Risk of cocaine addiction after methylphenidate plus SSRI combination treatment

哌醋甲酯联合 SSRI 联合治疗后可卡因成瘾的风险

• 批准号: 8453351
• 负责人: Michela Marinelli
• 金额: $ 8.6万
• 依托单位: ROSALIND FRANKLIN UNIV OF MEDICINE & SCI
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8453351
• 关键词: Affect; Animals; Area; Attention deficit hyperactivity disorder; Behavior; Behavioral; Behavioral Paradigm; Brain; Brain region; Cocaine; Cocaine Dependence; Cocaine Users; Corpus striatum structure; Development; Dopamine; Dopamine Uptake Inhibitors; Dopaminergic Agents; Drug Combinations; Exposure to; Future; Goals; Human; Individual; Laboratories; Literature; Locomotion; Measures; Mental Depression; Mental disorders; Methylphenidate; Modeling; Molecular; Motivation; Neurons; Nootropic Agents; Norepinephrine; Nucleus Accumbens; Outcome; Pharmaceutical Preparations; Property; Prozac; Psychostimulant dependence; Psychotropic Drugs; Rattus; Relapse; Research; Rewards; Risk; Ritalin; Safety; Selective Serotonin Reuptake Inhibitor; Self Administration; Self-Administered; Serotonin; Serotonin Agents; Shapes; Staging; Substance Use Disorder; Testing; Work; addiction; biobehavior; drug relapse; drug seeking behavior; extracellular; neurobehavioral; neurochemistry; psychostimulant; transmission process

DESCRIPTION (provided by applicant): Exposure to methylphenidate (a dopamine reuptake inhibitor) mimics several behavioral and molecular effects of cocaine. However, other "cocaine-like" effects are minimal, possibly because serotonin is not elevated by methylphenidate. This notion is supported by recent findings produced in the applicants' laboratories, showing that elevating serotonin with selective serotonin reuptake inhibitors (SSRIs) potentiates methylphenidate-induced psychomotor activity and neuronal adaptations in brain regions implicated in psychostimulant addiction. It is currently unknown if increasing the serotonin transmission with SSRIs in conjunction with methylphenidate could also promote addiction. This is of concern because many individuals are being exposed to a drug combination of methylphenidate (Ritalin) plus an SSRI. The objective of this application is to determine how methylphenidate+SSRI exposure modifies indicators of cocaine addiction liability. The hypothesis is that SSRIs potentiate the effects of methylphenidate, making it more "cocaine-like". Repeated exposure to methylphenidate+SSRI will thus facilitate the subsequent development of cocaine self-administration behavior, which is an indicator of cocaine addiction liability. This will be tested in rats, using paradigms that allow inferring sensitivity and "motivation" to self-administer cocaine (Aim 1a) and "compulsive" drug taking (Aim 1b). Exposure to methylphenidate+SSRI could also trigger relapse in ex-cocaine users. This will be tested in rats, using paradigms that measure reinstatement of drug seeking behavior (Aim 2). Successful completion of these aims is significant, as it will inform a decision of whether or not methylphenidate+SSRI drug combinations should be avoided in the future because of their potential to facilitate behavioral changes related to psychostimulant addiction.

描述（由申请人提供）：暴露于哌甲酯（一种多巴胺再摄取抑制剂）模仿可卡因的几种行为和分子效应。然而，其他“可卡因样”作用很小，可能是因为哌醋甲酯不会升高血清素。这一观点得到了申请人实验室最近的研究结果的支持，该研究结果表明，用选择性血清素再摄取抑制剂（SSRI）提高血清素会增强哌醋甲酯诱导的精神运动活动和与精神兴奋剂成瘾有关的大脑区域的神经元适应。目前尚不清楚 SSRIs 与哌醋甲酯联合使用增加血清素传输是否也会促进成瘾。这是令人担忧的，因为许多人正在接触哌醋甲酯（利他林）加 SSRI 的药物组合。本应用的目的是确定哌醋甲酯+SSRI 暴露如何改变可卡因成瘾倾向指标。假设认为 SSRI 会增强哌醋甲酯的作用，使其更像“可卡因”。因此，反复接触哌醋甲酯+SSRI将促进可卡因自我给药行为的后续发展，这是可卡因成瘾倾向的指标。这将在大鼠中进行测试，使用允许推断自我服用可卡因（目标 1a）和“强迫性”吸毒（目标 1b）的敏感性和“动机”的范式。接触哌醋甲酯+SSRI 也可能引发前可卡因吸食者复吸。这将在老鼠身上进行测试，使用测量药物寻求行为恢复的范式（目标 2）。成功完成这些目标意义重大，因为它将决定未来是否应避免哌醋甲酯+SSRI药物组合，因为它们有可能促进与精神兴奋剂成瘾相关的行为改变。