Lower Dopamine Levels Research Articles

Alkaloid Fraction of Alstonia Boonei Stem Bark Demonstrate Antiobesity Potential on High Fat Diet Induced Obesity in Male Sprague‐Dawley Rats

The aim of this study was to investigate the anti‐obesity potential of alkaloid fraction of Alstonia boonei stem bark on high fat diet (HFD) induced obesity in male Sprague‐dawley rats.Preparation of neutral alkaloid fraction (NAF) was done through solvent partitioning of the methanol extract of Alstonia boonei stem bark, and NAF was subjected to LCMS‐MS analysis. To induce obesity, rats were fed with HFD (60% fat content) for 12 weeks preceding oral treatment with 125 and 250 mg/kg body weight of NAF for 4 weeks. Experimental procedures involving rats followed the European Community guidelines (EEC Directive of 1986; 86/609/EEC) for animal use.The major compounds found in NAF includes: Ajmalicine, 16‐Methoxy‐2,3‐dihydro‐3‐hydroxytabersonine, Vincamine, Aspidofractine, 3‐Hydroxyquinidine, 16‐Methoxytabersonine, Mitraphylline, 18‐Hydroxyyohimbine and Catharanthine. NAF significantly (p < 0.05) decreased body weight, white adipose tissue, triglycerides, total cholesterol, low density lipoprotein cholesterol, very low density lipoprotein cholesterol, leptin, insulin and dopamine levels, but increased significantly (p < 0.05) the high density lipoprotein cholesterol, cortisol, serotonin and noradrenaline levels in the treated groups compared to HFD control. However, there were no significant (p > 0.05) changes in food intake, blood glucose, thyroxine, triiodothyronine and thyroid stimulating hormone levels in animals given NAF when compared to HFD control. The photomicrograph of liver of the rats treated with NAF showed slight fat changes unlike that of the HFD obese controls which showed presence of numerous prominent fat deposits on the livers.The findings in this study suggests that the alkaloid fraction of A. boonei possess antiobesity properties as indicated in improved lipid profile, leptin sensitivity, and decreased body weight of animals.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Understanding of Burning Mouth Syndrome Based on Psychological Aspects.

Burning mouth syndrome (BMS) is a chronic pain condition characterised by a persistent burning sensation in clinically normal oral mucosa. BMS most commonly occurs in middleaged and elderly women. Various local and systemic factors can cause oral burning symptoms. When all possible local and systemic factors are excluded, burning mouth symptoms can be diagnosed as BMS. Psychophysical tests and histopathological data suggest the involvement of peripheral and central neuropathic mechanisms in BMS etiopathogenesis. Psychological problems are frequently observed in BMS patients. Several mechanisms, including increased parafunctional habits, steroid dysregulation, central disinhibition due to taste dysfunction, and low dopamine levels in the brain, have been proposed as an explanation for the role of psychological factors in BMS pathophysiology. However, the causal relationship between BMS and psychological problems remains controversial. Given the neuropathic nature of BMS, treatment for it is similar to other neuropathic pain conditions. Although various treatment modalities, including pharmacological intervention, behavioural therapy and psychotherapy, have been proposed, there is no definitive treatment always effective for the majority of BMS patients. In conclusion, for better understanding of the relationship between BMS and psychological factors, well-designed prospective studies are needed. In addition, the evaluation and treatment of psychological problems are essential for successful management of BMS patients.

Levels of sex hormones, sex hormone binding globulin, antisperm antibodies and dopamine in postmanopausal women of nomadic and settled aboriginal and local caucasoid populations of the arctic territories.

Positive changes in the society led to an improvement in quality and lifetime; as a result the menopause in women lengthens much longer, in light of this the relevance of studying hormonal changes increases, especially among the representatives of different groups living in the Arctic territories. The study was carried out on 138 women who included nomadic and settled aboriginal and local Caucasoid postmenopausal populations, permanently residing in the Arctic territories of Russia. The greatest difference in the studied blood indicators was shown between the local Caucasoid and aboriginal population. A greater imbalance in the content of dopamine in Aborigines compared with the European population was combined with a higher levels of prolactin, sex hormone binding globulin, antisperm antibodies and with lower concentrations of lutropine, progesterone, total and free testosterone. In the settled aboriginal population compared with nomadic one there were shown the larger proportion of people with low levels of dopamine, lutropine, follitropin and high levels of prolactin, sex hormone binding globulin in the presence of increased number of feedbacks in the hypothalamic-pituitary-gonadal system, which suggested more pronounced reduction of its activity. The evident imbalance of the dopamine content in the aboriginal population was combined with the absence of connections between dopamine level and the parameters of the hypothalamic-pituitary-gonadal system. Positive correlation between the contents of dopamine and lutropin in the European population suggested the stimulating effect of dopamine on the hypothalamic-pituitary-gonadal system. Affected by imbalanced dopamine content the decreased activity of gonadotropic pituitary gland function as well as the peripheral part of the hypothalamic-pituitary-gonadal system was registered in the aboriginal Arctic population in comparison with the local European one, which was more pronounced in the settled aboriginals.

Predictors of early-onset post-ischemic stroke depression: a cross-sectional study

BackgroundPost-stroke depression (PSD) seriously affects the rehabilitation of nerve function and quality of life. However, the pathogenesis of PSD is still not clear. This study aimed to investigate the demographic, clinical, and biochemical factors in patients with PSD.MethodsPatients with an acute ischemic stroke, who met the inclusion criteria at Shanghai Tenth People’s Hospital from April 2016 to September 2016, were recruited for this study. The stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS), and the mental state was assessed using Mini-Mental State Examination (MMSE), Hamilton Depression Scale (HAMD), and Hamilton Anxiety Scale (HAMA) at 1 week of admission. The patients were divided into PSD and non-PSD groups. The demographic and clinical characteristics, as well as the biochemical factors, were compared between the two groups. A logistic regression analysis was performed to identify the risk factors for depression following stroke.ResultsA total of 83 patients with acute ischemic stroke were recruited. Of these, 36 (43.4%) developed depression. The multivariate logistic regression analysis indicated that high NIHSS [odds ratio (OR): 1.84, 95% confidence interval (CI): 1.09–3.12, P = 0.023] and high HAMD scores (OR: 2.38, 95% CI: 1.61–3.50, P < 0.001) were independent risk predictors for PSD and so were lower dopamine level (OR: 0.64, 95% CI: 0.45–0.91, P = 0.014), lower 5-hydroxytryptamine level (OR: 0.99, 95% CI: 0.98–1.00, P = 0.046), higher tumor necrosis factor-α level (OR: 1.05, 95% CI: 1.00–1.09, P = 0.044), and lower nerve growth factor level (OR: 0.06, 95% CI: 0.01–0.67, P = 0.022).ConclusionsThe identification of higher NIHSS scores, higher HAMD scores, lower dopamine level, lower 5-hydroxytryptamine level, higher tumor necrosis factor-α level, and lower nerve growth factor level might be useful for clinicians in recognizing and treating depression in patients after a stroke.

RLS patients show better nocturnal performance in the Simon task due to diminished visuo-motor priming

ObjectiveThe restless legs syndrome (RLS) is characterized by sensory-motor symptoms which usually occur predominantly at rest in the evening and at night. It is assumed that this circadian rhythm is caused by low dopamine levels in the evening. Yet, it has never been investigated whether RLS patients show diurnal variations in cognitive functions modulated by dopamine and what neurophysiological and functional neuroanatomical processes underlie such modulations. MethodsWe used a Simon task combined with EEG and source localization to investigate whether top-down response selection and/or automatic visuo-motor priming are subject to diurnal changes in RLS patients, as compared to matched healthy controls. ResultsWe found that RLS patients showed better task performance due to reduced visuo-motor priming in the evening, as reflected by smaller early lateralized readiness potential (e-LRP) amplitudes and decreased activation of the superior parietal cortex and premotor cortex. Top-down response selection and early attentional processing were unaffected by RLS. ConclusionsCounterintuitively, RLS patients show enhanced task performance in the evening, i.e. when experiencing dopaminergic deficiency. Yet, this may be explained by deficits in visuo-motor priming that lead to reduced false response tendencies. SignificanceThis study reveals a counterintuitive circadian variation of cognitive functions in RLS patients.

Light/dark phase-dependent spontaneous activity is maintained in dopamine-deficient mice

Dopamine is important for motor control and involved in the regulation of circadian rhythm. We previously found that dopamine-deficient (DD) mice became hyperactive in a novel environment 72 h after the last injection of L-3,4-dihydroxyphenylalanine (L-DOPA) when dopamine was almost completely depleted. DD mice did not initially exhibit hyperactivity in their home cages, but the animals exhibited hyperactivity several hours after the last L-DOPA injection. The regulation of motor activity in a novel environment and in home cages may be different. A previous study reported that DD mice became active again approximately 24 h after the last L-DOPA injection. One speculation was that light/dark phase-dependent spontaneous activity might be maintained despite dopamine deficiency. The present study investigated whether spontaneous home cage activity is maintained in DD mice 24–43 h and 72–91 h after the last L-DOPA injection. Spontaneous activity was almost completely suppressed during the light phase of the light/dark cycle in DD mice 24 and 72 h after the last L-DOPA injection. After the dark phase began, DD mice became active 24 and 72 h after the last L-DOPA injection. DD mice exhibited a similar amount of locomotor activity as wildtype mice 24 h after the last L-DOPA injection. Although DD mice presented a decrease in activity 72 h after the last L-DOPA injection, they maintained dark phase-stimulated locomotor activation. Despite low levels of dopamine in DD mice, they exhibited feeding behavior that was similar to wildtype mice. Although grooming and rearing behavior significantly decreased, DD mice retained their ability to perform these activities. Haloperidol treatment significantly suppressed all of these behaviors in wildtype mice but not in DD mice. These results indicate that DD mice maintain some aspects of light/dark phase-dependent spontaneous activity despite dopamine depletion, suggesting that compensatory dopamine-independent mechanisms might play a role in the DD mouse phenotype.

P.4.f.006 - Cardiovascular reactions to psychosocial stress, Type D personality and trait anxiety in patients with coronary artery disease

The relation between high levels of psychosocial stress and the development of coronary artery disease (CAD) has been increasingly recognized, especially in women. We hypothesized that simple biomarkers of stress, urinary catecholamines/cortisol levels, are associated with more coronary artery calcium (CAC), an indicator of CAD, and that this relation is stronger in women compared with men. Using data from the Multi-Ethnic Study of Atherosclerosis Stress study, we examined the relation between urinary catecholamines/cortisol and CAC. The study cohort (n = 654) was 53% women, and 56.4% of the cohort had detectable CAC. Multivariable regression analyses assessed the relation between urinary catecholamines/cortisol and CAC (odds CAC >0 through logistic and ln CAC through Tobit model). There was an association between increased cortisol and increased CAC and an inverse association between dopamine and CAC. These relations were seen in men and women, with no difference between the genders. In conclusion, higher cortisol and lower dopamine levels are independently associated with higher CAC to a similar degree in men and women. These simple urinary biomarkers contribute to our understanding of the role of stress in the pathogenesis of CAD and may be incorporated into future strategies to prevent and treat CAD.

Phosphorylation at serine 31 targets tyrosine hydroxylase to vesicles for transport along microtubules

Tyrosine hydroxylase (TH) catalyzes the conversion of l-tyrosine into l-DOPA, which is the rate-limiting step in the synthesis of catecholamines, such as dopamine, in dopaminergergic neurons. Low dopamine levels and death of the dopaminergic neurons are hallmarks of Parkinson's disease (PD), where α-synuclein is also a key player. TH is highly regulated, notably by phosphorylation of several Ser/Thr residues in the N-terminal tail. However, the functional role of TH phosphorylation at the Ser-31 site (THSer(P)-31) remains unclear. Here, we report that THSer(P)-31 co-distributes with the Golgi complex and synaptic-like vesicles in rat and human dopaminergic cells. We also found that the TH microsomal fraction content decreases after inhibition of cyclin-dependent kinase 5 (Cdk5) and ERK1/2. The cellular distribution of an overexpressed phospho-null mutant, TH1-S31A, was restricted to the soma of neuroblastoma cells, with decreased association with the microsomal fraction, whereas a phospho-mimic mutant, TH1-S31E, was distributed throughout the soma and neurites. TH1-S31E associated with vesicular monoamine transporter 2 (VMAT2) and α-synuclein in neuroblastoma cells, and endogenous THSer(P)-31 was detected in VMAT2- and α-synuclein-immunoprecipitated mouse brain samples. Microtubule disruption or co-transfection with α-synuclein A53T, a PD-associated mutation, caused TH1-S31E accumulation in the cell soma. Our results indicate that Ser-31 phosphorylation may regulate TH subcellular localization by enabling its transport along microtubules, notably toward the projection terminals. These findings disclose a new mechanism of TH regulation by phosphorylation and reveal its interaction with key players in PD, opening up new research avenues for better understanding dopamine synthesis in physiological and pathological states.

Vegetated land cover near residence is associated with reduced allostatic load and improved biomarkers of neuroendocrine, metabolic and immune functions

BackgroundGreater exposure to urban green spaces has been linked to reduced risks of depression, cardiovascular disease, diabetes and premature death. Alleviation of chronic stress is a hypothesized pathway to improved health. Previous studies linked chronic stress with a biomarker-based composite measure of physiological dysregulation known as allostatic load. ObjectiveThis study's objective was to assess the relationship between vegetated land cover near residences and allostatic load. MethodsThis cross-sectional population-based study involved 206 adult residents of the Durham-Chapel Hill, North Carolina metropolitan area. Exposure was quantified using high-resolution metrics of trees and herbaceous vegetation within 500 m of each residence derived from the U.S. Environmental Protection Agency's EnviroAtlas land cover dataset. Eighteen biomarkers of immune, neuroendocrine, and metabolic functions were measured in serum or saliva samples. Allostatic load was defined as a sum of potentially unhealthy biomarker values dichotomized at 10th or 90th percentile of sample distribution. Regression analysis was conducted using generalized additive models with two-dimensional spline smoothing function of geographic coordinates, weighted measures of vegetated land cover allowing decay of effects with distance, and geographic and demographic covariates. ResultsAn inter-quartile range increase in distance-weighted vegetated land cover was associated with 37% (95% Confidence Limits 46%; 27%) reduced allostatic load; significantly reduced adjusted odds of having low level of norepinephrine, dopamine, and dehydroepiandrosterone, and high level of epinephrine, fibrinogen, vascular cell adhesion molecule-1, and interleukin-8 in serum, and α-amylase in saliva; and reduced odds of previously diagnosed depression. ConclusionsThe observed effects of vegetated land cover on allostatic load and individual biomarkers are consistent with prevention of depression, cardiovascular disease and premature mortality.

Creativity Assessment in Subjects with Tourette Syndrome vs. Patients with Parkinson's Disease: A Preliminary Study.

(1) Background: Literature suggests that high levels of dopamine are associated with creative thoughts. Tourette Syndrome (TS) patients have high dopamine levels, while Parkinson’s Disease (PD) subjects have low dopamine levels. Consequently, TS individuals are supposed to have a major and PD patients less creative output. Moreover, dopamine medications may alter the level of creativity, and therefore Quality of Life, in both pathologies. (2) Methods: The aim of the study was to verify the hypothesis of TS patients having higher creative scores than PD patients. The assessment consisted of the administration of the Creative Thinking ASK Test. There were 54 participants—36 males and 18 females—i.e., 27 TS patients and 27 PD subjects. Age of the sample was 35 to 57 years old, high school certificate was required. (3) Results: TS sample (103.11 ASK average score) was more creative than PD sample (94.11 ASK average score). (4) Conclusions: The results supported the aforementioned hypothesis: TS sample resulted in having higher creative scores than PD sample. Dopamine and other neurotransmitters of TS and PS appear to affect subject’s creativity. Further studies with creative assessments in TS and PD patients are needed to support the preliminary results of our study.

NEUROIMAGING SIGNATURE OF DOPAMINE SYSTEM COMT GENOTYPE IN OLDER ADULTS

Robust dopaminergic signaling is key for proper function in several brain regions susceptible to degeneration in Alzheimer's disease (AD). Dopamine is catabolized by the enzyme catechol-O-methyltransferase (COMT), which is coded by the COMT gene. It would be expected that val allele homozygotes of the COMT gene, indicating lower dopamine levels, would have steeper declines in cognitive performance with aging than met allele carriers. However, results to date are conflicting, and therefore we aimed to investigate the neuroimaging mechanisms of this association. Gray matter volumes (GMV) were obtained from T1 weighted MRIs carried out at the University of Pittsburgh Magnetic Resonance Research Center. Intracranial volume was defined as the total volume inside the skull. Mediotemporal and frontostriatal regions of interest (ROIs) were selected for analysis based on the importance of dopaminergic signaling in those areas and their implications in AD. Using ANCOVA we evaluated the relationship of COMT genotype with GMV in the ROIs of interest in older adults in the Health, Aging, and Body Composition Healthy Brain sub-study (N=314; median age =82.0; 57.6% female, 40.5% Black, 85.7% at least high school education). In sex-stratified ANCOVA models adjusted for race and intracranial volume, met/met genotype was associated with greater gray matter volume in males, but not females, in left and right parahippocampi (p=0.025 and p=0.045 respectively). Other associations were ns (p>.05). The COMT genotype may indicate subgroups with varying levels of protection against brain atrophy in brain regions implicated in Alzheimer's disease. Future sex-stratified longitudinal assessments of neuroimaging markers are needed to evaluate longitudinal changes in brain volume in relationship to COMT genotype.

Unified neural field theory of brain dynamics underlying oscillations in Parkinson’s disease and generalized epilepsies

The mechanisms underlying pathologically synchronized neural oscillations in Parkinson’s disease (PD) and generalized epilepsies are explored in parallel via a physiologically-based neural field model of the corticothalamic-basal ganglia (CTBG) system. The basal ganglia (BG) are approximated as a single effective population and their roles in the modulation of oscillatory dynamics of the corticothalamic (CT) system and vice versa are analyzed. In addition to normal EEG rhythms, enhanced activity around 4 Hz and 20 Hz exists in the model, consistent with the characteristic frequencies observed in PD. These rhythms result from resonances in loops formed between the BG and CT populations, analogous to those that underlie epileptic oscillations in a previous CT model, and which are still present in the combined CTBG system. Dopamine depletion is argued to weaken the dampening of these loop resonances in PD, and network connections then explain the significant coherence observed between BG, thalamic, and cortical population activity around 4–8 Hz and 20 Hz. Parallels between the afferent and efferent connection sites of the thalamic reticular nucleus (TRN) and BG predict low dopamine to correspond to a reduced likelihood of tonic-clonic (grand mal) seizures, which agrees with experimental findings. Furthermore, the model predicts an increased likelihood of absence (petit mal) seizure resulting from pathologically low dopamine levels in accordance with experimental observations. Suppression of absence seizure activity is demonstrated when afferent and efferent BG connections to the CT system are strengthened, which is consistent with other CTBG modeling studies. The BG are demonstrated to have a suppressive effect on activity of the CTBG system near tonic-clonic seizure states, which provides insight into the reported efficacy of current treatments in BG circuits. Sleep states of the TRN are also found to suppress pathological PD activity in accordance with observations. Overall, the findings demonstrate strong parallels between coherent oscillations in generalized epilepsies and PD, and provide insights into possible comorbidities.

Relation of Stress Hormones (Urinary Catecholamines/Cortisol) to Coronary Artery Calcium in Men Versus Women (from the Multi-Ethnic Study of Atherosclerosis [MESA

The relation between high levels of psychosocial stress and the development of coronary artery disease (CAD) has been increasingly recognized, especially in women. We hypothesized that simple biomarkers of stress, urinary catecholamines/cortisol levels, are associated with more coronary artery calcium (CAC), an indicator of CAD, and that this relation is stronger in women compared with men. Using data from the Multi-Ethnic Study of Atherosclerosis Stress study, we examined the relation between urinary catecholamines/cortisol and CAC. The study cohort (n= 654) was 53% women, and 56.4% of the cohort had detectable CAC. Multivariable regression analyses assessed the relation between urinary catecholamines/cortisol and CAC (odds CAC >0 through logistic and ln CAC through Tobit model). There was an association between increased cortisol and increased CAC and an inverse association between dopamine and CAC. These relations were seen in men and women, with no difference between the genders. In conclusion, higher cortisol and lower dopamine levels are independently associated with higher CAC to a similar degree in men and women. These simple urinary biomarkers contribute to our understanding of the role of stress in the pathogenesis of CAD and may be incorporated into future strategies to prevent and treat CAD.

Involvement of Host Defense Mechanisms against Toxoplasma gondii Infection in Anhedonic and Despair-Like Behaviors in Mice

Toxoplasma gondii is a pathogen relevant to psychiatric disorders. We recently showed that reactivation of chronic T. gondii infection induced depression-like behaviors in mice. Furthermore, it has been hypothesized that depression-like behaviors are mediated via a host defense mechanism against invading pathogens; proximate mechanisms of this behavioral hypothesis remain unclear. In the present study, we investigate the contribution of indoleamine 2,3-dioxygenase (IDO), inflammation, and interferon gamma (IFN-γ) to anhedonic and despair-related behaviors in T. gondii-infected mice by using sucrose preference and forced-swim tests, respectively. First, we confirmed that BALB/c mice exhibited both sickness and depression-like behaviors during acute infection. Treatment of infected wild-type mice with minocycline (anti-inflammatory drug) abated sickness and anhedonic and despair-like behaviors, whereas in T. gondii-infected mice, treatment normalized kynurenine/tryptophan (Kyn/Trp) ratios in both plasma and brain tissue. Additionally, T. gondii infection failed to induce anhedonic and despair-like behaviors or increase the Kyn/Trp ratio in immunocompromised (IFN-γ-/-) mice, whereas sickness behavior was observed in both immunocompetent and IFN-γ-/- mice following infection. Furthermore, treatment with 1-methyl tryptophan (an IDO inhibitor) did not affect locomotor activity, attenuated clinical scores and anhedonic and despair-like behaviors, and resulted in normal Kyn/Trp ratios in T. gondii-infected wild-type mice. Although low levels of serotonin and dopamine were observed in the brain during acute and chronic infections, anhedonic and despair-like behaviors were not detected in the chronic stage of infection. Collectively, our results demonstrated that immune enhancement in response to infection with T. gondii resulted in IFN-γ production, IDO activation, and inflammation associated with anhedonic and despair-like behaviors.

Efecto del inhibidor de amida hidrolasa de ácidos grasos en el daño neuronal dopaminérgico inducido por MPTP

IntroductionParkinson's disease (PD) is a neurodegenerative disorder characterised by balance problems, muscle rigidity, and slow movement due to low dopamine levels and loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The endocannabinoid system is known to modulate the nigrostriatal pathway through endogenous ligands such as anandamide (AEA), which is hydrolysed by fatty acid amide hydrolase (FAAH). The purpose of this study was to increase AEA levels using FAAH inhibitor URB597 to evaluate the modulatory effect of AEA on dopaminergic neuronal death induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MethodsOur study included 4 experimental groups (n = 6 mice per group): a control group receiving no treatment, a group receiving URB597 (0.2mg/kg) every 3 days for 30 days, a group treated with MPTP (30mg/kg) for 5 days, and a group receiving URB597 and subsequently MPTP injections. Three days after the last dose, we conducted a series of behavioural tests (beam test, pole test, and stride length test) to compare motor coordination between groups. We subsequently analysed immunoreactivity of dopaminergic cells and microglia in the SNpc and striatum. ResultsMice treated with URB597 plus MPTP were found to perform better on behavioural tests than mice receiving MPTP only. According to the immunohistochemistry study, mice receiving MPTP showed fewer dopaminergic cells and fibres in the SNpc and striatum. Animals treated with URB597 plus MPTP displayed increased tyrosine hydroxylase immunoreactivity compared to those treated with MPTP only. Regarding microglial immunoreactivity, the group receiving MPTP showed higher Iba1 immunoreactivity in the striatum and SNpc than did the group treated with URB597 plus MPTP. ConclusionOur results show that URB597 exerts a protective effect since it inhibits dopaminergic neuronal death, decreases microglial immunoreactivity, and improves MPTP-induced motor alterations.

Insulin-Like Growth Factor Binding Protein-3 Deficiency Leads to Behavior Impairment with Monoaminergic and Synaptic Dysfunction

Insulin-like growth factor binding protein (IGFBP)-3 regulates IGF bioactivity, induces apoptosis, and inhibits cell growth independent of IGFs, but the functional role of IGFBP3 in the brain is not clear. In the present study, we revealed the effect of IGFBP3 on the brain by characterizing the phenotype of Igfbp3-null mice. Compared with wild-type mice, Igfbp3-null mice had significantly decreased IGF-1 content in the brain but no change in weights of brain and body. In Igfbp3-null mice, the number of dendritic spines was significantly reduced, and the dendritic diameter was thickening. In addition, in Igfbp3-null mice, a decrease in phosphorylated Akt and ERK1/2 significantly reduced PSD-95 expression, and GAD65/67 expression was significantly decreased. These results indicate that IGFBP3 deficiency impairs neuronal structure and signaling. In behavioral studies, Igfbp3-null mice were hyperactive, and a Y-maze alternation test revealed impaired spatial working memory but no anxiety-like behavior. Monoaminergic analysis using high-performance liquid chromatography indicated that Igfbp3-null mice had lower levels of dopamine and serotonin compared with wild-type mice, suggesting an abnormal monoaminergic neurotransmission. In conclusion, our studies found that the deletion of IGFBP3 results in behavioral impairments that are associated with abnormal synaptic function and monoaminergic neurotransmission, which helps to characterize the critical role of IGFBP3 in the brain.

The impacts of Val158Met in Catechol-O-methyltransferase (COMT) gene on moral permissibility and empathic concern

Dopamine levels in the brain influence emotional experiences and empathic responses to others' misfortune. Inspired by roles of Catechol-O-methyltransferase (COMT) in dopamine degradation and the link between moral judgment and empathic responses, this study investigated to what extent the Val158Met polymorphism of COMT gene contributes to individual differences in moral permissibility and empathic dispositions. One thousand two hundred and seventy-two Chinese Han college students, who were differentiated with the COMT Val158Met (rs4680) polymorphism, rated permissibility of harm in moral dilemmas and scored their empathic dispositions with Interpersonal Reactivity Index. The results showed a significant association between COMT Val158Met and the moral permissibility of committing harm. Individuals with the Val/Val genotype, which is associated with lower levels of dopamine, endorsed impersonal harm as more impermissible than those with the Val/Met and Met/Met genotypes. Results also showed that individuals with the Val/Val genotype showed higher empathic concern for others' misfortune. The findings provide the first evidence for the link between COMT gene and the moral permissibility, highlighting the roles of dopamine in social cognition.

Dopaminergic Medication Modulates Learning from Feedback and Error-Related Negativity in Parkinson's Disease: A Pilot Study.

Dopamine systems mediate key aspects of reward learning. Parkinson’s disease (PD) represents a valuable model to study reward mechanisms because both the disease process and the anti-Parkinson medications influence dopamine neurotransmission. The aim of this pilot study was to investigate whether the level of levodopa differently modulates learning from positive and negative feedback and its electrophysiological correlate, the error related negativity (ERN), in PD. Ten PD patients and ten healthy participants performed a two-stage reinforcement learning task. In the Learning Phase, they had to learn the correct stimulus within a stimulus pair on the basis of a probabilistic positive or negative feedback. Three sets of stimulus pairs were used. In the Testing Phase, the participants were tested with novel combinations of the stimuli previously experienced to evaluate whether they learned more from positive or negative feedback. PD patients performed the task both ON- and OFF-levodopa in two separate sessions while they remained on stable therapy with dopamine agonists. The electroencephalogram (EEG) was recorded during the task. PD patients were less accurate in negative than positive learning both OFF- and ON-levodopa. In the OFF-levodopa state they were less accurate than controls in negative learning. PD patients had a smaller ERN amplitude OFF- than ON-levodopa only in negative learning. In the OFF-levodopa state they had a smaller ERN amplitude than controls in negative learning. We hypothesize that high tonic dopaminergic stimulation due to the dopamine agonist medication, combined to the low level of phasic dopamine due to the OFF-levodopa state, could prevent phasic “dopamine dips” indicated by the ERN needed for learning from negative feedback.

Stem Cells for Modeling and Therapy of Parkinson's Disease.

Parkinson's disease (PD) is the second most frequent neurodegenerative disease after Alzheimer's disease, which is characterized by a low level of dopamine being expressing in the striatum and a deterioration of dopaminergic neurons (DAn) in the substantia nigra pars compacta. Generation of PD-derived DAn, including differentiation of human embryonic stem cells, human neural stem cells, human-induced pluripotent stem cells, and direct reprogramming, provides an ideal tool to model PD, creating the possibility of mimicking key essential pathological processes and charactering single-cell changes in vitro. Furthermore, thanks to the understanding of molecular neuropathogenesis of PD and new advances in stem-cell technology, it is anticipated that optimal functionally transplanted DAn with targeted correction and transgene-free insertion will be generated for use in cell transplantation. This review elucidates stem-cell technology for modeling PD and offering desired safe cell resources for cell transplantation therapy.

Dopamine and temporal attention: An attentional blink study in Parkinson's disease patients on and off medication

The current study aimed to shed more light on the role of dopamine in temporal attention. To this end, we pharmacologically manipulated dopamine levels in a large sample of Parkinson's disease patients (n=63) while they performed an attentional blink (AB) task in which they had to identify two targets (T1 and T2) presented in close temporal proximity among distractors. We specifically examined 1) differences in the magnitude of the AB between unmedicated Parkinson patients, who have depleted levels of striatal dopamine, and healthy controls, and 2) effects of two dopaminergic medications (l-DOPA and dopamine agonists) on the AB in the Parkinson patients at the group level and as a function of individual baseline performance. In line with the notion that relatively low levels of striatal dopamine may impair target detection in general, Parkinson patients OFF medications displayed overall poor target perception compared to healthy controls. Moreover, as predicted, effects of dopaminergic medication on AB performance critically depended on individual baseline AB size, although this effect was only observed for l-DOPA. l-DOPA generally decreased the size of the AB in patients with a large baseline AB (i.e., OFF medications), while l-DOPA generally increased the AB in patients with a small baseline AB. These findings may support a role for dopamine in the AB and temporal attention, more generally and corroborate the notion that there is an optimum dopamine level for cognitive function. They also emphasize the need for more studies that examine the separate effects of DA agonists and l-DOPA on cognitive functioning.