Drug-induced neuroadaptations in the mPFC have been implicated in addictive behaviors. Repeated cocaine exposure has been shown to increase pyramidal neuron excitability in the prelimbic (PL) region of the mouse mPFC, an adaptation attributable to a suppression of G protein-gated inwardly rectifying K⁺ (GIRK) channel activity. After establishing that this neuroadaptation is not seen in adjacent GABA neurons, we used viral GIRK channel ablation and complementary chemogenetic approaches to selectively enhance PL pyramidal neuron excitability in adult mice, to evaluate the impact of this form of plasticity on PL-dependent behaviors. GIRK channel ablation decreased somatodendritic GABA_B receptor-dependent signaling and rheobase in PL pyramidal neurons. This manipulation also enhanced the motor-stimulatory effect of cocaine but did not impact baseline activity or trace fear learning. In contrast, selective chemogenetic excitation of PL pyramidal neurons, or chemogenetic inhibition of PL GABA neurons, increased baseline and cocaine-induced activity and disrupted trace fear learning. These effects were mirrored in male mice by selective excitation of PL pyramidal neurons projecting to the VTA, but not NAc or BLA. Collectively, these data show that manipulations enhancing the excitability of PL pyramidal neurons, and specifically those projecting to the VTA, recapitulate behavioral hallmarks of repeated cocaine exposure in mice.

SIGNIFICANCE STATEMENT Prolonged exposure to drugs of abuse triggers neuroadaptations that promote core features of addiction. Understanding these neuroadaptations and their implications may suggest interventions capable of preventing or treating addiction. While previous work showed that repeated cocaine exposure increased the excitability of pyramidal neurons in the prelimbic cortex (PL), the behavioral implications of this neuroadaptation remained unclear. Here, we used neuron-specific manipulations to evaluate the impact of increased PL pyramidal neuron excitability on PL-dependent behaviors. Acute or persistent excitation of PL pyramidal neurons potentiated cocaine-induced motor activity and disrupted trace fear conditioning, effects replicated by selective excitation of the PL projection to the VTA. Our work suggests that hyperexcitability of this projection drives key behavioral hallmarks of addiction.

mPFC 中药物诱导的神经适应与成瘾行为有关。重复接触可卡因已被证明会增加小鼠 mPFC 前缘 (PL) 区域的锥体神经元兴奋性，这种适应归因于抑制 G 蛋白门控向内整流 K ⁺ (GIRK) 通道活动。在确定这种神经适应在相邻的 GABA 神经元中没有出现后，我们使用病毒 GIRK 通道消融和互补的化学遗传方法来选择性地增强成年小鼠的 PL 锥体神经元兴奋性，以评估这种形式的可塑性对 PL 依赖性行为的影响。GIRK 通道消融减少体细胞树突 GABA _BPL锥体神经元中的受体依赖性信号传导和rheobase。这种操作还增强了可卡因的运动刺激作用，但不会影响基线活动或追踪恐惧学习。相比之下，PL 锥体神经元的选择性化学遗传激发，或 PL GABA 神经元的化学遗传抑制，增加了基线和可卡因诱导的活动，并破坏了微量恐惧学习。通过选择性激发投射到 VTA 而不是 NAc 或 BLA 的 PL 锥体神经元，这些效果在雄性小鼠中得到了反映。总的来说，这些数据表明，增强 PL 锥体神经元兴奋性的操作，特别是那些投射到 VTA 的操作，重现了小鼠反复接触可卡因的行为特征。

意义声明长期接触滥用药物会触发神经适应，从而促进成瘾的核心特征。了解这些神经适应及其影响可能表明干预措施能够预防或治疗成瘾。虽然以前的工作表明，反复接触可卡因会增加前边缘皮层 (PL) 锥体神经元的兴奋性，但这种神经适应的行为影响仍不清楚。在这里，我们使用特定于神经元的操作来评估增加的 PL 锥体神经元兴奋性对 PL 依赖行为的影响。PL 锥体神经元的急性或持续兴奋增强了可卡因诱导的运动活动，并破坏了微量恐惧条件反射，通过选择性激发 PL 投射到 VTA 来复制效果。