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NEUROPHARMACOLOGY

Effects of Exogenous and Endogenous Cannabinoids on GABAergic Neurotransmission between the Caudate-Putamen and the Globus Pallidus in the Mouse

Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Albert-Ludwigs-Universität, Freiburg, Germany

Globus pallidus neurons receive GABAergic input from the caudate-putamen via the striatopallidal pathway. Anatomical studies indicate that many CB₁ cannabinoid receptors are localized on terminals of striatopallidal axons. Accordingly, the hypothesis of the present work was that activation of CB₁ receptors presynaptically inhibits neurotransmission between striatopallidal axons and globus pallidus neurons. In sagittal mouse brain slices, striatopallidal axons were electrically stimulated in the caudate-putamen, and the resulting GABAergic inhibitory postsynaptic currents (IPSCs) were recorded in globus pallidus neurons. The synthetic cannabinoid receptor agonists R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl] pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)-methanone mesylate (WIN55212-2) and (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)-phenyl]-trans-4-(3-hydroxy-propyl)-cyclohexanol (CP55940) decreased the amplitude of IPSCs. The CB₁ receptor antagonist rimonabant prevented the inhibition by WIN55212-2, pointing to involvement of CB₁ receptors. Depolarization of globus pallidus neurons induced a weak and short-lasting suppression of IPSCs [i.e., depolarization-induced suppression of inhibition (DSI) occurred]. Prevention of DSI by rimonabant indicates that endocannabinoids released from the postsynaptic neurons acted on CB₁ receptors to suppress synaptic transmission. WIN55212-2 did not modify currents in globus pallidus neurons elicited by GABA released from its chemically bound ("caged") form by a flash pulse, suggesting that WIN55212-2 depressed neurotransmission presynaptically. For studying the mechanism of the inhibition of GABA release, terminals of striatopallidal axons were labeled with a calcium-sensitive fluorescent dye. WIN55212-2 depressed the action potential-evoked increase in axon terminal calcium concentration. The results show that activation of CB₁ receptors by exogenous and endogenous cannabinoids leads to presynaptic inhibition of neurotransmission between striatopallidal axons and globus pallidus neurons. Depression of the action potential-evoked calcium influx into axon terminals is the probable mechanism of this inhibition.

Address correspondence to: Dr. Bela Szabo, Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Albert-Ludwigs-Universität, Albertstrasse 25, D-79104 Freiburg i. Br., Germany. E-mail: szabo{at}pharmakol.uni-freiburg.de

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