Biobehavioral Studies of Opioid Seeking Behavior

描述（由申请人提供）：这个竞争性更新的总体目标是系统地研究应激增强阿片类药物寻找和生物行为反应的机制。拟议的目标是在非常富有成效的人类实验室范例和该项目初始资助周期的重大发现的基础上程序化地建立起来的。我们结合了敏感选择递进比（指数级上升反应要求）程序、完善的主观药物效应和情绪状态测量、创新的海马/前额叶皮质与背侧纹状体依赖的学习任务，以及交感神经和hpa介导的反应的生理指标（即心期变异性、血压、体温、唾液皮质醇和1-淀粉酶）。主要的药物寻求结果将使用敏感的行为经济学方法进行分析。三个拟议的研究将系统地将这个有用的实验室模型扩展到重要的、创新的和有影响力的方向（包括验证替代压力源）。建议的研究设计是合理的，并采用受试者内、随机交叉、安慰剂对照、双盲方法。我们的目标是推进理论理解（例如，生物行为反应应该对压力源有不同的敏感性），并为实际应用（例如药物开发）产生假设。目的1。使用基于Prelim调整的优化模型（方法）充分表征育亨宾增强阿片类药物寻找和生物行为反应。研究4的发现)，并与自然的压力源（中度大声，间歇性，不可避免的哭泣/痛苦婴儿的配乐）进行比较。目标2。使用另一种神经药理学应激源范例（瑞波西汀/氢化可的松剂量组合）来确定去甲肾上腺素能（不适用）和糖皮质激素传递的激活是否会增加阿片寻求和生物行为反应。目标3。确定12a -肾上腺素能（胍法辛1毫克）、5-HT1A（丁螺环酮30毫克）、CB1（大麻二酚1000毫克）和GABAB（巴氯芬40毫克）受体的神经调节剂是否对育亨宾增强的阿片寻求和生物行为反应有差异调节。

DESCRIPTION (provided by applicant): The overarching goal of this competing renewal is to investigate systematically the mechanisms of stress- potentiated opioid seeking and biobehavioral responses. The proposed aims build programmatically on the very productive human laboratory paradigm and significant findings from this project's initial funding cycle. We combine a sensitive choice progressive ratio (exponentially escalating response requirement) procedure, well- established subjective drug effect and mood state measures, innovative hippocampal/prefrontal cortical vs. dorsal striatal-dependent learning tasks, and physiological indices of sympathetic- and HPA-mediated responses (i.e. heart period variability, blood pressure, body temperature, and salivary cortisol and 1-amylase). The primary drug-seeking outcomes will be analyzed using sensitive behavioral economic methods. Three proposed studies will systematically extend this useful laboratory model in significant, innovative and impactful directions (including validation of alternative stressors). The proposed study designs are sound and employ within-subject, randomized crossover, placebo-controlled, double-blind methodology. Our goal is to advance theoretical understanding (e.g. biobehavioral responses should be differentially sensitive to the stressors) and generate hypotheses for practical applications (e.g. medication development). Aim 1. Fully characterize yohimbine-potentiated opioid seeking and biobehavioral responses using an optimized model (methods adjusted based on Prelim. Study 4 findings) and compare to a naturalistic stressor (moderately loud, intermittent, inescapable soundtrack of crying/distressed infants). Aim 2. Use an alternative neuropharmacological stressor paradigm (reboxetine/hydrocortisone dose combinations) to determine whether activation of noradrenergic (Not applicable) and glucocorticoid transmission increases opioid seeking and biobehavioral responses. Aim 3. Determine whether neuromodulating agents at 12A-adrenergic (guanfacine 1 mg), 5-HT1A (buspirone 30 mg), CB1 (cannabidiol 1000 mg), and GABAB (baclofen 40 mg) receptors differentially modulate yohimbine- potentiated opioid seeking and biobehavioral responses.