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We studied the effects of the multi-modal antidepressant, vortioxetine and the SSRI, paroxetine on pineal melatonin and monoamine synthesis in a sub-chronic tryptophan (TRP) depletion model of depression based on a low TRP diet.Female Sprague-Dawley rats were randomised to groups a) control, b) low TRP diet, c) low TRP diet + paroxetine and d) low TRP diet + vortioxetine. Vortioxetine was administered via the diet (0.76 mg/kg of food weight) and paroxetine via drinking water (10 mg/kg/day) for 14 days.Both drugs resulted in SERT occupancies > 90%. Vortioxetine significantly reversed TRP depletion-induced reductions of pineal melatonin and serotonin (5-HT) and significantly increased pineal noradrenaline NA. Paroxetine did none of these things.Other studies suggest pineal melatonin synthesis may involve N-methyl-D-aspartate (NMDA) receptors and glutamatergic modulation. Here observed changes may be mediated via vortioxetine's strong 5-HT reuptake blocking action together with possible additional effects on glutamate neurotransmission in the pineal via NMDA receptor-modulation and possibly with added impetus from increased NA output.The effects of vortioxetine and paroxetine on pineal melatonin and monoamines in a tryptophan depletion model of depression were studied.Adult female Sprague-Dawley rats were used. Vortioxetine was administered via the diet and paroxetine via drinking water for 14 days.Vortioxetine reversed TRP depletion-induced reductions of melatonin and 5-HT and increased pineal NA. Paroxetine did not.Observed changes may be mediated via vortioxetine's 5-HT reuptake blocking action.There may be additional effects on glutamate synthesis in the pineal via NMDA receptor-modulation plus added impetus from increased NA output.