Risk of cocaine addiction after methylphenidate plus SSRI combination treatment

描述(由申请人提供)：暴露于哌甲酸甲酯(一种多巴胺再摄取抑制剂)可以模拟可卡因的几种行为和分子效应。然而，其他类似可卡因的影响是微乎其微的，可能是因为5-羟色胺不会被哌醋甲酯升高。申请人实验室最近的研究结果支持了这一观点，该发现表明，用选择性5-羟色胺再摄取抑制剂(SSRIs)升高5-羟色胺可增强哌醋甲酯诱导的精神运动活性和与精神刺激剂成瘾有关的大脑区域的神经元适应。目前尚不清楚联合使用SSRIs增加5-羟色胺传递是否也能促进成瘾。这是令人担忧的，因为许多人正暴露在由哌醋甲酯(利他林)和SSRI组成的药物组合中。本应用程序的目的是确定哌醋甲酯SSRI暴露如何改变可卡因成瘾倾向的指标。假设是SSRI增强了哌甲酸甲酯的作用，使其更像可卡因。因此，反复暴露于哌甲酸甲酯SSRI将促进随后的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，使用允许推断自我管理可卡因(目标1a)和“强制”吸毒(目标1b)的敏感性和“动机”的范式。暴露于哌酸甲酯SSRI也可能引发前可卡因使用者的复发。这将在大鼠身上进行测试，使用衡量寻求毒品行为恢复的范式(目标2)。这些目标的成功完成具有重要意义，因为它将为决定未来是否应该避免使用哌醋甲酯SSRI药物组合提供信息，因为它们有可能促进与精神刺激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.