Investigating the Potential Role of Serotonin-2B Receptor Antagonism in the Neuronal Actions of Adjunctive Aripiprazole

Abstract

Introduction: Using serotonin-2B (5-HT2B) receptor knockout (KO) mice, previous research has demonstrated that 5-HT2B receptors contribute to the antidepressant-like response. Several serotonin-dopamine partial agonists (i.e. aripiprazole; previously known as atypical antipsychotics) that exhibit high affinity antagonism at the 5-HT2B receptor have been successfully used in combination with selective 5-HT reuptake inhibitors (SSRIs) in difficult to treat major depressive disorder. However, the exact contribution of the antagonistic action of aripiprazole on 5-HT2B receptors in the context of adjunct therapy is not known. Methods: In-vivo electrophysiological recordings of ventral tegmental area (VTA) dopamine (DA), prelimbic and infralimbic medial prefrontal cortical (mPFC) pyramidal and dorsal CA3 hippocampal pyramidal neurons were conducted in anaesthetized Sprague-Dawley rats. Results: Acute administration of the 5-HT2B receptor agonist BW723c86 (6 mg/kg, intravenously [i.v.]) decreased the firing and bursting activity of DA neurons, which was abolished by pre-administration of the selective 5-HT2B receptor antagonist RS127445 (2 mg/kg, subcutaneously [s.c.]). After two days, an SSRI-induced (escitalopram 10 mg/kg/day, s.c.) decrease in DA firing activity was rescued by co-administration of the selective 5-HT2B receptor antagonist LY266097 (0.6 mg/kg/day, intraperitoneally [i.p.]). Aripiprazole (2 mg/kg/day, s.c.) administered alone or in combination with escitalopram for 14 days increased mPFC neuron firing and bursting activity, however escitalopram alone did not. LY266097 alone or the addition of LY266097 for the last three days of a 14-day escitalopram treatment increased mPFC pyramidal neuron firing and bursting activity more so than escitalopram alone. Finally, acute ejection of BW723c86 via microiontophoresis impaired SSRI binding to the serotonin transporter (5-HTT) in dorsal hippocampal pyramidal neurons. Conclusions: 5-HT2B receptor blockade rescues an SSRI-mediated decrease in DA firing activity. The increase in mPFC pyramidal neuron firing and bursting activity mediated by aripiprazole and in combination with escitalopram may be, at least partly, moderated by 5-HT2B receptors expressed in this brain area. Lastly, 5-HT2B receptor agonism may impair SSRI binding to 5-HTT in the hippocampus. Altogether, these results strengthen the view that 5-HT2B receptor antagonism contributes to the therapeutic effect of aripiprazole.