AMPA receptors modulate enhanced dopamine neuronal activity induced by the combined administration of venlafaxine and brexpiprazole

Addition of dopamine (DA)/serotonin (5-HT) partial agonists to 5-HT/norepinephrine (NE) reuptake inhibitors are commonly used to enhance the antidepressant response. The simultaneous inhibition of 5-HT and NE transporters with venlafaxine and its combination of brexpiprazole, which blocks the α₂-adrenergic autoreceptor on NE terminals, could constitute a superior strategy. Anesthetized rats received venlafaxine and brexpiprazole for 2 and 14 days, then the firing activity of dorsal raphe nucleus 5-HT, locus coeruleus NE, and ventral tegmental area DA neurons were assessed. Net 5-HT and NE neurotransmissions were evaluated by assessing the tonic activation of 5-HT_1A, and α₁- and α₂-adrenergic receptors in the hippocampus. The combination of brexpiprazole with venlafaxine resulted in normalized 5-HT and NE neuron activity, which occurred earlier than that with venlafaxine alone. A significant enhancement of the tonic activation of 5-HT_1A receptors and α₂-adrenoceptors in the hippocampus was observed following administration of the combination for 14 days. The combination more than doubled the number of DA neurons per electrode descent, after both 2 and 14 days, while this increase was observed only after 14 days of venlafaxine administration. This increase in population activity was prevented by NBQX, an AMPA receptor antagonist. In conclusion, early during administration, the combination of venlafaxine with brexpiprazole normalized firing activity of 5-HT and NE neurons, and increased the population activity of DA neurons through AMPA receptors. In the hippocampus, there was an overall increase in both 5-HT and NE transmissions. These results imply that this strategy could be a rapid-acting approach to treat depression.