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: 7588021
• 负责人: Angie Cason
• 金额: $ 5.01万
• 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/7588021
• 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，这预示着被动或主动（即自我）滥用药物的施用。最初，人们认为滥用药物会产生条件性味觉厌恶，类似于厌恶剂氯化锂引起的味道厌恶。然而，最近的证据表明，滥用药物的抑制作用是由于预期可获得更有效的药物奖励而导致自然奖励（即糖精提示）贬值而引起的。这种现象被称为奖励比较[18]，当被动给予可卡因时，雄性和雌性大鼠都会发生这种现象，并且每种性别的大鼠中糖精摄入量存在很大的个体差异。与小型抑制大鼠或盐水对照相比，大型抑制大鼠表现出对糖精提示的更大程度的回避。当对男性进行静脉注射自我给药测试时，更多地避免糖精提示与更多的可卡因自我给药高度相关[23]。有趣的是，在我们看来，女性似乎比男性更能抵抗可卡因引起的 CS 摄入抑制，并且在这种情况下她们服用的药物更少。这一发现有些出人意料，因为大量文献表明雌性大鼠比雄性大鼠服用更多的药物，并且对药物无条件刺激（US）的更大偏好应该与更多而不是更少地避免不太有价值的味觉提示相关。这种分歧使我们推测，糖精提示的可用性（即使每天仅 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。具体目标 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取和恢复，以及这种效应在雌性大鼠中是否更大。具体目标 2 测试此现象是否需要雌激素。最后，Specific Aim 3 测试了追踪自然奖励和滥用药物之间比较的伏隔多巴胺在雌性大鼠中是否更敏感。如果我们的预测被证明是正确的，数据将表明，虽然在没有其他自然奖励的情况下，对奖励的敏感性增加可能会使女性容易上瘾，但当有有价值的自然奖励可用时，它也可能具有高度保护作用。