Phosphodiesterase 7(PDE7) inhibitors: a new target to treat drug addiction

Drug addiction not only causes addicts health damage, but also leads serious social, economic and public health problems, which threaten our harmonious society. The neurobiological mechanism of drug addiction has not been fully elucidated that is still lack of ideal treatment and intervention models. Especially, relapse is a worldwide problem, the high relapse rate after detoxification treatment more than 95%. The nucleotide phosphodiesterase (PDE) type 7 family includes two members, PDE7A and PDE7B, which are cyclic-AMP-specific PDEs expressed in brain dopaminergic regions linked to addiction, such as the nucleus accumbens (NAc) and ventral tegmental area (VTA). Here we assessed the role of PDE7 in addiction by evaluating selective PDE7 inhibitors (PDE7i) Compound A and Compound B in rat models of durg self-administration and relapse to drug seeking by behavior test. Our results showed that PDE7 inhibition by Compound A or Compound B significantly reduced fixed-ratio 3 and progressive ratio nicotine self-administration. In preclinical model of relapse we found that Compound A and Compound B also attenuated cue- and yohimbine-induced reinstatement of nicotine seeking. In rats implanted bilaterally with intracranial cannulas aimed at the VTA, we found that site specific injection of Compound A or Compound B into this brain area significantly reduced nicotine self-administration under both FR-3 and PR schedule of reinforcement suggesting a role of corticomesolimbic dapaminergic circuitries in PDE7i effects. In cocaine addiction experiments, the results showed that PDE7 inhibitor Compound B (low dose, intermediate dose and high dose) significantly reduced cue-induced relapse to cocaine seeking. The reinstatement experiments showed that PDE7 inhibitor exhibited significant effects in preventing stress-induced relapse to cocaine seeking behavior at the doses tested (low dose and high dose). The same results were found in heroin addiction test. The PDE7 inhibitor Compound A (intermediate dose and high dose) significantly reduced heroin-seeking behavior after extinction. The reinstatement experiments showed that PDE7 inhibitor Compound A exhibited significant effects in preventing cue-induced relapse to heroin seeking behavior at the doses tested (low dose, intermediate dose and high dose). Further, PDE7 inhibitor (intermediate dose and high dose) significantly reduced alcohol self-administration. The reinstatement experiments showed that PDE7 inhibitor exhibited significant effects in preventing stress- and cue-induced relapse to alcohol seeking behavior. These findings suggest that PDE7 could be a novel therapeutic target for drug addiction.