Association of genetic ancestry with striatal dopamine D2/D3 receptor availability

Wiers, Corinde E.; Towb, Par; Hodgkinson, Colin A.; Shen, Pei‐Hong; Freeman, Clara; Miller, Gregg; Lindgren, Elsa; Shokri‐Kojori, Ehsan; Demiral, Şükrü Barış; Kim, Sunny; Tomasi, Dardo; Sun, Hui; Wang, Gene‐Jack; Goldman, David; Volkow, Nora D.

doi:10.1038/mp.2017.208

Cited by 21 publications

(20 citation statements)

References 57 publications

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“…Our primary analysis fitted a linear regression model with striatal dopamine synthesis capacity as the dependent variable, and anterior cingulate cortex glutamate concentrations as predictor. Given the possible effects of age, 21 sex, 22 , 23 and ethnicity 24 on imaging measures, we did secondary exploratory analyses that adjusted for these demographic factors. Additionally, as antipsychotic treatment could influence imaging measures and symptom severity ratings 25 , 26 we added medication status at time of scan (on antipsychotic treatment or drug free) to this model.…”

Section: Methodsmentioning

confidence: 99%

The relationship between cortical glutamate and striatal dopamine in first-episode psychosis: a cross-sectional multimodal PET and magnetic resonance spectroscopy imaging study

Jauhar

McCutcheon

Borgan

et al. 2018

The Lancet Psychiatry

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SummaryBackgroundThe pathophysiology of psychosis is incompletely understood. Disruption in cortical glutamatergic signalling causing aberrant striatal dopamine synthesis capacity is a proposed model for psychosis, but has not been tested in vivo. We therefore aimed to test the relationship between cortical glutamate concentrations and striatal dopamine synthesis capacity, and psychotic symptoms.MethodsIn this cross-sectional multimodal imaging study, 28 individuals with first-episode psychosis and 28 healthy controls underwent 18F-DOPA PET (measuring striatal dopamine synthesis capacity), and proton magnetic resonance spectroscopy (measuring anterior cingulate cortex glutamate concentrations). Participants were recruited from first-episode psychosis services in London, UK and were required to be in the first episode of a psychotic illness, with no previous illness or treatment episodes. Exclusion criteria for all participants were: history of substantial head trauma, dependence on illicit substances, medical comorbidity (other than minor illnesses), and contraindications to scanning (such as pregnancy). Symptoms were measured using the Positive and Negative Syndrome Scale. The primary endpoint was the relationship between anterior cingulate cortex glutamate concentrations and striatal dopamine synthesis capacity in individuals with their first episode of psychosis as shown by imaging, examined by linear regression. Linear regression was used to examine relationships between measures.FindingsGlutamate concentrations showed a significant inverse relationship with striatal dopamine synthesis capacity in patients with psychosis (R2=0·16, p=0·03, β −1·71 × 10−4, SE 0·76 × 10−4). This relationship remained significant after the addition of age, gender, ethnicity, and medication status to the model (p=0·015). In healthy controls, there was no significant relationship between dopamine and glutamate measures (R2=0·04, p=0·39). Positive and Negative Syndrome Scale positive psychotic symptoms were positively associated with striatal dopamine synthesis capacity (R2=0·14, p=0·046, β 2546, SE 1217) and showed an inverse relationship with anterior cingulate glutamate concentrations (R2=0·16, p=0·03, β −1·71 × 10−4, SE 7·63 × 10−5). No relationships were seen with negative symptoms (positive symptoms, mean [SD] −18·4 (6·6) negative symptoms, mean [SD] −15·4 [6·1]).InterpretationThese observations are consistent with the hypothesis that cortical glutamate dysfunction is related to subcortical dopamine synthesis capacity and psychosis. Although the precise mechanistic relationship between cortical glutamate and dopamine in vivo remains unclear, our findings support further studies to test the effect of modulating cortical glutamate in the treatment of psychosis.FundingMedical Research Council, Wellcome Trust, Biomedical Research Council, South London and Maudsley NHS Foundation Trust, JMAS Sim Fellowship, Royal College of Physicians (Edinburgh) (SJ).

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Section: Methodsmentioning

confidence: 99%

The relationship between cortical glutamate and striatal dopamine in first-episode psychosis: a cross-sectional multimodal PET and magnetic resonance spectroscopy imaging study

Jauhar

McCutcheon

Borgan

et al. 2018

The Lancet Psychiatry

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“…Furthermore, there is preliminary evidence of lower CB 1 availability in healthy subjects of Indian ancestry compared to those of European and African ancestry [39]. A recent analysis of raclopride studies demonstrated significant differences in binding based on ancestry [106]; thus, ancestry may deserve greater consideration in human PET studies than previously assumed. Other confounding factors could include length of illness and symptom severity, which were correlated with CB 1 availability in some studies (Supplemental Tables 1 and 2).…”

Section: Discussionmentioning

confidence: 95%

Endocannabinoid signaling in psychiatric disorders: a review of positron emission tomography studies

et al. 2018

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Endocannabinoid signaling is implicated in an array of psychopathologies ranging from anxiety to psychosis and addiction. In recent years, radiotracers targeting the endocannabinoid system have been used in positron emission tomography (PET) studies to determine whether individuals with psychiatric disorders display altered endocannabinoid signaling. We comprehensively reviewed PET studies examining differences in endocannabinoid signaling between individuals with psychiatric illness and healthy controls. Published studies evaluated individuals with five psychiatric disorders: cannabis use disorder, alcohol use disorder, schizophrenia, post-traumatic stress disorder, and eating disorders. Most studies employed radiotracers targeting cannabinoid receptor 1 (CB). Cannabis users consistently demonstrated decreased CB binding compared to controls, with normalization following short periods of abstinence. Findings in those with alcohol use disorder and schizophrenia were less consistent, with some studies demonstrating increased CB binding and others demonstrating decreased CB binding. Evidence of aberrant CB binding was also found in individuals with anorexia nervosa and post-traumatic stress disorder, but limited data have been published to date. Thus, existing evidence suggests that alterations in endocannabinoid signaling are present in a range of psychiatric disorders. Although recent efforts have largely focused on evaluating CB binding, the synthesis of new radiotracers targeting enzymes involved in endocannabinoid degradation, such as fatty acid amide hydrolase, will allow for other facets of endocannabinoid signaling to be evaluated in future studies.

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“…Surprisingly, we saw the effect of decreasing DAT with increasing age in opioid and not alcohol users, but since this effect is seen in healthy humans as well [57], it might not be opioid specific. Especially when interpreting the result of lower D2 receptor availability in alcohol and in opioid users, other moderating factors than those we could investigate in our analyses must be kept in mind, since former research on D2 receptor availably in non-users revealed further possible influencing factors as, for example, the influence of social dominance [58], genetic ancestry [59] or sleep deprivation [60].…”

Section: Discussionmentioning

confidence: 99%

Effects of sedative drug use on the dopamine system: a systematic review and meta-analysis of in vivo neuroimaging studies

Kamp

Proebstl

Penzel

et al. 2018

Neuropsychopharmacol

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Use of alcohol, cannabis and opioids is highly prevalent and is associated with global disease burden and high economic costs. The exact pathophysiology of abuse or addiction associated with these sedative substances is not completely understood, but previous research implicates the important role of the striatal dopamine system in the addiction process. Multiple studies investigated changes in the striatal dopamine systems of users of sedative substances, but currently these results are very heterogeneous. Therefore, we conducted a meta-analysis of in vivo neuroimaging studies investigating dopaminergic alterations in the striatum of users of alcohol, opioids or cannabis. Analyses for each substance were conducted separately for the availability of D2/D3 dopamine receptors, dopamine transporters and dopamine synthesis capacity. In total, 723 substance users and 752 healthy controls were included. The results indicated a significant lower striatal D2/D3 receptor availability in alcohol users compared to controls (g = 0.46) but no difference in dopamine transporter availability or dopamine synthesis capacity. Our analysis indicated that changes of dopamine receptors and transporters are moderated by the duration of abstinence. Comparing opioid users with controls revealed a significant lower D2/D3 receptor availability (g = 1.17) and a significantly lower transporter availability (g = 1.55) in opioid users. For cannabis users, there was no significant difference in receptor availability compared to controls and too few studies provided information on dopamine transporter availability or synthesis capacity. Our analysis provides strong evidence for a central role of the striatal dopamine system in use of alcohol or opioids. Further studies are needed to clarify the impact of the dopamine system in cannabis users.

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Association of genetic ancestry with striatal dopamine D2/D3 receptor availability

Cited by 21 publications

References 57 publications

The relationship between cortical glutamate and striatal dopamine in first-episode psychosis: a cross-sectional multimodal PET and magnetic resonance spectroscopy imaging study

The relationship between cortical glutamate and striatal dopamine in first-episode psychosis: a cross-sectional multimodal PET and magnetic resonance spectroscopy imaging study

Endocannabinoid signaling in psychiatric disorders: a review of positron emission tomography studies

Effects of sedative drug use on the dopamine system: a systematic review and meta-analysis of in vivo neuroimaging studies

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