PMID- 25463524 OWN - NLM STAT- MEDLINE DCOM- 20150914 LR - 20181113 IS - 1873-7544 (Electronic) IS - 0306-4522 (Print) IS - 0306-4522 (Linking) VI - 286 DP - 2015 Feb 12 TI - Methamphetamine differentially affects BDNF and cell death factors in anatomically defined regions of the hippocampus. PG - 97-108 LID - S0306-4522(14)01008-2 [pii] LID - 10.1016/j.neuroscience.2014.11.042 [doi] AB - Methamphetamine exposure reduces hippocampal long-term potentiation (LTP) and neurogenesis and these alterations partially contribute to hippocampal maladaptive plasticity. The potential mechanisms underlying methamphetamine-induced maladaptive plasticity were identified in the present study. Expression of brain-derived neurotrophic factor (BDNF; a regulator of LTP and neurogenesis), and its receptor tropomyosin-related kinase B (TrkB) were studied in the dorsal and ventral hippocampal tissue lysates in rats that intravenously self-administered methamphetamine in a limited access (1h/day) or extended access (6h/day) paradigm for 17days post baseline sessions. Extended access methamphetamine enhanced expression of BDNF with significant effects observed in the dorsal and ventral hippocampus. Methamphetamine-induced enhancements in BDNF expression were not associated with TrkB receptor activation as indicated by phospho (p)-TrkB-706 levels. Conversely, methamphetamine produced hypophosphorylation of N-methyl-d-aspartate (NMDA) receptor subunit 2B (GluN2B) at Tyr-1472 in the ventral hippocampus, indicating reduced receptor activation. In addition, methamphetamine enhanced expression of anti-apoptotic protein Bcl-2 and reduced pro-apoptotic protein Bax levels in the ventral hippocampus, suggesting a mechanism for reducing cell death. Analysis of Akt, a pro-survival kinase that suppresses apoptotic pathways and pAkt at Ser-473 demonstrated that extended access methamphetamine reduces Akt expression in the ventral hippocampus. These data reveal that alterations in Bcl-2 and Bax levels by methamphetamine were not associated with enhanced Akt expression. Given that hippocampal function and neurogenesis vary in a subregion-specific fashion, where dorsal hippocampus regulates spatial processing and has higher levels of neurogenesis, whereas ventral hippocampus regulates anxiety-related behaviors, these data suggest that methamphetamine self-administration initiates distinct allostatic changes in hippocampal subregions that may contribute to the altered synaptic activity in the hippocampus, which may underlie enhanced negative affective symptoms and perpetuation of the addiction cycle. CI - Copyright (c) 2014 IBRO. Published by Elsevier Ltd. All rights reserved. FAU - Galinato, M H AU - Galinato MH AD - Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Neurosciences, University of California San Diego, La Jolla, CA 92037, USA. FAU - Orio, L AU - Orio L AD - Departamento de Psicobiologia, Facultad Psicologia, Universidad Complutense de Madrid, Campus Somosaguas, 28223 Pozuelo de Alarcon, Madrid, Spain. FAU - Mandyam, C D AU - Mandyam CD AD - Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Neurosciences, University of California San Diego, La Jolla, CA 92037, USA. Electronic address: cmandyam@scripps.edu. LA - eng GR - P50 AA006420/AA/NIAAA NIH HHS/United States GR - AA06420/AA/NIAAA NIH HHS/United States GR - R01 AA020098/AA/NIAAA NIH HHS/United States GR - K01 DA022473/DA/NIDA NIH HHS/United States GR - DA022473/DA/NIDA NIH HHS/United States GR - DA034140/DA/NIDA NIH HHS/United States GR - AA020098/AA/NIAAA NIH HHS/United States GR - T32 NS061847/NS/NINDS NIH HHS/United States GR - R01 DA034140/DA/NIDA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20141126 PL - United States TA - Neuroscience JT - Neuroscience JID - 7605074 RN - 0 (Bax protein, rat) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (NR2B NMDA receptor) RN - 0 (Proto-Oncogene Proteins c-bcl-2) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - 0 (bcl-2-Associated X Protein) RN - 44RAL3456C (Methamphetamine) RN - EC 2.7.10.1 (Receptor, trkB) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) SB - IM MH - Animals MH - Apoptosis/drug effects MH - Brain-Derived Neurotrophic Factor/*metabolism MH - Cell Death/drug effects MH - Hippocampus/*drug effects MH - Male MH - Methamphetamine/*administration & dosage MH - Phosphorylation MH - Proto-Oncogene Proteins c-akt/metabolism MH - Proto-Oncogene Proteins c-bcl-2/metabolism MH - Rats MH - Rats, Wistar MH - Receptor, trkB/*metabolism MH - Receptors, N-Methyl-D-Aspartate/metabolism MH - Self Administration MH - bcl-2-Associated X Protein/metabolism PMC - PMC4298458 MID - NIHMS645497 OTO - NOTNLM OT - Bax OT - Bcl-2 OT - GluN2B OT - TrkB OT - self-administration OT - ventral hippocampus EDAT- 2014/12/03 06:00 MHDA- 2015/09/15 06:00 PMCR- 2016/02/12 CRDT- 2014/12/03 06:00 PHST- 2014/09/19 00:00 [received] PHST- 2014/10/25 00:00 [revised] PHST- 2014/11/08 00:00 [accepted] PHST- 2014/12/03 06:00 [entrez] PHST- 2014/12/03 06:00 [pubmed] PHST- 2015/09/15 06:00 [medline] PHST- 2016/02/12 00:00 [pmc-release] AID - S0306-4522(14)01008-2 [pii] AID - 10.1016/j.neuroscience.2014.11.042 [doi] PST - ppublish SO - Neuroscience. 2015 Feb 12;286:97-108. doi: 10.1016/j.neuroscience.2014.11.042. Epub 2014 Nov 26.