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Brain Research May 2023Identifying neurobiological characteristics that predict the development of cocaine use disorder would be of great value in prevention efforts. Because of their...
Identifying neurobiological characteristics that predict the development of cocaine use disorder would be of great value in prevention efforts. Because of their importance in mediating the abuse-related effects of cocaine, brain dopamine receptors are logical candidates for investigation. We analyzed data from two recently published studies that characterized availability of dopamine D2-like receptors (D2R) with [C]raclopride PET imaging and dopamine D receptor (DR) sensitivity with quinpirole-induced yawning in cocaine-naïve rhesus monkeys who subsequently acquired cocaine self-administration and completed a cocaine self-administration dose-effect curve. The present analysis compared D2R availability in several brain areas and characteristics of quinpirole-induced yawning, both acquired when monkeys were drug-naïve, with measures of initial sensitivity to cocaine. D2R availability in the caudate nucleus was negatively correlated with the ED of the cocaine self-administration curve, although the significance of this relationship was driven by an outlier and was not present after the outlier was removed. No other significant associations were observed between D2R availability in any examined brain region and measures of sensitivity to cocaine reinforcement. However, there was a significant negative correlation between DR sensitivity, represented by the ED of the quinpirole-induced yawning curve, and the dose at which monkeys acquired cocaine self-administration. We also report no change from baseline D2R availability when a second PET scan was conducted after completion of the dose-effect curves. These data suggest the utility of DR sensitivity, but not D2R availability, as a biomarker for vulnerability and resilience to cocaine. The well-established relationships between dopamine receptors and cocaine reinforcement in cocaine-experienced humans and animals may require extensive cocaine exposure.
Topics: Humans; Animals; Male; Cocaine; Dopamine; Quinpirole; Macaca mulatta; Receptors, Dopamine D3; Dopamine Agonists; Receptors, Dopamine D2; Self Administration; Dose-Response Relationship, Drug
PubMed: 36914041
DOI: 10.1016/j.brainres.2023.148323 -
Technology in Cancer Research &... 2021The dopamine receptors (DRs) family includes 5 members with differences in signal transduction and ligand affinity. Abnormal DRs expression has been correlated multiple... (Review)
Review
The dopamine receptors (DRs) family includes 5 members with differences in signal transduction and ligand affinity. Abnormal DRs expression has been correlated multiple tumors with their clinical outcome. Thus, it has been proposed that DRs-targeting drugs-developed for other diseases as schizophrenia or Parkinson's disease-could be helpful in managing neoplastic diseases. In this review, we discuss the role of DRs and the effects of DRs-targeting in tumor progression and cancer cell biology using multiple high-prevalence neoplasms as examples. The evidence shows that DRs are valid therapeutic targets for certain receptor/disease combinations, but the data are inconclusive or contradictory for others. In either case, further studies are required to define the precise role of DRs in tumor progression and propose better therapeutic strategies for their targeting.
Topics: Animals; Dopamine Agonists; Dopamine Antagonists; Humans; Molecular Targeted Therapy; Neoplasms; Receptors, Dopamine; Signal Transduction
PubMed: 34212819
DOI: 10.1177/15330338211027913 -
ACS Chemical Neuroscience Mar 2020Kinetic analysis of dopamine receptor activation and inactivation and the study of dopamine-dependent signaling requires precise simulation of the presynaptic release of...
Kinetic analysis of dopamine receptor activation and inactivation and the study of dopamine-dependent signaling requires precise simulation of the presynaptic release of the neurotransmitter dopamine and tight temporal control over the release of dopamine receptor antagonists. The 8-cyano-7-hydroxyquinolinyl (CyHQ) photoremovable protecting group was conjugated to dopamine and the dopamine receptor antagonist sulpiride to generate "caged" versions of these neuromodulators (CyHQ--DA and CyHQ-sulpiride, respectively) that could release their payloads with 365 or 405 nm light or through 2-photon excitation (2PE) at 740 nm. These compounds are stable under physiological conditions in the dark, yet photolyze rapidly and cleanly to yield dopamine or sulpiride and the caging remnant CyHQ-OH. CyHQ--DA mediated the light activation of dopamine-1 (D1) receptors on the breast cancer cell line MDA-MB-231 in culture. In mouse brain slice from the substantia nigra pars compacta, localized flash photolysis of CyHQ--DA accurately mimicked the natural presynaptic release of dopamine and activation of dopamine-2 (D2) receptors, causing a robust, concentration-dependent, and repeatable G protein-coupled inwardly rectifying potassium channel-mediated outward current in whole-cell voltage clamp recordings that was amplified by cocaine and blocked by sulpiride. Photolysis of CyHQ-sulpiride rapidly blocked synaptic activity, enabling measurement of the unbinding rates of dopamine and quinpirole, a D2 receptor agonist. These tools will enable more detailed study of dopamine receptors, their interactions with other GPCRs, and the physiology of dopamine signaling in the brain.
Topics: Animals; Dopamine; Dopamine Agonists; Dopaminergic Neurons; Kinetics; Mice; Quinpirole; Receptors, Dopamine D1; Sulpiride
PubMed: 32077679
DOI: 10.1021/acschemneuro.9b00675 -
Drugs Oct 2019Bipolar disorder is a chronic, disabling, and costly illness with frequent relapses and recurrences, high rates of co-morbid conditions, and poor adherence to treatment.... (Review)
Review
Bipolar disorder is a chronic, disabling, and costly illness with frequent relapses and recurrences, high rates of co-morbid conditions, and poor adherence to treatment. Mood stabilizers and antipsychotics are the cornerstones of treatment. Dopamine receptor partial agonists are a novel class of antipsychotic agents with original pharmacodynamic properties. Among them, two have been approved by the US Food and Drug Administration for the treatment of bipolar disorder. Aripiprazole (oral formulation) has been approved as monotherapy for the treatment of manic/mixed episodes in adult and pediatric populations and for maintenance treatment in adults, and as adjunctive treatment to mood stabilizers, for the acute treatment of manic/mixed episodes and for maintenance in adults. An intramuscular formulation of aripiprazole has been approved for the treatment of agitation in mania and a long-acting injectable formulation has been approved as maintenance treatment. In the USA, cariprazine has been approved as monotherapy for the acute treatment of manic/mixed as well as bipolar depressive episodes. Brexpiprazole is not yet approved to treat bipolar disorder. The evidence supporting these indications is reviewed via an analysis of clinical registration trials as well as additional studies, on the basis of a systematic literature search. Further studies dealing with other aspects of bipolar illness are also presented. Aripiprazole and cariprazine are efficacious and generally well tolerated agents that have shown cost effectiveness, and may therefore enrich our therapeutic armamentarium for bipolar illness. Brexpiprazole, which displays an overall promising tolerability profile, deserves further efficacy studies.
Topics: Antipsychotic Agents; Aripiprazole; Bipolar Disorder; Dopamine Agonists; Humans; Piperazines; Receptors, Dopamine; United States; United States Food and Drug Administration
PubMed: 31468317
DOI: 10.1007/s40265-019-01189-8 -
General Physiology and Biophysics Jul 2020It is known that early-life stress events induce profound consequences on emotional brain regions including amygdala, involved in emotional processing and the ventral...
Dopamine concentrations and dopamine receptor gene expression in emotion-related brain structures of female adult rats exposed to stress of chronic isolation from weaning.
It is known that early-life stress events induce profound consequences on emotional brain regions including amygdala, involved in emotional processing and the ventral tegmental area (VTA), which contains neuron cell bodies of the mesolimbic dopaminergic system. The aim of this study is to test the hypothesis that stress induced by long-term social isolation from weaning in female rats is associated with alterations in amygdalar dopamine receptor gene expression and VTA dopamine concentrations. Rats were weaned on postnatal day 21 and then exposed to stress of chronic isolation for 9 weeks. Control animals were housed socially. Amygdalar dopamine D1 but not D2 receptor gene expression was decreased in isolated rats compared to controls. Dopamine concentrations in the VTA were enhanced following chronic isolation. A negative correlation was observed between amygdalar D1 gene expression and dopamine concentrations in the VTA. In conclusion, a reduction of dopamine D1 receptor gene expression in the amygdala in response to stress induced by chronic isolation in female rats was accompanied by an increase in dopamine concentration in the VTA. Further studies are needed to understand the physiological significance, if any, of negative association of amygdalar dopamine receptor D1 gene expression and dopamine concentrations in the VTA.
Topics: Animals; Dopamine; Emotions; Female; Rats; Receptors, Dopamine D2; Social Isolation; Stress, Psychological; Ventral Tegmental Area; Weaning
PubMed: 32902408
DOI: 10.4149/gpb_2020015 -
Clinical Cancer Research : An Official... Apr 2019Dopamine receptor D2 (DRD2) is a G protein-coupled receptor antagonized by ONC201, an anticancer small molecule in clinical trials for high-grade gliomas and other...
PURPOSE
Dopamine receptor D2 (DRD2) is a G protein-coupled receptor antagonized by ONC201, an anticancer small molecule in clinical trials for high-grade gliomas and other malignancies. DRD5 is a dopamine receptor family member that opposes DRD2 signaling. We investigated the expression of these dopamine receptors in cancer and their influence on tumor cell sensitivity to ONC201.
EXPERIMENTAL DESIGN
The Cancer Genome Atlas was used to determine DRD2/DRD5 expression broadly across human cancers. Cell viability assays were performed with ONC201 in >1,000 Genomic of Drug Sensitivity in Cancer and NCI60 cell lines. IHC staining of DRD2/DRD5 was performed on tissue microarrays and archival tumor tissues of glioblastoma patients treated with ONC201. Whole exome sequencing was performed in RKO cells with and without acquired ONC201 resistance. Wild-type and mutant DRD5 constructs were generated for overexpression studies.
RESULTS
DRD2 overexpression broadly occurs across tumor types and is associated with a poor prognosis. Whole exome sequencing of cancer cells with acquired resistance to ONC201 revealed a Q366R mutation in the DRD5 gene. Expression of Q366R DRD5 was sufficient to induce tumor cell apoptosis, consistent with a gain-of-function. DRD5 overexpression in glioblastoma cells enhanced DRD2/DRD5 heterodimers and DRD5 expression was inversely correlated with innate tumor cell sensitivity to ONC201. Investigation of archival tumor samples from patients with recurrent glioblastoma treated with ONC201 revealed that low DRD5 expression was associated with relatively superior clinical outcomes.
CONCLUSIONS
These results implicate DRD5 as a negative regulator of DRD2 signaling and tumor sensitivity to ONC201 DRD2 antagonism.
Topics: Antineoplastic Agents; Biomarkers; Cell Line, Tumor; Cell Survival; Dopamine D2 Receptor Antagonists; Drug Resistance; Gene Expression; Humans; Imidazoles; Immunohistochemistry; Magnetic Resonance Imaging; Neoplasm Grading; Neoplasm Staging; Neoplasms; Prognosis; Protein Binding; Pyridines; Pyrimidines; Receptors, Dopamine D2; Receptors, Dopamine D5; Signal Transduction
PubMed: 30559168
DOI: 10.1158/1078-0432.CCR-18-2572 -
Scientific Reports Jun 2023The striatum integrates dense neuromodulatory inputs from many brain regions to coordinate complex behaviors. This integration relies on the coordinated responses from...
The striatum integrates dense neuromodulatory inputs from many brain regions to coordinate complex behaviors. This integration relies on the coordinated responses from distinct striatal cell types. While previous studies have characterized the cellular and molecular composition of the striatum using single-cell RNA-sequencing at distinct developmental timepoints, the molecular changes spanning embryonic through postnatal development at the single-cell level have not been examined. Here, we combine published mouse striatal single-cell datasets from both embryonic and postnatal timepoints to analyze the developmental trajectory patterns and transcription factor regulatory networks within striatal cell types. Using this integrated dataset, we found that dopamine receptor-1 expressing spiny projection neurons have an extended period of transcriptional dynamics and greater transcriptional complexity over postnatal development compared to dopamine receptor-2 expressing neurons. Moreover, we found the transcription factor, FOXP1, exerts indirect changes to oligodendrocytes. These data can be accessed and further analyzed through an interactive website ( https://mouse-striatal-dev.cells.ucsc.edu ).
Topics: Animals; Mice; Neurons; Corpus Striatum; Neostriatum; Transcription Factors; Receptors, Dopamine
PubMed: 37270616
DOI: 10.1038/s41598-023-36255-5 -
Journal of Chemical Information and... Jun 2021Targeting the D3 dopamine receptor (D3R) is a promising pharmacotherapeutic strategy for the treatment of many disorders. The structure of the D3R is similar to the D2...
Targeting the D3 dopamine receptor (D3R) is a promising pharmacotherapeutic strategy for the treatment of many disorders. The structure of the D3R is similar to the D2 dopamine receptor (D2R), especially in the transmembrane spanning regions that form the orthosteric binding site, making it difficult to identify D3R selective pharmacotherapeutic agents. Here, we examine the molecular basis for the high affinity D3R binding and D3R vs D2R binding selectivity of substituted phenylpiperazine thiopheneamides. We show that removing the thiophenearylamide portion of the ligand consistently decreases the affinity of these ligands at D3R, while not affecting their affinity at the D2R. Our long (>10 μs) molecular dynamics simulations demonstrated that both dopamine receptor subtypes adopt two major conformations that we refer to as closed or open conformations, with D3R sampling the open conformation more frequently than D2R. The binding of ligands with conjoined orthosteric-allosteric binding moieties causes the closed conformation to populate more often in the trajectories. Also, significant differences were observed in the extracellular loops (ECL) of these two receptor subtypes leading to the identification of several residues that contribute differently to the ligand binding for the two receptors that could potentially contribute to ligand binding selectivity. Our observations also suggest that the displacement of ordered water in the binding pocket of D3R contributes to the affinity of the compounds containing an allosteric binding motif. These studies provide a better understanding of how a bitopic mode of engagement can determine ligands that bind selectively to D2 and D3 dopamine receptor subtypes.
Topics: Ligands; Molecular Conformation; Protein Binding; Receptors, Dopamine D3; Structure-Activity Relationship
PubMed: 33988991
DOI: 10.1021/acs.jcim.1c00036 -
Acta Physiologica (Oxford, England) Jan 2016Antineuronal autoantibodies are associated with the involuntary movement disorder Sydenham chorea (SC) and paediatric autoimmune neuropsychiatric disorders associated... (Review)
Review
Antineuronal autoantibodies are associated with the involuntary movement disorder Sydenham chorea (SC) and paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) which are characterized by the acute onset of tics and/or obsessive compulsive disorder (OCD). In SC and PANDAS, autoantibodies signal human neuronal cells and activate calcium calmodulin-dependent protein kinase II (CaMKII). Animal models immunized with group A streptococcal antigens demonstrate autoantibodies against dopamine receptors and concomitantly altered behaviours. Human monoclonal antibodies (mAbs) derived from SC target and signal the dopamine D2L (long) receptor (D2R). Antibodies against D2R were elevated over normal levels in SC and acute-onset PANDAS with small choreiform movements, but were not elevated over normal levels in PANDAS-like chronic tics and OCD. The expression of human SC-derived anti-D2R autoantibody V gene in B cells and serum of transgenic mice demonstrated that the human autoantibody targets dopaminergic neurones in the basal ganglia and other types of neurones in the cortex. Here, we review current evidence supporting the hypothesis that antineuronal antibodies, specifically against dopamine receptors, follow streptococcal exposures and may target dopamine receptors and alter central dopamine pathways leading to movement and neuropsychiatric disorders.
Topics: Animals; Autoantibodies; Autoimmunity; Chorea; Humans; Movement Disorders; Receptors, Dopamine; Streptococcal Infections
PubMed: 26454143
DOI: 10.1111/apha.12614 -
Journal of Cellular and Molecular... Mar 2018Acromegaly is a hormonal disorder resulting from excessive growth hormone (GH) secretion frequently produced by pituitary adenomas and consequent increase in...
Acromegaly is a hormonal disorder resulting from excessive growth hormone (GH) secretion frequently produced by pituitary adenomas and consequent increase in insulin-like growth factor 1 (IGF-I). Elevated GH and IGF-I levels result in a wide range of somatic, cardiovascular, endocrine, metabolic and gastrointestinal morbidities. Somatostatin analogues (SSAs) form the basis of medical therapy for acromegaly and are currently used as first-line treatment or as second-line therapy in patients undergoing unsuccessful surgery. However, a considerable percentage of patients do not respond to SSAs treatment. Somatostatin receptors (SSTR1-5) and dopamine receptors (DRD1-5) subtypes play critical roles in the regulation of hormone secretion. These receptors are considered important pharmacological targets to inhibit hormone oversecretion. It has been proposed that decreased expression of SSTRs may be associated with poor response to SSAs. Here, we systematically examine SSTRs and DRDs expression in human somatotroph adenomas by quantitative PCR. We observed an association between the response to SSAs treatment and DRD4, DRD5, SSTR1 and SSTR2 expression. We also examined SSTR expression by immunohistochemistry and found that the immunohistochemical detection of SSTR2 in particular might be a good predictor of response to SSAs.
Topics: Adenoma; Adult; Female; Gene Expression; Growth Hormone-Secreting Pituitary Adenoma; Humans; Immunohistochemistry; Male; Middle Aged; Protein Isoforms; Receptors, Dopamine; Receptors, Somatostatin; Retrospective Studies; Reverse Transcriptase Polymerase Chain Reaction; Somatostatin
PubMed: 29266696
DOI: 10.1111/jcmm.13440