Opposing actions of chronic Δ9-tetrahydrocannabinol and cannabinoid antagonists on hippocampal long-term potentiation
Opposing actions of chronic Δ9-tetrahydrocannabinol and cannabinoid antagonists on hippocampal long-term potentiation
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DOI：
10.1101/lm.439007
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发表时间：
2007-01-01
影响因子：
2
通讯作者：
Lupica, Carl R.
中科院分区：
文献类型：
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作者：
Hoffman, Alexander F.;Oz, Murat;Lupica, Carl R.
大麻产生的记忆缺陷部分是通过精神活性成分Delta（9）-tetrahydrocannabinol（Delta（9）-THC）与海马体中的大麻素受体的相互作用而产生的。尽管大麻素能急性减少谷氨酸释放并阻断海马长时程增强（LTP）（一种学习和记忆的潜在底物），但对长期暴露于δ（9）-THC对海马功能的影响知之甚少.大鼠腹腔注射Delta（9）-THC（10 mg/kg，i. p.的情况下，Q. d.）1、3、7 d，末次注射后1 d在海马脑片上进行电生理记录。此时，使用液相色谱-质谱法（LC-MS）在海马中检测不到Δ（9）-THC。在7-d Delta（9）-THC处理的动物的脑切片中未观察到使用高频（HFS）或θ爆发刺激产生的海马LTP。Δ（9）-THC在治疗3天后也阻断HFS-LTP，但在治疗1天后不阻断.在最后一次Delta（9）-THC注射后，LTP的完全阻断持续3天，在Delta（9）-THC停药后14天未观察到LTP缺陷的完全逆转。在每次Delta（9）-THC注射前给予大麻素拮抗剂AM 251（2 mg/kg）防止了LTP的阻断，并且单独用AM 251治疗7天显著增加了LTP的水平。慢性δ（9）-THC也产生对突触GABA的抑制的耐受性，但不产生对激动剂WIN55，212 - 2的谷氨酸释放的耐受性。这些数据定义了重复Delta（9）-THC暴露对海马体突触可塑性的影响，这可能有助于解释人类长期使用大麻后的记忆障碍。
Memory deficits produced by marijuana arise partly via interaction of the psychoactive component, Delta(9)-tetrahydrocannabinol (Delta(9)-THC), with cannabinoid receptors in the hippocampus. Although cannabinoids acutely reduce glutamate release and block hippocampal long- term potentiation (LTP), a potential substrate for learning and memory, the consequences of prolonged exposure to Delta(9)-THC for hippocampal function are poorly understood. Rats were injected with Delta(9)-THC (10 mg/ kg, i. p., q. d.) for 1, 3, or 7 d, and electrophysiological recordings were performed in hippocampal slices 1d after the final injection. At this time, Delta(9)-THC was undetectable in hippocampus using liquid chromatography-mass spectrometry (LC-MS). Hippocampal LTP generated using high- frequency (HFS) or theta burst stimulation was not observed in brain slices from the 7-d Delta(9)-THC-treated animals. Delta(9)-THC also blocked HFS- LTP after 3 d, but not 1 d of treatment. The complete blockade of LTP persisted for 3 d after the last Delta(9)-THC injection, and full reversal of the LTP deficit was not observed up to 14 d following Delta(9)-THC withdrawal. The cannabinoid antagonist AM251 (2 mg/kg), administered before each Delta(9)-THC injection prevented the blockade of LTP, and 7-d treatment with AM251 alone significantly increased the level of LTP. Chronic Delta(9)-THC also produced tolerance to the inhibition of synaptic GABA, but not glutamate release by the agonist WIN55,212-2. These data define consequences of repeated Delta(9)-THC exposure for synaptic plasticity in the hippocampus that may help explain memory impairments in humans following chronic marijuana use.