Both control (H3.3 WT) and knockdown
(H3.3Q5A) animals displayed similar levels
of cocaine-induced locomotor sensitization
(fig. S8, D and E).
We demonstrated that a previously un-
characterized chromatin modification, his-
tone dopaminylation, is critically involved in
regulating aberrant neuronal gene expression
patterns in the VTA in response to cocaine
consumption. The increased expression of
H3Q5dop that follows prolonged withdrawal
from extended, but not restricted, access to
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like behaviors. It does so, in part, through the
dysregulated transcription of addiction- and
synaptic plasticity–related genes in the VTA,
as well as through aberrant dopamine release
dynamics in the NAc after cocaine withdrawal
(fig. S9, model). Gaining a better understand-
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mediating permissive compared with repressive
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through this mechanism, will greatly improve
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ACKNOWLEDGMENTS
We would like to thank T. Muir and R. Thompson (Princeton Univ.)
for generating dopaminylated peptides for use in antibody
generation. We would also like to thank A. G. DiFeliceantonio
(Virginia Tech) for providing supporting code for yoked cocaine
experiments, K. Brennand and S. Powell (ISMMS) for providing
hPSC-derived dopaminergic neurons for use in antibody control
experiments, and A. Soshnev (Rockefeller Univ.) for help with
illustrations. The NIDA Drug Supply Program generously gifted
the cocaine used in these studies.Funding:This work was
supported by grants from the National Institutes of Health [DP1
DA042078 (I.M.), R21 DA044767 (I.M.), P50 MH096890 (I.M.),
R01 DA025983 (P.J.K.), R01 MH108842 (Z.Y.), R01 DA037257
(D.M.D.), R21 DA044486 (D.M.D.), F99 NS108543 (J.A.M.),
R00 DA042111 (E.S.C.), and F31 DA045428 (A.E.L.)] as well as
the MQ Mental Health Research Charity [MQ15FIP100011 (I.M.)],
Alfred P. Sloan Foundation Fellowship in Neuroscience (I.M.), Brain
Research Foundation’s Fay/Frank Seed Grant Award (I.M.), Brain
and Behavior Research Foundation (E.S.C. and A.C.W.S.), Whitehall
Foundation (E.S.C.), and Edward Mallinckrodt, Jr. Foundation
(E.S.C.).Author contributions:I.M. conceived of the project with
input from A.E.L., D.M.D., and P.J.K. A.E.L., C.T.W., A.F.S., S.L.F.,
P.Z., L.A.F., A.C.W.S., Y.L., R.M.B., J.A.M., S.M., R.M.O., Z.-J.W.,
H.M., Z.Y., E.S.C., D.M.D., P.J.K., and I.M. designed the experiments
and interpreted the data. A.R. and L.S. performed the sequencing-
based bioinformatics with input from A.E.L. and I.M. G.T. provided
human postmortem tissues. A.E.L., P.J.K., and I.M. wrote the
manuscript.Competing interests:P.J.K. is a cofounder of Eolas
Therapeutics, Inc. The remaining authors declare no competing
interests, financial or otherwise.Data and materials availability:
Data from RNA-seq experiments have been deposited in the
National Center for Biotechnology Information Gene Expression
Omnibus database under accession number GSE124055. We
declare that the data supporting findings for this study are
available within the article and supplementary materials.
No restrictions on data availability apply.SUPPLEMENTARY MATERIALS
science.sciencemag.org/content/368/6487/197/suppl/DC1
Materials and Methods
Extended Captions for Figs. 1 to 4
Figs. S1 to S9
Tables S1 to S5
References ( 16 – 30 )1 February 2019; accepted 14 February 2020
10.1126/science.aaw8806SCIENCEsciencemag.org 10 APRIL 2020•VOL 368 ISSUE 6487 201
Fig. 4. Reducing H3Q5dop in the VTA attenuates cocaine seeking.(A) Experimental timeline of cocaine
SA drug-seeking experiments after viral transduction. (BandC) After 10 days of extended access to
cocaine, rats were infected intra-VTA with one of the three viral vectors (on day 11) (B), followed by 30 days
of WD and 1 hour of cocaine seeking (C). Data presented as averages ± SEM.
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