Baimel Corey, Borgland Stephanie L
Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada, and Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada
J Neurosci. 2015 May 6;35(18):7295-303. doi: 10.1523/JNEUROSCI.4385-14.2015.
Dopamine neurons in the ventral tegmental area (VTA) are a key target of addictive drugs, and neuroplasticity in this region may underlie some of the core features of addiction. From the very first exposure, all drugs of abuse induce synaptic plasticity in the VTA. However, it is not well understood how this diverse group of drugs brings about common synaptic change. Orexin (also known as hypocretin) is a lateral hypothalamic neuropeptide released into the VTA that promotes drug-seeking behaviors and potentiates excitatory synaptic transmission onto VTA dopamine neurons. Here we show that signaling at orexin receptor type 1 (OxR1) in the VTA is required for morphine-induced plasticity of dopamine neurons. Systemic or intra-VTA administration of the OxR1 antagonist SB 334867 in rats blocked a morphine-induced increase in the AMPAR/NMDAR ratio, an increase in presynaptic glutamate release, and a postsynaptic change in AMPAR number or function, including a switch in subunit composition. Furthermore, SB 334867 blocked a morphine-induced decrease in presynaptic GABA release, and a morphine-induced shift in the balance of excitatory and inhibitory synaptic inputs to dopamine neurons. These findings identify a novel role for orexin in morphine-induced plasticity in the VTA and provide a mechanism by which orexin can gate the output of dopamine neurons.
腹侧被盖区（VTA）中的多巴胺神经元是成瘾性药物的关键作用靶点，该区域的神经可塑性可能是成瘾一些核心特征的基础。从首次接触开始，所有滥用药物都会在VTA中诱导突触可塑性。然而，目前尚不清楚这类不同的药物是如何导致共同的突触变化的。食欲素（也称为下丘脑泌素）是一种从下丘脑外侧释放到VTA的神经肽，它促进觅药行为并增强对VTA多巴胺神经元的兴奋性突触传递。在此我们表明，VTA中1型食欲素受体（OxR1）的信号传导是吗啡诱导多巴胺神经元可塑性所必需的。在大鼠中全身或VTA内给予OxR1拮抗剂SB 334867可阻断吗啡诱导的AMPAR/NMDAR比值增加、突触前谷氨酸释放增加以及AMPAR数量或功能的突触后变化，包括亚基组成的转换。此外，SB 334867可阻断吗啡诱导的突触前GABA释放减少以及吗啡诱导的多巴胺神经元兴奋性和抑制性突触输入平衡的改变。这些发现确定了食欲素在VTA中吗啡诱导的可塑性中的新作用，并提供了一种食欲素可调节多巴胺神经元输出的机制。
