Individual differences in novelty-seeking predict differential responses to chronic antidepressant treatment through sex- and phenotype-dependent neurochemical signatures

Women experience major depression at roughly twice the rate of men. Inconclusive clinical evidences assist the notion that responsiveness to antidepressant pharmacotherapy is sexually dimorphic with the two sexes presenting differential responses when treated with tricyclic antidepressants (TCAs). Notably, responsiveness to antidepressive agents presents marked inter-individual variability, the biological basis of which remains elusive. Herein, we sought to investigate putative sex differences to chronic antidepressant treatment with the TCA clomipramine in rats selected on the basis of their reactions to novelty. Our data revealed that high novelty-seeker (HR) male rats were more responsive to clomipramine treatment as far as the alleviation of anxiety and nociception are concerned, compared to low novelty-seeker (LR) males and HR/LR female rats. Surprisingly, chronic clomipramine treatment attenuated depressive-like symptomatology in the forced swim test (FST) of behavioral despair in both sexes albeit in the opposite novelty-seeking phenotypes (i.e. in male HR and female LR). Interestingly in male HR rats, clomipramine treatment diminished serotonergic neurochemical responses post-FST exposure in all limbic brain regions examined, while these were boosted in their LR counterparts. Dopaminergic and glutamatergic neurochemistry also presented phenotype-related alterations. On the contrary, in females the neurochemical substrate was only modestly affected. Notably, corticosteroid responses were augmented in female but attenuated in male drug-treated rats. Overall, the current dataset lends further support that the male sex may benefit to a greater extent when treated with TCAs and reveals that individual differences are associated with qualitative and quantitative sex-related behavioral and neurochemical manifestations in response to chronic antidepressant treatment.

► Novelty-seeking may predict responses to chronic antidepressant treatment.
► Antidepressant effects were evidenced in both sexes but in the opposite phenotypes.
► Male HR rats responded better to chronic clomipramine treatment.
► In males, the neurochemical substrate presented phenotype-related alterations.
► Corticosterone levels were boosted in females but attenuated in drug-treated males.