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

Abstract

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␤-carbomethoxy-3␤-(4-fluorophenyl)tropane (WIN 35,428), were compared quantitatively with the combinations of cocaine with the N-butyl,4Ј,4Љ-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 ϳ700% 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.

2-Substituted 3 -Aryltropane Cocaine Analogs Produce Atypical Effects without Inducing Inward-Facing Dopamine Transporter Conformations

“…Many of the BZT analogs have muscarinic M 1 antagonist effects (Tanda et al, 2009), an off-target action thought by some to interfere with cocaine-like effects (Tanda et al, 2009;Reith et al, 2015). The present compounds have appreciably lower M 1 affinity, and results here are consistent with previous results showing that atypical DAT inhibitors can have effects different from cocaine without having affinity for M 1 receptors (Tanda et al, 2009;Reith et al, 2015).…”

“…Standard DAT inhibitors block DA uptake and in laboratory animals stimulate locomotor activity, fully substitute for cocaine in subjects trained to discriminate cocaine from saline injections, and are self-administered (reviewed by Johanson and Fischman, 1989;Tanda et al, 2009;Schmitt et al, 2013). The relationship between DAT binding affinities and potencies for behavioral effects among DAT inhibitors is the basis for the hypothesis that inhibition of DA uptake mediated by actions at the DAT is the basis for the abuse liability of cocaine, and that compounds with affinity for the DAT will have behavioral effects like those of cocaine (Kuhar et al, 1991).…”

CTDP-32476: A Promising Agonist Therapy for Treatment of Cocaine Addiction

“…Also, CTDP-32476 pretreatment dose-dependently inhibited cocaine-taking and cocaine-seeking behavior, as assessed by cocaine selfadministration under both FR2 and PR reinforcement and by a shift in the cocaine self-administration dose-response curve, suggesting that a reduction in cocaine's rewarding effects may underlie the reduction of cocaine selfadministration after CTDP-32476 administration. This action and the underlying mechanisms may be different from those produced by other DAT inhibitors such as GBR-12909, PTT, and some RTI compounds, although they also dose-dependently inhibit cocaine self-administration and attenuate cocaine intake (Glowa et al, 1996;Howell and Wilcox, 2001;Kimmel et al, 2008;Negus et al, 2009;Rothman et al, 2008;Tanda et al, 2009). The precise mechanisms underlying such actions remain unclear.…”

Quantitative Methods for Assessing Drug Synergism

“…23,24 in which various combinations including cocaine and remifentanil were examined in protocols involving self-administration in monkeys. Tanda et al 25 examined combinations of cocaine and other dopamine uptake inhibitors in mice.…”

“…It is theoretically equivalent to isobolar analysis and is sometimes more readily applied to the experimental design that is used. For example, this author adopted this approach in a study 25 that examined dopamine release by the combination of cocaine and the cocaine analog, WIN 35,428. Each agent alone produces graded dose-effect results (enhanced dopamine concentration).…”