Department of Pharmacology, University of Tennessee Health Science Center, 874 Union Avenue, Crowe 115, Memphis, TN 38163, USA.
Eur J Neurosci. 2012 Mar;35(5):775-83. doi: 10.1111/j.1460-9568.2012.08000.x. Epub 2012 Feb 6.
Continued cocaine use despite the negative consequences is a hallmark of cocaine addiction. One such consequence is punishment, which is often used by society to curb cocaine use. Unfortunately, we know little about the mechanism involved in regulation by punishment of cocaine use. The fact that cocaine addicts continue to use cocaine despite potentially severe punishment suggests that the mechanism may be impaired. Such impairment is expected to critically contribute to compulsive cocaine use. This study was aimed at testing the hypothesis that the central nucleus of the amygdala (CeN) plays a critical role in such regulation. To this end, rats were trained to press a lever to self-administer cocaine under a chained schedule: a response on one lever (cocaine-seeking lever) led to access to the other lever (cocaine-taking lever), on which a response was reinforced by cocaine and cues. Thereafter, responses on the seeking lever were punished by footshock with a probability of 0.5. Cocaine self-administration (SA) was significantly suppressed by punishment in an intensity-dependent manner. Interestingly, rats trained with daily 6-h (extended access) but not 2-h (limited access) sessions showed resistance to the lower intensity of punishment. Inactivation of the CeN induced a robust anti-punishment effect in both groups. These data provided evidence that the CeN is a critical neural substrate involved in regulation by punishment of cocaine SA. Rats with a history of extended cocaine SA appeared to be less sensitive to punishment. The decreased sensitivity could result from the neuroplastic changes induced by extended cocaine SA in the CeN.
尽管可卡因使用会带来负面影响，但仍继续使用可卡因是可卡因成瘾的一个特征。其中一个后果是惩罚，社会通常会用惩罚来抑制可卡因的使用。不幸的是，我们对惩罚调节可卡因使用所涉及的机制知之甚少。尽管可能会受到严重的惩罚，可卡因成瘾者仍继续使用可卡因，这表明该机制可能受到了损害。这种损害预计会严重导致强迫性使用可卡因。本研究旨在检验杏仁中央核（CeN）在这种调节中起关键作用的假设。为此，我们训练大鼠按压杠杆，根据连锁方案自行摄取可卡因：对一个杠杆（可卡因寻求杠杆）的反应会导致另一个杠杆（可卡因摄取杠杆）的通路，在该杠杆上，对反应进行可卡因强化和线索强化。此后，寻求杠杆的反应以 0.5 的概率受到电击惩罚。可卡因自我给药（SA）以强度依赖的方式被惩罚显著抑制。有趣的是，接受每日 6 小时（延长摄入）而不是 2 小时（有限摄入）训练的大鼠对较低强度的惩罚表现出抵抗。CeN 的失活在两组中都诱导出了强烈的抗惩罚效应。这些数据提供了证据表明 CeN 是涉及惩罚调节可卡因 SA 的关键神经基质。有延长可卡因 SA 史的大鼠对惩罚的敏感性似乎降低。敏感性降低可能是由于 CeN 中延长可卡因 SA 诱导的神经可塑性变化所致。
