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The Journal of Neuroscience, December 3, 2003, 23(35):11073-11077

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Cannabinoids Decrease Corticostriatal Synaptic Transmission via an Effect on Glutamate Uptake

Timothy M. Brown, Jonathan M. Brotchie, and Stephen M. Fitzjohn

School of Biological Sciences, University of Manchester, Manchester, M13 9PT, United Kingdom

Activation of cannabinoid CB₁ receptors reduces glutamatergic synaptic transmission in the rodent striatum and is involved in the normal control of motor function by the basal ganglia. Here we investigated CB₁ receptor regulation of glutamate release and uptake and synaptic transmission in the rat striatum. We show that CB₁ receptor activation reduces both the release and uptake of [³H]glutamate in striatal slices. We also demonstrate that both activation of CB₁ receptors and inhibition of glutamate uptake reduce corticostriatal synaptic transmission in a mutually occlusive manner and that both forms of depression are dependent on metabotropic glutamate receptor (mGluR) activation. We propose that CB₁ receptor activation in the striatum decreases glutamate transporter activity and that the resulting increase in synaptic cleft glutamate concentration causes the activation of presynaptic mGluRs, which then decrease glutamate release.

Key words: cannabinoid; striatum; glutamate; uptake; release; mGluR; tetrahydrocannabinol; basal ganglia

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Received June 27, 2003; revised October 10, 2003; accepted October 10, 2003.

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