Darna Mahesh, Beckmann Joshua S, Gipson Cassandra D, Bardo Michael T, Dwoskin Linda P
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA.
Department of Psychology, University of Kentucky, Lexington, KY 40536, USA.
Brain Res. 2015 Mar 2;1599:115-25. doi: 10.1016/j.brainres.2014.12.034. Epub 2014 Dec 20.
Recent studies have reported that rats raised in an enriched condition (EC) have decreased dopamine transporter (DAT) function and expression in medial prefrontal cortex (mPFC), as well as increased d-amphetamine-induced glutamate release in nucleus accumbens compared to rats raised in an isolated condition (IC). In these previous studies, DAT function and expression were evaluated using mPFC pooled from four rats for each condition to obtain kinetic parameters due to sparse DAT expression in mPFC. In contrast, accumbal glutamate release was determined using individual rats. The current study extends the previous work and reports on the optimization of DAT and serotonin transporter (SERT) functional assays, as well as cell surface expression assays using both mPFC and orbitofrontal cortex (OFC) from individual EC or IC rats. In addition, the effect of d-amphetamine on glutamate release in mPFC and OFC of EC and IC rats was determined using in vivo microdialysis. Results show that environmental enrichment decreased maximal transport velocity (Vmax) for [(3)H]dopamine uptake in mPFC, but increased Vmax for [(3)H]dopamine uptake in OFC. Corresponding changes in DAT cell surface expression were not found. In contrast, Vmax for [(3)H]serotonin uptake and cellular localization of SERT in mPFC and OFC were not different between EC and IC rats. Further, acute d-amphetamine (2mg/kg, s.c.) increased extracellular glutamate concentrations in mPFC of EC rats only and in OFC of IC rats only. Overall, these results suggest that enrichment produces long-lasting alterations in mPFC and OFC DAT function via a trafficking-independent mechanism, as well as differential glutamate release in mPFC and OFC. Rearing-induced modulation of DAT function and glutamate release in prefrontal cortical subregions may contribute to the known protective effects of enrichment on drug abuse vulnerability.
最近的研究报告称，与饲养在隔离环境（IC）中的大鼠相比，饲养在丰富环境（EC）中的大鼠内侧前额叶皮质（mPFC）中的多巴胺转运体（DAT）功能和表达降低，伏隔核中由右旋苯丙胺诱导的谷氨酸释放增加。在这些先前的研究中，由于mPFC中DAT表达稀少，使用每种条件下从四只大鼠汇集的mPFC来评估DAT功能和表达，以获得动力学参数。相比之下，伏隔核谷氨酸释放是使用个体大鼠来测定的。当前的研究扩展了先前的工作，并报告了DAT和5-羟色胺转运体（SERT）功能测定的优化，以及使用来自个体EC或IC大鼠的mPFC和眶额皮质（OFC）进行的细胞表面表达测定。此外，使用体内微透析法测定了右旋苯丙胺对EC和IC大鼠mPFC和OFC中谷氨酸释放的影响。结果表明，环境丰富化降低了mPFC中[³H]多巴胺摄取的最大转运速度（Vmax），但增加了OFC中[³H]多巴胺摄取的Vmax。未发现DAT细胞表面表达有相应变化。相比之下，EC和IC大鼠之间mPFC和OFC中[³H]5-羟色胺摄取的Vmax以及SERT的细胞定位没有差异。此外，急性右旋苯丙胺（2mg/kg，皮下注射）仅增加了EC大鼠mPFC中以及仅IC大鼠OFC中的细胞外谷氨酸浓度。总体而言，这些结果表明，丰富化通过一种不依赖于转运的机制在mPFC和OFC中产生持久的DAT功能改变，以及mPFC和OFC中谷氨酸释放的差异。饲养诱导的前额叶皮质亚区域中DAT功能和谷氨酸释放的调节可能有助于丰富化对药物滥用易感性的已知保护作用。
