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 (EC50H = 7.94 nM; EC50L = 7.08 μM) and control (EC50H = 7.24 nM; EC50L = 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 Gi/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.

The Role of the Dopamine System in Post-Stroke Mood Disorders in Newborn Rats

“…In contrast, after neonatal diffuse hypoxic–ischemic insults, reduced expression of DAT is reported in association with decreased DA concentration [ 13 , 27 ]. To better understand the apparently paradoxical response in our work, we studied the functionality of D2R, which plays a major role in psychotic and non-psychotic mania associated with abnormalities in the DA system [ 21 , 28 ]. No differences were found between SHAM and MCAO rats in the expression levels of D2R but a decreased response to agonists was observed for D2R in the ipsilateral as compared with the contralateral striatum.…”

“…The process has been reported in detail elsewhere [ 28 ]. In short, for brain cellular membrane preparation the left and right striatum were dissected and immediately stored at −70 °C until assay.…”

Three paradoxes related to the mode of action of pramipexole: The path from D2/D3 dopamine receptor stimulation to modification of dopamine-modulated functions

“…As D2 dopamine receptors are involved in mediating arousal in both the VTA-and SNcmodulated networks, it can be inferred that pramipexole would also enhance arousal in parallel with the promotion of reinforcement and locomotion. Dopaminergic neurones of the vPAG project to the cerebral cortex (Lewis and O'Donnell, 2000;Lu et al, 2006), where they can stimulate three types of dopamine receptor: D1/excitatory (Anastasiades et al, 2019;Lewis and O'Donnell, 2000;Mannoury la Cour et al, 2007), D2/excitatory (Robinson and Sohal, 2017) and D2/inhibitory (Egusquiza et al, 2021;Robinson and Sohal, 2017). Inhibitory presynaptic D2 receptors are also present on the dopaminergic neurone itself.…”

“…Dopaminergic neurones of the v PAG project to the cerebral cortex (Lewis and O’Donnell, 2000; Lu et al, 2006), where they can stimulate three types of dopamine receptor: D1/excitatory (Anastasiades et al, 2019; Lewis and O’Donnell, 2000; Mannoury la Cour et al, 2007), D2/excitatory (Robinson and Sohal, 2017) and D2/inhibitory (Egusquiza et al, 2021; Robinson and Sohal, 2017). Inhibitory presynaptic D2 receptors are also present on the dopaminergic neurone itself.…”