Phosphodiesterase 4 inhibitors and drugs of abuse: current knowledge and therapeutic opportunities

Abstract

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.

Unraveling the Mechanisms of Behaviors Associated With AUDs Using Flies and Worms

“…Comparing functional domains between different isoforms might aid in identification of putative sites within proteins for drug targets. A similar strategy has been proposed for rodents, in whom local or systemic application of PDE4 inhibitors interferes with alcohol intake and/or alcohol seeking, and PDE inhibitors have been suggested as targets for reducing excessive alcohol consumption (Logrip, ; Olsen and Liu, ).…”

Therapeutic targeting of 3′,5′-cyclic nucleotide phosphodiesterases: inhibition and beyond

“…). Other nervous system disorders for which preclinical evidence suggests a therapeutic potential of PDE4i's include ischemic stroke(132,(137)(138)(139)(140), traumatic brain injury(141), axon regeneration(142), and substance abuse disorders (both causes and consequences,(143)(144)(145)(146)). …”

PDE4 Inhibition Restores the Balance Between Excitation and Inhibition in VTA Dopamine Neurons Disrupted by Repeated In Vivo Cocaine Exposure

“…PDE4 inhibitors have been shown to reduce drug intake and/or drug seeking for psychostimulants, alcohol, and opioids (Hu et al, 2011;Lai et al, 2014), suggesting that PDE4 could be a therapeutic target for several classes of substance use disorders (Olsen and Liu, 2016;Wen et al, 2015). Most relevant to the present study are the findings that rolipram pretreatments block cocaine-induced increases in locomotor activity, behavioral sensitization, CPP and self-administration (Janes et al, 2009;Knapp et al, 1999;Thompson et al, 2004).…”

“…There are 11 subtypes of PDEs (PDE1-11); amongst them, PDE4 selectively hydrolyzes cAMP (Lugnier, 2006;Zhang, 2009). Non-selective PDE and PDE4-specific inhibitors reduce drug intake and/or drug seeking for psychostimulants, alcohol, and opioids (Olsen and Liu, 2016;Wen et al, 2015), suggesting that inhibitors of PDE4 or other PDE isoforms alter common drug-induced neuroadaptations in the reward circuitry of the brain. Selective PDE4 inhibitors such as rolipram significantly reduce cocaine-induced increases in locomotor activity, behavioral sensitization, conditioned place preference (CPP) and self-administration (Janes et al, 2009;Knapp et al, 1999;Thompson et al, 2004).…”

“…Selective PDE4 inhibitors such as rolipram significantly reduce cocaine-induced increases in locomotor activity, behavioral sensitization, conditioned place preference (CPP) and self-administration (Janes et al, 2009;Knapp et al, 1999;Thompson et al, 2004). PDE4 has thus emerged as a potential therapeutic target for the treatment of substance abuse and substance use disorders (Olsen and Liu, 2016;Wen et al, 2015).…”