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SK channel modulation rescues striatal plasticity and control over habit in cannabinoid tolerance

Nature Neuroscience volume 15, pages 284–293 (2012)Cite this article

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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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Figure 1: Cannabinoid tolerance abolishes eCB LTD in the DLS.
Figure 2: STDP at corticostriatal afferents on D2 MSNs.
Figure 3: HFS LTD in the DMS.
Figure 4: Synaptic depotentiation in the DLS of THC tolerant and naive mice.
Figure 5: SK channels are functionally expressed in the MSNs of the DLS where they modulate eCB LTD.
Figure 6: SK channel and mGluR5 modulation of synaptic depotentiation in the DLS.
Figure 7: Ex vivo and in vivo inhibition of SK channels rescues striatal eCB LTD in THC-tolerant mice.
Figure 8: In vivo modulation of SK channels in the DLS rescues goal-directed behavior in THC-tolerant mice.

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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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Author notes

  1. Cristiano Nazzaro and Barbara Greco: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia (IIT), Genova, Italy

    Cristiano Nazzaro, Barbara Greco, Massimo Trusel, Tatiana Tkatch, Fabio Benfenati & Raffaella Tonini

  2. School of Bioscience, Cardiff University, UK

    Milica Cerovic

  3. Res. Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK

    Paul Baxter & Paola Pedarzani

  4. DBSF, University of Insubria, Busto Arsizio (VA), Italy

    Tiziana Rubino & Daniela Parolaro

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Contributions

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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Correspondence to Raffaella Tonini.

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The authors declare no competing financial interests.

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Supplementary Figures 1–14, Supplementary Results and Supplementary Discussion (PDF 1654 kb)

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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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