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The Journal of Neuroscience, January 1, 2000, 20(1):51-58

Cannabinoids Decrease the K⁺ M-Current in Hippocampal CA1 Neurons

Paul Schweitzer

Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037

Cannabinoid effects on sustained conductances that control neuronal excitability have not been investigated in brain. Here, intracellular voltage-clamp recordings were performed using the rat hippocampal slice preparation to study the postsynaptic effect of cannabinoid agonists on CA1 pyramidal neurons. Superfusion of the cannabimimetics WIN55212-2 or methanandamide onto CA1 neurons elicited an inward steady-state current that reversed near the equilibrium potential for K⁺ and voltage-dependently activated from a threshold of approximately 70 mV. The cannabinoid receptor (CB1) antagonist SR141716 did not alter membrane properties but prevented this effect. Further investigation revealed that the inward current elicited by cannabinoids was caused by a decrease of the noninactivating voltage-dependent K⁺ M-current (I_M). Cannabinoids had no effect in slices pretreated with the M-channel blocker linopirdine. Assessment of the I_M relaxation indicated that cannabinoids decreased I_M in a concentration-dependent manner, with a maximum inhibition of 45 ± 3% with WIN55212-2 (EC₅₀ of 0.6 µM) and 41 ± 5% with methanandamide (EC₅₀ of 1 µM). Cannabinoids did not affect the inwardly rectifying cationic h-current (I_h). The cannabinoid-induced I_M decrease was prevented by SR141716 but remained unaffected by the muscarinic receptor antagonist atropine. Conversely, the cholinergic agonist carbamylcholine decreased I_M in the presence of SR141716, indicating that cannabinoid and muscarinic receptor activation independently diminish I_M. It is concluded that cannabinoids may postsynaptically augment the excitability of CA1 pyramidal neurons by specifically decreasing the persistent voltage-dependent I_M.

Key words: cannabinoid; brain; slice; voltage-clamp; potassium current; excitation

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Copyright © 2000 Society for Neuroscience  0270-6474/0/20151-08$05.00/0

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