KVA-D-88, a Novel Preferable Phosphodiesterase 4B Inhibitor, Decreases Cocaine-Mediated Reward Properties in Vivo.
KVA-D-88, a Novel Preferable Phosphodiesterase 4B Inhibitor, Decreases Cocaine-Mediated Reward Properties in Vivo.
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DOI：
10.1021/acschemneuro.0c00170
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发表时间：
2020-08-05
影响因子：
5
通讯作者：
Guo M
中科院分区：
文献类型：
--
作者：
Burkovetskaya ME;Liu Q;Vadukoot AK;Gautam N;Alnouti Y;Kumar S;Miczek K;Buch S;Hopkins CR;Guo M
Cocaine addiction remains a major public concern throughout the world especially in developed countries. In the last three decades, significant achievements have led to a greater understanding of the signaling pathways involved in the development of cocaine addiction; however, there are no FDA-approved treatments available to reverse or block this brain disease due to either the unsatisfactory therapeutic efficacy or severe side effects. Previous studies have demonstrated that chronic exposure to cocaine elevates levels of cyclic AMP (cAMP) as a neuroadaptative response in reward-related brain regions. Phosphodiesterase 4 (PDE4) inhibitors, which elevate cAMP levels, have been shown to block cocaine-mediated behavioral changes related to psychoactive and reinforcing properties. Unfortunately, previously studied PDE4 inhibitors induce severe side-effects which limit their clinical usage. In this study, we identified a novel PDE4B inhibitor KVA-D-88 with an improved selectivity profile compared to previous compounds (e.g., rolipram). Pharmacokinetic studies have shown this compound is brain penetrant and preferably acts on PDE4B compared to PDE4D in vitro, alluding to less unwanted side effects with KVA-D-88 in vivo. Interestingly, pre-treatment with KVA-D-88 significantly inhibited cocaine-induced hyper-locomotor activity. In cocaine self-administered mice with differential schedules, KVA-D-88 strikingly decreased the number of active nose-pokes, cocaine infusions and reduced the break point. Taken together, our findings demonstrate that this novel PDE4 inhibitor, KVA-D-88, could inhibit cocaine-mediated rewarding effects implying its potential clinical usage for cocaine addiction.
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影响因子：
2.5
作者：
Johansson, Emily M.;Reyes-Irisarri, Elisabeth;Mengod, Guadalupe
通讯作者：
Mengod, Guadalupe
影响因子：
3.6
作者：
Knapp, CM;Foye, MM;Kornetsky, C
通讯作者：
Kornetsky, C
DOI：
10.1073/pnas.172091899
发表时间：
2002-08-20
影响因子：
11.1
作者：
Barrot, M;Olivier, JDA;Nestler, EJ
通讯作者：
Nestler, EJ
DOI：
10.1111/acer.13616
发表时间：
2018-05
期刊：
Alcoholism, clinical and experimental research
影响因子：
--
作者：
Blednov YA;Da Costa AJ;Tarbox T;Ponomareva O;Messing RO;Harris RA
通讯作者：
Harris RA
影响因子：
3.2
作者：
Blednov, Yuri A.;Da Costa, Adriana J.;Messing, Robert O.
通讯作者：
Messing, Robert O.