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<p>Substance use disorder (SUD) represents a substantial challenge in neuropsychiatric medicine, with the molecular mechanisms underlying its etiology remaining elusive. The molecular underpinnings of SUD suggest a pivotal role for circular RNAs (circRNAs) in its pathophysiology. Herein, we present a study on <i>circHomer1</i>, a circRNA enriched in neurons, which is abnormal expression upon cocaine exposure. Employing models of repeated cocaine exposure and conditioning place preference (CPP), alongside virus-mediated gene regulation techniques, we revealed the contribution of <i>circHomer1</i> in cocaine-induced rewarding effects and synaptic adaptations. We found a notably downregulation of <i>circHomer1</i> expression in the prelimbic cortex consequent to repeated cocaine exposure in both rat model and patients with cocaine use disorder. Elevation of <i>circHomer1</i> levels resulted in a pronounced attenuation of cocaine-induced CPP, whereas suppression of <i>circHomer1</i> expression enhanced the rewarding effects. These outcomes were specifically observed in excitatory neurons, implicating a cell type-specific function of <i>circHomer1</i>. Furthermore, the restoration of <i>circHomer1</i> rescued the reduction of mushroom-type dendritic spines and rectified deficits in the frequency of spontaneous excitatory postsynaptic currents associated with prolonged cocaine exposure. Mechanistically, <i>circHomer1</i> appears to modulate cocaine-induced behavioral responses through dopamine D1 receptor signaling pathways. Notably, <i>circHomer1</i>’s behavioral effects showed specificity for psychostimulants (cocaine and methamphetamine), without affecting food- or opioid-associated rewards. Our findings highlight the significant role of <i>circHomer1</i> in regulating cocaine reward and identify a novel molecular regulator of the actions of cocaine on the brain’s reward circuitry, providing a new strategy for treating drug addiction.</p>

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Prefrontal circHomer1 regulates synaptic and behavioral adaptations induced by cocaine

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月8日

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  • Yun Chen,
  • Zhongyu Zhang,
  • Xianfeng Li,
  • Wenjun Chen,
  • Shihao Huang,
  • Guipeng Zhang,
  • Zhoulong Yu,
  • Libo Zhang,
  • Shiqiu Meng,
  • Jianfeng Liu,
  • Yan-Xue Xue,
  • Jie Shi

摘要

Substance use disorder (SUD) represents a substantial challenge in neuropsychiatric medicine, with the molecular mechanisms underlying its etiology remaining elusive. The molecular underpinnings of SUD suggest a pivotal role for circular RNAs (circRNAs) in its pathophysiology. Herein, we present a study on circHomer1, a circRNA enriched in neurons, which is abnormal expression upon cocaine exposure. Employing models of repeated cocaine exposure and conditioning place preference (CPP), alongside virus-mediated gene regulation techniques, we revealed the contribution of circHomer1 in cocaine-induced rewarding effects and synaptic adaptations. We found a notably downregulation of circHomer1 expression in the prelimbic cortex consequent to repeated cocaine exposure in both rat model and patients with cocaine use disorder. Elevation of circHomer1 levels resulted in a pronounced attenuation of cocaine-induced CPP, whereas suppression of circHomer1 expression enhanced the rewarding effects. These outcomes were specifically observed in excitatory neurons, implicating a cell type-specific function of circHomer1. Furthermore, the restoration of circHomer1 rescued the reduction of mushroom-type dendritic spines and rectified deficits in the frequency of spontaneous excitatory postsynaptic currents associated with prolonged cocaine exposure. Mechanistically, circHomer1 appears to modulate cocaine-induced behavioral responses through dopamine D1 receptor signaling pathways. Notably, circHomer1’s behavioral effects showed specificity for psychostimulants (cocaine and methamphetamine), without affecting food- or opioid-associated rewards. Our findings highlight the significant role of circHomer1 in regulating cocaine reward and identify a novel molecular regulator of the actions of cocaine on the brain’s reward circuitry, providing a new strategy for treating drug addiction.