Cocker P J, Lin M Y, Barrus M M, Le Foll B, Winstanley C A
Department of Psychology, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada.
Translational Addiction Research Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada.
Psychopharmacology (Berl). 2016 Sep;233(17):3135-47. doi: 10.1007/s00213-016-4355-1. Epub 2016 Jul 14.
Rats, like humans, are susceptible to the reinforcing effects of reward-related stimuli presented within a compound stimulus array, putatively analogous to the so-called near-miss effect. We have previously demonstrated using a rodent slot machine task (rSMT) that the reward expectancy these stimuli elicit is critically mediated by the dopamine D4 receptor. D4 receptors are principally located in prefrontal regions activated during slot machine play in humans, such as the insular cortex. The insula has recently attracted considerable interest as it appears to play a crucial role in substance and behavioral addictions. However, the insula is a heterogeneous area, and the relative contributions of subregions to addictive behaviors are unclear.
Male Long Evans rats were trained to perform the rSMT, and then bilateral cannula targeting either the granular or agranular insula were implanted. The effects of inactivation and local administration of a D4 agonist were investigated.
Temporary inactivation of the agranular, but not the granular insula impaired performance on the rSMT. In contrast, local infusion of the D4 agonist PD168077 into the agranular insula had no effect on task performance, but when administered into the granular insula, it improved animals' ability to differentiate winning from non-winning trials. The agranular insula may therefore modulate decision making when conflicting stimuli are present, potentially due to its role in generating a cohesive emotional percept based on both externally and internally generated signals, whereas the granular insular is not critical for this process. Nevertheless, D4 receptors within the granular insula may amplify the incentive salience of aversive environmental stimuli.
These data provide insight into the neurobiological mechanism underpinning maladaptive reward expectancy during gambling and provide further evidence that D4 receptors represent a potential target for developing pharmacotherapies for problem gambling.
与人类一样，大鼠易受复合刺激阵列中呈现的奖励相关刺激的强化作用影响，这可能类似于所谓的近失效应。我们之前使用啮齿动物老虎机任务（rSMT）证明，这些刺激引发的奖励预期主要由多巴胺D4受体介导。D4受体主要位于人类玩老虎机时激活的前额叶区域，如岛叶皮质。最近，岛叶引起了相当大的关注，因为它似乎在物质成瘾和行为成瘾中起关键作用。然而，岛叶是一个异质区域，各亚区域对成瘾行为的相对贡献尚不清楚。
对雄性朗·埃文斯大鼠进行rSMT训练，然后植入双侧套管，分别靶向颗粒状或无颗粒岛叶。研究了失活和局部给予D4激动剂的效果。
无颗粒岛叶的暂时失活会损害rSMT的表现，但颗粒岛叶失活则不会。相反，将D4激动剂PD168077局部注入无颗粒岛叶对任务表现没有影响，但注入颗粒岛叶时，它提高了动物区分赢和未赢试验的能力。因此，无颗粒岛叶可能在存在冲突刺激时调节决策，这可能是由于它在基于外部和内部产生的信号产生连贯的情绪感知方面所起的作用，而颗粒岛叶对这一过程并不关键。尽管如此，颗粒岛叶内的D4受体可能会放大厌恶环境刺激的激励显著性。
这些数据深入了解了赌博期间适应不良奖励预期的神经生物学机制，并进一步证明D4受体是开发问题赌博药物疗法的潜在靶点。
