Surgical adrenalectomy with diurnal corticosterone replacement slows escalation and prevents the augmentation of cocaine-induced reinstatement in rats self-administering cocaine under long-access conditions
Surgical adrenalectomy with diurnal corticosterone replacement slows escalation and prevents the augmentation of cocaine-induced reinstatement in rats self-administering cocaine under long-access conditions
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DOI：
10.1038/sj.npp.1301464
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发表时间：
2008-03-01
影响因子：
7.6
通讯作者：
Katz, Eric S.
中科院分区：
文献类型：
--
作者：
Mantsch, John R.;Baker, David A.;Katz, Eric S.
对可卡因使用失去控制和持续增加的药物复发易感性定义了人类可卡因成瘾，这是药物诱导的神经可塑性的后果，并且可以在每日长时间吸食（LgA）条件下对大鼠自我施用可卡因进行研究，因为药物摄入模式不断升级，并且对恢复的敏感性增加。本研究调查了 LgA 可卡因自我给药 (SA) 时糖皮质激素升高对成瘾相关神经可塑性的这些行为指数的潜在贡献。与在短时间接触（ShA；2小时）条件下自我给药的大鼠相比，给予可卡因6小时接触（LgA）14天的大鼠显示SA逐渐升高，并且更容易受到可卡因诱导的恢复（10mg/kg，腹腔注射）的影响。手术肾上腺切除术和皮质酮替代 (ADX/C) 方案消除了 SA 诱导的皮质酮 (CORT) 增加，同时维持了每日的分泌模式，但在慢性 LgA SA 测试之前而非之后应用时，未能改变 ShA 大鼠的 SA 或恢复，但减缓了 LgA 大鼠的升级并减弱了后期的恢复。虽然不能排除其他肾上腺激素的影响，但这些数据表明，LgA SA 对可卡因摄入和随后恢复的影响可能需要在接触可卡因时升高糖皮质激素。在每日 ShA SA 之前每日给予 CORT，其剂量不能重现 LgA SA 期间的反应，无法模拟 LgA SA 的效果，这表明 SA 期间糖皮质激素升高可能在可卡因诱导的神经可塑性中发挥许可作用，从而导致成瘾。
The loss of control over cocaine use and persistently heightened susceptibility to drug relapse that define human cocaine addiction are consequences of drug-induced neuroplasticity and can be studied in rats self-administering cocaine under conditions of daily long access (LgA) as escalating patterns of drug intake and heightened susceptibility to reinstatement. This study investigated the potential contribution of elevated glucocorticoids at the time of LgA cocaine self-administration (SA) to these behavioral indices of addiction-related neuroplasticity. Rats provided 14 days of 6-h access (LgA) to cocaine showed a progressive escalation of SA and were more susceptible to cocaine-induced reinstatement (10 mg/kg, i.p.) compared to rats self-administering under short-access (ShA; 2 h) conditions. A surgical adrenalectomy and corticosterone replacement (ADX/C) regimen that eliminated SA-induced increases in corticosterone (CORT) while maintaining the diurnal pattern of secretion failed to alter SA or reinstatement in ShA rats but slowed escalation and attenuated later reinstatement in LgA rats when applied before but not after chronic LgA SA testing. Although the contribution of other adrenal hormones cannot be ruled out, these data suggest that elevated glucocorticoids at the time of cocaine exposure may be required for the effects of LgA SA on cocaine intake and later reinstatement. The inability of daily CORT administration before daily ShA SA, at a dose that reproduced the response during LgA SA, to mimic the effects of LgA SA suggests that elevated glucocorticoids during SA may play a permissive role in cocaine-induced neuroplasticity that contributes to addiction.