Other regulatory effects on dopaminergic pathways were supported by the signal at PDE4B, which has been implicated in prior GWASs of disinhibition traits27. The phosphodiesterase (PDE) system has been proposed as a dopaminergic regulation mechanism34. Further, animal studies suggest that the PDE system is associated with down-regulation of drug-seeking behaviors across opioids, alcohol, and psychostimulants35. Notably, The PDE4B antagonist, ibudilast, has been shown to reduce heavy drinking among patients with AUD36,37 and also shown to reduce inflammation in methamphetamine use disorder38, and was significant in our drug repurposing analysis.
