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Neuropharmacology

Induction of brain cytochrome P450 2E1 boosts the locomotor-stimulating effects of ethanol in mice.


PMID 24863043

Abstract

In the central nervous system ethanol (EtOH) is metabolized into acetaldehyde by different enzymes. Brain catalase accounts for 60% of the total production of EtOH-derived acetaldehyde, whereas cerebral cytochrome P450 2E1 (CYP 2E1) produces 20% of this metabolite. Acetaldehyde formed by the activity of central catalase has been implicated in some of the neurobehavioral properties of EtOH, yet the contribution of CYP 2E1 to the pharmacological actions of this drug has not been investigated. Here we assessed the possible participation of CYP 2E1 in the behavioral effects of EtOH. Thus, we induced CYP 2E1 activity and expression by exposing mice to chronic acetone intake (1% v/v for 10 days) and examined its consequences on the stimulating and uncoordinating effects of EtOH (0-3.2 g/kg) injected intraperitoneally. Our data showed that 24 h after withdrawal of acetone brain expression and activity of CYP 2E1 was induced. Furthermore, the locomotion produced by EtOH was boosted over the same interval of time. Locomotor stimulation produced by amphetamine or tert-butanol was unchanged by previous treatment with acetone. EtOH-induced motor impairment as evaluated in a Rota-Rod apparatus was unaffected by the preceding exposure to acetone. These results indicate that cerebral CYP 2E1 activity could contribute to the locomotor-stimulating effects of EtOH, and therefore we suggest that centrally produced acetaldehyde might be a possible mediator of some EtOH-induced pharmacological effects.