Serotonergic Regulation of Prefrontal Cortical Circuitries Involved in Cognitive Processing: A Review of Individual 5-HT Receptor Mechanisms and Concerted Effects of 5-HT Receptors Exemplified by the Multimodal Antidepressant Vortioxetine

Abstract

It has been known for several decades that serotonergic neurotransmission is a key regulator of cognitive function, mood, and sleep. Yet with the relatively recent discoveries of novel serotonin (5-HT) receptor subtypes, as well as an expanding knowledge of their expression level in certain brain regions and localization on certain cell types, their involvement in cognitive processes is still emerging. Of particular interest are cognitive processes impacted in neuropsychiatric and neurodegenerative disorders. The prefrontal cortex (PFC) is critical to normal cognitive processes, including attention, impulsivity, planning, decision-making, working memory, and learning or recall of learned memories. Furthermore, serotonergic dysregulation within the PFC is implicated in many neuropsychiatric disorders associated with prominent symptoms of cognitive dysfunction. Thus, it is important to better understand the overall makeup of serotonergic receptors in the PFC and on which cell types these receptors mediate their actions. In this Review, we focus on 5-HT receptor expression patterns within the PFC and how they influence cognitive behavior and neurotransmission. We further discuss the net effects of vortioxetine, an antidepressant acting through multiple serotonergic targets given the recent findings that vortioxetine improves cognition by modulating multiple neurotransmitter systems.

A Sensitive Precolumn Derivatization Method for Determination of Piperazine in Vortioxetine Hydrobromide Using a C8 Column and High-Performance Liquid Chromatography–Mass Spectrometry

“…[2][3][4] VT was jointly developed by the pharmaceutical companies Lundbeck A/S and Takeda Pharmaceutical Company Ltd. to treat major depressive disorders. [5][6][7] Piperazine is used as a starting material in the synthesis of VT and may represent a residual compound in the active pharmaceutical ingredient (API) product.…”

Effects of exposure to 5-MeO-DIPT during adolescence on brain neurotransmission and neurotoxicity in adult rats

“…5-HT 1A receptor stimulation leads to inhibition of neuronal activity [34]. These receptors were shown to be located on GABAergic interneurons in the frontal cortex [36]. Thus, the possibility of decreased density as shown by attenuated expression of inhibitory 5-HT 1A receptors and subsequent increase in GABA levels may result in weaker responses of DA neurons in the striatum (Fig.…”

Neural connection supporting endogenous 5-hydroxytryptamine influence on autonomic activity in medial prefrontal cortex

“…By altering K + and/or Ca 2+ conductance via 5-HT receptor coupled G-protein signaling, 5-HT 2 , 5-HT 4 , 5-HT 6 or 5-HT 7 receptors mediate membrane depolarization of pyramidal neurons, while 5-HT 1 receptors produce hyperpolarization (Aghajanian and Marek, 1997;Beique et al, 2004;Leiser et al, 2015). In parallel with this, 5-HT 1A suppresses postsynaptic NMDA currents; while 5-HT 2A can either increase glutamate release and/or postsynaptic AMPA/NMDA currents, or decrease postsynaptic GABA A currents, thus facilitating excitation of mPFC neurons (Aghajanian and Marek, 1999;Arvanov et al, 1999;Yuen et al 2005 and.…”

“…However, these previous studies did not distinguish between cell subtypes. It is very likely that mPFC-DVC neurons may demonstrate distinct 5-HT receptor expression profile(s) and intrinsic physiological properties (Leiser et al, 2015). Different 5-HT receptor subtypes can interact, resulting in complex effects.…”