强迫性用药行为的神经生物学机制研究进展

Neurobiological mechanisms involved in the development of compulsive drug use

药物成瘾行为的核心特征是强迫性用药,即成瘾者对药物的寻求和摄取失控.药物成瘾行为的形成过程是由最初的目标导向性模式(A-O)向习惯化模式(S-R)的过渡,并最终发展为强迫性觅药和用药.成瘾行为形成过程的演变伴随腹侧纹状体(VS)到背侧纹状体(DS)多巴胺(DA)系统控制的转移;在DS中,中外侧纹状体(MLS)与长时程训练的觅药过程有关,而背外侧纹状体(DLS)则选择性参与强迫性觅药的调控.最新的研究还发现,长期用药导致的前额叶(PFC)功能的损害与强迫性行为的产生直接相关,且PFC不同亚区到纹状体的谷氨酸能投射对于觅药行为的调控存在竞争关系.此外,除了DA系统,五羟色胺(5-HT)系统对强迫性用药行为的形成也具有重要作用.本文将重点讨论成瘾相关的脑环路在强迫性觅药或用药过程中发挥的调控作用及其功能转换的潜在分子机制.

Compulsive drug use, or continual drug use despite punishment, is the core symptom of addiction. Drug addiction is associated with a shift from the response-outcome （R-O） process to the stimulus-response （S-R） process, such that it becomes habitual and ultimately compulsive. Previous studies have shown that this shift represents a transition at the neural level from ventral to more dorsal domains of the stdatum, which is mediated by dopaminergic circuitry. However, a recent study indicated novel differentiation in dorsal striatum function. The midlateral striatum is involved in all stages of drug seeking after chronic self-administration training, whereas the dorsolateral striatum selectively participates in compulsive drug seeking. In addition, there is increasing evidence that chronic drug use can damage the prefrontal cortex. Indeed, different glutamatergic projections from the prefrontal cortex to the striatum play competing roles in drug seeking. These neural transitions depend on molecular mechanisms of neuroplasticity. An increasing number of studies have shown that low levels of D2 receptors predict a switch to compulsive drug use. Additionally, recent studies indicated that 5-hydroxytryptamine also plays an important role in compulsive drug use.