Kaneda Katsuyuki, Deyama Satoshi, Li Xueting, Zhang Tong, Sasase Hitoki
Laboratory of Molecular Pharmacology, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University.
Nihon Yakurigaku Zasshi. 2020;155(3):135-139. doi: 10.1254/fpj.19147.
Stress potentiates craving for addictive drugs including cocaine. To elucidate neural mechanisms underlying this effect of stress, we developed an experimental paradigm combining cocaine-induced conditioned place preference (CPP) with a restraint stress. Acute restraint stress exposure immediately before posttest significantly increased cocaine CPP scores. It has been suggested that the extracellular noradrenaline (NA) level is increased by stress in the laterodorsal tegmental nucleus (LDT), which sends cholinergic projections to dopamine (DA) neurons in the ventral tegmental area (VTA), and medial prefrontal cortex (mPFC), which receives DA input from the VTA. Thus, we investigated the roles of NA in these brain regions. Intra-LDT injection of an α2 or a β adrenoceptor antagonist attenuated the stress-induced enhancement of cocaine CPP. In vitro whole-cell recordings revealed that α2 adrenoceptor stimulation reduced GABAergic inputs to LDT cholinergic neurons that were obtained from cocaine-, but not saline-, treated rats. On the other hand, α1, but not α2 or β, adrenoceptor stimulation excited mPFC pyramidal neurons. Intra-mPFC injection of an α1 adrenoceptor antagonist attenuated the stress-induced enhancement of cocaine CPP. Additionally, chemogenetic silencing of mPFC excitatory neurons also reduced the stress-induced enhancement of cocaine CPP. These findings suggest that stress-induced increases in neuronal activity of the LDT and mPFC may contribute to the enhancement of cocaine craving.
应激会增强对包括可卡因在内的成瘾性药物的渴望。为了阐明应激产生这种作用的神经机制，我们开发了一种将可卡因诱导的条件性位置偏爱（CPP）与束缚应激相结合的实验范式。在测试后立即进行急性束缚应激暴露显著提高了可卡因CPP评分。有人提出，应激会使外侧背盖核（LDT）中的细胞外去甲肾上腺素（NA）水平升高，LDT向腹侧被盖区（VTA）中的多巴胺（DA）神经元发出胆碱能投射，而内侧前额叶皮质（mPFC）则接收来自VTA的DA输入。因此，我们研究了NA在这些脑区中的作用。向LDT内注射α2或β肾上腺素能受体拮抗剂可减弱应激诱导的可卡因CPP增强效应。体外全细胞记录显示，α2肾上腺素能受体刺激减少了从可卡因处理而非生理盐水处理的大鼠获得的对LDT胆碱能神经元的GABA能输入。另一方面，α1肾上腺素能受体刺激而非α2或β肾上腺素能受体刺激可兴奋mPFC锥体神经元。向mPFC内注射α1肾上腺素能受体拮抗剂可减弱应激诱导的可卡因CPP增强效应。此外，mPFC兴奋性神经元的化学遗传学沉默也减少了应激诱导的可卡因CPP增强效应。这些发现表明，应激诱导的LDT和mPFC神经元活动增加可能有助于增强对可卡因的渴望。
