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Review
. 2015 Aug 7;16(8):18474-506.
doi: 10.3390/ijms160818474.

Functional Selectivity and Antidepressant Activity of Serotonin 1A Receptor Ligands

Zdzisław Chilmonczyk  1   2 , Andrzej Jacek Bojarski  3 , Andrzej Pilc  4 , Ingebrigt Sylte  5
Affiliations
Review

Functional Selectivity and Antidepressant Activity of Serotonin 1A Receptor Ligands

Zdzisław Chilmonczyk et al. Int J Mol Sci. .

Abstract

Serotonin (5-HT) is a monoamine neurotransmitter that plays an important role in physiological functions. 5-HT has been implicated in sleep, feeding, sexual behavior, temperature regulation, pain, and cognition as well as in pathological states including disorders connected to mood, anxiety, psychosis and pain. 5-HT1A receptors have for a long time been considered as an interesting target for the action of antidepressant drugs. It was postulated that postsynaptic 5-HT1A agonists could form a new class of antidepressant drugs, and mixed 5-HT1A receptor ligands/serotonin transporter (SERT) inhibitors seem to possess an interesting pharmacological profile. It should, however, be noted that 5-HT1A receptors can activate several different biochemical pathways and signal through both G protein-dependent and G protein-independent pathways. The variables that affect the multiplicity of 5-HT1A receptor signaling pathways would thus result from the summation of effects specific to the host cell milieu. Moreover, receptor trafficking appears different at pre- and postsynaptic sites. It should also be noted that the 5-HT1A receptor cooperates with other signal transduction systems (like the 5-HT1B or 5-HT2A/2B/2C receptors, the GABAergic and the glutaminergic systems), which also contribute to its antidepressant and/or anxiolytic activity. Thus identifying brain specific molecular targets for 5-HT1A receptor ligands may result in a better targeting, raising a hope for more effective medicines for various pathologies.

Keywords: antidepressant activity; receptor trafficking; serotonin 1A receptors.

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Figures

Figure 1
Figure 1
Raphe neurons with low (A) and high (B) 5-HT1A receptor density. Mice with high somatodendritic 5-HT1A expression have lower basal firing rate (and elevated behavioral despair level). Blue dots—serotonin, red shape—SERT, green shape—5-HT1A receptor (according to [13,14]).
Figure 2
Figure 2
Signal transduction pathways of the 5-HT1A receptor [22,23,24].
Figure 3
Figure 3
Main elements of the receptor tyrosine kinase pathway.
Figure 4
Figure 4
Pharmacological profile (pEC50 for cAMP inhibition and ERK1/2 phosphorylation on the Y axis) of F15599 (brown), F13714 (green), and 5-HT (dark blue) [55].
Figure 5
Figure 5
Adult 5-HT raphe-PFC circuitry in anxiety and depression model (according to Albert et al.) [161]. The model shows 5-HT neurons (brown) projecting to prefrontal cortex GABAergic interneurons (yellow) and glutamatergic pyramidal neurons (blue) with transmitter release illustrated as small circles of the same colors. Receptors: 5-HT1A (green), 5-HT2A (light green), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-glutamate (purple) and GABAA receptors (blue). The response in the target neurons (red ovals): stimulatory (+), inhibitory (−). (↑)—elevation, (↓)—decrease. 5-HT1A heteroreceptors and GABAA receptors reduce the activity of the pyramidal neurons while 5-HT2A receptors activate the neurons.
Figure 6
Figure 6
The potential mechanism underlying the augmenting effects of 5-HT2A receptor blockade. (A) Increased extracellular 5-HT concentration may activate limbic monoamine system; (B) Blockade of activating 5-HT2A receptors may reduce a potential hyperactivity of the monoamine system (according to [2]).
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