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Assessment of Cocaine-induced Behavioral Sensitization and Conditioned Place Preference in Mice
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P53 knockout mice are protected from cocaine-induced kindling behaviors via inhibiting mitochondrial oxidative

Huynh Nhu Mai1, Naveen Sharma1, Ji Hoon Jeong2

  • 1Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, 24341, Republic of Korea.

Neurochemistry International
|January 1, 2019
PubMed

Insights

The tumor suppressor protein p53 plays a key role in cocaine-induced neurotoxicity. Depleting p53 reduces seizures and protects the brain by mitigating mitochondrial dysfunction and apoptosis.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Pharmacology

Background:

  • The tumor suppressor protein p53 is known to mediate dopaminergic neurotoxicity.
  • The role of p53 in psychostimulant-induced excitotoxicity, like that from cocaine, remains largely unexplored.

Purpose of the Study:

  • To investigate the involvement of p53 in cocaine-induced neurotoxicity and associated behavioral and molecular changes.
  • To determine if p53 depletion offers neuroprotection against cocaine-induced excitotoxicity.

Main Methods:

  • Mice lacking the p53 gene were used to assess cocaine-induced behaviors and molecular alterations.
  • Levels of p53 expression, c-Fos immunoreactivity, oxidative stress markers, and mitochondrial function were analyzed.
  • Mitochondrial p53 translocation and apoptotic markers were evaluated in response to cocaine exposure.

Main Results:

  • Cocaine administration significantly increased p53 expression, particularly in the hippocampus.
  • Genetic depletion of p53 markedly reduced cocaine-induced convulsive behaviors and neuroinflammation.
  • p53 deficiency attenuated mitochondrial dysfunction, oxidative stress, and apoptosis signaling pathways triggered by cocaine.

Conclusions:

  • p53 plays a critical role in mediating the neurotoxic effects of cocaine.
  • Depleting p53 confers significant anticonvulsant and neuroprotective effects against cocaine-induced excitotoxicity.
  • These protective effects are primarily mediated by reducing mitochondrial oxidative burden and inhibiting pro-apoptotic signaling.
Keywords:
Cocaine-kindling (convulsive) behaviorsHippocampusMitochondrial dysfunctionOxidative stressPro-apoptosisp53 knockout mice

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