Exposure to anandamide on young rats causes deficits in learning, temporal perception and induces changes in NMDA receptor expression

Abstract

Human use of marijuana at an early age has been reported to lead to cognitive impairment. However, researchers have not yet clearly determined whether this impairment is due to marijuana-induced alterations in the developing nervous system and whether this deficit persists into adulthood after marijuana use has ceased. We administered anandamide to developing rats to assess the effect of cannabinoids on development. We subsequently evaluated learning and performance on a temporal bisection task in adulthood and assessed the expression of genes encoding principal subunits of NMDA receptors (Grin1, Grin2A, and Grin2B) in the hippocampus and prefrontal cortex. Rats in two age groups, namely, 21-day-old and 150-day-old rats, received intraperitoneal injections of anandamide or the vehicle for 14 days. Both groups performed a temporal bisection test, which included listening to tones of different durations and classifying them as short or long. The expression of the Grin1, Grin2A and Grin2B mRNAs was evaluated using quantitative PCR in both age groups after extracting mRNA from the hippocampus and prefrontal cortex. We observed a learning impairment in the temporal bisection task (p < 0.05) and changes in the response latency (p < 0.05) in rats that received anandamide. Furthermore, these rats exhibited decreased expression of Grin2b (p = 0.001) compared to those that received the vehicle. In human subjects, the use of cannabinoids during development induces a long-term deficit, but this deficit is not observed in subjects who use cannabinoids in adulthood. Rats treated with anandamide earlier in development took longer to learn the task, suggesting that anandamide exerts a harmful effect on cognition in developing rats. Administration of anandamide during early stages of development induced deficits in learning and other cognitive processes that depend on an adequate estimation of time. The cognitive demands of the environment must be considered when evaluating the cognitive effects of cannabinoids on developing or mature brains. High cognitive demands might induce differential expression of NMDA receptors that improves cognitive capacity, overcoming altered glutamatergic function.

Keywords: Anandamide; Cannabinoids; Grin1; Grin2A; Grin2B; NMDA; Temporal bisection task.