Led by Leonard Howell, PhD, an associate professor in Yerkes' Neuroscience Division, the Yerkes researchers observed the innovative combination of dopamine transporter (DAT) inhibition and serotonin transporter (SERT) inhibition was effective in limiting cocaine use in rhesus macaques who are trained to self-administer cocaine. "It appears DAT inhibition serves to substitute for cocaine, while SERT inhibition may limit the abuse potential of the medication," said Howell. "Our results, therefore, showing a combination of DAT and SERT inhibition were more effective than either alone are very promising."
This first-time finding was the promising end result of a several-step process. Howell and his colleagues began by administering a pretreatment of DAT inhibitors to confirm their effectiveness in reducing drug use. DAT inhibitors have long been used in addiction studies because they elicit reinforcing properties in the brain similar to those experienced as a result of taking cocaine.
The research team then substituted the DAT inhibitors for cocaine in order to determine their effectiveness in maintaining the use of the medications. Finally, Howell and the team administered a pretreatment with combined DAT inhibition and SERT inhibition, which is known to block the chemical effects of cocaine in the brain and reduce addictive properties, to determine if cocaine use was further reduced. "Pretreatments with the combination therapy were very effective in eliminating cocaine use. Moreover, drug substitution tests with the medication indicated it should have limited abuse potential in humans," added Howell.
The research was supported by the U.S. Public Health Service and the National Institutes of Health.
At the annual meeting of the College of Problems of Drug Dependence in San Juan, Puerto Rico, Howell will present a subsequent study in which his team determined fluoxetine (Prozac), a SERT inhibitor, enhanced the effectiveness of a DAT inhibitor in reducing cocaine self-administration.
Howell's next step is to determine an optimal dosing level for this combination strategy in order to develop the best potential treatment for cocaine addiction.
