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Cerebral Cortex (New York, N.Y. : 1991) Jul 2019Dopamine modulation in the prefrontal cortex (PFC) mediates diverse effects on neuronal physiology and function, but the expression of dopamine receptors at...
Dopamine modulation in the prefrontal cortex (PFC) mediates diverse effects on neuronal physiology and function, but the expression of dopamine receptors at subpopulations of projection neurons and interneurons remains unresolved. Here, we examine D1 receptor expression and modulation at specific cell types and layers in the mouse prelimbic PFC. We first show that D1 receptors are enriched in pyramidal cells in both layers 5 and 6, and that these cells project to intratelencephalic targets including contralateral cortex, striatum, and claustrum rather than to extratelencephalic structures. We then find that D1 receptors are also present in interneurons and enriched in superficial layer VIP-positive (VIP+) interneurons that coexpresses calretinin but absent from parvalbumin-positive (PV+) and somatostatin-positive (SOM+) interneurons. Finally, we determine that D1 receptors strongly and selectively enhance action potential firing in only a subset of these corticocortical neurons and VIP+ interneurons. Our findings define several novel subpopulations of D1+ neurons, highlighting how modulation via D1 receptors can influence both excitatory and disinhibitory microcircuits in the PFC.
Topics: Animals; Female; Interneurons; Male; Mice; Mice, Transgenic; Neurons, Efferent; Prefrontal Cortex; Receptors, Dopamine D1
PubMed: 30566584
DOI: 10.1093/cercor/bhy299 -
Basic & Clinical Pharmacology &... Jan 2019The effect of risperidone treatment in patients with schizophrenia varies according to the dopamine receptor genes. This study aimed to evaluate the relationship between... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The effect of risperidone treatment in patients with schizophrenia varies according to the dopamine receptor genes. This study aimed to evaluate the relationship between genes of the dopamine receptors (D1, D2, and D3) and the effect of risperidone treatment.
METHODS
Three electronic databases (PubMed, Embase, and Cochrane Library) were searched for relevant cohort or case-control studies published before 9 May 2018. A systematic review and meta-analysis was performed for qualitative and quantitative assessment of the relationship between the dopamine receptors D1, D2, and D3 (DRD1, 2, and 3) and the effect of risperidone treatment. The summary odds ratio (OR) and weighted mean difference (WMD) in a random-effects model were used to measure these relationships.
RESULTS
Twelve studies involving 24 SNPs were included. DRD2 (Ser311Cys, rs1801028 Ser/Ser) significantly lowered the improvement rate (determined by the PANSS score) unlike Ser/Cys (WMD: -11.58, 95% CI: -17.35 to -5.18). For Asian patients, A241G (rs1799978) AA carriers showed greater improvement after risperidone therapy (P < 0.05). The polymorphisms of 141C Ins/Del (rs1799732), T939C (rs6275), rs6277, and TaqID (rs1800498) may also influence the treatment effect. TaqIA (rs1800497) and TaqIB (rs17294542) were not associated with the rate of response to risperidone. DRD3 was not associated with an improvement in the PANSS total score; however, Ser9Gly might be related to a change in negative symptoms. No significant effect of DRD1 (rs5326, rs4867798, rs4532, and rs11749676) was found.
CONCLUSIONS
Our result supported the hypothesis that DRD2 affected risperidone treatment. DRD1 had no significant effect on the response to risperidone, whereas DRD3 might be associated with an improvement in negative symptoms. Larger observational studies are warranted to verify these findings and identify other genetic factors involved.
Topics: Antipsychotic Agents; Humans; Pharmacogenomic Variants; Polymorphism, Single Nucleotide; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Dopamine D3; Risperidone; Schizophrenia; Treatment Outcome
PubMed: 30103286
DOI: 10.1111/bcpt.13111 -
Brain, Behavior, and Immunity Nov 2021Parkinson's disease (PD) is a chronic neurodegenerative disease. Recently, neuroinflammation driven by CD4 T cells has been involved in PD pathophysiology. Human and...
Parkinson's disease (PD) is a chronic neurodegenerative disease. Recently, neuroinflammation driven by CD4 T cells has been involved in PD pathophysiology. Human and murine lymphocytes express all the five subtypes of dopamine receptors (DRs), DRD1 to DRD5. However, roles of DRs particularly DRD2 expressed on CD4 T cells in PD remain elucidated. Global Drd1- or Drd2-knockout (Drd1 or Drd2) mice or CD4 T cell-specific Drd2-knockout (Drd2/CD4) mice were intraperitoneally injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce PD with the different mutants. On the 7th day following MPTP injection, mice were assessed for dopaminergic neurodegeneration, locomotor impairments, microglial activation, as well as CD4 T-cell differentiation and function. Furthermore, in vitro CD4 T cells were exposed to DRD2 agonist and antagonist and then differentiation and function of the cells were determined. MPTP induced dopaminergic neuronal loss in the nigrostriatal system, motor coordinative and behavioral impairments, microglial activation, and CD4 T-cell polarization to pro-inflammatory T-helper (Th)1 and Th17 phenotypes. Importantly, either Drd2 or Drd2/CD4 mice manifested more severe dopaminergic neurodegeneration, motor deficits, microglial activation, and CD4 T-cell bias towards Th1 and Th17 phenotypes in response to MPTP, but Drd1 did not further alter MPTP intoxication. DRD2 agonist sumanirole inhibited shift of CD4 T cells obtained from MPTP-intoxicated mice to Th1 and Th17 phenotypes and DRD2 antagonist L-741,626 reversed sumanirole effects. These findings suggest that DRD2 expressed on CD4 T cells is protective against neuroinflammation and neurodegeneration in PD. Thus, developing a therapeutic strategy of stimulating DRD2 may be promising for mitigation of PD.
Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Disease Models, Animal; Dopaminergic Neurons; Mice; Mice, Inbred C57BL; Neurodegenerative Diseases; Neuroinflammatory Diseases; Parkinson Disease; Receptors, Dopamine D2; Receptors, Dopamine D5; Th17 Cells
PubMed: 34403737
DOI: 10.1016/j.bbi.2021.08.220 -
Neuropharmacology Sep 2020The striatum undergoes significant neuroplasticity both in Parkinson's Disease (PD) and following dopamine (DA) replacement therapy with l-DOPA. Unfortunately, these...
The striatum undergoes significant neuroplasticity both in Parkinson's Disease (PD) and following dopamine (DA) replacement therapy with l-DOPA. Unfortunately, these changes also contribute to the emergence of l-DOPA-induced dyskinesia (LID). While convergent strategies have demonstrated independent roles for DA D1 -receptors (D1R) and D2-receptors (D2R) in LID, DA receptor cooperativity, either by cellular or circuit mechanisms, has also been implicated in the dyskinetic brain. How this cooperativity is substantiated is vitally important given that l-DOPA, once converted to DA, stimulates all DA receptors. The present experiments sought to characterize the effect of individual or collective stimulation of D1R and D2R-like receptors both systemically and intrastriatally. In experiment 1, hemiparkinsonian l-DOPA-primed rats received systemic doses of the D1R agonist SKF38393 and D2R-like agonist quinpirole. Dyskinesia and motor improvement were monitored using the abnormal involuntary movements scale (AIMs) and the forepaw adjustment steps test (FAS), respectively. In experiment 2, SKF38393 and quinpirole were administered intrastriatally via reverse-phase in vivo microdialysis while coincident changes in striatal glutamate and gamma-Aminobutyric acid (GABA) were monitored. SKF38393 and quinpirole dose-dependently increased AIMs. When threshold DA agonist doses were co-administered, AIMs and motor performance were synergistically enhanced. Like systemic experiments, striatal co-administration of threshold concentrations of DA agonists resulted in synergistic exacerbation of AIMs, and concurrent increases in GABA efflux. These data highlight the role of striatal DA receptor cooperativity in LID and suggest a central role for striatal GABA release in these effects.
Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Corpus Striatum; Dopamine Agonists; Dyskinesia, Drug-Induced; Male; Motor Activity; Parkinsonian Disorders; Rats; Rats, Sprague-Dawley; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2; Synaptic Transmission; gamma-Aminobutyric Acid
PubMed: 32492451
DOI: 10.1016/j.neuropharm.2020.108138 -
The Journals of Gerontology. Series A,... Aug 2021The physiopathological mechanisms that regulate menopausal and sex differences in colonic transit, inflammatory processes, and efficacy of treatments have not been...
The physiopathological mechanisms that regulate menopausal and sex differences in colonic transit, inflammatory processes, and efficacy of treatments have not been clarified. The dopaminergic system and renin-angiotensin system coexist in the gut and regulate different processes such as motility, absorption/secretion, and inflammation. We investigated the changes in expression of major angiotensin and dopamine receptors in the colon of male, female, and ovariectomized female mice. Possible interaction between both systems was investigated using male and female mice deficient (ko) for major angiotensin and dopamine receptors. In wild-type mice, colonic tissue from females showed lower angiotensin type 1/angiotensin type 2 ratio (an index of pro-inflammatory/anti-inflammatory renin-angiotensin system balance), lower dopamine D1 and D2 receptor expression, and lower levels of pro-inflammatory and pro-oxidative markers relative to males. Interestingly, ovariectomy increased the expression of pro-inflammatory angiotensin type 1 receptor expression and decreased anti-inflammatory angiotensin type 2 receptor expression, increased D1 and D2 receptor expression, and increased the levels of pro-inflammatory and pro-oxidative markers. Ovariectomy-induced changes were blocked by estrogen replacement. The present results suggest a mutual regulation between colonic angiotensin and dopamine receptors and sex differences in this mutual regulation. Estrogen regulates changes in both angiotensin and dopamine receptor expression, which may be involved in sex- and surgical menopause-related effects on gut motility, permeability, and vulnerability to inflammatory processes.
Topics: Angiotensins; Animals; Colon; Estrogens; Female; Male; Menopause; Mice; Ovariectomy; Receptors, Dopamine; Sex Characteristics
PubMed: 32991714
DOI: 10.1093/gerona/glaa244 -
Neuropharmacology Nov 2016Histone deacetylase 6 (Hdac6), a multifunctional cytoplasmic deacetylase, is abundant in brain. We previously demonstrated that global Hdac6 depletion causes aberrant...
Histone deacetylase 6 (Hdac6), a multifunctional cytoplasmic deacetylase, is abundant in brain. We previously demonstrated that global Hdac6 depletion causes aberrant emotional behaviors in mice. Identification of affected brain systems and its molecular basis will lead to new insights into relations between protein acetylation events and psychiatric disorders. Here we report the dopaminergic abnormalities in Hdac6 KO mice. The dopamine transmission mediated by D1-like and D2-like G protein-coupled dopamine receptors is known to play roles in controlling movement, cognition, and motivational processes, and its dysfunction causes psychiatric disorders. We found that Hdac6 KO mice showed significantly increased locomotor response to novel, but not to habituated environment. In addition, Hdac6 KO mice showed a long-lasting sensitivity to psychostimulants, increased locomotor response to D2-like, but not D1 dopamine receptor agonists, and rapid locomotor response to apomorphine, a direct dopamine agonist, in dopamine-depleted condition. Hdac6 protein was expressed in dopaminergic neurons and their terminals in adult mice brain, and Hdac6-depletion augmented acetylation levels of dopamine-enriched synaptosomal proteins. In Hdac6 KO mice, the striatal content of dopamine and its metabolites was normal in basal condition, but mRNA level of D2 dopamine receptor in the striatum was decreased by 30%. Taken together, our results provide evidence that Hdac6 deficiency leads to aberrant dopamine-dependent behaviors by enhancing postsynaptic dopamine D2 receptor response. This study points out the possibility that Hdac6 and reversible-acetylation events play a regulatory role in D2 dopamine receptor signaling, and thus participate in the pathology of the dopamine-related psychiatric disorders such as schizophrenia.
Topics: Animals; Apomorphine; Central Nervous System Stimulants; Corpus Striatum; Dopamine; Dopamine Agents; Dopaminergic Neurons; Histone Deacetylase 6; Male; Methamphetamine; Mice, 129 Strain; Mice, Knockout; Motor Activity; RNA, Messenger; Receptors, Dopamine D1; Receptors, Dopamine D2; Schizophrenia
PubMed: 27544826
DOI: 10.1016/j.neuropharm.2016.08.018 -
The Journal of Neuroscience : the... Jan 2022Neuronal activity in the prefrontal cortex (PFC) controls dominance hierarchies in groups of animals. Dopamine (DA) strongly modulates PFC activity mainly through D1...
Neuronal activity in the prefrontal cortex (PFC) controls dominance hierarchies in groups of animals. Dopamine (DA) strongly modulates PFC activity mainly through D1 receptors (D1Rs) and D2 receptors (D2Rs). Still, it is unclear how these two subpopulations of DA receptor-expressing neurons in the PFC regulate social dominance hierarchy. Here, we demonstrate distinct roles for prefrontal D1R- and D2R-expressing neurons in establishing social hierarchy, with D1R neurons determining dominance and D2R neurons for subordinate. whole-cell recordings revealed that the dominant status of male mice correlates with rectifying AMPAR transmission and stronger excitatory synaptic strength onto D1R neurons in PFC pyramidal neurons. In contrast, the submissive status is associated with higher neuronal excitability in D2R neurons. Moreover, simultaneous manipulations of synaptic efficacy of D1R neurons in dominant male mice and neuronal excitability of D2R neurons of their male subordinates switch their dominant-subordinate relationship. These results reveal that prefrontal D1R and D2R neurons have distinct but synergistic functions in the dominance hierarchy, and DA-mediated regulation of synaptic strengths acts as a powerful behavioral determinant of intermale social rank. Dominance hierarchy exists widely among animals who confront social conflict. Studies have indicated that social status largely relies on the neuronal activity in the PFC, but how dopamine influences social hierarchy via subpopulation of prefrontal neurons is still elusive. Here, we explore the cell type-specific role of dopamine receptor-expressing prefrontal neurons in the dominance-subordinate relationship. We found that the synaptic strength of D1 receptor-expressing neurons determines the dominant status, whereas hyperactive D2-expressing neurons are associated with the subordinate status. These findings highlight how social conflicts recruit distinct cortical microcircuits to drive different behaviors and reveal how D1- and D2-receptor enriched neurocircuits in the PFC establish a social hierarchy.
Topics: Animals; Dopaminergic Neurons; Male; Mice; Patch-Clamp Techniques; Prefrontal Cortex; Receptors, Dopamine D1; Receptors, Dopamine D2; Social Dominance
PubMed: 34844989
DOI: 10.1523/JNEUROSCI.0741-21.2021 -
Molecular Neurobiology Mar 2020Disruption of sensorimotor gating causes "flooding" of irrelevant sensory input and is considered a congenital trait in several neurodevelopmental disorders. Prepulse...
Disruption of sensorimotor gating causes "flooding" of irrelevant sensory input and is considered a congenital trait in several neurodevelopmental disorders. Prepulse inhibition of acoustic startle response (PPI) is the operational measurement and has a high translational validity. Pharmacological studies in rodents have linked alterations in serotonin, dopamine and glutamate signalling to PPI disruption. How PPI response is associated with gene expression levels of these receptors is unknown. PPI response was assessed in 39 genetically heterogeneous National Institutes of Health-Heterogeneous Stock (NIH-HS) rats. Animals were classified as high, medium or low PPI. Expression levels of glutamate metabotropic receptor 2 (Grm2), dopamine receptor D2 (Drd2), dopamine receptor D1 (Drd1), serotonin receptor 1A (Htr1a), serotonin receptor 2A (Htr2a) and homer scaffolding protein 1 (Homer1) were investigated in prefrontal cortex (PFC) and striatum (STR). When comparing the two extreme phenotypes, only Drd2 in STR showed increased expression in the low PPI group. A multinomial model fitting all genes and all groups indicated that Grm2 in PFC, and Grm2 and Drd2 in the STR predicted PPI group. This was corroborated by a linear relationship of Grm2 with PPI in PFC, and Drd2 with PPI in STR. An interaction between levels of H3K27 trimethylation, associated with transcriptional repression, and PPI phenotype was observed for Drd2 in STR. Gene set enrichment analysis on a microarray dataset on Lewis rats confirmed enrichment of Drd2 in PFC in relation to PPI. These findings contribute to the understanding of the genetic substrate behind alterations in sensorimotor gating, relevant for its linkage to neurodevelopmental disorders.
Topics: Acoustic Stimulation; Animals; Dopamine; Male; Prefrontal Cortex; Rats; Receptors, Dopamine; Receptors, Metabotropic Glutamate; Reflex, Startle; Sensory Gating
PubMed: 31782106
DOI: 10.1007/s12035-019-01829-w -
Pharmacological Reports : PR Apr 2017The human dopamine D2 receptor gene has three polymorphic variants that alter its amino acid sequence: alanine substitution by valine in position 96 (V96A), proline...
BACKGROUND
The human dopamine D2 receptor gene has three polymorphic variants that alter its amino acid sequence: alanine substitution by valine in position 96 (V96A), proline substitution by serine in position 310 (P310S) and serine substitution by cysteine in position 311 (S311C). Their functional role has never been the object of extensive studies, even though there is some evidence that their occurrence correlates with schizophrenia.
METHODS
The HEK293 cell line was transfected with dopamine D1 and D2 receptors (or genetic variants of the D2 receptor), coupled to fluorescent proteins which allowed us to measure the extent of dimerization of these receptors, using a highly advanced biophysical approach (FLIM-FRET). Additionally, Fluoro-4 AM was used to examine changes in the level of calcium release after ligand stimulation of cells expressing different combinations of dopamine receptors.
RESULTS
Using FLIM-FRET experiments we have shown that in HEK 293 expressing dopamine receptors, polymorphic mutations in the D2 receptor play a role in dimmer formation with the dopamine D1 receptor. The association level of dopamine receptors is affected by ligand administration, with variable effects depending on polymorphic variant of the D2 dopamine receptor. We have found that the level of heteromer formation is reflected by calcium ion release after ligand stimulation and have observed variations of this effect dependent on the polymorphic variant and the ligand.
CONCLUSION
The data presented in this paper support the hypothesis on the role of calcium signaling regulated by the D1-D2 heteromer which may be of relevance for schizophrenia etiology.
Topics: Calcium; Calcium Signaling; Cell Line; Genetic Variation; HEK293 Cells; Humans; Protein Multimerization; Receptors, Dopamine D1; Receptors, Dopamine D2; Schizophrenia
PubMed: 28119185
DOI: 10.1016/j.pharep.2016.10.016 -
BMC Neuroscience Sep 2022Paraoxonase 2 (PON2) is an intracellular antioxidant enzyme located at the inner mitochondrial membrane. Previous studies have found PON2 to be an important antioxidant...
BACKGROUND
Paraoxonase 2 (PON2) is an intracellular antioxidant enzyme located at the inner mitochondrial membrane. Previous studies have found PON2 to be an important antioxidant in a variety of cellular systems, such as the cardiovascular and renal system. Recent work has also suggested that PON2 plays an important role in the central nervous system (CNS), as decreased PON2 expression in the CNS leads to higher oxidative stress and subsequent cell toxicity. However, the precise role of PON2 in the CNS is still largely unknown, and what role it may play in specific regions of the brain remains unexamined. Dopamine metabolism generates considerable oxidative stress and antioxidant function is critical to the survival of dopaminergic neurons, providing a potential mechanism for PON2 in the dopaminergic system.
METHODS
In this study, we investigated the role of PON2 in the dopaminergic system of the mouse brain by comparing transcript and protein expression of dopaminergic-related genes in wildtype (WT) and PON2 deficient (PON2-def) mouse striatum, and exposing WT cultured primary neurons to dopamine receptor agonists.
RESULTS
We found alterations in multiple key dopaminergic genes at the transcript level, however many of these changes were not observed at the protein level. In cultured neurons, PON2 mRNA and protein were increased upon exposure to quinpirole, a dopamine receptor 2/3 (DRD2/3) agonist, but not fenoldopam, a dopamine receptor 1/5 (DRD1/5) agonist, suggesting a receptor-specific role in dopamine signaling.
CONCLUSIONS
Our findings suggest PON2 deficiency significantly impacts the dopaminergic system at the transcript level and may play a role in mitigating oxidative stress in this system further downstream through dopamine receptor signaling.
Topics: Animals; Antioxidants; Aryldialkylphosphatase; Brain; Dopamine; Mice; Oxidative Stress; Receptors, Dopamine
PubMed: 36056313
DOI: 10.1186/s12868-022-00738-4