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Naunyn-Schmiedeberg's Archives of... Jan 2020Repeated administration of stimulants induces conditioned place preference (CPP). Dopamine receptor supersensitivity is developed in stimulant-induced CPP animals;...
Repeated administration of stimulants induces conditioned place preference (CPP). Dopamine receptor supersensitivity is developed in stimulant-induced CPP animals; however, dopamine receptor subtypes associated with the development of supersensitivity in CPP animals are largely unknown. The present preclinical study aimed to examine whether dopamine D1 or D2 receptor antagonists exert inhibitory effects on stimulant-induced psychological behaviors. Additionally, the authors aimed to elucidate the role of dopamine receptor supersensitivity on the development of reward-related behavior. Sprague Dawley rats subjected to methamphetamine- and cocaine-induced CPP tests were treated with dopamine D1 (SCH23390) or D2 (sulpiride) receptor antagonists. Following the CPP experiment, rats were challenged with apomorphine (dopamine receptor agonist), and locomotor activity was measured. Methamphetamine- and cocaine-induced CPP was reduced with the administration of SCH23390, but not sulpiride. In addition, the apomorphine challenge evoked an increase in locomotor activity in stimulant-pre-treated rats, reflecting dopamine receptor supersensitivity. SCH23390 pre-treatment inhibited the development of dopamine receptor supersensitivity, while sulpiride demonstrated no inhibitory effects. These results suggest that the dopamine D1 receptor antagonist SCH23390 inhibits the development of dopamine receptor supersensitivity which is associated with the development of CPP.
Topics: Animals; Benzazepines; Central Nervous System Stimulants; Cocaine; Conditioning, Psychological; Dopamine Antagonists; Locomotion; Male; Methamphetamine; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1; Receptors, Dopamine D2; Sulpiride
PubMed: 31372696
DOI: 10.1007/s00210-019-01694-3 -
BMC Cancer Dec 2022Dopamine receptors have been reported to play important roles in cancer progression. However, the role of dopamine receptor D3 (DRD3) in hepatocellular carcinoma (HCC)...
BACKGROUND
Dopamine receptors have been reported to play important roles in cancer progression. However, the role of dopamine receptor D3 (DRD3) in hepatocellular carcinoma (HCC) remains unclear.
METHODS
The expression of DRD3 was detected by immunohistochemistry and real-time qPCR. The prognostic value of DRD3 in patients was investigated by analyzing selected databases, including cBioPortal and Kaplan-Meier plotter. Cell growth was tested by CCK8 assay, and Transwell assays were performed to assess cancer cell migration and invasion. The cAMP/ERK/CREB signaling pathway was evaluated by Western blot analysis and ELISA. An HCC xenograft model was established for in vivo experiments.
RESULTS
DRD3 mRNA expression was significantly higher in nontumor tissues than in tumor tissues. Lower protein expression of DRD3 was related to poor recurrence-free survival (RFS) and overall survival (OS). Kaplan-Meier plotter analysis showed that higher expression of DRD3 mRNA was associated with better OS, RFS, disease-specific survival (DSS), and progression-free survival (PFS). cBioPortal analysis revealed that the alteration group, which harbored genetic mutations in DRD3, exhibited poor OS, RFS, DSS and PFS. According to CCK8 and Transwell assays, stable DRD3 overexpression cell line (ex-DRD3-SK-HEP-1) showed weaker proliferation, migration and invasion behaviors. PD128907, a DRD3 agonist, suppressed proliferation, migration and invasion in HCC cell lines, while U99194, a DRD3 antagonist, enhanced proliferation, migration and invasion in HCC cell lines. Western blot analysis and ELISA revealed that stable DRD3 knock-down cell line (sh-DRD3-PLC/PRF/5) and U99194 both increased the protein levels of cAMP, p-ERK and p-CREB; on the other hand, ex-DRD3-SK-HEP-1 and PD128907 decreased the protein levels of cAMP, p-ERK and p-CREB. SCH772984, an ERK antagonist, abolished the effect of U99194 on the malignant biological behaviors of HCC cells. In vivo, PD128907 suppressed tumor growth, and U99194 enhanced tumor growth.
CONCLUSION
Our results suggest that down-regulation of DRD3 is strongly involved in the progression of HCC, and DRD3 might be consider as an independent prognostic factor for HCC. Furthermore, DRD3 agonists may be a promising strategy for HCC therapy.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Prognosis; Receptors, Dopamine D3; RNA, Messenger
PubMed: 36456906
DOI: 10.1186/s12885-022-10368-y -
Tijdschrift Voor Psychiatrie 2021Current antipsychotic treatment is suboptimal. There is an urgent need for new antipsychotics with new mechanisms of action. SEP-363856 is a trace amine-associated... (Review)
Review
BACKGROUND
Current antipsychotic treatment is suboptimal. There is an urgent need for new antipsychotics with new mechanisms of action. SEP-363856 is a trace amine-associated receptor 1 (TAAR1) agonist and a serotonin 5-HT1a agonist with potential antipsychotic properties.
AIM
To describe the rationale for the development of SEP-363856, the pharmacology of TAAR1/5-HT1a agonists, and the clinical efficacy of SEP-363856.
METHOD
A narrative review of the literature using PubMed, Embase and PsychINFO.
RESULTS
Six publications were identified, one of which was a phase 2 clinical trial with SEP-363856. This phase 2 study shows that SEP-363856 is an effective and well-tolerated antipsychotic; positive, but also negative symptoms decreased; motor side effects (akathisia) and prolactin increase did not occur, while metabolic side effects hardly occurred. Reported side-effects were somnolence and nausea. The antipsychotic activity of SEP-363856 appears to be (pre)clinical not based on D2 antagonism, but on TAAR1 and 5-HT1a agonism.
CONCLUSION
TAAR1 and 5-HT1a agonists such as SEP-363856 may be a treatment option for psychosis. Hopefully they can be further developed into an antipsychotic with a favorable effectiveness and tolerability profile.
Topics: Antipsychotic Agents; Humans; Psychotic Disorders; Receptors, Dopamine; Serotonin 5-HT1 Receptor Agonists; Treatment Outcome
PubMed: 34851520
DOI: No ID Found -
Biomolecules Mar 2021Dopamine receptors (DRs) are generally considered as mediators of vasomotor functions. However, when used in pharmacological studies, dopamine and/or DR agonists may not...
Dopamine receptors (DRs) are generally considered as mediators of vasomotor functions. However, when used in pharmacological studies, dopamine and/or DR agonists may not discriminate among different DR subtypes and may even stimulate alpha1 and beta-adrenoceptors. Here, we tested the hypothesis that D2R and/or D3R may specifically induce vasoconstriction in isolated mouse aorta. Aorta, isolated from wild-type (WT) and D3R/ mice, was mounted in a wire myograph and challenged with cumulative concentrations of phenylephrine (PE), acetylcholine (ACh), and the D3R agonist 7-hydrxy-N,N-dipropyl-2-aminotetralin (7-OH-DPAT), with or without the D2R antagonist L741,626 and the D3R antagonist SB-277011-A. The vasoconstriction to PE and the vasodilatation to ACh were not different in WT and D3R/; in contrast, the contractile responses to 7-OH-DPAT were significantly weaker in D3R/, though not abolished. L741,626 did not change the contractile response induced by 7-OH-DPAT in WT or in D3R/, whereas SB-277011-A significantly reduced it in WT but did not in D3R/. D3R mRNA (assessed by qPCR) was about 5-fold more abundant than D2R mRNA in aorta from WT and undetectable in aorta from D3R/. Following transduction with lentivirus (72-h incubation) delivering synthetic microRNAs to specifically inactivate D2R (LV-miR-D2) or D3R (LV-miR-D3), the contractile response to 7-OH-DPAT was unaffected by LV-miR-D2, while it was significantly reduced by LV-miR-D3. These data indicate that, at least in mouse aorta, D3R stimulation induces vasoconstriction, while D2R stimulation does not. This is consistent with the higher expression level of D3R. The residual vasoconstriction elicited by high concentration D3R agonist in D3R/ and/or in the presence of D3R antagonist is likely to be unrelated to DRs.
Topics: Animals; Aorta; Indoles; Male; Mice, Inbred C57BL; Mice, Knockout; Nitriles; Piperidines; RNA, Messenger; Receptors, Dopamine D2; Receptors, Dopamine D3; Tetrahydroisoquinolines; Tetrahydronaphthalenes; Vasoconstriction; Mice
PubMed: 33799860
DOI: 10.3390/biom11030418 -
Cerebral Cortex (New York, N.Y. : 1991) Jan 2020Dopaminergic modulation of prefrontal cortex plays an important role in numerous cognitive processes, including attention. The frontal eye field (FEF) is modulated by...
Dopaminergic modulation of prefrontal cortex plays an important role in numerous cognitive processes, including attention. The frontal eye field (FEF) is modulated by dopamine and has an established role in visual attention, yet the underlying circuitry upon which dopamine acts is not known. We compared the expression of D1 and D2 dopamine receptors (D1Rs and D2Rs) across different classes of FEF neurons, including those projecting to dorsal or ventral extrastriate cortex. First, we found that both D1Rs and D2Rs are more prevalent on pyramidal neurons than on several classes of interneurons and are particularly prevalent on putatively long-range projecting pyramidals. Second, higher proportions of pyramidal neurons express D1Rs than D2Rs. Third, overall a higher proportion of inhibitory neurons expresses D2Rs than D1Rs. Fourth, among inhibitory interneurons, a significantly higher proportion of parvalbumin+ neurons expresses D2Rs than D1Rs, and a significantly higher proportion of calbindin+ neurons expresses D1Rs than D2Rs. Finally, compared with D2Rs, virtually all of the neurons with identified projections to both dorsal and ventral extrastriate visual cortex expressed D1Rs. Our results demonstrate that dopamine tends to act directly on the output of the FEF and that dopaminergic modulation of top-down projections to visual cortex is achieved predominately via D1Rs.
Topics: Animals; Frontal Lobe; Interneurons; Macaca mulatta; Male; Neural Pathways; Neuroanatomical Tract-Tracing Techniques; Neurons; Receptors, Dopamine D1; Receptors, Dopamine D2; Visual Cortex
PubMed: 31038690
DOI: 10.1093/cercor/bhz078 -
Clinical Science (London, England :... Aug 2022Systemic arterial hypertension is one of the leading causes of morbidity and mortality in the general population, being a risk factor for many cardiovascular diseases.... (Review)
Review
Systemic arterial hypertension is one of the leading causes of morbidity and mortality in the general population, being a risk factor for many cardiovascular diseases. Although its pathogenesis is complex and still poorly understood, some systems appear to play major roles in its development. This review aims to update the current knowledge on the interaction of the intrarenal renin-angiotensin system (RAS) and dopaminergic system in the development of hypertension, focusing on recent scientific hallmarks in the field. The intrarenal RAS, composed of several peptides and receptors, has a critical role in the regulation of blood pressure (BP) and, consequently, the development of hypertension. The RAS is divided into two main intercommunicating axes: the classical axis, composed of angiotensin-converting enzyme, angiotensin II, and angiotensin type 1 receptor, and the ACE2/angiotensin-(1-7)/Mas axis, which appears to modulate the effects of the classical axis. Dopamine and its receptors are also increasingly showing an important role in the pathogenesis of hypertension, as abnormalities in the intrarenal dopaminergic system impair the regulation of renal sodium transport, regardless of the affected dopamine receptor subtype. There are five dopamine receptors, which are divided into two major subtypes: the D1-like (D1R and D5R) and D2-like (D2R, D3R, and D4R) receptors. Mice deficient in any of the five dopamine receptor subtypes have increased BP. Intrarenal RAS and the dopaminergic system have complex interactions. The balance between both systems is essential to regulate the BP homeostasis, as alterations in the control of both can lead to hypertension.
Topics: Animals; Arterial Pressure; Blood Pressure; Dopamine; Humans; Hypertension; Kidney; Mice; Receptors, Dopamine; Renin; Renin-Angiotensin System
PubMed: 35979889
DOI: 10.1042/CS20220338 -
Behavioral Neuroscience Feb 2022Long-term social bonds are critical for survival and reproductive success in many species. Although courtship and pair-bond formation are relatively well studied, much...
Long-term social bonds are critical for survival and reproductive success in many species. Although courtship and pair-bond formation are relatively well studied, much less is known about the neural regulation of behaviors that occur after pair bonding that reinforce the bond and contribute to reproductive success. Dopamine and opioids in the nucleus accumbens (NAc) alter motivational state and reward by binding to receptor subtypes that engage distinct and opposing second messenger systems, and there is evidence that receptor ratios may influence social behavior. We used quantitative real-time PCR to explore relationships between messenger RNA ratios for dopamine D1 and D2 receptors (D1:D2) and mu and kappa opioid receptors (MOR:KOR) in NAc and behaviors implicated in reproductive investment and pair-bond maintenance in established male-female zebra finch pairs. In males, D1:D2 expression in NAc related negatively, whereas MOR:KOR related positively, to undirected song production. D1:D2 receptors also related positively to physical contact with a female. For females, D1:D2 expression was lower in females exposed to high compared to low rates of the partner's undirected song, and MOR:KOR expression in females related positively to undirected song exposure and allopreening. Analyses of single genes did not yield the same results. These findings suggest that the ratio of D1 to D2 and MOR to KOR receptor signaling in NAc causes differences in behavior or that behavior (or the partner's behavior) causes receptor ratio changes to modulate behaviors that maintain pair bonds and promote reproductive investment. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
Topics: Animals; Dopamine; Female; Finches; Male; Nucleus Accumbens; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Opioid
PubMed: 34618494
DOI: 10.1037/bne0000494 -
Trends in Pharmacological Sciences Mar 2020Tetrahydroprotoberberines (THPBs) are a class of compounds that target both dopamine D1 and D2 families of receptors, making them attractive candidates for treating... (Review)
Review
Tetrahydroprotoberberines (THPBs) are a class of compounds that target both dopamine D1 and D2 families of receptors, making them attractive candidates for treating substance use disorder (SUD). The binding of some THPBs to serotonin and adrenergic receptors, in addition to dopamine receptors, gives rise to complex pharmacological profiles. Significant progress has been made over the last decade in examining these compounds for their therapeutic potential. Here, we evaluate recent discoveries relating to the neural mechanism and therapeutic effects of THPBs, focusing on compounds that have shown promise in animal models of SUD and preliminary clinical studies. Advancements in structure-activity relationship studies and in silico modeling of THPB binding to dopamine receptors have facilitated the synthesis of novel THPBs with enhanced therapeutic properties and provide insights regarding use of the THPB scaffold to serve as a template for innovative drug designs.
Topics: Animals; Berberine; Berberine Alkaloids; Receptors, Dopamine D1; Receptors, Dopamine D2; Substance-Related Disorders
PubMed: 31987662
DOI: 10.1016/j.tips.2019.12.007 -
Molecular Cell Mar 2021The dopamine system, including five dopamine receptors (D1R-D5R), plays essential roles in the central nervous system (CNS), and ligands that activate dopamine receptors...
The dopamine system, including five dopamine receptors (D1R-D5R), plays essential roles in the central nervous system (CNS), and ligands that activate dopamine receptors have been used to treat many neuropsychiatric disorders. Here, we report two cryo-EM structures of human D3R in complex with an inhibitory G protein and bound to the D3R-selective agonists PD128907 and pramipexole, the latter of which is used to treat patients with Parkinson's disease. The structures reveal agonist binding modes distinct from the antagonist-bound D3R structure and conformational signatures for ligand-induced receptor activation. Mutagenesis and homology modeling illuminate determinants of ligand specificity across dopamine receptors and the mechanisms for G protein coupling. Collectively our work reveals the basis of agonist binding and ligand-induced receptor activation and provides structural templates for designing specific ligands to treat CNS diseases targeting the dopaminergic system.
Topics: Benzopyrans; Cryoelectron Microscopy; GTP-Binding Protein alpha Subunits, Gi-Go; HEK293 Cells; Humans; Models, Molecular; Multiprotein Complexes; Oxazines; Pramipexole; Protein Domains; Receptors, Dopamine D3; Structure-Activity Relationship
PubMed: 33548201
DOI: 10.1016/j.molcel.2021.01.003 -
Biological Psychiatry Sep 2023A large body of evidence highlights the importance of genetic variants in the development of psychiatric and metabolic conditions. Among these, the TaqIA polymorphism is...
BACKGROUND
A large body of evidence highlights the importance of genetic variants in the development of psychiatric and metabolic conditions. Among these, the TaqIA polymorphism is one of the most commonly studied in psychiatry. TaqIA is located in the gene that codes for the ankyrin repeat and kinase domain containing 1 kinase (Ankk1) near the dopamine D receptor (D2R) gene. Homozygous expression of the A1 allele correlates with a 30% to 40% reduction of striatal D2R, a typical feature of addiction, overeating, and other psychiatric pathologies. The mechanisms by which the variant influences dopamine signaling and behavior are unknown.
METHODS
Here, we used transgenic and viral-mediated strategies to reveal the role of Ankk1 in the regulation of activity and functions of the striatum.
RESULTS
We found that Ankk1 is preferentially enriched in striatal D2R-expressing neurons and that Ankk1 loss of function in the dorsal and ventral striatum leads to alteration in learning, impulsivity, and flexibility resembling endophenotypes described in A1 carriers. We also observed an unsuspected role of Ankk1 in striatal D2R-expressing neurons of the ventral striatum in the regulation of energy homeostasis and documented differential nutrient partitioning in humans with or without the A1 allele.
CONCLUSIONS
Overall, our data demonstrate that the Ankk1 gene is necessary for the integrity of striatal functions and reveal a new role for Ankk1 in the regulation of body metabolism.
Topics: Humans; Dopamine; Receptors, Dopamine D2; Behavior, Addictive; Neurons; Reward
PubMed: 36805080
DOI: 10.1016/j.biopsych.2023.02.010