Metabotropic Glutamate Receptor Subtype 5 in Males With Autism Spectrum Disorder: Preliminary Findings of a [11C]ABP688 Positron Emission Tomography Study

Background: Preclinical investigations suggesting a therapeutic potential for metabotropic glutamate receptor subtype 5 (mGluR5) antagonists in fragile X syndrome raised interest in mGluR5 in neurodevelopment disorders in general, including autism spectrum disorder (ASD) (Davenport et al, 2016; Gogliotti and Conn, 2016; Scharf et al, 2015). To investigate the role of mGluR5 in ASD in vivo we carried out a positron emission tomography (PET) study with the mGluR5-selective radiotracer [11C]ABP688 in subjects with ASD and healthy controls. Methods: Seventeen male subjects with ASD and 22 healthy male age-matched controls participated in this study. As our previous work showed that smoking profoundly and enduringly alters mGluR5 (Akkus et al, 2013), we matched both samples for smoking. As a result, the ASD sample included 11 non-smokers, 2 ex-smokers and four current smokers, and the control group 15 non-smokers, 2 exsmokers and five current smokers. We assessed psychopathology in both study groups with the Structured Clinical Interview for DSM-IV Axis I (SCID-I), Beck Anxiety Inventory (BAI), and Beck Depression Inventory (BDI). In addition, we evaluated subjects with ASD using the Autism Diagnostic Observation Schedule (ADOS), Yale-Brown Obsessive Compulsive Scale (Y-BOCS), Obsessive Compulsive Inventory-Revised (OCI-R), Autism Quotient (AQ), and Empathy Quotient questionnaires (EQ). We acquired PET data with a bolus/infusion protocol, as previously reported (Burger et al, 2010). In brief, [11C]ABP688 was administered in a 50- mL volume with an infusion pump. Our previous work shows that 40 min after the start of radioligand infusion equilibrium between [11C]ABP688 in tissue and blood is achieved. To calculate the relative distribution volume (DVR), we normalized the average of PET images acquired at 45-60 min after scan onset to the radioactivity concentration in the cerebellum. We used PMOD (PNEUROTool) and R for data analysis. We compared mGluR5 DVR in both groups in 33 brain regions using two-tailed Welch’s t-tests, without correction for multiple comparisons. Results: Age did not differ significantly between subjects with ASD and controls when comparing the entire samples or their subgroups (all p-values>0.05, two-tailed). Overall, subjects with ASD scored higher in BAI and BDI (p<0.05, two-tailed). We found no significant differences in mGluR5 DVR in any of the brain regions when comparing the entire samples comprising smokers, ex-smokers, and non-smokers (all p-values > 0.05, two-tailed). As expected, in both samples, smokers displayed globally decreased mGluR5 DVR (p0.05, two-tailed). Exploratory correlation analyses involving BAI, BDI, AQ, EQ, and mGluR5 DVR in the straight gyrus, posterior superior temporal gyrus, and postcentral gyrus in nonsmokers with ASD yielded only one significant relationship: higher, i.e., more aberrant, mGluR5 DVR in the postcentral gyrus corresponded to lower, i.e., more aberrant, EQ score (Spearman’s rho = -0.64, p<0.05, two-tailed, uncorrected for multiple comparisons). Conclusions: To our knowledge, this is the first in vivo investigation of mGluR5 in persons with ASD. Our findings suggest increased mGluR5 DVR in the straight gyrus, the posterior superior temporal gyrus, and the postcentral gyrus in male non-smokers with ASD. Due to the small sample size and the exploratory nature of the statistical analyses, these results remain preliminary. Nevertheless, our findings provide a preliminary support for the involvement of mGluR5 in ASD, encourage the study of mGluR5 in larger samples, and suggest a therapeutic potential for agents targeting the mGluR5 in autism (Mehta et al, 2011; Silverman et al, 2010). Keywords: mGluR5 Receptors, Autism Spectrum Disorder, PET Imaging Disclosure: Nothing to Disclose

Predicting relapse in bulimia nervosa: Neural and behavioral response to catecholamine depletion

Background: Bulimia nervosa (BN) is a severe psychiatric disorder characterized by recurrent binge eating episodes followed by inappropriate compensatory behavior such as purging or excessive exercise. Frank proposed in his model of eating disorders that BN is associated with a desensitized dopamine system (Frank, 2016). However, direct investigations on the causal effect of a hypofunction of the dopamine system on neural activity, bulimic and depressive symptoms, and on the course of the illness are still missing. Catecholamine depletion induced by alpha-methyl-paratyrosine (AMPT) is an instructive paradigm to investigate directly the relationship between dopaminergic neurotransmission and the symptoms and course of BN. In our previous behavioral study, experimental catecholamine depletion provoked mild eating disorder symptoms in fully remitted BN (Grob et al, 2015). The purpose of this study was to examine the effect of catecholamine depletion on neural activity in BN. Furthermore, we were interested in the relationship between this effect and the risk for relapse. Methods: In a randomized, double-blind, crossover design, catecholamine depletion was achieved using the oral administration of AMPT over 24 hours in 18 remitted bulimic (rBN) and 22 healthy (HC) female participants. Cerebral blood flow (CBF) was measured using a pseudo continuous arterial spin labeling (pCASL) sequence. AMPT-induced mood and eating disorder symptoms were examined using the Montgomery-Åsberg Depression Scale (MADRS) (Schmidtke et al, 1988), the Eating Disorder Examination-Questionnaire (EDE-Q) (Hilbert and Tuschen-Caffier, 2006), and the vigor subscale of the Profile of Mood States (POMS) (McNair et al, 1981). Bulimic relapse was assessed in a follow-up telephone interview (latency varied between 18 and 42 months) after study participation. Results: RBN participants revealed no increases of eating disorder symptoms following AMPT administration. However, AMPT reduced POMS vigor in both groups, and this effect was stronger in rBN participants. Furthermore, in rBN participants, AMPT decreased CBF in the pallidum and posterior midcingulate cortex (pMCC), whereas in HC participants, we did not find AMPT-induced alterations in CBF in these brain regions. AMPT-induced depressive symptoms and reductions in CBF in the hippocampus/ parahippocampal gyrus predicted relapse in rBN participants. In contrast, AMPT-induced CBF increase in the hippocampus/ parahippocampal gyrus predicted remission. Conclusions: We demonstrated that AMPT decreased CBF in the pallidum and pMCC in rBN participants. In the context of the Frank model (Frank, 2016), these regions can be considered as neural correlates of the desensitized dopamine system in BN. In contrast to our previous study (Grob et al, 2015), we did not observe an AMPT-induced increase of eating disorder symptoms. However, our earlier investigation was carried out in a controlled environment, without food cues and with regular, standardized meals (Grob et al, 2015). The uncontrolled environment in which this study was conducted might have overridden the effect of AMPT on eating disorder symptoms. In rBN participants, AMPT reduced vigor more strongly than in healthy individuals. This vigor reduction might trigger eating disorder symptoms to counteract dopamine deficiency and the related depression-like mental state. AMPT-induced depressive symptoms and CBF reduction in the hippocampus predicted bulimic relapse. Binge eating was reported to have an anti-depressive and dopamine elevating effect (Jahng et al, 2012). Therefore, dopamine deficiency and a dysfunctional hippocampus activity might trigger inappropriate behavior, such as binge eating to reduce negative emotions and anhedonia. Our findings expand Frank’s model of eating disorders (Frank, 2016), and emphasize the importance of depressive symptoms and the stress system in the course of bulimia nervosa. Keywords: Bulimia Nervosa, Catecholamine Depletion, Relapse, Cerebral Blood Flow, Neuroimaging. Disclosure: Nothing to disclose