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Framework for internal sensation of pleasure using constraints from disparate findings in nucleus accumbens

World Journal of Psychiatry 2021年第10期11卷 681-695页

作者： Kunjumon Ittira Vadakkan Division of Neuroscience Neurosearch CenterToronto M5S2M3OntarioCanada

It is necessary to find a mechanism that generates first-person inner sensation of pleasure to understand what causes addiction and associated behaviour by drugs of abuse.The actual mechanism is expected to explain several disparate findings in nucleus accumbens(NAc),a brain region associated with pleasure,in an interconnected manner.Previously,it was possible to derive a mechanism for natural learning and explain:(1)Generation of inner sensation of memory using changes generated by learning;and(2)Long-term potentiation as an experimental delayed scaled-up change by the same mechanism that occur during natural learning.By extending these findings and by using disparate third person observations in NAc from several studies,present work provides a framework of a mechanism that generates internal sensation of pleasure that can provide interconnected explanations for:(1)Ability to induce robust long-term depression(LTD)in NAc from naïve animals;(2)Impaired ability to induce LTD in“addicted”state;(3)Attenuation of postsynaptic potentials by cocaine;and(4)Reduced firing of medium spiny neurons in response to cocaine or dopamine.Findings made by this work are testable.

关键词： Pleasure Internal sensation Mind Memory Long-term potentiation Longterm depression Nucleus accumbens Drug addiction

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3-Arylisothiazoloquinols as potent ligands for the benzodiazepine site of GABA_(A) receptors

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Journal of Biomedical science and Engineering 2012年第1期5卷 1-9页

作者： Jakob Nilsson Elsebet Φstergaard Nielsen Tommy Liljefors Mogens Nielsen Olov sterner Division of Organic Chemistry Lund UniversityLundSweden neurosearch a/s BallerupDenmark Faculty of Pharmaceutical sciences University of CopenhagenCopenhagenDenmark

3-Arylisothiazolo[5,4-b]quinolin-4(9H)-ones and 3-arylisoxazolo[5,4-b]quinolin-4(9H)-ones were synthesized and assayed for affinity for the benzodiazepine binding site of the GABAA receptors. While the 3-arylisothiazoloquinolin-4-ones were found to be potent ligands, with affinities (expressed as the affinity Ki value) down to 1 nM, the 3-arylisoxazoloquinolin-4-ones are less potent. This is suggested to depend on sterical repulsive interaction of the 3-arylisoxazoloquinolin-4-ones with the receptor essential volume of the binding site, and a higher electron density at the nitrogen in the azole ring (N-2) as well as the carbonyl oxygen in the isothiazoloquinolin-4-ones enabling them to interact stronger with hydrogen bond donor sites at the binding site.

关键词： Isothiazolo[5,4-b]quinolin-4(9H)-ones Isoxazolo[5,4-b]quinolin-4(9H)-ones Benzodiazepine Binding site GABAA Receptors GABA_(A) Receptor subtypes Pharmacophore Model

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