Behavioral/Systems/Cognitive 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 an

Cerebral morphology and dopamine D 2 /D 3 receptor distribution in humans: A combined [ 18 F]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-byvoxel 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. © 2009 Elsevier Inc. All rights reserved. Introduction Over the past two decades positron emission tomography (PET) imaging of dopamine (DA) receptor levels and structural magnetic resonance imaging (MRI) have dramatically expanded our understanding of psychopathology and other behavioral phenotypes. In the clinical realm for example, PET imaging with DA receptor radioligands and MRI have been instrumental in identifying localized changes in DA receptor expression and brain morphology in schizophrenia and substance abuse disorders To date, the relationship between brain morphology and DA receptor levels has not been systematically investigated in humans. This is surprising given evidence that DA neurotransmission may influence cerebral morphology during development and adulthood. Disruption or depletion of normal neonatal DA function results in reduced pyramidal cell dendrite length, especially in cortical areas that receive significant DA projections such as the anterior cingulate and prefrontal cortex (PFC

Mesolimbic dopamine reward system hypersensitivity in individuals with psychopathic traits

nature neuroscience VOLUME 13 | NUMBER 4 | APRIL 2010 4 1 9 B r i e f c o m m u n i c at i o n s The net annual burden of crime in the US has been estimated to exceed $1 trillion 1 , making criminal behavior a costly large-scale social problem and a critical target for scientific investigation. Although the risk architecture underlying criminality is complex, psychopathy has emerged as a particularly robust predictor of criminal behavior and recidivism. Psychopathy is a personality disorder characterized by a combination of superficial charm, persistent instrumental antisocial behavior, marked sensation-seeking and poor reflection, blunted empathy and punishment sensitivity, and shallow emotional experiences 2 . Recent research on the neural substrates of psychopathy has focused on the profound emotional deficits seen in psychopaths and has emphasized the possible contributions of amygdala and ventromedial prefrontal cortex dysfunction to deficient fear processing and empathy 3 . However, although emotional and interpersonal deficits are often considered to be core features of the disorder, the empirical linkage of such deficits to criminality (particularly, to risk for committing violent crimes) is mixed Prior research has also shown that psychopathic individuals have a markedly increased risk of developing substance use problems 8 . Such associations mirror preclinical work demonstrating that impulsive traits predict enhanced susceptibility to drug-seeking and relapse 9 . Given the strong link between psychopathy and substance abuse, previous studies indicating that the mesolimbic dopamine (DA) system is important in the pathophysiology of substance use disorders and evidence that individual differences in the mesolimbic DA system predispose the development of substance abuse 9 , we hypothesized that psychopathic traits would be associated with dysfunction in mesolimbic DA reward circuitry. To test the prediction that individuals with psychopathic traits are characterized by alterations in mesolimbic DA neurochemistry and neurophysiology, we used positron emission tomography (PET) imaging of psychostimulantinduced DA release, in concert with a functional magnetic resonance imaging (fMRI) probe of the reward system. Psychopathic traits were measured with the psychopathic personality inventory (PPI), a wellvalidated trait measure of psychopathy, in a sample of community volunteers with no prior history of substance abuse (see Supplementary Data and Supplementary Discussion). Prior studies have shown that the PPI is composed of two underlying latent factors: a 'fearless dominance' (PPI-FD) factor indexing emotional-interpersonal facets of psychopathy and an 'impulsive antisociality' (PPI-IA) factor linked to socially deviant behavior To examine the relationship between psychopathic traits and DA release, we performed voxel-wise correlation analyses between PPI factor scores and maps of the percentage change in [ 18 F]fallypride binding potential between placebo and amphetamine (0.43 mg per kg of body weight; two-day, single-blind protocol, n = 30; Supplementary Methods an

Molecular Imaging of Therapeutic Response to Epidermal Growth Factor Receptor Blockade in Colorectal Cancer

PURPOSE: To evaluate noninvasive molecular imaging methods as correlative biomarkers of therapeutic efficacy of cetuximab in human colorectal cancer cell line xenografts grown in athymic nude mice. The correlation between molecular imaging and immunohistochemical analysis to quantify epidermal growth factor (EGF) binding, apoptosis, and proliferation was evaluated in treated and untreated tumor-bearing cohorts. EXPERIMENTAL DESIGN: Optical imaging probes targeting EGF receptor (EGFR) expression (NIR800-EGF) and apoptosis (NIR700-Annexin V) were synthesized and evaluated in vitro and in vivo. Proliferation was assessed by 3′-[(18)F]fluoro-3′-deoxythymidine ([(18)F] FLT) positron emission tomography. Assessment of inhibition of EGFR signaling by cetuximab was accomplished by concomitant imaging of NIR800-EGF, NIR700-Annexin V, and [(18)F] FLT in cetuximab-sensitive (DiFi) and insensitive (HCT-116) human colorectal cancer cell line xenografts. Imaging results were validated by measurement of tumor size and immunohistochemical analysis of total and phosphorylated EGFR, caspase-3, and Ki-67 immediately following in vivo imaging. RESULTS: NIR800-EGF accumulation in tumors reflected relative EGFR expression and EGFR occupancy by cetuximab. NIR700-Annexin V accumulation correlated with cetuximab-induced apoptosis as assessed by immunohistochemical staining of caspase-3. No significant difference in tumor proliferation was noted between treated and untreated animals by [(18)F] FLT positron emission tomography or Ki-67 immunohistochemistry. CONCLUSIONS: Molecular imaging can accurately assess EGF binding, proliferation, and apoptosis in human colorectal cancer xenografts. These imaging approaches may prove useful for serial, noninvasive monitoring of the biological effects of EGFR inhibition in preclinical studies. It is anticipated that these assays can be adapted for clinical use