Adams C E, Stevens K E, Kem W R, Freedman R
Department of Psychiatry, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
Brain Res. 2000 Sep 22;877(2):235-44. doi: 10.1016/s0006-8993(00)02677-9.
The hippocampus rapidly inhibits its response to repetitive auditory stimulation, an example of an auditory sensory gating mechanism involved in human psychopathology. The neuronal basis of this inhibitory gating mechanism has been investigated in rats. Activation of the alpha 7 nicotinic receptor is required. alpha 7 nicotinic receptor activation also releases nitric oxide in the hippocampus and blockade of nitric oxide synthase reduces inhibitory gating of auditory response. There has not been a direct demonstration that blockade of nitric oxide synthase specifically prevents alpha 7 nicotinic receptor activation of the inhibition of auditory response. Therefore, the goal of the present study was to determine whether this functional effect of alpha 7 receptor activation requires release of nitric oxide. Lesions of the fimbria-fornix disrupt auditory gating by preventing cholinergic stimulation of the hippocampus. Following recovery from this surgery, rats were administered 3-(2,4-dimethoxybenzylidene) anabaseine (DMXB-A; 10 mg/kg, sc), an agonist at the alpha 7 receptor. DMXB-A restored auditory gating in the fimbria-fornix-lesioned rats, indicating that activation of the alpha 7 nicotinic receptor alone is sufficient to restore auditory gating following lesions of the fimbria-fornix. However, intracerebroventricular infusion of N(omega)-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase, blocked the DMXB-A-mediated restoration of auditory gating; infusion of the inactive D-enantiomer did not. Restoration of auditory gating by DMXB-A in the fimbria-fornix-lesioned rats was blocked by intracerebroventricular infusion of alpha-bungarotoxin, but not by mecamylamine or dihydro-beta-erythroidine. Together, these data support the hypothesis that nitric oxide mediates alpha 7 nicotinic receptor activation of gating of auditory response in rat hippocampus.
海马体对重复性听觉刺激的反应会迅速受到抑制，这是人类精神病理学中涉及的听觉感觉门控机制的一个例子。这种抑制性门控机制的神经元基础已在大鼠中进行了研究。需要激活α7烟碱受体。α7烟碱受体的激活还会在海马体中释放一氧化氮，而一氧化氮合酶的阻断会降低听觉反应的抑制性门控。目前尚未有直接证据表明一氧化氮合酶的阻断能特异性地阻止α7烟碱受体对听觉反应抑制的激活。因此，本研究的目的是确定α7受体激活的这种功能效应是否需要一氧化氮的释放。穹窿海马伞损伤会通过阻止海马体的胆碱能刺激而破坏听觉门控。在从该手术恢复后，给大鼠注射3-(2,4-二甲氧基亚苄基)去甲烟碱（DMXB-A；10毫克/千克，皮下注射），一种α7受体激动剂。DMXB-A恢复了穹窿海马伞损伤大鼠的听觉门控，表明单独激活α7烟碱受体就足以在穹窿海马伞损伤后恢复听觉门控。然而，脑室内注入一氧化氮合酶抑制剂N(ω)-硝基-L-精氨酸甲酯会阻断DMXB-A介导的听觉门控恢复；注入无活性的D-对映体则不会。脑室内注入α-银环蛇毒素可阻断DMXB-A对穹窿海马伞损伤大鼠听觉门控的恢复，但美加明或二氢-β-刺桐啶则不会。这些数据共同支持了这样一种假说，即一氧化氮介导了大鼠海马体中α7烟碱受体对听觉反应门控的激活。
