The cannabinoid receptor 2 agonist, β-caryophyllene, reduced voluntary alcohol intake and attenuated ethanol-induced place preference and sensitivity in mice

Pharmacol Biochem Behav. 2014 Sep;124:260-8. doi: 10.1016/j.pbb.2014.06.025. Epub 2014 Jul 3.


Several recent studies have suggested that brain CB2 cannabinoid receptors play a major role in alcohol reward. In fact, the implication of cannabinoid neurotransmission in the reinforcing effects of ethanol (EtOH) is becoming increasingly evident. The CB2 receptor agonist, β-caryophyllene (BCP) was used to investigate the role of the CB2 receptors in mediating alcohol intake and ethanol-induced conditioned place preference (EtOH-CPP) and sensitivity in mice. The effect of BCP on alcohol intake was evaluated using the standard two-bottle choice drinking method. The mice were presented with increasing EtOH concentrations and its consumption was measured daily. Consumption of saccharin and quinine solutions was measured following the EtOH preference tests. Finally, the effect of BCP on alcohol reward and sensitivity was tested using an unbiased EtOH-CPP and loss of righting-reflex (LORR) procedures, respectively. BCP dose-dependently decreased alcohol consumption and preference. Additionally, BCP-injected mice did not show any difference from vehicle mice in total fluid intake in a 24-hour paradigm nor in their intake of graded concentrations of saccharin or quinine, suggesting that the CB2 receptor activation did not alter taste function. More importantly, BCP inhibited EtOH-CPP acquisition and exacerbated LORR duration. Interestingly, these effects were abrogated when mice were pre-injected with a selective CB2 receptor antagonist, AM630. Overall, the CB2 receptor system appears to be involved in alcohol dependence and sensitivity and may represent a potential pharmacological target for the treatment of alcoholism.

Keywords: AM630; CB(2) receptors; Conditioned place preference; LORR; Two-bottle choice; β-Caryophyllene.

MeSH terms

  • Alcohol Drinking / prevention & control*
  • Animals
  • Conditioning, Classical*
  • Ethanol / pharmacology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Polycyclic Sesquiterpenes
  • Receptor, Cannabinoid, CB2 / agonists*
  • Sesquiterpenes / pharmacology*


  • Polycyclic Sesquiterpenes
  • Receptor, Cannabinoid, CB2
  • Sesquiterpenes
  • Ethanol
  • caryophyllene