Prefrontal cortical network activity: Opposite effects of psychedelic hallucinogens and D1/D5 dopamine receptor activation
Prefrontal cortical network activity: Opposite effects of psychedelic hallucinogens and D1/D5 dopamine receptor activation
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DOI：
10.1016/j.neuroscience.2006.12.048
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发表时间：
2007-03-30
期刊：
影响因子：
3.3
通讯作者：
Aghajanian, G. K.
中科院分区：
文献类型：
--
作者：
Lambe, E. K.;Aghajanian, G. K.
网络活动的微调对信息在大脑中的处理和解释方式产生了调制影响。在这里，我们使用大鼠前额叶皮质的脑片来研究已知的改变正常皮质功能的神经调节剂如何影响经常性的网络活动。我们先前确定，谷氨酸溢出和刺激突触外N-甲基-D-天冬氨酸(NMDA)受体是支持迷幻剂诱导的皮质网络活动所必需的。由于微透析研究表明致幻迷幻剂和多巴胺D1/D5受体激动剂对前额叶皮质细胞外谷氨酸的作用相反，我们假设这两类精神活性药物对皮质网络活动具有相反的影响。我们发现，2，5二甲氧基-4-碘苯乙胺(DOI)(一种迷幻迷幻剂，是5-HT2A/2C受体的部分激动剂)可以增强皮质网络活动，而选择性D1/D5激动剂SKF 38393则抑制。这种抑制可以通过用Forsklin直接激活腺苷环化酶或通过添加cAMP类似物来模拟。这些发现与以前的工作一致，表明腺苷环化酶的激活可以上调神经元谷氨酸转运体，从而减少谷氨酸的突触溢出。与这一假说一致，低浓度的谷氨酸转运体抑制剂苏氨酸-β-苯甲酰天冬氨酸(TBOA)在选择性的D1/D5激动剂存在的情况下恢复电诱发的重复活动，而在低水平的GABAA拮抗剂荷包牡丹碱存在的情况下恢复电诱发的重复活动；不抵抗D1/D5激动剂的抑制。通过激活D1/D5受体来缓和网络的向上状态，可能对建议使用D1/D5激动剂治疗精神分裂症有一定的意义。(C)2007年IBRO。爱思唯尔有限公司出版。保留所有权利。
The fine-tuning of network activity provides a modulating influence on how information is processed and interpreted in the brain. Here, we use brain slices of rat prefrontal cortex to study how recurrent network activity is affected by neuromodulators known to alter normal cortical function. We previously determined that glutamate spillover and stimulation of extrasynaptic N-methyl-D-aspartic acid (NMDA) receptors are required to support hallucinogen-induced cortical network activity. Since microdialysis studies suggest that psychedelic hallucinogens and dopamine D1/D5 receptor agonists have opposite effects on extracellular glutamate in prefrontal cortex, we hypothesized that these two families of psychoactive drugs would have opposite effects on cortical network activity.We found that network activity can be enhanced by 2,5dimethoxy-4-iodidamphetamirie (DOI) (a psychedelic hallucinogen that is a partial agonist of 5-HT2A/2C receptors) and suppressed by the selective D1/D5 agonist SKF 38393. This suppression could be mimicked by direct activation of adenylyl cyclase with forskolin or by addition of a cAMP analog. These findings are consistent with previous work showing that activation of adenylyl cyclase can upregulate neuronal glutamate transporters, thereby decreasing synaptic spillover of glutamate. Consistent with this hypothesis, a low concentration of the glutamate transporter inhibitor threo-beta-benzoylaspartic acid (TBOA) restored electrically-evoked recurrent activity in the presence of a selective D1/D5 agonist, whereas recurrent activity in the presence of a low level of the GABAA antagonist bicuculline was; not resistant to suppression by the D1/D5 agonist. The tempering of network UP states by D1/D5 receptor activation may have implications for the proposed use of D1/D5 agonists in the treatment of schizophrenia. (c) 2007 IBRO. Published by Elsevier Ltd. All rights reserved.