Abstract
Endocannabinoids (eCBs) regulate neuronal activity in the dorso-lateral striatum (DLS), a brain region that is involved in habitual behaviors. How synaptic eCB signaling contributes to habitual behaviors under physiological and pathological conditions remains unclear. Using a mouse model of cannabinoid tolerance, we found that persistent activation of the eCB pathway impaired eCB-mediated long-term depression (LTD) and synaptic depotentiation in the DLS. The loss of eCB LTD, occurring preferentially at cortical connections to striatopallidal neurons, was associated with a shift in behavioral control from goal-directed action to habitual responding. eCB LTD and behavioral alterations were rescued by in vivo modulation of small-conductance calcium activated potassium channel (SK channel) activity in the DLS, which potentiates eCB signaling. Our results reveal a direct relationship between drug tolerance and changes in control of instrumental performance by establishing a central role for eCB LTD in habit expression. In addition, SK channels emerge as molecular targets to fine tune the eCB pathway under pathological conditions.
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Acknowledgements
We are grateful to V. Di Marzo, L. Gasparini and F. Papaleo for critical reading of the manuscript, and D. Piomelli for helpful discussion of the results. This research was supported by the Istituto Italiano di Tecnologia. P.P. acknowledges support from the Medical Research Council (CEG G0100066).
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C.N. conducted the majority of the electrophysiological experiments. B.G. designed and performed the behavioral experiments. M.C. and P.B. obtained the preliminary electrophysiological data on the effect of THC tolerance on striatal synaptic plasticity. T.T. carried out the PCR profiling of MSNs. T.R. and D.P. performed the autoradiographic studies. M.T. performed the histochemical experiments. F.B. supervised B.G. and contributed to data discussion. P.P. contributed to data discussion and interpretation and wrote the manuscript. R.T. supervised the project, directed and performed the experiments and wrote the manuscript.
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Nazzaro, C., Greco, B., Cerovic, M. et al. SK channel modulation rescues striatal plasticity and control over habit in cannabinoid tolerance. Nat Neurosci 15, 284–293 (2012). https://doi.org/10.1038/nn.3022
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DOI: https://doi.org/10.1038/nn.3022
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