okadaic-acid and 3-(2-hydroxy-4-(1-1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol

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.

Topics: Animals; Apamin; Benzamides; Biophysics; Cannabinoids; Carbamates; Conditioning, Operant; Corpus Striatum; Cyclohexanols; Dose-Response Relationship, Drug; Dronabinol; Drug Tolerance; Electric Stimulation; Enzyme Inhibitors; Excitatory Postsynaptic Potentials; Guanosine 5'-O-(3-Thiotriphosphate); Habits; Long-Term Synaptic Depression; Male; Mice; Mice, Inbred C57BL; Motor Activity; Okadaic Acid; Patch-Clamp Techniques; Piperidines; Protein Binding; Pyrazoles; Rimonabant; Small-Conductance Calcium-Activated Potassium Channels; Sodium Channel Blockers; Tritium

Exogenously administered cannabinoids are neuroprotective in several different cellular and animal models. In the current study, two cannabinoid CB1 receptor ligands (WIN 55,212-2, CP 55,940) markedly reduced hippocampal cell death, in a time-dependent manner, in cultured neurons subjected to high levels of NMDA (15 microM). WIN 55,212-2 was also shown to inhibit the NMDA-induced increase in intracellular calcium concentration ([Ca2+](i)) indicated by FURA-2 fluorescence imaging in the same cultured neurons. Changes in [Ca2+](i) occurred with similar concentrations (25-100 nM) and in the same time-dependent manner (pre-exposure 1-15 min) as CB1 receptor mediated neuroprotective actions. Both effects were blocked by the CB1 receptor antagonist SR141716A. An underlying mechanism was indicated by the fact that (1) the NMDA-induced increase in [Ca2+](i) was inhibited by ryanodine, implicating a ryanodine receptor (RyR) coupled intracellular calcium channel, and (2) the cannabinoid influence involved a reduction in cAMP cAMP-dependent protein kinase (PKA) dependent phosphorylation of the same RyR levels that regulate channel. Moreover the time course of CB1 receptor mediated inhibition of PKA phosphorylation was directly related to effective pre-exposure intervals for cannabinoid neuroprotection. Control studies ruled out the involvement of inositol-trisphosphate (IP3) pathways, enhanced calcium reuptake and voltage sensitive calcium channels in the neuroprotective process. The results suggest that cannabinoids prevent cell death by initiating a time and dose dependent inhibition of adenylyl cyclase, that outlasts direct action at the CB1 receptor and is capable of reducing [Ca2+](i) via a cAMP/PKA-dependent process during the neurotoxic event.

Topics: Animals; Benzoxazines; Calcium; Cell Culture Techniques; Cell Death; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclohexanols; Dantrolene; Drug Interactions; Estrenes; Fetus; Hippocampus; Macrocyclic Compounds; Morpholines; N-Methylaspartate; Naphthalenes; Neurons; Neuroprotective Agents; Okadaic Acid; Oxazoles; Piperidines; Pyrazoles; Pyrrolidinones; Rats; Rats, Inbred Strains; Receptor, Cannabinoid, CB1; Rimonabant; Ryanodine; Thionucleotides