Roles for Type‐2 Cannabinoid Receptors in the Retrieval and Retention of Fear Memory in Mice

Abstract

Demand for medical marijuana is rising, but psychotropic harm is the major problem for its clinical use. Harnessing only beneficial effects of cannabis is critical for its therapeutic application, but has been difficult because only one type of cannabinoid receptor—CB1R—is known to be expressed in the brain and mediate both beneficial and detrimental effects of cannabis. Recent discoveries of type‐2 cannabinoid receptors (CB2Rs) in the brain challenge the status of CB1Rs as the only cannabinoid receptor in the nervous system, and require the determination of medical benefits, if any, of CB2Rs. CB2R knockout mice display reduction in fear memory, suggesting that CB2Rs might have therapeutic potential for fear memory management. We hypothesize that pharmacological blockade of CB2Rs might modulate aversive fear memory in mice. First, the effect of CB2R blockade on fear memory retrieval was tested. C57BL/6J mice were injected with the CB2R antagonist SR144528 (1 mg/kg; i.p.) or vehicle once a day for 2 weeks. After the drug treatment, the mice were fear‐conditioned with foot shocks and tones. Contextual and cued fear memory was assayed from freezing behavior 24 hours after the conditioning. SR144528 had little effect on the retrieval of contextual or cued fear memory. Second, the effect of CB2R blockade on fear memory retention was examined. Drug‐naive C57BL/6J mice were fear‐conditioned, and then, daily treated with SR144528 (1 mg/kg; i.p.) or vehicle for 1 week. After the 1‐week treatment, the mice were tested for fear memory. The post‐conditioning treatment with SR144528 increased cued, but not contextual, fear memory. In summary, our data indicate that pharmacological blockade of CB2Rs after, but not before, adverse experience elevates the retention of hippocampus‐independent fear memory. Unveiling more detailed roles of CB2Rs in modulating fear memory will provide insights into the cannabinoid‐mediated treatment of aversive memory in conflict‐affect individuals.Support or Funding InformationThis work was supported by the Medical Scholars Program of Medical College of Georgia, Augusta University.