SK channel modulation rescues striatal plasticity and control over habit in cannabinoid tolerance.
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.
Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genova, Italy.
Cristiano
C
Nazzaro
Barbara
B
Greco
Milica
M
Cerovic
Paul
P
Baxter
Tiziana
T
Rubino
Massimo
M
Trusel
Daniela
D
Parolaro
Tatiana
T
Tkatch
Fabio
F
Benfenati
Paola
P
Pedarzani
Raffaella
R
Tonini
D000818:Animals; D001030:Apamin / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D001703:Biophysics; D002186:Cannabinoids / Q000008:administration & dosage* / Q000819:agonists / Q000037:antagonists & inhibitors; D002219:Carbamates / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects*; D003511:Cyclohexanols / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000494:pharmacology; D004361:Drug Tolerance / Q000502:physiology*; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D006184:Habits; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D019319:Okadaic Acid / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D000077285:Rimonabant; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D014316:Tritium / Q000493:pharmacokinetics
D001549:Benzamides; D002186:Cannabinoids; D002219:Carbamates; D003511:Cyclohexanols; D004791:Enzyme Inhibitors; D010880:Piperidines; D011720:Pyrazoles; D051640:Small-Conductance Calcium-Activated Potassium Channels; D026941:Sodium Channel Blockers; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; D014316:Tritium; D019319:Okadaic Acid; D001030:Apamin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C103505:AM 251; D013759:Dronabinol; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D000077285:Rimonabant