Drugs of Abuse, Gender Differences, and Protection by Sweets

药物滥用、性别差异和糖果的保护

• 批准号: 7765607
• 负责人: Angie Cason
• 金额: $ 5.22万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7765607
• 关键词: Behavior; Cocaine; Cues; Data; Dopamine; Estrogens; Female; Hand; Individual Differences; Intake; Literature; Lithium Chloride; Pharmaceutical Preparations; Rattus; Resistance; Rewards; Saccharin; Saline; Self Administration; Self-Administered; Sex Characteristics; Solutions; Stimulus; Taste Perception; Testing; addiction; drug of abuse; drug reward; male; preference; protective effect; response; sex

DESCRIPTION (provided by candidate): Rats will suppress intake of a saccharin solution that predicts either the passive or the active (i.e., self-) administration of a drug of abuse. Initially, it was believed that drugs of abuse were producing a conditioned taste aversion, similar to that induced by the aversive agent, lithium chloride. More recent evidence, however, suggests that the supressive effects of drugs of abuse are caused by devaluation of the natural reward (i.e., the saccharin cue) in anticipation of the availability of the more potent drug reward. This phenomenon, referred to reward comparison [18], occurs in both male and female rats when the cocaine is administered passively and large individual differences in saccharin intake are evident amongst rats of each sex. The large suppressing rats show greater avoidance of the saccharin cue than do either small suppressing rats or the saline controls. When tested using iv self-administration in males, greater avoidance of the saccharin cue is highly correlated with greater cocaine self-administration [23]. Interestly, in our hands, females appear to be more resistant to cocaine-induced suppression of CS intake than males and they take less drug in this paradigm. This finding was somewhat unexpected because a substantial amount of literature shows that female rats take more drug than male rats and greater preference for the drug unconditioned stimulus (US) should be associated with more, rather than less, avoidance of the less valuable taste cue. This disjunction led us to hypothesize that the availability of the saccharin cue (even for just 5 min/day) is sufficient to reduce cocaine self-administration behavior and, moreover, that these protective effects of the sweet are greater in female than in male rats. Specific Aim 1 tests whether the availability of the saccharin cue serves to reduce acquisition and reinstatement of cocaine selfadministration and whether this effect is greater in female rats. Specific Aim 2 tests whether estrogen is required for this phenomenon. Finally, Specific Aim 3 tests whether accumbens dopamine, which tracks the comparison between natural rewards and drugs of abuse, is more sensitive in the female rat. If our predictions prove correct, the data will suggest that, while increased sensitivity to reward may predispose females to addiction in the absence of alternative natural rewards, it also may be highly protective when a valued natural reward is available.

描述（由候选人提供）：大鼠会抑制糖精溶液的摄入，这预示着药物滥用的被动或主动（即自我）管理。最初，人们认为滥用药物会产生一种条件性的味觉厌恶，类似于厌恶剂氯化锂引起的厌恶。然而，最近的证据表明，滥用药物的抑制作用是由于预期可以获得更有效的药物奖励而使自然奖励（即糖精提示）贬值造成的。这种被称为奖励比较[18]的现象，在被动给药的情况下，雄性和雌性大鼠都出现了这种现象，而且在不同性别的大鼠中，糖精摄入量的个体差异非常明显。与小抑制鼠或生理盐水对照组相比，大抑制鼠对糖精的回避程度更高。当对男性进行静脉自我给药测试时，对糖精信号的回避程度越高，可卡因自我给药程度就越高。有趣的是，在我们的研究中，女性似乎比男性更能抵抗可卡因引起的CS摄入抑制，在这种情况下，她们服用的药物更少。这一发现有些出乎意料，因为大量的文献表明，雌性大鼠比雄性大鼠服用更多的药物，对药物无条件刺激（US）的更大偏好应该与更多而不是更少地回避价值较低的味觉线索有关。这种分离使我们假设，糖精提示的可用性（即使每天只有5分钟）足以减少可卡因的自我给药行为，而且，甜味的这些保护作用在雌性大鼠中比在雄性大鼠中更大。特异性目的1测试糖精提示的可用性是否有助于减少可卡因自我给药的获得和恢复，以及这种作用是否在雌性大鼠中更大。特异性目标2测试是否需要雌激素来治疗这种现象。最后，Specific Aim 3测试伏隔多巴胺是否在雌性大鼠中更敏感。伏隔多巴胺可以追踪自然奖励和滥用药物之间的比较。如果我们的预测被证明是正确的，那么数据将表明，虽然对奖励的敏感度增加可能会使女性在缺乏其他自然奖励的情况下容易上瘾，但当有价值的自然奖励时，它也可能具有高度的保护作用。