Cognitive-enhancing DA Medications for Cocaine Dependence

描述（由申请人提供）：可卡因依赖与多巴胺（DA）脑系统缺陷密切相关。慢性可卡因使用者在已知与DA相关的认知过程中表现出损伤（例如，决策、行为抑制、注意偏差）。这些认知障碍预示着更高的辍学率、更低的治疗效果和更大的复发可能性。旨在通过DA调节增强认知功能的治疗药物可能会减少退出并提高临床结果。该项目将通过联合使用两种多巴胺能药物：左旋多巴和罗匹尼罗，研究针对可卡因使用和认知缺陷的DA增强疗法的疗效。通过增强突触前多巴胺释放（左旋多巴）和突触后D2受体功能（罗匹尼罗），联合方案有望共同靶向与慢性可卡因使用和认知功能相关的多巴胺缺陷。这种双靶点方法得到了经验数据的支持，数据显示单一药物对可卡因治疗是安全且有希望的。此外，联合DA疗法已转化为治疗帕金森病和其他由DA耗竭引起的神经精神疾病的广泛疗效。本研究拟进行随机、双盲、双虚拟对照临床试验，比较左旋多巴/卡比多巴联合罗匹尼罗与单左旋多巴/卡比多巴和安慰剂的疗效。200名寻求治疗的可卡因依赖患者将接受为期12周的研究药物治疗以及基于证据的认知行为疗法。假设左旋多巴/卡比多巴联合罗匹尼罗可改善治疗结果（可卡因使用、滞留），并支持剂量-反应关系：[左旋多巴/卡比多巴+ 4mg /d罗匹尼罗]>[左旋多巴/卡比多巴+ 2mg /d罗匹尼罗]>[左旋多巴/卡比多巴+安慰剂]>[安慰剂+安慰剂]。此外，假设治疗（左旋多巴/卡比多巴+罗匹尼罗）对结果（可卡因使用、滞留）的影响将通过观察到的决策、行为抑制、奖励动机和注意偏差的行为/认知测量的改善间接发生。这个项目的意义在于，它有可能通过结合同时作用于多巴胺的药物来提高可卡因治疗的成功率。该项目在测试一种新的药理学补救方法和识别认知机制方面具有创新性，通过DA药物可以改变可卡因的使用，为可卡因相关缺陷的严重程度和治疗相关改善提供潜在的神经行为标记或代理。联合首席研究员（Schmitz和Lane）在临床试验研究、实验室行为测量和精神药理学方面具有互补和综合的专业知识。UT-Houston成瘾神经行为研究中心（CNRA）的科学环境将有助于项目的成功。

DESCRIPTION (provided by applicant): Cocaine dependence has been linked closely to deficits in the dopamine (DA) brain system. Chronic cocaine users show impairments in cognitive processes known to be associated with DA (e.g., decision-making, behavioral inhibition, attentional bias). These cognitive impairments have been shown to predict higher drop-out rates, less efficacious therapy, and greater likelihood of relapse. Treatment medications aimed at bolstering cognitive functions via DA modulation might decrease drop-out and enhance clinical outcome. This project will examine the efficacy of DA enhancement therapy that targets cocaine use and cognitive deficits by combining two dopaminergic medications: levodopa and ropinirole. By enhancing presynaptic dopamine release (levodopa) and post-synaptic D2 receptor function (ropinirole), the combined regimen is expected to jointly target dopamine deficits associated with chronic cocaine use and cognitive functions. This dual-target approach is supported empirically by data showing the single medications to be safe and promising for cocaine treatment. Further, combination DA therapy has translated into broad efficacy for the treatment of Parkinson's disease and other neuropsychiatric conditions resulting from DA depletion. The proposed randomized, double-blind, double-dummy controlled clinical trial will compare the combination of levodopa/carbidopa plus ropinirole with levodopa/carbidopa only and placebo. Two-hundred treatment-seeking cocaine-dependent patients will receive 12 weeks of study medication along with evidence-based cognitive-behavioral therapy. It is hypothesized that the combination of levodopa/carbidopa plus ropinirole will improve treatment outcome (cocaine use, retention) and that a dose-response relationship will be supported: [levodopa/carbidopa + 4 mg/d ropinirole] > [levodopa/carbidopa + 2 mg/d ropinirole] > [levodopa/carbidopa + placebo] > [placebo + placebo]. Further, it is hypothesized that the effect of treatment (levodopa/carbidopa + ropinirole) on outcome (cocaine use, retention) will occur indirectly via improved performance on observed behavioral/cognitive measures of decision-making, behavioral inhibition, reward motivation, and attentional bias. The significance of this project lies in its potential to improve cocaine treatment success by combining medications that act simultaneously on dopamine. This project is innovative in testing a new pharmacological remediation approach and in identifying cognitive mechanisms by which DA medications may operate to change cocaine use, providing a potential neurobehavioral marker or proxy for severity of cocaine-related deficits and treatment-related improvement. The Co-Principal Investigators (Schmitz and Lane) have complementary and integrated expertise in clinical trial research, laboratory behavioral measurement, and psychopharmacology. The scientific environment of the UT-Houston Center for Neurobehavioral Research on Addictions (CNRA) will contribute to the success of the project. PUBLIC HEALTH RELEVANCE: Most cocaine dependent patients suffer from deficits in cognitive function that, if left untreated, predict poor outcome. The present study investigates a pharmacotherapeutic intervention designed to improve cocaine treatment success by combining medications that act simultaneously on dopamine, the brain system that is critically associated with chronic cocaine use and cognitive functions. Treatment with levodopa/carbidopa plus ropinirole (tested at two doses) will be compared to levodopa/carbidopa alone, and placebo. Measurement of performance on behavioral/cognitive measures of decision-making, behavioral inhibition, reward motivation, and attentional bias will be conducted at treatment entry and at repeated time points during the 12-week treatment. It is hypothesized that treatment with levodopa/carbidopa + ropinirole will produce superior outcomes in terms of reduced cocaine use and increased treatment retention and that these effects will occur indirectly via improved performance on observed cognitive mechanisms. There is a significant public health need to improve the outcome of treatments for cocaine dependence. This project responds to the current RFA-DA-10-006 by evaluating a pharmacotherapeutic intervention that may jointly improve cognitive functioning and attenuate drug use.