Evaluating Serotonin 2C and Dopamine D3 Receptor Ligands, Alone and in Mixtures, as Candidate Medications for Substance Use Disorders

Abstract

<b>Abstract ID 22400</b> <b>Poster Board 213</b> Substance use disorders (SUDs) remain debilitating public health crises that have only escalated in economic severity and lethality over the last decade. Serotonin 2C (5-HT2C) and dopamine D3 (DAD3) receptor ligands have shown promise as candidate SUD medications, as they can attenuate drug-taking in preclinical SUD models. However, their potential for adverse side effects and ineffectiveness in clinical trials represent translational hurdles. Two potential approaches to circumvent these issues are to enhance the selectivity of the ligands and/or develop polypharmacy approaches targeting multiple receptors. Therefore, the first goal of this study was to characterize the potential of a selective 5-HT2C receptor agonist (CP-809,101; 0.32-10 mg/kg, IP) and a selective DAD3 receptor partial agonist (VK4-40, 1-32 mg/kg, IP) and a DAD3 receptor antagonist (VK4-116, 1-32 mg/kg, IP) to reduce responding for cocaine (0.32 mg/kg/inf), methamphetamine (0.056 mg/kg/inf), fentanyl (0.0032 mg/kg/inf), and sucrose (1 sucrose pellet) in male (n=6-8 per group) and female (n=6-8 per group) Sprague Dawley rats. Rats were trained to receive a delivery of each reinforcer under a progressive ratio schedule of reinforcement. Once responding stabilized (≤2 reinforcers earned over two consecutive sessions), rats were pretreated with each compound 15 min prior to test sessions to generate inhibition functions. CP-809,101 reduced responding across drug conditions, was more potent than either of the DAD3 receptor ligands, and had a lesser effect on rats responding for sucrose reinforcers. VK4-40 was more effective at reducing responses for fentanyl than VK4-116, but VK4-116 was more effective than VK4-40 in rats that self-administered cocaine. These data informed our approach to evaluating mixtures. Next, we sought to evaluate the effectiveness of 5-HT2C and DAD3 receptor ligand mixtures to reduce drug taking, with the hypothesis that such a polypharmacy approach would be more potent and/or effective at reducing drug taking than would be expected based on the effects of the ligands alone. When the compounds were evaluated as mixtures, combinations of CP-809,101 and VK4-40 as well as CP-809,101 and VK4-116 effectively produced reductions in drug taking at doses indicating additive or synergistic interactions. Mixtures of 5-HT2C and DAD3 ligands were more potent in the reduction of responding for intravenous drugs as compared to responding for sucrose reinforcers. These studies show that selective 5-HT2C and DAD3 receptor ligands can be useful for the reduction of drug-taking in rats, and suggest that a polypharmacy approach targeting these two receptors may provide a novel, and broad-spectrum strategy to treat SUDs. This research is supported by the U.S. Department of Veterans Affairs (I01BX004550; BM, GTC).