Article

# Nature or Nurture? Determining the Heritability of Human Striatal Dopamine Function: an &lsqb;18F&rsqb;-DOPA PET Study

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1] Psychiatric Imaging Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London, UK [2] Centre for Neuropsychopharmacology, Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK.
(Impact Factor: 7.05). 10/2012; 38(3). DOI: 10.1038/npp.2012.207
Source: PubMed

ABSTRACT

Striatal dopamine function is important for normal personality, cognitive processes and behavior, and abnormalities are linked to a number of neuropsychiatric disorders. However, no studies have examined the relative influence of genetic inheritance and environmental factors in determining striatal dopamine function. Using [18F]-DOPA positron emission tomography (PET), we sought to determine the heritability of presynaptic striatal dopamine function by comparing variability in uptake values in same sex monozygotic (MZ) twins to dizygotic (DZ) twins. Nine MZ and 10 DZ twin pairs underwent high-resolution [18F]-DOPA PET to assess presynaptic striatal dopamine function. Uptake values for the overall striatum and functional striatal subdivisions were determined by a Patlak analysis using a cerebellar reference region. Heritability, shared environmental effects and non-shared individual-specific effects were estimated using a region of interest (ROI) analysis and a confirmatory parametric analysis. Overall striatal heritability estimates from the ROI and parametric analyses were 0.44 and 0.33, respectively. We found a distinction between striatal heritability in the functional subdivisions, with the greatest heritability estimates occurring in the sensorimotor striatum and the greatest effect of individual-specific environmental factors in the limbic striatum. Our results indicate that variation in overall presynaptic striatal dopamine function is determined by a combination of genetic factors and individual-specific environmental factors, with familial environmental effects having no effect. These findings underline the importance of individual-specific environmental factors for striatal dopaminergic function, particularly in the limbic striatum, with implications for understanding neuropsychiatric disorders such as schizophrenia and addictions.Neuropsychopharmacology advance online publication, 24 October 2012; doi:10.1038/npp.2012.207.

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Available from: Paul Robert Alexander Stokes, Jan 09, 2014
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• "The mechanisms involved are still far from clear and undoubtedly complex. However, several recent lines of evidence suggest, for example, that striatal dopamine function is adaptive to individual environmental stressors (Martinez et al., 2010; Stokes et al., 2013) and, therefore, provides at least one plausible explanation for how trauma increases the risk for AH across diagnostic boundaries. Thus, based on the available data, exposure to significant social stressors should be associated with elevated DA synthesis, which in turn should lead to greater difficulty in reality filtering (i.e., inhibitory control) and a corresponding increase in the tendency to hallucinate—regardless of diagnosis. "
##### Article: A synthesis of evidence on inhibitory control and auditory hallucinations based on the Research Domain Criteria (RDoC) framework
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ABSTRACT: The National Institute of Mental Health initiative called the Research Domain Criteria (RDoC) project aims to provide a new approach to understanding mental illness grounded in the fundamental domains of human behavior and psychological functioning. To this end the RDoC framework encourages researchers and clinicians to think outside the [diagnostic] box, by studying symptoms, behaviors or biomarkers that cut across traditional mental illness categories. In this article we examine and discuss how the RDoC framework can improve our understanding of psychopathology by zeroing in on hallucinations- now widely recognized as a symptom that occurs in a range of clinical and non-clinical groups. We focus on a single domain of functioning-namely cognitive [inhibitory] control-and assimilate key findings structured around the basic RDoC "units of analysis," which span the range from observable behavior to molecular genetics. Our synthesis and critique of the literature provides a deeper understanding of the mechanisms involved in the emergence of auditory hallucinations, linked to the individual dynamics of inhibitory development before and after puberty; favors separate developmental trajectories for clinical and non-clinical hallucinations; yields new insights into co-occurring emotional and behavioral problems; and suggests some novel avenues for treatment.
Full-text · Article · Mar 2014 · Frontiers in Human Neuroscience
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• "Taken together with the finding that genetic variation in DDC activity predicts disinhibitory sensation seeking tendencies in healthy individuals (Derringer et al., 2010), our results suggest that the link between behavioral disinhibition and ventral striatal DA synthesis capacity is likely to be, to a significant extent, genetically mediated. At the same time, we acknowledge that there are substantial (potentially shared) environmental influences on ventral striatal DA synthesis capacity (Stokes et al., 2013), behavioral disinhibition (Lomanowska et al., 2011) and externalizing (Hicks et al., 2013). As in our earlier study of Parkinson's disease, here we found that only the r-NS facet-level scale NS3 (Extravagance vs. Reserve) was related to ventral striatal DA synthesis capacity. "
##### Article: Lawrence AD, Brooks DJ. Ventral striatal dopamine synthesis capacity is associated with individual differences in behavioral disinhibition. Front Behav Neurosci 8: 86
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ABSTRACT: Pathological gambling, alongside addictive and antisocial disorders, forms part of a broad psychopathological spectrum of externalizing disorders, which share an underlying genetic vulnerability. The shared externalizing propensity is a highly heritable, continuously varying trait. Disinhibitory personality traits such as impulsivity and novelty seeking (NS) function as indicators of this broad shared externalizing tendency, which may reflect, at the neurobiological level, variation in the reactivity of dopaminergic (DAergic) brain reward systems centered on the ventral striatum (VS). Here, we examined whether individual differences in ventral striatal dopamine (DA) synthesis capacity were associated with individual variation in disinhibitory personality traits. Twelve healthy male volunteers underwent 6-[(18)F]Fluoro-L-DOPA (FDOPA) positron emission tomography (PET) scanning to measure striatal DA synthesis capacity, and completed a measure of disinhibited personality (NS). We found that levels of ventral, but not dorsal, striatal DA synthesis capacity were significantly correlated with inter-individual variation in disinhibitory personality traits, particularly a propensity for financial extravagance and irresponsibility. Our results are consistent with preclinical models of behavioral disinhibition and addiction proneness, and provide novel insights into the neurobiology of personality based vulnerability to pathological gambling and other externalizing disorders.
Full-text · Article · Mar 2014 · Frontiers in Behavioral Neuroscience
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• "healthy participants , in whom data was acquired on an ECAT HR+ 962 PET camera as part of ongo - ing investigations ( Egerton et al . , 2013 ) . The second cohort con - sisted of 19 healthy participants , in whom data had been acquired on a ECAT / EXACT3D PET camera as part of other studies ( Howes et al . , 2009 , 2011 ; Shotbolt et al . , 2011 ; Stokes et al . , 2013 ) . All study participants were recruited by public advertisement . In both cohorts , exclusion criteria included history of psychiatric , neurologic or other medical illness , pregnancy or other contraindication to PET imaging , history of head injury and substance dependence with the exception of smoking . All volun - teers gave writt"
##### Article: Does human presynaptic striatal dopamine function predict social conformity?
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ABSTRACT: Socially desirable responding (SDR) is a personality trait which reflects either a tendency to present oneself in an overly positive manner to others, consistent with social conformity (impression management (IM)), or the tendency to view one's own behaviour in an overly positive light (self-deceptive enhancement (SDE)). Neurochemical imaging studies report an inverse relationship between SDR and dorsal striatal dopamine D2/3 receptor availability. This may reflect an association between SDR and D2/3 receptor expression, synaptic dopamine levels or a combination of the two. In this study, we used a [(18)F]-DOPA positron emission tomography (PET) image database to investigate whether SDR is associated with presynaptic dopamine function. Striatal [(18)F]-DOPA uptake, ( $${k}_{i}^{\hbox{ cer }}$$ , min-1), was determined in two independent healthy participant cohorts (n=27 and 19), by Patlak analysis using a cerebellar reference region. SDR was assessed using the revised Eysenck Personality Questionnaire (EPQ-R) Lie scale, and IM and SDE were measured using the Paulhus Deception Scales. No significant associations were detected between Lie, SDE or IM scores and striatal [(18)F]-DOPA $${k}_{i}^{\hbox{ cer }}$$ . These results indicate that presynaptic striatal dopamine function is not associated with social conformity and suggests that social conformity may be associated with striatal D2/3 receptor expression rather than with synaptic dopamine levels.
Full-text · Article · Nov 2013 · Journal of Psychopharmacology