Methamphetamine differentially affects BDNF and cell death factors in anatomically defined regions of the hippocampus

Abstract

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 (1 h/day) or extended access (6 h/day) paradigm for 17 days 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 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.

Update of neurotrophic factors in neurobiology of addiction and future directions

“…It was previously shown that there are increased total TrkB levels in the hippocampus and the NAc shell after amphetamine-induced conditioned place preference (Shen et al, 2006), but these data were not confirmed in later studies by McGinty et al (2011) and Galinato et al (2015). The more recent data shows changes in phosphorylated form of TrkB.…”

“…Recently Galinato et al (2015) reported that self-administration of methamphetamine increases BDNF expression in the rat hippocampus. Furthermore, enhanced level of BDNF did not cause alteration of total TrkB or phosphorylated TrkB expression 16–20 h after the last self-administration of the drug (Galinato et al, 2015).…”

“…Furthermore, enhanced level of BDNF did not cause alteration of total TrkB or phosphorylated TrkB expression 16–20 h after the last self-administration of the drug (Galinato et al, 2015). In addition, McGinty et al (2011) observed an increase of phosphorylated TrkB level, but not total TrkB, in the caudate putamen and NAc and not in the dorsomedial PFC, two hours after a single i.p.…”

Wheel running reduces ethanol seeking by increasing neuronal activation and reducing oligodendroglial/neuroinflammatory factors in the medial prefrontal cortex

“…Western blot procedures optimized for measuring levels of both phosphoproteins and total proteins were employed (Graham et al, 2007, Kim et al, 2014, Galinato et al, 2015). Tissue punches from 500-um thick sections of mPFC were homogenized by sonication in ice-cold buffer (320 mM sucrose, 5 mM HEPES, 1 mM EGTA, 1 mM EDTA, 1% SDS, with Protease Inhibitor Cocktail and Phosphatase Inhibitor Cocktails II and III diluted 1:100; Sigma, St. Louis, MO), and protein concentration was determined using a detergent-compatible Lowry method (Bio-Rad, Hercules, CA).…”

Chronic methamphetamine self-administration disrupts cortical control of cognition

“…LgA meth SA also interferes with hippocampal neurogenesis in the dentate gyrus [141, 142], which seems restricted to dorsal areas of the hippocampus [143]. However, to date, only one study has investigated the behavioral consequences of meth-induced reduction of hippocampal neurogenesis by comparing ShA and LgA meth rats [144].…”