delivery of psychostimulants has been associated with their positive euphoric effects and potential addiction liability. However, information on individual differences in onset of d-amphetamine's effects remains scarce. We examined individual differences in the time to peak subjective and physiological effects and the pharmacokinetics/pharmacodynamics of oral d-amphetamine. We considered two independent studies that used different dosing regimens where subjects completed the drug effects questionnaire at multiple time points post d-amphetamine. Based on the observation of distinct individual differences in time course of drug effects questionnaire "feel", "high", and "like" ratings (DEQH+L+F) in Study 1, subjects in both studies were categorized as early peak responders (peak within 60 minutes), late peak responders (peak > 60 minutes) or nonresponders; 20-25% of participants were categorized as early peak responders, 50-55% as late peak responders and 20-30% as nonresponders. Physiological (both studies) and plasma d-amphetamine (Study 1) were compared among these groups. Early peak responders exhibited an earlier rise in plasma d-amphetamine levels and more sustained elevation in heart rate compared to late peak responders. The present data illustrate the presence of significant individual differences in the temporal pattern of responses to oral d-amphetamine, which may contribute to heightened abuse potential.

Caudate asymmetry is related to attentional impulsivity and an objective measure of ADHD-like attentional problems in healthy adults.

Case-control studies comparing ADHD with typically developing individuals suggest that anatomical asymmetry of the caudate nucleus is a marker of attention deficit hyperactivity disorder (ADHD). However, there is no consensus on whether the asymmetry favors the right or left caudate nucleus in ADHD, or whether the asymmetry is increased or decreased in ADHD. The current study aimed to clarify this relationship by applying a dimensional approach to assessing ADHD symptoms that, instead of relying on clinical classification, utilizes the natural behavioral continuum of traits related to ADHD. Structural T1-weighted MRI was collected from 71 adults between 18 and 35 years and analyzed for caudate asymmetry. ADHD-like attentional symptoms were assessed with an objective measure of attentional problems, the ADHD score from the Test of Variables of Attention (TOVA). Impulsivity, a core feature in ADHD, was measured using the Barratt Impulsiveness Scale, a self-report measure that assesses attentional, non-planning, and motor features of impulsivity. We found that larger right relative to left caudate volumes correlated with both higher attentional impulsiveness and worse ADHD scores on the TOVA. Higher attentional impulsiveness also correlated with worse ADHD scores, establishing coherence between the objective measure and the self-report measure of attentional problems. These results suggest that a differential passage of information through frontal-striatal networks may produce instability leading to attentional problems. The findings also demonstrate the utility of a dimensional approach to understanding structural correlates of ADHD symptoms.

Occupancy of striatal and extrastriatal dopamine D2/D3 receptors by olanzapine and haloperidol.

There have been conflicting reports as to whether olanzapine produces lower occupancy of striatal dopamine D(2)/D(3) receptor than typical antipsychotic drugs and preferential occupancy of extrastriatal dopamine D(2)/D(3) receptors. We performed [(18)F] fallypride PET studies in six schizophrenic subjects treated with olanzapine and six schizophrenic subjects treated with haloperidol to examine the occupancy of striatal and extrastriatal dopamine receptors by these antipsychotic drugs. [(18)F] setoperone PET studies were performed in seven olanzapine-treated subjects to determine 5-HT(2A) receptor occupancy. Occupancy of dopamine D(2)/D(3) receptors by olanzapine was not significantly different from that seen with haloperidol in the putamen, ventral striatum, medial thalamus, amygdala, or temporal cortex, that is, 67.5-78.2% occupancy; olanzapine produced no preferential occupancy of dopamine D(2)/D(3) receptors in the ventral striatum, medial thalamus, amygdala, or temporal cortex. There was, however, significantly lower occupancy of substantia nigra/VTA dopamine D(2)/D(3) receptors in olanzapine-treated compared to haloperidol-treated subjects, that is, 40.2 vs 59.3% (p=0.0014, corrected for multiple comparisons); in olanzapine-treated subjects, the substantia nigra/VTA was the only region with significantly lower dopamine D(2)/D(3) receptor occupancy than the putamen, that is, 40.2 vs 69.2% (p<0.001, corrected for multiple comparison). Occupancy of 5-HT(2A) receptors was 85-93% in the olanzapine- treated subjects. The results of this study demonstrated that olanzapine does not produce preferential occupancy of extrastriatal dopamine D(2)/D(3) receptors but does spare substantia nigra/VTA receptors. Sparing of substantia nigra/VTA dopamine D(2)/D(3) receptor occupancy may contribute to the low incidence of extrapyramidal side effects in olanzapine-treated patients.