Schilström B, Fagerquist M V, Zhang X, Hertel P, Panagis G, Nomikos G G, Svensson T H
Karolinska Institutet, Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, S-171 77 Stockholm, Sweden.
Synapse. 2000 Dec 15;38(4):375-83. doi: 10.1002/1098-2396(20001215)38:4<375::AID-SYN2>3.0.CO;2-Y.
We have previously provided evidence that the stimulatory action of systemic nicotine on dopamine release in the rat nucleus accumbens is initiated in the ventral tegmental area (VTA), and that it appears to be mediated partly through an indirect, presynaptic mechanism. Thus, it was found that blockade of N-methyl-D-aspartate (NMDA) receptors in the VTA attenuates the enhancing effect of nicotine on extracellular levels of dopamine in the nucleus accumbens. Moreover, the nicotine-induced dopamine output in the nucleus accumbens was found to be blocked by pretreatment with methyllycaconitine (MLA) in the VTA, indicating a role for alpha7* nicotinic acetylcholine receptors (nAChRs) in this mechanism. Thus, nicotine may exert its effects in the VTA through stimulation of alpha7* nAChRs localized on excitatory amino acid (EAA)ergic afferents. To test this hypothesis, we here measured extracellular concentrations of glutamate and aspartate in the VTA in response to systemic nicotine, with or without concurrent infusion of MLA in the VTA, using microdialysis in anaesthetized rats. Since the medial prefrontal cortex is an important source of EAA input to the VTA, we also assessed the density of alpha-bungarotoxin binding sites in the VTA in rats lesioned bilaterally in the prefrontal cortex with ibotenic acid and in sham-lesioned rats by means of quantitative autoradiography. Nicotine (0.5 mg/kg, s.c.) significantly increased extracellular levels of both aspartate and glutamate in the VTA. MLA (0.3 mM) infused locally in the VTA prevented the nicotine-induced increase in glutamate and aspartate levels. Ibotenic acid lesions of the prefrontal cortex decreased the density of alpha-bungarotoxin binding sites in the VTA by about 30%. These data indicate that nicotine increases the extracellular levels of excitatory amino acids in the VTA through stimulation of nAChRs in the VTA and that part of the alpha7* nAChR population in the VTA is localized on neurons originating in the prefrontal cortex.
我们之前已经提供证据表明，全身尼古丁对大鼠伏隔核中多巴胺释放的刺激作用起始于腹侧被盖区（VTA），且这种作用似乎部分是通过一种间接的突触前机制介导的。因此，研究发现，阻断VTA中的N-甲基-D-天冬氨酸（NMDA）受体可减弱尼古丁对伏隔核中多巴胺细胞外水平的增强作用。此外，研究发现，在VTA中预先用甲基lycaconitine（MLA）处理可阻断尼古丁诱导的伏隔核中多巴胺释放，这表明α7烟碱型乙酰胆碱受体（nAChRs）在该机制中发挥作用。因此，尼古丁可能通过刺激位于兴奋性氨基酸（EAA）能传入纤维上的α7 nAChRs在VTA中发挥作用。为了验证这一假设，我们在此使用微透析技术，在麻醉大鼠中测量了全身给予尼古丁后，VTA中谷氨酸和天冬氨酸的细胞外浓度，同时或不同时在VTA中注入MLA。由于内侧前额叶皮质是VTA的EAA输入的重要来源，我们还通过定量放射自显影法评估了用鹅膏蕈氨酸双侧损伤前额叶皮质的大鼠和假损伤大鼠VTA中α-银环蛇毒素结合位点的密度。尼古丁（0.5mg/kg，皮下注射）显著增加了VTA中天冬氨酸和谷氨酸的细胞外水平。在VTA中局部注入MLA（0.3mM）可阻止尼古丁诱导的谷氨酸和天冬氨酸水平升高。前额叶皮质的鹅膏蕈氨酸损伤使VTA中α-银环蛇毒素结合位点的密度降低了约30%。这些数据表明，尼古丁通过刺激VTA中的nAChRs增加了VTA中兴奋性氨基酸的细胞外水平，且VTA中部分α7* nAChR群体位于起源于前额叶皮质的神经元上。
