Relative Contribution of Dopamine, Norepinephrine, and Serotonin to the Discriminative Stimulus Effects of MDPV

Abstract

The abuse of synthetic cathinones (“bath salts”) has increased worldwide over the past decade. Bath salt preparations often contain multiple synthetic cathinones in addition to other stimulants such as cocaine or caffeine. Synthetic cathinones are known to interact with dopamine, norepinephrine, and serotonin transporters (DAT, NET, and SERT, respectively). Although recent studies suggest that interactions with DAT are crucial for the reinforcing effects of synthetic cathinones, actions at SERT were found to negatively modulate reinforcing effectiveness. The goal of the current study was to characterize the relative contributions of dopamine, norepinephrine, and serotonin to the discriminative stimulus effects of MDPV by evaluating the substitution profiles of 1) a series of structurally related cathinones (MDPBP, MDPPP, α‐PPP, and α‐PVP) and cocaine, and 2) direct‐acting dopamine (quinpirole [D2/3], SKF 82958 [D1/5], and apomorphine [D1‐5]), and norepinephrine (phenylephrine [α1], and clonidine [α2]) receptor agonists in male Sprague‐Dawley rats (n=8) trained to discriminate 1.0 mg/kg MDPV from saline under a fixed ratio 10 schedule of sucrose pellet delivery. The mu‐opioid receptor agonist fentanyl served as a negative control. As expected, each of the cathinones and cocaine produced dose‐dependent increases in MDPV‐appropriate responding, whereas fentanyl failed to increase MDPV‐appropriate responding at doses smaller than those that suppressed responding. The rank order potency of the synthetic cathinones to increase MDPV‐appropriate responding is positively correlated with their potency to inhibit DAT and NET, but not SERT, and is consistent with the rank order to maintain self‐administration. The D2/3 receptor‐preferring agonist quinpirole dose‐dependently increased MDPV‐appropriate responding whilst SKF 82958 [D1/5], apomorphine [D1‐5], phenylephrine [α1], and clonidine [α2] failed to increase MDPV‐appropriate responding at doses smaller than those that suppressed responding. Together, these data provide evidence that the discriminative stimulus effects of MDPV are primarily mediated by its capacity to inhibit DAT, and the subsequent activation of dopamine D2 and/or D3 receptors. Moreover, these studies suggest do not support a role for serotonergic or adrenergic systems in mediating/modulating the discriminative stimulus effects of MDPV. Future studies will utilize antagonists of dopamine, adrenergic, and serotoninergic receptors to better characterize their relative contributions to the discriminative stimulus effects of MDPV.Support or Funding InformationThis work was supported by NIH/NIDA grant (R01 DA039146; GTC) and NIDA‐ and NIAAA‐IRPs (KCR)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.