Combined effects of phenmetrazine and nor‐binaltorphimine on dopamine function and motivation to self‐administer cocaine

Abstract

Despite numerous clinical trials, the FDA has not approved any medication assisted treatment for cocaine addiction. Our laboratory has shown that chronic cocaine self‐administration reduced overall dopamine (DA) neurotransmission, resulting in a hypodopaminergic state. Other studies have shown that repeated, non‐contingent cocaine exposure resulted in a hyper‐functioning kappa opioid receptor (KOR) system. Thus, this study aims to examine the effectiveness of a combination therapy, targeting the dopamine transporter and the KOR, in reducing cocaine‐seeking behaviors in rats chronically exposed to cocaine.In order to understand the impacts of cocaine self‐administration on the DA and KOR systems, we used ex vivo fast scan cyclic voltammetry in the nucleus accumbens core to examine DA dynamics after chronic cocaine exposure (40 infusions of cocaine for 5 consecutive days). We found that cocaine exposure reduced stimulated DA release and attenuated cocaine potency at the dopamine transporter. Additionally, we examined KOR function through activation of KORs using the agonist U50,488, which inhibited DA release. We observed that responses to U50,488 were augmented post‐cocaine exposure.Male Sprague Dawley rats were used to determine the individual and combined behavioral effects of the DA releaser phenmetrazine and the KOR antagonist nor‐binaltorphimine (nor‐BNI). After rats self‐administered forty infusions of cocaine (1.5 mg/kg/infusion) on a fixed‐ratio 1 schedule for five consecutive days, a progressive ratio schedule was used to determine cocaine breakpoints (0.1875 mg/kg/infusion) at baseline, and following phenmetrazine (25 mg/kg/day; osmotic mini‐pump), nor‐BNI (10 mg/kg; i.p.), or a combination of the two drugs. Administration of phenmetrazine alone significantly reduced breakpoints (60% of baseline), while nor‐BNI had no effect as a monotherapy. Interestingly, cocaine breakpoints were further attenuated by the combination (20% of baseline), indicating augmented effects of targeting both the DA and KOR systems.In this study, voltammetry results showed that chronic cocaine exposure reduced DA transmission and augmented KOR function. Dual targeting of the DA and KOR systems through a combination therapy approach revealed a greater decrease in motivation to take cocaine compared to either monotherapy. Taken together, these data support the potential beneficial effects of the dopamine transporter and KOR as dual‐cellular targets to treat multiple aspects of the withdrawal syndrome, ultimately decreasing the risk of relapse in individuals with cocaine dependence.Support or Funding InformationSupport for this work was provided by R01 DA014030, P50 DA006634, and T32 DA041329This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.