{"doi":"10.3389/fpubh.2025.1594872","title":"Targeting pro-dopaminergic agonism to attenuate depression in patients displaying genetic/epigenetic predisposition to hypodopaminergia","abstract":"Since 1990, substantial evidence from association studies has identified the D(2) dopamine receptor (DRD2) gene as a factor in the development of alcoholism [1][2][3][4]. The DRD2 gene has also been linked to other substance use disorders, including dependencies on cocaine, nicotine, and opioids, as well as obesity [5][6][7][8][9][10][11]. Dopamine in the brain, often referred to as the \"stressrelief molecule,\" plays a central role in managing stress responses [12].The relationship between dopaminergic neurotransmission and various forms of stress has been known for many years. The current understanding is that numerous genes interacting with dopaminergic pathways may comprise promising therapeutic targets, particularly in addiction treatment [13]. Li et al. identified 396 genes that together influence dopamine and glutamate release in addiction contexts [14]. The consistent evidence supporting dopamine's role in addiction has driven the development of therapies focused on modulating dopaminergic signaling [7].A significant limitation in suppressing the dopaminergic system to induce drug extinction is the potential for mood disturbances and an increased risk of suicidal ideation. These side effects are counter-productive to the aim of the approach. Our laboratory has proposed that long-term, gentle stimulation of dopamine receptors could induce the \"normalization\" of reduced dopamine D2 receptor density [15].Our laboratory has promoted the extended-term use of dopaminergic agonist therapies to reduce cravings for substances such as glucose based on the understanding that individuals carrying the DRD2 Taq A1 allele exhibit compromised D2 receptor density [16,17]. Positron emission tomography (PET) imaging studies have revealed substantial variability in dopamine D2 receptor density across in vivo human striatum. Low D2 receptor binding in vivo has been consistently associated with dependence on alcohol and other substances. The DRD2 A1 allele has been potentially linked to a subtype of alcoholism and reduced D2 receptor density in vitro. Pohjalainen et al. [18] conducted a study involving 54 healthy Finnish participants using PET imaging with [11C] raclopride to evaluate D2 receptor characteristics, including binding density (Bmax), affinity (Kd), and availability (Bmax/Kd). They observed that the A1/A2 genotype group exhibited significantly reduced D2 receptor availability compared to the A2/A2 group, indicating an alteration in receptor density. No difference in receptor affinity (Kd) was observed between the groups. The association between the A1 allele and low D2 receptor availability in healthy subjects indicates that the A1 allele of the TaqIA polymorphism may be in linkage disequilibrium with a promoter/regulatory mutation affecting dopamine D2 receptor expression. This research provides an in vivo neurobiological correlation between the A1 allele and lower D2 receptor availability in healthy individuals, aligning with our laboratory's work to underscore the importance of targeted interventions to address the neurobiological underpinnings of dopamine dysfunction in individuals with genetic predispositions [17].Understanding why D2 receptor density was lower in A1 allele carriers provided the impetus to suggest that raising D2 receptor density may reduce aberrant craving behavior, providing a homeostatic state toward normalization. This concept was initially supported by Boundy et al. [19], whose research with radiolabeled antagonists demonstrated that both agonists and antagonists could induce up-regulation of D2 dopamine receptors in cells transfected to express D2L or D2S receptors. Notably, receptor regulation induced by agonists was synergistic with cAMP analogs, and the time courses of the effects varied between agonists and antagonists. Further studies extended these findings by utilizing radiolabeled agonists to examine agonistand antagonist-induced regulation of the high-affinity state of the D2L dopamine recepto","journal":"Frontiers in Public Health","year":2025,"id":547153,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9618,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":460951,"name":"Kenneth Blum","orcid":"0000-0001-6727-803X","position":1,"is_corresponding":false},{"id":1424608,"name":"Alexander P. L. Lewandrowski","orcid":null,"position":2,"is_corresponding":false},{"id":430661,"name":"Panayotis K. Thanos","orcid":"0000-0002-5663-3478","position":3,"is_corresponding":false},{"id":1304102,"name":"Albert Pinhasov","orcid":"0000-0001-8116-4565","position":4,"is_corresponding":false},{"id":1245128,"name":"Alireza Sharafshah","orcid":"0000-0001-8048-9587","position":5,"is_corresponding":false},{"id":109350,"name":"David Baron","orcid":"0000-0001-7670-2613","position":6,"is_corresponding":false},{"id":475300,"name":"Mark S. Gold","orcid":"0000-0001-7138-8047","position":7,"is_corresponding":false},{"id":903542,"name":"Catherine A. Dennen","orcid":null,"position":8,"is_corresponding":false},{"id":683912,"name":"Igor Elman","orcid":"0000-0002-1345-2677","position":9,"is_corresponding":false},{"id":533277,"name":"Abdalla Bowirrat","orcid":"0000-0001-8185-0688","position":10,"is_corresponding":false},{"id":533278,"name":"Edward J. Modestino","orcid":"0000-0001-7611-5144","position":11,"is_corresponding":false},{"id":1148602,"name":"Foojan Zeine","orcid":"0009-0006-7709-5580","position":12,"is_corresponding":false},{"id":1148601,"name":"Nicole Jafari","orcid":"0000-0001-7762-9673","position":13,"is_corresponding":false},{"id":1148958,"name":"Keerthy Sunder","orcid":null,"position":14,"is_corresponding":false},{"id":1148600,"name":"Milan Makale","orcid":"0000-0001-5414-0517","position":15,"is_corresponding":false},{"id":1148954,"name":"John Giordano","orcid":null,"position":16,"is_corresponding":false},{"id":462389,"name":"Marjorie C. Gondré‐Lewis","orcid":null,"position":17,"is_corresponding":false},{"id":1439585,"name":"Marco Lindenau","orcid":null,"position":18,"is_corresponding":false},{"id":1304105,"name":"Brian Fuehrlein","orcid":"0000-0002-3202-8089","position":19,"is_corresponding":false},{"id":533279,"name":"Rajendra D. Badgaiyan","orcid":"0000-0001-5586-5114","position":20,"is_corresponding":false},{"id":1439171,"name":"Chynna Levin","orcid":"0000-0002-8710-1757","position":21,"is_corresponding":false},{"id":1245129,"name":"Sergio L. 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