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Cellular and molecular responses to acute cocaine treatment in neuronal-like N2a cells

Title: Cellular and molecular responses to acute cocaine treatment in neuronal-like N2a cells: potential mechanism for its resistance in cell death.
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Name(s): Badisa, Ramesh B, author
Wi, Sungsool, author
Jones, Zachary, author
Mazzio, Elizabeth, author
Zhou, Yi, author
Rosenberg, Jens T, author
Latinwo, Lekan M, author
Grant, Samuel C, author
Goodman, Carl B, author
Type of Resource: text
Genre: Journal Article
Text
Date Issued: 2018-07-17
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: Cocaine is a highly abused drug that causes psychiatric and neurological problems. Its entry into neurons could alter cell-biochemistry and contribute in the manifestation of early pathological symptoms. We have previously shown the acute cocaine effects in rat C6 astroglia-like cells and found that these cells were highly sensitive to cocaine in terms of manifesting certain pathologies known to underlie psychological disorders. The present study was aimed to discern acute cocaine effects on the early onset of various changes in Neuro-2a (N2a) cells. Whole-cell patch-clamp recording of differentiated cells displayed the functional voltage-gated Na and K channels, which demonstrated the neuronal characteristics of the cells. Treatment of these cells with acute cocaine (1 h) at in vivo (nM to μM) and in vitro (mM) concentrations revealed that the cells remained almost 100% viable. Cocaine administration at 6.25 μM or 4 mM doses significantly reduced the inward currents but had no significant effect on outward currents, indicating the Na channel-blocking activity of cocaine. While no morphological change was observed at in vivo doses, treatment at in vitro doses altered the morphology, damaged the neurites, and induced cytoplasmic vacuoles; furthermore, general mitochondrial activity and membrane potential were significantly decreased. Mitochondrial dysfunction enabled the cells switch to anaerobic glycolysis, evidenced by dose-dependent increases in lactate and HS, resulting unaltered ATP level in the cells. Further investigation on the mechanism of action unfolded that the cell's resistance to cocaine was through the activation of nuclear factor E2-related factor-2 () gene and subsequent increase of antioxidants (glutathione [GSH], catalase and GSH peroxidase [GPx]). The data clearly indicate that the cells employed a detoxifying strategy against cocaine. On a broader perspective, we envision that extrapolating the knowledge of neuronal resistance to central nervous system (CNS) diseases could delay their onset or progression.
Identifier: FSU_pmch_30210816 (IID), 10.1038/s41420-018-0078-x (DOI), PMC6133924 (PMCID), 30210816 (RID), 30210816 (EID), 78 (PII)
Grant Number: G12 MD007582, P20 MD006738, R01 MH115188, R25 GM107777
Publication Note: This NIH-funded author manuscript originally appeared in PubMed Central at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133924.
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_pmch_30210816
Host Institution: FSU
Is Part Of: Cell death discovery.
2058-7716
Issue: vol. 4

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Badisa, R. B., Wi, S., Jones, Z., Mazzio, E., Zhou, Y., Rosenberg, J. T., … Goodman, C. B. (2018). Cellular and molecular responses to acute cocaine treatment in neuronal-like N2a cells: potential mechanism for its resistance in cell death. Cell Death Discovery. Retrieved from http://purl.flvc.org/fsu/fd/FSU_pmch_30210816