Phosphodiesterase 4 inhibitors and drugs of abuse: current knowledge and therapeutic opportunities. Front Biol (Beijing) 2016 Oct;11(5):376-386
Date
10/05/2017Pubmed ID
28974957Pubmed Central ID
PMC5617368DOI
10.1007/s11515-016-1424-0Scopus ID
2-s2.0-84991738449 (requires institutional sign-in at Scopus site) 18 CitationsAbstract
BACKGROUND: Long-term exposure to drugs of abuse causes an up-regulation 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.
Author List
Olsen CM, Liu QSAuthors
Qing-song Liu PhD Professor in the Pharmacology and Toxicology department at Medical College of WisconsinChristopher M. Olsen PhD Associate Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
