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. 2020 Aug 25;12:285–300. doi: 10.2147/JEP.S256586

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© 2020 Yu et al.

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Complex regulation of 5-HT projections to prefrontal cortex. 1. “Proximal” regulatory loop includes feedback collateral branches and 5-HT_1A autoreceptors, whose activation by excessive neurotransmitter results in reduced 5-HT synthesis and neuronal firing rate. Feedback collaterals also synapse with 5-HT_2B receptors on DNR GABA interneurons. Inhibition of these receptors may be one of the principal regulators of 5-HT tonic neurotransmission. Viloxazine, for instance, may inhibit 5-HT_2B receptors leading to inhibition of GABAergic transmission and consequently to upregulation of 5-HT tonic neurotransmission in mPFC, which may explain the increase of 5-HT in PFC observed in current microdialysis study. 2. At the terminal end 5-HT_1B/1D autoreceptors regulate the 5-HT release. Serotoninergic projections in mPFC interface with SST-expressing and PV-expressing GABA interneurons as well as directly modulate glutamatergic pyramidal neurons via postsynaptic inhibitory 5-HT_1A receptors and excitatory 5-HT_2A receptors. SST GABA interneurons have a primary role in “signal-to-noise” gating of pyramidal neurons, while PV interneurons via axonal receptors regulate “volume” of glutamate transmission. 3. Serotoninergic input, indirectly, via mPFC GABA interneurons, and directly, via pyramidal neurons, regulates initiation of the “distal” regulatory loop. Additionally, the balance between activation of 5-HT_2C receptors on GABA interneurons vs direct stimulation of 5-HT_2C receptors located on pyramidal neurons, ultimately tunes glutamatergic output from mPFC. 4. Glutamatergic projections from mPFC to LC noradrenergic neurons, VTA dopaminergic neurons, and DNR/MNR serotoninergic neurons, as well as their corresponding GABA interneurons, directly and indirectly regulate function of the brainstem monoaminergic nuclei. Local balance between stimulation of 5-HT_2C receptors on GABA interneurons vs ones located directly on VTA DA neurons, modulates DA output from the nucleus. At the termination point of the “distal” loop, glutamate fibers via excitatory AMPA and NMDA receptors located on 5-HT neurons and adjacent GABA interneurons, provide balanced regulatory input to serotoninergic nuclei.

Notes: Artigas F. 2013, Pharmacol Ther. 137:119–131. Cathala et al, 2019, Experimental Neurology, 311:57–66. Leggio et al, 2009, Neuropharmacology, 56: 507–513.

Abbreviations: 5-HT, 5-hydroxytryptamine, AMPA, α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid; DNR, dorsal nuclei raphe; GABA, gamma-aminobutyric acid; Glu, glutamate; LC, locus coeruleus; mGluR, metabotropic glutamate receptor; MnR, median raphe; mPFC, medial prefrontal cortex; NMDA, N-methyl-D-aspartate; PV, parvalbumin; SST, somatostatin; VTA, ventral tegmental area.