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Contrasting the Role of xCT and GLT-1 Upregulation in the Ability of Ceftriaxone to Attenuate the Cue-Induced Reinstatement of Cocaine Seeking and Normalize AMPA Receptor Subunit Expression.
J Neurosci 2017; 37(24):5809-5821JN

Abstract

Long-term treatment with ceftriaxone attenuates the reinstatement of cocaine seeking while increasing the function of the glutamate transporter 1 (GLT-1) and system xC- (Sxc) in the nucleus accumbens core (NAc). Sxc contributes the majority of nonsynaptic extracellular glutamate in the NAc, while GLT-1 is responsible for the majority of glutamate uptake. Here we used antisense to decrease the expression of GLT-1 and xCT (a catalytic subunit of Sxc) to determine the relative importance of both proteins in mediating the ability of ceftriaxone to prevent cue-induced reinstatement of cocaine seeking and normalize glutamatergic proteins in the NAc of rats. Intra-NAc xCT knockdown prevented ceftriaxone from attenuating reinstatement and from upregulating GLT-1 and resulted in increased surface expression of AMPA receptor subunits GluA1 and GluA2. Intra-NAc GLT-1 knockdown also prevented ceftriaxone from attenuating reinstatement and from upregulating xCT expression, without affecting GluA1 and GluA2 expression. In the absence of cocaine or ceftriaxone treatment, xCT knockdown in the NAc increased the expression of both GluA1 and GluA2 without affecting GLT-1 expression while GLT-1 knockdown had no effect. PCR and immunoprecipitation of GLT-1 revealed that ceftriaxone does not upregulate GLT-1 and xCT through a transcriptional mechanism, and their coregulation by ceftriaxone is not mediated by physical interaction. These data support important and distinct roles for xCT and GLT-1 in the actions of ceftriaxone and add to a body of literature finding evidence for coregulation of these transporters. Our results also point to xCT expression and subsequent basal glutamate levels as being a key mediator of AMPA receptor expression in the NAc.SIGNIFICANCE STATEMENT Ceftriaxone attenuates the reinstatement of cocaine, alcohol, and heroin seeking. The mechanism of action of this behavioral effect has been attributed to glutamate transporter 1 (GLT-1) and xCT (a catalytic subunit of Sxc)/Sxc upregulation in the nucleus accumbens core. Here we used an antisense strategy to knock down GLT-1 or xCT in the nucleus accumbens core and examined the behavioral and molecular consequences. While upregulation of both xCT and GLT-1 are essential to the ability of ceftriaxone to attenuate cue-induced reinstatement of cocaine seeking, each protein uniquely affects the expression of other glutamate receptor and transporter proteins. We also report that reducing basal glutamate levels through the manipulation of xCT expression increases the surface expression of AMPA receptor subunits, providing insight to the mechanism by which cocaine alters AMPA surface expression.

Authors+Show Affiliations

Psychology Department, University of Florida, Gainesville, Florida 32611.Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio 45267.Department of Psychology and Neuroscience, University of North Carolina, Chapel Hill, North Carolina 27599, and.Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio 45267.Department of Psychology and Neuroscience, University of North Carolina, Chapel Hill, North Carolina 27599, and.Psychology Department, University of Florida, Gainesville, Florida 32611.Psychology Department, University of Florida, Gainesville, Florida 32611, knack@ufl.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

28495973

Citation

LaCrosse, Amber L., et al. "Contrasting the Role of xCT and GLT-1 Upregulation in the Ability of Ceftriaxone to Attenuate the Cue-Induced Reinstatement of Cocaine Seeking and Normalize AMPA Receptor Subunit Expression." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 37, no. 24, 2017, pp. 5809-5821.
LaCrosse AL, O'Donovan SM, Sepulveda-Orengo MT, et al. Contrasting the Role of xCT and GLT-1 Upregulation in the Ability of Ceftriaxone to Attenuate the Cue-Induced Reinstatement of Cocaine Seeking and Normalize AMPA Receptor Subunit Expression. J Neurosci. 2017;37(24):5809-5821.
LaCrosse, A. L., O'Donovan, S. M., Sepulveda-Orengo, M. T., McCullumsmith, R. E., Reissner, K. J., Schwendt, M., & Knackstedt, L. A. (2017). Contrasting the Role of xCT and GLT-1 Upregulation in the Ability of Ceftriaxone to Attenuate the Cue-Induced Reinstatement of Cocaine Seeking and Normalize AMPA Receptor Subunit Expression. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 37(24), pp. 5809-5821. doi:10.1523/JNEUROSCI.3717-16.2017.
LaCrosse AL, et al. Contrasting the Role of xCT and GLT-1 Upregulation in the Ability of Ceftriaxone to Attenuate the Cue-Induced Reinstatement of Cocaine Seeking and Normalize AMPA Receptor Subunit Expression. J Neurosci. 2017 06 14;37(24):5809-5821. PubMed PMID: 28495973.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Contrasting the Role of xCT and GLT-1 Upregulation in the Ability of Ceftriaxone to Attenuate the Cue-Induced Reinstatement of Cocaine Seeking and Normalize AMPA Receptor Subunit Expression. AU - LaCrosse,Amber L, AU - O'Donovan,Sinead M, AU - Sepulveda-Orengo,Marian T, AU - McCullumsmith,Robert E, AU - Reissner,Kathryn J, AU - Schwendt,Marek, AU - Knackstedt,Lori A, Y1 - 2017/05/11/ PY - 2016/12/02/received PY - 2017/04/28/revised PY - 2017/05/01/accepted PY - 2017/5/13/pubmed PY - 2017/8/19/medline PY - 2017/5/13/entrez KW - glutamate KW - glutamate transporters KW - microdialysis KW - nucleus accumbens KW - relapse SP - 5809 EP - 5821 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J. Neurosci. VL - 37 IS - 24 N2 - Long-term treatment with ceftriaxone attenuates the reinstatement of cocaine seeking while increasing the function of the glutamate transporter 1 (GLT-1) and system xC- (Sxc) in the nucleus accumbens core (NAc). Sxc contributes the majority of nonsynaptic extracellular glutamate in the NAc, while GLT-1 is responsible for the majority of glutamate uptake. Here we used antisense to decrease the expression of GLT-1 and xCT (a catalytic subunit of Sxc) to determine the relative importance of both proteins in mediating the ability of ceftriaxone to prevent cue-induced reinstatement of cocaine seeking and normalize glutamatergic proteins in the NAc of rats. Intra-NAc xCT knockdown prevented ceftriaxone from attenuating reinstatement and from upregulating GLT-1 and resulted in increased surface expression of AMPA receptor subunits GluA1 and GluA2. Intra-NAc GLT-1 knockdown also prevented ceftriaxone from attenuating reinstatement and from upregulating xCT expression, without affecting GluA1 and GluA2 expression. In the absence of cocaine or ceftriaxone treatment, xCT knockdown in the NAc increased the expression of both GluA1 and GluA2 without affecting GLT-1 expression while GLT-1 knockdown had no effect. PCR and immunoprecipitation of GLT-1 revealed that ceftriaxone does not upregulate GLT-1 and xCT through a transcriptional mechanism, and their coregulation by ceftriaxone is not mediated by physical interaction. These data support important and distinct roles for xCT and GLT-1 in the actions of ceftriaxone and add to a body of literature finding evidence for coregulation of these transporters. Our results also point to xCT expression and subsequent basal glutamate levels as being a key mediator of AMPA receptor expression in the NAc.SIGNIFICANCE STATEMENT Ceftriaxone attenuates the reinstatement of cocaine, alcohol, and heroin seeking. The mechanism of action of this behavioral effect has been attributed to glutamate transporter 1 (GLT-1) and xCT (a catalytic subunit of Sxc)/Sxc upregulation in the nucleus accumbens core. Here we used an antisense strategy to knock down GLT-1 or xCT in the nucleus accumbens core and examined the behavioral and molecular consequences. While upregulation of both xCT and GLT-1 are essential to the ability of ceftriaxone to attenuate cue-induced reinstatement of cocaine seeking, each protein uniquely affects the expression of other glutamate receptor and transporter proteins. We also report that reducing basal glutamate levels through the manipulation of xCT expression increases the surface expression of AMPA receptor subunits, providing insight to the mechanism by which cocaine alters AMPA surface expression. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/28495973/Contrasting_the_Role_of_xCT_and_GLT_1_Upregulation_in_the_Ability_of_Ceftriaxone_to_Attenuate_the_Cue_Induced_Reinstatement_of_Cocaine_Seeking_and_Normalize_AMPA_Receptor_Subunit_Expression_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=28495973 DB - PRIME DP - Unbound Medicine ER -