Effects of combined dopamine and serotonin transporter inhibitors on cocaine self-administration in rhesus monkeys.
Dopamine transporter (DAT) inhibitors may represent a promising class of drugs in the development of cocaine pharmacotherapies. In the present study, the effects of pretreatments with the selective DAT inhibitor 3beta-(4-chlorophenyl)tropane-2beta-[3-(4'-methylphenyl)isoxazol-5-yl] hydrochloride (RTI-336) (0.3-1.7 mg/kg) were characterized in rhesus monkeys trained to self-administer cocaine (0.1 and 0.3 mg/kg/injection) under a multiple second-order schedule of i.v. drug or food delivery. In addition, RTI-336 (0.01-1.0 mg/kg/injection) was substituted for cocaine to characterize its reinforcing effects. Last, the dose of RTI-336 that reduced cocaine-maintained behavior by 50% (ED(50)) was coadministered with the selective serotonin transporter (SERT) inhibitors fluoxetine (3.0 mg/kg) and citalopram (3.0 mg/kg) to characterize their combined effects on cocaine self-administration. PET neuroimaging with the selective DAT ligand [(18)F]8-(2-[(18)F]fluoroethyl)-2beta-carbomethoxy-3beta-(4-chlorophenyl)nortropane quantified DAT occupancy at behaviorally relevant doses of RTI-336. Pretreatments of RTI-336 produced dose-related reductions in cocaine self-administration, and the ED(50) dose resulted in approximately 90% DAT occupancy. RTI-336 was reliably self-administered, but responding maintained by RTI-336 was lower than responding maintained by cocaine. Doses of RTI-336 that maintained peak rates of responding resulted in approximately 62% DAT occupancy. Co-administration of the ED(50) dose of RTI-336 in combination with either SERT inhibitor completely suppressed cocaine self-administration without affecting DAT occupancy. Hence, at comparable levels of DAT occupancy, coadministration of SERT inhibitors with RTI-336 produced more robust reductions in cocaine self-administration compared with RTI-336 alone. Collectively, the results indicate that combined inhibition of DAT and SERT warrants consideration as a viable approach in the development of cocaine medications.
Howell
Leonard L
LL
Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA. leonard@rmy.emory.edu
Carroll
F Ivy
FI
Votaw
John R
JR
Goodman
Mark M
MM
Kimmel
Heather L
HL
D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology; D008253:Macaca mulatta; D008297:Male; D012646:Self Administration; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D014326:Tropanes / Q000097:blood / Q000494:pharmacology
D003042:Cocaine; D050483:Dopamine Plasma Membrane Transport Proteins; D005473:Fluoxetine; D017367:Selective Serotonin Reuptake Inhibitors; D014326:Tropanes; C506585:3beta-(4-chlorophenyl) tropane-2beta-(3-(4'-methylphenyl) isoxazol-5-yl) hydrochloride