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Small animal PET imaging of the type 1 cannabinoid receptor in a rodent model for anorexia nervosa

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Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusion

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.

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Acknowledgments

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.

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Authors and Affiliations

  1. Division of Nuclear Medicine, University Hospital and KU Leuven, Herestraat 49 bus 7003, 3000, Leuven, Belgium

    Cindy Casteels, Nathalie Gérard, Lies Pottel & Koen Van Laere

  2. Molecular Small Animal Imaging Center (MoSAIC), KU Leuven, Leuven, Belgium

    Cindy Casteels, Nathalie Gérard, Lies Pottel, Guy Bormans & Koen Van Laere

  3. Laboratory for Experimental Functional Neurosurgery, KU Leuven, Leuven, Belgium

    Kris van Kuyck & Bart Nuttin

  4. Laboratory for Radiopharmacy, University Hospital and KU Leuven, Leuven, Belgium

    Guy Bormans

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  1. Cindy Casteels
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Correspondence to Cindy Casteels.

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Supplementary Fig. 1

Brain and plasma kinetics of [18F]MK-9470 in ABA. Average tissue-activity curves in the cortex (a) and average metabolite-corrected plasma input curves (b) of ABA (○) and CONTROL (□) rats (n = 2/group). Insert: detail of curves in b between 0 and 600 min. Data are given as mean ± SD. (TIFF 552 kb) (JPEG 12 kb)

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Casteels, C., Gérard, N., van Kuyck, K. et al. Small animal PET imaging of the type 1 cannabinoid receptor in a rodent model for anorexia nervosa. Eur J Nucl Med Mol Imaging 41, 308–321 (2014). https://doi.org/10.1007/s00259-013-2522-8

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  • DOI: https://doi.org/10.1007/s00259-013-2522-8

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