Effect of tetrahydrocannabinol on COMT activity in mice prefrontal cortex

Abstract

Tetrahydrocannabinol (THC) is the principal psychoactive constituent of cannabis and its effects are modulated by dopaminergic neurotransmission. Dopamine availability in prefrontal cortex is mostly controlled by catechol-o-methyltransferase (COMT) and it has been suggested that THC induced psychosis and cognitive impairment are dependent on COMT genotype. However the effect of THC in COMT activity is not known.This study aims to evaluate the effect of THC on COMT activity and monoamines tissue levels in mice prefrontal cortex. COMT activity in vitro and in vitro ex-vivo was evaluate in the pre-frontal cortex from C57BL/6J mice. For 10 days, mice were treated either with vehicle or THC (10 mg/Kg bw, total daily dose).In vitro, THC produced a concentration dependent inhibition in brain COMT activity with an IC 50 value of 232 µM. In vivo, THC treatment did not change monoamines or dopamine metabolites in prefrontal cortex. Nevertheless a significant decrease in 5-hydroxyindoleacetic acid (0.35±0.1, 0.54±0.02 pmol/mg tissue for control and THC respectively) was observed. In vitro-ex-vivo, COMT activity in the pre-frontal cortex showed no differences in the enzyme kinetics parameters when comparing THC to control animals. Analysis from the saturation curves found that the Vmax values (in nmol/mg prot/h) were 2.73 (2.4, 3.1) and 2.70 (2.3, 3.1) for CT and THC respectively.In conclusion, THC decreases COMT activity in vitro only in high concentrations (above 100 µM), however when administrated in vivo no significant effect was observed in enzyme activity or dopamine prefrontal cortex metabolism.