Risk of cocaine addiction after methylphenidate plus SSRI combination treatment

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）模拟可卡因的几种行为和分子效应。然而，其他“可卡因样”的影响是最小的，可能是因为5-羟色胺不会被哌甲酯升高。这一观点得到了申请人实验室最近发现的支持，这些发现表明，用选择性5-羟色胺再摄取抑制剂（SSRI）升高5-羟色胺增强了哌甲酯诱导的精神活动和涉及精神兴奋剂成瘾的脑区域中的神经元适应。目前尚不清楚SSRIs与哌醋甲酯联合使用是否会增加5-羟色胺的传递也会促进成瘾。这是令人担忧的，因为许多人正在接触哌甲酯（利他林）加SSRI的药物组合。本申请的目的是确定哌甲酯+SSRI暴露如何改变可卡因成瘾倾向的指标。假设是SSRIs增强了哌醋甲酯的作用，使其更像可卡因。因此，重复暴露于哌甲酯+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，使用允许推断自我施用可卡因（目标1a）和“强迫性”吸毒（目标1b）的敏感性和“动机”的范例。暴露于哌甲酯+SSRI也可能引发前可卡因使用者的复发。这将在大鼠中进行测试，使用测量药物寻求行为恢复的范例（目的2）。这些目标的成功完成是重要的，因为它将告知决定是否哌醋甲酯+SSRI药物组合应避免在未来，因为他们的潜力，以促进与精神兴奋剂成瘾相关的行为变化。

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.