-
Neuroscience and Biobehavioral Reviews Nov 2019A major hypothesis in the addiction field suggests deficits in dopamine signaling during abstinence as a driving mechanism for the relapsing course of the disorder....
A major hypothesis in the addiction field suggests deficits in dopamine signaling during abstinence as a driving mechanism for the relapsing course of the disorder. Paradoxically, blockade of mu-opioid receptors (MORs) intended to suppress dopamine release and alcohol reward is a widely used treatment for preventing relapse in alcohol use disorder (AUD). To elucidate this apparent discrepancy, we systematically survey the literature on experimental studies in AUD subjects and animal models, which assessed striatal dopamine levels and D1, D2-like receptor, dopamine transporter and MOR via positron emission tomography (PET) and ex vivo receptor binding assays. The reported evidence indicates a changing dopaminergic signaling over time, which is associated with concomitant alterations in MOR, thus suggesting a highly dynamic regulation of the reward system during abstinence. Such a view can reconcile the various evidences from in vivo and postmortem studies, but makes developing an effective pharmacological intervention that specifically targets either dopamine receptors or the transporter system a daunting task.
Topics: Alcoholism; Animals; Autopsy; Craving; Humans; Positron-Emission Tomography; Receptors, Dopamine; Receptors, Opioid, mu; Reward
PubMed: 30243576
DOI: 10.1016/j.neubiorev.2018.09.010 -
European Journal of Nuclear Medicine... Jun 2023Dopaminergic scintigraphic imaging is a cornerstone to support the diagnosis in dementia with Lewy bodies. To clarify the current state of knowledge on this imaging... (Review)
Review
INTRODUCTION
Dopaminergic scintigraphic imaging is a cornerstone to support the diagnosis in dementia with Lewy bodies. To clarify the current state of knowledge on this imaging modality and its impact on clinical diagnosis, we performed an updated systematic review of the literature.
METHODS
This systematic review was carried out according to PRISMA guidelines. A comprehensive computer literature search of PubMed/MEDLINE, EMBASE, and Cochrane Library databases for studies published through June 2022 was performed using the following search algorithm: (a) "Lewy body" [TI] OR "Lewy bodies" [TI] and (b) ("DaTscan" OR "ioflupane" OR "123ip" OR "123?ip" OR "123 ip" OR "123i-FP-CIT" OR "FPCIT" OR "FP-CIT" OR "beta?CIT" OR "beta CIT" OR "CIT?SPECT" OR "CIT SPECT" OR "Dat?scan*" OR "dat scan*" OR "dat?spect*" OR "SPECT"). Risk of bias and applicability concerns of the studies were evaluated using the QUADAS-2 tool.
RESULTS
We performed a qualitative analysis of 59 studies. Of the 59 studies, 19 (32%) addressed the diagnostic performance of dopamine transporter imaging, 15 (25%) assessed the identification of dementia with Lewy bodies in the spectrum of Lewy body disease and 18 (31%) investigated the role of functional dopaminergic imaging in distinguishing dementia with Lewy bodies from other dementias. Dopamine transporter loss was correlated with clinical outcomes in 19 studies (32%) and with other functional imaging modalities in 15 studies (25%). Heterogeneous technical aspects were found among the studies through the use of various radioligands, the more prevalent being the [123I]N‑ω‑fluoropropyl‑2β‑carbomethoxy‑3β‑(4‑iodophenyl) nortropane (I-FP-CIT) in 54 studies (91.5%). Image analysis used visual analysis (9 studies, 15%), semi-quantitative analysis (29 studies, 49%), or a combination of both (16 studies, 27%).
CONCLUSION
Our systematic review confirms the major role of dopaminergic scintigraphic imaging in the assessment of dementia with Lewy bodies. Early diagnosis could be facilitated by identifying the prodromes of dementia with Lewy bodies using dopaminergic scintigraphic imaging coupled with emphasis on clinical neuropsychiatric symptoms. Most published studies use a semi-quantitative analytical assessment of tracer uptake, while there are no studies using quantitative analytical methods to measure dopamine transporter loss. The superiority of a purely quantitative approach to assess dopaminergic transmission more accurately needs to be further clarified.
Topics: Humans; Lewy Body Disease; Dopamine Plasma Membrane Transport Proteins; Iodine Radioisotopes; Tomography, Emission-Computed, Single-Photon; Tropanes
PubMed: 36920494
DOI: 10.1007/s00259-023-06154-y -
Sexual Medicine Reviews Oct 2020A growing number of genetic association studies have been performed to investigate the association between the genetic susceptibility alleles and the risk of premature...
INTRODUCTION
A growing number of genetic association studies have been performed to investigate the association between the genetic susceptibility alleles and the risk of premature ejaculation (PE); however, the results remain inconclusive.
OBJECTIVES
This systematic review aimed: (i) to determine whether an association exists between gene(s) or allelic variant(s) and PE; (ii) to assess whether the associations are consistent across studies in magnitude and direction, and (iii) to identify any limitation, gap, or shortcoming in the included studies.
METHODS
The literature search was conducted in PubMed, MEDLINE, Scopus, Cochrane Library, EMBASE, Academic Search Complete, Google Scholar, and CINAHL databases.
RESULTS
Different gene variants associated with PE were assessed. 25 genetic association studies met the inclusion criteria that investigated 11 genes, 2,624 men with PE compared with 9,346 men as controls, twins, and siblings. 19 studies demonstrated a significant association with PE, whereas 4 studies denied such a relationship. SLC6A4 gene polymorphism was investigated in 11 studies (7 studies demonstrated a significant relationship with PE, and 4 studies denied such a relationship). Dopamine transporter gene (DAT1) polymorphism was investigated in 4 studies exhibiting a significant relationship. Androgen receptor gene polymorphisms were investigated in 2 studies, 1 with a significant relationship and the other with a non-significant relationship. Oxytocin gene polymorphisms and tryptophan hydroxylase 2 gene polymorphisms were investigated in 2 studies with a significant relationship.
CONCLUSION
While this review has highlighted several genes that may be potentially associated with PE such as SLC6A4, limitations such as variance in study methods, lack of robust findings, small sample sizes, lack of reproducibility, quality of reporting, and quality of assessment remain a major concern. Further efforts such as standardizing reporting, exploring complementary designs, and the use of genome-wide association studies technology are warranted to test the reproducibility of these early findings. Mostafa T, Abdel-Hamid IA, Taymour M, et al. Gene Variants in Premature Ejaculation: Systematic Review and Future Directions. Sex Med Rev 2020;8:586-602.
Topics: Dopamine Plasma Membrane Transport Proteins; Genetic Association Studies; Humans; Male; Oxytocin; Polymorphism, Genetic; Premature Ejaculation; Receptors, Androgen; Receptors, Serotonin; Reproducibility of Results; Serotonin Plasma Membrane Transport Proteins; Tryptophan Hydroxylase
PubMed: 32800770
DOI: 10.1016/j.sxmr.2020.07.002 -
Biomedicines Aug 2023Major Depressive Disorder (MDD) is a disabling and particularly persistent mental disorder that is considered to be a priority public health problem. The active human... (Review)
Review
Major Depressive Disorder (MDD) is a disabling and particularly persistent mental disorder that is considered to be a priority public health problem. The active human dopamine transporter (DAT), which is encoded by the gene, regulates the dopamine concentration in the synaptic cleft. In this sense, this neurotransmitter is primordial in modulating human emotions. This systematic review aims to verify the gene variant's SS (9R/9R) genotype and S (9R) allele frequency fluctuation and its influence on the modulation of pharmacotherapy in MDD. For this purpose, we searched different databases, and after applying the eligibility criteria, six articles were selected. Studies have shown an association between the SS (9R/9R) genotypic and S (9R) allelic presence with the risk of developing MDD, in addition to influencing the decrease in response to antidepressant therapy. However, despite the findings, disagreements were observed between other studies. For this reason, further studies with the () variant in different populations are necessary to understand this polymorphism's role in the onset of this disease.
PubMed: 37626766
DOI: 10.3390/biomedicines11082270 -
Biological Psychiatry Oct 2019Many polymorphisms in dopamine genes are reported to affect cognitive, imaging, or clinical phenotypes. It is often inferred or assumed that such associations are... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Many polymorphisms in dopamine genes are reported to affect cognitive, imaging, or clinical phenotypes. It is often inferred or assumed that such associations are causal, mediated by a direct effect of the polymorphism on the gene product itself. However, the supporting evidence is not always clear.
METHODS
We conducted systematic reviews and meta-analyses to assess the empirical evidence for functional polymorphisms in genes encoding dopaminergic enzymes (COMT, DBH, DDC, MAOA, MAOB, and TH), dopamine receptors (DRD1, DRD2, DRD3, DRD4, and DRD5), the dopamine transporter (DAT), and vesicular transporters (VMAT1 and VMAT2). We defined functionality as an effect of the polymorphism on the expression, abundance, activity, or affinity of the gene product.
RESULTS
We screened 22,728 articles and identified 255 eligible studies. We found robust and medium to large effects for polymorphisms in 4 genes. For catechol-O-methyltransferase (COMT), the ValMet polymorphism (rs4680) markedly affected enzyme activity, protein abundance, and protein stability. Dopamine β-hydroxylase (DBH) activity was associated with rs1611115, rs2519152, and the DBH-STR polymorphism. Monoamine oxidase A (MAOA) activity was associated with a 5' VNTR polymorphism. Dopamine D receptor (DRD2) binding was influenced by the Taq1A (rs1800497) polymorphism, and rs1076560 affected DRD2 splicing.
CONCLUSIONS
Some widely studied dopaminergic polymorphisms clearly and substantially affect the abundance or activity of the encoded gene product. However, for other polymorphisms, evidence of such an association is negative, inconclusive, or lacking. These findings are relevant when selecting polymorphisms as "markers" of dopamine function, and for interpreting the biological plausibility of associations between these polymorphisms and aspects of brain function or dysfunction.
Topics: Brain; Dopamine; Dopamine Plasma Membrane Transport Proteins; Humans; Polymorphism, Single Nucleotide; Receptors, Dopamine
PubMed: 31303260
DOI: 10.1016/j.biopsych.2019.05.014 -
Tremor and Other Hyperkinetic Movements... 2024Tardive Dyskinesia (TD) is a neurological disorder characterized by involuntary movements, often caused by dopamine receptor antagonists. Vesicular Monoamine Transporter... (Comparative Study)
Comparative Study Review
BACKGROUND
Tardive Dyskinesia (TD) is a neurological disorder characterized by involuntary movements, often caused by dopamine receptor antagonists. Vesicular Monoamine Transporter 2 (VMAT2) inhibitors, such as valbenazine and deutetrabenazine, have emerged as promising therapies for TD and several clinical trials have shown their efficacy. This study aims to compare the efficacy and safety profile of VMAT2 inhibitors, focusing on a recent trial conducted in the Asian population.
METHODS
We reviewed the PubMed, Cochrane Library, Embase database, and clinicaltrials.gov between January 2017 and October 2023, using the keywords "tardive dyskinesia" AND ("valbenazine" [all fields] OR " deutetrabenazine " [all fields]) AND "clinical trial". The reviewed articles were studied for efficacy and side effects.
RESULTS
An initial search yielded 230 articles, of which 104 were duplicates. Following the title and abstract screening, 25 additional articles were excluded. A full-text review resulted in the exclusion of 96 more articles. Ultimately, four double-blind clinical trials met the inclusion criteria. The deutetrabenazine studies demonstrated significant improvements in Abnormal Involuntary Movement Scale (AIMS) scores compared to placebo, with no difference in adverse events. The valbenazine studies showed favorable results in reducing TD symptoms and were well-tolerated.
DISCUSSION
The studies reviewed in this analysis underscore the potential of deutetrabenazine and valbenazine as valuable treatment options for TD in diverse populations. Both medications demonstrated significant improvements in AIMS scores, suggesting their effectiveness in managing TD symptoms. Additionally, they exhibited favorable safety profiles, with low rates of serious adverse events and no significant increase in QT prolongation, parkinsonism, suicidal ideation, or mortality.
CONCLUSION
The studies reviewed highlight the promising efficacy and tolerability of deutetrabenazine and valbenazine as treatments for Tardive Dyskinesia, providing new hope for individuals affected by this challenging condition.
Topics: Humans; Randomized Controlled Trials as Topic; Tardive Dyskinesia; Tetrabenazine; Valine; Vesicular Monoamine Transport Proteins
PubMed: 38497033
DOI: 10.5334/tohm.842 -
Molecular Psychiatry Jul 2023Impairment of insulin action and metabolic dysregulation have traditionally been associated with schizophrenia, although the molecular basis of such association remains... (Meta-Analysis)
Meta-Analysis
Impairment of insulin action and metabolic dysregulation have traditionally been associated with schizophrenia, although the molecular basis of such association remains still elusive. The present meta-analysis aims to assess the impact of insulin action manipulations (i.e., hyperinsulinemia, hypoinsulinemia, systemic or brain insulin resistance) on glutamatergic, dopaminergic, γ-aminobutyric acid (GABA)ergic, and serotonergic pathways in the central nervous system. More than one hundred outcomes, including transcript or protein levels, kinetic parameters, and other components of the neurotransmitter pathways, were collected from cultured cells, animals, or humans, and meta-analyzed by applying a random-effects model and adopting Hedges'g to compare means. Two hundred fifteen studies met the inclusion criteria, of which 180 entered the quantitative synthesis. Significant impairments in key regulators of synaptic plasticity processes were detected as the result of insulin handlings. Specifically, protein levels of N-methyl-D-aspartate receptor (NMDAR) subunits including type 2A (NR2A) (Hedges' g = -0.95, 95%C.I. = -1.50, -0.39; p = 0.001; I = 47.46%) and 2B (NR2B) (Hedges'g = -0.69, 95%C.I. = -1.35, -0.02; p = 0.043; I = 62.09%), and Postsynaptic density protein 95 (PSD-95) (Hedges'g = -0.91, 95%C.I. = -1.51, -0.32; p = 0.003; I = 77.81%) were found reduced in insulin-resistant animal models. Moreover, insulin-resistant animals showed significantly impaired dopamine transporter activity, whereas the dopamine D2 receptor mRNA expression (Hedges'g = 3.259; 95%C.I. = 0.497, 6.020; p = 0.021; I = 90.61%) increased under insulin deficiency conditions. Insulin action modulated glutamate and GABA release, as well as several enzymes involved in GABA and serotonin synthesis. These results suggest that brain neurotransmitter systems are susceptible to insulin signaling abnormalities, resembling the discrete psychotic disorders' neurobiology and possibly contributing to the development of neurobiological hallmarks of treatment-resistant schizophrenia.
Topics: Humans; Animals; Schizophrenia; Insulin; Neurobiology; Disks Large Homolog 4 Protein; Receptors, N-Methyl-D-Aspartate; gamma-Aminobutyric Acid; Neurotransmitter Agents
PubMed: 37085712
DOI: 10.1038/s41380-023-02065-4 -
Frontiers in Neuroscience 2020The dopaminergic system is involved in many psychiatric disorders as a GABAergic, serotonergic, and glutamatergic system. A systematic review and meta-analysis was...
The dopaminergic system is involved in many psychiatric disorders as a GABAergic, serotonergic, and glutamatergic system. A systematic review and meta-analysis was performed to elucidate the alteration of the dopaminergic system in anxiety and compulsive disorders. The databases of Pubmed, Embase, and ScienceDirect were searched and articles reporting the involvement of the dopaminergic system in patients with anxiety disorder and obsessive compulsive disorder (OCD) were recognized. The key research data were extracted from the included articles and standardized mean differences were calculated using meta-analyses if there were more than two studies with obtainable data. Sensitivity analyses were further performed to detect the stability of results, and the qualities of all the included studies were assessed using the Newcastle Ottawa scale. Finally, we identified 8 and 11 studies associated with anxiety disorder and OCD for further analysis, respectively. Most consistently, the striatal dopamine D receptor (DR) of OCD patients had decreased while no significant correlation was found between striatal D2R and disease severity. The striatal dopamine transporter (DAT) had not been significantly altered in both the anxiety disorder and OCD patients. The heterogeneity values from the meta-analyses were extremely high while those results remained stable after sensitivity analyses. Inconsistent data were found in the striatal DR of patients with anxiety disorder. Limited data had suggested that dopamine synthesis increased in most regions of the cerebral cortex and cerebellum in OCD patients. The most convincing finding was that the D receptor decreased in patients with obsessive compulsive disorder. The dopamine transporter may have no relationship with anxiety and compulsive disorder.
PubMed: 33343291
DOI: 10.3389/fnins.2020.608520 -
Psychopharmacology Mar 2021Although numerous studies have suggested that pharmacological alteration of the dopamine (DA) system modulates reward discounting, these studies have produced... (Meta-Analysis)
Meta-Analysis
RATIONALE
Although numerous studies have suggested that pharmacological alteration of the dopamine (DA) system modulates reward discounting, these studies have produced inconsistent findings.
OBJECTIVES
Here, we conducted a systematic review and pre-registered meta-analysis to evaluate DA drug-mediated effects on reward discounting of time, probability, and effort costs in studies of healthy rats. This produced a total of 1343 articles to screen for inclusion/exclusion. From the literature, we identified 117 effects from approximately 1549 individual rats.
METHODS
Using random effects with maximum-likelihood estimation, we meta-analyzed placebo-controlled drug effects for (1) DA D1-like receptor agonists and (2) antagonists, (3) D2-like agonists and (4) antagonists, and (5) DA transporter-modulating drugs.
RESULTS
Meta-analytic effects showed that DAT-modulating drugs decreased reward discounting. While D1-like and D2-like antagonists both increased discounting, agonist drugs for those receptors had no significant effect on discounting behavior. A number of these effects appear contingent on study design features like cost type, rat strain, and microinfusion location.
CONCLUSIONS
These findings suggest a nuanced relationship between DA and discounting behavior and urge caution when drawing generalizations about the effects of pharmacologically manipulating dopamine on reward-based decision-making.
Topics: Animals; Biological Transport; Brain; Decision Making; Delay Discounting; Dopamine Agonists; Dopamine Antagonists; Dose-Response Relationship, Drug; Male; Rats; Receptors, Dopamine D1; Receptors, Dopamine D2; Reward
PubMed: 33215269
DOI: 10.1007/s00213-020-05723-5 -
Movement Disorders Clinical Practice Jun 2024As the diagnosis of Parkinson's disease (PD) is fundamentally clinical, the usefulness of ioflupane (I) single-photon emission computed tomography (SPECT) or DaTSCAN as... (Review)
Review
BACKGROUND
As the diagnosis of Parkinson's disease (PD) is fundamentally clinical, the usefulness of ioflupane (I) single-photon emission computed tomography (SPECT) or DaTSCAN as a diagnostic tool has been a matter of debate for years. The performance of DaTSCAN is generally recommended in the follow-up of patients with a clinically uncertain diagnosis, especially in those with a suspected essential tremor, drug-induced parkinsonism, or vascular parkinsonism. However, there is a dearth of DaTSCAN findings regarding neurodegenerative parkinsonisms besides PD and atypical parkinsonisms. To date, a specific nigrostriatal dopamine uptake pattern that would help differentiate PD from the most frequent atypical parkinsonisms is yet to be described. This fact is further complicated by the possible visualization of abnormalities in the uptake pattern in patients with rarer neurodegenerative parkinsonisms.
OBJECTIVES
We aimed to summarize the current literature regarding DaTSCAN findings in patients with rare neurodegenerative parkinsonisms.
METHODS
The PubMed database was systematically screened for studies in English or Spanish up to October 15, 2023, using search terms "DaTSCAN", "ioflupane", "DaT-SPECT", "123I-FP-CIT SPECT", "dopamine transporter imaging", and "[123I] FP-CIT SPECT". Duplicated publications and studies regarding PD, atypical parkinsonisms, dystonia-parkinsonism, essential tremor, and parkinsonism due to non-degenerative causes were excluded.
RESULTS
The obtained results were reviewed and summarized, including DaTSCAN findings in fragile X-associated tremor/ataxia syndrome, prion diseases, Huntington's disease, spinocerebellar ataxia, hereditary spastic paraparesis, metabolic disorders, and other diseases (anti-IgLON5 disease, ring chromosome 20 syndrome, chorea-acanthocytosis, and neuronal ceroid lipofuscinosis).
CONCLUSIONS
This review highlights the need to determine in the future the utility and cost-effectiveness of DaTSCAN, both as a diagnostic and a prognostic tool, in patients with parkinsonian symptoms in rare neurodegenerative diseases.
Topics: Humans; Tomography, Emission-Computed, Single-Photon; Parkinsonian Disorders; Tropanes; Parkinson Disease
PubMed: 38693679
DOI: 10.1002/mdc3.14055