Wang Fan, Chen Hao, Sharp Burt M
Department of Pharmacology, University of Tennessee Health Science Center, Memphis, Tennesse, USA.
J Neurochem. 2008 Jul;106(2):943-56. doi: 10.1111/j.1471-4159.2008.05456.x. Epub 2008 May 3.
Nicotine self-administration causes adaptation in the mesocorticolimbic glutamatergic system, including the up-regulation of ionotropic glutamate receptor subunits. We therefore determined the effects of nicotine self-administration and extinction on NMDA-induced glutamate neurotransmission between the medial prefrontal cortex (mPFC) and ventral tegmental area (VTA). On day 19 of nicotine SA, both regions were microdialyzed for glutamate while mPFC was sequentially perfused with Kreb's Ringer buffer (KRB), 200 microM NMDA, KRB, 500 microM NMDA, KRB, and 100 mM KCl. Basal glutamate levels were unaffected, but nicotine self-administration significantly potentiated mPFC glutamate release to 200 microM NMDA, which was ineffective in controls. Furthermore, in VTA, nicotine self-administration significantly amplified glutamate responses to both mPFC infusions of NMDA. This hyper-responsive glutamate neurotransmission and enhanced glutamate subunit expression were reversed by extinction. Behavioral studies also showed that a microinjection of 2-amino-5-phosphonopentanoic acid (NMDA-R antagonist) into mPFC did not affect nicotine or sucrose self-administration. However, in VTA, NBQX (AMPA-R antagonist) attenuated both nicotine and sucrose self-administration. Collectively, these studies indicate that mesocortical glutamate neurotransmission adapts to chronic nicotine self-administration and VTA AMPA-R may be involved in the maintenance of nicotine self-administration.
尼古丁自我给药会导致中脑皮质边缘谷氨酸能系统发生适应性变化，包括离子型谷氨酸受体亚基的上调。因此，我们确定了尼古丁自我给药和消退对内侧前额叶皮质（mPFC）和腹侧被盖区（VTA）之间NMDA诱导的谷氨酸能神经传递的影响。在尼古丁自我给药的第19天，对这两个区域进行谷氨酸微透析，同时mPFC依次用克雷布斯林格缓冲液（KRB）、200微摩尔/升NMDA、KRB、500微摩尔/升NMDA、KRB和100毫摩尔/升KCl灌注。基础谷氨酸水平未受影响，但尼古丁自我给药显著增强了mPFC对200微摩尔/升NMDA的谷氨酸释放，而这在对照组中无效。此外，在VTA中，尼古丁自我给药显著放大了对mPFC注入NMDA的谷氨酸反应。这种高反应性谷氨酸能神经传递和增强的谷氨酸亚基表达在消退后被逆转。行为学研究还表明，向mPFC微量注射2-氨基-5-磷酸戊酸（NMDA-R拮抗剂）不影响尼古丁或蔗糖自我给药。然而，在VTA中，NBQX（AMPA-R拮抗剂）减弱了尼古丁和蔗糖自我给药。总的来说，这些研究表明，中脑皮质谷氨酸能神经传递适应慢性尼古丁自我给药，且VTA的AMPA-R可能参与尼古丁自我给药的维持。
