Combination of escitalopram and a 5-HT1A receptor antagonist selectively decreases the extracellular levels of dopamine in the nucleus accumbens relative to striatum through 5-HT2C receptor stimulation; suggestive of antipsychotic potential

Abstract

Serotonin 5-HT2C receptors are widely distributed throughout the brain located on GABAergic interneurons and afferent neurons in the ventral tegmental area and substantia nigra. Consequently, activation of this receptor modulates the dopaminergic neurotransmission. The antipsychotic potential of the combined treatment with escitalopram, in therapeutic relevant doses, and the 5-HT1A receptor antagonist, WAY-100635, has been evaluated by assessment of conditioned avoidance (CAR) behaviour and the use of microdialysis in freely moving rats. The combined treatment was found to decrease both CAR behaviour without affecting escape failures and the basal extracellular levels of dopamine (DA) in the nucleus accumbens (NAc) acutely without affecting DA levels in the striatum, suggesting an antipsychotic-like effect with mesolimbic selectivity. The escitalopram/WAY-100635-induced changes in CAR behaviour and DA were prevented by pretreatment with the 5-HT2C receptor antagonist, SB242084, indicating that the effects are mediated by stimulation of the 5-HT2C receptor. Thus, indirect activation of the 5-HT2C receptor may induce antipsychotic-like effects. The observations on DA levels were in line with the findings made with the selective 5-HT2C receptor agonist, vabicaserin, which was also shown to produce a mesolimbic selective decrease in DA levels in the present study. In addition, it was demonstrated that escitalopram, in combination with the partial 5-HT1A agonist, (-)-pindolol, decreased basal DA levels in the NAc. A potential therapeutic effect could readily be assessed, since both escitalopram and (-)-pindolol are already on the market.