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Inhibition of striatal dopamine release by CB1 receptor activation requires nonsynaptic communication involving GABA, H(2)O(2), and K(ATP) channels.

Sidló Z, Reggio PH, Rice ME

Department of Neurosurgery, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA; Department of Physiology and Neuroscience, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.

The main psychoactive component of marijuana, Delta(9)-tetrahydrocannabinol (THC), acts in the CNS via type 1 cannabinoid receptors (CB1Rs). The behavioral consequences of THC or synthetic CB1R agonists include suppression of motor activity. One explanation for movement suppression might be inhibition of striatal dopamine (DA) release by CB1Rs, which are densely localized in motor striatum; however, data from previous studies are inconclusive. Here we examined the effect of CB1R activation on locally evoked DA release monitored with carbon-fiber microelectrodes and fast-scan cyclic voltammetry in striatal slices. Consistent with previous reports, DA release evoked by a single stimulus pulse was unaffected by WIN55,212-2, a cannabinoid receptor agonist. However, when DA release was evoked by a train of stimuli, WIN55,212-2 caused a significant decrease in evoked extracellular DA concentration ([DA](o)), implicating the involvement of local striatal circuitry, with similar suppression seen in guinea pig, rat, and mouse striatum. Pulse-train evoked [DA](o) was not altered by either AM251, an inverse CB1R agonist, or VCHSR1, a neutral antagonist, indicating the absence of DA release regulation by endogenous cannabinoids with the stimulation protocol used. However, both CB1R antagonists prevented and reversed suppression of evoked [DA](o) by WIN55,212-2. The effect of WIN55,212-2 was also prevented by picrotoxin, a GABA(A) receptor antagonist, and by catalase, a metabolizing enzyme for hydrogen peroxide (H(2)O(2)). Furthermore, blockade of ATP-sensitive K(+) (K(ATP)) channels by tolbutamide or glybenclamide prevented the effect of WIN55,212-2 on DA release. Together, these data indicate that suppression of DA release by CB1R activation within striatum occurs via a novel nonsynaptic mechanism that involves GABA release inhibition, increased generation of the diffusible messenger H(2)O(2), and activation of K(ATP) channels to inhibit DA release. In addition, the findings suggest a possible physiological substrate for the motor effects of cannabinoid agonist administration.

Published 17 December 2007 in Neurochem Int, 52(1): 80-8.
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