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Nucleus accumbens GLT-1a overexpression reduces glutamate efflux during reinstatement of cocaine-seeking but is not sufficient to attenuate reinstatement.
Neuropharmacology 2018; 135:297-307N

Abstract

Cocaine use disorder is a chronically relapsing disease without FDA-approved treatments. Using a rodent model of cocaine relapse, we and others have previously demonstrated that the beta-lactam antibiotic ceftriaxone attenuates cue- and cocaine-primed reinstatement of cocaine-seeking. Ceftriaxone restores cocaine-induced deficits in both system xc- and GLT-1 expression and function in the nucleus accumbens core (NAc). We recently demonstrated that restoration of GLT-1 expression in the NAc is necessary for ceftriaxone to attenuate reinstatement of cocaine-seeking. Here we used an adeno-associated virus (AAV) to overexpress GLT-1a in the NAc to investigate whether such restoration is sufficient to attenuate cue- and cocaine-primed reinstatement. Rats self-administered cocaine for two weeks and received injections of either AAV-GFAP-GLT-1a or AAV-GFAP-eGFP in the NAc following the last day of self-administration. Rats then underwent three weeks of extinction training (during which time transduction and expression occurred) before undergoing a cue- or cocaine-primed reinstatement test. Microdialysis for the quantification of glutamate efflux in the NAc was conducted during the cocaine-primed test. Rats that received AAV-GFAP-GLT-1a reinstated cue-primed cocaine-seeking in a similar manner as rats that received the control AAV-GFAP-eGFP. Upregulation of GLT-1a attenuated glutamate efflux during a cocaine-primed reinstatement test, but was not sufficient to attenuate reinstatement. We confirmed that GLT-1a upregulation resulted in functional upregulation of glutamate transport and expression, without affecting sodium-independent glutamate uptake, indicating system xc-was not altered. These results indicate that upregulation of NAc GLT-1 transporters alone is not sufficient to prevent the reinstatement of cocaine-seeking and implicate additional mechanisms in regulating glutamate efflux.

Authors+Show Affiliations

Psychology Department, University of Florida, Gainesville, FL, United States. Electronic address: clogan10@ufl.edu.Psychology Department, University of Florida, Gainesville, FL, United States.Psychology Department, University of Florida, Gainesville, FL, United States; Center for Addiction Research and Education, University of Florida, Gainesville, FL, United States.

Pub Type(s)

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

Language

eng

PubMed ID

29567092

Citation

Logan, Carly N., et al. "Nucleus Accumbens GLT-1a Overexpression Reduces Glutamate Efflux During Reinstatement of Cocaine-seeking but Is Not Sufficient to Attenuate Reinstatement." Neuropharmacology, vol. 135, 2018, pp. 297-307.
Logan CN, LaCrosse AL, Knackstedt LA. Nucleus accumbens GLT-1a overexpression reduces glutamate efflux during reinstatement of cocaine-seeking but is not sufficient to attenuate reinstatement. Neuropharmacology. 2018;135:297-307.
Logan, C. N., LaCrosse, A. L., & Knackstedt, L. A. (2018). Nucleus accumbens GLT-1a overexpression reduces glutamate efflux during reinstatement of cocaine-seeking but is not sufficient to attenuate reinstatement. Neuropharmacology, 135, pp. 297-307. doi:10.1016/j.neuropharm.2018.03.022.
Logan CN, LaCrosse AL, Knackstedt LA. Nucleus Accumbens GLT-1a Overexpression Reduces Glutamate Efflux During Reinstatement of Cocaine-seeking but Is Not Sufficient to Attenuate Reinstatement. Neuropharmacology. 2018;135:297-307. PubMed PMID: 29567092.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Nucleus accumbens GLT-1a overexpression reduces glutamate efflux during reinstatement of cocaine-seeking but is not sufficient to attenuate reinstatement. AU - Logan,Carly N, AU - LaCrosse,Amber L, AU - Knackstedt,Lori A, Y1 - 2018/03/20/ PY - 2017/11/10/received PY - 2018/03/14/revised PY - 2018/03/17/accepted PY - 2018/3/24/pubmed PY - 2019/2/5/medline PY - 2018/3/24/entrez KW - Addiction KW - Microdialysis KW - Relapse KW - glutamate transport KW - xCT SP - 297 EP - 307 JF - Neuropharmacology JO - Neuropharmacology VL - 135 N2 - Cocaine use disorder is a chronically relapsing disease without FDA-approved treatments. Using a rodent model of cocaine relapse, we and others have previously demonstrated that the beta-lactam antibiotic ceftriaxone attenuates cue- and cocaine-primed reinstatement of cocaine-seeking. Ceftriaxone restores cocaine-induced deficits in both system xc- and GLT-1 expression and function in the nucleus accumbens core (NAc). We recently demonstrated that restoration of GLT-1 expression in the NAc is necessary for ceftriaxone to attenuate reinstatement of cocaine-seeking. Here we used an adeno-associated virus (AAV) to overexpress GLT-1a in the NAc to investigate whether such restoration is sufficient to attenuate cue- and cocaine-primed reinstatement. Rats self-administered cocaine for two weeks and received injections of either AAV-GFAP-GLT-1a or AAV-GFAP-eGFP in the NAc following the last day of self-administration. Rats then underwent three weeks of extinction training (during which time transduction and expression occurred) before undergoing a cue- or cocaine-primed reinstatement test. Microdialysis for the quantification of glutamate efflux in the NAc was conducted during the cocaine-primed test. Rats that received AAV-GFAP-GLT-1a reinstated cue-primed cocaine-seeking in a similar manner as rats that received the control AAV-GFAP-eGFP. Upregulation of GLT-1a attenuated glutamate efflux during a cocaine-primed reinstatement test, but was not sufficient to attenuate reinstatement. We confirmed that GLT-1a upregulation resulted in functional upregulation of glutamate transport and expression, without affecting sodium-independent glutamate uptake, indicating system xc-was not altered. These results indicate that upregulation of NAc GLT-1 transporters alone is not sufficient to prevent the reinstatement of cocaine-seeking and implicate additional mechanisms in regulating glutamate efflux. SN - 1873-7064 UR - https://www.unboundmedicine.com/medline/citation/29567092/Nucleus_accumbens_GLT_1a_overexpression_reduces_glutamate_efflux_during_reinstatement_of_cocaine_seeking_but_is_not_sufficient_to_attenuate_reinstatement_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(18)30133-3 DB - PRIME DP - Unbound Medicine ER -