Behavioral Neuroscience Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD 21224, USA.
Neuropsychopharmacology. 2013 Aug;38(9):1763-9. doi: 10.1038/npp.2013.75. Epub 2013 Mar 27.
Cocaine has actions in the peripheral nervous system that reliably precede--and thus predict--its soon-to-follow central rewarding effects. In cocaine-experienced animals, the peripheral cocaine signal is relayed to the central nervous system, triggering excitatory input to the ventral tegmental origin of the mesocorticolimbic dopamine system, the system that mediates the rewarding effects of the drug. We used cocaine methiodide, a cocaine analog that does not cross the blood-brain barrier, to isolate the peripheral actions of cocaine and determine their central and behavioral effects in animals first trained to lever-press for cocaine hydrochloride (the centrally acting and abused form of the drug). We first confirmed with fast-scan cyclic voltammetry that cocaine methiodide causes rapid dopamine release from dopamine terminals in cocaine hydrochloride-trained rats. We then compared the ability of cocaine hydrochloride and cocaine methiodide to establish conditioned place preferences in rats with self-administration experience. While cocaine hydrochloride established stronger place preferences, cocaine methiodide was also effective and its effectiveness increased (incubated) over weeks of cocaine abstinence. Cocaine self-administration was extinguished when cocaine methiodide or saline was substituted for cocaine hydrochloride in the intravenous self-administration paradigm, but cocaine hydrochloride and cocaine methiodide each reinstated non-rewarded lever-pressing after extinction. Rats extinguished by cocaine methiodide substitution showed weaker cocaine-induced reinstatement than rats extinguished by saline substitution. These findings suggest that the conditioned peripheral effects of cocaine can contribute significantly to cocaine-induced (but not stress-induced) cocaine craving, and also suggest the cocaine cue as an important target for cue-exposure therapies for cocaine addiction.
可卡因在周围神经系统中的作用可靠地先于——并因此预测——其随后的中枢奖赏效应。在有可卡因经验的动物中，外周可卡因信号被传递到中枢神经系统，引发腹侧被盖起源的中脑边缘多巴胺系统的兴奋性输入，该系统介导药物的奖赏效应。我们使用了可卡因甲碘化物，一种不能穿过血脑屏障的可卡因类似物，以分离可卡因的外周作用，并确定其在首次接受可卡因盐酸盐（药物的中枢作用和滥用形式） lever-press 训练的动物中的中枢和行为效应。我们首先通过快速扫描循环伏安法证实，可卡因甲碘化物可导致可卡因盐酸盐训练的大鼠多巴胺末梢中的多巴胺快速释放。然后，我们比较了可卡因盐酸盐和可卡因甲碘化物在有自我给药经验的大鼠中建立条件性位置偏好的能力。虽然可卡因盐酸盐能建立更强的位置偏好，但可卡因甲碘化物也有效，而且随着可卡因戒断数周的增加其有效性也会增加（孵育）。当可卡因甲碘化物或生理盐水替代可卡因盐酸盐用于静脉内自我给药范式时，可卡因自我给药被消除，但可卡因盐酸盐和可卡因甲碘化物都在消退后重新引发非奖赏 lever-pressing。与用生理盐水替代可卡因甲碘化物消除的大鼠相比，用可卡因甲碘化物替代可卡因消除的大鼠表现出较弱的可卡因诱发复吸。这些发现表明，可卡因的条件外周效应可以显著促进可卡因引起的（而不是应激引起的）可卡因渴望，也表明可卡因线索是可卡因成瘾线索暴露疗法的重要目标。
