Disease progression-dependent neurobehavioral phenotypes of agitation, anxiety, and depression in MC903-induced chronic itch.

Pruritus is closely associated with anxiety and depression, yet irritability and agitation in patients with chronic itch remain poorly characterized in preclinical studies. Using an MC903-induced chronic itch model, we evaluated emotional behaviors across varying durations (7-18 days) and doses (50-100 μM). MC903 induced sequential emotional disturbances: agitation-like behavior emerged early (day 7), coexisted with anxiety by mid-stage (day 12), and progressed to depression at late stage (day 18). A higher dose (100 μM) accelerated this progression, eliciting agitation and depression with anhedonia within 7 days. We demonstrated that the forced swim test is confounded by cutaneous damage and active pruritus, rendering it unsuitable for affective assessment in skin disease models. Neural mapping identified significant c-Fos activation in the nucleus accumbens and central amygdala during agitation. Chemogenetic inhibition of GABAergic neurons in both regions reversed agitation-like behaviors, establishing their causal role. Female mice exhibited accelerated and more severe emotional disturbances under conditions producing only mild agitation in males. This study identifies itch-induced agitation; describes a time-, dose-, and sex-dependent emotional progression; and establishes nucleus accumbens and central amygdala as causal neural substrates, suggesting specific targets for therapeutic intervention in chronic itch-associated psychiatric comorbidities.

Abstract from PubMed