Olfactory regulation by dopamine and DRD2 receptor in the nose.

SignificanceDespite the identification of neural circuits and circulating hormones in olfactory regulation, the peripheral targets for olfactory modulation remain relatively unexplored. Here we show that dopamine D2 receptor (DRD2) is expressed in the cilia and somata of mature olfactory sensory neurons (OSNs), while nasal dopamine (DA) is mainly released from the sympathetic nerve terminals, which innervate the mouse olfactory mucosa (OM). We further demonstrate that DA-DRD2 signaling in the nose plays important roles in regulating olfactory function using genetic and pharmacological approaches. Moreover, the local DA synthesis in mouse OM is reduced during hunger, which contributes to starvation-induced olfactory enhancement. Altogether, we demonstrate that nasal DA and DRD2 receptor can serve as the potential peripheral targets for olfactory modulation.

Reorganization of dopamine circuitry in the anterior corpus callosum between early adolescence and adulthood in the mouse.

The maturation of forebrain dopamine circuitry occurs over multiple developmental periods, extending from early postnatal life until adulthood, with the precise timing of maturation defined by the target region. We recently demonstrated in the adult mouse brain that axon terminals arising from midbrain dopamine neurons innervate the anterior corpus callosum and that oligodendrocyte lineage cells in this white matter tract express dopamine receptor transcripts. Whether corpus callosal dopamine circuitry undergoes maturational changes between early adolescence and adulthood is unknown but may be relevant to understanding the dramatic micro- and macro-anatomical changes that occur in the corpus callosum of multiple species during early adolescence, including in the degree of myelination. Using quantitative neuroanatomy, we show that dopamine innervation in the forceps minor, but not the rostral genu, of the corpus callosum, is greater during early adolescence (P21) compared to adulthood (>P90) in wild-type mice. We further demonstrate with RNAscope that, as in the adult, Drd1 and Drd2 transcripts are expressed at higher levels in oligodendrocyte precursor cells (OPCs) and decline as these cells differentiate into oligodendrocytes. In addition, the number of OPCs that express Drd1 transcripts during early adolescence is double the number of those expressing the transcript during early adulthood. These data further implicate dopamine in axon myelination and myelin regulation. Moreover, because developmental (activity-independent) myelination peaks during early adolescence, with experience-dependent (activity-dependent) myelination greatest during early adulthood, our data suggest that potential roles of dopamine on callosal myelination shift between early adolescence and adulthood, from a developmental role to an experience-dependent role.

Dopamine D2 receptors in pyramidal neurons in the medial prefrontal cortex regulate social behavior.

Drugs acting on dopamine D2 receptors are widely used for the treatment of several neuropsychiatric disorders, including schizophrenia and depression. Social deficits are a core symptom of these disorders. Pharmacological manipulation of dopamine D2 receptors (Drd2), a Gi-coupled subtype of dopamine receptors, in the medial prefrontal cortex (mPFC) has shown that Drd2 is implicated in social behaviors. However, the type of neurons expressing Drd2 in the mPFC and the underlying circuit mechanism regulating social behaviors remain largely unknown. Here, we show that Drd2 were mainly expressed in pyramidal neurons in the mPFC and that the activation of the Gi-pathway in Drd2+ pyramidal neurons impaired social behavior in male mice. In contrast, the knockdown of D2R in pyramidal neurons in the mPFC enhanced social approach behaviors in male mice and selectively facilitated the activation of mPFC neurons projecting to the nucleus accumbens (NAc) during social interaction. Remarkably, optogenetic activation of mPFC-to-NAc-projecting neurons mimicked the effects of conditional D2R knockdown on social behaviors. Altogether, these results demonstrate a cell type-specific role for Drd2 in the mPFC in regulating social behavior, which may be mediated by the mPFC-to-NAc pathway.

DRD2 TaqIA polymorphism-related functional connectivity between anterior insula and dorsolateral prefrontal cortex predicts the retention time in heroin-dependent individuals under methadone maintenance treatment.

BACKGROUND: Dopamine receptor D2 (DRD2) TaqIA polymorphism has an influence on addiction treatment response and prognosis by mediating brain dopaminergic system efficacy. Insula is crucial for conscious urges to take drugs and maintain drug use. However, it remains unclear about the contribution of DRD2 TaqIA polymorphism to the regulation of insular on addiction behavioral and its relation with the therapeutic effect of methadone maintenance treatment (MMT). METHODS: 57 male former heroin dependents receiving stable MMT and 49 matched male healthy controls (HC) were enrolled. Salivary genotyping for DRD2 TaqA1 and A2 alleles, brain resting-state functional MRI scan and a 24-month follow-up for collecting illegal-drug-use information was conducted and followed by clustering of functional connectivity (FC) patterns of HC insula, insula subregion parcellation of MMT patients, comparing the whole brain FC maps between the A1 carriers and non-carriers and analyzing the correlation between the genotype-related FC of insula sub-regions with the retention time in MMT patients by Cox regression. RESULTS: Two insula subregions were identified: the anterior insula (AI) and the posterior insula (PI) subregion. The A1 carriers had a reduced FC between the left AI and the right dorsolateral prefrontal cortex (dlPFC) relative to no carriers. And this reduced FC was a poor prognostic factor for the retention time in MMT patients. CONCLUSION: DRD2 TaqIA polymorphism affects the retention time in heroin-dependent individuals under MMT by mediating the functional connectivity strength between left AI and right dlPFC, and the two brain regions are promising therapeutic targets for individualized treatment.

Potential Mechanism Linking Peer Relationships and Adolescent Prosocial Behavior: Mediation of Cognitive Empathy and Moderations of OXTR and DRD2.

Peers are important socializers of adolescent prosocial behavior. Still, the proximal cognitive and emotional process underlying this link and the sources of individual differences in sensitivity to peer influence have yet to be explored. Utilizing the gene-gene-environment (G × G × E) approach and multi-informant measurement, this study investigated how peer relationships operate to influence adolescent prosocial behavior by examining the mediating role of cognitive and emotional empathy, and the moderating role of the OXTR and DRD2 genes. The study utilized longitudinal data from a community sample of Chinese adolescents (N = 1080, Mage = 13.32 years at T1). Results showed that cognitive empathy rather than emotional empathy mediated the link between peer acceptance/rejection and prosocial behavior. Furthermore, the association among peer acceptance, cognitive empathy, and prosocial behavior was moderated by OXTR and DRD2. Specifically, adolescents with the combinations of AA/AA or G/G genotypes of OXTR/DRD2 benefited more from peer acceptance compared to their counterparts carrying other combined genotypes. The findings highlight cognitive empathy as a proximal process linking peer interaction to prosocial behavior and lend support to the interaction between oxytocinergic and dopaminergic systems on environmental sensitivity.

The molecular architecture of a complex social behavior: gregarious song.

The medial preoptic area (mPOA) regulates the probability and intensity of singing behavior in birds. Polzin and colleagues examined the molecular changes in the mPOA that were associated with gregarious song in European starlings (Sturnus vulgaris). High-throughput transcriptome analyses identified glutamate and dopamine pathways were highly enriched with gregarious song.

Rasd2 Mediates Acute Fasting-Induced Antidepressant-Like Effects via Dopamine D2 Receptor Activation in Ovariectomized Mice.

BACKGROUND: Previous studies have shown that estrogen and acute fasting for 9 hours have antidepressant-like effects by reducing immobility time in the forced swimming test. Estrogen and acute fasting share a common regulatory gene, Rasd2. RASD2 regulates dopamine D2 receptor (DRD2) transmission, but the role of Rasd2 in the DRD2-mediated antidepressant-like effect of acute fasting has not been examined. METHODS: In this study, open field test, forced swimming test, tail suspension test and sucrose preference test were used for behavioral assessments. RNA-seq, western blot, enzyme-linked immunosorbent assay, and co-immunoprecipitation were used to explore the role of Rasd2 in a depression model induced by ovariectomy and the antidepressant-like effects of 9-hour fasting. RESULTS: The RNA seq results showed that acute fasting induced a significant change in Rasd2 gene expression. Depression-like behaviors induced by ovariectomy were associated with decreased RASD2 and DRD2 protein levels in the hippocampus, and Rasd2 overexpression in the hippocampus alleviated depression-like behaviors and increased DRD2 expression. Nine-hour fasting had antidepressant-like effects in ovariectomized mice by upregulating the protein levels of RASD2, DRD2, CREB-BDNF, Akt, and estrogen receptor beta, and these effects can be blocked by DRD2 antagonists. CONCLUSIONS: Our results suggest that Rasd2 and DRD2 play pivotal roles in depression-like behavior induced by ovariectomy. Rasd2 regulates DRD2-mediated antidepressant-like effects of acute fasting in ovariectomized mice. Rasd2 can therefore be postulated to be a potential therapeutic target for depression and perhaps also a potential predictive marker for depression.

Progressive Degeneration and Adaptive Excitability in Dopamine D1 and D2 Receptor-Expressing Striatal Neurons Exposed to HIV-1 Tat and Morphine.

The striatum is especially vulnerable to HIV-1 infection, with medium spiny neurons (MSNs) exhibiting marked synaptodendritic damage that can be exacerbated by opioid use disorder. Despite known structural defects in MSNs co-exposed to HIV-1 Tat and opioids, the pathophysiological sequelae of sustained HIV-1 exposure and acute comorbid effects of opioids on dopamine D1 and D2 receptor-expressing (D1 and D2) MSNs are unknown. To address this question, Drd1-tdTomato- or Drd2-eGFP-expressing reporter and conditional HIV-1 Tat transgenic mice were interbred. MSNs in ex vivo slices from male mice were assessed by whole-cell patch-clamp electrophysiology and filled with biocytin to explore the functional and structural effects of progressive Tat and acute morphine exposure. Although the excitability of both D1 and D2 MSNs increased following 48 h of Tat exposure, D1 MSN firing rates decreased below control (Tat-) levels following 2 weeks and 1 month of Tat exposure but returned to control levels after 2 months. D2 neurons continued to display Tat-dependent increases in excitability at 2 weeks, but also returned to control levels following 1 and 2 months of Tat induction. Acute morphine exposure increased D1 MSN excitability irrespective of the duration of Tat exposure, while D2 MSNs were variably affected. That D1 and D2 MSN excitability would return to control levels was unexpected since both subpopulations displayed significant synaptodendritic degeneration and pathologic phospho-tau-Thr205 accumulation following 2 months of Tat induction. Thus, despite frank morphologic damage, D1 and D2 MSNs uniquely adapt to sustained Tat and acute morphine insults.

Dopamine receptors D1 and D2 show prognostic significance and potential therapeutic applications for endometrial cancer patients.

OBJECTIVE: Catecholaminergic signaling has been a target for therapy in different type of cancers. In this work, we characterized the ADRß2, DRD1 and DRD2 expression in healthy tissue and endometrial tumors to evaluate their prognostic significance in endometrial cancer (EC), unraveling their possible application as an antitumor therapy. METHODS: 109 EC patients were included. The expression of the ADRß2, DRD1 and DRD2 proteins was evaluated by immunohistochemistry and univariate and multivariate analysis to assess their association with clinic-pathological and outcome variables. Finally, HEC1A and AN3CA EC cell lines were exposed to different concentrations of selective dopaminergic agents alone or in combination to study their effects on cellular viability. RESULTS: ADRß2 protein expression was not associated with clinico-pathological parameters or prognosis. DRD1 protein expression was reduced in tumors samples but showed a significant inverse association with tumor size and stage. DRD2 protein expression was significantly associated with non-endometrioid EC, high grade tumors, tumor size, worse disease-free survival (HR = 3.47 (95%CI:1.35-8.88)) and overall survival (HR = 2.98 (95%CI:1.40-6.34)). The DRD1 agonist fenoldopam showed a reduction of cellular viability in HEC1A and AN3CA cells. The exposure to domperidone, a DRD2 antagonist, significantly reduced cell viability compared to the control. Finally, DRD1 agonism and DRD2 antagonism combination induced a significant reduction in cell viability of the AN3CA cells compared to monotherapy, close to being an additive response than a synergistic effect (CI of 1.1 at 0.5% Fa). CONCLUSION: DRD1 and DRD2 expression levels showed a significant association with clinico-pathological parameters. Both the combined activation of DRD1 and blockage of DRD2 may form an innovative strategy to inhibit tumor growth in EC.

Association of DRD2, DRD4 and COMT genes variants and their gene-gene interactions with antipsychotic treatment response in patients with schizophrenia.

Antipsychotic drugs are the first line of treatment in schizophrenia; although antipsychotic responses indicate a wide interindividual variety in patients with schizophrenia. This study aimed to investigate the association between four polymorphisms in DRD2, DRD4 and COMT genes and their gene-gene interactions with antipsychotic treatment response in patients with schizophrenia. A total of 101 patients with schizophrenia were recruited and stratified in treatment responder and treatment resistant groups based on the published criteria of resistant to treatment using PANSS. Clinical and demographic factors were analyzed. Genomic DNA was extracted from whole blood and genotyping for the four polymorphisms were done by ARMS-PCR, PCR-RFLP and gap-PCR. Gene-gene interactions were analyzed by logistic regression. In case of DRD2 A-241G, G allele was significantly associated with resistant to treatment. Regarding DRD4 120-bp duplication, 240/240 genotype was significantly associated with resistant to treatment comparing to other genotypes in a dominant model. The genotype combination of DRD4 240/240 and COMT Val/Val was significantly associated with treatment resistant. Among DRD2 AA genotype, COMT met allele carriers which also had a 120 bp allele of DRD4 had a significantly better response to antipsychotics. Moreover, analysis of clinical and demographic factors demonstrated a significantly longer duration of hospitalization and higher chlorpromazine-equivalent daily dose in resistant to treatment patients. Discovering the polymorphisms which effect treatment response to antipsychotics will provide the possibility of genetic screening before starting an antipsychotic treatment which enhances the chance of responding to antipsychotics and decreases drugs side effects and costs.

Associated and intermediate factors between genetic variants of the dopaminergic D2 receptor gene and harmful alcohol use in young adults.

Dopamine receptor D2 (DRD2) and ankyrin repeat and kinase domain-containing protein 1 (ANKK1) genes have received considerable attention for their involvement in alcohol use disorder (AUD), but many questions remain on their exact role. We conducted a population-based case-control and genetic association study in a large sample of young adults. Our aim was to assess the association between DRD2 and ANKK1 single nucleotide polymorphisms (SNPs) and harmful alcohol use, disentangling associated and possible intermediate factors. A total of 1841 college students from the French region Champagne-Ardennes, aged between 18 and 21 years and who reported at least one lifetime alcohol consumption, were included in this study. Allele frequencies were analysed according to harmful alcohol use (assessed through the Alcohol Use Disorder Identification Test [AUDIT] questionnaire). Different substance use disorders, including nicotine and cannabis dependences, were also assessed through questionnaires, as was a list of potential associated factors (e.g., major depressive episode, conduct disorder, attention-deficit/hyperactivity disorder [ADHD], school failure, sugar consumption, sexual trauma, parents' use of alcohol, tobacco or cannabis). We found that DRD2 rs1800498 was associated with harmful alcohol use. Many factors were detected, but a global path analysis revealed that DRD2 rs1800498 had a significant direct effect on harmful alcohol use and that early age at first alcohol consumption and depressive symptoms moderated this effect. This study suggests an interplay between harmful alcohol use, DRD2 genotypes and other risk factors that, with a full understanding, could be useful for preventive purposes.

Clinical and genetic factors associated with post-operative nausea and vomiting after propofol anaesthesia.

BACKGROUND: The incidence of post-operative nausea and vomiting (PONV) remains at about 30% despite all therapeutic efforts to reduce it. The clinical risk factors guiding the prophylactic treatment are well established, but genetic factors associated with PONV remain poorly known. The aim of this study was to explore clinical and genetic factors impacting PONV by performing a genome-wide association study (GWAS) together with relevant clinical factors as covariates, and systematically attempt to replicate previously reported PONV associations. Relevant clinical factors are explored with logistic regression model. METHODS: This was an observational case control study in Helsinki University Hospital between 1 August 2006 and 31 December 2010. One thousand consenting women with elevated risk for PONV, undergoing breast cancer surgery with standardised propofol anaesthesia and antiemetics. After exclusions for clinical reasons and failed genotyping, 815 patients were included with 187 PONV cases and 628 controls. Emergence of PONV up to 7th post-operative day was recorded. PONV at 2-24 h after surgery was selected to be the primary outcome. The GWAS explored associations between PONV and 653 034 genetic variants. Replication attempts included 31 variants in 16 genes. RESULTS: The overall incidence of PONV up to 7th post-operative day was 35%, where 3% had PONV at 0-2 h and 23% at 2-24 h after surgery. Age, American Society of Anaesthesiologists status, the amount of oxycodone used in the post-anaesthesia care unit, smoking status, previous PONV, and history of motion sickness were statistically significant predictive factors in the logistic model. The receiver operating characteristic-area under the curve of 0.75 (95% CI 0.71-0.79) was calculated for the model. The GWAS identified six variants with suggestive association to PONV (p < 1 × 10-5 ). Of the previously reported variants, association with the DRD2 variant rs18004972 (TaqIA) was replicated (p = .028). CONCLUSIONS: Our GWAS approach did not identify any high-impact PONV susceptibility variants. The results provide some support for a role of dopamine D2 receptors in PONV.

Genetic Contributors to PTSD: the Role of SNVs, Gene Interactions and Haplotypes for Developing PTSD Prevention Measures. A Comprehensive Review.

BACKGROUND: Post-traumatic stress disorder (PTSD) is a trauma- or stressor-related mental health condition with high socioeconomic burden. We aimed in this review to identify promising genetic markers predisposing for PTSD, which might serve in the design subsequent studies aiming to develop PTSD prevention and remediation measures. SUBJECTS AND METHODS: Our search queries in the PubMed database yielded 547 articles, of which 20 met our inclusion criteria for further analysis: published between 2018 and 2022, original research, containing molecular-genetic and statistical data, containing diagnosis verification methods, PTSD as a primary condition, and a sample of at least 60 patients. RESULTS: Among the 20 analyzed studies were reports of significant associations between PTSD and: FKBP5 variants rs9470080, regardless of the C or T allele; two FKBP5 haplotypes (A-G-C-C and A-G-C-T); gene-gene DRDхANNK1-COMT (rs1800497 × rs6269) and OXTR-DRD2 (rs2268498 × rs1801028); C-allele of CRHR1 (rs1724402). Other findings, such as the association of FKBP5 haplotypes (A-G-C-C, A-G-C-T) and the FKBP5-CRHR1 genotype, were of lesser statistical significance and less extensively studied. CONCLUSIONS: Although our literature analysis implicates certain genetic factors in PTSD, our understanding of the polygenic nature underlying the disorder remains limited, especially considering the hitherto underexplored epigenetic mechanisms. Future research endeavors should prioritize exploring these aspects to provide a more nuanced understanding of PTSD and its genetic underpinnings.

ß-Arrestin2-biased Drd2 agonist UNC9995 alleviates astrocyte inflammatory injury via interaction between ß-arrestin2 and STAT3 in mouse model of depression.

BACKGROUND: Major depressive disorder (MDD) is a prevalent and devastating psychiatric illness. Unfortunately, the current therapeutic practice, generally depending on the serotonergic system for drug treatment is unsatisfactory and shows intractable side effects. Multiple evidence suggests that dopamine (DA) and dopaminergic signals associated with neuroinflammation are highly involved in the pathophysiology of depression as well as in the mechanism of antidepressant drugs, which is still in the early stage of study and well worthy of investigation. METHODS: We established two chronic stress models, including chronic unpredictable mild stress (CUMS), and chronic social defeat stress (CSDS), to complementarily recapitulate depression-like behaviors. Then, hippocampal tissues were used to detect inflammation-related molecules and signaling pathways. Pathological changes in depressive mouse hippocampal astrocytes were examined by RNA sequencing. After confirming the dopamine receptor 2 (Drd2)/ß-arrestin2 signaling changes in the depressive mice brain, we then established the depressive mouse model using the ß-arrestin2 knockout mice or administrating the ß-arrestin2-biased Drd2 agonist to investigate the roles. Label-free mass spectrometry was used to identify the ß-arrestin2-binding proteins as the underlying mechanisms. We modeled neuroinflammation with interleukin-6 (IL-6) and corticosterone treatment and characterized astrocytes using multiple methods including cell viability assay, flow cytometry, and confocal immunofluorescence. RESULTS: Drd2-biased ß-arrestin2 pathway is significantly changed in the progression of depression, and genetic deletion of ß-arrestin2 aggravates neuroinflammation and depressive-like phenotypes. Mechanistically, astrocytic ß-arrestin2 retains STAT3 in the cytoplasm by structural combination with STAT3, therefore, inhibiting the JAK-STAT3 pathway-mediated inflammatory activation. Furtherly, pharmacological activation of Drd2/ß-arrestin2 pathway by UNC9995 abolishes the inflammation-induced loss of astrocytes and ameliorates depressive-like behaviors in mouse model for depression. CONCLUSIONS: Drd2/ß-arrestin2 pathway is a potential therapeutic target for depression and ß-arrestin2-biased Drd2 agonist UNC9995 is identified as a potential anti-depressant strategy for preventing astrocytic dysfunctions and relieving neuropathological manifestations in mouse model for depression, which provides insights for the therapy of depression.

Fatigue in breast cancer patients on chemotherapy: a cross-sectional study exploring clinical, biological, and genetic factors.

BACKGROUND: Cancer-related fatigue (CRF) is one of the most common and distressing complaints reported by cancer patients during chemotherapy considerably impacting all aspects of a patient's life (physical, psychosocial, professional, and socioeconomic). The aim of this study was to assess the severity of cancer-related fatigue in a group of breast cancer patients undergoing chemotherapy and explore the association between fatigue scores and sociodemographic, clinical, biological, psychiatric, and genetic factors. METHODS: A cross-sectional pilot study carried out at the oncology outpatient unit of Hôtel-Dieu de France University Hospital recruited 67 breast cancer patients undergoing chemotherapy between November 2017 and June 2019 to evaluate fatigue using the EORTC QLQ-C30 scale (European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire). Genotyping for seven gene polymorphisms (COMT, DRD2, OPRM1, CLOCK, PER2, CRY2, ABCB1) was performed using the Lightcycler® (Roche). RESULTS: The prevalence of fatigue was 46.3%. Multivariable analysis taking the fatigue score as the dependent variable showed that a higher number of cycles and a lower hemoglobin level were significantly associated with higher odds of exhibiting fatigue. Moreover, having at least one C allele for DRD2 SNP (vs. TT) was significantly associated with a 4.09 higher odds of expressing fatigue compared to TT patients. Finally, patients with at least one C allele for CLOCK SNP tended to display higher fatigue levels than TT patients. CONCLUSIONS: Our study showed that anemic breast cancer patients with a high number of chemotherapy cycles and those carrying at least one C allele for DRD2 and CLOCK SNPs are at greater risk of exhibiting fatigue. Since no previous research has reported such genetic results, future studies are necessary to confirm our findings.

The behavioral neuroendocrinology of dopamine systems in differently reared juvenile male rhesus monkeys (Macaca mulatta).

Dopamine (DA) is a critical neuromodulator of behavior. With propensities for addiction, hyper-activity, cognitive impairment, aggression, and social subordinance, monkeys enduring early maternal deprivation evoke human disorders involving dopaminergic dysfunction. To examine whether DA system alterations shape the behavioral correlates of adverse rearing, male monkeys (Macaca mulatta) were either mother-reared (MR: N = 6), or separated from their mothers at birth and nursery-reared (NR: N = 6). Behavior was assessed during 20-minute observations of subjects interacting with same- or differently-reared peers. Cerebrospinal fluid (CSF) biogenic amines, and serum testosterone (T), cortisol (CORT), and prolactin (PRL) were collected before and after pharmacologic challenge with saline or the DA receptor-2 (DRD2) antagonist Raclopride (RAC). Neuropeptide correlations observed in MR were non-existent in NR monkeys. Compared to MR, NR showed reduced DA tone; higher basal serum T; and lower CSF serotonin (5-HT). RAC increased PRL, T and CORT, but the magnitude of responses varied as a function of rearing. Levels of PRL significantly increased following RAC in MR, but not NR. Elevations in T following RAC were only significant among MR. Contrastingly, the net change (RAC CORT - saline CORT) in CORT was greater in NR than MR. Finally, observations conducted during the juvenile phase in a novel play-arena revealed more aggressive, self-injurious, and repetitive behaviors, which negatively correlated with indexes of dopaminergic tone in NR monkeys. In conclusion, early maternal deprivation alters brain DA systems, and thus may be associated with characteristic cognitive, social, and addiction outcomes.

Salvianolic acid A relieves cognitive disorder after chronic cerebral ischemia: Involvement of Drd2/Cryab/NF-κB pathway.

Chronic cerebral ischemia (CCI) refers to long-term hypoperfusion of cerebral blood flow with the main clinical manifestations of progressive cognitive impairment. The pathological mechanism of CCI is complex, and there is a lack of effective treatments. Salvianolic acid A (SalA) is a neuroprotective extract of Salvia miltiorrhiza with the effects of anti-inflammation and anti-apoptosis. In this study, the effect of SalA on cognitive function and Drd2/Cryab/NF-κB signaling pathway in rats with CCI was investigated. Morris water maze and open field test were used to observe the effects of SalA on the cognitive function of CCI rats. The pathological changes in the brain were observed by HE, Nissl, and LFB staining. TUNEL staining, enzyme-linked immunosorbent assay, and western blot analysis were used to detect the inflammatory and apoptosis in the cortex and hippocampus. The expression of Drd2/Cryab/NF-κB pathway-related molecules and Drd2 localization were detected by western blotting and dual immunofluorescence, respectively. SH-SY5Y cells were exposed to chronic hypoglycemic and hypoxic injury in vitro, and Drd2 inhibitor haloperidol was used to verify the involved pathway. The results showed that SalA could improve the cognitive function of CCI rats, reduce pathological damage of cortex and hippocampus, inhibit neuroinflammation and apoptosis, and suppress the activation of NF-κB by regulating Drd2/Cryab pathway. And SalA inhibited NF-κB activation and nuclear translocation in SH-SY5Y cells by upregulating Drd2/Cryab pathway, which was reversed by haloperidol interference. In conclusion, SalA could relieve CCI-induced cognitive impairment in rats, at least partly through the Drd2/Cryab/NF-κB pathway.

Dopamine D2R is Required for Hippocampal-dependent Memory and Plasticity at the CA3-CA1 Synapse.

Dopamine receptors play an important role in motivational, emotional, and motor responses. In addition, growing evidence suggests a key role of hippocampal dopamine receptors in learning and memory. It is well known that associative learning and synaptic plasticity of CA3-CA1 requires the dopamine D1 receptor (D1R). However, the specific role of the dopamine D2 receptor (D2R) on memory-related neuroplasticity processes is still undefined. Here, by using two models of D2R loss, D2R knockout mice (Drd2-/-) and mice with intrahippocampal injections of Drd2-small interfering RNA (Drd2-siRNA), we aimed to investigate how D2R is involved in learning and memory as well as in long-term potentiation of the hippocampus. Our studies revealed that the genetic inactivation of D2R impaired the spatial memory, associative learning, and the classical conditioning of eyelid responses. Similarly, deletion of D2R reduced the activity-dependent synaptic plasticity in the hippocampal CA1-CA3 synapse. Our results demonstrate the first direct evidence that D2R is essential in behaving mice for trace eye blink conditioning and associated changes in hippocampal synaptic strength. Taken together, these results indicate a key role of D2R in regulating hippocampal plasticity changes and, in consequence, acquisition and consolidation of spatial and associative forms of memory.

Association between DRD2/ANKK1 TaqIA Allele Status and Striatal Dopamine D2/3 Receptor Availability in Alcohol Use Disorder.

BACKGROUND: The association between blunted dopaminergic neurotransmission and alcohol use disorder (AUD) is well-known. In particular, the impairment of postsynaptic dopamine 2 and 3 receptors (DRD2/3) in the ventral and dorsal striatum during the development and maintenance of alcohol addiction has been investigated in several positron emission tomography (PET) studies. However, it is unclear whether these changes are the result of adaptation or genetic predisposition. METHODS: Here we investigated the association between DRD2/ankyrin repeat and kinase domain-containing 1 (ANKK1) TaqIA allele (rs1800497) status and striatal DRD2/3 availability measured by 18F-fallypride PET in 12 AUD patients and 17 sex-matched healthy controls. Age and smoking status were included as covariates. RESULTS: Contrary to our expectations, TaqIA allele status was not associated with striatal DRD2/3 availability in either group and there was no significant difference between groups, possibly due to the relatively small sample size (N = 29). CONCLUSIONS: Nonetheless, this is the first in vivo study investigating the relationship between dopamine receptor availability and genetic factors in AUD. The pitfalls of assessing such relationships in a relatively small sample are discussed. CLINICAL TRIAL REGISTRATION: The published analysis is an additional, post hoc analysis to the preregistered trial with clinical trial number NCT01679145 available on https://clinical-trials.gov/ct2/show/NCT01679145.

A Randomized, Sham-Controlled Trial of Repetitive Transcranial Magnetic Stimulation Targeting M1 and S2 in Central Poststroke Pain: A Pilot Trial.

OBJECTIVES: Central poststroke pain (CPSP), a neuropathic pain condition, is difficult to treat. Repetitive transcranial magnetic stimulation (rTMS) targeted to the primary motor cortex (M1) can alleviate the condition, but not all patients respond. We aimed to assess a promising alternative rTMS target, the secondary somatosensory cortex (S2), for CPSP treatment. MATERIALS AND METHODS: This prospective, randomized, double-blind, sham-controlled three-arm crossover trial assessed navigated rTMS (nrTMS) targeted to M1 and S2 (10 sessions, 5050 pulses per session at 10 Hz). Participants were evaluated for pain, depression, anxiety, health-related quality of life, upper limb function, and three plasticity-related gene polymorphisms including Dopamine D2 Receptor (DRD2). We monitored pain intensity and interference before and during stimulations and at one month. A conditioned pain modulation test was performed using the cold pressor test. This assessed the efficacy of the descending inhibitory system, which may transmit TMS effects in pain control. RESULTS: We prescreened 73 patients, screened 29, and included 21, of whom 17 completed the trial. NrTMS targeted to S2 resulted in long-term (from baseline to one-month follow-up) pain intensity reduction of ≥30% in 18% (3/17) of participants. All stimulations showed a short-term effect on pain (17-20% pain relief), with no difference between M1, S2, or sham stimulations, indicating a strong placebo effect. Only nrTMS targeted to S2 resulted in a significant long-term pain intensity reduction (15% pain relief). The cold pressor test reduced CPSP pain intensity significantly (p = 0.001), indicating functioning descending inhibitory controls. The homozygous DRD2 T/T genotype is associated with the M1 stimulation response. CONCLUSIONS: S2 is a promising nrTMS target in the treatment of CPSP. The DRD2 T/T genotype might be a biomarker for M1 nrTMS response, but this needs confirmation from a larger study.