Cocaine drives aversive conditioning via delayed activation of dopamine-responsive habenular and midbrain pathways
Many strong rewards, including abused drugs, also produce aversive effects that are poorly understood. For example, cocaine can produce aversive conditioning after its rewarding effects have dissipated, consistent with opponent process theory, but the neural mechanisms involved are not well known. U...
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Published in | The Journal of neuroscience Vol. 33; no. 17; pp. 7501 - 7512 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Society for Neuroscience
24.04.2013
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Subjects | |
Online Access | Get full text |
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Summary: | Many strong rewards, including abused drugs, also produce aversive effects that are poorly understood. For example, cocaine can produce aversive conditioning after its rewarding effects have dissipated, consistent with opponent process theory, but the neural mechanisms involved are not well known. Using electrophysiological recordings in awake rats, we found that some neurons in the lateral habenula (LHb), where activation produces aversive conditioning, exhibited biphasic responses to single doses of intravenous cocaine, with an initial inhibition followed by delayed excitation paralleling cocaine's shift from rewarding to aversive. Recordings in LHb slice preparations revealed similar cocaine-induced biphasic responses and further demonstrated that biphasic responses were mimicked by dopamine, that the inhibitory phase depended on dopamine D2-like receptors, and that the delayed excitation persisted after drug washout for prolonged durations consistent with findings in vivo. c-Fos experiments further showed that cocaine-activated LHb neurons preferentially projected to and activated neurons in the rostromedial tegmental nucleus (RMTg), a recently identified target of LHb axons that is activated by negative motivational stimuli and inhibits dopamine neurons. Finally, pharmacological excitation of the RMTg produced conditioned place aversion, whereas cocaine-induced avoidance behaviors in a runway operant paradigm were abolished by lesions of LHb efferents, lesions of the RMTg, or by optogenetic inactivation of the RMTg selectively during the period when LHb neurons are activated by cocaine. Together, these results indicate that LHb/RMTg pathways contribute critically to cocaine-induced avoidance behaviors, while also participating in reciprocally inhibitory interactions with dopamine neurons. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Author contributions: T.C.J., C.H.G., C.S.R., A.F.H., C.R.L., and S.I. designed research; T.C.J., C.H.G., C.S.R., S.-p.X., H.W., N.W.B., and A.F.H. performed research; T.C.J., C.H.G., and C.S.R. analyzed data; T.C.J. and C.H.G. wrote the paper. C. Good's present address: Translational Neuroscience Branch, Army Research Laboratory, Aberdeen Proving Ground, MD 21005. T.C.J., C.H.G., C.R.L., and S.I. contributed equally to this work. |
ISSN: | 0270-6474 1529-2401 1529-2401 |
DOI: | 10.1523/jneurosci.3634-12.2013 |