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Uncoupling nNOS-PSD-95 in mPFC inhibits morphine priming-induced reinstatement after extinction training

Xiao-Lin Kou1, Yan Tao1, Jia-Yun Xian1

  • 1Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, People's Republic of China.

Biochemical and Biophysical Research Communications
|March 2, 2020
PubMed

Insights

Drug relapse is a major challenge. Scientists found that blocking the link between nNOS and PSD-95 in the medial prefrontal cortex can prevent morphine relapse in mice, potentially by restoring CREB function.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Pharmacology

Background:

  • Drug abuse relapse rates remain critically high, posing a significant public health challenge.
  • Environmental cues are known triggers for relapse, but the underlying molecular mechanisms are not fully understood.
  • The medial prefrontal cortex (mPFC) is implicated in drug-seeking behaviors and relapse.

Purpose of the Study:

  • To investigate the role of neuronal nitric oxide synthase (nNOS) and postsynaptic density-95 (PSD-95) coupling in the mPFC in morphine relapse.
  • To explore the potential of targeting the nNOS-PSD-95 interaction to prevent drug-induced reinstatement.

Main Methods:

  • Utilized a morphine conditioned place preference (CPP) model in mice.
  • Examined nNOS-PSD-95 coupling and c-Fos expression in the mPFC after morphine CPP extinction.
  • Administered ZL006 to dissociate nNOS-PSD-95 and assessed its effect on morphine-priming-induced reinstatement.
  • Investigated the impact on cAMP-response element binding protein (CREB) phosphorylation in the mPFC.

Main Results:

  • Morphine CPP extinction led to increased nNOS-PSD-95 coupling and c-Fos expression in the mPFC.
  • Dissociation of nNOS-PSD-95 by ZL006 significantly inhibited the reinstatement of morphine CPP.
  • Morphine exposure after extinction training resulted in reduced CREB phosphorylation, which was reversed by uncoupling nNOS-PSD-95.
  • The effects of ZL006 were dependent on its interaction with nNOS-PSD-95.

Conclusions:

  • The nNOS-PSD-95 interaction in the mPFC is crucial for the reinstatement of morphine-induced CPP.
  • Disrupting this interaction may prevent relapse by normalizing CREB dysfunction.
  • Targeting the nNOS-PSD-95 pathway presents a potential therapeutic strategy for preventing drug abuse relapse.
Keywords:
CPPCREBMedial prefrontal cortexMorphineZL006nNOS-PSD-95

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