Escalation of cocaine self-administration does not depend on altered cocaine-induced nucleus accumbens dopamine levels
Escalation of cocaine self-administration does not depend on altered cocaine-induced nucleus accumbens dopamine levels
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DOI：
10.1046/j.1471-4159.2003.01833.x
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发表时间：
2003-07-01
影响因子：
4.7
通讯作者：
Parsons, LH
中科院分区：
文献类型：
--
作者：
Ahmed, SH;Lin, D;Parsons, LH
以前的研究表明，长期接触可卡因或海洛因自我给药(LGA)会导致药物摄入量的上升，但在获得药物的机会有限(Short Access，或SHA)时没有观察到。本实验采用体内微透析法，研究可卡因摄入量增加时，药物药代动力学和/或药效的改变对伏核(NAcc)多巴胺(DA)水平的影响。实验一采用被动静脉注射可卡因(0.125-1 mg/只)的方法刺激沙鼠和大鼠。无论测试的剂量如何，两组之间在可卡因增加NAcc DA水平的能力方面没有差异，在透析液中可卡因水平的时间分布方面也没有差异。在实验2中，测量了可卡因自身给药过程中可卡因和多巴胺的浓度。自我给药使NAcc的DA持续增加，LGA大鼠(基线的750%)比SHA大鼠(基线的400%)维持更稳定的DA水平。LGA组和SHA组大鼠之间的差异不是由于可卡因升高DA水平的效果或可卡因代谢率的差异，而是与自身给药的可卡因数量直接相关。这些发现表明，可卡因药效或药代动力学的变化在可卡因摄入量增加中并不起关键作用。
Previous studies showed that prolonged access to cocaine or heroin self-administration (long access, or LgA) produces an escalation in drug intake not observed with limited access to the drug (short access, or ShA). The present experiment employed in vivo microdialysis to test the role of alterations in drug pharmacokinetics and/or efficacy in increasing dopamine (DA) levels in the nucleus accumbens (NAcc) during cocaine intake escalation. In experiment 1, both ShA and LgA rats were challenged with passive intravenous administration of cocaine (0.125-1 mg/injection). Regardless of the doses tested, there was no difference between groups in the ability of cocaine to increase NAcc DA levels and no group differences in the temporal profile of dialysate cocaine levels. In experiment 2, cocaine and DA concentrations were measured during cocaine self-administration. Self-administration produced sustained increases of DA in the NAcc with LgA rats maintaining greater steady levels of DA (750% of baseline) than ShA rats (400% of baseline). The difference in the LgA versus ShA rats was not due to differences in the efficacy of cocaine to elevate DA levels, or in the rate of cocaine metabolism, but was directly related to the amount of self-administered cocaine. These findings show that changes in cocaine efficacy or pharmacokinetics do not play a critical role in cocaine intake escalation.