CB2 Receptor Potentiation Mediates Antipsychotic‐like Efficacy in Mice

Abstract

Although the cannabinoid type‐2 receptor (CB2) is highly expressed in the immune system, emerging evidence points to CB2 playing a key role in regulating neuronal function in the central nervous system (CNS). Recent preclinical literature indicates that CB2 is expressed on numerous neuronal subtypes including midbrain dopamine neurons projecting to the striatum. The ability of CB2 to regulate mesolimbic dopamine signaling could make it an intriguing target with which to modulate mood regulation, substance abuse, motivation, and psychomotor behaviors in rodents. These findings are interesting in light of clinical studies showing that lower CB2 expression is linked to an increased risk of schizophrenia in Japanese populations and that Caucasian suicide victims exhibit altered CB2 expression. Here, we demonstrate that a CB2 positive allosteric modulator (PAM) has antipsychotic‐like efficacy in reversing amphetamine‐disrupted prepulse inhibition (PPI) in C57BL/6N mice, and this effect was blocked by administering the CB2 antagonist AM630 prior to the CB2 PAM. Furthermore, administration of the CB2 PAM reversed amphetamine and MK‐801 induced hyperlocomotion, indicating that CB2 potentiation can reverse deficits induced by pharmacological manipulation of dopaminergic and glutamatergic systems relevant to schizophrenia. The CB2 PAM did not show efficacy in reducing immobility time during Forced Swim Test (TST) and Tail Suspension Test (TST). These findings suggest that CB2 PAMs may represent a novel therapeutic strategy for treating patients with schizophrenia, and warrant further investigating of CB2 as a target for schizophrenia‐relevant behaviors in preclinical models.