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 α-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 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-HT and/or dopamine D 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.

Quantitative profiling of neurotransmitter abnormalities in brain, cerebrospinal fluid, and serum of experimental diabetic encephalopathy male rat

“…Large numbers of studies have confirmed that the metabolic disorders of monoamine neurotransmitters are closely related to a series of neurodegenerative diseases, which have been recognized to play major regulatory roles in cognitive function (Bouwmans, Leentjens, Mess, & Weber, ; Millan, Rivet, & Gobert, ; Tadaiesky et al, ), where Trp metabolism has been singled out to be one of the important branches. Trp, a significant precursor for the synthesis of neurotransmitters in the human body, can adjust the mental rhythm and improve sleep.…”

“…Large numbers of studies have confirmed that the metabolic disorders of monoamine neurotransmitters are closely related to a series of neurodegenerative diseases, which have been recognized to play major regulatory roles in cognitive function (Bouwmans, Leentjens, Mess, & Weber, 2016;Millan, Rivet, & Gobert, 2016;Tadaiesky et al, 2008),…”

Comparative Pro-cognitive and Neurochemical Profiles of Glycine Modulatory Site Agonists and Glycine Reuptake Inhibitors in the Rat: Potential Relevance to Cognitive Dysfunction and Its Management

“…Accordingly, we compared the glycine modulatory site agonists (glycine, D-serine, D-cycloserine and S18841) and GlyT1 inhibitors (sarcosine and ORG25935) on microdialysis levels of glycine and D-serine and other neurotransmitters thought to regulate cognition in the prefrontal cortex (PFC) of rats [37]. These compounds were also compared in three cognitive tasks: social recognition, novel object recognition (NOR) and an associative conditioned freezing response (CFR) task (selected for translational relevance to schizophrenia from consensus reviews [38,39], and whose predictive validity will be considered in the discussion). In addition, we employed a microinjection procedure to examine the role of the PFC in the action of S18841.…”

Rethinking schizophrenia through the lens of evolution: shedding light on the enigma

“…Secondly, the substantial fecundity disadvantage of people with a diagnosis of schizophrenia, reduced to about 50% compared to healthy individuals (Crow 1995b, Brune 2004, Power et al 2013, Markow 1994, McGrath et al 1999) and, to finish with a significantly increased risk of mortality compared to healthy individuals (Saha et al 2007, Liu et al 2017, Tsuang and Simpson 1988, Allebeck 1989, Brown 1997, Harris and Barraclough 1998, Olfson et al 2015.…”