Clinical studies have reported that the psychedelic lysergic acid diethylamide (LSD) enhances empathy and social behavior (SB) in humans, but its mechanism of action remains elusive. Using a multidisciplinary approach including in vivo electrophysiology, optogenetics, behavioral paradigms, and molecular biology, the effects of LSD on SB and glutamatergic neurotransmission in the medial prefrontal cortex (mPFC) were studied in male mice. Acute LSD (30 μg/kg) injection failed to increase SB. However, repeated LSD (30 μg/kg, once a day, for 7 days) administration promotes SB, without eliciting antidepressant/anxiolytic-like effects. Optogenetic inhibition of mPFC excitatory neurons dramatically inhibits social interaction and nullifies the prosocial effect of LSD. LSD potentiates the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and 5-HT_2A, but not N-methyl-D-aspartate (NMDA) and 5-HT_1A, synaptic responses in the mPFC and increases the phosphorylation of the serine-threonine protein kinases Akt and mTOR. In conditional knockout mice lacking Raptor (one of the structural components of the mTORC1 complex) in excitatory glutamatergic neurons (Raptor^f/f:Camk2alpha-Cre), the prosocial effects of LSD and the potentiation of 5-HT_2A/AMPA synaptic responses were nullified, demonstrating that LSD requires the integrity of mTORC1 in excitatory neurons to promote SB. Conversely, in knockout mice lacking Raptor in GABAergic neurons of the mPFC (Raptor^f/f:Gad2-Cre), LSD promotes SB. These results indicate that LSD selectively enhances SB by potentiating mPFC excitatory transmission through 5-HT_2A/AMPA receptors and mTOR signaling. The activation of 5-HT_2A/AMPA/mTORC1 in the mPFC by psychedelic drugs should be explored for the treatment of mental diseases with SB impairments such as autism spectrum disorder and social anxiety disorder.

临床研究报告说，迷幻的麦角酸二乙酰胺（LSD）增强了人类的移情和社交行为（SB），但其作用机理仍然难以捉摸。使用包括体内电生理学，光遗传学，行为范式和分子生物学在内的多学科方法，研究了雄性小鼠中LSD对内侧前额叶皮层（mPFC）中SB和谷氨酸能神经传递的影响。急性LSD（30μg/ kg）注射未能增加SB。但是，反复服用LSD（30μg/ kg，每天一次，连续7天）可促进SB，而不会引起抗抑郁/抗焦虑作用。mPFC兴奋性神经元的光遗传学抑制作用极大地抑制了社交互动，并使LSD的亲社会作用无效。LSD增强了丙酸α-氨基-3-羟基-5-羟基-5-甲基-4-异恶唑（AMPA）和5-HT_在图2A中，但不是在N-甲基-D-天冬氨酸（NMDA）和5-HT _1A中，mPFC中的突触反应增加了丝氨酸-苏氨酸蛋白激酶Akt和mTOR的磷酸化。在兴奋性谷氨酸能神经元（Raptor ^{f / f}：Camk2alpha-Cre）中缺乏Raptor（mTORC1复合物的结构成分之一）的条件敲除小鼠中，LSD的亲社会作用和5-HT _2A / AMPA突触反应的增强是无效，表明LSD需要兴奋性神经元中mTORC1的完整性来促进SB。相反，在敲除小鼠的mPFC的GABA能神经元中缺少Raptor（Raptor ^{f / f}：Gad2-Cre），LSD会提升SB。这些结果表明，LSD通过增强通过5-HT _2A / AMPA受体的mPFC兴奋性传递和mTOR信号传导来选择性增强SB 。迷幻药应激活mPFC中的5-HT _2A / AMPA / mTORC1，以治疗患有SB障碍的精神疾病，例如自闭症谱系障碍和社交焦虑症。