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Chronic methadone treatment and repeated withdrawal impair cognition and increase the expression of apoptosis-related proteins in mouse brain

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Abstract

Objectives

This study analyzes the effects of prolonged administration of methadone and withdrawal on sensorimotor and cognitive performance in mice and explores the associated changes in brain expression of proteins regulating the extrinsic (FasL, Fas, and caspase-8) and the mitochondrial (Bcl-2, Bcl-xL, Bad, and Bax) apoptotic pathways.

Results

Our findings indicate that, although acute methadone administration impairs some sensorimotor abilities, tolerance to most of the deleterious effects develops after chronic administration. Cognitive abilities in the Morris water maze were impaired by chronic methadone and, to a greater extent, by exposure to precipitated withdrawal every week in the course of methadone treatment. Both the chronic methadone and repeated withdrawal groups showed up-regulation of several pro-apoptotic proteins (FasL, the active fragment of caspase-8, and Bad) in the cortex and hippocampus, indicating activation of both the death-receptor and mitochondrial apoptotic pathways. In contrast, reduced expression of the apoptosis regulatory proteins FasL and Bad was found after a single administration of methadone.

Conclusions

Our data suggest that neural apoptotic damage could contribute to impairment of the cognitive abilities of mice observed after chronic methadone administration and withdrawal.

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Acknowledgment

This work was supported by research grants from the Ministerio de Educación y Ciencia (SAF2002-01392) and Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III (Red G03/005). The authors wish to thank N. García Iglesias for her technical assistance.

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Authors and Affiliations

  1. Departamento de Fisiología y Farmacología, Universidad de Cantabria, Santander, Spain

    Mónica Tramullas & Carmen Martínez-Cué

  2. Departamento de Fisiología y Farmacología, Unidad de Biomedicina-CISC, Facultad de Medicina, Universidad de Cantabria, 39011, Santander, Spain

    María A. Hurlé

Authors
  1. Mónica Tramullas
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  2. Carmen Martínez-Cué
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  3. María A. Hurlé
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Correspondence to María A. Hurlé.

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Mónica Tramullas and Carmen Martínez-Cué contributed equally to the development of this work.

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Tramullas, M., Martínez-Cué, C. & Hurlé, M.A. Chronic methadone treatment and repeated withdrawal impair cognition and increase the expression of apoptosis-related proteins in mouse brain. Psychopharmacology 193, 107–120 (2007). https://doi.org/10.1007/s00213-007-0751-x

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  • DOI: https://doi.org/10.1007/s00213-007-0751-x

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