title: Regional distribution of serotonergic receptors: a systems neuroscience perspective on the downstream effects of the multimodal-acting antidepressant vortioxetine on excitatory and inhibitory neurotransmission.
abstract: Previous work from this laboratory hypothesized that the multimodal antidepressant vortioxetine enhances cognitive function through a complex mechanism, using serotonergic (5-hydroxytryptamine, 5-HT) receptor actions to modulate gamma-butyric acid (GABA) and glutamate neurotransmission in key brain regions like the prefrontal cortex (PFC) and hippocampus. However, serotonergic receptors have circumscribed expression patterns, and therefore vortioxetine's effects on GABA and glutamate neurotransmission will probably be regionally selective. In this article, we attempt to develop a conceptual framework in which the effects of 5-HT, selective serotonin reuptake inhibitors (SSRIs), and vortioxetine on GABA and glutamate neurotransmission can be understood in the PFC and striatum-2 regions with roles in cognition and substantially different 5-HT receptor expression patterns. Thus, we review the anatomy of the neuronal microcircuitry in the PFC and striatum, anatomical data on 5-HT receptor expression within these microcircuits, and electrophysiological evidence on the effects of 5-HT on the behavior of each cell type. This analysis suggests that 5-HT and SSRIs will have markedly different effects within the PFC, where they will induce mixed effects on GABA and glutamate neurotransmission, compared to the striatum, where they will enhance GABAergic interneuron activity and drive down the activity of medium spiny neurons. Vortioxetine is expected to reduce GABAergic interneuron activity in the PFC and concomitantly increase cortical pyramidal neuron firing. However in the striatum, vortioxetine is expected to increase activity at GABAergic interneurons and have mixed excitatory and inhibitory effects in medium spiny neurons. Thus the conceptual framework developed here suggests that vortioxetine will have regionally selective effects on GABA and glutamate neurotransmission.
authors.affiliation: 1External Sourcing and Scientific Excellence,Lundbeck Research USA,Inc., Paramus,New Jersey,USA.
authors.forename: Alan L
authors.initials: AL
authors.lastname: Pehrson
authors.affiliation: 1External Sourcing and Scientific Excellence,Lundbeck Research USA,Inc., Paramus,New Jersey,USA.
authors.forename: Theepica
authors.initials: T
authors.lastname: Jeyarajah
authors.affiliation: 1External Sourcing and Scientific Excellence,Lundbeck Research USA,Inc., Paramus,New Jersey,USA.
authors.forename: Connie
authors.initials: C
authors.lastname: Sanchez
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D018698:Glutamic Acid / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism; D009488:Neurosciences; D010879:Piperazines / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000494:pharmacology; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000494:pharmacology; D018490:Serotonin Agents / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013440:Sulfides / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects*; D049490:Systems Biology; D000078784:Vortioxetine; D005680:gamma-Aminobutyric Acid / Q000187:drug effects / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D018698:Glutamic Acid; D010879:Piperazines; D011985:Receptors, Serotonin; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D058831:Serotonin 5-HT3 Receptor Antagonists; D018490:Serotonin Agents; D017367:Selective Serotonin Reuptake Inhibitors; D013440:Sulfides; D000078784:Vortioxetine; D005680:gamma-Aminobutyric Acid
keywords: 5-HT receptor; GABA; Lu AA21004; glutamate; vortioxetine