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

Abstract

NMDA receptor blockade in rodents is commonly used to induce schizophrenia-like behavioral abnormalities, including cognitive deficits and social dysfunction. Aberrant glutamate and GABA transmission, particularly in adolescence, is implicated in these behavioral abnormalities. The endocannabinoid system modulates glutamate and GABA transmission, but the impact of endocannabinoid modulation on cognitive and social dysfunction is unclear. Here, we asked whether late-adolescence administration of the anandamide hydrolysis inhibitor URB597 can reverse behavioral deficits induced by early-adolescence administration of the NMDA receptor blocker MK-801. In parallel, we assessed the impact of MK-801 and URB597 on mRNA expression of glutamate and GABA markers. We found that URB597 prevented MK-801-induced novel object recognition deficits and social interaction abnormalities in adult rats, and reversed glutamate and GABA aberrations in the prelimbic PFC. URB597-mediated reversal of MK-801-induced social interaction deficits was mediated by the CB1 receptor, whereas the reversal of cognitive deficits was mediated by the CB2 receptor. This was paralleled by the reversal of CB1 and CB2 receptor expression abnormalities in the basolateral amygdala and prelimbic PFC, respectively. Together, our findings show that interfering with NMDA receptor function in early adolescence has a lasting impact on phenotypes resembling the negative symptoms and cognitive deficits of schizophrenia and on glutamate and GABA marker expression in the PFC. Prevention of behavioral and molecular abnormalities by late-adolescence URB597 via CB1 and CB2 receptors suggests that endocannabinoid stimulation may have therapeutic potential in addressing treatment-resistant symptoms.

Chemogenetic attenuation of PFC pyramidal neurons restores deficits in recognition memory following adolescent NMDA receptor blockade

“…In a previous study, we showed that when administered chronically in adolescence, NMDAr blockade in rats leads to recognition memory impairments and social interaction deficits in the adult animal. In parallel, we observed changes in the expression of glutamate and GABA markers, suggesting a dysregulated E/I balance (Bauminger, Zaidan, Akirav, & Gaisler-Salomon, 2022). Despite the centrality of adolescence for maturation of the E/I balance and relevance for cognitive and social functions, less attention has focused on examining the long-term impact of chronic NMDAr blockade on excitatory and inhibitory transmission in mPFC.…”

Enhancing Endocannabinoid Signaling via β-Catenin in the Nucleus Accumbens Attenuates PTSD- and Depression-like Behavior of Male Rats

“…If the non-reinforced arm was chosen, the rat was retrained on the discrimination of the previous day and tested again 24 h later. If the reinforced arm was chosen, the rat was trained on the reversal of that discrimination, i.e., the platform was moved to the opposite arm [ 41 ]. In both phases, the number of correct trials was recorded until the rat reached five consecutive correct trials.…”

Epigenetic (re)programming of gene expression changes of CB1R and FAAH in the medial prefrontal cortex in response to early life and adolescence stress exposure

“…The movements of the rat were recorded and analyzed for 15 min using a video tracking system (Ethovision × T 14.0, Noldus Information Technology) to measure locomotion (measured as distance moved in cm). Time spent in the center (s) in the first 5 min was used as a measure of anxiety-like behavior (Bauminger et al, 2022).…”