Updating neuropathology and neuropharmacology of monoaminergic systems

Abstract

Due to the great progress and development of modern technology, our understanding of the biological, physiological and metabolic processes of neuropsychiatric disorders has advanced tremendously. However, we still face many challenges in drug discovery and development targeting because neuropsychiatric disorders have a complex aetiology with multiple points of possible intervention. This is also apparent when taking into consideration the plurality of targets that bind antipsychotics, anti-Parkinsonian or antidepressant drugs, indicating the need to develop multi-target compounds for a polypharmacological approach (Hopkins, 2008).Understanding the interactions of neurotransmission systems especially among monoamines is an important step for the optimization of therapeutic strategies for many if not all of these neuropsychiatric disorders. Neurotransmitters such as dopamine, 5-HT (serotonin), noradrenaline and histamine play a central role in the pathophysiology of major neuropsychiatric illnesses, including anxiety and mood disorders, schizophrenia, autism spectrum disorders, Parkinson's disease, epilepsy and dementias (De Deurwaerdère and Di Giovanni, 2016;Simic et al., 2016;Venzi et al., 2016). Numerous medicines targeting monoaminergic systems have been used successfully, but most require adjustments due to the emergence of side effects. However, the efficacy of these medicines suggests that the strategy to correct abnormal signalling of monoaminergic neurotransmitters is appropriate. A further complication arises in that monoaminergic systems establish close relationships with other neurotransmitter systems (Chesselet, 1984), so it is likely that a pharmacological effect on one system will more or less directly affect the other one. This is highlighted by well-known associations such as the 5-HT/dopamine interaction De Deurwaerdère and Di Giovanni, 2016), the glutamate/dopamine interaction (Carlsson and Carlsson, 1990) and the 5-HT/GABA interaction (Soubrie, 1986;Crunelli and Di Giovanni, 2014). Moreover, neurotransmitter-binding proteins such as receptors, transporters and common metabolic enzymes have commonalities in their binding sites that must be considered as the starting points for development of new tools to diagnose and drugs to treat specific clusters of symptoms.The European Cooperation in Science and Technology (Figure 1) Action CM1103 'Structure-based drug design for diagnosis and treatment of neurological diseases: dissecting and modulating complex function in the monoaminergic systems of the brain' is a good example of the advances possible through interdisciplinary collaboration on these difficult problems (http://www.cost.eu/COST_Actions/cmst/CM1103).During the 4 year life of the Action, different European laboratories using innovative computational approaches have contributed to the analysis of the pharmacophores, identified novel hits and verified the suitability of new compounds against multiple The purpose of this special issue is to collect relevant research and review papers covering ...

The regulatory role of AP-2β in monoaminergic neurotransmitter systems: insights on its signalling pathway, linked disorders and theragnostic potential

“…On the other hand, current treatment options targeting different proteins in monoaminergic systems are far from optimal. In particular, tricyclic antidepressants (TCA), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs) and catechol-O-methyltransferase inhibitors (COMTIs) are associated with serious adverse and off-target effects as well as interactions with foods and other drugs, resulting in poor patient compliance and treatment outcomes [11][12][13][14][15][16][17][18].…”