Serotonin-2B receptor antagonism increases the activity of dopamine and glutamate neurons in the presence of selective serotonin reuptake inhibition


Previous research has implicated the serotonin-2B (5-HT2B) receptor as a possible contributor to the antidepressant-like response. Aripiprazole has been successfully used in combination with selective serotonin reuptake inhibitors (SSRIs) in treatment-resistant depression and it, among all receptors, exhibits the highest affinity for the 5-HT2B receptor. However, the potential contribution of such an antagonistic action on 5-HT2B receptors in the context of adjunct therapy is not known. In vivo electrophysiological recordings of ventral tegmental area (VTA) dopamine (DA) neurons, dorsal raphe nucleus (DRN) 5-HT neurons and pyramidal neurons in the medial prefrontal cortex (mPFC), and the hippocampus were conducted in anaesthetized Sprague-Dawley rats after the administration of 5-HT2B receptor ligands alone or in combination with the SSRI escitalopram. An escitalopram-induced decrease in DA, but not 5-HT firing activity, was rescued by 2-day co-administration of the selective 5-HT2B receptor antagonist LY266097. In the mPFC, 14-day escitalopram administration alone had no effect on pyramidal neuron firing and burst activity, whereas, aripiprazole administered alone or in combination with escitalopram for 14 days increased pyramidal neuron firing and burst activity. Likewise, the administration of LY266097 alone or its addition on the last 3 days of a 14-day escitalopram regimen increased pyramidal neuron firing and burst activity. These results indicated that 5-HT2B receptors play, at least in part, a role in this enhancement. In the hippocampus, 5-HT2B receptor activation by BW723c86 decreased escitalopram-induced inhibition of 5-HT reuptake, which was reversed by a 5-HT2B receptor antagonist. Altogether, these results put into evidence the possibility that 5-HT2B receptor blockade contributes to the therapeutic effect of aripiprazole addition to SSRIs in depression.

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Fig. 1: 5-HT2B receptors modulate firing and burst activity of DA neurons.
Fig. 2: Blockade of 5-HT2B receptors reverses escitalopram-induced inhibition of DA neurons.
Fig. 3: Blockade of 5-HT2B receptors does not rescue escitalopram-induced inhibition of 5-HT neurons.
Fig. 4: Blockade of 5-HT2B receptors increases mPFC pyramidal neurons firing and burst activity.
Fig. 5: 5-HT2B receptor agonism but not antagonism impairs 5-HTT function.


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RH contributed to the conception, acquisition, analysis, and interpretation of data, as well as drafting and revisions of the paper. MEM contributed to the conception and interpretation of data, as well as drafting, revisions, and final approval of the paper. PB contributed to the conception and interpretation of data, as well as drafting, revisions, and final approval of the paper.

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Correspondence to Rami Hamati.

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Hamati, R., El Mansari, M. & Blier, P. Serotonin-2B receptor antagonism increases the activity of dopamine and glutamate neurons in the presence of selective serotonin reuptake inhibition. Neuropsychopharmacol. (2020).

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