Neurotensin and Alcohol Use Disorders: Towards a Pharmacological Treatment
Abstract
:1. Introduction
2. Neurotensin and NT Receptors
2.1. Neurotensin
2.2. Brain Distribution of Neurotensin
2.3. Neurotensin Receptors
2.3.1. NTR1
2.3.2. NTR2
2.3.3. NTR3/Sortilin
2.4. Neurotensin Signaling Pathways
3. Neurotensin, Reward, and Alcohol
3.1. Brain Reward Circuits
3.2. NT, Reward, and Stress
3.3. NT and Alcohol
4. NT Receptors Ligands as Possible Pharmacological Treatments of AUD
5. Conclusions and Future Perspectives
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Compounds | Experimental Model | In Vitro Studies | References |
Hetero bivalents DR2-NTR1 (agonist/antagonist properties) | Cultured CHO cells expressing receptors | Radioligand saturation and BRET assays to determine affinities and promotion of D2R homodimerization and heterodimerization. | [55,56] |
NT8–13 analogs | Cultured CHO-K1 cells expressing rat and human NTR | Radioligand saturation analysis for determination of crucial amino acid positions related to receptor affinity and PI turnover and stability. | [128,129,130] |
Small non-peptide ligands of NTR: SRI-9829, RTI-3a, SR-48692, SR142948A | Transfected cultured HEK293, COS-7 cultured cells | Structural, ligand binding, and signaling assays. | [59] |
NT8–13 and SR142948A | Transfected cultured HEK293 cells | Structural dynamics of NTR1 with analysis of its global motions. | [123] |
Derivatives of SR-48692 antagonist | CHO-K1 cell line expressing NTR1 | Calcium mobilization assays | [131] |
SR-48692 antagonist | Cultured transfected COS-7 cells, and brain tissue, form different species, | Radioligand binding assays | [132,133] |
Nonpeptide ML314 biased agonist of NTR1 | β-arrestin conjugated (GFP) reporter expressed in a U2OS cell line | Activates the β-arrestin pathway and blocks G-protein -dependent signaling. | [135,136] |
Quinazoline NTR1 modulator, SBI-553 | In vitro radioligand binding, NTR1-β-arrestin-GFP, and calcium flux assays in HEK-293 transfected cells | Activates β-arrestin signaling and inhibits Gq-protein-dependent calcium signaling. | [137] |
Quinazoline NTR1 modulator, SBI-553 | In vitro assays in HEK 293 and U2OS transfected cells | Promotes receptor phosphorylation, receptor internalization, and β-arrestin activation. | [138] |
Compounds | Experimental Model | In Vivo Studies | References |
Nonpeptide ML314 biased agonist of NTR1 | Injection in rats | Inhibits amphetamine self-administration. | [136] |
Silencing of lateral septum neurotensin-positive neurons | In vivo suppression of NT neurons in LS in C57BL/6J mice | Promotion of palatable feeding. | [139] |
In vivo genetic ablation septum neurotensin-positive neurons (LSNT) | Male and female C57BL/6J mice | LSNT modulates social interaction and social reward (stress susceptibility). | [140] |
NTR1 agonist PD- 149,163, and antagonist SR-48692 | Brain microinjections in male Sprague–Dawley rats | PD-149163 induces anxiogenic effects when injected into the prelimbic region of the medial prefrontal cortex. | [105] |
Nonpeptide ML314 biased agonist of NTR1 | Intraperitoneal injection in C57BL/6J mice | Attenuates methamphetamine-induced hyperlocomotion and methamphetamine-associated conditioned place preference. | [136] |
Quinazoline NTR1 modulator, SBI-553 | Intraperitoneal injection and oral administration to DAT KO C57BL/6J mice (dopamine-depleted dopamine transporter knockout) | Attenuates hyperdopaminergic activity. | [137] |
Quinazoline NTR1 modulator, SBI-55 | Intraperitoneal injection in cocaine self-administration in C57BL/6J mice | Attenuates cocaine-induced hyperlocomotion without producing non-desired side effects dependent on Gq protein activation. | [138] |
Selective NTR2 agonist JMV-431 | Brain injection in rats consuming alcohol (chronic consumption) | Chronic and excessive alcohol consumption induces behavioral changes, partly mediated by the NTR2. | [112] |
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Rodríguez, F.D.; Sánchez, M.L.; Coveñas, R. Neurotensin and Alcohol Use Disorders: Towards a Pharmacological Treatment. Int. J. Mol. Sci. 2023, 24, 8656. https://doi.org/10.3390/ijms24108656
Rodríguez FD, Sánchez ML, Coveñas R. Neurotensin and Alcohol Use Disorders: Towards a Pharmacological Treatment. International Journal of Molecular Sciences. 2023; 24(10):8656. https://doi.org/10.3390/ijms24108656
Chicago/Turabian StyleRodríguez, Francisco D., Manuel Lisardo Sánchez, and Rafael Coveñas. 2023. "Neurotensin and Alcohol Use Disorders: Towards a Pharmacological Treatment" International Journal of Molecular Sciences 24, no. 10: 8656. https://doi.org/10.3390/ijms24108656