KVA-D-88, a Novel Preferable Phosphodiesterase 4B Inhibitor, Decreases Cocaine-Mediated Reward Properties in Vivo

Maria E. Burkovetskaya, Qiaoling Liu, Anish K. Vadukoot, Nagsen Gautam, Yazen Alnouti, Sushil Kumar, Klaus Miczek, Shilpa Buch, Corey R. Hopkins, Minglei Guo

Research output: Contribution to journalArticle

Abstract

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 that 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, pretreatment with KVA-D-88 significantly inhibited cocaine-induced hyperlocomotor activity. In cocaine self-administering mice with differential schedules, KVA-D-88 strikingly decreased the number of active nose-pokes and 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.

Original languageEnglish (US)
Pages (from-to)2231-2242
Number of pages12
JournalACS Chemical Neuroscience
Volume11
Issue number15
DOIs
StatePublished - Aug 5 2020

Keywords

  • PDE4 inhibitors
  • cAMP
  • cocaine
  • drug addiction
  • locomotor activity
  • self-administration

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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