Pharmacological activation of dopamine D4 receptor modulates morphine-induced changes in the expression of GAD65/67 and GABAB receptors in the basal ganglia

Negrete-Díaz, José Vicente; Shumilov, Kirill; Real, M. Ángeles; Medina-Luque, José; Valderrama-Carvajal, Alejandra; Flores, Gonzalo; Rodríguez‐Moreno, Antonio; Rivera, Alicia

doi:10.1016/j.neuropharm.2019.01.024

Cited by 18 publications

(19 citation statements)

References 56 publications

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“…It has been proposed that the reinforcing effects of opioid agonists are, at least, partially dependent on their actions on mesolimbic DA circuits [ 312 , 313 , 314 , 315 ]. Interactions between the DA and endogenous opioid systems are well-established within mesocorticolimbic brain circuits [ 316 , 317 , 318 , 319 , 320 ] and play a role in behavioral responses to opioids and in relief of pain in animals [ 321 , 322 , 323 ]. It is reasonable to posit that extensive ELS-related dysfunctions in DA circuits could, therefore, influence sensitivity to opioids and vulnerability for OUD.…”

Section: Role Of Dopamine Neurotransmitter System In Els and Oudmentioning

confidence: 99%

Early Life Stress and Risks for Opioid Misuse: Review of Data Supporting Neurobiological Underpinnings

Oswald

Dunn

Seminowicz

et al. 2021

JPM

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A robust body of research has shown that traumatic experiences occurring during critical developmental periods of childhood when neuronal plasticity is high increase risks for a spectrum of physical and mental health problems in adulthood, including substance use disorders. However, until recently, relatively few studies had specifically examined the relationships between early life stress (ELS) and opioid use disorder (OUD). Associations with opioid use initiation, injection drug use, overdose, and poor treatment outcome have now been demonstrated. In rodents, ELS has also been shown to increase the euphoric and decrease antinociceptive effects of opioids, but little is known about these processes in humans or about the neurobiological mechanisms that may underlie these relationships. This review aims to establish a theoretical model that highlights the mechanisms by which ELS may alter opioid sensitivity, thereby contributing to future risks for OUD. Alterations induced by ELS in mesocorticolimbic brain circuits, and endogenous opioid and dopamine neurotransmitter systems are described. The limited but provocative evidence linking these alterations with opioid sensitivity and risks for OUD is presented. Overall, the findings suggest that better understanding of these mechanisms holds promise for reducing vulnerability, improving prevention strategies, and prescribing guidelines for high-risk individuals.

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Section: Role Of Dopamine Neurotransmitter System In Els and Oudmentioning

confidence: 99%

Early Life Stress and Risks for Opioid Misuse: Review of Data Supporting Neurobiological Underpinnings

Oswald

Dunn

Seminowicz

et al. 2021

JPM

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“…10,11 Additional research has explored D 4 R agonism as a strategy to reduce the adverse effects of opioid drugs like morphine. 12,13 D 4 R antagonism may be useful to treat substance use disorders (SUDs), particularly psychostimulant addiction, and l -DOPA-induced dyskinesias. 10,14−20 The importance of targeting D 4 Rs in treating these complex pathologies, especially with regards to the extent of receptor activation or inhibition, remains unknown, partially because of a lack of suitable compounds for investigating these pathways.…”

Section: Introductionmentioning

confidence: 99%

Dopamine D₄ Receptor-Selective Compounds Reveal Structure–Activity Relationships that Engender Agonist Efficacy

et al. 2019

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The dopamine D4 receptor (D4R) plays important roles in cognition, attention, and decision making. Novel D4R-selective ligands have promise in medication development for neuropsychiatric conditions, including Alzheimer’s disease and substance use disorders. To identify new D4R-selective ligands, and to understand the molecular determinants of agonist efficacy at D4R, we report a series of eighteen novel ligands based on the classical D4R agonist A-412997 (1, 2-(4-(pyridin-2-yl)piperidin-1-yl)-N-(m-tolyl)acetamide). Compounds were profiled using radioligand binding displacement assays, β-arrestin recruitment assays, cyclic AMP inhibition assays, and molecular dynamics computational modeling. We identified several novel D4R-selective (Ki ≤ 4.3 nM and >100-fold vs other D2-like receptors) compounds with diverse partial agonist and antagonist profiles, falling into three structural groups. These compounds highlight receptor–ligand interactions that control efficacy at D2-like receptors and may provide insights into targeted drug discovery, leading to a better understanding of the role of D4Rs in neuropsychiatric disorders.

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“…Unfortunately, none of them has yet received clinical approval due to failures of the pharmacokinetics or safety profiles [51]. Similarly, D 4 R agonism has been implicated in the management of cognitive deficits associated with schizophrenia [52] and attention-deficit/hyperactivity disorder [53] and also to reduce the adverse effects of opioids [54].…”

Section: Discussionmentioning

confidence: 99%

Novel Diels–Alder Type Adducts from Morus alba Root Bark Targeting Human Monoamine Oxidase and Dopaminergic Receptors for the Management of Neurodegenerative Diseases

Paudel

Park

Seong

et al. 2019

IJMS

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In this study, we delineate the human monoamine oxidase (hMAO) inhibitory potential of natural Diels–Alder type adducts, mulberrofuran G (1), kuwanon G (2), and albanol B (3), from Morus alba root bark to characterize their role in Parkinson’s disease (PD) and depression, focusing on their ability to modulate dopaminergic receptors (D1R, D2LR, D3R, and D4R). In hMAO-A inhibition, 1–3 showed mild effects (50% inhibitory concentration (IC50): 54‒114 μM). However, 1 displayed moderate inhibition of the hMAO-B isozyme (IC50: 18.14 ± 1.06 μM) followed by mild inhibition by 2 (IC50: 57.71 ± 2.12 μM) and 3 (IC50: 90.59 ± 1.72 μM). Our kinetic study characterized the inhibition mode, and the in silico docking predicted that the moderate inhibitor 1 would have the lowest binding energy. Similarly, cell-based G protein-coupled receptors (GPCR) functional assays in vector-transfected cells expressing dopamine (DA) receptors characterized 1–3 as D1R/D2LR antagonists and D3R/D4R agonists. The half-maximum effective concentration (EC50) of 1–3 on DA D3R/D4R was 15.13/17.19, 20.18/21.05, and 12.63/‒ µM, respectively. Similarly, 1–3 inhibited 50% of the DA response on D1R/D2LR by 6.13/2.41, 16.48/31.22, and 7.16/18.42 µM, respectively. A computational study revealed low binding energy for the test ligands. Interactions with residues Asp110, Val111, Tyr365, and Phe345 at the D3R receptor and Asp115 and His414 at the D4R receptor explain the high agonist effect. Likewise, Asp187 at D1R and Asp114 at D2LR play a crucial role in the antagonist effects of the ligand binding. Our overall results depict 1–3 from M. alba root bark as good inhibitors of hMAO and potent modulators of DA function as D1R/D2LR antagonists and D3R/D4R agonists. These active constituents in M. alba deserve in-depth study for their potential to manage neurodegenerative disorders (NDs), particularly PD and psychosis.

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Pharmacological activation of dopamine D4 receptor modulates morphine-induced changes in the expression of GAD65/67 and GABAB receptors in the basal ganglia

Cited by 18 publications

References 56 publications

Early Life Stress and Risks for Opioid Misuse: Review of Data Supporting Neurobiological Underpinnings

Early Life Stress and Risks for Opioid Misuse: Review of Data Supporting Neurobiological Underpinnings

Dopamine D₄ Receptor-Selective Compounds Reveal Structure–Activity Relationships that Engender Agonist Efficacy

Novel Diels–Alder Type Adducts from Morus alba Root Bark Targeting Human Monoamine Oxidase and Dopaminergic Receptors for the Management of Neurodegenerative Diseases

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Pharmacological activation of dopamine D4 receptor modulates morphine-induced changes in the expression of GAD65/67 and GABAB receptors in the basal ganglia

Cited by 18 publications

References 56 publications

Early Life Stress and Risks for Opioid Misuse: Review of Data Supporting Neurobiological Underpinnings

Early Life Stress and Risks for Opioid Misuse: Review of Data Supporting Neurobiological Underpinnings

Dopamine D4 Receptor-Selective Compounds Reveal Structure–Activity Relationships that Engender Agonist Efficacy

Novel Diels–Alder Type Adducts from Morus alba Root Bark Targeting Human Monoamine Oxidase and Dopaminergic Receptors for the Management of Neurodegenerative Diseases

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Product

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Dopamine D₄ Receptor-Selective Compounds Reveal Structure–Activity Relationships that Engender Agonist Efficacy