Margolis Elyssa B, Hjelmstad Gregory O, Bonci Antonello, Fields Howard L
Joint University of California San Francisco/University of California, Berkeley Bioengineering Graduate Group, San Francisco, California 94143-0775, USA.
J Neurosci. 2003 Nov 5;23(31):9981-6. doi: 10.1523/JNEUROSCI.23-31-09981.2003.
Dopaminergic neurons of the ventral tegmental area (VTA) play a critical role in motivation and reinforcement of goal-directed behaviors. Furthermore, excitation of these neurons has been implicated in the addictive process initiated by drugs such as morphine that act at the micro-opioid receptor (MOR). In contrast, kappa-opioid receptor (KOR) activation in the VTA produces behavioral actions opposite to those elicited by MOR activation. The mechanism underlying this functional opposition, however, is poorly understood. VTA neurons have been categorized previously as principal, secondary, or tertiary on the basis of electrophysiological and pharmacological characteristics. In the present study using whole-cell patch-clamp recordings, we demonstrate that a selective KOR agonist (U69593, 1 microm) directly inhibits a subset of principal and tertiary but not secondary neurons in the VTA. This KOR-mediated inhibition occurs via the activation of a G-protein-coupled inwardly rectifying potassium channel and is blocked by the selective KOR antagonist nor-Binaltorphimine (100 nm). Significantly, regardless of cell class, KOR-mediated inhibition was found only in tyrosine hydroxylase-immunoreactive and thus dopaminergic neurons. In addition, we found a subset of principal neurons that exhibited both disinhibition by a selective MOR agonist ([d-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin) (3 microm) and direct inhibition by KOR agonists. These results provide a cellular mechanism for the opposing behavioral effects of KOR and MOR agonists and shed light on how KORs might regulate the motivational effects of both natural rewards and addictive drugs.
腹侧被盖区（VTA）的多巴胺能神经元在动机形成和目标导向行为的强化中起着关键作用。此外，这些神经元的兴奋与由作用于微阿片受体（MOR）的药物（如吗啡）引发的成瘾过程有关。相反，VTA中κ-阿片受体（KOR）的激活产生与MOR激活所引发的行为相反的行为作用。然而，这种功能对立背后的机制尚不清楚。VTA神经元先前已根据电生理和药理学特征被分类为主要、次要或三级神经元。在本研究中，我们使用全细胞膜片钳记录表明，选择性KOR激动剂（U69593，1微摩尔）直接抑制VTA中主要和三级神经元的一个子集，但不抑制次要神经元。这种KOR介导的抑制通过激活一种G蛋白偶联内向整流钾通道而发生，并被选择性KOR拮抗剂nor-Binaltorphimine（100纳米）阻断。重要的是，无论细胞类型如何，KOR介导的抑制仅在酪氨酸羟化酶免疫反应阳性且因此为多巴胺能的神经元中发现。此外，我们发现了一个主要神经元子集，它们既表现出被选择性MOR激动剂（[d-Ala2，N-Me-Phe4，Gly-ol5]-脑啡肽）（3微摩尔）去抑制，又表现出被KOR激动剂直接抑制。这些结果为KOR和MOR激动剂相反的行为效应提供了一种细胞机制，并揭示了KOR如何调节自然奖赏和成瘾药物的动机效应。
