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Reciprocal effects of combined administration of serotonin, noradrenaline and dopamine reuptake inhibitors on serotonin and dopamine levels in the rat prefrontal cortex: the role of 5-HT_1A receptors

NeuroSearch A/S, Ballerup, Denmark, piw{at}neurosearch.dk

Jan Kehr

Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden

Jørgen Scheel-Krüger

NeuroSearch A/S, Ballerup, Denmark

The purpose of the present study was to examine, by in vivo microdialysis technique, the effects of triple acting monoamine reuptake inhibitors, constructed by combinations of a selective serotonin reuptake inhibitor citalopram with a noradrenaline/dopamine reuptake inhibitor methylphenidate and a serotonin/noradrenaline reuptake inhibitor venlafaxine with a dopamine reuptake inhibitor GBR12909, on extracellular levels of serotonin (5-HT), noradrenaline (NA) and dopamine (DA) in the prefrontal cortex (PFC) of anaesthetized rats. At the highest dose tested, adjunctive methylphenidate (10 mg/kg s.c.) to citalopram markedly attenuated by 63% the extracellular levels of 5-HT as compared to the levels induced by citalopram (5 mg/kg i.p.) alone, whereas the overall DA concentrations significantly increased to about 149% of those induced by methylphenidate alone. Similarly, the combination of venlafaxine with GBR12909 (10 mg/kg s.c.) caused a reduction of 5-HT levels to 66% of the levels induced by venlafaxine (10 mg/kg i.p.) alone, whereas the overall DA levels increased to 151% of the venlafaxine-treated group. The extracellular levels of NA were only marginally affected by the treatments with combined reuptake inhibitors compared to the effects induced by methylphenidate or venlafaxine alone. The modulatory effects of combined administration of the DA/NA reuptake inhibitors with the 5-HT reuptake inhibitors (citalopram and venlafaxine) on potentiation of DA and attenuation of 5-HT efflux were completely reversed by a pre-treatment with the 5-HT_1A receptor antagonist WAY-100635. These findings suggest a crucial role played by the 5-HT_1A receptors in balancing the reuptake inhibitory efficacy for the enhancement of 5-HT and DA transmission in the PFC by the drugs combining the reuptake inhibition of all three monoamines.

Key Words: antidepressants • augmentation therapy • microdialysis • citalopram • methylphenidate • venlafaxine • GBR12909 • WAY-100635 • prefrontal cortex

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