%A Christopher M. Olsen,Qing-Song Liu %T Phosphodiesterase 4 inhibitors and drugs of abuse: current knowledge and therapeutic opportunities %0 Journal Article %D 2016 %J Front. Biol. %J Frontiers in Biology %@ 1674-7984 %R 10.1007/s11515-016-1424-0 %P 376-386 %V 11 %N 5 %U {https://journal.hep.com.cn/fib/EN/10.1007/s11515-016-1424-0 %8 2016-11-04 %X

BACKGROUND: Long-term exposure to drugs of abuse causes an upregulation of the cAMP-signaling pathway in the nucleus accumbens and other forebrain regions, this common neuroadaptation is thought to underlie aspects of drug tolerance and dependence. Phosphodiesterase 4 (PDE4) is an enzyme that the selective hydrolyzes intracellular cAMP. It is expressed in several brain regions that regulate the reinforcing effects of drugs of abuse.

OBJECTIVE: Here, we review the current knowledge about central nervous system (CNS) distribution of PDE4 isoforms and the effects of systemic and brain-region specific inhibition of PDE4 on behavioral models of drug addiction.

METHODS: A systematic literature search was performed using the Pubmed.

RESULTS: Using behavioral sensitization, conditioned place preference and drug self-administration as behavioral models, a large number of studies have shown that local or systemic administration of PDE4 inhibitors reduce drug intake and/or drug seeking for psychostimulants, alcohol, and opioids in rats or mice.

CONCLUSIONS: Preclinical studies suggest that PDE4 could be a therapeutic target for several classes of substance use disorder. We conclude by identifying opportunities for the development of subtype-selective PDE4 inhibitors that may reduce addiction liability and minimize the side effects that limit the clinical potential of non-selective PDE4 inhibitors. Several PDE4 inhibitors have been clinically approved for other diseases. There is a promising possibility to repurpose these PDE4 inhibitors for the treatment of drug addiction as they are safe and well-tolerated in patients.