Fallon S, Shearman E, Sershen H, Lajtha A
Nathan Kline Institute, Orangeburg, NY 10962, USA.
Neurochem Res. 2007 Apr-May;32(4-5):535-53. doi: 10.1007/s11064-006-9113-z. Epub 2006 Aug 15.
In the present study, we tested the effects of glutamate and GABA receptor antagonists on nicotine-induced neurotransmitter changes in the hippocampal (dorsal and ventral) and cortical (medial temporal and prefrontal) brain areas of conscious freely moving rats via microdialysis. Both the antagonists and nicotine were administered intracerebrally. The antagonists tested were NMDA, AMPA-kainate, and metabotropic glutamate receptor subtype antagonists (MK801, CNQX, and LY 341495, respectively) and GABA(A) and GABA(B) receptor subtype antagonists (bicuculline and hydroxysaclofen, respectively). We assayed nicotine-induced changes in dopamine (DA), norepinephrine (NE), serotonin (5-HT), and their metabolites. We found with the antagonists, both decreases and increases in nicotine-induced neurotransmitter responses. In the presence of nicotine all the antagonists (except LY 341495) caused a decrease in DA levels in the regions tested. NE levels were decreased in the cortex by all antagonists. In the hippocampus, GABA antagonists decreased NE levels, as did the metabotropic glutamate antagonist, LY 341495, while the other glutamate antagonists increased NE levels. The results of the 5-HT assay were more variable and dependent on the region and antagonist examined; increases were found slightly more often than decreases. The changes in metabolites were not often parallel with changes in their associated neurotransmitters, indicating that the antagonists also affect the metabolism of the neurotransmitters. The effect of the antagonists in the absence of nicotine was mostly to decrease the level of neurotransmitters, although increases were seen in a few cases. The results suggest that the excitatory glutamatergic- and inhibitory GABAergic-amino acid receptors are both involved in mediating nicotine-induced neurotransmitter responses, and their inhibitory or stimulatory effects are receptor subtype and brain region dependent.
在本研究中，我们通过微透析测试了谷氨酸和γ-氨基丁酸（GABA）受体拮抗剂对清醒自由活动大鼠海马体（背侧和腹侧）及皮质（内侧颞叶和前额叶）脑区尼古丁诱导的神经递质变化的影响。拮抗剂和尼古丁均通过脑内给药。所测试的拮抗剂分别为N-甲基-D-天冬氨酸（NMDA）、α-氨基-3-羟基-5-甲基-4-异恶唑丙酸-海人藻酸（AMPA-海人藻酸）和代谢型谷氨酸受体亚型拮抗剂（分别为MK801、CNQX和LY 341495）以及GABA(A)和GABA(B)受体亚型拮抗剂（分别为荷包牡丹碱和羟舒芬太尼）。我们检测了尼古丁诱导的多巴胺（DA）、去甲肾上腺素（NE）、5-羟色胺（5-HT）及其代谢产物的变化。我们发现，使用拮抗剂后，尼古丁诱导的神经递质反应既有降低也有增加。在存在尼古丁的情况下，所有拮抗剂（LY 341495除外）均导致所测试区域的DA水平降低。所有拮抗剂均使皮质中的NE水平降低。在海马体中，GABA拮抗剂降低了NE水平，代谢型谷氨酸拮抗剂LY 341495也有此作用，而其他谷氨酸拮抗剂则提高了NE水平。5-HT检测结果的变异性更大，且取决于所检测的区域和拮抗剂；5-HT水平升高的情况略多于降低的情况。代谢产物的变化通常与其相关神经递质的变化不平行，这表明拮抗剂也会影响神经递质的代谢。在不存在尼古丁的情况下，拮抗剂的作用大多是降低神经递质水平，不过在少数情况下也观察到了升高。结果表明，兴奋性谷氨酸能和抑制性GABA能氨基酸受体均参与介导尼古丁诱导的神经递质反应，其抑制或刺激作用取决于受体亚型和脑区。
