Boosting anandamide in adolescent rats reversed schizophrenia-like cognitive and social deficits through CB1 and CB2 receptors

What the researchers found

The anandamide hydrolysis inhibitor URB597, given in late adolescence, reversed both novel object recognition deficits (via CB2 receptors) and social interaction abnormalities (via CB1 receptors) induced by early-adolescence MK-801 administration, while also normalizing glutamate and GABA marker expression in the prefrontal cortex.

Why it matters

This study identifies specific endocannabinoid receptor pathways for distinct schizophrenia symptoms, suggesting that targeting CB1 vs. CB2 receptors could address different symptom domains.

The numbers in context

CB1 receptor mediated the reversal of social deficits; CB2 receptor mediated the reversal of cognitive deficits. URB597 also reversed glutamate and GABA abnormalities in the prelimbic prefrontal cortex.

How the study worked

Male rats received the NMDA receptor blocker MK-801 in early adolescence to induce schizophrenia-like symptoms, then received the anandamide hydrolysis inhibitor URB597 in late adolescence. Behavioral testing (novel object recognition, social interaction) and mRNA expression analysis of glutamate and GABA markers were performed in adulthood.

What this study cannot tell us

Animal model only. MK-801 model does not fully replicate human schizophrenia. Only male rats tested. The therapeutic window (late adolescence) may not translate directly to human clinical application.

How to read the evidence

Rigorous animal study with clear mechanistic findings, but translation to humans is uncertain.

When this study was published

Published in 2022.

The bigger picture

The finding that different cannabinoid receptors mediate rescue of different symptom types (social vs. cognitive) suggests the endocannabinoid system could be a target for treatment-resistant symptoms of schizophrenia, which current antipsychotics often fail to address.

Questions still open

• Would similar effects be seen in female rats? Could selective CB2 agonists improve cognition in people with schizophrenia? Is there a critical window for endocannabinoid intervention?

Common questions

Read the original research

Anandamide Hydrolysis Inhibition Reverses the Long-Term Behavioral and Gene Expression Alterations Induced by MK-801 in Male Rats: Differential CB1 and CB2 Receptor-Mediated Effects.

Schizophrenia bulletin, 48(4), 795-803

Citation

Bauminger, Hagar; Zaidan, Hiba; Akirav, Irit; Gaisler-Salomon, Inna. (2022). Anandamide Hydrolysis Inhibition Reverses the Long-Term Behavioral and Gene Expression Alterations Induced by MK-801 in Male Rats: Differential CB1 and CB2 Receptor-Mediated Effects.. Schizophrenia bulletin, 48(4), 795-803. https://doi.org/10.1093/schbul/sbab153

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