Xu Haiyang, Das Sasmita, Sturgill Marc, Hodgkinson Colin, Yuan Qiaoping, Goldman David, Grasing Kenneth
Substance Abuse Research Laboratory, 151, Kansas City Veterans Affairs Medical Center, 4801 Linwood Boulevard, Kansas City, MO, 64128, USA.
Molecular Bio-Nanotechnology, Imaging and Therapeutic Research Unit, 151, Kansas City Veterans Affairs Medical Center, 4801 Linwood Boulevard, Kansas City, MO, 64128, USA.
Psychopharmacology (Berl). 2017 Aug;234(16):2475-2487. doi: 10.1007/s00213-017-4640-7. Epub 2017 May 26.
The low self-administration (LS)/Kgras (LS) and high self-administration (HS)/Kgras (HS) rat lines were generated by selective breeding for low- and high-intravenous cocaine self-administration, respectively, from a common outbred Wistar stock (Crl:WI). This trait has remained stable after 13 generations of breeding.
The objective of the present study is to compare cocaine preference, neurotransmitter release, and dopamine receptor activation in LS and HS rats.
Levels of dopamine, acetylcholine, and cocaine were measured in the nucleus accumbens (NA) shell of HS and LS rats by tandem mass spectrometry of microdialysates. Cocaine-induced locomotor activity and conditioned-place preference were compared between LS and HS rats.
HS rats displayed greater conditioned-place preference scores compared to LS and reduced basal extracellular concentrations of dopamine and acetylcholine. However, patterns of neurotransmitter release did not differ between strains. Low-dose cocaine increased locomotor activity in LS rats, but not in HS animals, while high-dose cocaine augmented activity only in HS rats. Either dose of cocaine increased immunoreactivity for c-Fos in the NA shell of both strains, with greater elevations observed in HS rats. Activation identified by cells expressing both c-Fos and dopamine receptors was generally greater in the HS strain, with a similar pattern for both D1 and D2 dopamine receptors.
Diminished levels of dopamine and acetylcholine in the NA shell, with enhanced cocaine-induced expression of D1 and D2 receptors, are associated with greater rewarding effects of cocaine in HS rats and an altered dose-effect relationship for cocaine-induced locomotor activity.
低自我给药（LS）/Kgras（LS）和高自我给药（HS）/Kgras（HS）大鼠品系分别通过从普通远交Wistar种群（Crl:WI）中对低剂量和高剂量静脉注射可卡因自我给药进行选择性育种而产生。经过13代繁殖后，这一特性一直保持稳定。
本研究的目的是比较LS和HS大鼠对可卡因的偏好、神经递质释放和多巴胺受体激活情况。
通过对微透析液进行串联质谱分析，测量HS和LS大鼠伏隔核（NA）壳中的多巴胺、乙酰胆碱和可卡因水平。比较LS和HS大鼠之间可卡因诱导的运动活动和条件性位置偏好。
与LS大鼠相比，HS大鼠表现出更高的条件性位置偏好得分，且多巴胺和乙酰胆碱的基础细胞外浓度降低。然而，不同品系之间神经递质释放模式没有差异。低剂量可卡因增加了LS大鼠的运动活动，但对HS大鼠没有影响，而高剂量可卡因仅增加了HS大鼠的活动。两种剂量的可卡因均增加了两个品系NA壳中c-Fos的免疫反应性，HS大鼠中升高更为明显。在HS品系中，由同时表达c-Fos和多巴胺受体的细胞所确定的激活通常更强，D1和D2多巴胺受体的模式相似。
NA壳中多巴胺和乙酰胆碱水平降低，同时可卡因诱导的D1和D2受体表达增强，与HS大鼠中可卡因更强的奖赏效应以及可卡因诱导的运动活动剂量-效应关系改变有关。
