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Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 391, Issue 4, pp 423–434 | Cite as

Methamphetamine withdrawal induces activation of CRF neurons in the brain stress system in parallel with an increased activity of cardiac sympathetic pathways

  • Juan Antonio García-Carmona
  • Polymnia Georgiou
  • Panos Zanos
  • Alexis Bailey
  • Maria Luisa Laorden
Original Article

Abstract

Methamphetamine (METH) addiction is a major public health problem in some countries. There is evidence to suggest that METH use is associated with increased risk of developing cardiovascular problems. Here, we investigated the effects of chronic METH administration and withdrawal on the activation of the brain stress system and cardiac sympathetic pathways. Mice were treated with METH (2 mg/kg, i.p.) for 10 days and left to spontaneous withdraw for 7 days. The number of corticotrophin-releasing factor (CRF), c-Fos, and CRF/c-Fos neurons was measured by immunohistochemistry in the paraventricular nucleus of the hypothalamus (PVN) and the oval region of the bed nucleus of stria terminalis (ovBNST), two regions associated with cardiac sympathetic control. In parallel, levels of catechol-o-methyl-transferase (COMT), tyrosine hydroxylase (TH), and heat shock protein 27 (Hsp27) were measured in the heart. In the brain, chronic-METH treatment enhanced the number of c-Fos neurons and the CRF neurons with c-Fos signal (CRF+/c-Fos+) in PVN and ovBNST. METH withdrawal increased the number of CRF+ neurons. In the heart, METH administration induced an increase in soluble (S)-COMT and membrane-bound (MB)-COMT without changes in phospho (p)-TH, Hsp27, or pHsp27. Similarly, METH withdrawal increased the expression of S- and MB-COMT. In contrast to chronic treatment, METH withdrawal enhanced levels of (p)TH and (p)Hsp27 in the heart. Overall, our results demonstrate that chronic METH administration and withdrawal activate the brain CRF systems associated with the heart sympathetic control and point towards a METH withdrawal induced activation of sympathetic pathways in the heart. Our findings provide further insight in the mechanism underlining the cardiovascular risk associated with METH use and proposes targets for its treatment.

Keywords

Methamphetamine Addiction Withdrawal CRF COMT Hsp27 Heart 

Notes

Acknowledgements

The authors want to thank Dr. Julie Howarth and Ms. Ashleigh Thompson for her assistance with cardiac histopathology.

Funding information

Funding for this study was provided by a Royal Society grant (RG120556; P.I. Alexis Bailey). The sponsors had no involvement in the design of the study and in the collection, analyses, and interpretation of the data nor in the writing of the manuscript and the decision to submit this article for publication.

Compliance with ethical standards

All experimental procedures were conducted in accordance with the UK Animal Scientific Procedures Act (1986).

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pharmacology, Faculty of MedicineUniversity of MurciaMurciaSpain
  2. 2.Unit of Acute PsychiatryReina Sofía University HospitalMurciaSpain
  3. 3.Department of Biochemistry, Faculty of Health and Medical SciencesUniversity of SurreyGuildfordUK
  4. 4.Department of PsychiatryUniversity of Maryland School of MedicineBaltimoreUSA
  5. 5.Institute of Medical and Biomedical EducationSt. George’s University of LondonLondonUK

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