A low repeated dose of Δ9-tetrahydrocannabinol affects memory performance through serotonergic signalling in mice

Abstract

Cannabis is the most widely used illicit drug worldwide. Its principal psychoactive component, ∆9-tetrahydrocannabinol (THC), acts as a partial agonist of the main cannabinoid receptor in the brain, the cannabinoid type-1 receptor (CB1R), being the main responsible for the central effects of THC including memory impairment. CB1Rs may form heterodimers with the serotonin 5-HT2A receptor (5-HT2AR) which were found responsible for the memory impairment produced by acute high dose of THC in mice. In this study we investigated whether a repeated low dose of THC (1 mg/kg), with no acute consequence on memory performance, could eventually have deleterious cognitive effects. We found that such a low dose of THC impairs novel object-recognition memory and fear conditioning memory after repeated treatment (7 days). This deficit was also detected 24 h after the last THC administration. At that time, a general enhancement of c-Fos expression was observed in several brain regions of THC-exposed animals. In addition, THC-treated mice showed a decreased spine density at CA1 pyramidal neurons and reduced long-term potentiation at Schaffer collateral-CA1 synapses. Interestingly, an up-regulation in the expression of CB1R/5-HT2AR heterodimers was observed in the hippocampus of THC-exposed mice and a pre-treatment with the 5-HT2AR antagonist MDL 100,907 (0.01 mg/kg) prevented enhanced heterodimerization and the THC-associated memory impairment. Together, these results reveal the significance of serotonergic signalling through 5-HT2ARs in the memory-impairing effects of repeated low doses of THC.