Dept. of Psychiatry and Behavioral Sciences, Rush University Medical Center, Chicago, IL 60612, United States; Center for Compulsive Behavior and Addiction, Rush University Medical Center, Chicago, IL 60612, United States.
Dept of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, United States; Center for Compulsive Behavior and Addiction, Rush University Medical Center, Chicago, IL 60612, United States.
Prog Neuropsychopharmacol Biol Psychiatry. 2020 Aug 30;102:109942. doi: 10.1016/j.pnpbp.2020.109942. Epub 2020 Apr 6.
Addictions involve a spectrum of behaviors that encompass features of impulsivity and compulsivity, herein referred to as impulsive-compulsive spectrum disorders (ICSDs). The etiology of ICSDs likely involves a complex interplay among neurobiological, psychological and social risk factors. Neurobiological risk factors include the status of the neuroanatomical circuits that govern ICSDs. These circuits can be altered by disease, as well as exogenous influences such as centrally-acting pharmacologics. The 'poster child' for this scenario is Parkinson's disease (PD) medically managed by pharmacological treatments. PD is a progressive neurodegenerative disease that involves a gradual loss of dopaminergic neurons largely within nigrostriatal projections. Replacement therapy includes dopamine receptor agonists that directly activate postsynaptic dopamine receptors (bypassing the requirement for functioning presynaptic terminals). Some clinically useful dopamine agonists, e.g., pramipexole and ropinirole, exhibit high affinity for the D2/D3 receptor subtypes. These agonists provide excellent relief from PD motor symptoms, but some patients exhibit debilitating ICSD. Teasing out the neuropsychiatric contribution of PD-associated pathology from the drugs used to treat PD motor symptoms is challenging. In this review, we posit that modern clinical and preclinical research converge on the conclusion that dopamine replacement therapy can mediate addictions in PD and other neurological disorders. We provide five categories of evidences that align with this position: (i) ICSD prevalence is greater with D2/D3 receptor agonist therapy vs PD alone. (ii) Capacity of dopamine replacement therapy to produce addiction-like behaviors is independent of disease for which the therapy is being provided. (iii) ICSD-like behaviors are recapitulated in laboratory rats with and without PD-like pathology. (iv) Behavioral pathology co-varies with drug exposure. (v) ICSD Features of ICSDs are consistent with agonist pharmacology and neuroanatomical substrates of addictions. Considering the underpinnings of ICSDs in PD should not only help therapeutic decision-making in neurological disorders, but also apprise ICSDs in general.
成瘾涉及一系列行为，包括冲动和强迫特征，在此称为冲动-强迫谱障碍（ICSDs）。ICSD 的病因可能涉及神经生物学、心理和社会风险因素之间的复杂相互作用。神经生物学风险因素包括控制 ICSD 的神经解剖回路的状态。这些回路可以被疾病以及中枢作用的药物等外源性影响改变。这种情况的“典型代表”是帕金森病（PD），其通过药物治疗进行医学管理。PD 是一种进行性神经退行性疾病，涉及黑质纹状体投射中多巴胺能神经元的逐渐丧失。替代疗法包括直接激活突触后多巴胺受体的多巴胺受体激动剂（绕过对功能前突末梢的需求）。一些临床上有用的多巴胺激动剂，例如普拉克索和罗匹尼罗，对 D2/D3 受体亚型表现出高亲和力。这些激动剂提供了极好的 PD 运动症状缓解，但一些患者表现出衰弱的 ICSD。从用于治疗 PD 运动症状的药物中梳理出与 PD 相关病理相关的神经精神贡献具有挑战性。在这篇综述中，我们假设现代临床和临床前研究得出的结论是，多巴胺替代疗法可以介导 PD 和其他神经障碍中的成瘾。我们提供了五个类别的证据来支持这一立场：（i）与单独使用 PD 相比，D2/D3 受体激动剂治疗的 ICSD 患病率更高。（ii）多巴胺替代疗法产生类似成瘾的行为的能力与提供治疗的疾病无关。（iii）在具有和不具有 PD 样病理的实验室大鼠中再现类似 ICSD 的行为。（iv）行为病理学与药物暴露共变。（v）ICSD 的 ICSD 特征与激动剂药理学和成瘾的神经解剖学基础一致。考虑到 PD 中 ICSD 的基础，不仅应该有助于神经障碍的治疗决策，还应该了解一般的 ICSD。
