Meshul C K, Noguchi K, Emre N, Ellison G
Research Services, VA Medical Center, Department of Pathology, Oregon Health Sciences University, Portland 97201, USA.
Synapse. 1998 Oct;30(2):211-20. doi: 10.1002/(SICI)1098-2396(199810)30:2<211::AID-SYN11>3.0.CO;2-4.
We previously reported that subchronic administration of cocaine for 5 days via slow-release pellets results in pronounced degeneration in the lateral habenula (LHB) and its primary efferent tract, the fasciculus retroflexus [Ellison (1992): Brain Res 598:353-356; Ellison and Switzer (1993): Neuroreport 5:17-20]. The lateral habenula receives both GABA and glutamate afferents. In order to test the hypothesis that the cocaine-induced degeneration of the fasciculus retroflexus may be related to changes in synaptic activity of either GABA or glutamate nerve terminals within the LHB, the density of nerve terminal immunolabeling of either neurotransmitter was quantified after 5 days of chronic drug administration followed by either 1 or 14 days off the drug. The shell of the nucleus accumbens (NACs) was also analyzed, since this area is thought to be associated with the reward aspects of addictive stimulant drug administration and was previously shown not to be associated with fiber degeneration. We found that cocaine treatment resulted in a significant decrease in the density of nerve-terminal GABA immunolabeling located within the LHB in animals taken off the drug for either 1 or 14 days, while there was no change in the density of glutamate immunolabeling. In the NACs, there was a decrease in the density of glutamate immunolabeling within nerve terminals 1 day but not 14 days after cocaine administration. There was no change in the density of GABA immunolabeling within the NACs following the 1 or 14 day-off period. These results suggest that there are long-term changes in the density of GABA immunolabeling within the LHB and that the effects seen in glutamate synapses within the NACs are transitory. The long-term decrease in GABA immunolabeling within the LHB is consistent with the hypothesis that a decrease in inhibitory synaptic activity, leading to increased excitatory influence on LHB neurons, may result in neurotoxicity and the subsequent degeneration of the fasciculus retroflexus.
我们之前报道过，通过缓释微丸对可卡因进行5天的亚慢性给药会导致外侧缰核（LHB）及其主要传出通路——后屈束出现明显退化[埃里森（1992年）：《脑研究》598：353 - 356；埃里森和斯威策（1993年）：《神经报告》5：17 - 20]。外侧缰核接受γ-氨基丁酸（GABA）和谷氨酸能传入纤维。为了检验可卡因诱导的后屈束退化可能与LHB内GABA或谷氨酸神经末梢突触活动变化有关这一假设，在慢性药物给药5天后，接着停药1天或14天，对这两种神经递质的神经末梢免疫标记密度进行了量化。伏隔核壳（NACs）也进行了分析，因为该区域被认为与成瘾性刺激药物给药的奖赏方面有关，并且之前已表明与纤维退化无关。我们发现，在停药1天或14天的动物中，可卡因治疗导致LHB内神经末梢GABA免疫标记密度显著降低，而谷氨酸免疫标记密度没有变化。在NACs中，可卡因给药后1天神经末梢内谷氨酸免疫标记密度降低，但14天后没有变化。在停药1天或14天后，NACs内GABA免疫标记密度没有变化。这些结果表明，LHB内GABA免疫标记密度存在长期变化，并且在NACs内谷氨酸突触中观察到的效应是短暂的。LHB内GABA免疫标记的长期降低与以下假设一致，即抑制性突触活动的降低导致对LHB神经元兴奋性影响增加，可能会导致神经毒性以及随后的后屈束退化。
