Dopamine D2 Receptor Research Articles

Effects of manipulating prefrontal activity and dopamine D1 receptor signaling in an appetitive feature-negative discrimination learning task.

Effects of manipulating prefrontal activity and dopamine D1 receptor signaling in an appetitive feature-negative discrimination learning task.

Chemokinergic and Dopaminergic Signalling Collaborates through the Heteromer Formed by CCR9 and Dopamine Receptor D5 Increasing the Migratory Speed of Effector CD4+ T-Cells to Infiltrate the Colonic Mucosa.

Inflammatory bowel diseases (IBDs) involve chronic inflammation of the gastrointestinal tract, where effector CD4+ T-cells play a central role. Thereby, the recruitment of T-cells into the colonic mucosa represents a key process in IBD. We recently found that CCR9 and DRD5 might form a heteromeric complex on the T-cell surface. The increase in CCL25 production and the reduction in dopamine levels associated with colonic inflammation represent a dual signal stimulating the CCR9:DRD5 heteromer, which promotes the recruitment of CD4+ T-cells into the colonic lamina propria. Here, we aimed to analyse the molecular requirements involved in the heteromer assembly as well as to determine the underlying cellular mechanisms involved in the colonic tropism given by the stimulation of the CCR9:DRD5 complex. The results show that dual stimulation of the CCR9:DRD5 heteromer potentiates the phosphorylation of the myosin light chain 2 (MLC2) and the migration speed in confined microchannels. Accordingly, disrupting the CCR9:DRD5 assembly induced a sharp reduction in the pMLC2 in vitro, decreased the migratory speed in confined microchannels, and dampened the recruitment of CD4+ T-cells into the inflamed colonic mucosa. Furthermore, in silico analysis confirmed that the interface of interaction of CCR9:DRD5 is formed by the transmembrane segments 5 and 6 from each protomer. Our findings demonstrated that the CCR9:DRD5 heteromeric complex plays a fundamental role in the migration of CD4+ T-cells into the colonic mucosa upon inflammation. Thereby, the present study encourages the design of strategies for disassembling the formation of the CCR9:DRD5 as a therapeutic opportunity to treat IBD.

Changes in nucleus accumbens core translatome accompanying incubation of cocaine craving.

In the 'incubation of cocaine craving' model of relapse, rats exhibit progressive intensification (incubation) of cue-induced craving over several weeks of forced abstinence from cocaine self-administration. The expression of incubated craving depends on plasticity of excitatory synaptic transmission in nucleus accumbens core (NAcC) medium spiny neurons (MSN). Previously, we found that the maintenance of this plasticity and the expression of incubation depends on ongoing protein translation, and the regulation of translation is altered after incubation of cocaine craving. Here we used male and female rats that express Cre recombinase in either dopamine D1 receptor- or adenosine 2a (A2a) receptor-expressing MSN to express a GFP-tagged ribosomal protein in a cell-type specific manner, enabling us to use Translating Ribosome Affinity Purification (TRAP) to isolate actively translating mRNAs from both MSN subtypes for analysis by RNA-seq. We compared rats that self-administered saline or cocaine. Saline rats were assessed on abstinence day (AD) 1, while cocaine rats were assessed on AD1 or AD40-50. For both D1-MSN and A2a-MSN, there were few differentially translated genes between saline and cocaine AD1 groups. In contrast, pronounced differences in the translatome were observed between cocaine rats on AD1 and AD40-50, and this was far more robust in D1-MSN. Notably, all comparisons revealed sex differences in translating mRNAs. Sequencing results were validated by qRT-PCR for several genes of interest. This study, the first to combine TRAP-seq, transgenic rats, and a cocaine self-administration paradigm, identifies translating mRNAs linked to incubation of cocaine craving in D1-MSN and A2a-MSN of the NAcC.

Activation of D2-like dopamine receptors improves the neuronal network and cognitive function of PPT1KI mice.

Palmitoyl-protein thioesterase 1 (PPT1) is a lysosomal depalmitoylation enzyme that mediates protein posttranslational modifications. Loss-of-function mutation of PPT1 causes a failure of the lysosomal degradation of palmitoylated proteins and results in a congenital disease characterized by progressive neuronal degeneration referred to as infantile neuronal ceroid lipofuscinosis (INCL). A mouse knock-in model of PPT1 (PPT1-KI) was established by introducing the R151X mutation into exon 5 of the PPT1 gene, which exhibited INCL-like pathological lesions. We previously reported that hippocampal γ oscillations were impaired in PPT1 mice. Hippocampal γ oscillations can be enhanced by selective activation of the dopamine D4 receptor (DR4), a dopamine D2-like receptor. In this study, we investigated the changes in DR expression and the effects of dopamine and various DR agonists on neural network activity, cognition and motor function in PPT1KI mice. Cognition and motor defects were evaluated via Y-maze, novel object recognition and rotarod tests. Extracellular field potentials were elicited in hippocampal slices, and neuronal network oscillations in the gamma frequency band (γ oscillations) were induced by perfusion with kainic acid (200 nM). PPT1KI mice displayed progressive impairments in γ oscillations and hippocampus-related memory, as well as abnormal expression profiles of dopamine receptors with preserved expression of DR1 and 3, increased membrane expression of DR4 and decreased DR2 levels. The immunocytochemistry analysis revealed the colocalization of PPT1 with DR4 or DR2 in the soma and large dendrites of both WT and PPT1KI mice. Immunoprecipitation confirmed the interaction between PPT1 and DR4 or DR2. The impaired γ oscillations and cognitive functions were largely restored by the application of exogenous dopamine, the selective DR2 agonist quinpirole or the DR4 agonist A412997. Furthermore, the administration of A412997 (0.5 mg/kg, i.p.) significantly upregulated the activity of CaMKII in the hippocampus of 5-month-old PPT1KI mice. Collectively, these results suggest that the activation of D2-like dopamine receptors improves cognition and network activity in PPT1KI mice and that specific DR subunits may be potential targets for the intervention of neurodegenerative disorders, such as INCL.

Endogenous Regulator of G protein Signaling 14 (RGS14) suppresses cocaine-induced emotionally motivated behaviors in female mice.

Addictive drugs hijack the neuronal mechanisms of learning and memory in motivation and emotion processing circuits to reinforce their own use. Regulator of G-protein Signaling 14 (RGS14) is a natural suppressor of post-synaptic plasticity underlying learning and memory in the hippocampus. The present study used immunofluorescence and RGS14 knockout mice to assess the role of RGS14 in behavioral plasticity and reward learning induced by chronic cocaine in emotional-motivational circuits. We report that RGS14 is strongly expressed in discrete regions of the ventral striatum and extended amygdala in wild-type mice, and is co-expressed with D1 and D2 dopamine receptors in neurons of the nucleus accumbens (NAc). Of note, we found that RGS14 is upregulated in the NAc in mice with chronic cocaine history following acute cocaine treatment. We found significantly increased cocaine-induced locomotor sensitization, as well as enhanced conditioned place preference and conditioned locomotor activity in RGS14-deficient mice compared to wild-type littermates. Together, these findings suggest that endogenous RGS14 suppresses cocaine-induced plasticity in emotional-motivational circuits, implicating RGS14 as a protective agent against the maladaptive neuroplastic changes that occur during addiction.

Synthesis and Evaluation of 18F-Labeled Phenylpiperazine-like Dopamine D3 Receptor Radioligands for Positron Emission Tomography Imaging.

The dopamine D3 receptor (D3R) is important in the pathophysiology of various neuropsychiatric disorders, such as depression, bipolar disorder, schizophrenia, drug addiction, and Parkinson's disease. Positron emission tomography (PET) with innovative radioligands provides an opportunity to assess D3R in vivo and to elucidate D3R-related disease mechanisms. Herein, we present the synthesis of eight 18F-labeled phenylpiperazine-like D3R-selective radioligands possessing good radiochemical purity (>97%), in vitro stability (>95%), and befitting lipophilicity. Based on in vitro binding assays and static microPET studies, the phenylpiperazine-like radioligands [18F]FBPC01 and [18F]FBPC03 were chosen as lead radioligands targeting D3R. Molecular docking further elucidated their binding mechanism. Radiolabeling conditions were optimized and then applied to an automated radiolabeling process, affording products with high specific activity (>112 GBq/μmol). Dynamic rat PET study demonstrated the specific binding of [18F]FBPC01 and [18F]FBPC03 to D3R in the brain ventricles and the pituitary gland. Validated by dynamic PET data analysis, biodistribution study, and metabolism analysis, [18F]FBPC03 exhibited the highest PET signal-to-noise ratio, good D3R-specific binding in the brain ventricles and pituitary gland of rats with few off-target binding, negligible defluorination, and stable brain metabolism, which indicated that [18F]FBPC03 was a promising D3R radioligand.

Retinoic acid-mediated homeostatic plasticity drives cell type-specific CP-AMPAR accumulation in nucleus accumbens core and incubation of cocaine craving.

Incubation of cocaine craving, a translationally relevant model for the persistence of drug craving during abstinence, ultimately depends on strengthening of nucleus accumbens core (NAcc) synapses through synaptic insertion of homomeric GluA1 Ca 2+ -permeable AMPA receptors (CP-AMPARs). Here we tested the hypothesis that CP-AMPAR upregulation results from a form of homeostatic plasticity, previously characterized in vitro and in other brain regions, that depends on retinoic acid (RA) signaling in dendrites. Under normal conditions, ongoing synaptic transmission maintains intracellular Ca 2+ at levels sufficient to suppress RA synthesis. Prolonged blockade of neuronal activity results in disinhibition of RA synthesis, leading to increased GluA1 translation and synaptic insertion of homomeric GluA1 CP-AMPARs. Using slice recordings, we found that increasing RA signaling in NAcc medium spiny neurons (MSN) from drug-naïve rats rapidly upregulates CP-AMPARs, and that this pathway is operative only in MSN expressing the D1 dopamine receptor. In MSN recorded from rats that have undergone incubation of craving, this effect of RA is occluded; instead, interruption of RA signaling in the slice normalizes the incubation-associated elevation of synaptic CP-AMPARs. Paralleling this in vitro finding, interruption of RA signaling in the NAcc of 'incubated rats' normalizes the incubation-associated elevation of cue-induced cocaine seeking. These results suggest that RA signaling becomes tonically active in the NAcc during cocaine withdrawal and, by maintaining elevated CP-AMPAR levels, contributes to the incubation of cocaine craving.

Dopamine D2 receptors in the accumbal core region mediates the effects of fentanyl on sleep-wakefulness

Fentanyl, a potent analgesic and addictive substance, significantly impacts sleep-wakefulness (S-W). Acutely, it promotes wake, whereas chronic abuse leads to severe sleep disruptions, including insomnia, which contributes to opioid use disorders (OUD), a chronic brain disease characterized by compulsive opioid use and harmful consequences. Although the critical association between sleep disruptions and fentanyl addiction is acknowledged, the precise mechanisms through which fentanyl influences sleep remain elusive. Recent studies highlight the role of the dopaminergic system of the nucleus accumbens (NAc) in S-W regulation, but its specific involvement in mediating fentanyl’s effects on S-W remains unexplored. We hypothesized that dopamine D2 receptors mediate fentanyl-induced effects on S-W. To test this hypothesis, male C57BL/6J mice, instrumented with sleep recording electrodes and bilateral guide cannulas above the accumbal core region (NAcC), were utilized in this study. At dark onset, animals were bilaterally administered sulpiride (D2 receptors antagonist; 250 ng/side) in the NAcC followed by an intraperitoneal injection of fentanyl (1.2 mg/Kg). S-W was examined for the next 12 h. We found that systemic administration of fentanyl significantly increased wakefulness during the first 6 h of the dark which was followed by a significant increase in NREM and REM sleep during the second 6 h of the dark period. D2-receptor blockade significantly reduced this effect as evidenced by a significant reduction in fentanyl-induced wakefulness during first 6 h of dark period and sleep rebound during the second 6 h. Our findings suggest that D2 receptors in the NAcC plays a vital role in mediating the fentanyl-induced changes in S-W.

Supplemental Material for Effects of Manipulating Prefrontal Activity and Dopamine D1 Receptor Signaling in an Appetitive Feature-Negative Discrimination Learning Task

Supplemental Material for Effects of Manipulating Prefrontal Activity and Dopamine D1 Receptor Signaling in an Appetitive Feature-Negative Discrimination Learning Task

Dopamine D1 receptors activation rescues hippocampal synaptic plasticity and cognitive impairments in the MK-801 neonatal schizophrenia model

Schizophrenia is a disorder with a higher cognitive decline in early adulthood, causing impaired retention of episodic memories. However, the physiological and behavioral functions that underlie cognitive deficits with a potential mechanism to ameliorate and improve cognitive performance are unknown. In this study, we used the MK-801 neurodevelopmental schizophrenia-like model. Rats were divided into two groups: one received MK-801, and the other received saline for five consecutive days (7–11 postnatal days, PND). We evaluated synaptic plasticity late-LTP and spatial memory consolidation in early adolescence and young adulthood using extracellular field recordings in acute hippocampal slices and the Barnes maze task. Next, we examined D1 receptor (D1R) activation as a mechanism to ameliorate cognitive impairments. Our results suggest that MK-801 neonatal treatment induces impairment in late-LTP expression and deficits in spatial memory retrieval in early adolescence that is maintained until young adulthood. Furthermore, we found that activation of dopamine D1R ameliorates the impairments and promotes a robust expression of late-LTP and an improved performance in the Barnes maze task, suggesting a novel and potential therapeutic role in treating cognitive impairments in schizophrenia.

YAP/TAZ Signaling in the Pathobiology of Pulmonary Fibrosis.

Pulmonary fibrosis (PF) is a severe, irreversible lung disease characterized by progressive scarring, with idiopathic pulmonary fibrosis (IPF) being the most prevalent form. IPF's pathogenesis involves repetitive lung epithelial injury leading to fibroblast activation and excessive extracellular matrix (ECM) deposition. The prognosis for IPF is poor, with limited therapeutic options like nintedanib and pirfenidone offering only modest benefits. Emerging research highlights the dysregulation of the yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) signaling pathway as a critical factor in PF. YAP and TAZ, components of the Hippo pathway, play significant roles in cell proliferation, differentiation, and fibrosis by modulating gene expression through interactions with TEA domain (TEAD) transcription factors. The aberrant activation of YAP/TAZ in lung tissue promotes fibroblast activation and ECM accumulation. Targeting the YAP/TAZ pathway offers a promising therapeutic avenue. Preclinical studies have identified potential treatments, such as trigonelline, dopamine receptor D1 (DRD1) agonists, and statins, which inhibit YAP/TAZ activity and demonstrate antifibrotic effects. These findings underscore the importance of YAP/TAZ in PF pathogenesis and the potential of novel therapies aimed at this pathway, suggesting a new direction for improving IPF treatment outcomes. Further research is needed to validate these approaches and translate them into clinical practice.

Dysfunction of the NMDA Receptor in the Pathophysiology of Schizophrenia and/or the Pathomechanisms of Treatment-Resistant Schizophrenia.

For several decades, the dopamine hypothesis contributed to the discovery of numerous typical and atypical antipsychotics and was the sole hypothesis for the pathophysiology of schizophrenia. However, neither typical nor atypical antipsychotics, other than clozapine, have been effective in addressing negative symptoms and cognitive impairments, which are indices for the prognostic and disability outcomes of schizophrenia. Following the development of atypical antipsychotics, the therapeutic targets for antipsychotics expanded beyond the blockade of dopamine D2 and serotonin 5-HT2A receptors to explore the partial agonism of the D2 receptor and the modulation of new targets, such as D3, 5-HT1A, 5-HT7, and metabotropic glutamate receptors. Despite these efforts, to date, psychiatry has not successfully developed antipsychotics with antipsychotic properties proven to be superior to those of clozapine. The glutamate hypothesis, another hypothesis regarding the pathophysiology/pathomechanism of schizophrenia, was proposed based on clinical findings that N-methyl-D-aspartate glutamate receptor (NMDAR) antagonists, such as phencyclidine and ketamine, induce schizophrenia-like psychotic episodes. Large-scale genome-wide association studies (GWASs) revealed that approximately 30% of the risk genes for schizophrenia (the total number was over one hundred) encode proteins associated with glutamatergic transmission. These findings supported the validation of the glutamate hypothesis, which was inspired by the clinical findings regarding NMDAR antagonists. Additionally, these clinical and genetic findings suggest that schizophrenia is possibly a syndrome with complicated pathomechanisms that are affected by multiple biological and genetic vulnerabilities. The glutamate hypothesis has been the most extensively investigated pathophysiology/pathomechanism hypothesis, other than the dopamine hypothesis. Studies have revealed the possibility that functional abnormalities of the NMDAR play important roles in the pathophysiology/pathomechanism of schizophrenia. However, no antipsychotics derived from the glutamatergic hypothesis have yet been approved for the treatment of schizophrenia or treatment-resistant schizophrenia. Considering the increasing evidence supporting the potential pro-cognitive effects of glutamatergic agents and the lack of sufficient medications to treat the cognitive impairments associated with schizophrenia, these previous setbacks cannot preclude research into potential novel glutamate modulators. Given this background, to emphasize the importance of the dysfunction of the NMDAR in the pathomechanism and/or pathophysiology of schizophrenia, this review introduces the increasing findings on the functional abnormalities in glutamatergic transmission associated with the NMDAR.

Rewarding properties of L-Dopa in experimental parkinsonism are mediated by sensitized dopamine D1 receptors in the dorsal striatum.

Treatment of Parkinson's disease (PD) is based on the use of dopaminergic drugs, such as L-Dopa and dopamine receptor agonists. These substances counteract motor symptoms, but their administration is accompanied by motor and non-motor complications. Among these latter conditions a neurobehavioral disorder similar to drug abuse, known as dopamine dysregulation syndrome (DDS), is attracting increasing interest because of its profound negative impact on the patients' quality of life. Here we replicate DDS in a PD mouse model based on a bilateral injection of 6-hydroxydopamine (6-OHDA) into the dorsal striatum. Administration of L-Dopa induced locomotor sensitization and conditioned place preference in 6-OHDA lesion, but not in control mice, indicative of the acquisition of addictive-like properties following nigrostriatal dopamine depletion. These behavioral effects were accompanied by abnormal dopamine D1 receptor (D1R) signaling in the medium spiny neurons of the dorsal striatum, leading to hyperactivation of multiple signaling cascades and increased expression of ΔFosB, a stable transcription factor involved in addictive behavior. Systemic administration of the D1R antagonist, SCH23390, abolished these effects and the development of place preference, thereby counteracting the psychostimulant-like effect of L-Dopa. The rewarding properties of L-Dopa were also prevented by chemogenetic inactivation of D1R-expressing neurons in the dorsal striatum. Our results indicate the association between abnormal D1R-mediated transmission and DDS in PD and identify potential approaches for the treatment of this disorder.

Abstract P391: Role of Renal Dopamine D2 Receptor in Inverse Salt Sensitivity and Salt Sensitivity of Blood Pressure: Insights from Nephron Segment-Specific Deletion Models

The renal dopamine D2 receptor (D2R) is essential in renal and blood pressure (BP) homeostasis. In mice, global Drd2 deletion or renal-selective Drd2 silencing increases the renal expression of proinflammatory factors, renal injury markers, and BP. The D2R is expressed in several nephron segments, including the proximal and distal convoluted tubules. To study the differential effects of D2R in these segments, we generated two mouse models: one with Drd2 deletion only in the S1 and S2 segments of the proximal tubule P SGLT2 ::Cre+ Drd2 fl/fl ( Sglt2 cKO ) and their littermates as controls, P SGLT2 ::Cre- Drd2 fl/fl (Sglt2 WT) and another with deletion of the receptor in the whole nephron P CDHR16 ::Cre+ Drd2 fl/fl ( Cdhr16 cKO ) and their littermates as controls, P CDHR16 ::Cre- Drd2 fl/fl (Cdhr16 WT). In male Sglt2 cKO mice, compared with Sglt2 WT mice, D2R expression in the renal cortex was decreased by 25% (P<0.05, n=5-6/group). In Cdhr16 cKO mice, compared with Cdhr16 WT mice, D2R expression was decreased by 30% (P<0.05; n=3/group). In Sglt2 cKO mice, tubular lumen expansion, an indication of tubular damage, was higher on low salt (0.09%NaCl; LS) than on normal salt (0.4%NaCl; NS) (25.5±.8 vs. 11.4±.0.3; P<0.001) diet. In Cdhr16 cKO mice tubular lumen expansion was also higher on LS than NS (13.9±0.4 vs 8.7±0.2; P<0.001) diet. In Sglt2 cKO mice, BP (carotid artery under anesthesia) was higher on LS (130±2 mm Hg) than on NS (107±2 mm Hg) or HS (4% NaCl) (100±3 mm Hg) (n=10/group) (P<0.05) diet. In Cdhr16 cKO mice, BP (tail cuff, CODA under anesthesia, confirmed by telemetry) was higher on LS (110±8 mm Hg, P<0.02; n=4-5/group) and HS (119±9 mm Hg, P<0.05; n=4/group) diets than on NS diet (84±5 mmHg). On LS diet, UNaV was lower in Sglt2 cKO than Sglt2 WT (1±0.3 vs 7±2 µEq/24h; P< 0.05; n=4-6/group) mice. On LS diet, UNaV was also lower in Cdhr16 cKO than Cdhr16 WT (5±0.9 vs 34±14 µEq/24h; P<0.05; n=3-4/group) mice. These results indicate that a decrease in D2R expression only in the proximal tubule results in inverse salt sensitivity of BP, i.e., BP higher on LS than NS or HS diets, while downregulation of its expression in the whole nephron results in inverse salt sensitivity, as well as salt sensitivity.

Effect of Salinity and Salmon Pituitary Extract on the Expression of Reproduction and/or Salinity-Related Genes in the Pituitary Cells of Japaneses Eel.

Artificial sexual maturation of eel (Anguilla japonica) involves rearing in seawater and injecting salmon pituitary extract (SPE). The salinity of seawater and components of SPE influence hormonal activities of the eel pituitary, leading to gonad development. This study investigated the direct effects of salinity change and SPE treatment on the eel pituitary gland using primary cell cultures. Pituitary cells were cultured into four experimental groups: control culture (control), SPE-treated culture (SPE), NaCl-treated culture (NaCl) and NaCl+SPE treated culture (NaCl+SPE). We investigated the expression of genes presumably related to reproduction and/or salinity, including luteinizing hormone (LHβ), follicle stimulating hormone (FSHβ), progesterone receptor-like (pgrl), prolactin (PRL), dopamine receptor D4 (drd4), neuropeptide B/W receptor 2 (NPBWR2) and relaxin family peptide receptor 3-2b (rxfp3-2b). Gene expression analysis revealed significant upregulation of LHβ in SPE and NaCl+SPE groups compared to control and NaCl (p<0.05). FSHβ expression did not show any significant changes. PRL showed a significant decrease in the NaCl group (p<0.05). Pgrl, NPBWR2, drd4, and rxfp3-2b displayed the highest expression in the control group, with downregulation observed in all treatment groups (NaCl, SPE, and NaCl+SPE) (p<0.05). This study demonstrated the direct effects of salinity changes and SPE treatment on the eel pituitary. Results from this study also suggest that salinity change is necessary but work together with SPE to induce reproductive process, and that LHβ, pgrl, PRL, drd4, NPBWR2, and rxfp3-2b genes are obviously associated with reproduction and salinity changes in eels.

SARS-CoV-2 spike protein acts as a β-adrenergic receptor agonist: A potential mechanism for cardiac sequelae of long COVID.

Currently, pathophysiological mechanisms of post-acute sequelae of coronavirus disease-19-cardiovascular syndrome (PASC-CVS) remain unknown. Patients with PASC-CVS exhibited significantly higher circulating levels of severe acute respiratory syndrome-coronavirus-2 spike protein S1 than the non-PASC-CVS patients and healthy controls. Moreover, individuals with high plasma spike protein S1 concentrations exhibited elevated heart rates and normalized low frequency, suggesting cardiac β-adrenergic receptor (β-AR) hyperactivity. Microscale thermophoresis (MST) assay revealed that the spike protein bound to β1- and β2-AR, but not to D1-dopamine receptor. These interactions were blocked by β1- and β2-AR blockers. Molecular docking and MST assay of β-AR mutants revealed that the spike protein interacted with the extracellular loop 2 of both β-ARs. In cardiomyocytes, spike protein dose-dependently increased the cyclic adenosine monophosphate production with or without epinephrine, indicating its allosteric effects on β-ARs. Severe acute respiratory syndrome-coronavirus-2 spike proteins act as an allosteric β-AR agonist, leading to cardiac β-AR hyperactivity, thus contributing to PASC-CVS.

Dopamine D2 receptor partial agonists in the treatment of schizophrenia -example of brexpiprazole.

Since the 1950s, there have been rapid developments in psychiatric pharmacotherapy, resulting not only in more effective treatment of patients, but also in improvements in minimizing adverse effects of therapy. Modern third-generation antipsychotics, in addition to antagonism toward D2 receptors, also exhibit partial agonism toward dopamine receptors. Such a mechanism of action is intended to regulate dopaminergic transmission - inhibit (antagonism) it in pathways where it is excessive (excessive transmission in the mesolimbic pathway in psychotic patients, excessive transmission in the tuberoinfundibular pathway in patients with hyperprolactinemia) and stimulate (agonism) it in pathways where it is too low (mesocortical pathway). This has a beneficial effect on both the reduction of adverse symptoms and the negative, affective and cognitive symptoms of patients suffering from schizophrenia. The purpose of this review article is to present the most important clinical aspects of the use of dopamine D2 receptor partial agonists in the treatment of schizophrenia, using brexpiprazole as an example, and to define the profile of patients to whom this drug could be dedicated - based on recent studies.

The interplay of ADHD, social media usage, and dopamine receptors in adolescents: A literature review

ADHD is a neurodevelopmental disorder marked by symptoms such as inattentiveness, hyperactivity, and impulsivity, with a prevalence rate exceeding 5%. The pathophysiology of ADHD includes cognitive and functional brain abnormalities, particularly in the anterior cingulate gyrus and dorsolateral prefrontal cortex, as well as decreased activity in the frontostriatal region. Diagnosis involves comprehensive assessments based on behavioral criteria outlined in the DSM-5. Treatment primarily includes stimulant medications, which are effective in about 70% of patients, and non-stimulant options such as atomoxetine and antidepressants. The review explores the effects of social media on adolescents, highlighting both negative impacts, such as social isolation, depression, and cyberbullying, and positive aspects, such as enhanced communication and knowledge sharing. Adolescents with ADHD are particularly vulnerable to behavioral addictions due to their poor impulse control, making them susceptible to excessive social media use. Additionally, the role of D2-dopamine receptors in ADHD is discussed, noting that genetic components like the DRD2 gene can affect dopamine neurotransmission, impacting attention and pleasure experiences. The pleasure principle, as proposed by Freud, is also analyzed in the context of ADHD, suggesting that individuals with ADHD may engage in behaviors that provide immediate gratification to avoid discomfort. Therefore, this review underscores the correlation between ADHD symptoms, social media usage, dopamine receptor function, and the underlying psychological drives in adolescents, providing a comprehensive understanding of these interrelated factors.

Single-cell RNA-seq Reveals that Methamphetamine Inhibits Liver Immunity with Involvement of Dopamine Receptor D1.

Methamphetamine (METH) is a highly addictive psychostimulant that causes physical and psychological damage and immune system disorder, especially in the liver that contains a significant number of immune cells. Dopamine, a key neurotransmitter in METH addiction and immune regulation, plays a crucial role in this process. Here, we developed a chronic METH administration model and conducted single-cell RNA sequencing (scRNA-seq) to investigate the effect of METH on liver immune cells and involvement of dopamine receptor D1 (DRD1). Our findings reveal that chronic exposure to METH induces immune cell identity shifts from Ifitm3+Macrophage (Mac) and Ccl5+Mac to Cd14+Mac, and from Fyn+CD4+T effector (Teff), CD8+T, and natural killer T cells (NKT) to Fos+CD4+T and Rora+ group 2 innate lymphoid cells (ILC2), along with suppression of multiple functional immune pathways. DRD1 is implicated in regulating certain pathways and identity shifts among the hepatic immune cells. Our results provide valuable insights into development of targeted therapies to mitigate METH-induced immune impairment.

Specific Activation of Dopamine Receptor D1 Expressing Neurons in the PrL Alleviates CSDS-Induced Anxiety-Like Behavior Comorbidity with Postoperative Hyperalgesia in Male Mice.

Postoperative pain is a type of pain that occurs in clinical patients after surgery. Among the factors influencing the transition from acute postoperative pain to chronic postoperative pain, chronic stress has received much attention in recent years. Here, we investigated the role of dopamine receptor D1/D2 expressing pyramidal neurons in the prelimbic cortex (PrL) in modulating chronic social defeat stress (CSDS)-induced anxiety-like behavior comorbidity with postoperative hyperalgesia in male mice. Our results showed that preoperative CSDS induced anxiety-like behavior and significantly prolonged postoperative pain caused by plantar incision, but did not affect plantar wound recovery and inflammation. Reduced activation of dopamine receptor D1 or D2 expressing neurons in the PrL is a remarkable feature of male mice after CSDS, and chronic inhibition of dopamine receptor D1 or D2 expressing neurons in the PrL induced anxiety-like behavior and persistent postoperative pain. Further studies found that activation of D1 expressing but not D2 expressing neurons in the PrL ameliorated CSDS-induced anxiety-like behavior and postoperative hyperalgesia. Our results suggest that dopamine receptor D1 expressing neurons in the PrL play a crucial role in CSDS-induced anxiety-like behavior comorbidity with postoperative hyperalgesia in male mice.