Targeting Phosphodiesterases in Pharmacotherapy for Substance Dependence

Substance dependence is a chronic relapsing brain disorder associated with adaptational changes in synaptic plasticity and neuronal functions. The high levels of substance consumption and relapse rate suggest more reliable medications are in need to better address the underlying causes of this disease. It has been well established that the intracellular second messengers cyclic AMP (cAMP) and cyclic GMP (cGMP) and their signaling systems play an important role in the molecular mechanisms of substance taking behaviors. On this basis, the phosphodiesterase (PDE) superfamily, which crucially controls cyclic nucleotide levels by catalyzing their hydrolysis, has been proposed as a novel class of therapeutic targets for substance use disorders. This chapter reviews the expression patterns of PDEs in the brain with regard to neural structures underlying the dependent process and highlights available evidence for a modulatory role of PDEs in substance dependence.