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Transient neuronal inhibition reveals opposing roles of indirect and direct pathways in sensitization


Dorsal striatum is important for the development of drug addiction; however, a precise understanding of the roles of striatopallidal (indirect) and striatonigral (direct) pathway neurons in regulating behaviors remains elusive. Using viral-mediated expression of an engineered G protein–coupled receptor (hM4D), we found that activation of hM4D receptors with clozapine-N-oxide (CNO) potently reduced striatal neuron excitability. When hM4D receptors were selectively expressed in either direct or indirect pathway neurons, CNO did not change acute locomotor responses to amphetamine, but did alter behavioral plasticity associated with repeated drug treatment. Specifically, transiently disrupting striatopallidal neuronal activity facilitated behavioral sensitization, whereas decreasing excitability of striatonigral neurons impaired its persistence. These findings suggest that acute drug effects can be parsed from the behavioral adaptations associated with repeated drug exposure and highlight the utility of this approach for deconstructing neuronal pathway contributions to behavior.

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Figure 1: Transient and targeted attenuation of striatal cell signaling.
Figure 2: Transiently reducing excitability of striatopallidal or striatonigral neurons had opposing effects on amphetamine sensitization.

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This work was supported by US National Institutes of Health grants K99 DA024762 (S.M.F.), T32 GM07266 and T32 GM07108 (D.E.), T32 AA009455 and F32 DA026273 (M.J.W.), R21 DA021793 (P.E.M.P.), R01 DA023206 (Y.D.), U19MH82441 and the National Institute of Mental Health Psychoactive Drug Screening Program (B.L.R.), and R21 DA021273 (J.F.N.), an Achievement Rewards for College Scientists (D.E.), and a National Alliance for Research on Schizophrenia and Depression Distinguished Investigator Award (B.L.R.).

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S.M.F. and D.E. generated the viral vector constructs. S.M.F. did the behavioral and immunohistochemical experiments. M.I. and Y.D. did the electrophysiology experiments. M.J.W. and P.E.M.P. did the voltammetry experiments. B.L.R. provided the hM4D plasmids and assisted with experimental design. S.M.F. and J.F.N. designed the overall study and wrote the manuscript. All of the authors contributed to data interpretation and manuscript editing.

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Correspondence to John F Neumaier.

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The authors declare no competing financial interests.

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Ferguson, S., Eskenazi, D., Ishikawa, M. et al. Transient neuronal inhibition reveals opposing roles of indirect and direct pathways in sensitization. Nat Neurosci 14, 22–24 (2011).

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