The frontal cortex as a network hub controlling mood and cognition: Probing its neurochemical substrates for improved therapy of psychiatric and neurological disorders

Abstract

The highly-interconnected and neurochemically-rich frontal cortex plays a crucial role in the regulation of mood and cognition, domains disrupted in depression and other central nervous system disorders, and it is an important site of action for their therapeutic control. For improving our understanding of the function and dysfunction of the frontal cortex, and for identifying improved treatments, quantification of extracellular pools of neuromodulators by microdialysis in freely-moving rodents has proven indispensable. This approach has revealed a complex mesh of autoreceptor and heteroceptor interactions amongst monoaminergic pathways, and led from selective 5-HT reuptake inhibitors to novel classes of multi-target drugs for treating depression like the mixed α₂-adrenoceptor/5-HT reuptake inhibitor, S35966, and the clinically-launched vortioxetine and vilazodone. Moreover, integration of non-monoaminergic actions resulted in the discovery and development of the innovative melatonin receptor agonist/5-HT_2C receptor antagonist, Agomelatine. Melatonin levels, like those of corticosterone and the “social hormone”, oxytocin, can now be quantified by microdialysis over the full 24 h daily cycle. Further, the introduction of procedures for measuring extracellular histamine and acetylcholine has provided insights into strategies for improving cognition by, for example, blockade of 5-HT₆ and/or dopamine D₃ receptors. The challenge of concurrently determining extracellular levels of GABA, glutamate, d-serine, glycine, kynurenate and other amino acids, and of clarifying their interactions with monoamines, has also been resolved. This has proven important for characterizing the actions of glycine reuptake inhibitors that indirectly augment transmission at N-methyl-d-aspartate receptors, and of “glutamatergic antidepressants” like ketamine, mGluR5 antagonists and positive modulators of AMPA receptors (including S47445). Most recently, quantification of the neurotoxic proteins Aβ42 and Tau has extended microdialysis studies to the pathogenesis of neurodegenerative disorders, and another frontier currently being broached is microRNAs. The present article discusses the above themes, focusses on recent advances, highlights opportunities for clinical “translation”, and suggests avenues for further progress.