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In Vivo [18F] FDG PET Imaging Reveals that p-Chloroamphetamine Neurotoxicity is Associated with Long-Term Cortical and Hippocampal Hypometabolism

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Abstract

Purpose

p-Chloroamphetamine (PCA) is a neurotoxin that selectively degenerates the serotonin (5-HT) axon terminals. In order to study the brain metabolic consequences induced by serotonergic denervation, a single dose of PCA (2.5 or 10 mg/kg i.p.) was administered to male adult rats.

Procedures

In vivo regional brain metabolism was evaluated 3 and 21 days after PCA (2.5 or 10 mg/kg; i.p.) injection by 2-deoxy-2-[18F] fluoro-d-glucose ([18F] FDG) positron emission tomography (PET). At day 22, the following markers of neurotoxicity were determined: (a) 5-HT axon terminal lesion by 5-HT transporter (SERT) autoradiography, (b) reactive gliosis by glial fibrillary acidic protein immunohistochemistry, and (c) eventual neurodegeneration by DAPI/Fluoro-Jade C labeling.

Results

An average of 20 % reduction of [18F] FDG uptake in most brain areas was observed at day 21 under 10 mg/kg PCA treatment. Instead, 2.5 mg/kg PCA only reduced metabolic activity in neocortex. Likewise, the high dose of PCA exerted a strong decrease (>30 %) in SERT density in several 5-HT innervated regions, but no effect was found in midbrain raphe nuclei, the main source of serotonergic neurons. Although PCA induced astroglial activation both in hippocampus and cortex in response to axotomy, no signs of neuronal death in these areas were detected.

Conclusions

Overall, [18F] FDG PET revealed that the reduction of the brain metabolic activity induced by PCA is related to 5-HT axon terminal lesion, with no apparent affectation of neuronal viability.

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Acknowledgments

We thank Dr. José Luis López-Lacomba, director of the Instituto de Estudios Biofuncionales UCM, and Dr. Enrique Martínez-Campos for their assistance in the use of the fluorescence microscope.

This work was financially supported by grants from the Spanish Ministerio de Ciencia e Innovación (SAF2009-09020) and Comunidad de Madrid (I2M2, S2010/BMD-2349).

Conflict of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Departamento de Farmacología, Facultad de Farmacia, Universidad Complutense de Madrid, Plaza Ramón y Cajal s/n, 28040, Madrid, Spain

    Luis García-García, Paloma Bermejo-Bescós & Sagrario Martín-Aragón

  2. Unidad de Cartografía Cerebral, Instituto Pluridisciplinar, Universidad Complutense de Madrid, Paseo Juan XXIII, 1, 28040, Madrid, Spain

    Luis García-García, Mercedes Delgado, Ahmed Anis Al-Sayed, Pablo Bascuñana, Rubén Fernández de la Rosa, Paloma Bermejo-Bescós, Sagrario Martín-Aragón & Miguel A. Pozo

  3. Instituto Tecnológico PET, C/ Manuel Bartolomé Cossío, 10, 28040, Madrid, Spain

    Miguel A. Pozo

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  1. Luis García-García
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  2. Mercedes Delgado
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Correspondence to Luis García-García.

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García-García, L., Delgado, M., Al-Sayed, A.A. et al. In Vivo [18F] FDG PET Imaging Reveals that p-Chloroamphetamine Neurotoxicity is Associated with Long-Term Cortical and Hippocampal Hypometabolism. Mol Imaging Biol 17, 239–247 (2015). https://doi.org/10.1007/s11307-014-0794-4

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