Metabotropic glutamate receptor 5 binding in bulimia nervosa: Preliminary findings of a [11C]ABP688 positron emission tomography study

Hasler, Gregor; Akkus, Funda (2016). Metabotropic glutamate receptor 5 binding in bulimia nervosa: Preliminary findings of a [11C]ABP688 positron emission tomography study. Neuropsychopharmacology, 41, S455-S630. Nature Publishing Group

Background: Substance addiction is suggested to undergo three stages: a binge/intoxication stage, a withdrawal/negative effect stage, and a preoccupation/anticipation stage (Koob & Volkow, 2016). Substantial preclinical evidence implicates metabotropic glutamate receptor subtype 5 (mGluR5) in the binge/intoxication phase (Mihov & Hasler, 2016). Furthermore, positron emission tomography (PET) studies in clinical samples show aberrant mGluR5 binding in substance addiction. In recent years, the phenotypical similarities between binge behavior in substance addiction and eating disorders have received increasing attention (Smith & Robbins, 2013), suggesting a partially shared underlying pathophysiology, which likely involves mGluR5. To investigate mGluR5 in bulimia nervosa (BN) in vivo we designed a PET study with the mGluR5-specific radiotracer 3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-11C-methyl-oxime ([11C]ABP688).

Methods: [11C]ABP688 PET was carried out in 15 female participants with BN and 14 healthy female controls. Due to the strong impact of smoking on mGluR5 shown in our previous work (Akkus et al., 2013) groups were matched for smoking status. This resulted in two groups, BN and controls, each comprising three subgroups (non-smokers, ex-smokers, and current smokers). Psychopathology in cases and controls was assessed by the Structured Clinical Interview for DSM-IV Axis I (SCID-I), Beck Anxiety Inventory (BAI), and Beck Depression Inventory (BDI). Participants with BN filled out the Eating Disorder Examination Questionnaire (EDE-Q) and the Eating Disorder Inventory (EDI-2).

We applied a bolus/infusion protocol, previously evaluated for PET with [11C]ABP688, which normalizes PET images to the cerebellar radioactivity concentration, allows reliable measurement of the relative distribution volume (DVR), and reduces potential bias due to arterial blood sampling needed for absolute quantification. With this protocol equilibrium between the tracer in tissue and blood is achieved 40 min after the start of radioligand infusion. A total of 600–800 MBq of [11C]ABP688 in a 50- mL volume was administered using an infusion pump. Analyses were conducted with the PNEURO-Tool in PMOD and with SPSS. Groups were compared with Welch’s t-tests; correlations were tested with Spearman’s rho. All reported p-values refer to two-tailed tests, uncorrected for multiple comparisons. Descriptive statistics are reported as mean± standard error of the mean.

Results: Each group comprised five current smokers, two ex-smokers, and seven (control sample) or eight (BN) non-smokers. Both groups and their smoking subgroups were age-matched (p≥ 0.7). Persons with BN reported higher BAI scores (13.3± 2.5 versus 4.9± 1.1, p= 0.006) and higher BDI scores (18.9± 3 versus 2.3± 0.5, p< 0.001) than controls.

Analysis of PET data revealed significantly increased mGluR5 binding in BN (p= 0.038) in the anterior cingulate gyrus (ACC) and non-signifcant trends (0.05< p< 0.1) for increased mGluR5 in BN in several other regions: the straight gyrus, medial orbital gyrus, pre-subgenual anterior cingulate, amygdala, lateral part of the anterior temporal lobe, posterior part of the superior temporal gyrus, middle and inferior temporal gyrus, fusiform gyrus, and nucleus accumbens.

Our previous work has shown a marked global reduction in mGluR5 binding in smokers (Akkus et al., 2013). Therefore, we carried out additional analyses within smoking and within non-smoking participants. The mGluR5 binding increase in the ACC in BN was significant in current smokers (p= 0.037, n= 5 per group) but not in non-smokers (p= 0.15, n= 7 or 8 per group). To test if this discrepancy reflects a systematic interaction between group and smoking an analysis of variance (ANOVA) was calculated with the fixed effects „sample “and „smoking “. Current and ex-smokers were clustered into one factor level (smoking, n= 7 per group), whereas non-smokers constituted the other factor level. This resulted in a 2 x 2 ANOVA design, yielding a significant effect of sample (F= 4.95; p= 0.035), a significant effect of smoking (F= 4.85; p= 0.037), and a non-significant smoking-by-sample interaction (F= 0.113; p= 0.74). Overall, these results confirm our previous findings of smoking-related decrease in mGluR5 binding and show increased mGluR5 binding in the ACC in smoking and non-smoking persons with BN.

We did not find significant correlations between ACC mGluR5 and any of the EDE-Q subscales within the entire BN sample or its smoking subgroups (p≥ 0.11). On the EDI-2, in non-smokers (n= 8), higher ACC mGluR5 binding was related to lower „drive for thinness “(rho= -0.86; p= 0.007). No significant correlations between BDI or BAI scores and mGluR5 binding in the ACC were found within the BN sample and its smoking subsamples (p ≥.13).

Conclusions: To our knowledge, this is the first in vivo study of mGluR5 in BN. Our preliminary findings suggest abnormal mGluR5 in BN. Together with consistent preclinical evidence that drugs targeting the mGluR5 reduce binging behavior in addiction, these results indicate that mGluR5 could be considered as a new pharmacological target in the treatment of BN.

Keywords: mGluR5 Receptors, Bulimia Nervosa, PET Study.

Disclosure: Nothing to disclose.

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