Exogenous and Endogenous Cannabinoids Suppress Inhibitory Neurotransmission in the Human Neocortex
Exogenous and Endogenous Cannabinoids Suppress Inhibitory Neurotransmission in the Human Neocortex
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DOI：
10.1038/npp.2011.262
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发表时间：
2012-04-01
影响因子：
7.6
通讯作者：
Szabo, Bela
中科院分区：
文献类型：
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作者：
Kovacs, Flora E.;Knop, Tim;Szabo, Bela
外源性大麻素（如δ（9）-四氢大麻酚）和突触后神经元释放的内源性大麻素（endocannabinoids）激活轴突末端上的CB 1受体，导致神经传递的突触前抑制。本研究的目的是描述大麻素对人类新皮层GABA能突触传递的影响。从手术切除以消除致痫灶的新皮质组织制备脑切片。用膜片钳技术在假定的锥体神经元中记录自发GABA能抑制性突触后电流（sIPSC）。为了增强大麻素敏感的突触前轴突的活性，毒蕈碱受体持续刺激卡巴胆碱。合成大麻素受体激动剂WIN 55212 -2降低了sIPSC的累积幅度。CB 1拮抗剂利莫那班阻止了这种作用，证实了CB 1受体的参与。WIN 55212 -2降低了在河豚毒素存在下记录的微型IPSC（mIPSC）的频率，但不改变其振幅，表明神经传递在突触前被抑制。突触后锥体神经元的去极化诱导了sIPSC的抑制。由于利莫那班阻止了这种抑制，很可能是由于内源性大麻素作用于CB 1受体。这是第一次证明外源性大麻素抑制人类新皮层的突触传递，而突触后神经元释放的内源性大麻素抑制人类大脑的突触传递。大麻素激动剂和拮抗剂对皮层突触传递的干扰可以解释这些药物引起的认知和记忆缺陷。Neuropsychopharmacology（2012）37，1104-1114; doi：10.1038/npp.2011.262; 2011年11月2日在线发表
Activation of CB1 receptors on axon terminals by exogenous cannabinoids (eg, Delta(9)-tetrahydrocannabinol) and by endogenous cannabinoids (endocannabinoids) released by postsynaptic neurons leads to presynaptic inhibition of neurotransmission. The aim of this study was to characterize the effect of cannabinoids on GABAergic synaptic transmission in the human neocortex. Brain slices were prepared from neocortical tissues surgically removed to eliminate epileptogenic foci. Spontaneous GABAergic inhibitory postsynaptic currents (sIPSCs) were recorded in putative pyramidal neurons using patch-clamp techniques. To enhance the activity of cannabinoid-sensitive presynaptic axons, muscarinic receptors were continuously stimulated by carbachol. The synthetic cannabinoid receptor agonist WIN55212-2 decreased the cumulative amplitude of sIPSCs. The CB1 antagonist rimonabant prevented this effect, verifying the involvement of CB1 receptors. WIN55212-2 decreased the frequency of miniature IPSCs (mIPSCs) recorded in the presence of tetrodotoxin, but did not change their amplitude, indicating that the neurotransmission was inhibited presynaptically. Depolarization of postsynaptic pyramidal neurons induced a suppression of sIPSCs. As rimonabant prevented this suppression, it is very likely that it was due to endocannabinods acting on CB1 receptors. This is the first demonstration that an exogenous cannabinoid inhibits synaptic transmission in the human neocortex and that endocannabinoids released by postsynaptic neurons suppress synaptic transmission in the human brain. Interferences of cannabinoid agonists and antagonists with synaptic transmission in the cortex may explain the cognitive and memory deficits elicited by these drugs. Neuropsychopharmacology (2012) 37, 1104-1114; doi:10.1038/npp.2011.262; published online 2 November 2011