Signs of antidepressant-like effects of temozolomide as measured in the forced-swim test in adult rats.

BACKGROUND: Temozolomide is the gold standard chemotherapeutic agent for glioblastoma multiforme. Yet its pharmacological use has been linked to the emergence of depressive- and/or anxiety-like behaviors, probably through the inhibition of hippocampal neurogenesis. Since prior studies reporting these negative effects were based on prolonged treatment paradigms (from 2 weeks to up to 6 months), and given the lack of studies including females, our approach aimed at further characterizing the behavioral effects induced by temozolomide (25 mg/kg, 1 or 2 cycles, 5 days/cycle) in a adult rats of both sexes. METHODS: Rats were scored across time through specific behavioral tests that capture diverse manifestations of affective-like responses (forced-swim, open field, novelty-suppressed feeding, sucrose preference) or cognitive performance (Barnes maze). At the neurochemical level, we ascertained the effects of 2 cycles of temozolomide on an early stage of hippocampal neurogenesis (neural progenitors, NeuroD) and other potential neuroplasticity targets (mature BDNF, FADD). RESULTS: Temozolomide induced signs of antidepressant-like responses as measured in the forced-swim test in a treatment-duration manner. It also decreased NeuroD and hippocampal FADD, a neuroplastic marker previously associated with the acute and repeated actions of most antidepressants. These results suggested that other mechanisms of action might be associated with temozolomide's behavioral effects besides hippocampal neurogenesis, such as the correlative one described through the neuroplastic molecule FADD. CONCLUSIONS: In conjunction with the prior data, our results suggested cycle- and/or length-dependent treatment effects in terms of temozolomide's antidepressant- vs. depressant-like profile, while proposing a novel biomarker related to treatment response.