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
Nature Neuroscience January 8, 2012 DOI: 10.1038/nn.3022 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal study (mouse model of cannabinoid tolerance) Peer reviewed |
|---|---|
| Population | Mice (cannabinoid tolerance model) |
| Key points | Persistent endocannabinoid pathway activation in cannabinoid-tolerant mice impaired endocannabinoid-mediated LTD and synaptic depotentiation in the dorsolateral striatum, preferentially at cortical inputs to striatopallidal neurons, and was associated with a shift from goal-directed to habitual responding. Modulating SK channel activity in vivo rescued both LTD and the behavioral shift, suggesting SK channels as targets to tune endocannabinoid signaling. |
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.
Citations in the library
Cited by 5
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- Impairment of Synaptic Plasticity by Cannabis, Δ9-THC, and Synthetic Cannabinoids. Cold Spring Harbor perspectives in medicine May 3, 2021
- Adult Cellular Neuroadaptations Induced by Adolescent THC Exposure in Female Rats Are Rescued by Enhancing Anandamide Signaling. The International Journal of Neuropsychopharmacology November 1, 2018
- Selective effects of Δ9-tetrahydrocannabinol on medium spiny neurons in the striatum. PLoS One 2018
- Adolescent exposure to THC in female rats disrupts developmental changes in the prefrontal cortex. Neurobiology of Disease 2015
Cites 2
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