Dopamine D2 Receptor Research Articles

Regulation by Trace Amine-Associated Receptor 1 (TAAR1) of Dopaminergic-GABAergic Interaction in the Striatum: Effects of the Enhancer Drug (-)BPAP.

Although it is well documented that the striatal GABAergic projection neurons receive excitatory and inhibitory dopaminergic innervation via D1 and D2 receptors, the trace amine-associated receptor 1 (TAAR1)-mediated regulation of this neural connection is much less studied. The presence of TAAR1 was originally detected in brain aminergic neurons, with recent evidence indicating its presence in striatal GABAergic neurons as well. The objective of the present study was to demonstrate the role of TAAR1 and signaling in dopaminergic-GABAergic interaction in the neural circuitry of the striatum. Besides trace amines, which are considered natural ligands for TAAR1, series of different exogenous drugs were identified to act on this receptor. Using the dopaminergic activity enhancer compound (-)BPAP ((-)-1-(benzofuran-2-yl)-2-propylaminopentane HCl), a potential agonist for TAAR1, we have found that it increased the electrical stimulation-induced [3H]dopamine release in rat striatal slices. This effect of (-)BPAP occurred parallel with increases of [3H]GABA release in striatum when used in 10-13-10-11mol/L concentrations. The effects of (-)BPAP on the release of both neurotransmitters were bell-shaped. We speculated that the rising phase of the concentration-effect curves was evoked by an agonist effect of (-)BPAP on TAAR1 whereas the declining phase was a result of heterodimerization of TAAR1 with pre- and postsynaptic dopamine D2 receptors. The bell-shaped curves suggest that the (-)BPAP-induced heterodimerization of TAAR1 with dopamine D2 receptors may switch off TAAR1 signaling and switch on transduction coupled to D2 receptors. We also suggest that (-)BPAP increases synaptic strength in a hypothetical quadrilateral neuronal organization consisting of dopaminergic nerve ending, GABAergic neurons, trace amine-producing D cells, and supportive glial cell processes.

Vasoinhibin is generated by the Renin-Angiotensin System.

Vasoinhibin is a fragment of the hormone prolactin (PRL) that inhibits angiogenesis, vasopermeability, and vasodilation. Cathepsin D (CTSD) cleaves the N-teminal of PRL to generate vasoinhibin in the retina of neonate mice as revealed by the CTSD inhibitor, pepstatin A (PA). However, PA also inhibits renin. Because renin is expressed in the retina and the renin-angiotensin system (RAS) gives rise to peptides with positive and negative effects on blood vessel growth and function, we investigated whether renin cleaves PRL to vasoinhibin in the newborn mouse retina and in the circulation. Newborn mouse retinal extracts from wild-type and CTSD-null newborn mice cleaved PRL to a 14 kDa vasoinhibin and such cleavage was prevented by heat-inactivation, PA, and the selective renin inhibitor VTP-27999 suggesting the contribution of renin. In agreement, recombinant renin cleaved different species PRLs to the expected 14 kDa vasoinhibin, a mass consistent with a consensus renin cleavage site located at Leu124-Leu125 in rat and mouse PRLs and at Leu126-Leu127 in human, bovine, and ovine PRLs. Dehydration followed by rehydration (D/R) in rats increased the levels of renin and PRL in plasma. Further increase in PRL circulating levels by the dopamine D2 receptor blocker, sulpiride, enabled detection of 14 kDa vasoinhibin in D/R rats. Moreover, the incubation of PRL with plasma from D/R rats generated a 14 kDa vasoinhibin that was prevented by VTP-27999. These findings add renin to the list of PRL-cleaving proteases and introduce vasoinhibin as a putative RAS-mediated mechanism for regulating blood vessel growth and function.

Choroidal thickening and retinal dopamine increase in mice at high altitude.

The mechanisms underlying the low incidence of myopia at high altitudes remain unclear. Choroidal thickness and the dopaminergic system have been shown to be closely associated with myopia development. This study aimed to investigate the effects of high altitude exposure on choroidal thickness and the dopaminergic system. Mice were subjected to acute hypobaric hypoxia at an altitude of 5000m for durations ranging from 2 to 72h, as well as chronic exposure at an altitude of 3670m for a period of 3 months. Choroidal thickness was assessed using hematoxylin and eosin (H&E) staining of ocular tissues. The retinal dopamine (DA) levels and its primary metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), were quantified via high-performance liquid chromatography (HPLC). The expression levels of dopamine D1 receptor (D1R) and dopamine D2 receptor (D2R) were evaluated using immunofluorescence techniques. Study results indicated that choroidal thickness significantly increased after 6h of high altitude exposure. Retinal dopamine levels showed significant increases in both the 2-10h and 3 months high altitude groups. Conversely, retinal DOPAC levels decreased in the 2h and 4h groups but increased significantly at 72h. Following high altitude exposure, D1R expression correlated positively with DA levels, while D2R expression exhibited a negative correlation. In conclusion, high-altitude exposure is associated with significant increases in choroidal thickness and retinal DA levels, with D1R and D2R expression patterns varying in response to changes in retinal DA. These findings may represent a key molecular mechanism contributing to the lower incidence of myopia observed at high altitudes.

The Utility of Prolonged Chronic Unpredictable Stress to Study the Effects of Chronic Fluoxetine, Eicosapentaenoic Acid, and Lipopolysaccharide on Anxiety-Like Behavior and Hippocampal Transcriptomic Responses in Male Rats.

Chronic stress is a common trigger of multiple neuropsychiatric illnesses. Animal models are widely used to study stress-induced brain disorders and their interplay with neuroinflammation and other neuroimmune processes. Here, we apply the prolonged 12-week chronic unpredictable stress (PCUS) model to examine rat behavioral and hippocampal transcriptomic responses to stress and to chronic 4-week treatment with a classical antidepressant fluoxetine, an anti-inflammatory agent eicosapentaenoic acid (EPA), a pro-inflammatory agent lipopolysaccharide and their combinations. Overall, PCUS evoked anxiety-like behavioral phenotype in rats, corrected by chronic fluoxetine (alone or combined with other drugs), and EPA. PCUS also evoked pronounced transcriptomic responses in rat hippocampi, involving > 200 differentially expressed genes. While pharmacological manipulations did not affect hippocampal gene expression markedly, Gpr6, Drd2 and Adora2a were downregulated in stressed rats treated with fluoxetine, EPA and fluoxetine + EPA, suggesting their respective protein products (G protein-coupled receptor 6, dopamine D2 receptor and adenosine A2A receptor) as potential evolutionarily conserved targets under chronic stress. Overall, these findings support the validity of rat PCUS paradigm as a useful model to study stress-related anxiety pathogenesis, and call for further research probing how various conventional and novel drugs may (co)modulate behavioral and neurotranscriptomic biomarkers of chronic stress.

Serotonin neurons integrate GABA and dopamine inputs to regulate meal initiation.

Obesity is a growing global health epidemic with limited orally administered therapeutics. Serotonin (5-HT) is one neurotransmitter which remains an excellent target for new weight-loss therapies, but a gap remains in understanding the mechanisms involved in 5-HT produced in the dorsal Raphe nucleus (DRN) and its involvement in meal initiation. Using an optogenetic feeding paradigm, we showed that the 5-HTDRN➔arcuate nucleus (ARH) circuit plays a role in meal initiation. Incorporating electrophysiology and ChannelRhodopsin-2-Assisted Circuit Mapping, we demonstrated that 5-HTDRN neurons receive inhibitory input partially from GABAergic neurons in the DRN, and the 5-HT response can be enhanced by hunger. Additionally, deletion of the GABAA receptor subunit in 5-HT neurons inhibits meal initiation with no effect on the satiation process. Finally, we identified the role of dopaminergic inputs via dopamine receptor D2 in enhancing the response to GABA-induced feeding. Thus, our results indicate that 5-HTDRN neurons are inhibited by synergistic inhibitory actions of GABA and dopamine, for the initiation of a meal.

The Role of ΔFosB in the Pathogenesis of Levodopa-Induced Dyskinesia: Mechanisms and Therapeutic Strategies.

Levodopa-induced dyskinesia (LID) represents a significant complication associated with the long-term administration of levodopa (L-DOPA) for the treatment of Parkinson's disease (PD). This review examines the critical role of ΔFosB, a transcription factor, in the pathogenesis of LID and explores potential therapeutic interventions. ΔFosB accumulates within the striatum in response to chronic dopaminergic stimulation, thereby driving maladaptive changes that culminate in dyskinesia. Its persistent expression modifies gene transcription, influencing neuronal plasticity and contributing to the sustained presence of dyskinetic movements. This study explains how ΔFosB functions at the molecular level, focusing on its connections with dopamine D1 receptors, the cAMP/PKA signaling pathway, and its regulatory effects on downstream targets such as DARPP-32 and GluA1 AMPA receptor subunits. Additionally, it examines how neuronal nitric oxide synthase (nNOS) affects ΔFosB levels and the development of LID. This review also considers the interactions between ΔFosB and other signaling pathways, such as ERK and mTOR, in the context of LID and striatal plasticity. Emerging therapeutic strategies targeting ΔFosB and its associated pathways include pharmacological interventions like ranitidine, 5-hydroxytryptophan, and carnosic acid. Furthermore, this study addresses the role of JunD, another component of the AP-1 transcription factor complex, in the pathogenesis of LID. Understanding the molecular mechanisms by which ΔFosB contributes to LID offers promising avenues for developing novel treatments that could mitigate dyskinesia and improve the quality of life for PD patients undergoing long-term L-DOPA therapy.

Associations between inflammation and striatal dopamine D2-receptor availability in aging

BackgroundNormal brain aging is associated with dopamine decline, which has been linked to age-related cognitive decline. Factors underlying individual differences in dopamine integrity at older ages remain, however, unclear. Here we aimed at investigating: (i) whether inflammation is associated with levels and 5-year changes of in vivo dopamine D2-receptor (DRD2) availability, (ii) if DRD2-inflammation associations differ between men and women, and (iii) whether inflammation and cerebral small-vessel disease (white-matter lesions) serve as two independent predictors of DRD2 availability.MethodsAnalyses were performed in a sample of healthy adults > 60 years assessed at two measurement occasions separated by 5 years. At both occasions, DRD2 availability was estimated by 11C-raclopride PET, and white-matter lesions by MRI. Inflammation was assessed by two C-reactive protein-associated DNA methylation scores at study baseline.ResultsIndividuals with higher DNA methylation scores at baseline showed reduced striatal DRD2 availability. An interaction was found between DNA methylation scores and sex in relation to striatal DRD2 availability, such that associations were found in men but not in women. DNA methylation scores at study entrance were not significantly associated with 5-year striatal DRD2 decline rates. No significant association was found between DNA methylation scores and white-matter lesions, but higher scores as well as higher lesion burden were independently associated with reduced striatal DRD2 availability in men.ConclusionsThese findings suggest negative associations between one proxy of inflammation and DRD2 availability in older adults, selectively for men who had higher DNA methylation scores. Future studies should investigate other inflammatory markers in relation to dopamine integrity.

Nitrous oxide exerts rewarding effect via regulating D1 receptor and BDNF pathway in ventral tegmental area-nucleus accumbens dopamine circuit

Recreational use of nitrous oxide (N2O) has risen dramatically over the past decades. This study aimed to examine its rewarding effect and the underlying mechanisms. The exposure of mice to a subanesthetic concentration (20%) of N2O for 30 min for 4 consecutive days paired with N2O in the morning and paired with the air in the afternoon produced apparent rewarding behavior in the conditioned place preference (CPP) paradigm. This was abrogated by microinjection into the nucleus accumbens (NAc) of the dopamine (DA) D1 receptor antagonist SCH23390, but not the D2 antagonist haloperidol. N2O robustly enhanced DAergic neuronal activity of the ventral tegmental area (VTA) and the concentration of DA in the NAc. The repeated N2O exposure also upregulated the expression of brain-derived neurotrophic factor (BDNF) in the VTA and its multiple downstream mediators in the NAc. Conversely, VTA focal knockdown of BDNF and the inhibition of the downstream mediators suppressed the N2O-induced rewarding effect and the DAergic neuronal activity of the VTA. Further, the combined intervention of BDNF knockdown and D1 antagonist significantly inhibited the N2O-induced rewarding effect in mice, which was greater than that of BDNF knockdown alone, but was not significantly different from that of D1 antagonist alone. These results indicate that the rewarding properties of N2O at subanesthetic concentration are associated with its upregulation of the VTA-NAc DA reward pathway probably via mediation of D1 receptor and BDNF/TrkB signaling. Among them, the modulation of BDNF may be the upstream of D1 receptor involved in N2O rewarding effect.

Access to high-fat diet results in increased sensitivity to the psychostimulant effects of MDPV in mice.

The current study investigated the effects of high-fat diet on acute response to 3,4-methylenedioxypyrovalerone (MDPV) in mice. MDPV is a beta-cathinone derivative endowed with psychostimulant activity. Similarly to recreational substances, consumption of palatable food stimulates the mesolimbic dopaminergic system, resulting in neuroadaptive changes. Adolescent C57BL/6N mice were fed either control diet (CD), 10% of kcal from fat, or high-fat diet (HFD), 60% of kcal from fat. After eight weeks, one group of HFD-fed mice had their diet changed to CD for an additional two weeks. Fasting glucose levels and glucose tolerance were measured to detect impairment in glucose metabolism. Subsequently, the mice were treated with either MDPV (1mg/kg) or saline, and their locomotor activity was measured. Using reverse transcriptase quantitative polymerase chain reaction (RT-qPCR), the expression of dopamine receptor D1 (Drd1), dopamine receptor D2 (Drd2), and FBJ osteosarcoma oncogene B (FosB) genes was measured in the striatum of mice. Feeding with HFD caused obesity and glucose intolerance in mice. Restriction of fat reduced body mass and reversed impairment of glucose metabolism. HFD-fed mice responded to MDPV with higher potency than CD-fed counterparts, with an increased incidence of stereotypies. A change of diet partially reversed this effect. Downregulation of Drd2 was observed in the mice that switched from HFD to CD, whereas treatment with MDPV caused upregulation of FosB only in the CD-fed mice. Current results suggest that obesity may increase sensitivity to psychostimulant effects of MDPV and elevate the risk of addiction as mice fed with HFD responded to acute treatment with MDPV with higher potency and showed tolerance of FosB induction in response to the drug.

Latest Advancements in the Management of H3K27M-Mutant Diffuse Intrinsic Pontine Glioma: A Narrative Review

Despite recent advancements in radiotherapy for Diffuse Intrinsic Pontine Glioma (DIPG), the prognosis of this disease remains poor, highlighting the need for new treatment strategies to improve outcomes. Adding stereotactic biopsy to the diagnostic process for children with DIPG has been crucial in improving the management of this disease. Indeed, the discovery of the H3K27M mutation as a key driver of DIPG has led to the development of new drugs that are more effective than traditional ones. These include nimotuzumab (an anti-EGFR drug) and vinorelbine (a semisynthetic vinca alkaloid) in combination, Panobinostat (a histone deacetylase inhibitor), ONC201 (a drug that blocks the dopamine receptor D2 and inactivates Akt and ERK kinases), and chimeric antigen receptor (CAR) T cells. In terms of local therapy, identifying the H3K27M mutation can help us explore how genetic changes affect treatment response, recurrence patterns, and survival. Beyond the time to first recurrence, specific patterns of tumor recurrence, like leptomeningeal spread, can influence treatment plans. For example, radiotherapy can be adjusted in terms of doses and volumes, based on tumor aggressiveness. Because the H3K27M mutation is linked to higher malignancy, a slightly higher dose could be used for the second round of local irradiation. Additionally, irradiating the entire craniospinal axis could help control both local and leptomeningeal disease.

D1 dopamine receptor antagonists as a new therapeutic strategy to treat autistic-like behaviours in lysosomal storage disorders.

Lysosomal storage disorders characterized by defective heparan sulfate (HS) degradation, such as Mucopolysaccharidosis type IIIA-D (MPS-IIIA-D), result in neurodegeneration and dementia in children. However, dementia is preceded by severe autistic-like behaviours (ALBs), presenting as hyperactivity, stereotypies, social interaction deficits, and sleep disturbances. The absence of experimental studies on ALBs' mechanisms in MPS-III has led clinicians to adopt symptomatic treatments, such as antipsychotics, which are used for non-genetic neuropsychiatric disorders. However, they have limited efficacy in MPS-III and lead to higher extrapyramidal effects, leaving ALBs in MPS-IIIA as an unmet medical need with a significant burden on patients and their families. Using mouse and cellular models of MPS-IIIA, we have previously shown that ALBs result from increased proliferation of mesencephalic dopamine neurons during embryogenesis. In adulthood, MPS-IIIA mice exhibit an imbalance of dopaminergic receptor subtypes, resulting in striatal overstimulation of the D1 dopamine receptor (D1R)-direct pathway, contrasting with a downregulation of the D2 dopamine receptor (D2R)-indirect pathway. In this study, we aimed to provide an evidence-based pharmacological approach for managing ALBs in MPS-IIIA. We hypothesized that rebalancing dopaminergic receptor signalling with a D1R antagonist, rather than a D2 antagonist, would lead to safe and effective treatment. Neither risperidone nor methylphenidate improves ALBs in the MPS-IIIA mouse model, with the former showing increased cataleptic (extrapyramidal-like) side effects compared to littermate wild-type animals. Methylphenidate, however, showed some beneficial effects on neuroinflammation and later manifesting dementia-like behaviours. In contrast, ecopipam, a D1 antagonist already used in the clinic for other neuropsychiatric disorders, rescues ALBs, cognition, D1 hyperactivity, and does not worsen neurodegenerative signs. These results align with recent evidence highlighting the clinical relevance of D1 antagonists for neuropsychiatric disorders and pave the way for their use in managing psychotic symptoms in neurodegenerative disorders such as dementia with Lewy bodies.

Exploring the impact of deleterious missense nonsynonymous single nucleotide polymorphisms in the DRD4 gene using computational approaches

Dopamine receptor D4 (DRD4) plays a vital role in regulating various physiological functions, including attention, impulse control, and sleep, as well as being associated with various neurological diseases, including attention deficit hyperactivity disorder, novelty seeking, and so on. However, a comprehensive analysis of harmful nonsynonymous single nucleotide polymorphisms (nsSNPs) of the DRD4 gene and their effects remains unexplored. The aim of this study is to uncover novel damaging missense nsSNPs and their structural and functional effects on the DRD4 receptor. From the dbSNP database, we found 677 nsSNPs, and then we analyzed their functional consequences, disease associations, and effects on protein stability with fifteen in silico tools. Five variants, including L65ICL1P (rs1459150721), V1163.33D (rs761875546), I1293.46S (rs751467198), I1564.46T (rs757732258), and F2015.47S (rs199609858), were identified as the most deleterious mutations that were also present in the conserved region and showed lower interactions with neighboring residues. To comprehensively understand their impact, we docked agonist dopamine and antagonist nemonapride at the binding site of the receptor, followed by 200 ns molecular dynamics simulations. We identified the V116D and I129S mutations as the most damaging, followed by F201S in the dopamine-bound states. Both the V116D and I129S variants demonstrated significantly high RMSD, Rg, and SASA, and low thermodynamic stability. The F201S-dopamine complex exhibited lower compactness and higher motions, along with a significant loss of hydrogen bonds and active site interactions. By contrast, while interacting with nemonapride, the impact of the I156T and L65P mutations was highly deleterious; both showed lower stability, higher flexibility, and higher motions. Additionally, nemonapride significantly lost interactions with the active site, notably in the I156T variant. We also found the V116D-nemonapride complex as structurally damaging; however, the interaction patterns of nemonapride were less altered in the MMPBSA analysis. Overall, this study revealed five novel deleterious variants along with a comprehensive understanding of their effect in the presence of an agonist and antagonist, which could be helpful for understanding disease susceptibility, precision medicine, and developing potential drugs.

Investigation of the Roles of the Adenosine A(2A) and Metabotropic Glutamate Receptor Type 5 (mGlu5) Receptors in Prepulse Inhibition and CREB Signaling in a Heritable Rodent Model of Psychosis

The metabotropic glutamate receptor type 5 (mGlu5) and adenosine A(2A) receptor form a mutually inhibitory heteromer with the dopamine D2 receptor, where the activation of either mGlu5 or A(2A) leads to reduced D2 signaling. This study investigated whether a mGlu5-positive allosteric modulator (PAM) or an A(2A) agonist treatment could mitigate sensorimotor gating deficits and alter cyclic AMP response element-binding protein (CREB) levels in a rodent neonatal quinpirole (NQ) model of psychosis. F0 Sprague–Dawley rats were treated with neonatal saline or quinpirole (1 mg/kg) from postnatal day 1 to 21 and bred to produce an F1 generation. F1 offspring underwent prepulse inhibition (PPI) testing from postnatal day 44 to 48 to assess sensorimotor gating. The rats were treated with mGlu5 PAM 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB) or A(2A) agonist CGS21680. Rats with at least one NQ-treated parent showed PPI deficits, which were alleviated by both CDPPB and CGS21680. Sex differences were noted across groups, with CGS21680 showing greater efficacy than CDPPB. Additionally, CREB levels were elevated in the nucleus accumbens (NAc), and both CDPPB and CGS21680 reduced CREB expression to control levels. These findings suggest that targeting the adenosinergic and glutamatergic systems alleviates sensorimotor gating deficits and abnormal CREB signaling, both of which are associated with psychosis.

Contribution of the dopaminergic system in toxoplasmic encephalitis neuroimmunopathogenesis.

Toxoplasma gondii (T. gondii), a parasitic intracellular protozoan, can establish a chronic infection in the host brain and cause significant neuropathology. The current study aimed to determine the role of Tyrosine Hydroxylase (TH), Dopamine Receptor D1 (D1R), Nuclear Receptor Related-1 (Nurr1), and Dopamine Transporter (DAT) expression in the neuroimmunopathogenesis of toxoplasmic encephalitis (TE) at 15, 30, 45, and 60 days after infection with T. gondii. Additionally, the study investigated whether there was a correlation between the markers on these critical days, which had yet to be explored. The results showed that TH expression in brain tissue of BALB/c mice was significantly increased in all infected groups compared with healthy controls (P<0.05). However, other striking findings of the study were that D1R, DAT, and Nurr1 expression were significantly decreased in all infected groups compared with healthy controls, in contrast to TH expression (P<0.05). Study findings regarding behavioral changes in chronic T. gondii-infected laboratory animals and humans with TE provide important evidence of the relationship between neuropsychiatric diseases and T. gondii infection. By elucidating the pathogenesis of the disease in detail, treatment protocols that consider these coordinated changes in expression that vary from day to day can be developed.

Nicotinic α7 receptors on cholinergic neurons in the striatum mediate cocaine-reinforcement, but not food reward.

The neurotransmitter acetylcholine has since long been implicated in reward learning and drug addiction. However, the role of specific cholinergic receptor subtypes on different neuronal populations remain elusive. Here, we studied the function of nicotinic acetylcholinergic alpha 7 receptors (α7 nAChRs) in cocaine and food-enforced behaviors. We found that global deletion of α7 nAChRs in mice attenuates cocaine seeking in a Pavlovian conditioned place preference paradigm and decreases operant responding to cocaine in a runway task and in self-administration, without influencing responding to palatable food. This effect can be attributed to alpha 7 receptor signaling in the striatum, as selective deletion of striatal α7 nAChRs using a viral vector approach resulted in a similar decrease in cocaine-preference as that of global deletion. To investigate which type of striatal neurons are responsible for this effect, we selectively targeted Cholinergic (ChAT-expressing) neurons and dopamine D1-receptor (D1R) expressing neurons. Mice with conditional deletion of α7 nAChRs in ChAT-neurons (α7 nAChR-ChATCre) exhibited decreased cocaine place preference and intact place preference for food, while α7 nAChR-D1RCre mice had no changes in reward learning to neither food nor cocaine. Cocaine induction of striatal immediate early gene expression of cFos, FosB, Arc and EGR2 was blocked in α7 nAChR-ChATCre mice, demonstrating the importance of α7 nAChRs on cholinergic neurons for striatal neuronal activity changes. Collectively, our findings show that α7 nAChRs on cholinergic interneurons in the striatum are pivotal for learning processes related to cocaine, but not food reward.

Zengye decoction regulated the expression of aquaporin in colon tissue of rats with constipation through miR-10a-5p targeting Drd2/AC/cAMP axis.

Slow transit constipation (STC) is a colonic motor disorder characterized by a marked delay in the movement of substances through the colon. Traditional Chinese medicine (TCM) is a treasure trove of natural compounds, which is effective in treating constipation with relatively minor side effects. Zengye decoction (ZYD), a classic herbal formula in TCM, is used for moistening the intestines and relieving constipation. However, the molecular mechanism of ZYD in the treatment of constipation remains unclear. The present study aimed to investigate the effect and molecular mechanism of ZYD on STC. A loperamide-induced rat model and IEC-18 cells were used in vitro and in vivo. We found that ZYD increased the intestinal transit rate and fecal water content of STC rats in a dose-dependent manner. Furthermore, ZYD dose-dependently decreased the expression of Aquaporin (AQP)3 and increased AQP9 expression in the colon tissue of STC rats. Mechanistically, ZYD reduced the level of miR-10a-5p, increased the expression of dopamine receptor D2 (Drd2), and inhibited the activity of adenylate cyclase (AC)/cyclic adenosine monophosphate (cAMP) signaling in the colon tissue of STC rats. However, miR-10a-5p overexpression reversed the improvement effect of ZYD on constipation. Moreover, miR-10a-5p targeted Drd2 and enhanced AC/cAMP signaling activation in IEC-18 cells. Also, miR-10a-5p regulated AQP3 and AQP9 expression in IEC-18 cells. Thus, ZYD alleviated constipation and aquaporin expression in STC rats, and its mechanism may be mediated by downregulating miR-10a-5p levels and inhibiting the Drd2/AC/cAMP axis. ZYD may be an efficient therapeutic strategy for constipation.

Mu opioid receptors expressed in striatal D2 medium spiny neurons have divergent contributions to cocaine and morphine reward.

While our understanding of the neurobiological mechanisms underlying cocaine and opiate reward has historically been dopamine-focused, evidence from genetic and pharmacological approaches indicates that µ-opioid receptors (MORs) in the striatum are important contributors. Within the striatum, MORs are expressed in both dopamine D1-receptor and D2-receptor expressing GABAergic medium spiny neurons (MSNs), as well as in interneurons and various afferents. Thus, it remains unclear how these distinct MOR populations regulate drug reward. To address this, we generated mice with a targeted deletion of MORs from dopamine D2 receptor-expressing MSNs (D2-MORKO) and tested the locomotor and conditioned rewarding effects of cocaine and morphine. D2-MORKO mice showed blunted acquisition of cocaine place preference and suppressed expression of preference when tested in the presence of cocaine. Conversely, the acute and sensitized locomotor responses to cocaine and morphine, as well as morphine conditioned place preference, were normal in D2-MORKOs. This indicates MORs expressed in D2-MSNs facilitate cocaine reward. Further, these data suggest these MORs play divergent roles in cocaine and morphine reward.

Molecular characterization of chicken DA systems reveals that the avian personality gene, DRD4, is expressed in the mitral cells of the olfactory bulb.

Animal personalities are stable, context-dependent behavioral differences. Associations between the personality of birds and polymorphisms in the dopamine receptor D4 (DRD4) gene have been repeatedly observed. In mammals, our understanding of the role of the dopamine (DA) system in higher cognitive functions and psychiatric disorders is improving, and we are beginning to understand the relationship between the neural circuits modulating the DA system and personality traits. However, to understand the phylogenetic continuity of the neural basis of personality, it is necessary to clarify the neural circuits that process personality in other animals and compare them with those in mammals. In birds, the DA system is anatomically and molecularly similar to that in mammals; however, the function of DRD4 remains largely unknown. In this study, we used chicks as model birds to reveal the expression regions of the DA neuron-related markers tyrosine hydroxylase (TH), dopa decarboxylase (DDC), dopamine β-hydroxylase (DBH), and DRD4, as well as other DRDs throughout the forebrain. We found that DRD4 was selectively expressed in the mitral cells of the olfactory bulb (OB). Furthermore, a detailed comparison of the expression regions of DA neurons and DRD4 in the OB revealed a cellular composition similar to that of mammals. Our findings suggest that the animal personality gene DRD4 is important for olfactory information processing in birds, providing a new basis for comparing candidate neural circuits for personality traits between birds and mammals.

Dedifferentiation of caudate functional organization is linked to reduced D1 dopamine receptor availability and poorer memory function in aging

Abstract Age-related alterations in cortico-striatal function have been highlighted as an important determinant of declines in flexible, higher-order, cognition in older age. However, the mechanisms underlying such alterations remain poorly understood. Computational accounts propose age-related dopaminergic decreases to impoverish neural gain control, possibly contributing to reduced specificity of cortico-striatal circuits, that are modulated by dopamine, in older age. Using multi-modal neuroimaging data (fMRI, PET) from a large lifespan cohort (n = 180), we assessed the relationship between dopamine D1-like receptors (D1DRs) and cortico-striatal function during rest and an n-back working memory task. The results revealed gradual age-related decreases in the specificity of functional coupling between the centrolateral caudate and cortical association networks during both rest and working memory, which in turn was associated with poorer short and long-term memory performance with older age. Critically, reduced D1DR availability in the caudate and the prefrontal cortex predicted less differentiated caudate-cortical coupling across the lifespan, in part accounting for the age-related declines observed on this metric. These findings provide novel empirical evidence for a key role of dopamine in maintaining functional specialization of cortico-striatal circuits as individuals age, bridging with computational models of deficient catecholaminergic neuromodulation underpinning age-related dedifferentiation of brain function.

Suppression of dopamine receptor 2 inhibits the formation of human prostate cancer PC‑3‑derived cancer stem cell‑like cells through AMPK inhibition.

Cancer stem cells (CSCs) contribute to the resistance of intractable prostate cancer, and dopamine receptor (DR)D2 antagonists exhibit anticancer activity against prostate cancer and CSCs. Human prostate cancer PC-3 cells were used to generate CSC-like cells, serving as a surrogate system to identify the specific DR subtype the inhibition of which significantly affects prostate-derived CSCs. Additionally, the present study aimed to determine the downstream signaling molecules of this DR subtype that exert more profound effects compared with other DR subtypes. The inhibitory effects of specific antagonists or small interfering (si)RNAs on DR subtypes were compared by analyzing morphological changes of cells, expression patterns of pluripotency markers, cell growth inhibitory activities and in vitro cell invasion. L-741,626, a specific DRD2 antagonist, induced morphological changes in PC-3-derived CSC-like cells, suppressed the expression of Oct4 (a pluripotency marker), and inhibited the growth of cells and tumors. The proliferation of heterozygous null PC-3 cells, generated using the CRISPR/Cas9 method, was slow, and their sphere-forming ability was substantially reduced, indicating a diminished capacity to produce CSCs. In addition, the phosphorylation of AMPK was suppressed by DRD2 siRNA and the heterozygous knockout of DRD2 in PC-3 cells, indicating that AMPK may be a putative downstream signaling molecule involved in the production and maintenance of PC-3-derived CSC-like cells. Specific inhibition or suppression of DRD2 caused PC-3-derived CSC-like cells to lose their properties and inhibited the formation of PC-3-derived CSC-like cells, followed by inhibition of the phosphorylation of AMPK, which is considered a putative downstream signaling molecule of DRD2. Further understanding of the mechanisms by which DRD2 regulates AMPK and the effects of AMPK inhibition on the properties of PC-3-derived CSC-like cells may provide valuable insights into the identification of molecular targets for treating intractable prostate cancer wherein AMPK is constitutively activated.