Kombian Samuel B, Ananthalakshmi Kethireddy V V, Zidichouski Jeffrey A, Saleh Tarek M
Department of Applied Therapeutics, Faculty of Pharmacy, Kuwait University, PO Box 24923, Safat 13110, Kuwait.
Eur J Neurosci. 2009 Apr;29(8):1579-87. doi: 10.1111/j.1460-9568.2009.06704.x.
Substance P (SP) has been reported to produce effects on excitatory synaptic transmission in the nucleus accumbens (NAc) that are similar to those induced by cocaine. To address the question of whether SP serves as an endogenous mediator producing cocaine-like effects that are known to be D1-receptor-mediated, we tested the hypothesis that the effects of SP and cocaine on excitatory postsynaptic currents (EPSCs) in the NAc occlude one another. We report here that SP and SP(5-11) actions occlude the effect of cocaine and vice versa. SP, SP(5-11) and cocaine all depressed evoked, non-N-methyl-D-aspartate (NMDA) receptor-mediated synaptic currents in a concentration-dependent manner, with EC50 values of 0.12, 0.17 and 8.3 microm, respectively. Although cocaine was the least potent, it was most efficacious. SP, SP(5-11) and cocaine all suppressed isolated NMDA receptor-mediated evoked EPSCs. SP(5-11) (1 microm)-induced EPSC depression was blocked by the neurokinin-1 antagonist L732138 and by the D1-like receptor antagonist SCH23390. Pretreatment of slices with cocaine (30 microm) depressed the EPSC by 39.1% +/- 4.8%. Application of SP or SP(5-11) (1 microm) at the peak of the cocaine depressive effect on the EPSC did not produce any additional diminution of the response (5.7% +/- 2.8%). In the reverse experiments, in which either SP or SP(5-11) was applied first, subsequent application of cocaine at the peak of the peptide's effect (30.3% +/- 2.3%) produced a further but smaller depression (15.5% +/- 3.6%) of the remaining EPSC. These data indicate that cocaine and SP produce similar effects on excitatory synaptic transmission in the NAc, and that their actions occlude one another. This suggests that SP may act like cocaine in its absence, and may be an endogenous trigger for the reward and behaviors associated with cocaine.
据报道，P物质（SP）对伏隔核（NAc）的兴奋性突触传递产生的作用与可卡因诱导的作用相似。为了解决SP是否作为一种内源性介质产生已知由D1受体介导的可卡因样效应这一问题，我们测试了SP和可卡因对NAc中兴奋性突触后电流（EPSCs）的作用是否相互抵消这一假设。我们在此报告，SP和SP(5 - 11)的作用可抵消可卡因的作用，反之亦然。SP、SP(5 - 11)和可卡因均以浓度依赖的方式抑制诱发的、非N - 甲基 - D - 天冬氨酸（NMDA）受体介导的突触电流，其半数有效浓度（EC50）值分别为0.12、0.17和8.3微摩尔。尽管可卡因的效力最低，但其效果最为显著。SP、SP(5 - 11)和可卡因均抑制孤立的NMDA受体介导的诱发EPSCs。SP(5 - 11)（1微摩尔）诱导的EPSC抑制被神经激肽 - 1拮抗剂L732138和D1样受体拮抗剂SCH23390阻断。用可卡因（30微摩尔）预处理切片可使EPSC降低39.1%±4.8%。在可卡因对EPSC的抑制作用达到峰值时应用SP或SP(5 - 11)（1微摩尔），并未使反应进一步减弱（5.7%±2.8%）。在反向实验中，先应用SP或SP(5 - 11)，随后在肽类作用达到峰值时应用可卡因（30.3%±2.3%），可使剩余的EPSC进一步但较小程度地降低（15.5%±3.6%）。这些数据表明，可卡因和SP对NAc中的兴奋性突触传递产生相似的作用，且它们的作用相互抵消。这表明在没有可卡因的情况下，SP可能起到类似可卡因的作用，并且可能是与可卡因相关的奖赏和行为的内源性触发因素。
