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Prelimbic to Accumbens Core Pathway Is Recruited in a Dopamine-Dependent Manner to Drive Cued Reinstatement of Cocaine Seeking.
J Neurosci 2016; 36(33):8700-11JN

Abstract

Glutamate inputs to nucleus accumbens (NAc) facilitate conditioned drug-seeking behavior and primarily originate from medial prefrontal cortex (mPFC), basolateral amygdala (BLA), and ventral subiculum of the hippocampus (vSub). These regions express Fos (a marker of neural activity) during cue-induced reinstatement of cocaine seeking, but only subpopulations of neurons within these regions drive drug seeking. One way to identify and functionally distinguish neural subpopulations activated during drug-seeking is to examine their projection targets. In rats, we examined Fos expression during cue-induced reinstatement of cocaine- and sucrose-seeking in prelimbic cortex (PL), infralimbic cortex (IL), BLA, and vSub neurons that project to NAc core (NAcC) or NAc shell (NAcSh). Neurons in PL, BLA, and vSub that project to NAcC, but not NAcSh, expressed Fos during cue-induced cocaine seeking, but not sucrose seeking. However, only activation of the PL-NAcC pathway positively correlated with cocaine reinstatement behavior, unlike BLA or vSub inputs to NAcC. To confirm a functional role for the PL-NAcC pathway, and to test the hypothesis that this pathway is recruited in a dopamine-dependent manner, we used a pharmacological disconnection approach whereby dopamine signaling was blocked in PL and glutamate signaling was blocked in the contralateral NAcC. This disconnection attenuated cue-induced reinstatement of cocaine seeking but had no effect on reinstatement of sucrose seeking. Our results highlight a role for the PL-NAcC pathway in cocaine seeking and show that these glutamatergic projections are recruited in a dopamine-dependent manner to drive reinstatement.

SIGNIFICANCE STATEMENT

Relapse represents a significant barrier to the successful treatment of cocaine addiction. Here, we characterize the relative activation of glutamatergic inputs to nucleus accumbens during cued reinstatement of cocaine seeking versus sucrose seeking. Prelimbic cortex (PL) projections to nucleus accumbens core (NAcC) uniquely expressed Fos in a manner that positively correlated with cocaine-seeking, but not sucrose-seeking, behavior. Additional functional experiments showed that the PL-NAcC pathway was recruited by drug-associated cues in a dopamine-dependent manner to drive cocaine-seeking, but not sucrose-seeking, behavior. These data highlight PL neurons that project to NAcC, and their regulation by dopamine, as potential targets for therapeutics designed to treat cocaine relapse that do not affect natural reward seeking.

Authors+Show Affiliations

Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29403, Brain Health Institute, Rutgers University and Rutgers Biomedical and Health Sciences, Piscataway, New Jersey 08854, and.Brain Health Institute, Rutgers University and Rutgers Biomedical and Health Sciences, Piscataway, New Jersey 08854, and.Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29403, Department of Neurobiology and Behavior, University of California, Irvine, California 92697.Brain Health Institute, Rutgers University and Rutgers Biomedical and Health Sciences, Piscataway, New Jersey 08854, and.Brain Health Institute, Rutgers University and Rutgers Biomedical and Health Sciences, Piscataway, New Jersey 08854, and aston.jones@rutgers.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27535915

Citation

McGlinchey, Ellen M., et al. "Prelimbic to Accumbens Core Pathway Is Recruited in a Dopamine-Dependent Manner to Drive Cued Reinstatement of Cocaine Seeking." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 36, no. 33, 2016, pp. 8700-11.
McGlinchey EM, James MH, Mahler SV, et al. Prelimbic to Accumbens Core Pathway Is Recruited in a Dopamine-Dependent Manner to Drive Cued Reinstatement of Cocaine Seeking. J Neurosci. 2016;36(33):8700-11.
McGlinchey, E. M., James, M. H., Mahler, S. V., Pantazis, C., & Aston-Jones, G. (2016). Prelimbic to Accumbens Core Pathway Is Recruited in a Dopamine-Dependent Manner to Drive Cued Reinstatement of Cocaine Seeking. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 36(33), pp. 8700-11. doi:10.1523/JNEUROSCI.1291-15.2016.
McGlinchey EM, et al. Prelimbic to Accumbens Core Pathway Is Recruited in a Dopamine-Dependent Manner to Drive Cued Reinstatement of Cocaine Seeking. J Neurosci. 2016 08 17;36(33):8700-11. PubMed PMID: 27535915.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Prelimbic to Accumbens Core Pathway Is Recruited in a Dopamine-Dependent Manner to Drive Cued Reinstatement of Cocaine Seeking. AU - McGlinchey,Ellen M, AU - James,Morgan H, AU - Mahler,Stephen V, AU - Pantazis,Caroline, AU - Aston-Jones,Gary, PY - 2015/04/03/received PY - 2016/06/30/accepted PY - 2016/8/19/entrez PY - 2016/8/19/pubmed PY - 2017/7/15/medline KW - basolateral amygdala KW - cocaine KW - dopamine KW - nucleus accumbens KW - prelimbic cortex KW - ventral subiculum SP - 8700 EP - 11 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J. Neurosci. VL - 36 IS - 33 N2 - UNLABELLED: Glutamate inputs to nucleus accumbens (NAc) facilitate conditioned drug-seeking behavior and primarily originate from medial prefrontal cortex (mPFC), basolateral amygdala (BLA), and ventral subiculum of the hippocampus (vSub). These regions express Fos (a marker of neural activity) during cue-induced reinstatement of cocaine seeking, but only subpopulations of neurons within these regions drive drug seeking. One way to identify and functionally distinguish neural subpopulations activated during drug-seeking is to examine their projection targets. In rats, we examined Fos expression during cue-induced reinstatement of cocaine- and sucrose-seeking in prelimbic cortex (PL), infralimbic cortex (IL), BLA, and vSub neurons that project to NAc core (NAcC) or NAc shell (NAcSh). Neurons in PL, BLA, and vSub that project to NAcC, but not NAcSh, expressed Fos during cue-induced cocaine seeking, but not sucrose seeking. However, only activation of the PL-NAcC pathway positively correlated with cocaine reinstatement behavior, unlike BLA or vSub inputs to NAcC. To confirm a functional role for the PL-NAcC pathway, and to test the hypothesis that this pathway is recruited in a dopamine-dependent manner, we used a pharmacological disconnection approach whereby dopamine signaling was blocked in PL and glutamate signaling was blocked in the contralateral NAcC. This disconnection attenuated cue-induced reinstatement of cocaine seeking but had no effect on reinstatement of sucrose seeking. Our results highlight a role for the PL-NAcC pathway in cocaine seeking and show that these glutamatergic projections are recruited in a dopamine-dependent manner to drive reinstatement. SIGNIFICANCE STATEMENT: Relapse represents a significant barrier to the successful treatment of cocaine addiction. Here, we characterize the relative activation of glutamatergic inputs to nucleus accumbens during cued reinstatement of cocaine seeking versus sucrose seeking. Prelimbic cortex (PL) projections to nucleus accumbens core (NAcC) uniquely expressed Fos in a manner that positively correlated with cocaine-seeking, but not sucrose-seeking, behavior. Additional functional experiments showed that the PL-NAcC pathway was recruited by drug-associated cues in a dopamine-dependent manner to drive cocaine-seeking, but not sucrose-seeking, behavior. These data highlight PL neurons that project to NAcC, and their regulation by dopamine, as potential targets for therapeutics designed to treat cocaine relapse that do not affect natural reward seeking. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/27535915/Prelimbic_to_Accumbens_Core_Pathway_Is_Recruited_in_a_Dopamine_Dependent_Manner_to_Drive_Cued_Reinstatement_of_Cocaine_Seeking_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=27535915 DB - PRIME DP - Unbound Medicine ER -