Nonhuman primate neuroimaging and cocaine medication development.

Area of Science:

• Neuroscience
• Pharmacology
• Addiction Research

Background:

• The dopamine transporter (DAT) plays a crucial role in cocaine addiction.
• Developing compounds targeting DAT is a rational strategy for treating cocaine abuse.

Purpose of the Study:

• To evaluate the efficacy of DAT inhibitors in reducing cocaine self-administration in nonhuman primates.
• To assess the abuse liability of DAT inhibitors.
• To investigate the neurobiological mechanisms underlying the effects of DAT and SERT inhibitors on cocaine use.

Main Methods:

• Nonhuman primate models of cocaine self-administration.
• Drug substitution studies to assess abuse liability.
• Positron emission tomography (PET) neuroimaging to quantify DAT occupancy, brain drug uptake, and cerebral blood flow.
• Evaluation of selective serotonin transporter (SERT) inhibitors and combined DAT/SERT inhibition.

Main Results:

• Selective DAT inhibitors reduced cocaine use, with significant effects at high DAT occupancy (>70%).
• DAT inhibitors had lower reinforcing effects than cocaine.
• SERT inhibitors also reduced cocaine use and blocked cocaine-induced neurobiological changes.
• Combined DAT and SERT inhibition was more effective than DAT inhibition alone.

Conclusions:

• High DAT occupancy is necessary for DAT inhibitors to reduce cocaine self-administration.
• Combined inhibition of DAT and SERT presents a potentially effective therapeutic strategy for cocaine addiction treatment.