Kuo Chi-Chung, Shen Hui, Harvey Brandon K, Yu Seong-Jin, Kopajtic Theresa, Hinkle Josh J, Kyrkanides Stephanos, Katz Jonathan L, Wang Yun
Intramural Research Program, National Institute on Drug Abuse, NIH, Baltimore, MD, 21224, USA.
Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli, Taiwan.
Psychopharmacology (Berl). 2016 Feb;233(4):661-72. doi: 10.1007/s00213-015-4134-4. Epub 2015 Nov 10.
Repeated administration of methamphetamine (Meth) induces behavioral sensitization which is characterized by a progressive increase in locomotor response after each injection. Previous studies have shown that Mu opioid receptors (MORs) can regulate Meth-mediated behavioral sensitization. However, the reported interactions are controversial; systemic activation of MORs either enhanced or suppressed Meth sensitization. It is possible that alteration of Meth sensitization after systemic administration of MOR ligands reflects the sum of distinct MOR reactions in multiple brain regions.
The purpose of the present study was to examine the actions of MORs on Meth sensitization after regionally selective overexpression of human MOR through an AAV6-based gene delivery system.
We demonstrated that adeno-associated virus (AAV)-MOR increased MOR immunoreactivity and binding in vitro. AAV-MOR or AAV-green fluorescent protein (GFP) was injected into the nucleus accumbens (NAc) or ventral tegmental area (VTA) of adult mice. Two weeks after viral infection, animals received Meth or saline for five consecutive days. Locomotor behavior and striatal dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) level were determined.
Repeated administration of Meth progressively increased locomotor activity; this sensitization reaction was attenuated by intra-NAc AAV-MOR microinjections. Infusion of AAV-MOR to VTA enhanced Meth sensitization. AAV-MOR significantly enhanced DA levels in VTA after VTA infection but reduced DOPAC/DA turnover in the NAc after NAc injection.
Our data suggest a differential modulation of Meth sensitization by overexpression of MOR in NAc and VTA. Regional manipulation of MOR expression through AAV may be a novel approach to control Meth abuse and psychomimetic activity.
重复给予甲基苯丙胺（冰毒）会诱发行为敏化，其特征是每次注射后运动反应逐渐增强。先前的研究表明，μ阿片受体（MORs）可调节冰毒介导的行为敏化。然而，所报道的相互作用存在争议；MORs的全身激活要么增强要么抑制冰毒敏化。全身给予MOR配体后冰毒敏化的改变可能反映了多个脑区不同MOR反应的总和。
本研究的目的是通过基于腺相关病毒6型（AAV6）的基因传递系统，在区域选择性过表达人MOR后，研究MORs对冰毒敏化的作用。
我们证明腺相关病毒（AAV）-MOR在体外增加了MOR免疫反应性和结合力。将AAV-MOR或AAV-绿色荧光蛋白（GFP）注射到成年小鼠的伏隔核（NAc）或腹侧被盖区（VTA）。病毒感染两周后，动物连续五天接受冰毒或生理盐水。测定运动行为以及纹状体多巴胺（DA）和3,4-二羟基苯乙酸（DOPAC）水平。
重复给予冰毒可逐渐增加运动活性；这种敏化反应通过NAc内注射AAV-MOR而减弱。向VTA注入AAV-MOR增强了冰毒敏化。VTA感染后，AAV-MOR显著提高了VTA中的DA水平，但NAc注射后降低了NAc中的DOPAC/DA周转率。
我们的数据表明，NAc和VTA中MOR的过表达对冰毒敏化有不同的调节作用。通过AAV对MOR表达进行区域操纵可能是控制冰毒滥用和拟精神病活性的一种新方法。
