PDF(Pubmed)
Abstract：
Addiction is a complex behavioral disorder characterized by compulsive drug-seeking and drug use despite harmful consequences. The prefrontal cortex (PFC) plays a crucial role in cocaine addiction, involving decision-making, impulse control, memory, and emotional regulation. The PFC interacts with the brain\'s reward system, including the ventral tegmental area (VTA) and nucleus accumbens (NAc). The PFC also projects to the lateral habenula (LHb), a brain region critical for encoding negative reward and regulating the reward system. In the current study, we examined the role of PFC-LHb projections in regulating cocaine reward-related behaviors. We found that optogenetic stimulation of the PFC-LHb circuit during cocaine conditioning abolished cocaine preference without causing aversion. In addition, increased c-fos expression in LHb neurons was observed in animals that received optic stimulation during cocaine conditioning, supporting the circuit\'s involvement in cocaine preference regulation. Molecular analysis in animals that received optic stimulation revealed that cocaine-induced alterations in the expression of GluA1 subunit of AMPA receptor was normalized to saline levels in a region-specific manner. Moreover, GluA1 serine phosphorylation on S845 and S831 were differentially altered in LHb and VTA but not in the PFC. Together these findings highlight the critical role of the PFC-LHb circuit in controlling cocaine reward-related behaviors and shed light on the underlying mechanisms. Understanding this circuit\'s function may provide valuable insights into addiction and contribute to developing targeted treatments for substance use disorders.
摘要：
成瘾是一种复杂的行为障碍，其特征是尽管有有害后果，但仍强迫性寻求毒品和吸毒。前额叶皮层（PFC）在可卡因成瘾中起着至关重要的作用，涉及决策，脉冲控制,记忆,和情绪调节。PFC与大脑的奖励系统相互作用，包括腹侧被盖区（VTA）和伏隔核（NAc）。PFC还投射到外侧habenula（LHb），对编码负面奖励和调节奖励系统至关重要的大脑区域。在目前的研究中,我们研究了PFC-LHb预测在调节可卡因奖励相关行为中的作用.我们发现，可卡因调节过程中PFC-LHb回路的光遗传学刺激消除了可卡因的偏爱，而不会引起厌恶。此外,在可卡因调理期间接受视神经刺激的动物中观察到LHb神经元中c-fos表达增加，支持赛道参与可卡因偏好监管。接受视神经刺激的动物的分子分析表明，可卡因诱导的AMPA受体GluA1亚基表达的改变以区域特异性方式标准化为盐水水平。此外，S845和S831上的GluA1丝氨酸磷酸化在LHb和VTA中差异改变，但在PFC中未改变。这些发现共同强调了PFC-LHb电路在控制可卡因奖励相关行为中的关键作用，并阐明了潜在的机制。了解该电路的功能可能会提供对成瘾的有价值的见解，并有助于开发针对物质使用障碍的有针对性的治疗方法。
