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Targeted disruption of cocaine-activated nucleus accumbens neurons prevents context-specific sensitization

Abstract

Learned associations between effects of abused drugs and the drug administration environment are important in drug addiction. Histochemical and electrophysiological studies suggest that these associations are encoded in sparsely distributed nucleus accumbens neurons that are selectively activated by drugs and drug-associated cues. Although correlations have been observed between nucleus accumbens neuronal activity and responsivity to drugs and drug cues, no technique exists for selectively manipulating these activated neurons and establishing their causal role in behavioral effects of drugs and drug cues. Here we describe a new approach, which we term the 'Daun02 inactivation method', that selectively inactivates a minority of neurons previously activated by cocaine in an environment repeatedly paired with cocaine to demonstrate a causal role for these activated neurons in context-specific cocaine-induced psychomotor sensitization in rats. This method provides a new tool for studying the causal roles of selectively activated neurons in behavioral effects of drugs and drug cues and in other learned behaviors.

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Figure 1: Environment modulates cocaine-induced locomotor activity and nucleus accumbens neuronal activity in sensitized rats (Experiment 1).
Figure 2: Schematic mechanism for Daun02 inactivation in c-fos–lacZ rats.
Figure 3: Timeline for Daun02 inactivation experiments.
Figure 4: Experiment 3.
Figure 5: Experiment 6: Although Daun02 attenuated locomotor activity when cocaine was previously injected in the Paired environment (context A), it did not alter cocaine-induced locomotor activity on test day in c-fos–lacZ rats that had been injected on induction day with cocaine in an alternate non-paired environment (context B).

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Acknowledgements

This research was supported by the Intramural Research Program of the National Institute on Drug Abuse. We thank E. Wentzell for her excellent editorial assistance, K. Knestaut for breeding the cfos-lacZ rats and T. Adams-Deutsch, C. Pickens and K. Wihbey for technical assistance. We are especially thankful to Y. Shaham for his comments over the years and for his help in writing this manuscript, and to R. Wise for providing the inspiration for this study.

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Authors and Affiliations

Authors

Contributions

E.K. and B.T.H. designed the behavioral experiments. E.K. performed these experiments with S.A.G., A.B., D.E.S., J.M.B., S.G.N., J.L.U., M.T.M., T.B.M., B.J.M. and B.T.H. E.K. performed the histological experiments. D.F. and S.C.G. synthesized the Daun02 compound. B.K.H. and D.H.G.-B. examined the prodrug properties of Daun02. E.K. and B.T.H. analyzed the data and wrote the paper.

Corresponding author

Correspondence to Bruce T Hope.

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Koya, E., Golden, S., Harvey, B. et al. Targeted disruption of cocaine-activated nucleus accumbens neurons prevents context-specific sensitization. Nat Neurosci 12, 1069–1073 (2009). https://doi.org/10.1038/nn.2364

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