The interactive effects of verapamil and CB1 cannabinoid receptor antagonist/inverse agonist, AM251 on passive avoidance learning and memory in rat

Behav Pharmacol. 2022 Apr 1;33(2&3):222-229. doi: 10.1097/FBP.0000000000000638.


There are reports regarding the effects of intracellular Ca2+ and synthesis and release of endocannabinoids. The secretion of endocannabinoids depends on the L-type calcium channel. The present study evaluated the involvement of the cannabinoid CB1 receptors in the effect of L-type calcium channel blocker verapamil on passive avoidance learning (PAL) in adult male rats. In this study, we examined the effects of an acute administration of the cannabinoid CB1 receptors antagonist/inverse agonist AM251 following a chronic administration of the Ca2+ channel blocker verapamil on PAL. Male Wistar rats were administered verapamil (10, 25 and 50 mg/kg) or saline intraperitoneally (i.p) daily for 13 days (n = 10/group). After this treatment period, a learning test (acquisition) was performed, and a retrieval test was performed the following day. The results indicated that chronic systemic administration of verapamil (in a dose-dependent manner) impaired memory acquisition and retrieval. Pre-training acute administration of a selective CB1 antagonist/inverse agonist, AM251 (5 mg/kg, i.p.) did not change memory acquisition and retrieval. Co-administration of the verapamil and AM251 significantly reversed verapamil-induced amnesia, suggesting a functional interaction between AM251 and verapamil. The results indicated the interactive effects of cannabinoid CB1 receptors and L-type calcium channel in passive avoidance learning and AM251 can counter the effects of verapamil on memory.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Avoidance Learning
  • Calcium / pharmacology
  • Calcium Channels, L-Type / pharmacology
  • Cannabinoid Receptor Agonists / pharmacology
  • Cannabinoid Receptor Antagonists* / pharmacology
  • Cannabinoids* / pharmacology
  • Endocannabinoids / pharmacology
  • Male
  • Piperidines
  • Pyrazoles
  • Rats
  • Rats, Wistar
  • Receptor, Cannabinoid, CB1
  • Verapamil / pharmacology


  • Calcium Channels, L-Type
  • Cannabinoid Receptor Agonists
  • Cannabinoid Receptor Antagonists
  • Cannabinoids
  • Endocannabinoids
  • Piperidines
  • Pyrazoles
  • Receptor, Cannabinoid, CB1
  • AM 251
  • Verapamil
  • Calcium