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

Cristiano Nazzaro, Barbara Greco, Milica Cerovic, Paul Baxter, Tiziana Rubino, Massimo Trusel, Daniela Parolaro, Tatiana Tkatch, Fabio Benfenati, Paola Pedarzani, Raffaella Tonini

Research output: Contribution to journalArticlepeer-review

82 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)284-293
Number of pages10
JournalNature neuroscience
Issue number2
StatePublished - Feb 2012
Externally publishedYes

ASJC Scopus subject areas

  • Neuroscience(all)


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