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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apamin / pharmacology
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Benzamides / pharmacology
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Biophysics
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Cannabinoids / administration & dosage*
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Cannabinoids / agonists
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Cannabinoids / antagonists & inhibitors
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Carbamates / pharmacology
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Conditioning, Operant / drug effects
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Corpus Striatum / cytology
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Corpus Striatum / drug effects*
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Cyclohexanols / pharmacokinetics
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Dose-Response Relationship, Drug
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Dronabinol / pharmacology
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Drug Tolerance / physiology*
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Electric Stimulation
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Enzyme Inhibitors / pharmacology
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Excitatory Postsynaptic Potentials / drug effects
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Guanosine 5'-O-(3-Thiotriphosphate) / pharmacokinetics
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Habits*
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Long-Term Synaptic Depression / drug effects
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Long-Term Synaptic Depression / physiology*
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Male
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Mice
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Mice, Inbred C57BL
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Motor Activity / drug effects
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Okadaic Acid / pharmacology
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Patch-Clamp Techniques
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Piperidines / pharmacology
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Protein Binding / drug effects
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Pyrazoles / pharmacology
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Rimonabant
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Small-Conductance Calcium-Activated Potassium Channels / metabolism*
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Sodium Channel Blockers / pharmacology
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Tritium / pharmacokinetics
Substances
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Benzamides
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Cannabinoids
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Carbamates
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Cyclohexanols
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Enzyme Inhibitors
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Piperidines
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Pyrazoles
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Small-Conductance Calcium-Activated Potassium Channels
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Sodium Channel Blockers
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cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester
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Tritium
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Okadaic Acid
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Apamin
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Guanosine 5'-O-(3-Thiotriphosphate)
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AM 251
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Dronabinol
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3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol
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Rimonabant