Phosphodiesterase 7 Inhibitor As A Potential Drug Treatment Of Nicotine Addiction Feasibility Study

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,PDE7 A and PDE7 B,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).Because PDE inhibitors have good application effect in central nervous system and cardiovascular disease,they not only have few side effects but also have a good protective effect on the nervous system.In this study,two PDE7 inhibitors were synthesized,namely compound A and compound B,the pharmacological activity of a synthetic PDE7 inhibitor(PDE7i)was assessed by the inhibitory effect of two inhibitors on nicotine addiction using a rat model of self-administration and recurrent drug seeking models.After intensive training in nicotine self-administration,the lever activity of rats injected with compounds A and B was significantly reduced.Our results showed that compounds A and B significantly reduced fixed-ratio and progressive ratio nicotine self-administration.At the same time,the break point of self-administration was reduced in rats,reflecting the fact that PDE7 inhibitor reduced the rats' motivation to take nicotine.Compared with compound B,compound A produced significant changes in the lever at low concentrations,indicating that compound A had better inhibitory effect than compound B.In preclinical model of relapse we found that compound A 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 inhibitors into this brain area significantly reduced nicotine self-administration under FR1 schedule of reinforcement suggesting a role of corticomesolimbic dapaminergic circuitries in PDE7 i effects.In the control group,the injection of PDE7 i inhibitor did not affect the normal feeding?The inactive lever response also remained unchanged,thus excluding drug-induced nonspecific motivational effects.This indicates that PDE7 inhibitor is a single selective inhibitor and will not have adverse effects on normal diet and physiological activities.These findings suggest that PDE7 inhibitors have excellent biological activity and are effective in treating drug addiction.However,if the synthetic phosphodiesterase 7 inhibitor is to be used in clinical trials,we still need to do further research on its related pharmacological mechanism and properties.