Celecoxib enhances the effect of reboxetine and fluoxetine on cortical noradrenaline and serotonin output in the rat.
A substantial number of patients with major depressive disorder (MDD) do not respond adequately to current antidepressant pharmacological treatments, which are all more or less based on a gradually increased enhancement of monoaminergic neurotransmission. Although a functional deficiency in monoaminergic neurotransmission may contribute to MDD, the etiology and pathophysiology are far from clarified. Recent studies suggest that inflammatory processes may contribute, since increased levels of pro-inflammatory cytokines and prostaglandin E(2) (PGE(2)) have repeatedly been observed in a subset of patients suffering from MDD. Interestingly, adjunct treatment with the anti-inflammatory drug celecoxib, a cyclo-oxygenase-2 (COX-2) inhibitor which blocks the PGE(2)-production, has shown to enhance the efficacy of both reboxetine, a selective noradrenaline reuptake inhibitor, as well as fluoxetine, a selective serotonin reuptake inhibitor, in treatment-resistant depression. To examine the neurobiological underpinnings to the clinical observations, we here studied the acute effects of a combined treatment with celecoxib and reboxetine on noradrenaline and dopamine output, as well as celecoxib and fluoxetine on 5-HT output in the medial prefrontal cortex, using in vivo microdialysis in awake freely moving rats. Celecoxib significantly potentiated the effects of reboxetine and fluoxetine on cortical noradrenaline and 5-HT output, respectively, but not the reboxetine-induced dopamine output. Moreover, celecoxib, when given alone, enhanced 5-HT output. These findings provide, in principle, novel experimental support for the clinical utility of combined treatment with antidepressant and anti-inflammatory drugs, such as COX-2 inhibitors, in MDD.
Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, S-171 77 Stockholm, Sweden.
Daniella
D
Johansson
Aki
A
Falk
Monica M
MM
Marcus
Torgny H
TH
Svensson
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D000068579:Celecoxib; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D004357:Drug Synergism; D005473:Fluoxetine / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis / Q000379:methods; D009025:Morpholines / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D000077593:Reboxetine; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology*
D018759:Adrenergic Uptake Inhibitors; D000068579:Celecoxib; D052246:Cyclooxygenase 2 Inhibitors; D004298:Dopamine; D005473:Fluoxetine; D009025:Morpholines; D009638:Norepinephrine; D011720:Pyrazoles; D000077593:Reboxetine; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D013449:Sulfonamides