Wang Bin, You Zhi-Bing, Wise Roy A
Behavioral Neuroscience Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland 21224, USA.
Biol Psychiatry. 2009 May 15;65(10):857-62. doi: 10.1016/j.biopsych.2009.01.018. Epub 2009 Feb 28.
Hypocretin (Hcrt), an arousal- and feeding-associated peptide, is expressed in lateral hypothalamic neurons that project to the ventral tegmental area (VTA). Intra-VTA Hcrt reinstates morphine-conditioned place preferences, and intracerebroventricular and intra-VTA corticotropin-releasing factor (CRF) reinstate cocaine seeking. Each is presumed to act, at least in part, through actions local to the VTA. Here, we examined the possibility that VTA perfusion of Hcrt reinstates cocaine seeking and, if so, whether it does so through the VTA mechanism that is implicated in reinstatement by CRF.
Rats were trained to lever-press for intravenous cocaine (2 weeks) and then underwent extinction training (saline substituted for cocaine: 3 weeks). Reinstatement behavior was tested and VTA dialysates were collected and assayed for glutamate or dopamine following footshock or perfusion of Hcrt or CRF, with or without Hcrt or CRF antagonists, into the VTA.
Ventral tegmental area perfusion of Hcrt-1 or footshock stress reinstated cocaine seeking and caused release of VTA glutamate and dopamine. The effects of Hcrt-1 were blocked by a selective Hcrt-1 antagonist, but not a CRF antagonist, and were not mimicked by Hcrt-2. The Hcrt-1 antagonist did not block CRF-dependent footshock-induced reinstatement or glutamate or dopamine release. The behavioral and neurochemical effects of Hcrt-1 were attenuated but not blocked by kynurenic acid, an ionotropic glutamate antagonist that blocks footshock-induced reinstatement and glutamate release.
While Hcrt and CRF are known to interact in some area of the brain, in the VTA proper they appear to have largely independent actions on the mesolimbic dopamine mechanisms of cocaine seeking.
下丘脑泌素（Hcrt）是一种与觉醒和进食相关的肽，在下丘脑外侧神经元中表达，这些神经元投射到腹侧被盖区（VTA）。VTA内注射Hcrt可恢复吗啡条件性位置偏好，而脑室内注射和VTA内注射促肾上腺皮质激素释放因子（CRF）可恢复对可卡因的觅求行为。据推测，它们至少部分是通过VTA局部作用发挥效应。在此，我们研究了VTA灌注Hcrt是否能恢复对可卡因的觅求行为，如果是，它是否通过与CRF恢复觅求行为相关的VTA机制发挥作用。
训练大鼠按压杠杆以静脉注射可卡因（2周），然后进行消退训练（用生理盐水替代可卡因：3周）。进行恢复行为测试，并在给予足底电击或向VTA灌注Hcrt或CRF（有无Hcrt或CRF拮抗剂）后，收集VTA透析液并检测谷氨酸或多巴胺水平。
向VTA灌注Hcrt-1或足底电击应激可恢复对可卡因的觅求行为，并导致VTA谷氨酸和多巴胺释放。Hcrt-1的作用被选择性Hcrt-1拮抗剂阻断，但未被CRF拮抗剂阻断，且Hcrt-2不能模拟其作用。Hcrt-1拮抗剂未阻断CRF依赖的足底电击诱导的恢复行为或谷氨酸或多巴胺释放。Hcrt-1的行为和神经化学作用被离子型谷氨酸拮抗剂犬尿氨酸减弱但未被阻断，犬尿氨酸可阻断足底电击诱导的恢复行为和谷氨酸释放。
虽然已知Hcrt和CRF在大脑的某些区域相互作用，但在VTA本身，它们似乎对可卡因觅求的中脑边缘多巴胺机制具有很大程度的独立作用。
