PKMζ alters oxycodone-taking in a dose- and sex-dependent manner

Area of Science:

• Neuroscience
• Molecular Biology
• Pharmacology

Background:

• Opioid use disorder disrupts glutamate homeostasis and dendritic spine density in the brain's reward system.
• Protein kinase M zeta (PKMζ), an atypical protein kinase C isoform, is crucial for postsynaptic glutamate signaling and dendritic spine maturation.

Purpose of the Study:

• To investigate the role of PKMζ in opioid-taking behaviors by examining oxycodone self-administration in PKMζ knockout mice.
• To determine sex-specific differences in the effects of PKMζ deletion on opioid use.

Main Methods:

• Two doses of oxycodone self-administration were tested in male and female mice with constitutive PKMζ deletion (knockout) and wildtype controls.
• Progressive ratio schedules assessed motivation for oxycodone.
• Locomotor activity and sensitization in response to oxycodone were measured.

Main Results:

• PKMζ deletion potentiated oxycodone self-administration at 0.25 mg/kg/infusion in both sexes.
• Increased motivation (higher breakpoint) for oxycodone was observed in male PKMζ knockout mice at 0.25 mg/kg/infusion.
• At 0.125 mg/kg/infusion, PKMζ knockout increased oxycodone self-administration and motivation specifically in female mice.
• PKMζ deletion decreased oxycodone-induced locomotion in males but potentiated it in females.

Conclusions:

• PKMζ plays a dampening role in oxycodone intake and motivation.
• Females exhibit greater sensitivity to the effects of PKMζ deletion on oxycodone-related behaviors.
• These findings highlight PKMζ as a potential therapeutic target for opioid use disorder, with sex-specific considerations.