Date Published:
2016 Mar

Publication Type:
Journal Article

Authors:

L. Yang
H. Yao
X. Chen
Y. Cai
S. Callen
S. Buch

Secondary:
Mol Neurobiol

Volume:
53

Pagination:
1329-1342

Issue:
2

PMID:
25631712

URL:
https://pubmed.ncbi.nlm.nih.gov/25631712

DOI:
10.1007/s12035-015-9094-5

Keywords:
Adult;AIDS Dementia Complex;Animals;Astrocytes;Cocaine;Cocaine-Related Disorders;Early Growth Response Protein 1;Enzyme Activation;External;Female;Glial Fibrillary Acidic Protein;Humans;Male;MAP Kinase Signaling System;Membrane Microdomains;Mice, Inbred C57BL;Middle Aged;Protein Transport;Receptors, sigma;RNA, Messenger;Up-Regulation

Abstract:
<p>Cocaine abuse has been shown to accelerate the progression of human immunodeficiency virus (HIV)-1-associated neurological disorders (HANDs) partially through increasing neuroinflammatory response mediated by activated astrocytes; however, the detailed molecular mechanism of cocaine-mediated astrocyte activation is unclear. In the current study, we demonstrated increased astrogliosis in the cortical regions of brains from HIV(+) cocaine abusers compared with the HIV(+) group without cocaine abuse. We next sought to explore whether cocaine exposure could result in increased expression of glial fibrillary acidic protein (GFAP), a filament protein critical for astrocyte activation. Exposure of cocaine to astrocytes resulted in rapid translocation of sigma receptor to the plasma membrane with subsequent activation of downstream signaling pathways. Using a pharmacological approach, we provide evidence that cocaine-mediated upregulation of GFAP expression involved activation of mitogen-activated protein kinase (MAPK) signaling with subsequent downstream activation of the early growth response gene 1 (Egr-1). Egr-1 activation, in turn, caused transcriptional regulation of GFAP. Corroboration of these findings in vivo demonstrated increased expression of GFAP in the cortical region of mice treated with cocaine compared with the saline injected controls. A thorough understanding of how cocaine mediates astrogliosis could have implications for the development of therapeutic interventions aimed at HIV-infected cocaine abusers.</p>