Ruboxistaurin Reduces Cocaine-Stimulated Increases in Extracellular Dopamine by Modifying Dopamine-Autoreceptor...

Area of Science:

• Neuroscience
• Pharmacology
• Addiction Research

Background:

• Cocaine abuse is a global health issue with no current chemical therapies.
• Cocaine increases extracellular dopamine by blocking the dopamine transporter (DAT).
• Protein kinase Cβ (PKCβ) inhibitors like ruboxistaurin have shown effects on amphetamine-induced behaviors.

Purpose of the Study:

• To investigate the effect of ruboxistaurin on cocaine-stimulated dopamine overflow and locomotor activity.
• To determine if ruboxistaurin's mechanism of action involves dopamine D2 autoreceptors.

Main Methods:

• Microdialysis was used to measure dopamine overflow in the nucleus accumbens.
• Locomotor behavior was simultaneously recorded.
• Experiments involved direct perfusion of ruboxistaurin and raclopride (D2 antagonist) into the brain, and genetic deletion of D2 receptors.

Main Results:

• Ruboxistaurin (1 μM) reduced cocaine-stimulated dopamine overflow and locomotion.
• The effect of ruboxistaurin was abrogated by D2 receptor blockade with raclopride.
• Ruboxistaurin was ineffective in D2 receptor knockout mice, indicating a D2-dependent mechanism for cocaine but not amphetamine.

Conclusions:

• Inhibition of PKCβ reduces cocaine-induced dopamine overflow and locomotion via D2 autoreceptors.
• The mechanism differs from ruboxistaurin's effect on amphetamine-stimulated activity.
• PKCβ inhibition represents a potential therapeutic strategy for cocaine and amphetamine abuse.