Positive Association Between Limbic Metabotropic Glutamate Receptor 5 Availability and Novelty-Seeking Temperament in Humans: An ¹⁸F-FPEB PET Study

Abstract

Heritable temperament traits have been linked to several neuropsychiatric illnesses, including disorders associated with metabotropic glutamate receptor 5 (mGluR5) and dopaminergic dysfunctions. Considering its modulating effect on neurotransmission, we hypothesized that cerebral mGluR5 availability is associated with temperament traits in healthy humans. Methods: Forty-four nonsmoking healthy volunteers (mean age ± SD, 40 ± 14 y; age range, 22-66 y; 22 women) were included in this cross-sectional investigation. Brain mGluR5 availability was quantified on both a voxel-by-voxel and a volume-of-interest basis using the total distribution volume of the radioligand 18 F-3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile ( 18 F-FPEB) with 90-min dynamic PET and arterial input function. Moreover, glutamate-glutamine concentrations in the anterior cingulate cortex were measured using MR spectroscopy. These measures were related to the temperament traits of the 240-item Cloninger temperament and character inventory using a regression analysis with age and sex as nuisance variables. Results: High novelty-seeking temperament was robustly associated with increased mGluR5 availability in various regions including the thalamus (r 5 0.71; the strongest association), amygdala, parahippocampus, insula, anterior and posterior cingulate cortex, and several primary sensory areas (all r . 0.58; P , 0.05, corrected for familywise error). These associations were specific because no correlations were found with other temperament scales or with spectroscopic measures of glutamatergic transmission. Conclusion: Overall, these data posit mGluR5 in key paralimbic areas as a strong determinant of the temperament trait novelty seeking. These data add to our understanding of how brain neurochemistry accounts for the variation in human behavior and strongly support further research on mGluR5 as a potential therapeutic target in neuropsychiatric disorders associated with abnormal novelty-seeking behaviors. Theneur obiologic substrates of human personality and behavior remain an important but complex area of neuroscience. More than 20 y ago, the Cloninger's theory of personality represented one of the first attempts to integrate neurotransmitter systems into personality research (1). This model identified 7 personality traits, that is, 4 temperaments and 3 characters. Temperaments are thought to be independently inherited with specific brain circuits and stable over a lifetime, whereas character dimensions are suggested to form over time through the interplay of genetic and environmental factors. Subsequently, genetic determinants of receptor expression and neuronal function in the normal variation of human behavior have been validated (2). Several temperament and personality traits, including novelty seeking (NS), harm avoidance, and impulsivity, have been associated with the vulnerability to mental illnesses (3,4) and have been directly related to receptors and neurotransmission using functional imaging (5-7). In parallel, dysregulation or disequi...

Altered metabotropic glutamate receptor 5 markers in PTSD: In vivo and postmortem evidence

“…18 F]FPEB PET study found a reduction in mGluR5 in alcohol addiction (57), and another study using the mGluR5 radioligand [ 11 C]ABP688 showed reduced binding in cocaine-dependent subjects (58). Conversely, we found no evidence of down-regulation of mGluR5, and the up-regulation of SHANK1 is consistent with increased expression of mGluR5 at the cell surface as shown by our PET findings.…”

Lower Limbic Metabotropic Glutamate Receptor 5 Availability in Alcohol Dependence

“…Healthy controls were recruited through local advertisement and underwent a full medical and mental assessment at study intake. The sample for the current study represents a subsample of a previous study (21) and was randomly selected on the basis of age by a person masked to both study protocols in order to obtain 2 age-matched controls for each alcohol-dependent subject (Table 1). Subjects reporting alcohol consumption at a rate of more than 7 units/wk (1 unit 5 10 g of alcohol) or regular binge drinking ($5 units per occasion) were excluded.…”

“…In the last 10 y, the highly selective and potent mGlu5 PET radioligand 18 F-3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile ( 18 F-FPEB) has allowed quantification of mGlu5 availability (20), thereby providing a unique opportunity to examine how mGlu5 may adapt across the different stages of alcohol dependence. Noteworthy, 18 F-FPEB PET has shown that limbic mGlu5 positively relates to novelty seeking (21), a heritable temperament trait associated with increased susceptibility to drug dependence (22). Moreover, genetic studies have demonstrated that individuals with specific mGlu5 polymorphisms are at higher risk for developing alcohol dependence (23,24).…”

Systems genetics of sensation seeking

“…Previous studies indicate that the heterotrimeric G protein coupled metabotropic glutamate receptor 5 (mGluR5) influences OSS in mice 17,38 and novelty seeking in humans. 39 Metabotropic glutamate receptors, including mGluR5 and mGluR7, have also been shown to affect alcohol and other drug use. 17,[40][41][42][43] As Gnb1 encodes the β1 subunit of heterotrimeric G proteins, one hypothesis is that Gnb1…”

“…Gnb1 expression in VTA, NAc and HIPP significantly covaried with active lever preference (Figure 3D-F) and alcohol-related phenotypes (Figure 3G-I): ethanol preference in the two bottle choice paradigm, 36 handling induced convulsions following ethanol injection, 37 and ethanol consumption using the drinking in the dark paradigm (GeneNetwork record IDs: 10140, 11380 and 18877).Previous studies indicate that the heterotrimeric G protein coupled metabotropic glutamate receptor 5 (mGluR5) influences OSS in mice17,38 and novelty seeking in humans 39. Metabotropic glutamate receptors, including mGluR5 and mGluR7, have also been shown to affect alcohol and other drug use 17,[40][41][42][43].…”