Behavioral Genetics Laboratory, Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts 02478, USA.
Cold Spring Harb Perspect Med. 2013 Feb 1;3(2):a012005. doi: 10.1101/cshperspect.a012005.
Psychostimulants such as amphetamine and cocaine are believed to produce dependence by causing rapid, supraphysiological elevations in synaptic dopamine (DA) within the nucleus accumbens (NAc) (Volkow et al. 2009, Neuropharmacology 56: 3-8). These changes in forebrain DA transmission are similar to those evoked by natural reinforcers (Louilot et al. 1991, Brain Res 553: 313-317; Roitman et al. 2004, J Neurosci 24: 1265-1271), but are of greater magnitude and longer duration. Repeated drug exposure causes compensatory neuroadaptations in neurons of the NAc, some of which may modulate excess DA in a homeostatic fashion. One such adaptation is the activation of the transcription factor CREB (cAMP response element-binding protein) within neurons of the NAc. Although elevated levels of transcriptionally active CREB appear to attenuate DA transmission by increasing expression of the endogenous κ opioid receptor (KOR) ligand dynorphin, increased dynorphin transmission may ultimately have undesirable effects that contribute to drug withdrawal states as well as comorbid psychiatric illnesses such as depression. This state may prompt a return to drug use to mitigate the adverse effects of withdrawal. This article summarizes our current understanding of how CREB and dynorphin contribute to the dysregulation of motivation and describes novel therapeutic strategies that derive from preclinical research in this area.
人们认为，安非他命和可卡因等精神兴奋剂通过在伏隔核（NAc）中引起突触多巴胺（DA）的快速、超生理升高，从而导致依赖（Volkow 等人，2009 年，《神经药理学》56：3-8）。这些前脑 DA 传递的变化类似于自然强化物引起的变化（Louilot 等人，1991 年，《大脑研究》553：313-317；Roitman 等人，2004 年，《神经科学杂志》24：1265-1271），但幅度更大，持续时间更长。反复的药物暴露会导致 NAc 神经元发生代偿性神经适应，其中一些适应可能以稳态的方式调节过量的 DA。这种适应之一是 NAc 神经元中转录因子 CREB（cAMP 反应元件结合蛋白）的激活。尽管转录活性 CREB 水平的升高似乎通过增加内源性 κ 阿片受体（KOR）配体强啡肽的表达来减弱 DA 传递，但强啡肽传递的增加最终可能产生不良影响，导致药物戒断状态以及抑郁等共患精神疾病。这种状态可能促使人们重新使用药物来减轻戒断的不良影响。本文总结了我们目前对 CREB 和强啡肽如何导致动机失调的理解，并描述了源自该领域的临床前研究的新治疗策略。
