Methamphetamine withdrawal induces activation of CRF neurons in the brain stress system in parallel with an increased activity of cardiac sympathetic pathways
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.
KeywordsMethamphetamine Addiction Withdrawal CRF COMT Hsp27 Heart
The authors want to thank Dr. Julie Howarth and Ms. Ashleigh Thompson for her assistance with cardiac histopathology.
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).
- Ammon-Treiber S, Grecksch G, Stumm R, Riechert U, Tischmeyer H, Reichenauer A, Höllt V (2004) Rapid, transient, and dose-dependent expression of hsp70 messenger RNA in the rat brain after morphine treatment. Cell Stress Chaperones 9(2):182–197. https://doi.org/10.1379/CSC-42.1 CrossRefPubMedPubMedCentralGoogle Scholar
- Francesconi W, Berton F, Repunte-Canonigo V, Hagihara K, Thurbon D, Lekic D, Specio SE, Greenwell TN, Chen SA, Rice KC, Richardson HN, O’Dell LE, Zorrilla EP, Morales M, Koob GF, Sanna PP (2009) Protracted withdrawal from alcohol and drugs of abuse impairs long-term potentiation of intrinsic excitability in the juxtacapsular bed nucleus of the stria terminalis. J Neurosci 29(17):5389–5401. https://doi.org/10.1523/JNEUROSCI.5129-08.2009 CrossRefPubMedPubMedCentralGoogle Scholar
- Garcia-Carmona JA, Martinez-Laorden E, Milanes MV, Laorden ML (2015) Sympathetic activity induced by naloxone-precipitated morphine withdrawal is blocked in genetically engineered mice lacking functional CRF1 receptor. Toxicol Appl Pharmacol 283(1):42–49. https://doi.org/10.1016/j.taap.2015.01.002 CrossRefPubMedGoogle Scholar
- Georgiou P, Zanos P, Ehteramyan M, Hourani S, Kitchen I, Maldonado R, Bailey A (2015) Differential regulation of mGlu5 R and MuOPr by priming- and cue-induced reinstatement of cocaine-seeking behaviour in mice. Addict Biol 20(5):902–912. https://doi.org/10.1111/adb.12208 CrossRefPubMedGoogle Scholar
- Georgiou P, Zanos P, Garcia-Carmona JA, Hourani S, Kitchen I, Laorden ML, Bailey A (2016) Methamphetamine abstinence induces changes in u-opioid receptor, oxytocin and CRF systems: association with an anxiogenic phenotype. Neuropharmacology 105:520–532. https://doi.org/10.1016/j.neuropharm.2016.02.012 CrossRefPubMedGoogle Scholar
- Gonzales R, Mooney L, Rawson RA (2010) The methamphetamine problem in the United States. Ann Rev Pub Health 31(1):385–398. https://doi.org/10.1146/annurev.publhealth.012809.103600 CrossRefGoogle Scholar
- Kasch S (1987) Serum catecholamines in cocaine intoxicated patients with cardiac symptoms. Ann Emerg Med 16:481Google Scholar
- Martínez-Laoden E, Hurle MA, Milanés MV, Laorden ML, Almela P (2012) Morphine withdrawal activates hypothalamic–pituitary–adrenal axis and heat shock protein 27 in the left ventricle: the role of extracellular signal regulated kinase. J Pharmacol Exp Ther 342(3):665–675. https://doi.org/10.1124/jpet.112.193581 CrossRefGoogle Scholar
- Martinez-Laorden E, Garcia-Carmona JA, Baroja-Mazo A, Romecin P, Atucha NM, Milanes MV, Laorden ML (2014) Corticotropin-releasing factor (CRF) receptor-1 is involved in cardiac noradrenergic activity observed during naloxone-precipitated morphine withdrawal. Br J Pharmacol 171(3):688–700. https://doi.org/10.1111/bph.12511 CrossRefPubMedPubMedCentralGoogle Scholar
- Nijsen MJ, Croiset G, Diamant M, De Wied D, Wiegant VM (2001) CRH signalling in the bed nucleus of the stria terminalis is involved in stress-induced cardiac vagal activation in conscious rats. Neuropsychopharmacology 24(1):1–10. https://doi.org/10.1016/S0893-133X(00)00167-6 CrossRefPubMedGoogle Scholar
- Nobis WP, Kash TL, Silberman Y, Winder DG (2011) β-Adrenergic receptors enhance excitatory transmission in the bed nucleus of the stria terminalis through a corticotrophin-releasing factor receptor-dependent and cocaine-regulated mechanism. Biol Psychiatry 69(11):1083–1090. https://doi.org/10.1016/j.biopsych.2010.12.030 CrossRefPubMedPubMedCentralGoogle Scholar
- Olive MF, Koenig HN, Nannini MA, Hodge CW (2002) Elevated extracellular CRF levels in the bed nucleus of the stria terminalis during ethanol withdrawal and reduction by subsequent ethanol intake. Pharmacol Biochem Behav 72(1-2):213–220. https://doi.org/10.1016/S0091-3057(01)00748-1 CrossRefPubMedGoogle Scholar
- Ongur D, An X, Price JL (1998) Prefrontal cortical projections to the hypothalamus in macaque monkeys. J Comp Neurol 401(4):480–505. https://doi.org/10.1002/(SICI)1096-9861(19981130)401:4<480::AID-CNE4>3.0.CO;2-F CrossRefPubMedGoogle Scholar
- Rogalla T, Ehrnsperger M, Preville X, Kotlyarov A, Lutsch G, Ducasse C, Paul C, Wieske M, Arrigo AP, Buchner J, Gaestel M (1999) Regulation of Hsp27 oligomerization, chaperone function, and protective activity against oxidative stress/tumor necrosis factor alpha by phosphorylation. J BiolChem 274:18947–18956Google Scholar
- Wagner GC, Ricaurte GA, Seiden LS, Schuster CR, Miller RJ, Westley J (1980) Long-lasting depletions of striatal dopamine and loss of dopamine uptake sites following repeated administration of methamphetamine. Brain Res 181(1):151–160. https://doi.org/10.1016/0006-8993(80)91265-2 CrossRefPubMedGoogle Scholar
- Yu Y, Wei SG, Zhang ZH, Weiss RM, Felder RB (2016) ERK1/2 MAPK signaling in hypothalamic paraventricular nucleus contributes to sympathetic excitation in rats with heart failure after myocardial infarction. Am J Physiol Heart Circ Physiol 310(6):H732–H739. https://doi.org/10.1152/ajpheart.00703.2015 CrossRefPubMedPubMedCentralGoogle Scholar