Akila Weerasekera

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

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 18F-3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile (18F-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 = 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.

High fat diet treatment impairs hippocampal long-term potentiation without alterations of the core neuropathological features of Alzheimer disease

Type 2 diabetes (T2DM) and obesity might increase the risk for AD by 2-fold. Different attempts to model the effect of diet-induced diabetes on AD pathology in transgenic animal models, resulted in opposite conclusions. Here, we used a novel knock-in mouse model for AD, which, differently from other models, does not overexpress any proteins. Long-term high fat diet treatment triggers a reduction in hippocampal N-acetyl-aspartate/myo-inositol metabolites ratio and impairs long term potentiation in hippocampal acute slices. Interestingly, these alterations do not correlate with changes in the core neuropathological features of AD, i.e. amyloidosis and Tau hyperphosphorylation. The data suggest that AD phenotypes associated with high fat diet treatment seen in other models for AD might be exacerbated because of the overexpressing systems used to study the effects of familial AD mutations. Our work supports the increasing insight that knock-in mice might be more relevant models to study the link between metabolic disorders and AD.

Glutamatergic Biomarkers for Cocaine Addiction: A Longitudinal Study Using MR Spectroscopy and mGluR5 PET in Self-Administering Rats

Cocaine addiction is a disorder that still lacks diagnostic biomarkers or effective pharmacotherapy. We present findings on a rat model of cocaine self-administration that was followed up longitudinally using the metabotropic glutamate receptor type 5 (mGluR5) tracer 18F-3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile (18F-FPEB) PET, proton MR spectroscopy (1H-MRS), and behavioral tests. Methods: Forty-two Wistar rats were scanned with 18F-FPEB PET and 1H-MRS before and after sucrose or intravenous cocaine self-administration, during withdrawal, and during relapse. All animals performed a rodent Iowa Gambling Task (rIGT) at baseline to evaluate decision making. Baseline values were used in a mixed model to assess associations with later cocaine use, and follow-up measurements were compared with the values before drug exposure. Results: Preexposure rIGT scores were significantly related to both cocaine and sucrose use during the drug-exposure phase. However, only cocaine self-administration induced a decrease in 18F-FPEB binding. This decrease was most pronounced bilaterally in the hippocampus, where mGluR5 availability correlated with the amount of cocaine used during relapse. Compared with the sucrose group, a larger decrease was observed in the hippocampo–prefrontal cortex pathway. Preexposure glutamate and glycine concentrations in the prefrontal cortex were significantly associated with cocaine use during the drug-exposure phase. Moreover, prefrontal glutamate exhibited a distinct, reversible decrease when animals had access to cocaine but not sucrose. Conclusion: Baseline values of prefrontal glutamate and glycine are associated with future cocaine use. Furthermore, baseline rIGT scores are associated with both sucrose and cocaine. Finally, both glutamate concentration and mGluR5 availability decrease during exposure to cocaine.

Effects of alcohol exposure on the glutamatergic system: a combined longitudinal 18F-FPEB and 1H-MRS study in rats: Biomarkers for alcohol use

To study the role of the glutamatergic system in alcohol abuse disorders, we conducted a longitudinal study of alcohol exposure in rats. Rats were followed with 1H‐magnetic resonance spectroscopy during a baseline, exposure and abstinence phase to measure prefrontal glutamate and glycine concentrations. Additionally, 18F‐FPEB PET was used to assess metabotropic glutamate receptor 5 (mGluR5) availability before and after exposure to alcohol or saccharin. Finally, individual anxiety levels were assessed with an open field test at baseline. We found that the total distance traveled in the open field test and mGluR5 availability in the nucleus accumbens were associated with future alcohol preference (P = 0.02). Furthermore, prefrontal glutamate concentration decreased significantly during alcohol exposure (> −1.25 ± 0.55 mmol/L, P = 0.038), but normalized during abstinence. Finally, 18F‐FPEB PET showed that self‐administration of alcohol resulted in decreased mGluR5 availability in the hippocampus (>14 ± 3 percent, pCluster = 0.047) and amygdala (>16 ± 2 percent, pCluster = 0.004), whereas saccharin induced decreases in the prefrontal cortex (>11 ± 1 percent, pCluster = 0.035) and hippocampus (>15 ± 2 percent, pCluster = 0.003). A direct comparison of both groups showed differences in mGluR5 availability in the bilateral striatum (−2 ± 4 percent versus +2 ± 2 percent, pCluster = <0.0001) and hippocampus (−16 ± 4 percent versus −5 ± 4 percent, pCluster = <0.0001). In conclusion, this study corroborates the anxiolytic effect of alcohol and provides evidence for mGluR5 downregulation in the amygdala as potential underlying mechanism. Saccharin and alcohol differentially affect prefrontal glutamate concentrations, but both induce an mGluR5 decrease, potentially to modulate the dopamine release elicited by these drugs.

Cerebral dopaminergic and glutamatergic transmission relate to different subjective responses of acute alcohol intake: an in vivo multimodal imaging study

Converging preclinical evidence links extrastriatal dopamine release and glutamatergic transmission via the metabotropic glutamate receptor 5 (mGluR5) to the rewarding properties of alcohol. To date, human evidence is lacking on how and where in the brain these processes occur. Mesocorticolimbic dopamine release upon intravenous alcohol administration and mGluR5 availability were measured in 11 moderate social drinkers by single‐session [18F]fallypride and [18F]FPEB positron emission tomography, respectively. Additionally, baseline and postalcohol glutamate and glutamine levels in the anterior cingulate cortex (ACC) were measured by using proton‐magnetic resonance spectroscopy. To investigate differences in reward domains linked to both neurotransmitters, regional imaging data were related to subjective alcohol responses. Alcohol induced significant [18F]fallypride displacement in the prefrontal cortex (PFC), temporal and parietal cortices and thalamus (P < 0.05, corrected for multiple comparisons). Dopamine release in the ACC and orbitofrontal and ventromedial PFCs were correlated with subjective ‘liking’ and ‘wanting’ effects (P < 0.05). In contrast, baseline mGluR5 availability was positively correlated with the ‘high’ effect of alcohol in dorsolateral, ventrolateral and ventromedial PFCs and in the medial temporal lobe, thalamus and caudate nucleus (P < 0.05). Although neither proton‐magnetic resonance spectroscopy glutamate nor glutamine levels were affected by alcohol, baseline ACC glutamate levels were negatively associated with the alcohol ‘liking’ effect (P < 0.003). These data reveal new mechanistic understanding and differential neurobiological underpinnings of the effects of acute alcohol consumption on human behavior. Specifically, prefrontal dopamine release may encode alcohol ‘liking’ and ‘wanting’ effects in specific areas underlying value processing and motivation, whereas mGluR5 availability in distinct prefrontal–temporal–subcortical regions is more related to the alcohol ‘high’ effect.