苯丙胺自我给药与多巴胺功能：Lewis大鼠和Fischer 344大鼠基因×环境相互作用的评估
Amphetamine self-administration and dopamine function: assessment of gene × environment interactions in Lewis and Fischer 344 rats.
作者信息
Meyer Andrew C, Bardo Michael T
机构信息
Department of Psychiatry, University of Vermont, UHC-SATC Room 1415, 1 So. Prospect Street, Burlington, VT, 05401, USA.
Department of Psychology, University of Kentucky, Lexington, KY, USA.
出版信息
Psychopharmacology (Berl). 2015 Jul;232(13):2275-85. doi: 10.1007/s00213-014-3854-1. Epub 2015 Jan 9.
RATIONALE
Previous research suggests both genetic and environmental influences on substance abuse vulnerability.
OBJECTIVES
The current work sought to investigate the interaction of genes and environment on the acquisition of amphetamine self-administration as well as amphetamine-stimulated dopamine (DA) release in nucleus accumbens shell using in vivo microdialysis.
METHODS
Inbred Lewis (LEW) and Fischer (F344) rat strains were raised in either an enriched condition (EC), social condition (SC), or isolated condition (IC). Acquisition of amphetamine self-administration (0.1 mg/kg/infusion) was determined across an incrementing daily fixed ratio (FR) schedule. In a separate cohort of rats, extracellular DA and the metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were measured in the nucleus accumbens shell following an acute amphetamine injection (1 mg/kg).
RESULTS
"Addiction-prone" LEW rats had greater acquisition of amphetamine self-administration on a FR1 schedule compared to "addiction-resistant" F344 rats when raised in the SC environment. These genetic differences were negated in both the EC and IC environments, with enrichment buffering against self-administration and isolation enhancing self-administration in both strains. On a FR5 schedule, the isolation-induced increase in amphetamine self-administration was greater in F344 than LEW rats. While no group differences were obtained in extracellular DA, gene × environment differences were obtained in extracellular levels of the metabolite DOPAC. In IC rats only, LEW rats showed attenuation in the amphetamine-induced decrease in DOPAC compared to F344 rats. IC LEW rats also had an attenuated DOPAC response to amphetamine compared to EC LEW rats.
CONCLUSIONS
The current results demonstrate gene × environment interactions in amphetamine self-administration and amphetamine-induced changes in extracellular DOPAC in nucleus accumbens (NAc) shell. However, the behavioral and neurochemical differences were not related directly, indicating that mechanisms independent of DA metabolism in NAc shell likely mediate the gene × environment effects in amphetamine self-administration.
理论依据
先前的研究表明，遗传和环境因素都会影响药物滥用易感性。
目的
当前的研究旨在利用体内微透析技术，研究基因与环境在苯丙胺自我给药以及伏隔核壳中苯丙胺刺激的多巴胺（DA）释放过程中的相互作用。
方法
将近交系Lewis（LEW）和Fischer（F344）大鼠品系分别饲养在丰富环境（EC）、社交环境（SC）或隔离环境（IC）中。通过递增的每日固定比率（FR）时间表来确定苯丙胺自我给药（0.1mg/kg/输注）的习得情况。在另一组大鼠中，在急性注射苯丙胺（1mg/kg）后，测量伏隔核壳中的细胞外DA和代谢物3,4-二羟基苯乙酸（DOPAC）。
结果
与“抗成瘾”的F344大鼠相比，当饲养在SC环境中时，“易成瘾”的LEW大鼠在FR1时间表上对苯丙胺自我给药的习得能力更强。在EC和IC环境中，这些遗传差异均消失，丰富环境对自我给药有缓冲作用，而隔离环境则增强了两个品系的自我给药能力。在FR5时间表上，隔离诱导的苯丙胺自我给药增加在F344大鼠中比LEW大鼠更大。虽然细胞外DA未观察到组间差异，但在代谢物DOPAC的细胞外水平上观察到了基因×环境差异。仅在IC大鼠中，与F344大鼠相比，LEW大鼠在苯丙胺诱导的DOPAC降低方面表现出减弱。与EC LEW大鼠相比，IC LEW大鼠对苯丙胺的DOPAC反应也减弱。
结论
当前结果表明，在苯丙胺自我给药以及伏隔核（NAc）壳中苯丙胺诱导的细胞外DOPAC变化方面存在基因×环境相互作用。然而，行为和神经化学差异并非直接相关，这表明独立于NAc壳中DA代谢的机制可能介导了苯丙胺自我给药中的基因×环境效应。
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