Cocaine-induced adaptation of dopamine D2S, but not D2L autoreceptors

The dopamine D2 receptor has two splice variants, D2S (Short) and D2L (Long). In dopamine neurons, both variants can act as autoreceptors to regulate neuronal excitability and dopamine release, but the roles of each variant are incompletely characterized. In a previous study we used viral receptor expression in D2 receptor knockout mice to show distinct effects of calcium signaling on D2S and D2L autoreceptor function (Gantz et al., 2015). However, the cocaine-induced plasticity of D2 receptor desensitization observed in wild type mice was not recapitulated with this method of receptor expression. Here we use mice with genetic knockouts of either the D2S or D2L variant to investigate cocaine-induced plasticity in D2 receptor signaling. Following a single in vivo cocaine exposure, the desensitization of D2 receptors from neurons expressing only the D2S variant was reduced. This did not occur in D2L-expressing neurons, indicating differential drug-induced plasticity between the variants.

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Distinct regulation of dopamine D2S and D2L autoreceptor signaling by calcium

eLife ◽

10.7554/elife.09358 ◽

2015 ◽

Vol 4 ◽

Cited By ~ 20

Author(s):

Stephanie C Gantz ◽

Brooks G Robinson ◽

David C Buck ◽

James R Bunzow ◽

Rachael L Neve ◽

...

Keyword(s):

D2 Receptor ◽

Dopamine Neurons ◽

Cocaine Exposure ◽

Drug Induced ◽

Calcium Dependent ◽

Midbrain Dopamine ◽

D2 Autoreceptor ◽

Inwardly Rectifying ◽

G Protein Coupled

D2 autoreceptors regulate dopamine release throughout the brain. Two isoforms of the D2 receptor, D2S and D2L, are expressed in midbrain dopamine neurons. Differential roles of these isoforms as autoreceptors are poorly understood. By virally expressing the isoforms in dopamine neurons of D2 receptor knockout mice, this study assessed the calcium-dependence and drug-induced plasticity of D2S and D2L receptor-dependent G protein-coupled inwardly rectifying potassium (GIRK) currents. The results reveal that D2S, but not D2L receptors, exhibited calcium-dependent desensitization similar to that exhibited by endogenous autoreceptors. Two pathways of calcium signaling that regulated D2 autoreceptor-dependent GIRK signaling were identified, which distinctly affected desensitization and the magnitude of D2S and D2L receptor-dependent GIRK currents. Previous in vivo cocaine exposure removed calcium-dependent D2 autoreceptor desensitization in wild type, but not D2S-only mice. Thus, expression of D2S as the exclusive autoreceptor was insufficient for cocaine-induced plasticity, implying a functional role for the co-expression of D2S and D2L autoreceptors.

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Increased dopamine D2 receptor activity in the striatum alters the firing pattern of dopamine neurons in the ventral tegmental area

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1500450112 ◽

2015 ◽

Vol 112 (12) ◽

pp. E1498-E1506 ◽

Cited By ~ 37

Author(s):

Sabine Krabbe ◽

Johanna Duda ◽

Julia Schiemann ◽

Christina Poetschke ◽

Gaby Schneider ◽

...

Keyword(s):

Ventral Tegmental Area ◽

Cognitive Deficits ◽

Dopamine D2 Receptor ◽

D2 Receptor ◽

Dopamine Neurons ◽

Tonic Activity ◽

Functional Deficits ◽

The Core ◽

Ventral Tegmental

There is strong evidence that the core deficits of schizophrenia result from dysfunction of the dopamine (DA) system, but details of this dysfunction remain unclear. We previously reported a model of transgenic mice that selectively and reversibly overexpress DA D2 receptors (D2Rs) in the striatum (D2R-OE mice). D2R-OE mice display deficits in cognition and motivation that are strikingly similar to the deficits in cognition and motivation observed in patients with schizophrenia. Here, we show that in vivo, both the firing rate (tonic activity) and burst firing (phasic activity) of identified midbrain DA neurons are impaired in the ventral tegmental area (VTA), but not in the substantia nigra (SN), of D2R-OE mice. Normalizing striatal D2R activity by switching off the transgene in adulthood recovered the reduction in tonic activity of VTA DA neurons, which is concordant with the rescue in motivation that we previously reported in our model. On the other hand, the reduction in burst activity was not rescued, which may be reflected in the observed persistence of cognitive deficits in D2R-OE mice. We have identified a potential molecular mechanism for the altered activity of DA VTA neurons in D2R-OE mice: a reduction in the expression of distinct NMDA receptor subunits selectively in identified mesolimbic DA VTA, but not nigrostriatal DA SN, neurons. These results suggest that functional deficits relevant for schizophrenia symptoms may involve differential regulation of selective DA pathways.

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Neuroprotective effects of dopamine D2 receptor agonist on neuroinflammatory injury in olfactory bulb neurons in vitro and in vivo in a mouse model of allergic rhinitis

NeuroToxicology ◽

10.1016/j.neuro.2021.10.001 ◽

2021 ◽

Author(s):

Peiqiang Liu ◽

Danxue Qin ◽

Hao Lv ◽

Wenjun Fan ◽

Zezhang Tao ◽

...

Keyword(s):

Allergic Rhinitis ◽

Mouse Model ◽

Olfactory Bulb ◽

Receptor Agonist ◽

Dopamine D2 Receptor ◽

D2 Receptor ◽

Neuroprotective Effects ◽

D2 Receptor Agonist

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Long-term Effects of Aripiprazole Treatment during Adolescence on Cognitive Function and Dopamine D2 Receptor Expression in Neurodevelopmentally Normal Rats

Clinical Psychopharmacology and Neuroscience ◽

10.9758/cpn.2019.17.3.400 ◽

2019 ◽

Vol 17 (3) ◽

pp. 400-408 ◽

Cited By ~ 1

Author(s):

Hyung Jun Choi ◽

Soo Jung Im ◽

Hae Ri Park ◽

Subin Park ◽

Chul-Eung Kim ◽

...

Keyword(s):

Cognitive Function ◽

Dopamine D2 Receptor ◽

D2 Receptor ◽

Receptor Expression ◽

Long Term Effects ◽

Dopamine D2

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Disruption of the Dopamine D2 Receptor Impairs Insulin Secretion and Causes Glucose Intolerance

Endocrinology ◽

10.1210/en.2009-0996 ◽

2010 ◽

Vol 151 (4) ◽

pp. 1441-1450 ◽

Cited By ~ 67

Author(s):

Isabel García-Tornadú ◽

Ana M. Ornstein ◽

Astrid Chamson-Reig ◽

Michael B. Wheeler ◽

David J. Hill ◽

...

Keyword(s):

Insulin Secretion ◽

Glucose Intolerance ◽

Dopamine D2 Receptor ◽

D2 Receptor ◽

Insulin Response ◽

Wild Type ◽

Β Cell ◽

Insulin Response To Glucose

The relationship between antidopaminergic drugs and glucose has not been extensively studied, even though chronic neuroleptic treatment causes hyperinsulinemia in normal subjects or is associated with diabetes in psychiatric patients. We sought to evaluate dopamine D2 receptor (D2R) participation in pancreatic function. Glucose homeostasis was studied in D2R knockout mice (Drd2−/−) mice and in isolated islets from wild-type and Drd2−/− mice, using different pharmacological tools. Pancreas immunohistochemistry was performed. Drd2−/− male mice exhibited an impairment of insulin response to glucose and high fasting glucose levels and were glucose intolerant. Glucose intolerance resulted from a blunted insulin secretory response, rather than insulin resistance, as shown by glucose-stimulated insulin secretion tests (GSIS) in vivo and in vitro and by a conserved insulin tolerance test in vivo. On the other hand, short-term treatment with cabergoline, a dopamine agonist, resulted in glucose intolerance and decreased insulin response to glucose in wild-type but not in Drd2−/− mice; this effect was partially prevented by haloperidol, a D2R antagonist. In vitro results indicated that GSIS was impaired in islets from Drd2−/− mice and that only in wild-type islets did dopamine inhibit GSIS, an effect that was blocked by a D2R but not a D1R antagonist. Finally, immunohistochemistry showed a diminished pancreatic β-cell mass in Drd2−/− mice and decreased β-cell replication in 2-month-old Drd2−/− mice. Pancreatic D2Rs inhibit glucose-stimulated insulin release. Lack of dopaminergic inhibition throughout development may exert a gradual deteriorating effect on insulin homeostasis, so that eventually glucose intolerance develops.

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Early social isolation disrupts latent inhibition and increases dopamine D2 receptor expression in the medial prefrontal cortex and nucleus accumbens of adult rats

Brain Research ◽

10.1016/j.brainres.2012.01.058 ◽

2012 ◽

Vol 1447 ◽

pp. 38-43 ◽

Cited By ~ 25

Author(s):

Xiao Han ◽

Nanxin Li ◽

Xiaofang Xue ◽

Feng Shao ◽

Weiwen Wang

Keyword(s):

Prefrontal Cortex ◽

Nucleus Accumbens ◽

Social Isolation ◽

Medial Prefrontal Cortex ◽

Latent Inhibition ◽

Dopamine D2 Receptor ◽

D2 Receptor ◽

Receptor Expression ◽

Adult Rats ◽

Dopamine D2

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Synthesis, Structural and Thermal Studies of 3-(1-Benzyl-1,2,3,6-tetrahydropyridin-4-yl)-5-ethoxy-1H-indole (D2AAK1_3) as Dopamine D2 Receptor Ligand

Molecules ◽

10.3390/molecules23092249 ◽

2018 ◽

Vol 23 (9) ◽

pp. 2249 ◽

Cited By ~ 4

Author(s):

Magda Kondej ◽

Agata Bartyzel ◽

Monika Pitucha ◽

Tomasz Wróbel ◽

Andrea Silva ◽

...

Keyword(s):

Molecular Dynamics ◽

Thermal Stability ◽

Dopamine D2 Receptor ◽

Thermal Studies ◽

D2 Receptor ◽

Thermal Characterization ◽

X Ray ◽

Good Thermal Stability ◽

Dopamine D2

Compound D2AAK1_3 was designed as a modification of the lead structure D2AAK1 (an in vivo active multi-target compound with nanomolar affinity to a number of aminergic GPCRs) and synthesized in the reaction of 5-ethoxyindole and 1-benzyl-4-piperidone. This compound has an affinity to the human dopamine D2 receptor with Ki of 151 nM. The aim of these studies was the structural and thermal characterization of the compound D2AAK1_3. In particular; X-ray studies; molecular docking and molecular dynamics as well as thermal analysis were performed. The studied compound crystallizes in orthorhombic system; in chiral space group P212121. The compound has a non-planar conformation. The studied compound was docked to the novel X-ray structure of the human dopamine D2 receptor in the inactive state (PDB ID: 6CM4) and established the main contact between its protonatable nitrogen atom and Asp (3.32) of the receptor. The obtained binding pose was stable in molecular dynamics simulations. Thermal stability of the compound was investigated using the TG-DSC technique in the air atmosphere, while TG-FTIR analyses in air and nitrogen atmospheres were also performed. The studied compound is characterized by good thermal stability. The main volatile products of combustion are the following gases: CO2; H2O toluene and CO while in the case of pyrolysis process in the FTIR spectra; the characteristic bands of NH3; piperidine and indole are additionally observed.

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PCM1 is necessary for focal ciliary integrity and is a candidate for severe schizophrenia

Nature Communications ◽

10.1038/s41467-020-19637-5 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Tanner O. Monroe ◽

Melanie E. Garrett ◽

Maria Kousi ◽

Ramona M. Rodriguiz ◽

Sungjin Moon ◽

...

Keyword(s):

Primary Cilium ◽

Antipsychotic Drugs ◽

Dopamine D2 Receptor ◽

D2 Receptor ◽

Postnatal Brain ◽

Physiological Relevance ◽

Rare Alleles ◽

Pericentriolar Material ◽

G Protein Coupled

AbstractThe neuronal primary cilium and centriolar satellites have functions in neurogenesis, but little is known about their roles in the postnatal brain. We show that ablation of pericentriolar material 1 in the mouse leads to progressive ciliary, anatomical, psychomotor, and cognitive abnormalities. RNAseq reveals changes in amine- and G-protein coupled receptor pathways. The physiological relevance of this phenotype is supported by decreased available dopamine D2 receptor (D2R) levels and the failure of antipsychotic drugs to rescue adult behavioral defects. Immunoprecipitations show an association with Pcm1 and D2Rs. Finally, we sequence PCM1 in two human cohorts with severe schizophrenia. Systematic modeling of all discovered rare alleles by zebrafish in vivo complementation reveals an enrichment for pathogenic alleles. Our data emphasize a role for the pericentriolar material in the postnatal brain, with progressive degenerative ciliary and behavioral phenotypes; and they support a contributory role for PCM1 in some individuals diagnosed with schizophrenia.

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