Cocaine Antagonists; Studies on Cocaine Self-Administration

Abstract

EditorialA series of recent studies by Dr. Jonathan Katz demonstrated preclinical efficacy of several compounds functioning as a cocaine antagonist using a drug self-administration procedure in rats. For example, 1) the atypical dopamine uptake inhibitors ( Figure 1) JHW 007, AHN 2-005 [1,2], and , and 2) the σ receptor (σR) antagonist (Figure 2) rimcazole and its analogues , all were able to shift dose-effect curves of cocaine self-administration down in a dose-dependent fashion when pre-treated.Their dose-dependent insurmountable antagonism of cocaine self-administration was relatively specific because comparable responding maintained by presentations of food pellets was insensitive to active doses of these compounds that decreased maximal responding maintained by cocaine injection [1][2][3][4]. The pattern of antagonism was similar to effects of the μ-opioid agonist methadone on heroin self-administration since methadone can also produce a dose-dependent insurmountable antagonism of heroin self-administration [5]. On the other hand, none of them maintained self-administration responding above vehicle levels when substituted cocaine [1,3,4], d-methamphetamine, heroin or ketamine [5]. However, the pattern of substitution was different from that of methadone since methadone can substitute for heroin or d-methamphetamine [5]. An excellent review article recently discussed potential mechanisms underlying their action as a cocaine antagonist [6]. There are several relatively viable mechanisms underlying their cocaine-antagonist effect. Dopamine Transporter (DAT)/σ R Dual InhibitionPretreatment with standard dopamine uptake inhibitors alone (Figure 3) shifted the doseeffect curves of cocaine self-administration to the left (i.e. potentiation) in a dose-dependent manner [1,3,4,7,8] while that of σR antagonists was virtually without effects on cocaine selfadministration [4,9-11].However, pretreatment with a σR antagonist dose-dependently shifted down dose-effect curves of cocaine self-administration when combined with a standard dopamine uptake inhibitor [4]. Thus it appears that DAT/σR dual inhibition can result in an insurmountableThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. HHS Public AccessAuthor manuscript J Alcohol Drug Depend. Author manuscript; available in PMC 2016 July 07. Author Manuscript Author ManuscriptAuthor Manuscript Author Manuscriptantagonism of reinforcing effects of cocaine. Interestingly all above-referenced compounds function as a cocaine antagonist except RTI-371, which also have considerable affinity to the DAT as well as σ1Rs (Table 1) relative to the standard dopamine uptake inhibitors except RTI-336.However, the atypical dopamine uptake inhibitor RTI-371 and the standard dopamine uptake inhibitor RTI-336 both commonly have high affinity to the DAT as well as σ2Rs, and low affinity to σ1Rs (Table 1) ...

DAT Conformation Does Not Predict the Ability of Atypical Dopamine Uptake Inhibitors to Substitute for Cocaine

“…These include the atypical DA uptake inhibitors, JHW 007 and RTI-371 [2,3,7]. The attributes that contribute to their atypical effects as DA reuptake inhibitors are unknown but there are several relatively viable hypotheses that address this issue [10,11]. One of such hypotheses is that conformational differences may affect DAT binding.…”

“…Differences in kinetic variables and DAT/σ-receptor dual inhibition are two remaining relative viable hypotheses for addressing the mechanisms underlying the reduced cocaine-like effects of atypical DA reuptake inhibitors [10,11,13]. Future studies to explore these two hypotheses should facilitate the development of effective medication(s) for cocaine abuse.…”