跨代证据表明啮齿动物多巴胺 D2 受体敏感性增加：对感觉运动门控、尼古丁和 BDNF 的行为反应的影响。
Transgenerational evidence of increases in dopamine D2 receptor sensitivity in rodents: Impact on sensorimotor gating, the behavioral response to nicotine and BDNF.
机构信息
James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.
Translational Science Laboratory, Florida State University College of Medicine, Tallahassee, FL, USA.
出版信息
J Psychopharmacol. 2021 Oct;35(10):1188-1203. doi: 10.1177/02698811211033927. Epub 2021 Jul 22.
BACKGROUND/AIMS: Neonatal quinpirole (NQ) treatment to rats increases dopamine D (DAD) receptor sensitivity in adult animals. We investigated if increased DAD sensitivity would be passed to the next (F1) generation, and if these animals demonstrated sensorimotor gating deficits and enhanced behavioral responses to nicotine.
METHODS
Male and female rats were intraperitoneal (IP) administered quinpirole (1 mg/kg) or saline (NS) from postnatal day (P)1-21. Animals were either behaviorally tested (F0) or raised to P60 and mated, creating F1 offspring.
RESULTS
Experiment 1 revealed that F1 generation animals that were the offspring of at least one NQ-treated founder increased yawning behavior, a DAD-mediated behavioral event, in response to acute quinpirole (0.1 mg/kg). F1 generation rats also demonstrated increased striatal β arrestin-2 and decreased phospho-AKT signaling, consistent with increased G-protein independent DAD signaling, which was equal to F0 NQ-treated founders, although this was not observed in all groups. RNA-Seq analysis revealed significant gene expression changes in the F1 generation that were offspring of both NQ-treated founders compared to F0 NQ founders and controls, with enrichment in sensitivity to stress hormones and cell signaling pathways. In Experiment 2, all F1 generation offspring demonstrated sensorimotor gating deficits compared to controls, which were equivalent to F0 NQ-treated founders. In Experiment 3, all F1 generation animals demonstrated enhanced nicotine behavioral sensitization and nucleus accumbens (NAcc) brain-derived neurotrophic factor (BDNF) protein. Further, F1 generation rats demonstrated enhanced adolescent nicotine conditioned place preference equivalent to NQ-treated founders conditioned with nicotine.
CONCLUSIONS
This represents the first demonstration of transgenerational effects of increased DAD sensitivity in a rodent model.
背景/目的：新生期腹腔注射喹吡罗（NQ）可增加成年动物多巴胺 D（DAD）受体的敏感性。我们研究了这种 DAD 敏感性增加是否会传递给下一代（F1），以及这些动物是否表现出感觉运动门控缺陷和对尼古丁的增强行为反应。
方法
雄性和雌性大鼠在出生后第 1-21 天接受腹腔内（IP）喹吡罗（1mg/kg）或生理盐水（NS）注射。动物进行行为测试（F0）或饲养至 60 天并交配，产生 F1 后代。
结果
实验 1 表明，至少有一个 NQ 处理的亲代所产生的 F1 代动物对急性喹吡罗（0.1mg/kg）的哈欠行为增加，这是一种 DAD 介导的行为事件。F1 代大鼠还表现出纹状体β-arrestin-2 增加和磷酸化 AKT 信号减少，这与 G 蛋白非依赖性 DAD 信号增加一致，与 F0 NQ 处理的亲代相当，尽管并非所有组都观察到这种情况。RNA-Seq 分析显示，与 F0 NQ 亲代和对照组相比，F1 代的许多基因表达发生了显著变化，这些变化与应激激素和细胞信号通路的敏感性增加有关。在实验 2 中，与对照组相比，所有 F1 代后代都表现出感觉运动门控缺陷，与 F0 NQ 处理的亲代相当。在实验 3 中，所有 F1 代动物都表现出增强的尼古丁行为敏化和伏隔核（NAcc）脑源性神经营养因子（BDNF）蛋白。此外，F1 代大鼠表现出增强的青少年尼古丁条件性位置偏好，与用尼古丁处理的 NQ 处理亲代相当。
结论
这代表了在啮齿动物模型中首次证明 DAD 敏感性增加的跨代效应。
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