Effects of extended access to high versus low cocaine doses on self-administration, cocaine-induced reinstatement and brain mRNA levels in rats
Effects of extended access to high versus low cocaine doses on self-administration, cocaine-induced reinstatement and brain mRNA levels in rats
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DOI：
10.1007/s00213-004-1778-x
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发表时间：
2004-08-01
影响因子：
3.4
通讯作者：
Kreek, MJ
中科院分区：
文献类型：
--
作者：
Mantsch, JR;Yuferov, V;Kreek, MJ
基本原理。对啮齿类动物可卡因自我给药（SA）在促进不断升级的摄入模式的条件下的调查可能提供对药物使用失去控制的见解，这是人类成瘾的核心。目标。本研究探讨了高或低可卡因剂量的每日长通路（LgA） SA对药物摄入、消退、恢复和脑mRNA水平的影响。方法。三组雄性Sprague-Dawley大鼠被训练在多次服用可卡因的过程中自我服用可卡因。每天对短通道（ShA）大鼠进行多剂量SA测试，然后在无可卡因可用的情况下在室内停留7小时。在多剂量SA后，LgA大鼠可在7小时内接受低剂量（每次注射0.5 mg/kg; LgA- ld）或高剂量（每次注射2.0 mg/kg; LgA- hd）可卡因。14天后，反应消失，测定可卡因诱导的恢复情况，并采用定量溶液杂交RNase保护法测定脑各区域前脑啡肽（ppENK）、前脑啡肽（ppDYN）、促肾上腺皮质激素释放因子（CRF）和多巴胺D-2受体（D2R） mRNA水平。结果。尽管SA在ShA大鼠中没有改变，仅在LgA-LD大鼠的“加载阶段”增加，但LgA-HD大鼠的摄入量普遍增加。LgA大鼠，特别是LgA- hd大鼠比ShA大鼠更容易恢复。LgA-HD大鼠尾壳核ppENK和伏隔核D2R mRNA水平升高。总体而言，D2R mRNA水平与恢复呈正相关。结论。LgA条件下可卡因SA的升高是剂量依赖性的，并与药物诱导复发的易感性增加有关。随着SA升级的神经生物学改变的特征应该有助于确定人类成瘾发生的机制。
Rationale. The investigation of rodent cocaine self-administration (SA) under conditions that promote escalating patterns of intake may provide insight into the loss of control over drug use that is central to human addiction. Objective. This study examines the effects of daily long-access (LgA) SA of high or low cocaine doses on drug intake, extinction, reinstatement, and brain mRNA levels. Methods. Three groups of male Sprague-Dawley rats were trained to self-administer cocaine during multiple-dose sessions. Short-access (ShA) rats were tested daily for multi-dose SA then remained in the chambers for 7 h with no cocaine available. LgA rats had access to low (0.5 mg/kg per infusion; LgA-LD) or high (2.0 mg/kg per infusion; LgA-HD) cocaine doses for 7 h after multi-dose SA. After 14 days, responding was extinguished, cocaine-induced reinstatement was determined, and preproenkephalin (ppENK), preprodynorphin (ppDYN), corticotropin releasing factor (CRF) and dopamine D-2 receptor (D2R) mRNA levels were measured in various brain regions using a quantitative solution hybridization RNase protection assay. Results. Whereas SA was not altered in ShA rats and only increased during the "loading phase" in LgA-LD rats, a general escalation of intake was found in LgA-HD rats. LgA, particularly LgA-HD, rats were more susceptible to reinstatement than ShA rats. Caudate-putamen ppENK and nucleus accumbens D2R mRNA levels were elevated in LgA-HD rats. Overall, D2R mRNA levels were positively correlated with reinstatement. Conclusions. The escalation of cocaine SA under LgA conditions is dose-dependent and is associated with heightened susceptibility to drug-induced relapse. The characterization of neurobiological alterations that accompany escalated SA should facilitate the identification of mechanisms underlying the onset of human addiction.