Pitchers Kyle K, Phillips Kyra B, Jones Jonte L, Robinson Terry E, Sarter Martin
Department of Psychology and Neuroscience Program, University of Michigan, Ann Arbor, Michigan 48109.
Department of Psychology and Neuroscience Program, University of Michigan, Ann Arbor, Michigan 48109
J Neurosci. 2017 Jul 26;37(30):7198-7208. doi: 10.1523/JNEUROSCI.0990-17.2017. Epub 2017 Jun 28.
Stimuli associated with taking drugs are notorious instigators of relapse. There is, however, considerable variation in the motivational properties of such stimuli, both as a function of the individual and the nature of the stimulus. The behavior of some individuals (sign trackers, STs) is especially influenced by cues paired with reward delivery, perhaps because they are prone to process information via dopamine-dependent, cue-driven, incentive salience systems. Other individuals (goal trackers, GTs) are better able to incorporate higher-order contextual information, perhaps because of better executive/attentional control over behavior, which requires frontal cortical cholinergic activity. We hypothesized, therefore, that a cue that "sets the occasion" for drug taking (a discriminative stimulus, DS) would reinstate cocaine seeking more readily in GTs than STs and that this would require intact cholinergic neurotransmission. To test this, male STs and GTs were trained to self-administer cocaine using an intermittent access schedule with periods of cocaine availability and unavailability signaled by a DS and a DS, respectively. Thereafter, half of the rats received an immunotoxic lesion that destroyed 40-50% of basal forebrain cholinergic neurons and later, after extinction training, were tested for the ability of noncontingent presentations of the DS to reinstate cocaine seeking behavior. The DS was much more effective in reinstating cocaine seeking in GTs than STs and this effect was abolished by cholinergic losses despite the fact that all rats continued to orient to the DS We conclude that vulnerability to relapse involves interactions between individual cognitive-motivational biases and the form of the drug cue encountered. The most predictable outcome of a diagnosis of addiction is a high chance for relapse. When addicts encounter cues previously associated with drug, their attention may be unduly attracted to such cues and these cues can evoke motivational states that instigate and maintain drug-seeking behavior. Although sign-tracking rats were previously demonstrated to exhibit greater relapse vulnerability to Pavlovian drug cues paired with drug delivery, here, we demonstrate that their counterparts, the goal trackers, are more vulnerable if the drug cue acts to signal drug availability and that the forebrain cholinergic system mediates such vulnerability. Given the importance of contextual cues for triggering relapse and the human cognitive-cholinergic capacity for the processing of such cues, goal trackers model essential aspects of relapse vulnerability.
与吸毒相关的刺激是复发的臭名昭著的诱因。然而，这类刺激的动机特性存在相当大的差异，这既取决于个体，也取决于刺激的性质。一些个体（信号追踪者，STs）的行为尤其受到与奖励发放配对的线索的影响，这可能是因为他们倾向于通过多巴胺依赖的、线索驱动的动机显著性系统来处理信息。其他个体（目标追踪者，GTs）能够更好地整合高阶情境信息，这可能是因为对行为有更好的执行/注意力控制，而这需要额叶皮质胆碱能活动。因此，我们假设，一个为吸毒“创造条件”的线索（辨别性刺激，DS）会比STs更易在GTs中恢复可卡因觅求行为，并且这需要完整的胆碱能神经传递。为了验证这一点，雄性STs和GTs被训练使用间歇性给药方案自我给药可卡因，可卡因可获得期和不可获得期分别由一个DS和一个DS信号指示。此后，一半的大鼠接受免疫毒性损伤，破坏了40 - 50%的基底前脑胆碱能神经元，随后，在消退训练后，测试非偶然性呈现DS恢复可卡因觅求行为的能力。DS在恢复GTs的可卡因觅求行为方面比STs更有效，并且尽管所有大鼠继续朝向DS，但胆碱能丧失消除了这种效应。我们得出结论，复发易感性涉及个体认知 - 动机偏差与所遇到的药物线索形式之间的相互作用。成瘾诊断最可预测的结果是复发的高可能性。当成瘾者遇到以前与药物相关的线索时，他们的注意力可能会过度被此类线索吸引，并且这些线索可以引发激发和维持药物觅求行为的动机状态。尽管先前已证明信号追踪大鼠对与药物发放配对的巴甫洛夫式药物线索表现出更大的复发易感性，但在此我们证明，如果药物线索用于指示药物可获得性，它们的对应物目标追踪者更易复发，并且前脑胆碱能系统介导这种易感性。鉴于情境线索对触发复发的重要性以及人类处理此类线索的认知 - 胆碱能能力，目标追踪者模拟了复发易感性的关键方面。
