Johnston Caitlin E, Herschel Daniel J, Lasek Amy W, Hammer Ronald P, Nikulina Ella M
Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, AZ, USA.
Neuropharmacology. 2015 Feb;89:325-34. doi: 10.1016/j.neuropharm.2014.10.010.
Social defeat stress causes social avoidance and long-lasting cross-sensitization to psychostimulants, both of which are associated with increased brain-derived neurotrophic factor (BDNF) expression in the ventral tegmental area (VTA). Moreover, social stress upregulates VTA mu-opioid receptor (MOR) mRNA. In the VTA, MOR activation inhibits GABA neurons to disinhibit VTA dopamine neurons, thus providing a role for VTA MORs in the regulation of psychostimulant sensitization. The present study determined the effect of lentivirus-mediated MOR knockdown in the VTA on the consequences of intermittent social defeat stress, a salient and profound stressor in humans and rodents. Social stress exposure induced social avoidance and attenuated weight gain in animals with non-manipulated VTA MORs, but both these effects were prevented by VTA MOR knockdown. Rats with non-manipulated VTA MOR expression exhibited cross-sensitization to amphetamine challenge (1.0 mg/kg, i.p.), evidenced by a significant augmentation of locomotion. By contrast, knockdown of VTA MORs prevented stress-induced cross-sensitization without blunting the locomotor-activating effects of amphetamine. At the time point corresponding to amphetamine challenge, immunohistochemical analysis was performed to examine the effect of stress on VTA BDNF expression. Prior stress exposure increased VTA BDNF expression in rats with non-manipulated VTA MOR expression, while VTA MOR knockdown prevented stress-induced expression of VTA BDNF. Taken together, these results suggest that upregulation of VTA MOR is necessary for the behavioral and biochemical changes induced by social defeat stress. Elucidating VTA MOR regulation of stress effects on the mesolimbic system may provide new therapeutic targets for treating stress-induced vulnerability to substance abuse.
社会挫败应激会导致社交回避以及对精神兴奋剂产生持久的交叉致敏，这两者都与腹侧被盖区（VTA）中脑源性神经营养因子（BDNF）表达增加有关。此外，社会应激会上调VTAμ-阿片受体（MOR）的mRNA。在VTA中，MOR激活会抑制GABA能神经元，从而解除对VTA多巴胺能神经元的抑制，因此VTA中的MOR在精神兴奋剂致敏调节中发挥作用。本研究确定了慢病毒介导的VTA中MOR基因敲低对间歇性社会挫败应激后果的影响，间歇性社会挫败应激是人类和啮齿动物中一种显著且深刻的应激源。社会应激暴露会导致社交回避，并使VTA MOR未被操纵的动物体重增加减弱，但VTA MOR基因敲低可预防这两种效应。VTA MOR表达未被操纵的大鼠对苯丙胺激发（1.0 mg/kg，腹腔注射）表现出交叉致敏，表现为运动显著增强。相比之下，VTA MOR基因敲低可预防应激诱导的交叉致敏，而不会减弱苯丙胺的运动激活作用。在与苯丙胺激发对应的时间点，进行免疫组织化学分析以检查应激对VTA BDNF表达的影响。先前的应激暴露会增加VTA MOR表达未被操纵的大鼠的VTA BDNF表达，而VTA MOR基因敲低可预防应激诱导的VTA BDNF表达。综上所述，这些结果表明VTA MOR的上调对于社会挫败应激诱导的行为和生化变化是必要的。阐明VTA MOR对应激对中脑边缘系统影响的调节作用可能为治疗应激诱导的药物滥用易感性提供新的治疗靶点。
