Marcus Madison M, Banks Matthew L
Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA 23298.
bioRxiv. 2023 Mar 31:2023.03.29.534800. doi: 10.1101/2023.03.29.534800.
Continued drug-taking despite adverse consequences is hypothesized to be an insidious behavioral hallmark of drug addiction. Although most preclinical research has focused on drug self-administration in the presence of positive punishment, another source of potential adverse consequences is behavioral allocation away from negative reinforcers (i.e., escape/avoid electric shock) and towards drug reinforcers. The goals of the present study were to establish a discrete-trial cocaine-vs-negative reinforcer choice procedure in male and female rats and determine sensitivity of choice behavior to environmental and pharmacological manipulations. Rats could make up to nine discrete choices between an intravenous cocaine infusion (0.32 - 1.8 mg/kg/inf) under a fixed-ratio (FR) 3 schedule and a negative reinforcer (escape or avoidance of electric shock, 0.1 - 0.7 mA) under an FR1 schedule. The negative reinforcer was consistently chosen over all cocaine doses. Lowering shock magnitude decreased negative reinforcer trials, increased omitted trials, and failed to promote behavioral reallocation towards cocaine. Increasing the negative reinforcement response requirement between sessions only increased omitted trials. Introduction of 12-hr extended access cocaine self-administration sessions across two weeks resulted in high daily cocaine intakes but failed to significantly increase cocaine choice. Acute diazepam pretreatment also did not impact choice behavior up to doses that produced behavioral depression. Overall, the lack of behavioral allocation between cocaine infusions and a negative reinforcer suggests these two reinforcers may be economic independents. Additionally, the failure of extended cocaine access to increase cocaine choice highlights the importance of alternative reinforcers and environmental context in preclinical models of drug addiction.
尽管存在不良后果仍持续用药被认为是药物成瘾的一种潜在行为特征。虽然大多数临床前研究集中在正性惩罚条件下的药物自我给药，但潜在不良后果的另一个来源是行为从负性强化物（即逃避/避免电击）转向药物强化物。本研究的目的是在雄性和雌性大鼠中建立一种离散试验的可卡因与负性强化物选择程序，并确定选择行为对环境和药理学操作的敏感性。大鼠可以在固定比率（FR）3程序下静脉注射可卡因（0.32 - 1.8毫克/千克/次）和FR1程序下的负性强化物（逃避或避免电击，0.1 - 0.7毫安）之间进行多达九次离散选择。在所有可卡因剂量下，负性强化物始终被优先选择。降低电击强度减少了负性强化物试验，增加了遗漏试验，并且未能促进行为向可卡因的重新分配。增加各 sessions 之间的负性强化反应要求仅增加了遗漏试验。在两周内引入12小时延长获取可卡因自我给药 sessions 导致每日可卡因摄入量很高，但未能显著增加可卡因选择。急性地西泮预处理在产生行为抑制的剂量范围内也未影响选择行为。总体而言，可卡因注射与负性强化物之间缺乏行为分配表明这两种强化物可能在经济上是独立的。此外，延长可卡因获取时间未能增加可卡因选择凸显了在药物成瘾临床前模型中替代强化物和环境背景的重要性。
