Loss of plasticity in the D2-accumbens pallidal pathway promotes cocaine seeking

Jasper A. Heinsbroek*, Daniela N. Neuhofer, William C. Griffin, Griffin S. Siegel, Ana Clara Bobadilla, Yonatan M. Kupchik, Peter W. Kalivas

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

88 Scopus citations


Distinct populations of D1- and D2-dopamine receptor-expressing medium spiny neurons (D1-/D2-MSNs) comprise the nucleus accumbens, and activity in D1-MSNs promotes, whereas activity in D2-MSNs inhibits, motivated behaviors. We used chemogenetics to extend D1-/D2-MSN cell specific regulation to cue-reinstated cocaine seeking in a mouse model of self-administration and relapse, and found that either increasing activity in D1-MSNs or decreasing activity in D2-MSNs augmented cue-induced reinstatement. Both D1- and D2-MSNs provide substantial GABAergic innervation to the ventral pallidum, and chemogenetic inhibition of ventral pallidal neurons blocked the augmented reinstatement elicited by chemogenetic regulation of either D1- or D2-MSNs. Because D1- and D2-MSNs innervate overlapping populations of ventral pallidal neurons, we next used optogenetics to examine whether changes in synaptic plasticity in D1- versus D2-MSN GABAergic synapses in the ventral pallidum could explain the differential regulation of VP activity. In mice trained to self-administer cocaine, GABAergic LTD was abolished in D2-, but not in D1-MSN synapses. A μ opioid receptor antagonist restored GABA currents in D2-, but not D1-MSN synapses of cocaine-trained mice, indicating that increased enkephalin tone on presynaptic μ opioid receptors was responsible for occluding the LTD. These results identify a behavioral function for D1-MSN innervation of the ventral pallidum, and suggest that losing LTDGABA in D2-MSN, but not D1-MSN input to ventral pallidum may promote cue-induced reinstatement of cocaine-seeking.

Original languageAmerican English
Pages (from-to)757-767
Number of pages11
JournalJournal of Neuroscience
Issue number4
StatePublished - 25 Jan 2017

Bibliographical note

Funding Information:
This research was supported in part by United States Public Health Service Grants DA012512, DA003906, and DA015369. We thank Dr. Jamie Peters and the members of the P.W.K. laboratory for helpful comments on the manuscript; and Victoria Chareunsouk and Lauryn Luderman for technical assistance.

Publisher Copyright:
© 2017 the authors.


  • Accumbens
  • Cocaine
  • GABA
  • LTD
  • Pallidum
  • Relapse


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