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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on October 7, 2005; DOI: 10.1124/jpet.105.092718


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Received for publication July 18, 2005.
Revised September 18, 2005.
Accepted for publication October 6, 2005.

Effects of exogenous and endogenous cannabinoids on GABAergic neurotransmission between the caudate-putamen and the globus pallidus in the mouse

Birgit Engler 1, Ilka Freiman 1, Michal Urbanski 1, Bela Szabo 1*

1 Dept. of Pharmacology, University of Freiburg

* Address correspondence to: E-mail: szabo{at}pharmakol.uni-freiburg.de

Abstract

Globus pallidus neurons receive GABAergic input from the caudate-putamen via the striato-pallidal pathway. Anatomical studies indicate that many CB1 cannabinoid receptors are localised on terminals of striato-pallidal axons. Accordingly, the hypothesis of the present work was that activation of CB1 receptors presynaptically inhibits neurotransmission between striato-pallidal axons and globus pallidus neurons. In sagittal mouse brain slices, striato-pallidal axons were electrically stimulated in the caudate-putamen and the resulting GABAergic inhibitory post-synaptic currents (IPSCs) were recorded in globus pallidus neurons. The synthetic cannabinoid receptor agonists WIN55212-2 and CP55940 decreased the amplitude of IPSCs. The CB1 receptor antagonist rimonabant prevented the inhibition by WIN55212-2, pointing to involvement of CB1 receptors. Depolarisation of globus pallidus neurons induced a weak and short-lasting suppression of IPSCs (i.e., depolarisation-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 striato-pallidal axons were labelled 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 striato-pallidal axons and globus pallidus neurons. Depression of the action potential-evoked calcium influx into axon terminals is the probable mechanism of this inhibition.


Key words: basal ganglia, cannabinoid, electrophysiology, endocannabinoids, presynaptic receptor, synaptic transmission


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