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）会模仿可卡因的几种行为和分子效应。然而，其他“可卡因样”的影响很小，可能是因为哌甲酯不会使血清素升高。这一观点得到了申请者实验室最近研究结果的支持，研究表明，使用选择性5 -羟色胺再摄取抑制剂（SSRIs）提高5 -羟色胺可以增强哌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联合哌醋甲酯是否也会增加血清素的传递。这是一个值得关注的问题，因为许多人正在服用哌甲酯（利他林）和SSRI的药物组合。本应用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，反复暴露于哌甲酯+SSRI将促进随后可卡因自我给药行为的发展，这是可卡因成瘾倾向的一个指标。这将在大鼠身上进行测试，使用允许推断自我服用可卡因（Aim 1a）和“强迫性”吸毒（Aim 1b）的敏感性和“动机”的范式。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式（目标2）。成功完成这些目标是非常重要的，因为它将决定是否应该避免哌甲酯+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。

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. PUBLIC HEALTH RELEVANCE: Serotonergic agents such as selective serotonin reuptake inhibitors (SSRIs, Prozac) and dopaminergic agents such as methylphenidate (Ritalin) are widely used in mental health disorders such as attention-deficit hyperactivity disorder and depression. In addition, methylphenidate is frequently used as a "cognitive enhancer". In these studies, we will establish if a combination treatment of methylphenidate (Ritalin) plus an SSRI (Prozac) produces "cocaine-like" behavioral changes indicative of increased addiction liability, and thus should be avoided.