Linalool inhalation‒induced anxiety-like effects occur independently of olfactory input and require cytochrome P450 activity

Multiple chemical sensitivity (MCS) is characterized by neuropsychological symptoms including anxiety, depression, and fatigue following exposure to environmental chemicals, yet its underlying mechanisms remain poorly understood. Linalool, a monoterpene alcohol widely used in consumer products, has been suggested as a potential contributor to MCS. To elucidate its neural effects, we examined the behavioral effects of linalool inhalation in mice. Linalool exposure induced both anxiety- and depression-like behaviors. While the depression-like behavior required olfactory input, the anxiety-like behavior occurred independently of olfactory perception. Our previous studies demonstrated that inhaled linalool accumulates in the brain and undergoes cytochrome P450 (P450)-dependent metabolism. We therefore tested whether P450-mediated metabolism contributes to the behavioral effects of linalool. Significantly, inhibition of P450 activity abolished the anxiety-like behavior. These findings reveal an olfactory-independent mechanism by which inhaled linalool induces anxiety-like behavior in mice and suggest that P450 activity is required for this effect, providing a basis for investigating fragrance-induced MCS-like neurobehavioral responses.