Potential Use of Slow-Onset Long-Acting Dopamine Transporter Inhibitors in the Treatment of Drug Dependence

The successful use of methadone, a long-acting opiate receptor agonist, in the treatment of opiate dependence suggests a potential use of slow-onset long-acting dopamine (DA) transporter (DAT) inhibitors in the treatment of psychostimulant addiction. To test this hypothesis, we have successfully developed a slow-onset long-acting DAT inhibitor called CTDP32, 467 (named by a NIDA Cocaine Treatment Development Program) and investigated its pharmacological action in animal models of addiction. We found that: (1) systemic administration of CTDP32, 476 (10-20 mg•kg^(-1), ip) produced a slow-onset long-lasting increase in extracellular DA in the nucleus accumbens (NAc); (2) drug naive rats did not self-administer CTDP32, 476, but reliably self-administered cocaine;(3) in cocaine self-administration rats, CTDP32, 476 maintained a low rate and irregular self-administration and displayed a distinction pattern of drug taking over time; (4) cocaine self-administration rats displayed lower break-point levels for CTDP32, 476 than for cocaine under a progressive-ratio reinforcement schedule; and finally; (5) pretreatment with the same doses of CTDP32, 476 produced a long-time (-24 h) reduction in cocaine self-administration in a dose-dependent manner. These findings suggest that: (1) CTDP32, 476 has lower addictive properties than cocaine; and (2) this compound or other slow-onset long-acting DAT inhibitors may have potential use for the treatment of addiction to cocaine or other psychostimulants.