1] Center for Addiction Research, University of Texas Medical Branch, Galveston, TX, USA [2] Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA.
Department of Psychiatry, Yale University, New Haven, CT, USA.
Neuropsychopharmacology. 2014 Jan;39(2):370-82. doi: 10.1038/npp.2013.199. Epub 2013 Aug 13.
Relapse vulnerability in cocaine dependence is rooted in genetic and environmental determinants, and propelled by both impulsivity and the responsivity to cocaine-linked cues ('cue reactivity'). The serotonin (5-hydroxytryptamine, 5-HT) 5-HT2C receptor (5-HT2CR) within the medial prefrontal cortex (mPFC) is uniquely poised to serve as a strategic nexus to mechanistically control these behaviors. The 5-HT2CR functional capacity is regulated by a number of factors including availability of active membrane receptor pools, the composition of the 5-HT2CR macromolecular protein complex, and editing of the 5-HT2CR pre-mRNA. The one-choice serial reaction time (1-CSRT) task was used to identify impulsive action phenotypes in an outbred rat population before cocaine self-administration and assessment of cue reactivity in the form of lever presses reinforced by the cocaine-associated discrete cue complex during forced abstinence. The 1-CSRT task reliably and reproducibly identified high impulsive (HI) and low impulsive (LI) action phenotypes; HI action predicted high cue reactivity. Lower cortical 5-HT2CR membrane protein levels concomitant with higher levels of 5-HT2CR:postsynaptic density 95 complex distinguished HI rats from LI rats. The frequency of edited 5-HT2CR mRNA variants was elevated with the prediction that the protein population in HI rats favors those isoforms linked to reduced signaling capacity. Genetic loss of the mPFC 5-HT2CR induced aggregate impulsive action/cue reactivity, suggesting that depressed cortical 5-HT2CR tone confers vulnerability to these interlocked behaviors. Thus, impulsive action and cue reactivity appear to neuromechanistically overlap in rodents, with the 5-HT2CR functional status acting as a neural rheostat to regulate, in part, the intersection between these vulnerability behaviors.
可卡因依赖的复发易感性根植于遗传和环境决定因素，并受到冲动性和对可卡因相关线索的反应性（“线索反应性”）的推动。中前额皮质（mPFC）内的 5-羟色胺（5-羟色胺，5-HT）5-HT2C 受体（5-HT2CR）具有独特的优势，可以作为一种策略枢纽，从机制上控制这些行为。5-HT2CR 的功能能力受到多种因素的调节，包括活性膜受体池的可用性、5-HT2CR 大分子蛋白复合物的组成以及 5-HT2CR 前体 mRNA 的编辑。单一选择序列反应时间（1-CSRT）任务用于在可卡因自我给药之前鉴定出杂合大鼠群体中的冲动行为表型，并以在强制戒断期间由可卡因相关离散线索复合物强化的杠杆按压形式评估线索反应性。1-CSRT 任务可靠且可重复地鉴定出高冲动（HI）和低冲动（LI）行为表型；HI 行为预测高线索反应性。皮质下 5-HT2CR 膜蛋白水平降低，5-HT2CR：突触后密度 95 复合物水平升高，可将 HI 大鼠与 LI 大鼠区分开来。编辑后的 5-HT2CR mRNA 变体的频率升高，预测 HI 大鼠中的蛋白质群体有利于与降低信号转导能力相关的那些同工型。mPFC 5-HT2CR 的遗传缺失导致冲动行为/线索反应性的总体增加，这表明皮质 5-HT2CR 紧张度降低使这些相互关联的行为容易发生。因此，冲动行为和线索反应性在啮齿动物中似乎在神经机制上重叠，5-HT2CR 的功能状态作为神经变阻器，部分调节这些易感性行为之间的交集。
