The Serotonin (5-HT) 5-HT2A Receptor is a Priority Target to Reduce Impulsive Action in Substance Use Disorders: Preclinical Evidence

The National Institute on Drug Abuse (NIDA) Division of Therapeutics and Medical Consequences (DTMC) recently highlighted the need for pharmacological targets to treat substance use disorders (SUDs) in the near term as well as entirely new mechanistic directions for SUDs research. A hallmark of SUDs is “continued drug use despite adverse consequences,” which aligns with the definition of impulsivity, a predisposition toward rapid unplanned reactions to stimuli without regard to negative consequences. Serotonin (5-HT) neurotransmission in the medial prefrontal cortex (mPFC) is an important neuromodulator of impulsive action (inability to withhold premature responses), and 5-HT actions at the G protein-coupled 5-HT2A receptor (5-HT2AR) regulate impulsive action and the attentional orienting to drug cues (cue reactivity) based upon extensive pharmacological studies with investigational 5-HT2AR antagonists/inverse agonists. We first established the potential for repurposing the recently FDA-approved 5-HT2AR antagonist/inverse agonist pimavanserin (Nuplazid®) as a therapeutic to forestall relapse vulnerability in cocaine use disorder (CUD). Pimavanserin suppressed impulsive action while baseline levels of impulsive action predicted the effectiveness of pimavanserin to suppress incubated cue reactivity in late abstinence from cocaine self-administration at doses that were ineffective in early abstinence. We then demonstrated that pimavanserin attenuated impulsive action evoked by the prescription opioid oxycodone, providing early evidence that pimavanserin may suppress impulsive opioid misuse. We explored the mPFC as a potential site of action for the 5-HT2AR to modulate impulsive action using viral-mediated knockdown of 5-HT2AR protein expression. However, 5-HT2AR knockdown in the mPFC did not alter impulsive action or 5-HT2AR ligand sensitivity, possibly due to the complex, cell type-specific architecture of the 5-HT2AR in mPFC. Lastly, we established a transcriptomic landscape in the mPFC that may characterize individual differences in impulsive action, proposing novel gene targets for future impulsivity research. Our cumulative evidence suggests that the 5-HT2AR is a promising target to improve the health status of SUDs patients in the near term, and we propose novel gene targets in the mPFC that provide entirely new directions for impulsivity research.