title: Effects of chronic inhalation of electronic cigarettes containing nicotine on glial glutamate transporters and α-7 nicotinic acetylcholine receptor in female CD-1 mice.
abstract: Alteration in glutamate neurotransmission has been found to mediate the development of drug dependence, including nicotine. We and others, through using western blotting, have reported that exposure to drugs of abuse reduced the expression of glutamate transporter-1 (GLT-1) as well as cystine/glutamate antiporter (xCT), which consequently increased extracellular glutamate concentrations in the mesocorticolimbic area. However, our previous studies did not reveal any changes in glutamate/aspartate transporter (GLAST) following exposure to drugs of abuse. In the present study, for the first time, we investigated the effect of chronic exposure to electronic (e)-cigarette vapor containing nicotine, for one hour daily for six months, on GLT-1, xCT, and GLAST expression in frontal cortex (FC), striatum (STR), and hippocampus (HIP) in outbred female CD1 mice. In this study, we also investigated the expression of alpha-7 nicotinic acetylcholine receptor (α-7 nAChR), a major pre-synaptic nicotinic receptor in the glutamatergic neurons, which regulates glutamate release. We found that inhalation of e-cigarette vapor for six months increased α-7 nAChR expression in both FC and STR, but not in the HIP. In addition, chronic e-cigarette exposure reduced GLT-1 expression only in STR. Moreover, e-cigarette vapor inhalation induced downregulation of xCT in both the STR and HIP. We did not find any significant changes in GLAST expression in any brain region. Finally, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) techniques, we detected high concentrations of nicotine and cotinine, a major metabolite of nicotine, in the FC tissues of e-cigarette exposed mice. These data provide novel evidence about the effects of chronic nicotine inhalation on the expression of key glial glutamate transporters as well as α-7 nAChR. Our work may suggest that nicotine exposure via chronic inhalation of e-cigarette vapor may be mediated in part by alterations in the glutamatergic system.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, The University of Toledo, Toledo, OH 43614, USA.
authors.forename: Fawaz
authors.initials: F
authors.lastname: Alasmari
authors.affiliation: Pulmonary and Critical Care Section, VA San Diego Healthcare System, 3350 La Jolla Village Dr, MC 111J, San Diego, CA 92161, USA; Department of Medicine, Division of Pulmonary and Critical Care, University of California at San Diego (UCSD), La Jolla, CA 92093, USA.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Crotty Alexander
authors.affiliation: Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, The University of Toledo, Toledo, OH 43614, USA.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Nelson
authors.affiliation: Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, The University of Toledo, Toledo, OH 43614, USA.
authors.forename: Isaac T
authors.initials: IT
authors.lastname: Schiefer
authors.affiliation: Department of Medicine, Division of Physiology, UCSD, La Jolla, CA 92093, USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Breen
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Drummond
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, The University of Toledo, Toledo, OH 43614, USA. Electronic address: youssef.sari@utoledo.edu.
authors.forename: Youssef
authors.initials: Y
authors.lastname: Sari
mesh_terms: D000280:Administration, Inhalation; D027322:Amino Acid Transport System X-AG / Q000096:biosynthesis*; D027182:Amino Acid Transport System y+ / Q000096:biosynthesis*; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism; D066300:Electronic Nicotine Delivery Systems; D027342:Excitatory Amino Acid Transporter 2 / Q000096:biosynthesis; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D051379:Mice; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D009538:Nicotine / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology*; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000096:biosynthesis*
chemical_list: D027322:Amino Acid Transport System X-AG; D027182:Amino Acid Transport System y+; D027342:Excitatory Amino Acid Transporter 2; C492255:Slc7a11 protein, mouse; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine
keywords: Cotinine; E-cigarettes; GLT-1; xCT; α-7 nAChR