Harris Glenda C, Wimmer Mathieu, Aston-Jones Gary
Laboratory of Neuromodulation and Behavior, Department of Psychiatry, University of Pennsylvania, 705 Stellar Chance/6100 422 Curie Blvd, Philadelphia, Pennsylvania 19104-6100, USA.
Nature. 2005 Sep 22;437(7058):556-9. doi: 10.1038/nature04071. Epub 2005 Aug 14.
The lateral hypothalamus is a brain region historically implicated in reward and motivation, but the identity of the neurotransmitters involved are unknown. The orexins (or hypocretins) are neuropeptides recently identified as neurotransmitters in lateral hypothalamus neurons. Although knockout and transgenic overexpression studies have implicated orexin neurons in arousal and sleep, these cells also project to reward-associated brain regions, including the nucleus accumbens and ventral tegmental area. This indicates a possible role for these neurons in reward function and motivation, consistent with previous studies implicating these neurons in feeding. Here we show that activation of lateral hypothalamus orexin neurons is strongly linked to preferences for cues associated with drug and food reward. In addition, we show that chemical activation of lateral hypothalamus orexin neurons reinstates an extinguished drug-seeking behaviour. This reinstatement effect was completely blocked by prior administration of an orexin A antagonist. Moreover, administration of the orexin A peptide directly into the ventral tegmental area also reinstated drug-seeking. These data reveal a new role for lateral hypothalamus orexin neurons in reward-seeking, drug relapse and addiction.
外侧下丘脑是一个在历史上与奖赏和动机相关的脑区，但其中涉及的神经递质身份尚不清楚。食欲肽（或下丘脑泌素）是最近在外侧下丘脑神经元中被鉴定为神经递质的神经肽。尽管基因敲除和转基因过表达研究表明食欲肽神经元与觉醒和睡眠有关，但这些细胞也投射到与奖赏相关的脑区，包括伏隔核和腹侧被盖区。这表明这些神经元在奖赏功能和动机中可能发挥作用，这与之前将这些神经元与进食联系起来的研究一致。在这里，我们表明外侧下丘脑食欲肽神经元的激活与对与药物和食物奖赏相关线索的偏好密切相关。此外，我们表明外侧下丘脑食欲肽神经元的化学激活可恢复已消退的觅药行为。这种恢复效应被预先给予的食欲肽A拮抗剂完全阻断。此外，将食欲肽A肽直接注入腹侧被盖区也可恢复觅药行为。这些数据揭示了外侧下丘脑食欲肽神经元在寻求奖赏、药物复吸和成瘾中的新作用。
