Dataset Information

Characterization of dopamine D₂ receptor coupling to G proteins in postmortem brain of subjects with schizophrenia.

ABSTRACT:

Background

Alterations of dopamine D₁ (D1R) and D₂ receptor (D2R) are proposed in schizophrenia but brain neuroimaging and postmortem studies have shown controversial results in relation to D1R and D2R density. Besides, scarce information on the functionality of brain D1R and D2R is available. The present study characterized G-protein activation by D1R and D2R agonists in postmortem human brain. Furthermore, D2R functional status was compared between schizophrenia and control subjects.

Methods

G-protein receptor coupling was assessed in control caudate nucleus and frontal cortex by [³⁵S]GTPγS-binding stimulation induced by increasing concentrations (10^-10-10^-3 M) of dopamine, and the selective dopaminergic agonists SKF38393 (D1R) and NPA (D2R). Concentration-response curves to NPA stimulation of [³⁵S]GTPγS binding were analyzed in antipsychotic-free (n = 10) and antipsychotic-treated (n = 7) schizophrenia subjects and matched controls (n = 17).

Results

In caudate, [³⁵S]GTPγS-binding responses to agonists were compatible with the existence of functional D2R. In contrast, stimulations in cortex showed responses that did not correspond to D1R or D2R. [³⁵S]GTPγS-binding activation by NPA in caudate displayed biphasic curves with similar profile in schizophrenia (EC_50H = 7.94 nM; EC_50L = 7.08 μM) and control (EC_50H = 7.24 nM; EC_50L = 15.14 μM) subjects. The presence or absence of antipsychotic medication did not influence the pharmacological parameters.

Conclusions

Feasibility of functional evaluation of dopamine receptors in postmortem human brain by conventional [³⁵S]GTPγS-binding assays appears to be restricted to signalling through inhibitory G_i/o proteins. These findings provide functional information about brain D2R status in subjects with schizophrenia and do not support the existence of D2R supersensitive in this mental disorder.

SUBMITTER: Egusquiza I

PROVIDER: S-EPMC8413194 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The status of serotonin 5-HT2A receptors (5-HT2ARs) in schizophrenia has been controversial. In vivo positron emission tomography neuroimaging and in vitro post-mortem binding studies have reported conflicting results about 5-HT2AR density. Radiotracers bind different receptor conformations depending on their agonist, antagonist or inverse agonist properties. This study investigates 5-HT2AR density in the post-mortem prefrontal cortex from subjects with schizophrenia and controls using three radiotracers with a different pharmacological profile. The specific binding parameters of the inverse agonist [18F]altanserin, the agonist [3H]lysergic acid diethylamide (LSD) and the antagonist [3H]MDL100907 to brain cortex membranes from 20 subjects with schizophrenia and 20 individually matched controls were evaluated under similar methodological conditions. Ten schizophrenia subjects were antipsychotic-free at death. Saturation curve analyses were performed by non-linear regression to obtain a maximal density of binding sites (Bmax) and the affinity of the respective radiotracers (Kd). In schizophrenia subjects, 5-HT2AR density was decreased when quantified by [18F]altanserin binding, whereas increased when evaluated by [3H]LSD binding. However, [3H]MDL100907 binding was unaltered. A slight loss of affinity (higher Kd) was observed exclusively in [3H]LSD binding. The findings were more evident in antipsychotic-free subjects than in antipsychotic-treated subjects. In conclusion, a higher proportion of the 5-HT2AR-active functional conformation, which is rather identified by agonist radiotracers, was observed in schizophrenia patients. A consequent reduction of the inactive 5-HT2AR conformation, which is preferentially identified by inverse agonist radiotracers, was also obtained. Antagonist radiotracers do not distinguish between molecular conformations of the receptor, and accordingly, the absence of changes was shown. These results are compatible with the proposed increased functional activity of brain cortical 5-HT2ARs in schizophrenia.

Dataset Information

Characterization of dopamine D₂ receptor coupling to G proteins in postmortem brain of subjects with schizophrenia.

Background

Methods

Results

Conclusions

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Characterization of dopamine D2 receptor coupling to G proteins in postmortem brain of subjects with schizophrenia.

Background

Methods

Results

Conclusions

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Characterization of dopamine D₂ receptor coupling to G proteins in postmortem brain of subjects with schizophrenia.