Cyclic nucleotide phosphodiesterases: potential therapeutic targets for alcohol use disorder

Abstract

Alcohol use disorder (AUD), which combines the criteria of both alcohol abuse and dependence, contributes as an important causal factor to multiple health and social problems. Given the limitation of current treatments, novel medications for AUD are needed to better control alcohol consumption and maintain abstinence. It has been well established that the intracellular signal transduction mediated by the second messengers cyclic AMP (cAMP) and cyclic GMP (cGMP) crucially underlies the genetic predisposition, rewarding properties, relapsing features, and systemic toxicity of compulsive alcohol consumption. On this basis, the upstream modulators phosphodiesterases (PDEs), which critically control intracellular levels of cyclic nucleotides by catalyzing their degradation, are proposed to play a role in modulating alcohol abuse and dependent process. Here, we highlight existing evidence that correlates cAMP and cGMP signal cascades with the regulation of alcohol-drinking behavior and discuss the possibility that PDEs may become a novel class of therapeutic targets for AUD.

Keywords: Alcohol dependence; Alcohol use disorder (AUD); Central nervous system; Phosphodiesterase (PDE); cAMP; cGMP.

Figure 1. Possible mechanisms of PDEs in modulating alcohol drinking behaviors

AC, adenylate cyclase; ATP, adenosine triphosphate; cAMP, 3′5′ cyclic adenosine monophosphate; CBP, CREB binding protein; CREB, cAMP-responsive element binding protein; GTP, guanosine triphosphate; PDEs, phosphodiesterases; PKA, protein kinase A; PKG, protein kinase G; ⊝, negatively correlated.

Figure 2. PDEs involved in substance dependence

METH, methamphetamine.