Small animal PET imaging of the type 1 cannabinoid receptor in a rodent model for anorexia nervosa
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Several lines of evidence strongly implicate a dysfunctional endocannabinoid system (ECS) in eating disorders. Using [18F]MK-9470 and small animal positron emission tomography (PET), we investigated for the first time cerebral changes in type 1 cannabinoid (CB1) receptor binding in vivo in the activity-based rat model of anorexia (ABA), in comparison to distinct motor- and food-related control conditions and in relation to gender and behavioural variables.
In total, experiments were conducted on 80 Wistar rats (23 male and 57 female). Male rats were assigned to the cross-sectional conditions: ABA (n = 12) and CONTROL (n = 11), whereas female rats were divided between two settings: (1) a cross-sectional design using ABA (n = 13), CONTROL (n = 9), and two extra control conditions for each of the variables manipulated in ABA, i.e. DIET (n = 8) and WHEEL (n = 9), and (2) a longitudinal one using ABA (n = 10) and CONTROL (n = 8) studied at baseline, during the model and upon recovery. The ABA group was subjected to food restriction in the presence of a running wheel, the DIET group to food restriction without wheel, the WHEEL group to a normal diet with wheel and CONTROL animals had a normal diet and no running wheel. Parametric CB1 receptor images of each group were spatially normalized to Paxinos space and analysed voxel-wise.
In the ABA model, absolute [18F]MK-9470 binding was significantly increased in all cortical and subcortical brain areas as compared to control conditions (male +67 %; female >51 %, all p cluster < 6.3×10−6) that normalized towards baseline values after weight gain. Additionally, relative [18F]MK-9470 binding was increased in the hippocampus, inferior colliculus and entorhinal cortex of female ABA (+4.6 %; p cluster < 1.3×10−6), whereas no regional differences were observed in male subjects. Again, relative [18F]MK-9470 binding values normalized upon weight gain.
These data point to a widespread transient disturbance of the endocannabinoid transmission, specifically for CB1 receptors in the ABA model. Our data also suggest (1) gender effects on regional CB1 receptor binding in the hippocampus and (2) add further proof to the validity of the ABA model to mimic aspects of human disease.
KeywordsType 1 cannabinoid receptor Anorexia nervosa ABA Small animal PET [18F]MK-9470
Merck & Co, Inc. is acknowledged for the availability of the [18F]MK-9470 precursor, and for their critical revision of this manuscript and their suggestions for improvement. The authors thank Peter Vermaelen and Ann Van Santvoort for their assistance in data acquisition, as well as the Leuven PET radiopharmacy team for tracer preparations. Financial support of the Research Council of the Katholieke Universiteit Leuven (OT/05/58), the Fund for Scientific Research, Flanders, Belgium (FWO/G.0548.06), the K.U. Leuven Molecular Small Animal Imaging Center (KUL EF/05/08) is gratefully acknowledged. Cindy Casteels and Kris van Kuyck are supported by a postdoctoral mandate of the Flemish Fund for Scientific Research. Koen Van Laere is a senior clinical investigator of the Flemish Fund for Scientific Research.
Conflicts of interest
- 2.American Psychiatric Association. Treatment of patients with eating disorders, third edition. American Psychiatric Association. Am J Psychiatry 2006; 163:4–54.Google Scholar
- 17.Rorato R, Reis WL, de Carvalho BB, Antunes-Rodrigues J, Elias LL. Cannabinoid CB(1) receptor restrains accentuated activity of hypothalamic corticotropin-releasing factor and brainstem tyrosine hydroxylase neurons in endotoxemia-induced hypophagia in rats. Neuropharmacology 2012;63:154–60.PubMedCrossRefGoogle Scholar
- 26.Casteels C, Bormans G, Van Laere K. The effect of anaesthesia on [(18)F]MK-9470 binding to the type 1 cannabinoid receptor in the rat brain. Eur J Nucl Med Mol Imaging 2010;37:1164–73.Google Scholar
- 43.Fride E, Bregman T, Kirkham TC. Endocannabinoids and food intake: newborn suckling and appetite regulation in adulthood. Exp Biol Med (Maywood) 2005;230:225–34.Google Scholar
- 44.Riad M, Zimmer L, Rbah L, Watkins KC, Hamon M, Descarries L. Acute treatment with the antidepressant fluoxetine internalizes 5-HT1A autoreceptors and reduces the in vivo binding of the PET radioligand [18F]MPPF in the nucleus raphe dorsalis of rat. J Neurosci 2004;24:5420–6.PubMedCrossRefGoogle Scholar
- 50.Aoki C, Sabaliauskas N, Chowdhury T, Min JY, Colacino AR, Laurino K, et al. Adolescent female rats exhibiting activity-based anorexia express elevated levels of GABA(A) receptor alpha4 and delta subunits at the plasma membrane of hippocampal CA1 spines. Synapse 2012;66:391–407.PubMedCentralPubMedCrossRefGoogle Scholar