Lower Dopamine Levels Research Articles

Dopaminergic Epistases in Schizophrenia

Background: The dopaminergic theory, the oldest and most comprehensively analyzed neurotransmitter theory of schizophrenia, remains a focal point of research. Methods: This systematic review examines the association between combinations of 14 dopaminergic genes and the risk of schizophrenia. The selected genes include dopamine receptors (DRD1–5), metabolizing enzymes (COMT, MAOA, MAOB, DBH), synthesizing enzymes (TH, DDC), and dopamine transporters (DAT, VMAT1, and VMAT2). Results: Recurring functional patterns show combinations with either hyperdopaminergic effects in limbic and striatal regions or high striatal and low prefrontal dopamine levels. The protective statuses of certain alleles or genotypes are often maintained in epistatic effects; however, exceptions exist. This complexity could explain the inconsistent results in previous genetic studies. Investigating individual alleles may be insufficient due to the heterozygous advantage observed in some studies. Conclusions: Schizophrenia may not be a monolithic disease, but rather a sum of different phenotypes which respond uniquely to different treatment and prevention approaches.

The interplay of dopaminergic genotype and parent-child relationship in relation to intra-individual response time variability in preschoolers: A replication study.

Intra-individual response time variability (IIRTV) during cognitive performance is increasingly recognized as an important indicator of attentional control (AC) and related brain region function. However, what determinants contribute to preschoolers' IIRTV received little attention. The present study explored the interaction of dopaminergic polygenic composite score (DPCS) and the parent-child relationship in relation to preschoolers' IIRTV. In the initial sample, 452 preschoolers (M age=5.17, SD=0.92) participated in the study. The modified Flanker task was used to evaluate children's IIRTV and their parents were requested to complete the Parent-Child Relationship Scale to assess the parent-child relationship (closeness/conflict). DNA data were extracted from children's saliva samples, and a DPCS was created by the number of COMT, DAT1, and DRD2 alleles associated with lower dopamine levels. Results showed that DPCS significantly interacted with the parent-child closeness to impact preschoolers' IIRTV. Specifically, preschoolers with higher DPCS exhibited lower IIRTV under higher levels of the parent-child closeness, and greater IIRTV under lower levels of the parent-child closeness compared to those with lower DPCS, which supported the differential susceptibility theory (DST). A direct replication attempt with 280 preschoolers (M age=4.80, SD=0.86) was conducted to investigate whether the results were in accordance with our exploratory outcomes. The interactive effect of DPCS and the parent-child closeness on IIRTV was confirmed. Additionally, the significant interactive effect of DPCS and the parent-child conflict on IIRTV was found in the replication study. The findings indicate that preschoolers' IIRTV, as an indicator of AC and related brain region function, is influenced by the interactions of dopaminergic genotypes and the parent-child relationship. RESEARCH HIGHLIGHTS: We investigated the Gene × Environment mechanism to underline the intra-individual response time variability as an indicator of attentional control (AC) in Chinese preschoolers. Dopaminergic polygenic composite score (COMT, DAT1, and DRD2) interacted with the parent-child relationship to predict preschoolers' intra-individual reaction time variability. A direct replication attempt has been conducted, and the results were in accordance with our exploratory outcomes, which increased the credibility of the present findings. The findings highlight the importance of considering precursors, including polygenic and environmental factors, which contribute to the development of early cognitive performance such as AC.

Synthesis of Yolk-Shell CoNi2S4 Spheres Modified Flexible Carbon Cloth Electrode for Highly Sensitive Detection of Neurotransmitter Dopamine

Dopamine (DA) is a neurotransmitter that is connected with transitory information in the mammalian central nervous system; changes in its concentration in the body are directly related to mental activity. The absence and/or low level of DA can cause symptoms of several disorders, including Parkinson’s and schizophrenia. As a result, detecting DA in patients is critical for regulating body function. Many efforts have been made to build electrochemical sensing devices to detect DA in human body or biological fluids due to its inherent advantages of high sensitivity, speed, simplicity, and affordability. However, surface modification with nanomaterials, polymers, pretreatments, or simple functionalization are required to improve the performance of these sensing electrodes. Further, exploration of earth-abundant electro-catalysts with high activity and stability is also important for the development of highly selective and sensitive electrochemical sensing interfaces. With these considerations in mind, our study describes the construction of yolk-shell CoNi2S4 spheres modified flexible carbon cloth (CC) electrode for the sensitive detection of DA. The synthesized material's surface and morphological study were examined, and the successful synthesis was confirmed. The yolk-shell CoNi2S4 spheres shown good electrochemical sensing performance towards DA detection due to their unique surface morphology with large specific surface area and synergistic effects. In comparison to unmodified CC, the yolk-shell CoNi2S4 spheres modified CC demonstrated a low detection limit (5.1 nM), great sensitivity, and a wide linear range (0.01 – 5.2 µM). The detection selectivity was also tested in the presence of a high quantity of the common interference ascorbic acid. Selectivity, stability, and repeatability have also been demonstrated to be satisfactory. Furthermore, the fabricated sensor’s flexibility endows it with significant potential in the fabrication of wearable and soft electronics for human healthcare monitoring.

Impaired dopamine signaling in early diabetic retina: Insights from D1R and D4R agonist effects on whole retina responses

The retina has low dopamine levels early in diabetes. To determine how low dopamine levels affected dopamine signaling, the effects of dopamine receptor agonists and mRNA localization were measured after 6 weeks of diabetes. Whole retina ex vivo electroretinogram (ERG) recordings were used to analyze how dopamine type 1 receptor (D1R) and type 4 (D4R) agonists change the light-evoked retinal responses of non-diabetic and 6-week diabetic (STZ injected) mouse retinas. Fluorescence in situ hybridization was utilized to analyze D4R and D1R mRNA locations and expression levels. D4R activation reduced A- and B-wave ERG amplitudes and increased B-wave implicit time and rise-time in the non-diabetic group without a corresponding change in the diabetic group. D1R activation increased B-wave rise-time and oscillatory potential peak time in the non-diabetic group also with no change in the diabetic group. The lack of responsivity to D1R or D4R agonists shows an impairment of dopamine signaling in the diabetic retina. D4R mRNA was found primarily in the outer nuclear layer where photoreceptor cell bodies reside. D1R mRNA was found in the inner nuclear layer and ganglion cell layer that contain bipolar, amacrine, horizontal and ganglion cells. There was no change in D4R or D1R mRNA expression between the non-diabetic and diabetic retinas. This suggests that the significant dopamine signaling changes observed were not from lower receptor expression levels but could be due to changes in dopamine receptor activity or protein levels. These studies show that changes in retinal dopamine signaling could be an important mechanism of diabetic retinal dysfunction.

Untargeted metabolomics reveals the mechanism of ultrasound combined with L-cysteine treatment inhibiting the browning of fresh-cut potatoes

Freshly cut potatoes tend to brown during processing and preservation, which is an important issue worldwide. Ultrasound (US) combined with L-cysteine (L-Cys) treatment (US-L-Cys) has been reported to inhibit the browning of fresh-cut potatoes in our laboratory. However, the underlying mechanism remains to be elucidated. Untargeted metabolomics, a popular high-throughput technique, has been used to investigate the biochemical changes that are closely associated with the browning of fresh-cut fruits and vegetables. The present study investigated the effect of US-L-Cys treatment on the browning index (BI), related enzyme activities, total phenolic content, antioxidant capacity, malondialdehyde (MDA) content, and relative electrical conductivity of fresh-cut potatoes during 6-d storage. Metabolomics was used to compare the metabolites of US-L-Cys-treated and control samples on days 0 and 6. The results showed that US-L-Cys treatment reduced BI; decreased polyphenol oxidase, peroxidase, and phenylalanine ammonia-lyase activities; maintained high total phenolic content; increased antioxidant capacity; and decreased MDA content and relative electrical conductivity in fresh-cut potatoes during storage. Metabolomic analysis revealed that tyrosine and amino acid metabolisms were enriched. Higher levels of alanine and lower levels of dopamine were observed in US-L-Cys-treated samples compared with control samples. Therefore, depressed tyrosine and activated alanine metabolisms may be involved in the mechanism through which US-L-Cys inhibits the enzymatic browning of fresh-cut potatoes during storage.

Agouti-Induced Anxiety-Like Behavior Is Mediated by Central Serotonergic Pathways in Zebrafish.

Overexpression of the agouti-signaling protein (asip1), an endogenous melanocortin antagonist, under the control of a constitutive promoter in zebrafish [Tg(Xla.Eef1a1:Cau.Asip1]iim4] (asip1-Tg) increases food intake by reducing sensitivity of the central satiety systems and abolish circadian activity rhythms. The phenotype also shows increased linear growth and body weight, yet no enhanced aggressiveness in dyadic fights is observed. In fact, asip1-Tg animals choose to flee to safer areas rather than face a potential threat, thus suggesting a potential anxiety-like behavior (ALB). Standard behavioral tests, i.e., the open field test (OFT), the novel object test (NOT), and the novel tank dive test (NTDT), were used to investigate thigmotaxis and ALB in male and female zebrafish. Results showed that the asip1-Tg strain exhibited severe ALB in every test, mainly characterized by pronounced freezing behavior and increased linear and angular swimming velocities. asip1-Tg animals exhibited low central serotonin (5-HT) and dopamine (DA) levels and high turnover rates, thus suggesting that central monoaminergic pathways might mediate melanocortin antagonist-induced ALB. Accordingly, the treatment of asip1-Tg animals with fluoxetine, a selective serotonin reuptake inhibitor (SSRI), reversed the ALB phenotype in NTDT as well as 5-HT turnover. Genomic and anatomical data further supported neuronal interaction between melanocortinergic and serotonergic systems. These results suggest that inhibition of the melanocortin system by ubiquitous overexpression of endogenous antagonist has an anxiogenic effect mediated by serotonergic transmission.

Evaluation of Neuroprotective Activity of Delonix Regia Leaves on Haloperidol Induced Parkinsonism in Experimental Animals

One of the most serious and fatal neurodegenerative disorders, Parkinson disease (PD) is characterized by low levels of dopamine. Reactive oxygen species (ROS) from both endogenous and exogenous sources have a role in the oxidative stress that leads to PD, which is a complex condition. Delo nix Regia is a prominent medicinal plant that is frequently used in Indian systems of medicine. The fruit, leaves, and bark of this plant have been utilised for its antifungal, antiemetic, larvicidal, hepatoprotective, antibacterial, antioxidant, anti-diarrheal, anti-inflammatory, wound-healing, and ant carcinogenic potential, according to Ayurvedic literature. The "antioxidant strategy" is the main topic of this study's therapeutic intervention for Parkinson's disease (PD). The investigation was completed in wistar rats, in which Parkinson’s disease (PD) was induced with haloperidol 2 mg/kg, P.O. The rats were randomly divided into six groups and the test animals received the ethanolic extract of Delo nix regia (DRLE) at a dose of 100, 250 and 500 mg/kg, orally for 15 days. Various behavioural and biochemical parameters were estimated in haloperidol exposed rats. The results of this study conclusively show that Delo nix regia has anti-oxidant activity and neuroprotective activity in haloperidol experimental model of PD.

Affective disorders in Parkinson's disease

Parkinson's disease is a progressive neurodegenerative disorder characterized by damage to dopaminergic neurons in the substantia nigra , pars compacta and nigrostriatal pathways. This translates into a low level of dopamine which is responsible for the appearance of specific motor manifestations such as tremors, rigidity, bradykinesia, akinesia and postural instability. The clinical picture of Parkinson's disease is complemented by non-motor symptoms such as affective disorders, psychotic manifestations, neurocognitive disorders, hypnic disorders or autonomic dysfunction.

DOPAMINE-DEPENDENT FORM OF ARTERIAL HYPERTENSION IN PATIENTS WITH A HIGH DEGREE OF NUTRITIONAL-CONSTITUTIONAL OBESITY

Objective: Despite significant advances in the study of the pathogenesis, clinical picture and treatment of arterial hypertension (AH), the role of the dopaminergic system in obese patients remains insufficiently studied. Aim: To evaluate the effectiveness of the use of D2 receptor agonists in patients with arterial hypertension (AH) and nutritional-constitutional obesity (NCO) of the 3rd degree. Design and method: We examined 151 patients aged 30-60 years (65 men, 86 women) with AH and NCO. The control group (CG) consisted of 78 hypertensive patients. Daily monitoring of blood pressure (BP), body mass index (BMI), daily excretion of dopamine, plasma levels of aldosterone, prolactin, leptin, adrenaline, creatinine, lipid spectrum - obese patients were divided into two groups. In addition to basic antihypertensive therapy, patients 1 group (n=74) were prescribed bromocriptine (0.08 mg/kg in three doses), patients 2 group (n=71) – pramipexole (0.125 mg 3 times/day). Results: During the baseline examination, daily dopamine excretion in obese patients was 1.6 times lower (p<0.001) than in control group patients. A negative correlation was found between dopamine excretion and BMI (r=-0.6; p<0.001). In patients with hypertension and NCO, a basic examination revealed a significant (p<0.001) increase in the plasma concentrations of prolactin (2.5 times), aldosterone (1.5 times), leptin (3.4 times) and adrenaline (by 1.3 times) compared to CG. Taking bromocriptine for 8 weeks in patients 1 group led to a decrease in blood pressure, BMI and plasma levels of prolactin and aldosterone. In 41.9% of patients 1 group with dopamine excretion levels less than 300 nmol/day, normalization of blood pressure was observed. In patients 2 group pramipexole was discontinued due to side effects. Conclusions: In the majority of patients with hypertension and NCO (58.1%), the main pathogenetic factor in increasing blood pressure is a low level of dopamine and a compensatory increase in prolactin, aldosterone, and adrenaline in plasma. The use of the D2-dopamine receptor agonist bromocriptine helps to normalize the daily excretion of dopamine, reduce the levels of prolactin, aldosterone and adrenaline, blood pressure and BMI. The use of pramipexole in patients with hypertension and NCO seems inappropriate

Early-life perfluorooctanoic acid exposure disrupts the function of dopamine transporter protein with glycosylation changes implicating the links between decreased dopamine levels and disruptive behaviors in larval zebrafish

Exposure to perfluorooctanoic acid (PFOA) during early embryonic development is associated with the increased risk of developmental neurotoxicity and neurobehavioral disorders in children. In our previous study, we demonstrated that exposure to PFOA affected locomotor activity and disrupted dopamine-related gene expression in zebrafish larvae. Consequently, we continue to study the dopaminergic system with a focus on dopamine levels and dopamine's effect on behaviors in relation to PFOA exposure. In the present study, we found a decrease in dopamine levels in larval zebrafish. We studied the dopamine transporter (DAT) protein, which is responsible for regulating dopamine levels through the reuptake of dopamine in neuronal cells. We demonstrated that exposure to PFOA disrupted the glycosylation process of DAT, inhibited its uptake function, and induced endoplasmic reticulum (ER) stress in dopaminergic cells. Besides, we conducted a light-dark preference test on larval zebrafish and observed anxiety/depressive-like behavioral changes following exposure to PFOA. Dopamine is one of the most prominent neurotransmitters that significantly influences human behavior, with low dopamine levels being associated with impairments such as anxiety and depression. The anxiety-like response in zebrafish larvae exposure to PFOA implies the link with the reduced dopamine levels. Taken together, we can deduce that glycosylation changes in DAT lead to dysfunction of DAT to regulate dopamine levels, which in turn alters behavior in larval zebrafish. Therefore, alternation in dopamine levels may play a pivotal role in the development of anxiety/depressive-like behavioral changes induced by PFOA.

Dopamine as a potential diagnostic biomarker in women's sexual dysfunction.

Dopamine and prolactin are the key mediators involved in sexual function in both males and females, but the role of dopamine in female sexual dysfunction (FSD) is still unclear. The aim was to investigate the possible role of dopamine and their relationship with sex steroid hormones (estrogen, progesterone and dehydroepiandrosterone; DHEA) and prolactin levels in Egyptian women suffering from sexual dysfunction. This study included 84 women having sexual dysfunction (FSD group) and 84 normal sexual function (control group). All women were subjected to the questionnaire to assess their demographic and gynecological data as well as female sexual function index (FSFI). Blood samples were collected from all women for measuring serum estradiol, progesterone, DHEA, prolactin and dopamine levels. FSD patients had significantly higher serum progesterone and DHEA and prolactin levels; while significantly lower dopamine and estradiol levels versus controls (p < 0.001). In all women, dopamine level appeared as a predictor of FSD at cut-off point ≤8.8 ng/mL with sensitivity (75%), specificity (92%) and accuracy (83%) (p < 0.001). The low levels of dopamine were associated with significantly higher prevalence in patients with low estradiol (p < 0.001) and high progesterone (p < 0.001), DHEA (p < 0.001) and prolactin (p = 0.004). Also, dopamine was significantly positive correlation with arousal score (r = 0.16, p = 0.04), and negative correlation with age (r = -0.31, p < 0.001), pain score (r = -0.19, p = 0.01), DHEA (r = -0.45, p < 0.001) and prolactin (r = -0.28, p < 0.001). Low serum dopamine level is a potential diagnostic biomarker in women's sexual dysfunction and their association with high prolactin and sex steroid hormones dysfunction.

The Connection between Dopamine and Marijuana

Known as the most commonly used illegal drug, marijuana has upheld its infamous reputation for decades. This psychoactive drug instills feelings of euphoria and energy when smoked or consumed. As its popularity increases, the perception of the harm induced by marijuana is declining. Uninformed individuals continue to smoke marijuana without considering it risky behavior. Without being aware of the risks that marijuana poses, more individuals are likely to develop addictions. Dopamine is a neurotransmitter in the brain that has many key roles for both the body and the brain. It is responsible for satisfaction, motivation, motor control, and arousal. Through examination of the molecular structure of dopamine, the molecular structure of marijuana, and dopaminergic pathways in the brain, it is evident that there is a connection between marijuana use and decreased levels of dopamine. Long-term usage of marijuana has been shown to dysregulate the mesolimbic dopaminergic pathway. The mesolimbic pathway is a branch of neurons projecting from the ventral augmented area to the ventral striatum. Major functions of this pathway include addiction, pleasure, and reward-seeking behavior. Based on these defenses, there is a reasonable conclusion that chronic marijuana use leads to lower levels of dopamine in the brain.

Dopamine antinociceptive system

The article presents modern views on structure and functioning of dopaminergic structures of the brain and spinal cord and their role in mechanisms of antinociception, formation, and chronification of different pain syndrome types. The paper provides a detailed description of analgesic effects of various dopamine receptors in the structures of the CNS (the spinal cord, ventral tegmental area, periaqueductal gray, corpus striatum, nucleus accumbens, hypothalamus, and medial prefrontal cortex) which function as the dopaminergic antinociceptive system. The results of numerous investigations carried out on models of neuropathic pain syndrome have shown that D2 dopamine receptors possess the greatest analgesic activity. Their antinociceptive mechanism of action is effectuated at the level of substantia gelatinosa of the spinal cord and cerebral dopaminergic structures. D1‑like receptors have lower analgesic activity and different mechanisms of action depending on localization within the brain. High availability of D2/D3 receptors in corpus striatum is indicative of a low synaptic level of endogenous dopamine and leads to reduction of pain perception threshold. On the contrary, low availability of D2/D3 receptors results in the increase of pain perception threshold. The dopaminergic antinociceptive system is characterized by a modulating effect on other neurotransmitter systems participating in nociception and antinociception. An important mechanism of antinociception of dopaminergic structures is connected with superadditivity and synergism of D2 receptors with opioid receptors. Proven participation of dopaminergic structures in pain perception and analgesia demonstrates a potential possible application of D2‑receptors agonists as an adjuvant method for achieving a greater effect in therapeutic multimodal schemes of analgesia.

Circulating serotonin and dopamine concentrations in osteoarthritis patients: a pilot study on the effect of pelotherapy

Balneotherapy has demonstrated clinical efficacy in the management of pathologies involving low-grade inflammation and stress. In rheumatic conditions such as osteoarthritis (OA), this therapy presents anti-inflammatory properties and potential to improve psychological well-being. Although the neurohormones serotonin and dopamine are known to be involved in these processes, surprisingly they have not been studied in this context. The objective was to evaluate the effect of a cycle of balneotherapy with peloids (pelotherapy) on circulating serotonin and dopamine concentrations in a group of aged individuals with OA, after comparing their basal state to that of an age-matched control group. In our pilot study, a pelotherapy program (10 days) was carried out in a group of 16 elderly patients with OA, evaluating its effects on circulating serotonin and dopamine concentrations (measured by ELISA). Individuals with OA showed higher levels of serotonin and lower dopamine levels, in line with the inflammatory roles of these mediators. After pelotherapy, serotonin concentrations significantly decreased, potentially contributing to the previously reported anti-inflammatory effects of balneotherapy.

Electrochemical evaluation of magnetic reduced graphene oxide nanosheet‐modified glassy carbon electrode on dopamine electrochemical sensor for Parkinson's diagnostic application

AbstractBackgroundDopamine is an important catecholamine neurotransmitter that plays a critical function as a chemical messenger that aids in the signal transmission in the brain and other important places. Dopamine is known to play an important role in several neurological diseases such as schizophrenia and Parkinson's disease in which a key factor in the development of Parkinson's disease is abnormally lower levels of dopamine compared to normal levels. However, these methods are expensive, requires manual labor and resources, and demands large number of reagents and chemicals. Therefore, it is essential to develop dopamine detection methods that are less costly, more stable, and easier to perform.ObjectiveTo develop a magnetic reduced graphene oxide (MRGO) nanosheet‐modified glassy carbon electrode (GCE) for the electrochemical detection of dopamine.MethodsMagnetic reduced graphene oxide (MRGO) nanosheet were prepared by the in situ coprecipitation of Fe3+ and Fe2+ in the GO solution. To prepare the MRGO nanosheet ink, 38 mg of MRGO nanosheet was mixed with 2 mg of acetylene black and 80 μL of Nafion solution (5%). The mixture was then mixed with 210 μL of deionized water and 210 μL of 2‐propanol and subjected to ultrasonication for 120 min using a sonicator to obtain a homogenous MRGO nanosheet ink. Furthermore, 3 μL of MRGO ink was dripped onto the surface of the GCE.ResultsMRGO consists of graphene layered tethered with the spherical Fe3O4. The oxygen‐based functional groups on the surface of MRGO could act as chemically active sites for the attachment of dopamine. The MRGO nanosheet has been proven to be an effective GCE modifier with a remarkable electroactive surface area of approximately 0.0104 cm2, demonstrating stable and sensitive electrochemical performance towards dopamine.ConclusionsThe MRGO nanosheets‐modified GCE presented a great potential as an electrocatalyst for dopamine detection, especially in the presence of interfering compounds like uric acid. By effectively discriminating dopamine and uric acid, MRGO nanosheets‐modified GCE have demonstrated a sensitive, stable, and specific electrochemical performance. This remarkable result underlines the immense potential of MRGO nanosheets‐modified GCE for real‐world applications, particularly in the medical field, where the ability to detect dopamine precisely and accurately is critical.

Estradiol and the Catechol-o-methyltransferase Gene Interact to Predict Working Memory Performance: A Replication and Extension.

Decades of evidence across taxa have established the importance of dopamine (DA) signaling in the pFC for successful working memory performance. Genetic and hormonal factors can shape individual differences in prefrontal DA tone. The catechol-o-methyltransferase (COMT) gene regulates basal prefrontal DA, and the sex hormone 17β-estradiol potentiates DA release. E. Jacobs and M. D'Esposito [Estrogen shapes dopamine-dependent cognitive processes: Implications for women's health. Journal of Neuroscience, 31, 5286-5293, 2011] investigated the moderating role of estradiol on cognition using the COMT gene and COMT enzymatic activity as a proxy for pFC DA tone. They found that increases in 17β-estradiol within women at two time points during the menstrual cycle influenced working memory performance in a COMT-dependent manner. Here, we aimed to replicate and extend the behavioral findings of Jacobs and D'Esposito by employing an intensive repeated-measures design across a full menstrual cycle. Our results replicated the original investigation. Within-person increases in estradiol were associated with improved performance on 2-back lure trials for participants with low basal levels of DA (Val/Val carriers). The association was in the opposite direction for participants with higher basal levels of DA (Met/Met carriers). Our findings support the role of estrogen in DA-related cognitive functions and further highlight the need to consider gonadal hormones in cognitive science research.

Profiling transcriptomic responses of human stem cell-derived medium spiny neuron-like cells to exogenous phasic and tonic neurotransmitters

Transcriptomic responses to neurotransmitters contribute to the complex processes driving memory and addiction. Advances in both measurement methods and experimental models continue to improve our understanding of this regulatory layer. Here we focus on the experimental potential of stem cell derived neurons, currently the only ethical model that can be used in reductionist and experimentally perturbable studies of human cells. Prior work has focused on generating distinct cell types from human stem cells, and has also shown their utility in modeling development and cellular phenotypes related to neurodegeneration. Here we seek an understanding of how stem cell derived neural cultures respond to perturbations experienced during development and disease progression. This work profiles transcriptomic responses of human medium spiny neuron-like cells with three specific goals. We first characterize transcriptomic responses to dopamine and dopamine receptor agonists and antagonists presented in dosing patterns mimicking acute, chronic, and withdrawal regimens. We also assess transcriptomic responses to low and persistent tonic levels of dopamine, acetylcholine, and glutamate to better mimic the in vivo environment. Finally, we identify similar and distinct responses between hMSN-like cells derived from H9 and H1 stem cell lines, providing some context for the extent of variability these types of systems will likely pose for experimentalists. The results here suggest future optimizations of human stem cell derived neurons to increase their in vivo relevance and the biological insights that can be garnered from these models.

PET imaging of dopamine transporters and D2/D3 receptors in female monkeys: effects of chronic cocaine self-administration.

Brain imaging studies using positron emission tomography (PET) have shown that long-term cocaine use is associated with lower levels of dopamine (DA) D2/D3 receptors (D2/D3R); less consistent are the effects on DA transporter (DAT) availability. However, most studies have been conducted in male subjects (humans, monkeys, rodents). In this study, we used PET imaging in nine drug-naïve female cynomolgus monkeys to determine if baseline measures of DAT, with [18F]FECNT, and D2/D3R availability, with [11C]raclopride, in the caudate nucleus, putamen and ventral striatum were associated with rates of cocaine self-administration and if these measures changed during long-term (~13 months) cocaine self-administration and following time-off (3-9 months) from cocaine. Cocaine (0.2 mg/kg/injection) and 1.0 g food pellets were available under a multiplefixed-interval (FI) 3-min schedule of reinforcement. In contrast to what has been observed in male monkeys, baseline D2/D3R availability was positively correlated with rates of cocaine self-administration only during the first week of exposure; DAT availability did not correlate with cocaine self-administration. D2/D3R availability decreased ~20% following cumulative intakes of 100 and 1000 mg/kg cocaine; DAT availability did not significantly change. These reductions in D2/D3R availability did not recover over 9 months of time-off from cocaine. To determine if these reductions were reversible, three monkeys were implanted with osmotic pumps that delivered raclopride for 30 days.We found that chronic treatment with the D2/D3R antagonist raclopride increased D2/D3R availability in the ventral striatum but not in the other regions when compared to baseline levels. Over 13 months of self-administration, tolerance did not develop to the rate-decreasing effects of self-administered cocaine on food-reinforced responding, but number of injections and cocaine intake significantly increased over the 13 months. These data extend previous findings to female monkeys and suggest sex differences in the relationship between D2/D3R availability related to vulnerability and long-term cocaine use.

Cerebrospinal fluid levels of 5-HIAA and dopamine in people with HIV and depression.

Depression is a common illness in people with HIV (PWH) and is associated with substantial morbidity and mortality. The mechanisms that underpin depression in PWH remain incompletely elucidated, and more research is therefore needed to develop effective treatments. One hypothesis is that neurotransmitter levels may be altered. These levels could be influenced by the chronic inflammation and viral persistence that occurs in PWH. We examined a panel of cerebrospinal fluid (CSF) neurotransmitters in PWH on suppressive antiretroviral therapy (ART), many of whom had a current depression diagnosis. CSF monoamine neurotransmitters and their metabolites were measured from participants in studies at the Emory Center for AIDS Research (CFAR). Only participants on stable ART with suppressed HIV RNA from both plasma and CSF were analyzed. Neurotransmitter levels were measured with high-performance liquid chromatography (HPLC). Neurotransmitters and their metabolites included dopamine (DA), homovanillic acid (HVA, a major metabolite of dopamine), serotonin (5-HT), 5-hydroxyindole-3-acetic acid (5-HIAA, a major metabolite of serotonin), and 4-hydroxy-3-methoxyphenylglycol (MHPG, a major metabolite of norepinephrine). Multivariable logistic regression was used to evaluate factors associated with depression. There were 79 PWH with plasma and CSF HIV RNA levels < 200 copies/mL at the time of the visit, and 25 (31.6%) carried a current diagnosis of depression. Participants with depression were significantly older (median age 53years versus 47years, P = 0.014) and were significantly less likely to be African American (48.0% versus 77.8%, P = 0.008). Participants with depression had significantly lower dopamine levels (median 0.49ng/mL versus 0.62ng/mL, P = 0.03) and significantly lower 5-HIAA levels (median 12.57ng/mL versus 15.41ng/mL, P = 0.015). Dopamine and 5-HIAA were highly correlated. In the multivariable logistic regression models, lower 5-HIAA was significantly associated with the depression diagnosis when accounting for other significant demographic factors. The associations between lower 5-HIAA, lower dopamine, and depression in PWH suggest that altered neurotransmission may contribute to these comorbid conditions. However, the effects of antidepressants on neurotransmitters cannot be ruled out as a factor in the 5-HIAA results.

Methylphenidate undermines or enhances divergent creativity depending on baseline dopamine synthesis capacity.

Catecholamine-enhancing psychostimulants, such as methylphenidate have long been argued to undermine creative thinking. However, prior evidence for this is weak or contradictory, stemming from studies with small sample sizes that do not consider the well-established large variability in psychostimulant effects across different individuals and task demands. We aimed to definitively establish the link between psychostimulants and creative thinking by measuring effects of methylphenidate in 90 healthy participants on distinct creative tasks that measure convergent and divergent thinking, as a function of individuals' baseline dopamine synthesis capacity, indexed with 18F-FDOPA PET imaging. In a double-blind, within-subject design, participants were administered methylphenidate, placebo or selective D2 receptor antagonist sulpiride. The results showed that striatal dopamine synthesis capacity and/or methylphenidate administration did not affect divergent and convergent thinking. However, exploratory analysis demonstrated a baseline dopamine-dependent effect of methylphenidate on a measure of response divergence, a creativity measure that measures response variability. Response divergence was reduced by methylphenidate in participants with low dopamine synthesis capacity but enhanced in those with high dopamine synthesis capacity. No evidence of any effect of sulpiride was found. These results show that methylphenidate can undermine certain forms of divergent creativity but only in individuals with low baseline dopamine levels.