Dawson L A, Nguyen H Q, Li P
Neuroscience Research, Wyeth Ayerst CN 8000, Princeton, NJ 08543-8000, USA.
Neuropsychopharmacology. 2001 Nov;25(5):662-8. doi: 10.1016/S0893-133X(01)00265-2.
Preclinical evidence has suggested a possible role for the 5-HT(6) receptor in the treatment of cognitive dysfunction. However, currently there is little neurochemical evidence suggesting the mechanism(s) which may be involved. Using the selective 5-HT(6) antagonist SB-271046 and in vivo microdialysis, we have evaluated the effects of this compound on the modulation of basal neurotransmitter release within multiple brain regions of the freely moving rat. SB-271046 produced no change in basal levels of dopamine (DA), norepinephrine (NE) or 5-HT in the striatum, frontal cortex, dorsal hippocampus or nucleus accumbens. Similarly, this compound had no effect on excitatory neurotransmission in the striatum or nucleus accumbens. Conversely, SB-271046 produced 3- and 2-fold increases in extracellular glutamate levels in both frontal cortex and dorsal hippocampus, respectively. These effects were completely attenuated by infusion of tetrodotoxin but unaffected by the muscarinic antagonist, atropine. Here we demonstrate for the first time the selective enhancement of excitatory neurotransmission by SB-271046 in those brain regions implicated in cognitive and memory function, and provide mechanistic evidence in support of a possible therapeutic role for 5-HT(6) receptor antagonists in the treatment of cognitive and memory dysfunction.
临床前证据表明5-HT(6)受体在治疗认知功能障碍中可能发挥作用。然而，目前几乎没有神经化学证据表明其可能涉及的机制。使用选择性5-HT(6)拮抗剂SB - 271046和体内微透析技术，我们评估了该化合物对自由活动大鼠多个脑区基础神经递质释放调节的影响。SB - 271046对纹状体、额叶皮质、背侧海马体或伏隔核中多巴胺（DA）、去甲肾上腺素（NE）或5 - HT的基础水平没有影响。同样，该化合物对纹状体或伏隔核中的兴奋性神经传递也没有作用。相反，SB - 271046分别使额叶皮质和背侧海马体中的细胞外谷氨酸水平提高了3倍和2倍。这些作用被河豚毒素灌注完全减弱，但不受毒蕈碱拮抗剂阿托品的影响。在这里，我们首次证明了SB - 271046在与认知和记忆功能相关的脑区中选择性增强兴奋性神经传递，并提供了支持5-HT(6)受体拮抗剂在治疗认知和记忆功能障碍中可能具有治疗作用的机制证据。
