Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, USA.
Neuropsychopharmacology. 2012 Dec;37(13):2863-9. doi: 10.1038/npp.2012.167. Epub 2012 Sep 5.
Heroin and cocaine have very different unconditioned receptor-mediated actions; however, in the brain circuitry of drug-reward and motivation, the two drugs establish common conditioned consequences. A single experience with either drug can change the sensitivity of ventral tegmental area (VTA) dopamine neurons to glutamatergic input. In the case of cocaine, repeated intravenous self-administration establishes de novo VTA glutamate release and dopaminergic activation in response to conditioned stimuli and mild footshock stress. Here we determined whether repeated self-administration of heroin would establish similar glutamate release and dopaminergic activation. Although self-administration of heroin itself did not cause VTA glutamate release, conditioned glutamate release was seen when rats expecting rewarding heroin were given nonrewarding saline in its place. Mild footshock stress also caused glutamate release in heroin-trained animals. In each case, the VTA glutamate release was accompanied by elevations in VTA dopamine levels, indicative of dopaminergic activation. In each case, infusion of the ionotropic glutamate antagonist kynurenic acid blocked the VTA dopamine release associated with VTA glutamate elevation. Although glutamate levels in the extinction and reinstatement tests were similar to those reported in cocaine studies, the effects of heroin self-administration itself were quite different from what has been seen during cocaine self-administration.
海洛因和可卡因具有非常不同的非条件受体介导作用；然而，在药物奖赏和动机的大脑回路中，这两种药物建立了共同的条件后果。单次使用这两种药物中的任何一种都可以改变腹侧被盖区（VTA）多巴胺神经元对谷氨酸能输入的敏感性。在可卡因的情况下，重复静脉内自我给药会导致新的 VTA 谷氨酸释放和多巴胺能激活，以响应条件刺激和轻度足底电击应激。在这里，我们确定重复给予海洛因是否会建立类似的谷氨酸释放和多巴胺能激活。尽管海洛因本身的自我给药本身不会引起 VTA 谷氨酸释放，但当给予期待海洛因的大鼠替代非奖赏性盐水时，会出现条件性谷氨酸释放。轻度足底电击应激也会引起海洛因训练动物的谷氨酸释放。在每种情况下，VTA 谷氨酸释放伴随着 VTA 多巴胺水平的升高，表明多巴胺能激活。在每种情况下，离子型谷氨酸拮抗剂 kynurenic 酸的输注都会阻断与 VTA 谷氨酸升高相关的 VTA 多巴胺释放。尽管在消退和重新出现测试中的谷氨酸水平与可卡因研究中报告的水平相似，但海洛因自我给药本身的作用与可卡因自我给药期间观察到的作用有很大不同。
