Cannabinoid CB2 receptors and hypersensitivity to methamphetamine: Vulnerability to schizophrenia

• Published in: Progress in neuro-psychopharmacology & biological psychiatry Vol. 130; p. 110924
• Main Authors: Canseco-Alba, Ana, Tabata, Koichi, Momoki, Yukihiko, Tabassum, Taharima, Horiuchi, Yasue, Arinami, Tadao, Onaivi, Emmanuel S, Ishiguro, Hiroki
• Format: Journal Article
• Language: English
• Published: England 02.03.2024
• Subjects: Animals; Cannabinoids - pharmacology; Drug Inverse Agonism; Humans; Methamphetamine - pharmacology; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptor, Cannabinoid, CB2 - genetics; Receptors, Cannabinoid; Schizophrenia - genetics; Schizophrenia; Dopaminergic neuron; Methamphetamine; Cannabinoid CB2 receptor
• ISSN: 0278-5846; 1878-4216
• DOI: 10.1016/j.pnpbp.2023.110924

The human cannabinoid receptor 2 (CB2R) gene CNR2 has been associated with schizophrenia development. Inbred mice treated with the CB2R inverse agonist AM630 and challenged with methamphetamine (MAP) showed reduced prepulse inhibition (%PPI) response and locomotor hyperactivity, both behavioral measures in rodents that correlate with psychosis. Mice lacking CB2R on striatal dopaminergic neurons exhibit a hyperdopaminergic tone and a hyperactivity phenotype. Hyperdopaminergia plays a role in the etiology of schizophrenia. This study aimed to determine the direct role of CB2R, heterozygous Cnr2 gene knockout (Het) mice treated with MAP to induce behavioral sensitivity mimicking a schizophrenia-like human phenotype. Additionally, the study aims to explore the unique modulation of dopamine activity by neuronal CB2R. Conditional knockout DAT-Cnr2 mice were evaluated in response to MAP treatments for this purpose. Sensorimotor gating deficits in DAT-Cnr2 mice were also evaluated. Het mice developed reverse tolerance (RT) to MAP-enhanced locomotor activity, and RT reduced the %PPI compared to wild-type (WT) mice. DAT-Cnr2 mice showed an increased sensitivity to stereotypical behavior induced by MAP and developed RT to MAP. DAT-Cnr2 mice exhibit a reduction in %PPI and alter social interaction, another core symptom of schizophrenia. These results demonstrate that there is an interaction between neuronal CB2R and MAP treatment, which increases the risk of schizophrenia-like behavior in this mouse model. This finding provides evidence for further studies targeting CB2R as a potential schizophrenia therapy.