Nowadays the most widely used antidepressants are selective serotonin reuptake inhibitors (SSRI) or noradrenaline reuptake inhibitors (NRI), however, these take four to eight weeks to exert their effects and each drug is efficacious only in 60-70% of patients. In an attempt to improve the efficacy of antidepressants, new drugs that also modify dopamine levels are being developed. The aim of this study was to investigate the impact of L-DOPA administration on the effect elicited by antidepressants on serotonergic and noradrenergic neurotransmission. To this end, single-unit extracellular recordings of the noradrenergic nucleus, locus coeruleus (LC), and the serotonergic nucleus, dorsal raphe (DRN) combined with behavioural approaches were performed. L-DOPA did not modify the basal neuronal activity in either the LC or the DRN or induce any change in the modified forced swimming test. However, L-DOPA enhanced the neuronal response to reboxetine in the LC and increased its antidepressant-like effects but counteracted the effect of fluoxetine on neurons in the LC and decreased its antidepressant-like effect. The sensitivity of neurons in the DRN to reboxetine and fluoxetine was not altered by the administration of L-DOPA. Taken together, these results indicate that L-DOPA modifies the effect of SSRI and NRI antidepressants in opposing ways.