Effects of exogenous and endogenous cannabinoids on GABAergic neurotransmission between the caudate-putamen and the globus pallidus in the mouse
Effects of exogenous and endogenous cannabinoids on GABAergic neurotransmission between the caudate-putamen and the globus pallidus in the mouse
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DOI：
10.1124/jpet.105.092718
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发表时间：
2006-02-01
影响因子：
3.5
通讯作者：
Szabo, B
中科院分区：
文献类型：
--
作者：
Engler, B;Freiman, I;Szabo, B
苍白球神经元通过纹状体-苍白球通路接受来自尾壳核的GABA能输入。解剖学研究表明，许多CB 1大麻素受体定位于纹体轴突的末端。因此，本工作的假设是，CB 1受体的激活突触前抑制纹状体苍白球神经元之间的神经传递。在矢状面小鼠脑切片中，电刺激尾壳核中的纹状体体轴索，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（IPSC）。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（WIN 55212 -2）和（-）-顺式-3-[2-羟基-4-（1，1-二甲基庚基）-苯基]-反式-4-（3-羟丙基）环己醇（CP 55940）降低了IPSC的幅度。CB 1受体拮抗剂利莫那班阻止了WIN 55212 -2的抑制作用，表明CB 1受体参与。苍白球神经元的去极化诱导了IPSC的微弱和短暂的抑制[即，发生去极化诱导的抑制抑制（DSI）。利莫那班预防DSI表明突触后神经元释放的内源性大麻素作用于CB 1受体，抑制突触传递。WIN 55212 -2没有改变由GABA通过闪光脉冲从其化学结合（“笼状”）形式释放引起的苍白球神经元电流，表明WIN 55212 -2抑制突触前神经传递。为了研究GABA释放抑制的机制，用钙敏感的荧光染料标记了纹状体体轴突的终末。WIN 55212 -2抑制动作电位诱发的轴突终末钙浓度增加。结果表明，外源性和内源性大麻素激活CB 1受体，导致突触前抑制纹状体-苍白球轴突和苍白球神经元之间的神经传递。抑制动作电位诱发的钙离子内流进入轴突终末是这种抑制的可能机制。
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)methanonemesylate (WIN55212-2) and (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)-phenyl]-trans-4-(3-hydroxypropyl)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.