In vivo potentiation of reboxetine and citalopram effect on extracellular noradrenaline in rat brain by α2-adrenoceptor antagonism

The therapeutic activity of noradrenaline reuptake inhibitors (NaRIs) and serotonin reuptake inhibitors (SSRIs) as antidepressant is based on their ability to increase monoamine concentrations in the synaptic cleft. α(2)-Adrenoceptors inhibit noradrenaline (NA) release, which modulates antidepressant neurochemical activity. The present study assesses the influence of the addition of the selective α(2)-adrenoceptor antagonist RS79948 to the NaRI reboxetine and the SSRI citalopram on brain extracellular NA. Dual-probe microdialysis technique in the locus coeruleus (LC) and prefrontal cortex (PFC) was performed in freely moving rats. Acute reboxetine (3 and 5 mg/kg i.p.) promoted a dose-dependent increase of NA in LC (164 ± 15%; 243 ± 24%) and PFC (140 ± 7%; 181 ± 30%). Acute citalopram (5 mg/kg i.p.) did not change NA in LC or PFC, but at 10 mg/kg i.p. increased NA in LC (144 ± 14%) and decreased it in PFC (-42 ± 7%). An inactive dose of RS79948 (0.1mg/kg i.p.) in rats pretreated with reboxetine (3 mg/kg i.p.) or citalopram (5mg/kg i.p.) induced a significant enhancement of NA in LC (reboxetine: 462 ± 137%; citalopram: 142 ± 11%) and PFC (reboxetine: 281 ± 56%; citalopram: 130 ± 16%). The results indicate that co-administration of selective α(2)-adrenoceptor antagonist drugs might improve the effects of NaRI or SSRI antidepressants by enhancing extracellular NA concentrations in the brain.