A novel perspective on the role of nucleus accumbens neurons in encoding associative learning.

The nucleus accumbens (NAc) has been considered a key brain region for encoding reward/aversion and cue-outcome associations. These processes are encoded by medium spiny neurons that express either dopamine receptor D1 (D1-MSNs) or D2 (D2-MSNs). Despite the well-established role of NAc neurons in encoding reward/aversion, the underlying processing by D1-/D2-MSNs remains largely unknown. Recent electrophysiological, optogenetic and calcium imaging studies provided insight on the complex role of D1- and D2-MSNs in these behaviours and helped to clarify their involvement in associative learning. Here, we critically discuss findings supporting an intricate and complementary role of NAc D1- and D2-MSNs in associative learning, emphasizing the need for additional studies in order to fully understand the role of these neurons in behaviour.

Dopamine relieves inflammatory responses through the D2 receptor after electroacupuncture at ST36 in a mouse model of chronic obstructive pulmonary disease.

OBJECTIVE: To detect the role of dopamine in the anti-inflammatory effect of electroacupuncture (EA) at ST36 in a mouse model of chronic obstructive pulmonary disease (COPD). METHODS: Twenty-eight male BALB/c mice were randomly divided into the control group, model group, sham EA (sham) group or ST36 EA (ST36) group in a 1:1:1:1 ratio (n = 7 each). The COPD mouse model was established through cigarette smoke (CS) exposure for 12 weeks. During the last 2 weeks, EA was applied at a sham point location or ST36 before CS exposure. Lung function, histopathological changes, inflammatory cell counts in bronchoalveolar lavage fluid (BALF), inflammatory cytokines in BALF, plasma, lung tissue homogenate (LTH), and plasma dopamine levels were detected in the different groups. Furthermore, the role of different dopamine receptors was explored through intraperitoneal injections of non-specific dopamine receptor antagonist chlorpromazine, specific dopamine D1 receptor antagonist SCH 23390 and specific dopamine D2 receptor antagonist eticlopride hydrochloride prior to ST36 EA and CS exposure. RESULTS: EA at ST36 improved lung function, alleviated lung and systemic inflammatory responses by reducing inflammatory cells and cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-8 and IL-1ß in BALF, plasma and lung tissue in this COPD mouse model. Plasma dopamine was greatly increased after EA at ST36, negatively correlated with lung histological lesions and inflammatory cytokine levels, and positively correlated with mice body weight and lung function indicators. Chlorpromazine and eticlopride hydrochloride inhibited the anti-inflammatory effect of EA at ST36, while SCH 23390 showed no neutralizing effect. CONCLUSION: EA at ST36 could alleviate inflammation in this mouse model of COPD through the dopamine D2 receptor pathway.

Decipher the inhibitory potential of phytocompounds from Leptadenia reticulata on dopamine D2 receptor to enhance prolactin secretion.

Dopamine is secreted by the hypothalamus, which inhibits the proliferation and effectiveness of lactotroph cells that release prolactin via dopamine D2 receptor (D2R). D2R activation inhibits lactotroph cell prolactin synthesis and regulates prolactin gene expression. Although, commercial medications are available for hypogalactia and agalactia, various plant sources significantly alleviate these problems. Leptadenia reticulata (Jivanti) is one of the important medicinal plants often consumed by nursing mothers to improve breast milk production. However, mechanism and chemical constituents involved in the inhibition of D2R by Jivanti is unclear. Therefore, in this study the phytocompounds reported from Jivanti were used for in-silico analysis to predict D2R inhibitory potential. The binding affinity value of campesterol and ß-sitosterol (- 10.1 and -10.0 kcal/mol) with D2R has high revealed by molecular docking and stable interaction reveled by molecular dynamics simulation. Thus, these lead compounds could exert more D2R inhibitory activity resulting into prolactin release, which may lead to an increase in breast milk production. Although all selected compounds had fine permeation, non-toxic, and non-carcinogenic characteristics predicted by ADMET, campesterol had good solubility, absorption characteristics compared to other. Therefore, Jivanti, which is traditionally known medicinal plant, could be explored as a medication candidate to boost breast milk production.

Use of a Bayesian Network Model to predict psychiatric illness in individuals with 'at risk mental states' from a general population cohort.

The 'at risk mental state' (ARMS) paradigm has been introduced in psychiatry to study prodromal phases of schizophrenia. With time it was seen that the ARMS state can also precede mental disorders other than schizophrenia, such as depression and anxiety. However, several problems hamper the paradigm's use in preventative medicine, such as varying transition rates across studies, the use of non-naturalistic samples, and the multifactorial nature of psychiatric disorders. To strengthen ARMS predictive power, there is a need for a holistic model incorporating-in an unbiased fashion-the small-effect factors that cause mental disorders. Bayesian networks, a probabilistic graphical model, was used in a populational cohort of 83 ARMS individuals to predict conversion to psychiatric illness. Nine predictors-including state, trait, biological and environmental factors-were inputted. Dopamine receptor 2 polymorphism, high private religiosity, and childhood trauma remained in the final model, which reached an 85.51% (SD = 0.1190) accuracy level in predicting conversion. This is the first time a robust model was produced with Bayesian networks to predict psychiatric illness among at risk individuals from the general population. This could be an important tool to strengthen predictive measures in psychiatry which should be replicated in larger samples to provide the model further learning.

Association between Polymorphism rs1799732 of DRD2 Dopamine Receptor Gene and Personality Traits among MMA Athletes.

Four factors-namely, harm avoidance, novelty seeking, reward addiction and persistence-represent the nature of temperament that is not genetically determined in itself. It was shown in earlier studies that a strong propensity to look for novelty or a tendency to engage in risky behavior is correlated with genetic variants in the area of the genes encoding dopamine receptors. Therefore, the aim of this study is to determine whether there is a relationship between personality traits and genetic variants in the area of the DRD2 dopamine receptor gene in MMA athletes. The participants consisted of 85 mixed martial arts (MMA) athletes and 284 healthy, non-MMA male participants. Their personality traits were measured using the Revised Temperament and Character Inventory. Blood was collected for genetic assays and all samples were genotyped using the real-time PCR method. We observed a statistically significant effect of a complex factor of the DRD2 rs1799732 genotype on MMA participants' control and reward dependence. Engaging in high-risk sport may be associated with several personality characteristics. The DRD2 rs1799732 polymorphism may be associated with reduced harm avoidance in martial arts athletes, thereby modulating athletes' predisposition to participate in high-risk sport.

Analysis of Selected Variants of DRD2 and ANKK1 Genes in Combat Athletes.

The level of physical activity is conditioned by many different factors, including, among others, the personality traits of a person. Important is the fact that personality traits are a moderately heritable factor and on the basis of the analysis of several genes, various lifetime outcomes can be predicted. One of the most important pathways influencing personality traits is connected to the dopaminergic system; hence, we decided to analyze the DRD2 PROM. rs1799732, DRD2 rs1076560, DRD2 Tag1D rs1800498, DRD2 Ex8 rs6276, DRD2Tag1B rs1079597 and ANKK1 Tag1A rs180049. The research group included 258 male athletes (mean age = 26.02; SD = 8.30), whereas the control group was 284 healthy male volunteers matched for age (mean age = 22.89; SD = 4.78), both of Caucasian origin and without history of substance dependency or psychosis. Genomic DNA was extracted from venous blood using standard procedures. Genotyping was conducted with the real-time PCR method. Differences in the frequency of the DRD2Tag1B rs1079597 gene polymorphism were found between people practicing combat sports and the control group, and the DRD2 PROM. rs1799732, DRD2 rs1076560, DRD2 Tag1D rs1800498, DRD2 Ex8 rs6276, DRD2Tag1B rs1079597 and ANKK1 Tag1A rs1800497 genotypes and allele frequencies in the studied sample did not differ between the analyzed groups. Hence, we considered these polymorphic places as an interesting area for the further search for unambiguous associations between personality traits and attitude towards physical effort.

Discovery of eight alkaloids with D1 and D2 antagonist activity in leaves of Nelumbo nucifera Gaertn. Using FLIPR assays.

ETHNOPHARMACOLOGICAL RELEVANCE: Dopamine receptors are long-standing primary targets in the treatment of mental diseases and there is growing evidence that suggests relationships between obesity and the dopamine system, especially dopamine D1 and D2 receptors. Leaves of Nelumbo nucifera Gaertn. (lotus leaves) have been medically used for helping long-term maintenance of weight loss. Whether and how components of lotus leaves function through the dopamine receptors remains unclear. AIM OF THE STUDY: This work aimed to discover dopamine receptor-active alkaloids isolated from the lotus leaves, to evaluate their potencies and to analyze their structure activity relationship. MATERIALS AND METHODS: Dried lotus leaves were prepared and total extract was divided into alkaloids and flavones. Eight alkaloids were separated and characterized by a combination of high-performance liquid chromatography, quadrupole time-of-flight mass spectrometry and nuclear magnetic resonance, and assayed by a fluorometric imaging plate reader platform. Human embryonic kidney 239 cell lines expressing dopamine D1, D2 and serotonin 2A (5-HT2A) receptors, respectively, were cultured and used in the assay. RESULTS: Alkaloids in the lotus leaves were the bioactive phytochemicals and inhibited dopamine from accessing the D1 and D2 receptors. All eight compounds functioned as D1-receptor antagonists and except N-nornuciferine, seven alkaloids functioned as D2-receptor antagonists. (S)-coclaurine and (R)-coclaurine are optical isomers and antagonized both D1 and D2 with equivalent potencies, suggesting that the optical rotation of the methylene linker in the monobenzyl isoquinoline backbone did not influence their activity. Among the eight alkaloids, O-nornuciferine was the potent antagonist to both receptors (the lowest IC50 values, D1: 2.09 ± 0.65 µM and D2: 1.14 ± 0.10 µM) while N-nornuciferine was found to be the least potent as it moderately antagonized D1 and was inactive on D2. O-nornuciferine was also a 5-HT2A antagonist (IC50~20 µM) while N-nornuciferine had no activity. These hinted the importance of a methyl group attached to the nitrogen atom in the aporphine backbone. Armepavine showed a nearly 10-fold selectivity to D2. CONCLUSIONS: In this work, eight alkaloids were isolated from the leaves of Nelumbo nucifera Gaertn. and assayed on the D1 and D2 receptors. They were D1/D2 antagonists with IC50 values in the mid- to low-micromolar range and O-nornuciferine was the most potent alkaloid among the eight. This family of alkaloids was biochemically evaluated on the dopamine receptors by the same platform for the first time.

Ninjin'yoeito, a traditional Japanese Kampo medicine, suppresses the onset of anhedonia induced by dysfunction in the striatal dopamine receptor type 2-expressing medium spiny neurons.

OBJECTIVE: Recent studies have suggested that ninjin'yoeito (NYT), a traditional Japanese Kampo medicine, improves diminished motivation in humans and animals, rendering it a novel therapeutic option for impaired motivation. To better characterize the effect of NYT on motivation, we examined its effect on motivated behaviors in mice. METHODS: Mouse models of neurodegeneration-related apathy, in which striatal dopamine receptor type 2-expressing medium spiny neurons (D2-MSNs) were progressively damaged by diphtheria toxin expression, were chosen. RESULTS: The decrease in effort-based operant responding for rewards (sucrose pellets), indicative of the mouse's motivated behavior, in the affected mice was not suppressed by chronic treatment with NYT suspended in drinking water at 1% (w/v). Mice were then subjected to a sucrose preference test, wherein they freely chose to ingest tap water and a sucrose solution without being required to exert effort. The affected mice showed a decline in preference for sucrose over tap water, relative to nonaffected controls, indicating anhedonia-like traits. In contrast to the diminished operant behavior, the anhedonic behavior in the affected mice was prevented by the NYT administration. Furthermore, NYT did not affect the size of Drd2 mRNA disappearance in the striatum of affected mice, suggesting that the NYT effect was unrelated to DTA-mediated neurodegeneration. CONCLUSION: These results demonstrate that the beneficial effect of NYT on motivation is mediated, at least in part, through the potentiation of hedonic capacity by certain neuromodulatory pathways.

Ursolic acid ameliorates stress and reactive oxygen species in C. elegans knockout mutants by the dopamine Dop1 and Dop3 receptors.

BACKGROUND: Depression and stress-related disorders are leading causes of death worldwide. Standard treatments elevating serotonin or noradrenaline levels are not sufficiently effective and cause adverse side effects. A connection between dopamine pathways and stress-related disorders has been suggested. Compounds derived from herbal medicine could be a promising alternative. We examined the neuroprotective effects of ursolic acid (UA) by focusing on dopamine signalling. METHODS: Trolox equivalent capacity assay was used to determine the antioxidant activities of UA in vitro. C. elegans N2 wildtype and dopamine receptor-knockout mutants (dop1-deficient RB665 and dop3-deficient LX703 strains) were used as in vivo models. H2DCFDA and acute juglone assays were applied to determine the antioxidant activity in dependency of dopamine pathways in vivo. Stress was assessed by heat and acute osmotic stress assays. The influence of UA on overall survival was analyzed by a life span assay. The dop1 and dop3 mRNA expression was determined by real time RT-PCR. We also examined the binding affinity of UA towards C. elegans Dop1 and Dop3 receptors as well as human dopamine receptors D1 and D3 by molecular docking. RESULTS: Antioxidant activity assays showed that UA exerts strong antioxidant activity. UA increased resistance towards oxidative, osmotic and heat stress. Additionally, UA increased life span of nematodes. Moreover, dop1 and dop3 gene expression was significantly enhanced upon UA treatment. Docking analysis revealed stronger binding affinity of UA to C. elegans and human dopamine receptors than the natural ligand, dopamine. Binding to Dop1 was stronger than to Dop3. CONCLUSION: UA reduced stress-dependent ROS generation and acted through Dop1 and to a lesser extent through Dop3 to reduce stress and prolong life span in C. elegans. These results indicate that UA could be a promising lead compound for the development of new antidepressant medications.

Pyridoxine induces glutathione synthesis via PKM2-mediated Nrf2 transactivation and confers neuroprotection.

Oxidative stress is a major pathogenic mechanism in Parkinson's disease (PD). As an important cellular antioxidant, glutathione (GSH) balances the production and incorporation of free radicals to protect neurons from oxidative damage. GSH level is decreased in the brains of PD patients. Hence, clarifying the molecular mechanism of GSH deficiency may help deepen our knowledge of PD pathogenesis. Here we report that the astrocytic dopamine D2 receptor (DRD2) regulates GSH synthesis via PKM2-mediated Nrf2 transactivation. In addition we find that pyridoxine can dimerize PKM2 to promote GSH biosynthesis. Further experiments show that pyridoxine supplementation increases the resistance of nigral dopaminergic neurons to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in wild-type mice as well as in astrocytic Drd2 conditional knockout mice. We conclude that dimerizing PKM2 may be a potential target for PD treatment.

Early weaning leads to disruption of homeostatic and hedonic eating behaviors and modulates serotonin (5HT) and dopamine (DA) systems in male adult rats.

Early weaning is associated with disruption of eating behavior. However, little is known about the mechanisms behind it. 5HT and DA systems are key regulators of homeostatic and hedonic eating behaviors, respectively. Thus, this study aims to evaluate the effects of early weaning on feeding behavior and 5HT and DA systems. For this, rats were submitted to regular (PND30) or early weaning (PND15) and between PND250 and PND300 were evaluated food intake of standard diet in response to 4 h food deprivation, during the 24 h period and per phase of the circadian cycle, in addition to the palatable food intake. Additionally, body mass and mRNA expression of 5HT1B, 5HT2C, SERT, DRD1 and DRD2 were evaluated in the hypothalamus and brainstem. The results demonstrate that early weaning promoted an increase in standard food intake in response to a 4 h food deprivation in the 24 h period and in the dark phase of the circadian cycle, in addition to an increased palatable food intake. No differences in body mass between regular or early weaning were observed. In the hypothalamus, increased mRNA expression of SERT and DRD1 was observed, but decreased 5HT1B mRNA expression. In the brainstem, the expression of 5HT1B, SERT, 5HT2C, DRD1 and DRD2 was increased in early weaned rats. In a nutshell, the stress promoted by early weaning has programmed the animals to be hyperphagic and to increase their palatable food intake, which was associated with modulation of 5HT and DA systems.

Personality Traits or Genetic Determinants-Which Strongly Influences E-Cigarette Users?

Presently, a growing popularity of electronic cigarettes may be observed. Used as a means of obtaining nicotine they allow to substitute traditional cigarettes. The origins of substance use disorders are conditioned by dopaminergic signaling which influences motivational processes being elementary factors conditioning the process of learning and exhibiting goal-directed behaviors. The study concentrated on analysis of three polymorphisms located in the dopamine receptor 2 (DRD2) gene-rs1076560, rs1799732 and rs1079597 using the PCR method, personality traits determined with the Big Five Questionnaire, and anxiety measured with the State Trait Anxiety Inventory. The study was conducted on a group of 394 volunteers, consisting e-cigarette users (n = 144) and controls (n = 250). Compared to the controls the case group subjects achieved significantly higher scores in regard to the STAI state and the trait scale, as well as the NEO-FFI Neuroticism and Openness scale. Likewise, in the case of the STAI state for DRD2 rs1076560 significant differences were found. Furthermore, while comparing the groups (e-cigarette users vs. controls) we noticed interactions for the NEO FFI Neuroticism and DRD2 rs1076560. The same was observed in the case of interactions significance while comparing groups (e-cigarette users vs. controls) for the STAI trait/scale and DRD2 rs1799732. Findings from this study demonstrate that psychological factors and genetic determinants should be analyzed simultaneously and comprehensively while considering groups of addicted patients. Since the use, and rapid increase in popularity, of electronic cigarettes has implications for public health, e-cigarette users should be studied holistically, especially younger groups of addicted and experimenting users.

Differential effects of D-cycloserine and amantadine on motor behavior and D2/3 receptor binding in the nigrostriatal and mesolimbic system of the adult rat.

D-cycloserine (DCS) and amantadine (AMA) act as partial NMDA receptor (R) agonist and antagonist, respectively. In the present study, we compared the effects of DCS and AMA on dopamine D2/3R binding in the brain of adult rats in relation to motor behavior. D2/3R binding was determined with small animal SPECT in baseline and after challenge with DCS (20 mg/kg) or AMA (40 mg/kg) with [123I]IBZM as radioligand. Immediately post-challenge, motor/exploratory behavior was assessed for 30 min in an open field. The regional binding potentials (ratios of the specifically bound compartments to the cerebellar reference region) were computed in baseline and post-challenge. DCS increased D2/3R binding in nucleus accumbens, substantia nigra/ventral tegmental area, thalamus, frontal, motor and parietal cortex as well as anterodorsal and posterior hippocampus, whereas AMA decreased D2/3R binding in nucleus accumbens, caudateputamen and thalamus. After DCS, ambulation and head-shoulder motility were decreased, while sitting was increased compared to vehicle and AMA. Moreover, DCS increased rearing relative to AMA. The regional elevations of D2/3R binding after DCS reflect a reduction of available dopamine throughout the mesolimbocortical system. In contrast, the reductions of D2/3R binding after AMA indicate increased dopamine in nucleus accumbens, caudateputamen and thalamus. Findings imply that, after DCS, nigrostriatal and mesolimbic dopamine levels are directly related to motor/exploratory activity, whereas an inverse relationship may be inferred for AMA.

Oral supplementation with ginseng polysaccharide promotes food intake in mice.

INTRODUCTION: Ginseng polysaccharide (GPS, same as Panax polysaccharide) is a kind of polysaccharide extracted from ginseng. It has been reported that GPS has the ability to activate innate immunity, regulates blood sugar balance, and improves antioxidant capacity, but the effect on feeding behavior and its mechanism remains unclear. METHOD: To investigate the possible effect of GPS on feeding behavior of animals, mice were supplied with GPS in water, and food intake, hedonic feeding behavior, anxiety-like behavior, expression of appetite-regulation peptides in the central nervous system and glucose-related hormone levels in the serum of mice were measured. RESULTS: Ginseng polysaccharide significantly increased the average daily food intake in mice and promoted hedonic eating behavior. Meanwhile, the levels of serum glucose and glucagon were significantly reduced by GPS, and GPS promoted hypothalamic neuropeptide Y expression, inhibited proopiomelanocortin (POMC) expression, and reduced dopamine D1 receptor (DRD1) levels in the midbrain. We also found that the anxiety level of mice was significantly lower after GPS intake. In conclusion, oral supplementation with GPS promoted food intake in mice, most likely through the regulation of circulating glucose levels.

Regulatory effects of Ningdong granule on dopaminergic and serotonergic neurotransmission in a rat model of Tourette syndrome assessed by PET.

Dysfunctions in dopamine (DA) and serotonin (5­HT) metabolism have been widely implicated in Tourette syndrome (TS); however, the exact nature of these dysfunctions remains unclear. The objective of the present study was to investigate the variation in DA and 5­HT metabolism in a rat model of TS, and to evaluate the therapeutic effect of Ningdong granule (NDG), a traditional Chinese medicine (TCM) preparation used specifically for the treatment of TS. Rats were treated with 3,3'­iminodipropionitrile for 7 days to induce the model of TS, and were then intragastrically administered NDG each day. After 8 weeks of treatment, micro­positron emission tomography was used to measure the binding of DA D2 receptors (D2Rs), DA transporters (DATs), 5­HT2A receptors (5­HT2ARs) and 5­HT transporters (SERTs) in brain regions of interest. The results indicated that NDG could significantly reduce the typical characteristics of TS in the rat model. Decreased D2R binding and increased DAT binding were detected in the striatum compared with the binding activities in untreated rats. The density of 5­HT2AR was also significantly increased in the striatum following NDG treatment; however, SERT levels were decreased in certain brain regions, including the striatum, cortex, nucleus accumbens and amygdala. Taken together, the current results demonstrated that NDG may be effective in treating patients with TS.

Hippocampal gene expression patterns in oxytocin male knockout mice are related to impaired social interaction.

Social interaction between animals is crucial for the survival and life in groups. It is well demonstrated that oxytocin (OT) and vasopressin (AVP) play critical roles in the regulation of social behaviors in mammals, however, other neurotransmitters and hormones are involved in the brain circuitry related to these behaviors. The present study aimed to investigate the gene expression of neurotransmitter receptors in the brain of OT knockout (OTKO) male mice. In this study, we evaluated the expression levels of the OT receptor (Oxtr), AVP receptors 1a and 1b (Avpr1a; Avpr1b), dopamine receptor 2 (Drd2), and the estrogen receptors alpha and beta (Esr1; Esr2) genes in the hippocampus (HPC), olfactory bulb (OB), hypothalamus (HPT) and prefrontal cortex (PFC). AVP gene (Avp) expression was analyzed in the HPT. Gene expression results were discussed regarding to social interaction and sexual behavior findings. Additionally, we analyzed the influence of OT absence on the Avp mRNA expression levels in the HPT. RNA extraction and cDNAs synthesis followed by quantitative polymerase chain reaction were performed for gene expression determination. Results were calculated with the 2-ΔΔCt method. Our main finding was that HPC is more susceptible to gene expression changes due to the lack of OT. OTKOs exhibited decreased expression of Drd2 and Avpr1b, but increased expression of Oxtr in the HPC. In the PFC, Esr2 was increased. In the HPT, there was a reduced Avp expression in the OTKO group. No differences were detected in the OB and HPT. Despite these changes in gene expression, sexual behavior was not affected. However, OTKO showed higher social investigation and lower aggressive performance than wild-type mice. Our data highlight the importance of OT for proper gene expression of neurotransmitter receptors related to the regulation of social interaction in male mice.

Dopamine receptor D2, but not D1, mediates descending dopaminergic pathway-produced analgesic effect in a trigeminal neuropathic pain mouse model.

Neuropathic pain represents a challenge to clinicians because it is resistant to commonly prescribed analgesics due to its largely unknown mechanisms. Here, we investigated a descending dopaminergic pathway-mediated modulation of trigeminal neuropathic pain. We performed chronic constriction injury of the infraorbital nerve from the maxillary branch of trigeminal nerve to induce trigeminal neuropathic pain in mice. Our retrograde tracing showed that the descending dopaminergic projection from hypothalamic A11 nucleus to spinal trigeminal nucleus caudalis is bilateral. Optogenetic/chemogenetic manipulation of dopamine receptors D1 and D2 in the spinal trigeminal nucleus caudalis produced opposite effects on the nerve injury-induced trigeminal neuropathic pain. Specific excitation of dopaminergic neurons in the A11 nucleus attenuated the trigeminal neuropathic pain through the activation of D2 receptors in the spinal trigeminal nucleus caudalis. Conversely, specific ablation of the A11 dopaminergic neurons exacerbated such pain. Our results suggest that the descending A11-spinal trigeminal nucleus caudalis dopaminergic projection is critical for the modulation of trigeminal neuropathic pain and could be manipulated to treat such pain.

Correlating blood-based DNA methylation markers and prostate cancer risk in African-American men.

The objective of this work was to investigate the clinical significance of promoter gene DNA methylation changes in whole blood from African-American (AA) men with prostate cancer (PCa). We used high throughput pyrosequencing analysis to quantify percentage DNA methylation levels in a panel of 8 genes (RARß2, TIMP3, SPARC, CDH13, HIN1, LINE1, CYB5R2 and DRD2) in blood DNA obtained from PCa and non-cancerous controls cases. Correlations of methylation status and various clinicopathological features were evaluated. Six genes tested achieved significant difference in DNA methylation levels between the PCa compared to control cases (P < 0.05). The TIMP3 loci demonstrated significant correlation of DNA methylation with age for all cases analyzed (p < 0.05). We observed an inverse correlation between CDH13 methylation (p = 0.045; r = -0.21) and serum vitamin D level whereas TIMP3 methylation (p = 0.021; r = -0.24) and DRD2 methylation (p = 0.056; r = -0.201) showed inverse correlation with supplementary vitamin D in the cancer cases. We also observed a direct correlation between methylation of RARß2 (p = 0.0036; r = 0.293) and SPARC (p = 0.0134; r = 0.20) loci with PSA level in the controls but not the cancer cases. In addition, alcohol cases significantly correlated with higher RARß2 methylation (p = 0.0314) in comparison with non-alcohol cases. Furthermore, we observed an inverse correlation of DRD2 methylation (p = 0.0349; r = -0.343) and Gleason score. Our data suggests that promoter methylation occurred more frequently in the blood of AA PCa and is associated with various clinicopathological features in AA men with PCa.

Persistent effects of obesity: a neuroplasticity hypothesis.

The obesity epidemic is a leading cause of health problems in the United States, increasing the risk of cardiovascular, endocrine, and psychiatric diseases. Although many people lose weight through changes in diet and lifestyle, keeping the weight off remains a challenge. Here, we discuss a hypothesis that seeks to explain why obesity is so persistent. There is a great degree of overlap in the circuits implicated in substance use disorder and obesity, and neural plasticity of these circuits in response to drugs of abuse is well documented. We hypothesize that obesity is also associated with neural plasticity in these circuits, and this may underlie persistent changes in behavior, energy balance, and body weight. Here, we discuss how obesity-associated reductions in motivation and physical activity may be rooted in neurophysiological alterations in these circuits. Such plasticity may alter how humans and animals use, expend, and store energy, even after weight loss.

Protective and restorative effects of the traditional Chinese medicine Jitai tablet against methamphetamine-induced dopaminergic neurotoxicity.

BACKGROUND: Methamphetamine (METH) is a psychostimulant with high abuse liability that affects the monoamine neurotransmitter systems, particularly the dopamine system. Currently there are no effective medications for the treatment of METH abuse to restore METH-induced dopaminergic dysfunction. The Jitai tablet (JTT), a commercial traditional Chinese medicinal preparation, has been shown to modulate the dopaminergic function both in heroin addicts and in morphine-dependent rats. The purpose of this study was to investigate, in a rodent model, whether JTT can protect against METH-induced neurotoxicity, and/or restore METH-damaged dopaminergic function. METHODS: Immunohistochemical staining and/or autoradiography staining were used to detect tyrosine hydroxylase (TH) expression in the substantia nigra, and to examine the levels of dopamine transporter (DAT), dopamine D2 receptor (D2R) and TH levels in the striatum. Using a stereotyped behavior rating scale, we evaluated the inhibitory effect of JTT on METH-induced behavioral sensitization. RESULTS: Repeated METH administration induced obvious stereotyped behavior and neurotoxicity on the dopaminergic system. Pre-treatment with JTT significantly attenuated METH-induced stereotyped responses, and interdicted METH-induced changes in the levels of DAT, D2R and TH expression. Treatment with JTT after METH administration restored DAT, D2R and TH expression to normal levels. CONCLUSIONS: Our results indicated that JTT protects against METH-induced neurotoxicity and restores the dopaminergic function, and thus might be a potential treatment for the dopaminergic deficits associated with METH abuse.