Engler Birgit, Freiman Ilka, Urbanski Michal, Szabo Bela
Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Albert-Ludwigs-Universität, Freiburg, Germany.
J Pharmacol Exp Ther. 2006 Feb;316(2):608-17. doi: 10.1124/jpet.105.092718. Epub 2005 Oct 7.
Globus pallidus neurons receive GABAergic input from the caudate-putamen via the striatopallidal pathway. Anatomical studies indicate that many CB(1) cannabinoid receptors are localized on terminals of striatopallidal axons. Accordingly, the hypothesis of the present work was that activation of CB(1) 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 CB(1) receptor antagonist rimonabant prevented the inhibition by WIN55212-2, pointing to involvement of CB(1) 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 CB(1) 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 CB(1) 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.
苍白球神经元通过纹状体苍白球通路接受来自尾状核 - 壳核的GABA能输入。解剖学研究表明，许多CB(1)大麻素受体定位于纹状体苍白球轴突的终末。因此，本研究的假设是CB(1)受体的激活在突触前抑制纹状体苍白球轴突与苍白球神经元之间的神经传递。在矢状位小鼠脑片中，在尾状核 - 壳核中电刺激纹状体苍白球轴突，并在苍白球神经元中记录由此产生的GABA能抑制性突触后电流（IPSCs）。合成大麻素受体激动剂R(+)-[2,3 - 二氢 - 5 - 甲基 - 3 - [(吗啉基)甲基]吡咯并[1,2,3 - de]-1,4 - 苯并恶嗪基]-(1 - 萘基)-甲磺酸甲酯（WIN55212 - 2）和(-)-顺式 - 3 - [2 - 羟基 - 4 - (1,1 - 二甲基庚基)-苯基]-反式 - 4 - (3 - 羟基丙基)-环己醇（CP55940）降低了IPSCs的幅度。CB(1)受体拮抗剂利莫那班可阻止WIN55212 - 2的抑制作用，表明CB(1)受体参与其中。苍白球神经元的去极化诱导了IPSCs的微弱且短暂的抑制[即发生了去极化诱导的抑制作用（DSI）]。利莫那班对DSI的阻止表明，从突触后神经元释放的内源性大麻素作用于CB(1)受体以抑制突触传递。WIN55212 - 2并未改变由闪光脉冲从其化学结合（“笼化”）形式释放的GABA所诱发的苍白球神经元中的电流，这表明WIN55212 - 2在突触前抑制神经传递。为了研究GABA释放抑制的机制，用钙敏荧光染料标记纹状体苍白球轴突的终末。WIN55212 - 2抑制了动作电位诱发的轴突终末钙浓度的增加。结果表明，外源性和内源性大麻素对CB(1)受体的激活导致纹状体苍白球轴突与苍白球神经元之间神经传递的突触前抑制。动作电位诱发的钙流入轴突终末的减少是这种抑制作用的可能机制。
