Instituto de Investigaciones en Salud, Universidad de Costa Rica, Costa Rica; Centro de Investigación en Neurociencias, Universidad de Costa Rica, Costa Rica.
Instituto de Investigaciones Psicológicas, Universidad de Costa Rica, Costa Rica; Centro de Investigación en Neurociencias, Universidad de Costa Rica, Costa Rica.
Eur J Pharmacol. 2021 Aug 5;904:174148. doi: 10.1016/j.ejphar.2021.174148. Epub 2021 May 5.
As drug addiction may result from pathological usurpations of learning and memory's neural mechanisms, we focused on the amphetamine-induced time-dependent neurochemical changes associated with neural plasticity. We used juvenile rats as the risk for drug abuse is higher during adolescence. Experiment 1 served to define the appropriate amphetamine dose and the neurochemical effects of a single administration. In experiment 2, rats received seven amphetamine or saline injections in the open-field test throughout a twelve-day period. We measured the mRNA levels of the brain-derived neurotrophic factor (BDNF), its tropomyosin receptor kinase B (TrkB), the cAMP response element-binding protein (CREB), the microRNA-132, the Rho GTPase-activating protein 32 (p250GAP), the corticotropin-releasing factor (CRF), and monoamines and amino-acids contents in the nucleus accumbens and the dorsal striatum 45, 90, and 180 min after the last injection. We found that amphetamine changed gene expression only at certain time points and in a dose and region-dependent manner. Repeated but not single administrations upregulated accumbal and striatal BDNF (180 min) and striatal pri-miR-132 (90 min) expression, while downregulated accumbal CREB levels (90 min). As only some drug users develop addiction, we compared brain parameters between low and high amphetamine responders. Prone subjects characterized by having reduced striatal 5-HT metabolism, higher accumbal BDNF and TrkB expression, and lower levels of CREB in the dorsal striatum and p250GAP in both regions. Thus, individual differences in drug-induced changes in neurotransmission and gene expression in nigrostriatal and mesolimbic dopaminergic pathways may underlie the plasticity adaptations associated with behavioral sensitization to amphetamine.
由于药物成瘾可能源于学习和记忆的神经机制的病理性篡夺，我们专注于与神经可塑性相关的安非他命诱导的时间依赖性神经化学变化。我们使用幼年大鼠作为药物滥用的风险在青春期更高。实验 1 用于确定适当的安非他命剂量和单次给药的神经化学效应。在实验 2 中，大鼠在 12 天的时间内接受了七次安非他命或生理盐水在开放场测试中的注射。我们测量了脑源性神经营养因子 (BDNF)、其原肌球蛋白受体激酶 B (TrkB)、cAMP 反应元件结合蛋白 (CREB)、microRNA-132、Rho GTPase 激活蛋白 32 (p250GAP)、促肾上腺皮质激素释放因子 (CRF) 以及核仁 accumbens 和背侧纹状体中的单胺和氨基酸含量。在最后一次注射后 45、90 和 180 分钟，我们发现安非他命仅在某些时间点以剂量和区域依赖的方式改变基因表达。重复但不是单次给药上调了伏隔核和纹状体 BDNF（180 分钟）和纹状体前 miR-132（90 分钟）的表达，而下调了伏隔核 CREB 水平（90 分钟）。由于只有一些药物使用者会成瘾，我们比较了低和高安非他命反应者之间的大脑参数。易感性个体的特征是纹状体 5-HT 代谢减少、伏隔核 BDNF 和 TrkB 表达增加、背侧纹状体 CREB 水平降低以及两个区域的 p250GAP 水平降低。因此，黑质纹状体和中脑边缘多巴胺能通路中神经传递和基因表达的药物诱导变化的个体差异可能是对安非他命行为敏感化相关的可塑性适应的基础。
