Mantsch John R, Yuferov Vadim, Mathieu-Kia Anne-Marie, Ho Ann, Kreek Mary Jeanne
The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, NY, USA.
Psychopharmacology (Berl). 2004 Aug;175(1):26-36. doi: 10.1007/s00213-004-1778-x. Epub 2004 Mar 20.
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.
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.
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 (D(2)R) mRNA levels were measured in various brain regions using a quantitative solution hybridization RNase protection assay.
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 D(2)R mRNA levels were elevated in LgA-HD rats. Overall, D(2)R mRNA levels were positively correlated with reinstatement.
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.
在促进摄入量逐步增加模式的条件下对啮齿动物可卡因自我给药（SA）进行研究，可能有助于深入了解对药物使用失去控制的情况，而这是人类成瘾的核心问题。
本研究考察高剂量或低剂量可卡因每日长时间给药（LgA）的自我给药对药物摄入、消退、复吸及脑内mRNA水平的影响。
三组雄性Sprague-Dawley大鼠在多次给药期间接受可卡因自我给药训练。短时间给药（ShA）大鼠每日进行多次剂量的SA测试，然后在无可卡因的情况下在实验箱中停留7小时。LgA大鼠在多次剂量的SA后可接触低剂量（每次输注0.5mg/kg；LgA-LD）或高剂量（每次输注2.0mg/kg；LgA-HD）可卡因7小时。14天后，停止反应，测定可卡因诱导的复吸情况，并使用定量溶液杂交核糖核酸酶保护测定法测量各个脑区前脑啡肽原（ppENK）、前强啡肽原（ppDYN）、促肾上腺皮质激素释放因子（CRF）和多巴胺D2受体（D2R）的mRNA水平。
ShA大鼠的SA未改变，LgA-LD大鼠仅在“加载阶段”增加，而LgA-HD大鼠出现了总体摄入量的逐步增加。LgA大鼠，尤其是LgA-HD大鼠，比ShA大鼠更容易复吸。LgA-HD大鼠尾壳核ppENK和伏隔核D2R的mRNA水平升高。总体而言，D2R的mRNA水平与复吸呈正相关。
在LgA条件下可卡因SA的逐步增加是剂量依赖性的，并且与药物诱导的复发易感性增加有关。伴随SA增加的神经生物学改变特征应有助于确定人类成瘾起始的潜在机制。
