Combinations of Cocaine with Other Dopamine Uptake Inhibitors: Assessment of Additivity

Drugs that inhibit dopamine (DA) reuptake through actions at the dopamine transporter (DAT) have been proposed as candidates for development as pharmacotherapies for cocaine abuse. Accordingly, it is important to understand the potential pharmacological interactions of cocaine with other drugs acting at the DAT. Effects of combinations of cocaine with a cocaine analog, 2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane (WIN 35,428), were compared quantitatively with the combinations of cocaine with the N-butyl, 4',4 ''-diF benztropine analog, 3-(bis(4-fluorophenyl) methoxy)-8-butyl-8-azabicyclo[3.2.1] octane (JHW 007), to determine whether their effects on DA levels in the shell of the nucleus accumbens (NAC) in mice differed. Each of the drugs alone produced dose-related elevations in NAC DA levels. In contrast to the other drugs, JHW 007 was less effective, producing maximal effects that approached 400% of control versus similar to 700% with the other drugs. In addition, the JHW 007 dose-effect curve was not as steep as those for cocaine and WIN 35,428. Combinations of cocaine with its analog, WIN 35,428, were most often greater than those predicted based on dose additivity. In contrast, combinations of cocaine with JHW 007 were most often subadditive. This outcome is consistent with recent studies suggesting that structurally divergent DA uptake inhibitors bind to different domains of the DAT, which can result in different DAT conformations. The conformational changes occurring with JHW 007 binding may result in functional outcomes that alter its abuse liability and its effects in combination with cocaine.