Behavioural and Clinical Neuroscience Institute and Department of Experimental Psychology, University of Cambridge, Downing Street, Cambridge, CB2 3EB, UK.
Psychopharmacology (Berl). 2012 Jan;219(2):401-10. doi: 10.1007/s00213-011-2572-1. Epub 2011 Nov 19.
Previous work has demonstrated a profound effect of N-methyl-D: -aspartic acid receptor (NMDAR) antagonism in the infralimbic cortex (IL) to selectively elevate impulsive responding in a rodent reaction time paradigm. However, the mechanism underlying this effect is unclear.
This series of experiments investigated the pharmacological basis of this effect in terms of excitatory and inhibitory neurotransmission. We tested several pharmacological mechanisms that might produce the effect of NMDAR antagonism via disruption or dampening of IL output.
Drugs known to affect brain GABA or glutamate function were tested in rats pre-trained on a five-choice serial reaction time task (5-CSRTT) following either their systemic administration or direct administration into the IL.
Systemic lamotrigine administration (15 mg/kg), which attenuates excess glutamate release, did not counteract the ability of the intra-IL NMDAR antagonist 3-((R)-2-carboxypiperazin-4-yl)-propyl-L: -phosphonic acid ((R)-CPP) to increase premature responding on the 5-CSRTT. Putative elevation of local extracellular glutamate via intra-IL infusions of the selective glutamate reuptake inhibitor DL: -threo-β-benzyloxyaspartate as well as local α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonism also had no effect on this task. However, intra-IL infusions of the GABA(A) receptor agonist muscimol produced qualitatively but not quantitatively comparable increases in impulsive responding to those elicited by (R)-CPP. Moreover, the GABA(A) receptor antagonist bicuculline blocked the increase in impulsivity produced by (R)-CPP when infused in the IL.
These findings implicate glutamatergic and GABAergic mechanisms in the IL in the expression of impulsivity and suggest that excessive glutamate release may not underlie increased impulsivity induced by local NMDA receptor antagonism.
先前的工作已经证明，N-甲基-D-天冬氨酸受体（NMDAR）拮抗剂在扣带回下边缘（IL）中具有深远的影响，可选择性地提高啮齿动物反应时范式中的冲动反应。然而，这种效应的机制尚不清楚。
本系列实验从兴奋性和抑制性神经传递的角度研究了这种效应的药理学基础。我们测试了几种药理学机制，这些机制可能通过破坏或抑制 IL 输出来产生 NMDAR 拮抗作用的效果。
在进行 5 种选择连续反应时任务（5-CSRTT）训练后，通过系统给药或直接给药到 IL，测试了已知影响大脑 GABA 或谷氨酸功能的药物。
系统给予拉莫三嗪（15mg/kg），可减轻谷氨酸释放过多，不能抵消 IL 内 NMDAR 拮抗剂 3-（R）-2-羧基哌嗪-4-基）-丙基-L：-膦酸（（R）-CPP）增加 5-CSRTT 中过早反应的能力。通过 IL 内输注选择性谷氨酸再摄取抑制剂 DL：-threo-β-苄氧基天冬氨酸（DL-threo-β-benzyloxyaspartate）来提高局部细胞外谷氨酸，以及局部α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体拮抗作用，对该任务也没有影响。然而，IL 内输注 GABA(A)受体激动剂 muscimol 会导致冲动反应的定性但不是定量增加，与（R）-CPP 引起的冲动反应相当。此外，当（R）-CPP 输注到 IL 中时，GABA(A)受体拮抗剂 bicuculline 阻断了冲动性增加。
这些发现表明，IL 中的谷氨酸能和 GABA 能机制参与了冲动性的表达，并表明局部 NMDA 受体拮抗作用引起的冲动性增加可能不是由于谷氨酸释放过多所致。
