Neurobiology and neuropharmacology of monoaminergic systems

Deurwaerdère, Philippe De; Ramsay, Rona R.; Giovanni, Giuseppe Di

doi:10.1016/j.pneurobio.2017.02.001

Cited by 13 publications

(9 citation statements)

References 14 publications

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“…8 ), but systematic analyses of their incidence, life-progression and causal link with treatment are not yet available. It is likely that the aberrant function of cortico-thalamo-cortical networks (underlying the generation of SWD and absence seizures) ( Crunelli and Leresche, 2002 a ; Blumenfeld, 2005 a ) combines with the abnormal activity of basal ganglia-limbic-monoamine networks (underlying attention deficits, cognitive impairments and mood disorders) ( De Deurwaerdère et al , 2017 ; Miskowiak and Petersen, 2019 ; Park et al , 2019 ) to generate the overall neuropsychiatric comorbid phenotype of absence seizure ( Fig. 8 , left).…”

Section: Introductionmentioning

confidence: 99%

Clinical and experimental insight into pathophysiology, comorbidity and therapy of absence seizures

Crunelli

Lőrincz

McCafferty

et al. 2020

Brain

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Absence seizures in children and teenagers are generally considered relatively benign because of their non-convulsive nature and the large incidence of remittance in early adulthood. Recent studies, however, show that 30% of children with absence seizures are pharmaco-resistant and 60% are affected by severe neuropsychiatric comorbid conditions, including impairments in attention, cognition, memory and mood. In particular, attention deficits can be detected before the epilepsy diagnosis, may persist even when seizures are pharmacologically controlled and are aggravated by valproic acid monotherapy. New functional MRI-magnetoencephalography and functional MRI-EEG studies provide conclusive evidence that changes in blood oxygenation level-dependent signal amplitude and frequency in children with absence seizures can be detected in specific cortical networks at least 1 min before the start of a seizure, spike-wave discharges are not generalized at seizure onset and abnormal cortical network states remain during interictal periods. From a neurobiological perspective, recent electrical recordings and imaging of large neuronal ensembles with single-cell resolution in non-anaesthetized models show that, in contrast to the predominant opinion, cortical mechanisms, rather than an exclusively thalamic rhythmogenesis, are key in driving seizure ictogenesis and determining spike-wave frequency. Though synchronous ictal firing characterizes cortical and thalamic activity at the population level, individual cortico-thalamic and thalamocortical neurons are sparsely recruited to successive seizures and consecutive paroxysmal cycles within a seizure. New evidence strengthens previous findings on the essential role for basal ganglia networks in absence seizures, in particular the ictal increase in firing of substantia nigra GABAergic neurons. Thus, a key feature of thalamic ictogenesis is the powerful increase in the inhibition of thalamocortical neurons that originates at least from two sources, substantia nigra and thalamic reticular nucleus. This undoubtedly provides a major contribution to the ictal decrease in total firing and the ictal increase of T-type calcium channel-mediated burst firing of thalamocortical neurons, though the latter is not essential for seizure expression. Moreover, in some children and animal models with absence seizures, the ictal increase in thalamic inhibition is enhanced by the loss-of-function of the astrocytic GABA transporter GAT-1 that does not necessarily derive from a mutation in its gene. Together, these novel clinical and experimental findings bring about paradigm-shifting views of our understanding of absence seizures and demand careful choice of initial monotherapy and continuous neuropsychiatric evaluation of affected children. These issues are discussed here to focus future clinical and experimental research and help to identify novel therapeutic targets for treating both absence seizures and their comorbidities.

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Section: Introductionmentioning

confidence: 99%

Clinical and experimental insight into pathophysiology, comorbidity and therapy of absence seizures

Crunelli

Lőrincz

McCafferty

et al. 2020

Brain

Self Cite

149

159

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“…β-adrenoceptors or 5-HT 3 receptors, respectively), are catabolized by monoamine oxidase and/or catechol- ο -methyltransferase (in the case of NE and DA) and are pumped back into their synaptic terminals by selective transporter proteins. Furthermore, these neurotransmitters are accumulated into synaptic vesicles inside the nerve terminals by specific transporters, and even within noradrenergic neurons the presence of the enzyme DA-β-hydroxylase can be considered as an additional site for the interaction of DA [ 1 , 2 ]. Moreover, several other compounds, including therapeutically useful and widely used recreational drugs which bind to more than one of these receptor proteins have been described [ 2 , 3 ].…”

Section: Introductionmentioning

confidence: 99%

3D similarities between the binding sites of monoaminergic target proteins

et al. 2018

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The study of binding site similarities can be relevant to understand the interaction of different drugs at several molecular targets. The increasing availability of protein crystal structures and the development of novel algorithms designed to evaluate three-dimensional similarities, represent a great opportunity to explore the existence of electronic and shape features shared by clinically relevant proteins, which could assist drug design and discovery. Proteins involved in the recognition of monoaminergic neurotransmitters, such as monoamine transporters or monoamine oxidases (MAO) have been related to several psychiatric and neurological disorders such as depression or Parkinson’s disease. In this work, we evaluated the possible existence of similarities among the binding sites of the serotonin transporter (SERT), the dopamine transporter (DAT), MAO-A and MAO-B. This study was carried out using molecular simulation methodologies linked to the statistical algorithm PocketMatch, which was modified in order to obtain similarities profiles. Our results show that DAT and SERT exhibit a high degree of 3-D similarities all along the pathway that is presumably involved in the substrate transport process. Distinct differences, on the other hand, were found both at the extracellular and the intracellular ends of the transporters, which might be involved in the selective initial recognition of the corresponding substrate. Similarities were also found between the active (catalytic) site of MAO-A and the extracellular vestibule of SERT (the S2 binding site). These results suggest some degree of structural convergence for these proteins, which have different functions, tissue distribution and genetic origin, but which share the same endogenous ligand (serotonin). Beyond the functional implications, these findings are valuable for the design of both selective and non-selective ligands.

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“…They exhibit higher activity in wakefulness but less during REM sleep 38 . At the spinal cord, NA and 5‐HT increase the excitability of the CPG via the coerulospinal and raphespinal tracts, respectively 39 . They also control nociception by acting on dorsal horn spinal neurons 39,40 .…”

Section: Lb Pathology and Neurotransmitters In Pdmentioning

confidence: 99%

Neurophysiological mechanisms of gait disturbance in advanced Parkinson's disease patients

Takakusaki

Takahashi

Noguchi

et al. 2022

Neurology & Clinical Neurosc

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This review considers pathophysiological mechanisms of posture-gait disturbances in Parkinson's disease (PD). Clinical studies have shown that posture-gait disturbance attributes to the dysfunction of the whole neuraxis in addition to the musculoskeletal system. The cerebral cortex, basal ganglia (BG), cerebellum, brainstem, and spinal cord temporally and spatially integrate and coordinate multisensory feedback and efferent copies of the motor command. Therefore, the extensive repertoire of voluntary movements can be coupled with anticipatory and reactive postural adjustments to provide the framework for supporting and stabilizing the goal-directed gait activity. Redundancies in the system allow adaptation and compensation through reward-oriented and error-based learning processes implemented through the BG and cerebellar pathways, respectively.However, the impairment of these systems in PD may considerably compromise the capacity to adapt and lead to maladaptive changes impairing posture-gait control. When these impairments occur, the risk of falls can significantly increase, and interventions are required to reduce morbidity. The damage in dopamine (DA) neurons is the primary cause of PD. Insufficient DA supply in the striatum disturbs the operation of intrinsic networks in the BG. This also pathologically increases GABAergic BG output to the cerebral cortex and brainstem, resulting in functional disconnection of other structures from the BG. The disconnection makes PD patients disable to achieve habitually acquired automatized gait control. Moreover, Lewy body degeneration in most brain areas, particularly in cholinergic and other monoaminergic systems vulnerable to neurodegeneration, further disturbs posture-gait control and alters non-motor symptoms of PD.

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Neurobiology and neuropharmacology of monoaminergic systems

Cited by 13 publications

References 14 publications

Clinical and experimental insight into pathophysiology, comorbidity and therapy of absence seizures

Clinical and experimental insight into pathophysiology, comorbidity and therapy of absence seizures

3D similarities between the binding sites of monoaminergic target proteins

Neurophysiological mechanisms of gait disturbance in advanced Parkinson's disease patients

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