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Strengthening the accumbal indirect pathway promotes resilience to compulsive cocaine use


A hallmark of addiction is the loss of control over drug intake, which is seen in only a fraction of those exposed to stimulant drugs such as cocaine. The cellular mechanisms underlying vulnerability or resistance to compulsive drug use remain unknown. We found that individual variability in the development of highly motivated and perseverative behavior toward cocaine is associated with synaptic plasticity in medium spiny neurons expressing dopamine D2 receptors (D2-MSNs) in the nucleus accumbens (NAc) of mice. Potentiation of glutamatergic inputs onto indirect pathway D2-MSNs was associated with resilience toward compulsive cocaine seeking. Inhibition of D2-MSNs using a chemicogenetic approach enhanced the motivation to obtain cocaine, whereas optogenetic activation of D2-MSNs suppressed cocaine self-administration. These results indicate that recruitment of D2-MSNs in NAc functions to restrain cocaine self-administration and serves as a natural protective mechanism in drug-exposed individuals.

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Figure 1: Individual variability in the behaviors toward cocaine after extended self-administration.
Figure 2: Potentiation of glutamatergic inputs on D1-MSNs after cocaine self-administration.
Figure 3: Synaptic potentiation at D2-MSNs correlates negatively with negative behavior scores.
Figure 4: Inhibition of indirect-pathway D2-MSNs increases motivation for cocaine.
Figure 5: Activation of indirect-pathway D2-MSNs inhibits cocaine self-administration.


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We are grateful to the staff of Fishers Lane Animal Center and to L. Chedester for technical support. We thank the members of the Alvarez laboratory, J.T. Williams, D.M. Lovinger and B.L. Sabatini for helpful comments on the manuscript. We also thank B. Roth (University of North Carolina) and K. Deisseroth (Stanford University) for their generosity in providing the constructs for hM4Di and ChR2, respectively, and B. Harvey (Optogenetics and Transgenic Technology Core at the National Institute on Drug Abuse) for the viral vector preparation. This study was funded by the Intramural Programs of the National Institute on Alcohol Abuse and Alcoholism and the National Institute of Neurological Disorders and Stroke (ZIA-AA000421).

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Authors and Affiliations



R.B. carried out the behavioral studies with help from C.H.C., E.M., P.F.K. and C.M.G. J.H.S. carried out all of the electrophysiological experiments with help from M.F.A. A.D. performed all of the two-photon glutamate uncaging experiments. A.R.K., C.M.G., R.B. and M.F.A. performed behavioral experiments with hM4Di and in vivo optogenetics. R.B., J.H.S. and V.A.A. designed the study and wrote the manuscript.

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Correspondence to Veronica A Alvarez.

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The authors declare no competing financial interests.

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Bock, R., Shin, J., Kaplan, A. et al. Strengthening the accumbal indirect pathway promotes resilience to compulsive cocaine use. Nat Neurosci 16, 632–638 (2013).

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