Cognitive Aspects of Addiction-Related Behavior

神经生物学的进展表明，功能失调的前额叶皮质不仅是可卡因成瘾的基础， 还有注意力缺陷多动障碍。此外，ADHD和可卡因成瘾通常是并存的。 关于兴奋剂药物的使用以及它是否会使青少年 治疗ADHD更容易或更不容易受到后来的可卡因成瘾的影响。继续我们的研究 成瘾相关行为的认知方面，我们建议使用一个经过验证的大鼠模型来研究 ADHD和静脉给药程序，ADHD之间的关系，在 青春期，对可卡因成瘾的易感性，在成年期进行评估。使用行为程序， 目的1研究ADHD与可卡因成瘾易感性的关系。我们将决定 如果ADHD表型的大鼠在青春期表现出1)前额叶皮质功能障碍，那就是 通过使用兴奋剂药物哌醋甲酯或非兴奋剂药物来预防 托莫西汀；2)如果从未用药，成年期对可卡因成瘾的易感性增加；3)更大 如果在青春期给予哌甲酯治疗，成年后易患可卡因成瘾 然后停止，但如果在青春期给予托莫西汀治疗，然后停止治疗，则不会；4) 如果使用哌醋甲酯和托莫西汀治疗，降低成年期间对可卡因成瘾的易感性 一直持续到成年。目标2将通过对选择性拮抗剂的药理分析来确定 前额叶皮质和眶前叶皮质突触后D_1和_A受体功能对脑功能的影响 调节成年后对可卡因成瘾的易感性。目标3将通过以下方式进行评估 前额叶皮质(前额叶和眼眶亚区)和纹状体的神经化学分析， 哌醋甲酯和托莫西汀诱导突触前DAT、Net和/或VMAT2转运蛋白的变化。 将使用测量摄取和清除功能以及亚细胞定位的程序。这 这项工作将促进我们对兴奋剂和非兴奋剂药物使用的后果的了解 患有ADHD的青少年对可卡因成瘾的易感性。突触前(转运蛋白功能和 局部性)和突触后(D1和2A受体功能)机制可能是易感性的基础 用这些药物治疗后的可卡因成瘾将被揭示。来自这些的信息 临床前研究可能有助于合理选择在生命周期内如何以及何时用药治疗ADHD 改善前额叶皮质相关的神经认知功能，同时降低物质使用障碍的风险。

Advances in neurobiology suggest that a dysfunctional prefrontal cortex underlies not only cocaine addiction, but also attention deficit hyperactivity disorder. Moreover, ADHD and cocaine addiction are often co-morbid. There remains disagreement concerning the use of stimulant medication and whether it makes adolescents treated for ADHD more vulnerable or less vulnerable to later cocaine addiction. To continue our studies on cognitive aspects of addiction-related behavior, we propose to investigate, using a validated rat model of ADHD and intravenous self-administration procedures, the relationship between ADHD, evaluated during adolescence, to vulnerability to cocaine addiction, evaluated during adulthood. Using behavioral procedures, Aim 1 will investigate the relationship between ADHD and vulnerability to cocaine addiction. We will determine if rats with an ADHD phenotype exhibit 1) dysfunction of the prefrontal cortex during adolescence that is prevented by treatment with either the stimulant medication methylphenidate or the non-stimulant medication atomoxetine; 2) augmented vulnerability to cocaine addiction during adulthood if never medicated; 3) a greater vulnerability to cocaine addiction during adulthood if methylphenidate treatment is given during adolescence and then discontinued, but not if atomoxetine treatment is given during adolescence and then discontinued; 4) reduced vulnerability to cocaine addiction during adulthood if methylphenidate and atomoxetine treatments are continued into adulthood. Aim 2 will determine, via pharmacological analysis with selective antagonists, the importance of postsynaptic D1 and ¿2A receptor function within the prelimbic and orbital prefrontal cortex for mediating the altered vulnerability to cocaine addiction during adulthood. Aim 3 will evaluate, via neurochemical analysis within prefrontal cortex (prelimbic and orbital subregions) and striatum, the methylphenidate- and atomoxetine-induced changes in presynaptic DAT, NET and/or VMAT2 transporters. Procedures measuring uptake and clearance functions as well as subcellular localization will be used. This work will advance our knowledge of the consequences of stimulant and non-stimulant medication use in adolescents with ADHD on later vulnerability to cocaine addiction. Presynaptic (transporter function and localization) and postsynaptic (D1 and ¿2A receptor function) mechanisms that may underlie vulnerability to cocaine addiction following treatment with these medications will be revealed. Information from these preclinical studies may assist in the rationale choice of how and when to medicate ADHD through the lifespan to improve prefrontal cortex-related neurocognitive functioning while reducing risk of substance use disorders.