Assessing the neuronal serotonergic target-based antidepressant stratagem: impact of in vivo interaction studies and knockout models

Abstract

Depression remains a challenge in the field of affective neuroscience, despite a steady research progress. Six out of nine basic antidepressant mechanisms rely on serotonin neurotransmitter system. Preclinical studies have demonstrated the significance of serotonin receptors (5-HT(1-3,6,7)), its signal transduction pathways and classical down stream targets (including neurotrophins, neurokinins, other peptides and their receptors) in antidepressant drug action. Serotonergic control of depression embraces the recent molecular requirements such as influence on proliferation, neurogenesis, plasticity, synaptic (re)modeling and transmission in the central nervous system. The present progress report analyses the credibility of each protein as therapeutically relevant target of depression. In vivo interaction studies and knockout models which identified these targets are foreseen to unearth new ligands and help them transform to drug candidates. The importance of the antidepressant assay selection at the preclinical level using salient animal models/assay systems is discussed. Such test batteries would definitely provide antidepressants with faster onset, efficacy in resistant (and co-morbid) types and with least adverse effects. Apart from the selective ligands, only those molecules which bring an overall harmony, by virtue of their affinities to various receptor subtypes, could qualify as effective antidepressants. Synchronised modulation of various serotonergic sub-pathways is the basis for a unique and balanced antidepressant profile, as that of fluoxetine (most exploited antidepressant) and such a profile may be considered as a template for the upcoming antidepressants. In conclusion, 5-HT based multi-targeted antidepressant drug discovery supported by in vivo interaction studies and knockout models is advocated as a strategy to provide classic molecules for clinical trials.

Keywords: Serotonin; depression; interaction studies; knockout models; preclinical screening; target.; trophic factors.

Fig. (1)

Schematic representation of different antidepressant mechanisms at the serotonergic synapse. The diagram depicts only those possible sites of action which have been associated with the molecular basis of depression till date. The SSRIs, SNRIs and SARIs inhibit 5-HT reuptake by acting on the transporter. SARIs also block the postsynaptic 5-HT₂ receptors. MAO inhibitors prevent 5-HT breakdown thereby increasing the synaptic concentrations. NaSSAs (α₂ antagonists) block postsynaptic 5-HT₂ and 5-HT₃ receptors. SREs, enhance the presynaptic 5-HT uptake and also prevent the susceptibility of 5-HT to MAO.

Fig. (2)

A simplified schematic representation of cellular events involving the neuronal metabotropic 5-HT receptors associated with depression. 5-HT_2,6,7 subtypes are post-synaptic receptors, whereas 5-HT_1A is a somatodendritic autoreceptor. To simplify the cellular events, all the receptors (somatodendritic and post-synaptic) have been depicted in a single diagram. The 5-HT_{1, 6, 7} and 5-HT₂ receptors through cAMP-PK and IP3–Ca²⁺ dependent protein kinase secondary messenger systems influence CREB. The agonists of 5-HT₆, or the antagonists of 5-HT₇ facilitate glutamate release. Increase in extracellular concentration of glutamate activates BDNF through AMPA receptors. BDNF and TrkB are target genes for CREB (transcription factor). BDNF in turn activates Arc. Altered expression of BDNF, CREB, TrkB and Arc are of potential benefit in depression. (Based on references [77] and [230]).