Research

15 pages, 2056 KiB

Open AccessArticle

Dopamine-Depleted Dopamine Transporter Knockout (DDD) Mice: Dyskinesia with L-DOPA and Dopamine D1 Agonists

by Vladimir M. Pogorelov, Michael L. Martini, Jian Jin, William C. Wetsel and Marc G. Caron

Biomolecules 2023, 13(11), 1658; https://doi.org/10.3390/biom13111658 - 17 Nov 2023

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L-DOPA is the mainstay of treatment for Parkinson’s disease (PD). However, over time this drug can produce dyskinesia. A useful acute PD model for screening novel compounds for anti-parkinsonian and L-DOPA-induced dyskinesia (LID) are dopamine-depleted dopamine-transporter KO (DDD) mice. Treatment with α-methyl-para [...] Read more.

L-DOPA is the mainstay of treatment for Parkinson’s disease (PD). However, over time this drug can produce dyskinesia. A useful acute PD model for screening novel compounds for anti-parkinsonian and L-DOPA-induced dyskinesia (LID) are dopamine-depleted dopamine-transporter KO (DDD) mice. Treatment with α-methyl-para-tyrosine rapidly depletes their brain stores of DA and renders them akinetic. During sensitization in the open field (OF), their locomotion declines as vertical activities increase and upon encountering a wall they stand on one leg or tail and engage in climbing behavior termed “three-paw dyskinesia”. We have hypothesized that L-DOPA induces a stereotypic activation of locomotion in DDD mice, where they are unable to alter the course of their locomotion, and upon encountering walls engage in “three-paw dyskinesia” as reflected in vertical counts or beam-breaks. The purpose of our studies was to identify a valid index of LID in DDD mice that met three criteria: (a) sensitization with repeated L-DOPA administration, (b) insensitivity to a change in the test context, and (c) stimulatory or inhibitory responses to dopamine D1 receptor agonists (5 mg/kg SKF81297; 5 and 10 mg/kg MLM55-38, a novel compound) and amantadine (45 mg/kg), respectively. Responses were compared between the OF and a circular maze (CM) that did not hinder locomotion. We found vertical counts and climbing were specific for testing in the OF, while oral stereotypies were sensitized to L-DOPA in both the OF and CM and responded to D1R agonists and amantadine. Hence, in DDD mice oral stereotypies should be used as an index of LID in screening compounds for PD. Full article

(This article belongs to the Special Issue Biogenic Amines, Their Receptors and Transporters in Health and Disease: Commemorative Issue in Honor of Professor Marc G. Caron (1946–2022))

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25 pages, 6486 KiB

Open AccessArticle

G Protein-Coupled Receptor Kinase 2 Selectively Enhances β-Arrestin Recruitment to the D₂ Dopamine Receptor through Mechanisms That Are Independent of Receptor Phosphorylation

by Marta Sánchez-Soto, Noelia M. Boldizsar, Kayla A. Schardien, Nora S. Madaras, Blair K. A. Willette, Laura R. Inbody, Christopher Dasaro, Amy E. Moritz, Julia Drube, Raphael S. Haider, R. Benjamin Free, Carsten Hoffman and David R. Sibley

Biomolecules 2023, 13(10), 1552; https://doi.org/10.3390/biom13101552 - 20 Oct 2023

Viewed by 1977

Abstract

The D2 dopamine receptor (D2R) signals through both G proteins and β-arrestins to regulate important physiological processes, such as movement, reward circuitry, emotion, and cognition. β-arrestins are believed to interact with G protein-coupled receptors (GPCRs) at the phosphorylated C-terminal tail or intracellular loops. [...] Read more.

The D2 dopamine receptor (D2R) signals through both G proteins and β-arrestins to regulate important physiological processes, such as movement, reward circuitry, emotion, and cognition. β-arrestins are believed to interact with G protein-coupled receptors (GPCRs) at the phosphorylated C-terminal tail or intracellular loops. GPCR kinases (GRKs) are the primary drivers of GPCR phosphorylation, and for many receptors, receptor phosphorylation is indispensable for β-arrestin recruitment. However, GRK-mediated receptor phosphorylation is not required for β-arrestin recruitment to the D2R, and the role of GRKs in D2R–β-arrestin interactions remains largely unexplored. In this study, we used GRK knockout cells engineered using CRISPR-Cas9 technology to determine the extent to which β-arrestin recruitment to the D2R is GRK-dependent. Genetic elimination of all GRK expression decreased, but did not eliminate, agonist-stimulated β-arrestin recruitment to the D2R or its subsequent internalization. However, these processes were rescued upon the re-introduction of various GRK isoforms in the cells with GRK2/3 also enhancing dopamine potency. Further, treatment with compound 101, a pharmacological inhibitor of GRK2/3 isoforms, decreased β-arrestin recruitment and receptor internalization, highlighting the importance of this GRK subfamily for D2R–β-arrestin interactions. These results were recapitulated using a phosphorylation-deficient D2R mutant, emphasizing that GRKs can enhance β-arrestin recruitment and activation independently of receptor phosphorylation. Full article

(This article belongs to the Special Issue Biogenic Amines, Their Receptors and Transporters in Health and Disease: Commemorative Issue in Honor of Professor Marc G. Caron (1946–2022))

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14 pages, 2768 KiB

Open AccessArticle

In Vitro and In Vivo Chaperone Effect of (R)-2-amino-6-(1R, 2S)-1,2-dihydroxypropyl)-5,6,7,8-tetrahydropterin-4(3H)-one on the C1473G Mutant Tryptophan Hydroxylase 2

by Alla B. Arefieva, Polina D. Komleva, Vladimir S. Naumenko, Nikita V. Khotskin and Alexander V. Kulikov

Biomolecules 2023, 13(10), 1458; https://doi.org/10.3390/biom13101458 - 27 Sep 2023

Viewed by 598

Abstract

Tryptophan hydroxylase 2 (TPH2) is the key and rate-limiting enzyme of serotonin (5-HT) synthesis in the mammalian brain. The 1473G mutation in the Tph2 gene decreases TPH2 activity in the mouse brain by twofold. (R)-2-amino-6-(1R, 2S)-1,2-dihydroxypropyl)-5,6,7,8-tetrahydropterin-4(3H)-one (BH₄) is a pharmacological chaperone [...] Read more.

Tryptophan hydroxylase 2 (TPH2) is the key and rate-limiting enzyme of serotonin (5-HT) synthesis in the mammalian brain. The 1473G mutation in the Tph2 gene decreases TPH2 activity in the mouse brain by twofold. (R)-2-amino-6-(1R, 2S)-1,2-dihydroxypropyl)-5,6,7,8-tetrahydropterin-4(3H)-one (BH₄) is a pharmacological chaperone for aromatic amino acid hydroxylases. In the present study, chaperone effects of BH₄ on the mutant C1473G TPH2 were investigated in vitro and in vivo. In vitro BH₄ increased the thermal stability (T₅₀ value) of mutant and wild-type TPH2 molecules. At the same time, neither chronic (twice per day for 7 days) intraperitoneal injection of 48.3 mg/kg of BH₄ nor a single intraventricular administration of 60 μg of the drug altered the mutant TPH2 activity in the brain of Balb/c mice. This result indicates that although BH₄ shows a chaperone effect in vitro, it is unable to increase the activity of mutant TPH2 in vivo. Full article

(This article belongs to the Special Issue Biogenic Amines, Their Receptors and Transporters in Health and Disease: Commemorative Issue in Honor of Professor Marc G. Caron (1946–2022))

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16 pages, 896 KiB

Open AccessEditor’s ChoiceArticle

Hyperactivity in Mice Induced by Opioid Agonists with Partial Intrinsic Efficacy and Biased Agonism Administered Alone and in Combination with Morphine

by Agnes Acevedo-Canabal, Travis W. Grim, Cullen L. Schmid, Nina McFague, Edward L. Stahl, Nicole M. Kennedy, Thomas D. Bannister and Laura M. Bohn

Biomolecules 2023, 13(6), 935; https://doi.org/10.3390/biom13060935 - 02 Jun 2023

Cited by 1 | Viewed by 2139

Abstract

Opioid analgesics such as morphine and fentanyl induce mu-opioid receptor (MOR)-mediated hyperactivity in mice. Herein, we show that morphine, fentanyl, SR-17018, and oliceridine have submaximal intrinsic efficacy in the mouse striatum using ³⁵S-GTPγS binding assays. While all of the agonists act as [...] Read more.

Opioid analgesics such as morphine and fentanyl induce mu-opioid receptor (MOR)-mediated hyperactivity in mice. Herein, we show that morphine, fentanyl, SR-17018, and oliceridine have submaximal intrinsic efficacy in the mouse striatum using ³⁵S-GTPγS binding assays. While all of the agonists act as partial agonists for stimulating G protein coupling in striatum, morphine, fentanyl, and oliceridine are fully efficacious in stimulating locomotor activity; meanwhile, the noncompetitive biased agonists SR-17018 and SR-15099 produce submaximal hyperactivity. Moreover, the combination of SR-17018 and morphine attenuates hyperactivity while antinociceptive efficacy is increased. The combination of oliceridine with morphine increases hyperactivity, which is maintained over time. These findings provide evidence that noncompetitive agonists at MOR can be used to suppress morphine-induced hyperactivity while enhancing antinociceptive efficacy; moreover, they demonstrate that intrinsic efficacy measured at the receptor level is not directly proportional to drug efficacy in the locomotor activity assay. Full article

(This article belongs to the Special Issue Biogenic Amines, Their Receptors and Transporters in Health and Disease: Commemorative Issue in Honor of Professor Marc G. Caron (1946–2022))

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23 pages, 2188 KiB

Open AccessArticle

Dopamine D₁ Agonists: First Potential Treatment for Late-Stage Parkinson’s Disease

by Mechelle M. Lewis, Lauren J. Van Scoy, Sol De Jesus, Jonathan G. Hakun, Paul J. Eslinger, Julio Fernandez-Mendoza, Lan Kong, Yang Yang, Bethany L. Snyder, Natalia Loktionova, Sridhar Duvvuri, David L. Gray, Xuemei Huang and Richard B. Mailman

Biomolecules 2023, 13(5), 829; https://doi.org/10.3390/biom13050829 - 12 May 2023

Cited by 2 | Viewed by 2190

Abstract

Current pharmacotherapy has limited efficacy and/or intolerable side effects in late-stage Parkinson’s disease (LsPD) patients whose daily life depends primarily on caregivers and palliative care. Clinical metrics inadequately gauge efficacy in LsPD patients. We explored if a D_1/5 dopamine agonist would have [...] Read more.

Current pharmacotherapy has limited efficacy and/or intolerable side effects in late-stage Parkinson’s disease (LsPD) patients whose daily life depends primarily on caregivers and palliative care. Clinical metrics inadequately gauge efficacy in LsPD patients. We explored if a D_1/5 dopamine agonist would have efficacy in LsPD using a double-blind placebo-controlled crossover phase Ia/b study comparing the D_1/5 agonist PF-06412562 to levodopa/carbidopa in six LsPD patients. Caregiver assessment was the primary efficacy measure because caregivers were with patients throughout the study, and standard clinical metrics inadequately gauge efficacy in LsPD. Assessments included standard quantitative scales of motor function (MDS-UPDRS-III), alertness (Glasgow Coma and Stanford Sleepiness Scales), and cognition (Severe Impairment and Frontal Assessment Batteries) at baseline (Day 1) and thrice daily during drug testing (Days 2–3). Clinicians and caregivers completed the clinical impression of change questionnaires, and caregivers participated in a qualitative exit interview. Blinded triangulation of quantitative and qualitative data was used to integrate findings. Neither traditional scales nor clinician impression of change detected consistent differences between treatments in the five participants who completed the study. Conversely, the overall caregiver data strongly favored PF-06412562 over levodopa in four of five patients. The most meaningful improvements converged on motor, alertness, and functional engagement. These data suggest for the first time that there can be useful pharmacological intervention in LsPD patients using D_1/5 agonists and also that caregiver perspectives with mixed method analyses may overcome limitations using methods common in early-stage patients. The results encourage future clinical studies and understanding of the most efficacious signaling properties of a D₁ agonist for this population. Full article

(This article belongs to the Special Issue Biogenic Amines, Their Receptors and Transporters in Health and Disease: Commemorative Issue in Honor of Professor Marc G. Caron (1946–2022))

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14 pages, 1975 KiB

Open AccessEditor’s ChoiceArticle

Dysregulation of AMPA Receptor Trafficking and Intracellular Vesicular Sorting in the Prefrontal Cortex of Dopamine Transporter Knock-Out Rats

by Giorgia Targa, Francesca Mottarlini, Beatrice Rizzi, Damiana Leo, Lucia Caffino and Fabio Fumagalli

Biomolecules 2023, 13(3), 516; https://doi.org/10.3390/biom13030516 - 11 Mar 2023

Cited by 1 | Viewed by 1572

Abstract

Dopamine (DA) and glutamate interact, influencing neural excitability and promoting synaptic plasticity. However, little is known regarding the molecular mechanisms underlying this crosstalk. Since perturbation of DA-AMPA receptor interaction might sustain pathological conditions, the major aim of our work was to evaluate the [...] Read more.

Dopamine (DA) and glutamate interact, influencing neural excitability and promoting synaptic plasticity. However, little is known regarding the molecular mechanisms underlying this crosstalk. Since perturbation of DA-AMPA receptor interaction might sustain pathological conditions, the major aim of our work was to evaluate the effect of the hyperactive DA system on the AMPA subunit composition, trafficking, and membrane localization in the prefrontal cortex (PFC). Taking advantage of dopamine transporter knock-out (DAT^−/−) rats, we found that DA overactivity reduced the translation of cortical AMPA receptors and their localization at both synaptic and extra-synaptic sites through, at least in part, altered intracellular vesicular sorting. Moreover, the reduced expression of AMPA receptor-specific anchoring proteins and structural markers, such as Neuroligin-1 and nCadherin, likely indicate a pattern of synaptic instability. Overall, these data reveal that a condition of hyperdopaminergia markedly alters the homeostatic plasticity of AMPA receptors, suggesting a general destabilization and depotentiation of the AMPA-mediated glutamatergic neurotransmission in the PFC. This effect might be functionally relevant for disorders characterized by elevated dopaminergic activity. Full article

(This article belongs to the Special Issue Biogenic Amines, Their Receptors and Transporters in Health and Disease: Commemorative Issue in Honor of Professor Marc G. Caron (1946–2022))

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36 pages, 4437 KiB

Open AccessArticle

Behavioral and Transcriptomic Changes Following Brain-Specific Loss of Noradrenergic Transmission

by Elsa Isingrini, Chloé Guinaudie, Léa Perret, Elisa Guma, Victor Gorgievski, Ian D. Blum, Jessica Colby-Milley, Maryia Bairachnaya, Sébastien Mella, Antoine Adamantidis, Kai-Florian Storch and Bruno Giros

Biomolecules 2023, 13(3), 511; https://doi.org/10.3390/biom13030511 - 10 Mar 2023

Cited by 3 | Viewed by 2048

Abstract

Noradrenaline (NE) plays an integral role in shaping behavioral outcomes including anxiety/depression, fear, learning and memory, attention and shifting behavior, sleep-wake state, pain, and addiction. However, it is unclear whether dysregulation of NE release is a cause or a consequence of maladaptive orientations [...] Read more.

Noradrenaline (NE) plays an integral role in shaping behavioral outcomes including anxiety/depression, fear, learning and memory, attention and shifting behavior, sleep-wake state, pain, and addiction. However, it is unclear whether dysregulation of NE release is a cause or a consequence of maladaptive orientations of these behaviors, many of which associated with psychiatric disorders. To address this question, we used a unique genetic model in which the brain-specific vesicular monoamine transporter-2 (VMAT2) gene expression was removed in NE-positive neurons disabling NE release in the entire brain. We engineered VMAT2 gene splicing and NE depletion by crossing floxed VMAT2 mice with mice expressing the Cre-recombinase under the dopamine β-hydroxylase (DBH) gene promotor. In this study, we performed a comprehensive behavioral and transcriptomic characterization of the VMAT2DBHcre KO mice to evaluate the role of central NE in behavioral modulations. We demonstrated that NE depletion induces anxiolytic and antidepressant-like effects, improves contextual fear memory, alters shifting behavior, decreases the locomotor response to amphetamine, and induces deeper sleep during the non-rapid eye movement (NREM) phase. In contrast, NE depletion did not affect spatial learning and memory, working memory, response to cocaine, and the architecture of the sleep-wake cycle. Finally, we used this model to identify genes that could be up- or down-regulated in the absence of NE release. We found an up-regulation of the synaptic vesicle glycoprotein 2c (SV2c) gene expression in several brain regions, including the locus coeruleus (LC), and were able to validate this up-regulation as a marker of vulnerability to chronic social defeat. The NE system is a complex and challenging system involved in many behavioral orientations given it brain wide distribution. In our study, we unraveled specific role of NE neurotransmission in multiple behavior and link it to molecular underpinning, opening future direction to understand NE role in health and disease. Full article

(This article belongs to the Special Issue Biogenic Amines, Their Receptors and Transporters in Health and Disease: Commemorative Issue in Honor of Professor Marc G. Caron (1946–2022))

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21 pages, 5668 KiB

Open AccessFeature PaperArticle

G Protein-Dependent Activation of the PKA-Erk1/2 Pathway by the Striatal Dopamine D1/D3 Receptor Heteromer Involves Beta-Arrestin and the Tyrosine Phosphatase Shp-2

by Federica Bono, Zaira Tomasoni, Veronica Mutti, Giulia Sbrini, Rajesh Kumar, Francesca Longhena, Chiara Fiorentini and Cristina Missale

Biomolecules 2023, 13(3), 473; https://doi.org/10.3390/biom13030473 - 03 Mar 2023

Cited by 1 | Viewed by 1680

Abstract

The heteromer composed of dopamine D1 and D3 receptors (D1R–D3R) has been defined as a structure able to trigger Erk1/2 and Akt signaling in a G protein-independent, beta-arrestin 1-dependent way that is physiologically expressed in the ventral striatum and is likely involved in [...] Read more.

The heteromer composed of dopamine D1 and D3 receptors (D1R–D3R) has been defined as a structure able to trigger Erk1/2 and Akt signaling in a G protein-independent, beta-arrestin 1-dependent way that is physiologically expressed in the ventral striatum and is likely involved in the control of locomotor activity. Indeed, abnormal levels of D1R-D3R heteromer in the dorsal striatum have been correlated with the development of L-DOPA-induced dyskinesia (LID) in Parkinson’s disease patients, a motor complication associated with striatal D1R signaling, thus requiring Gs protein and PKA activity to activate Erk1/2. Therefore, to clarify the role of the D1R/D3R heteromer in LID, we investigated the signaling pathway induced by the heteromer using transfected cells and primary mouse striatal neurons. Collectively, we found that in both the cell models, D1R/D3R heteromer-induced activation of Erk1/2 exclusively required the D1R molecular effectors, such as Gs protein and PKA, with the contribution of the phosphatase Shp-2 and beta-arrestins, indicating that heterodimerization with the D3R abolishes the specific D3R-mediated signaling but strongly allows D1R signals. Therefore, while in physiological conditions the D1R/D3R heteromer could represent a mechanism that strengthens the D1R activity, its pathological expression may contribute to the abnormal PKA-Shp-2-Erk1/2 pathway connected with LID. Full article

(This article belongs to the Special Issue Biogenic Amines, Their Receptors and Transporters in Health and Disease: Commemorative Issue in Honor of Professor Marc G. Caron (1946–2022))

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15 pages, 5170 KiB

Open AccessArticle

Short-Term Consequences of Single Social Defeat on Accumbal Dopamine and Behaviors in Rats

by Vsevolod V. Nemets, Alex L. Deal, Vladislav E. Sobolev, Vladimir P. Grinevich, Raul R. Gainetdinov and Evgeny A. Budygin

Biomolecules 2023, 13(1), 35; https://doi.org/10.3390/biom13010035 - 24 Dec 2022

Cited by 1 | Viewed by 2417

Abstract

The present study aimed to explore the consequences of a single exposure to a social defeat on dopamine release in the rat nucleus accumbens measured with a fast-scan cyclic voltammetry. We found that 24 h after a social defeat, accumbal dopamine responses, evoked [...] Read more.

The present study aimed to explore the consequences of a single exposure to a social defeat on dopamine release in the rat nucleus accumbens measured with a fast-scan cyclic voltammetry. We found that 24 h after a social defeat, accumbal dopamine responses, evoked by a high frequency electrical stimulation of the ventral tegmental area, were more profound in socially defeated rats in comparison with non-defeated control animals. The enhanced dopamine release was associated with the prolonged immobility time in the forced swim test. The use of the dopamine depletion protocol revealed no alteration in the reduction and recovery of the amplitude of dopamine release following social defeat stress. However, administration of dopamine D2 receptor antagonist, raclopride (2 mg/kg, i.p.), resulted in significant increase of the electrically evoked dopamine release in both groups of animals, nevertheless exhibiting less manifested effect in the defeated rats comparing to control animals. Taken together, our data demonstrated profound alterations in the dopamine transmission in the association with depressive-like behavior following a single exposure to stressful environment. These voltammetric findings pointed to a promising path for the identification of neurobiological mechanisms underlying stress-promoted behavioral abnormalities. Full article

(This article belongs to the Special Issue Biogenic Amines, Their Receptors and Transporters in Health and Disease: Commemorative Issue in Honor of Professor Marc G. Caron (1946–2022))

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13 pages, 1211 KiB

Open AccessFeature PaperArticle

Inhibition of PDE10A in a New Rat Model of Severe Dopamine Depletion Suggests New Approach to Non-Dopamine Parkinson’s Disease Therapy

by Ilya Sukhanov, Artem Dorotenko, Zoia Fesenko, Artem Savchenko, Evgeniya V. Efimova, Mikael S. Mor, Irina V. Belozertseva, Tatyana D. Sotnikova and Raul R. Gainetdinov

Biomolecules 2023, 13(1), 9; https://doi.org/10.3390/biom13010009 - 21 Dec 2022

Cited by 6 | Viewed by 1683

Abstract

Parkinson’s disease is the second most common neurodegenerative pathology. Due to the limitations of existing therapeutic approaches, novel anti-parkinsonian medicines with non-dopamine mechanisms of action are clearly needed. One of the promising pharmacological targets for anti-Parkinson drug development is phosphodiesterase (PDE) 10A. The [...] Read more.

Parkinson’s disease is the second most common neurodegenerative pathology. Due to the limitations of existing therapeutic approaches, novel anti-parkinsonian medicines with non-dopamine mechanisms of action are clearly needed. One of the promising pharmacological targets for anti-Parkinson drug development is phosphodiesterase (PDE) 10A. The stimulating motor effects of PDE10A inhibition were detected only under the conditions of partial dopamine depletion. The results raise the question of whether PDE10A inhibitors are able to restore locomotor activity when dopamine levels are very low. To address this issue, we (1) developed and validated the rat model of acute severe dopamine deficiency and (2) tested the action of PDE10A inhibitor MP-10 in this model. All experiments were performed in dopamine transporter knockout (DAT-KO) rats. A tyrosine hydroxylase inhibitor, α-Methyl-DL-tyrosine (αMPT), was used as an agent to cause extreme dopamine deficiency. In vivo tests included estimation of locomotor activity and catalepsy levels in the bar test. Additionally, we evaluated the tissue content of dopamine in brain samples by HPLC analysis. The acute administration of αMPT to DAT-KO rats caused severe depletion of dopamine, immobility, and catalepsy (Dopamine-Deficient DAT-KO (DDD) rats). As expected, treatment with the L-DOPA and carbidopa combination restored the motor functions of DDD rats. Strikingly, administration of MP-10 also fully reversed immobility and catalepsy in DDD rats. According to neurochemical studies, the action of MP-10, in contrast to L-DOPA + carbidopa, seems to be dopamine-independent. These observations indicate that targeting PDE10A may represent a new promising approach in the development of non-dopamine therapies for Parkinson’s disease. Full article

(This article belongs to the Special Issue Biogenic Amines, Their Receptors and Transporters in Health and Disease: Commemorative Issue in Honor of Professor Marc G. Caron (1946–2022))

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14 pages, 1641 KiB

Open AccessArticle

Gut Microbiota Alterations in Trace Amine-Associated Receptor 9 (TAAR9) Knockout Rats

by Ilya S. Zhukov, Anastasia N. Vaganova, Ramilya Z. Murtazina, Lyubov S. Alferova, Elena I. Ermolenko and Raul R. Gainetdinov

Biomolecules 2022, 12(12), 1823; https://doi.org/10.3390/biom12121823 - 06 Dec 2022

Cited by 1 | Viewed by 1561

Abstract

Trace amine-associated receptors (TAAR1-TAAR9) are a family of G-protein-coupled monoaminergic receptors which might have great pharmacological potential. It has now been well established that TAAR1 plays an important role in the central nervous system. Interestingly, deletion of TAAR9 in rats leads to alterations [...] Read more.

Trace amine-associated receptors (TAAR1-TAAR9) are a family of G-protein-coupled monoaminergic receptors which might have great pharmacological potential. It has now been well established that TAAR1 plays an important role in the central nervous system. Interestingly, deletion of TAAR9 in rats leads to alterations in the periphery. Previously, we found that knockout of TAAR9 in rats (TAAR9-KO rats) decreased low-density lipoprotein cholesterol levels in the blood. TAAR9 was also identified in intestinal tissues, and it is known that it responds to polyamines. To elucidate the role of TAAR9 in the intestinal epithelium, we analyzed TAAR9-co-expressed gene clusters in public data for cecum samples. As identified by gene ontology enrichment analysis, in the intestine, TAAR9 is co-expressed with genes involved in intestinal mucosa homeostasis and function, including cell organization, differentiation, and death. Additionally, TAAR9 was co-expressed with genes implicated in dopamine signaling, which may suggest a role for this receptor in the regulation of peripheral dopaminergic transmission. To further investigate how TAAR9 might be involved in colonic mucosal homeostasis, we analyzed the fecal microbiome composition in TAAR9-KO rats and their wild-type littermates. We identified a significant difference in the number of observed taxa between the microbiome of TAAR9-KO and wild-type rats. In TAAR9-KO rats, the gut microbial community became more variable compared with the wild-type rats. Furthermore, it was found that the family Saccharimonadaceae, which is one of the top 10 most abundant families in TAAR9-KO rat feces, is almost completely absent in wild-type animal fecal samples. Taken together, these data indicate a role of TAAR9 in intestinal function. Full article

(This article belongs to the Special Issue Biogenic Amines, Their Receptors and Transporters in Health and Disease: Commemorative Issue in Honor of Professor Marc G. Caron (1946–2022))

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14 pages, 2217 KiB

Open AccessArticle

The State of the Dopaminergic and Glutamatergic Systems in the Valproic Acid Mouse Model of Autism Spectrum Disorder

by Alexandre Maisterrena, Emmanuel Matas, Helene Mirfendereski, Anais Balbous, Sandrine Marchand and Mohamed Jaber

Biomolecules 2022, 12(11), 1691; https://doi.org/10.3390/biom12111691 - 15 Nov 2022

Cited by 6 | Viewed by 1844

Abstract

Autism Spectrum Disorder (ASD) is a progressive neurodevelopmental disorder mainly characterized by deficits in social communication and stereotyped behaviors and interests. Here, we aimed to investigate the state of several key players in the dopamine and glutamate neurotransmission systems in the valproic acid [...] Read more.

Autism Spectrum Disorder (ASD) is a progressive neurodevelopmental disorder mainly characterized by deficits in social communication and stereotyped behaviors and interests. Here, we aimed to investigate the state of several key players in the dopamine and glutamate neurotransmission systems in the valproic acid (VPA) animal model that was administered to E12.5 pregnant females as a single dose (450 mg/kg). We report no alterations in the number of mesencephalic dopamine neurons or in protein levels of tyrosine hydroxylase in either the striatum or the nucleus accumbens. In females prenatally exposed to VPA, levels of dopamine were slightly decreased while the ratio of DOPAC/dopamine was increased in the dorsal striatum, suggesting increased turn-over of dopamine tone. In turn, levels of D1 and D2 dopamine receptor mRNAs were increased in the nucleus accumbens of VPA mice suggesting upregulation of the corresponding receptors. We also report decreased protein levels of striatal parvalbumin and increased levels of p-mTOR in the cerebellum and the motor cortex of VPA mice. mRNA levels of mGluR1, mGluR4, and mGluR5 and the glutamate receptor subunits NR1, NR2A, and NR2B were not altered by VPA, nor were protein levels of NR1, NR2A, and NR2B and those of BDNF and TrkB. These findings are of interest as clinical trials aiming at the dopamine and glutamate systems are being considered. Full article

(This article belongs to the Special Issue Biogenic Amines, Their Receptors and Transporters in Health and Disease: Commemorative Issue in Honor of Professor Marc G. Caron (1946–2022))

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28 pages, 13510 KiB

Open AccessArticle

Discovery of Trace Amine-Associated Receptor 1 (TAAR1) Agonist 2-(5-(4′-Chloro-[1,1′-biphenyl]-4-yl)-4H-1,2,4-triazol-3-yl)ethan-1-amine (LK00764) for the Treatment of Psychotic Disorders

by Mikhail Krasavin, Alexey Lukin, Ilya Sukhanov, Andrey S. Gerasimov, Savelii Kuvarzin, Evgeniya V. Efimova, Mariia Dorofeikova, Anna Nichugovskaya, Andrey Matveev, Kirill Onokhin, Konstantin Zakharov, Maxim Gureev and Raul R. Gainetdinov

Biomolecules 2022, 12(11), 1650; https://doi.org/10.3390/biom12111650 - 07 Nov 2022

Cited by 3 | Viewed by 2019

Abstract

A focused in-house library of about 1000 compounds comprising various heterocyclic motifs in combination with structural fragments similar to β-phenylethylamine or tyramine was screened for the agonistic activity towards trace amine-associated receptor 1 (TAAR1). The screening yielded two closely related hits displaying EC50 [...] Read more.

A focused in-house library of about 1000 compounds comprising various heterocyclic motifs in combination with structural fragments similar to β-phenylethylamine or tyramine was screened for the agonistic activity towards trace amine-associated receptor 1 (TAAR1). The screening yielded two closely related hits displaying EC50 values in the upper submicromolar range. Extensive analog synthesis and testing for TAAR1 agonism in a BRET-based cellular assay identified compound 62 (LK00764) with EC₅₀ = 4.0 nM. The compound demonstrated notable efficacy in such schizophrenia-related in vivo tests as MK-801-induced hyperactivity and spontaneous activity in rats, locomotor hyperactivity of dopamine transporter knockout (DAT-KO) rats, and stress-induced hyperthermia (i.p. administration). Further preclinical studies are necessary to evaluate efficacy, safety and tolerability of this potent TAAR1 agonist for the potential development of this compound as a new pharmacotherapy option for schizophrenia and other psychiatric disorders. Full article

(This article belongs to the Special Issue Biogenic Amines, Their Receptors and Transporters in Health and Disease: Commemorative Issue in Honor of Professor Marc G. Caron (1946–2022))

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16 pages, 23687 KiB

Open AccessArticle

Effects of Atomoxetine on Motor and Cognitive Behaviors and Brain Electrophysiological Activity of Dopamine Transporter Knockout Rats

by Maria Ptukha, Zoia Fesenko, Anastasia Belskaya, Arina Gromova, Arseniy Pelevin, Natalia Kurzina, Raul R. Gainetdinov and Anna Volnova

Biomolecules 2022, 12(10), 1484; https://doi.org/10.3390/biom12101484 - 14 Oct 2022

Cited by 4 | Viewed by 1783

Abstract

Changes in dopaminergic and noradrenergic transmission are considered to be the underlying cause of attention deficit and hyperactivity disorder (ADHD). Atomoxetine (ATX) is a selective norepinephrine transporter (NET) inhibitor that is currently used for ADHD treatment. In this study, we aimed to evaluate [...] Read more.

Changes in dopaminergic and noradrenergic transmission are considered to be the underlying cause of attention deficit and hyperactivity disorder (ADHD). Atomoxetine (ATX) is a selective norepinephrine transporter (NET) inhibitor that is currently used for ADHD treatment. In this study, we aimed to evaluate the effect of atomoxetine on the behavior and brain activity of dopamine transporter knockout (DAT-KO) rats, which are characterized by an ADHD-like behavioral phenotype. Prepulse inhibition (PPI) was assessed in DAT-KO and wild type rats after saline and ATX injections, as well as behavioral parameters in the Hebb–Williams maze and power spectra and coherence of electrophysiological activity. DAT-KO rats demonstrated a pronounced behavioral and electrophysiological phenotype, characterized by hyperactivity, increased number of errors in the maze, repetitive behaviors and disrupted PPI, changes in cortical and striatal power spectra and interareal coherence. Atomoxetine significantly improved PPI and decreased repetitive behaviors in DAT-KO rats and influenced behavior of wild-type rats. ATX also led to significant changes in power spectra and coherence of DAT-KO and wild type rats. Assessment of noradrenergic modulation effects in DAT-KO provides insight into the intricate interplay of monoaminergic systems, although further research is still required to fully understand the complexity of this interaction. Full article

(This article belongs to the Special Issue Biogenic Amines, Their Receptors and Transporters in Health and Disease: Commemorative Issue in Honor of Professor Marc G. Caron (1946–2022))

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Biogenic Amines, Their Receptors and Transporters in Health and Disease: Commemorative Issue in Honor of Professor Marc G. Caron (1946–2022)

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