Disruption of dopamine D2/D3 system function impairs the human ability to understand the mental states of other people.

Difficulties in reasoning about others' mental states (i.e., mentalising/Theory of Mind) are highly prevalent among disorders featuring dopamine dysfunctions (e.g., Parkinson's disease) and significantly affect individuals' quality of life. However, due to multiple confounding factors inherent to existing patient studies, currently little is known about whether these sociocognitive symptoms originate from aberrant dopamine signalling or from psychosocial changes unrelated to dopamine. The present study, therefore, investigated the role of dopamine in modulating mentalising in a sample of healthy volunteers. We used a double-blind, placebo-controlled procedure to test the effect of the D2/D3 antagonist haloperidol on mental state attribution, using an adaptation of the Heider and Simmel (1944) animations task. On 2 separate days, once after receiving 2.5 mg haloperidol and once after receiving placebo, 33 healthy adult participants viewed and labelled short videos of 2 triangles depicting mental state (involving mentalistic interaction wherein 1 triangle intends to cause or act upon a particular mental state in the other, e.g., surprising) and non-mental state (involving reciprocal interaction without the intention to cause/act upon the other triangle's mental state, e.g., following) interactions. Using Bayesian mixed effects models, we observed that haloperidol decreased accuracy in labelling both mental and non-mental state animations. Our secondary analyses suggest that dopamine modulates inference from mental and non-mental state animations via independent mechanisms, pointing towards 2 putative pathways underlying the dopaminergic modulation of mental state attribution: action representation and a shared mechanism supporting mentalising and emotion recognition. We conclude that dopaminergic pathways impact Theory of Mind, at least indirectly. Our results have implications for the neurochemical basis of sociocognitive difficulties in patients with dopamine dysfunctions and generate new hypotheses about the specific dopamine-mediated mechanisms underlying social cognition.

Association between voriconazole-induced visual hallucination and dopamine in an analysis of the food and drug administration (FDA) adverse event reporting system database.

Voriconazole is a second-generation azole used to treat serious fungal infections. Visual hallucinations constitute a representative adverse event caused by voriconazole. However, its mechanism of action remains unclear. In patients with schizophrenia or Parkinson's disease, the frequency of visual hallucinations is associated with brain dopamine levels. This study investigated the frequency of visual hallucinations in patients treated with voriconazole alone or in combination with dopaminergic medicines or dopamine antagonists, using data collected from the Food and Drug Administration Adverse event Reporting System (FAERS). The frequency of visual hallucinations with voriconazole alone and in combination with a dopaminergic medicine (levodopa) or dopamine antagonists (risperidone and chlorpromazine) was compared using data from the FAERS between 2004 and 2023, using the reporting odds ratio (ROR) with relevant 95% confidence intervals (CI). The reference group comprised patients who had been administered voriconazole without dopaminergic medication or dopamine antagonists. Of the patients, 22,839, 90,810, 109,757, 6,435, 20, 83, and 26, respectively were treated with voriconazole, levodopa, risperidone, chlorpromazine, voriconazole plus levodopa, voriconazole plus risperidone, and voriconazole plus chlorpromazine. The occurrence of visual hallucinations increased when used in combination with levodopa (ROR = 12.302, 95% CI = 3.587-42.183). No increase in incidence was associated with the concomitant use of dopamine antagonists (risperidone, ROR = 1.721, 95% CI = 0.421-7.030; chlorpromazine, ROR = none, 95% CI = none). Dopaminergic medicine may increase the risk of visual hallucinations in patients treated with voriconazole. Whether voriconazole positively modulates dopamine production warrants further investigation using a translational research approach.

Dopamine, activation of ingestion and evaluation of response efficacy: a focus on the within-session time-course of licking burst number.

RATIONALE: Evidence on the effect of dopamine D1-like and D2-like receptor antagonists on licking microstructure and the forced swimming response led us to suggest that (i) dopamine on D1-like receptors plays a role in activating reward-directed responses and (ii) the level of response activation is reboosted based on a process of evaluation of response efficacy requiring dopamine on D2-like receptors. A main piece of evidence in support of this hypothesis is the observation that the dopamine D2-like receptor antagonist raclopride induces a within-session decrement of burst number occurring after the contact with the reward. The few published studies with a detailed analysis of the time-course of this measure were conducted in our laboratory. OBJECTIVES: The aim of this review is to recapitulate and discuss the evidence in support of the analysis of the within-session burst number as a behavioural substrate for the study of the mechanisms governing ingestion, behavioural activation and the related evaluation processes, and its relevance in the analysis of drug effects on ingestion. CONCLUSIONS: The evidence gathered so far suggests that the analysis of the within-session time-course of burst number provides an important behavioural substrate for the study of the mechanisms governing ingestion, behavioural activation and the related evaluation processes, and might provide decisive evidence in the analysis of the effects of drugs on ingestion. However, further evidence from independent sources is necessary to validate the use and the proposed interpretation of this measure.

Hippocampal D1-like dopamine receptor as a novel target for the effect of cannabidiol on extinction and reinstatement of methamphetamine-induced CPP.

Methamphetamine (METH) is a major health problem without effective pharmacological treatment. Cannabidiol (CBD), a component of the Cannabis sativa plant, is believed to have the potential to inhibit drug-related behavior. However, the neurobiological mechanisms responsible for the effects of CBD remain unclear. Several studies have proposed that the suppressing effects of CBD on drug-seeking behaviors could be through the modulation of the dopamine system. The hippocampus (HIP) D1-like dopamine receptor (D1R) is essential for forming and retrieving drug-associated memory. Therefore, the present study aimed to investigate the role of D1R in the hippocampal CA1 region on the effects of CBD on the extinction and reinstatement of METH-conditioned place preference (CPP). For this purpose, different groups of rats over a 10-day extinction period were administered different doses of intra-CA1 SCH23390 (0.25, 1, or 4 µg/0.5 µl, Saline) as a D1R antagonist before ICV injection of CBD (10 µg/5 µl, DMSO12%). In addition, a different set of animals received intra-CA1 SCH23390 (0.25, 1, or 4 µg/0.5 µl) before CBD injection (50 µg/5 µl) on the reinstatement day. The results revealed that the highest dose of SCH23390 (4 µg) significantly reduced the accelerating effects of CBD on the extinction of METH-CPP (P < 0.01). Furthermore, SCH23390 (1 and 4 µg) in the reinstatement phase notably reversed the preventive effects of CBD on the reinstatement of drug-seeking behavior (P < 0.05 and P < 0.001, respectively). In conclusion, the current study revealed that CBD made a shorter extinction period and suppressed METH reinstatement in part by interacting with D1-like dopamine receptors in the CA1 area of HIP.

Determining Ideal Management for Patients With Coexisting Prolactinomas and Psychiatric Symptoms: A Systematic Review.

OBJECTIVE: Prolactinomas-pituitary tumors that overproduce prolactin-can cause various troublesome symptoms. Dopamine agonists (DAs) reduce prolactin production in the prolactin pathway, making them the first-line treatment for prolactinomas. However, the main side effect of DA treatment, hyperdopaminergia, is an explicit etiology for psychiatric side effects. Psychiatric conditions are often treated with dopamine antagonists, which can induce hyperprolactinemia. This presents a challenge for patients with both a prolactinoma and a preexisting psychiatric condition, as treatment of one condition could worsen the other. This review seeks to identify an adequate therapeutic regimen for patients with coexisting prolactinomas and psychiatric symptoms. METHODS: This review examined PubMed citations from 1960 to 2023 published in English and involving human subjects. Case reports, case series, and cohort studies involving patients with concomitant prolactinomas and psychiatric symptoms, as validated by brain imaging, serologic prolactin levels, and medical history or chart reports of psychiatric symptoms, were included. RESULTS: Thematic analysis included 23 reports involving 42 participants; 27 of the 42 patients experienced a significant reduction in prolactin levels and psychiatric symptoms (64%). Treatment of those 42 patients included discontinuing or altering antipsychotic/dopamine antagonist therapy or discontinuing DA therapy to reduce psychiatric symptoms, with surgery or radiation postpharmacotherapy as a last-line strategy. However, in some cases (reported in Tables 2 to 4), either psychiatric or prolactin-related symptoms recurred despite adjustment. CONCLUSIONS: Clinicians may find it beneficial to prioritize specific antipsychotics (aripiprazole, olanzapine, ziprasidone, or clozapine) over others (risperidone, thioridazine, thiothixene, and remoxipride). Discontinuing DA medication at least periodically until the patient's condition improves may also be advisable. If these 2 initial approaches do not yield a significant improvement in symptom management, surgery or radiation therapy may be considered. As patients may respond differently to these therapies, our study still recommends a patient-centered approach.

1-(Phenylselanyl)-2-(p-tolyl)indolizine: A selenoindolizine with potential antidepressant-like activity in mice mediated by the modulation of dopaminergic and noradrenergic systems.

1-(Phenylselanyl)-2-(p-tolyl)indolizine (MeSeI) is a selenoindolizine with an antidepressant-like effect in mice by regulation of the serotonergic system. This study investigated the involvement of dopaminergic and noradrenergic systems in the antidepressant-like action of MeSeI. For this purpose, Swiss male mice were pretreated with different antagonists, after 15 min, the MeSeI was administrated by intragastric (i.g.) via; after 30 min, the mouse behavior was assessed in the forced swimming test (FST). The action of MeSeI on the activity of monoamine oxidase (MAO) was determined. The pretreatment of mice with haloperidol (0.05 mg/kg, intraperitoneally, i.p.; non-selective dopamine receptor antagonist), sulpiride (50 mg/kg, i.p.; D2 receptor antagonist), yohimbine (1 mg/kg, i.p.; α2 receptor antagonist), and propranolol (2 mg/kg, i.p.; non-selective ß receptor antagonist), inhibited the anti-immobility action of MeSeI (50 mg/kg, i.g.) in the FST. This blocking effect was not observed when SCH23390 (0.01 mg/kg, i.p.; D1 receptor antagonist), and prazosin (1 mg/kg, i.p.; α1 receptor antagonist) were administered. The coadministration of subeffective doses of bupropion (3 mg/kg. i.g.; dopamine and noradrenaline reuptake inhibitor) and MeSeI (0.5 mg/kg. i.g.) reduced the immobility time in the FST. Furthermore, MeSeI inhibited MAO-A and B activities in vitro and ex vivo tests. These results suggest that MeSeI exerts its antidepressant-like effect via regulation of the D2, α2, and ß1 receptors and the inhibition of MAO-A and B activities. Molecular docking investigations corroborated these results. This study provides comprehensive insights into the antidepressant-like mechanism of MeSeI in mice, suggesting its potential as a novel antidepressant candidate.

Dopaminergic Modulation and Computational ADMET Insights for the Antidepressant-like Effect of N-(3-(Phenylselanyl)prop-2-yn-1-yl)benzamide.

The compound N-(3-(phenylselanyl)prop-2-yn-1-yl)benzamide (SePB), which combines a selenium atom and a benzamide nucleus in an organic structure, has demonstrated a fast antidepressant-like effect in mice. This action is influenced by the serotonergic system and represents a promising development in the search for novel antidepressant drugs to treat major depressive disorder (MDD), which often resists conventional treatments. This study aimed to further explore the mechanism underlying the antidepressant-like effect of SePB by investigating the involvement of the dopaminergic and noradrenergic systems in the tail suspension test (TST) in mice and evaluating its pharmacokinetic profile in silico. Preadministration of the dopaminergic antagonists haloperidol (0.05 mg/kg, intraperitoneally (i.p.)), a nonselective antagonist of dopamine (DA) receptors, SCH23390 (0.01 mg/kg, subcutaneously (s.c.)), a D1 receptor antagonist, and sulpiride (50 mg/kg, i.p.), a D2/3 receptor antagonist, before SePB (10 mg/kg, intragastrically (i.g.)) prevented the anti-immobility effect of SePB in the TST, demonstrating that these receptors are involved in the antidepressant-like effect of SePB. Administration of the noradrenergic antagonists prazosin (1 mg/kg, i.p.), an α1-adrenergic antagonist, yohimbine (1 mg/kg, i.p.), an α2-adrenergic antagonist, and propranolol (2 mg/kg, i.p.), a ß-adrenergic antagonist, did not block the antidepressant-like effect of SePB on TST, indicating that noradrenergic receptors are not involved in this effect. Additionally, the coadministration of SePB and bupropion (a noradrenaline/dopamine reuptake inhibitor) at subeffective doses (0.1 and 3 mg/kg, respectively) produced antidepressant-like effects. SePB also demonstrated good oral bioavailability and low toxicity in computational absorption, distribution, metabolism, excretion, and toxicity (ADMET) analyses. These findings suggest that SePB has potential as a new antidepressant drug candidate with a particular focus on the dopaminergic system.

Current and emerging pharmacotherapy for the treatment of gastroparesis.

INTRODUCTION: Gastroparesis is a chronic disorder characterized by decreased gastric emptying and presents with nausea, vomiting, and abdominal pain which impacts patients' quality of life greatly. The treatment modalities available for gastroparesis have been expanding over the past 2 decades. Currently, there are multiple options available for gastroparesis, albeit with only one FDA-approved medication until June 2021. AREAS COVERED: We review the different treatments available for gastroparesis and discuss the recently FDA-approved intranasal formulation of metoclopramide. This nasal spray guarantees metoclopramide absorption within 15 min of application bypassing first pass metabolism in the liver and overcoming the limitations of the oral formulation not passing into the small intestine for absorption because of a gastroparetic stomach or a patient unable to take the oral metoclopramide because of nausea and vomiting. EXPERT OPINION: We now find ourselves in an oasis after spending many years in a 'desert' regarding pharmacologic therapies available for gastroparesis. The expansion of the research involving dopamine receptor antagonists and delving into alternative mechanisms of alleviating gastroparesis symptoms has been crucial in the landscape of gastroparesis. This is especially true as our knowledge of gastroparesis has proven that simply improving gastric emptying does not necessarily translate to clinical improvement.

SKF82958, a dopamine D1 receptor agonist, disrupts prepulse inhibition in the medial prefrontal cortex and nucleus accumbens in C57BL/6J mice.

Prepulse inhibition (PPI) is a crucial indicator of sensorimotor gating that is often impaired in neuropsychiatric diseases. Although dopamine D1 receptor agonists have been found to disrupt PPI in mice, the underlying mechanisms are not fully understood. In this study, we aimed to identify the brain regions responsible for the PPI-disruptive effect of the D1 agonist in mice. Results demonstrated that intraperitoneal administration of the selective dopamine D1 receptor agonist SKF82958 dramatically inhibited PPI, while the dopamine D1 receptor antagonist SCH23390 enhanced PPI. Additionally, local infusion of SKF82958 into the nucleus accumbens and medial prefrontal cortex disrupted PPI, but not in the ventral hippocampus. Infusion of SCH23390 into these brain regions also failed to enhance PPI. Overall, the study suggests that the nucleus accumbens and medial prefrontal cortex are responsible for the PPI-disruptive effect of dopamine D1 receptor agonists. These findings provide essential insights into the cellular and neural circuit mechanisms underlying the disruptive effects of dopamine D1 receptor agonists on PPI and may contribute to the development of novel treatments for neuropsychiatric diseases.

Dual roles of dopaminergic pathways in olfactory learning and memory in the oriental fruit fly, Bactrocera dorsalis.

Dopamine (DA) is a key regulator of associative learning and memory in both vertebrates and invertebrates, and it is widely believed that DA plays a key role in aversive conditioning in invertebrates. However, the idea that DA is involved only in aversive conditioning has been challenged in recent studies on the fruit fly (Drosophila melanogaster), ants and crabs, suggesting diverse functions of DA modulation on associative plasticity. Here, we present the results of DA modulation in aversive olfactory conditioning with DEET punishment and appetitive olfactory conditioning with sucrose reward in the oriental fruit fly, Bactrocera dorsalis. Injection of DA receptor antagonist fluphenazine or chlorpromazine into these flies led to impaired aversive learning, but had no effect on the appetitive learning. DA receptor antagonists impaired both aversive and appetitive long-term memory retention. Interestingly, the impairment on appetitive memory was rescued not only by DA but also by octopamine (OA). Blocking the OA receptors also impaired the appetitive memory retention, but this impairment could only be rescued by OA, not by DA. Thus, we conclude that in B. dorsalis, OA and DA pathways mediate independently the appetitive and aversive learning, respectively. These two pathways, however, are organized in series in mediating appetitive memory retrieval with DA pathway being at upstream. Thus, OA and DA play dual roles in associative learning and memory retrieval, but their pathways are organized differently in these two cognitive processes - parallel organization for learning acquisition and serial organization for memory retrieval.

Commonly used antiemetics for prophylaxis of postoperative nausea and vomiting after Caesarean delivery with neuraxial morphine: a network meta-analysis.

BACKGROUND: Dopamine antagonists, 5-HT3 antagonists, and dexamethasone are frequently used in obstetrics to prevent postoperative nausea and vomiting (PONV). However, the superiority of any drug class is yet to be established. This network meta-analysis aimed to compare the efficacy of these antiemetics for PONV prophylaxis in women receiving neuraxial morphine for Caesarean delivery. METHODS: We searched PubMed, Embase, CENTRAL, Web of Science, and Wanfang Data for eligible randomised controlled trials. Primary outcomes were the incidences of postoperative nausea (PON) and postoperative vomiting (POV) within 24 h after surgery. We used a Bayesian random-effects model and calculated odds ratios with 95% credible intervals for dichotomous data. We performed sensitivity and subgroup analyses for primary outcomes. RESULTS: A total of 33 studies with 4238 women were included. In the primary analyses of all women, 5-HT3 antagonists, dopamine antagonists, dexamethasone, and 5-HT3 antagonists plus dexamethasone significantly reduced PON and POV compared with placebo, and 5-HT3 antagonists plus dexamethasone were more effective than monotherapy. In the subgroup analyses, similar results were seen in women receiving epidural morphine or intrathecal morphine alone but not in women receiving intrathecal morphine with fentanyl or sufentanil. However, most included studies had some concerns or a high risk of bias, and the overall certainty of the evidence was low or very low. CONCLUSIONS: Combined 5-HT3 antagonists plus dexamethasone are more effective than monotherapy in preventing PONV associated with neuraxial morphine after Caesarean delivery. Future studies are needed to determine the role of prophylactic antiemetics in women receiving intrathecal morphine and lipophilic opioids. SYSTEMATIC REVIEW PROTOCOL: PROSPERO CRD42023454602.

Sex similarities and dopaminergic differences in interval timing.

Rodent behavioral studies have largely focused on male animals, which has limited the generalizability and conclusions of neuroscience research. Working with humans and rodents, we studied sex effects during interval timing that requires participants to estimate an interval of several seconds by making motor responses. Interval timing requires attention to the passage of time and working memory for temporal rules. We found no differences between human females and males in interval timing response times (timing accuracy) or the coefficient of variance of response times (timing precision). Consistent with prior work, we also found no differences between female and male rodents in timing accuracy or precision. In female rodents, there was no difference in interval timing between estrus and diestrus cycle stages. Because dopamine powerfully affects interval timing, we also examined sex differences with drugs targeting dopaminergic receptors. In both female and male rodents, interval timing was delayed after administration of sulpiride (D2-receptor antagonist), quinpirole (D2-receptor agonist), and SCH-23390 (D1-receptor antagonist). By contrast, after administration of SKF-81297 (D1-receptor agonist), interval timing shifted earlier only in male rodents. These data illuminate sex similarities and differences in interval timing. Our results have relevance for rodent models of both cognitive function and brain disease by increasing representation in behavioral neuroscience. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Dopamine D2 Receptor Modulates Exercise Related Effect on Cortical Excitation/Inhibition and Motor Skill Acquisition.

Exercise is known to benefit motor skill learning in health and neurological disease. Evidence from brain stimulation, genotyping, and Parkinson's disease studies converge to suggest that the dopamine D2 receptor, and shifts in the cortical excitation and inhibition (E:I) balance, are prime candidates for the drivers of exercise-enhanced motor learning. However, causal evidence using experimental pharmacological challenge is lacking. We hypothesized that the modulatory effect of the dopamine D2 receptor on exercise-induced changes in the E:I balance would determine the magnitude of motor skill acquisition. To test this, we measured exercise-induced changes in excitation and inhibition using paired-pulse transcranial magnetic stimulation (TMS) in 22 healthy female and male humans, and then had participants learn a novel motor skill-the sequential visual isometric pinch task (SVIPT). We examined the effect of D2 receptor blockade (800 mg sulpiride) on these measures within a randomized, double-blind, placebo-controlled design. Our key result was that motor skill acquisition was driven by an interaction between the D2 receptor and E:I balance. Specifically, poorer skill learning was related to an attenuated shift in the E:I balance in the sulpiride condition, whereas this interaction was not evident in placebo. Our results demonstrate that exercise-primed motor skill acquisition is causally influenced by D2 receptor activity on motor cortical circuits.

A Comprehensive Review of Solriamfetol to Treat Excessive Daytime Sleepiness.

Purpose of Review: This is a comprehensive review of the literature regarding the use of Solriamfetol for excessive daytime sleepiness. It covers the background and current therapeutic approaches to treating excessive daytime sleepiness, the management of common comorbidities, and the existing evidence investigating the use of Solriamfetol for this purpose. Recent Findings: Excessive daytime sleepiness leads to worse quality of life, a medical sequela and significant economic cost. There are multiple phenotypes of excessive daytime sleepiness depending on the comorbidity making treatment challenging. Due to the complexity of etiology there is not a cure for this ailment. Solriamfetol is a norepinephrine/dopamine dual reuptake antagonist that can be used to manage daytime sleepiness. Solriamfetol was first approved by the FDA in 2018 for use in excessive daytime sleepiness associated with obstructive sleep apnea and narcolepsy. Ongoing literature has proved this drug to be a safe and effective alternative pharmacotherapy. Summary: Recent epidemiological data estimate up to one-third of the general adult population suffers from excessive daytime sleepiness. There is no cure to daytime somnolence and current pharmacotherapeutic regimens have worrisome side effect profiles. Solriamfetol is a new class of drug that offers a safe and effective alternative option for clinical providers treating excessive daytime sleepiness.

Dopamine transmission in the tail striatum: Regional variation and contribution of dopamine clearance mechanisms.

The striatum can be divided into four anatomically and functionally distinct domains: the dorsolateral, dorsomedial, ventral and the more recently identified caudolateral (tail) striatum. Dopamine transmission in these striatal domains underlies many important behaviours, yet little is known about this phenomenon in the tail striatum. Furthermore, the tail is divided anatomically into four divisions (dorsal, medial, intermediate and lateral) based on the profile of D1 and D2 dopamine receptor-expressing medium spiny neurons, something that is not seen elsewhere in the striatum. Considering this organisation, how dopamine transmission occurs in the tail striatum is of great interest. We recorded evoked dopamine release in the four tail divisions, with comparison to the dorsolateral striatum, using fast-scan cyclic voltammetry in rat brain slices. Contributions of clearance mechanisms were investigated using dopamine transporter knockout (DAT-KO) rats, pharmacological transporter inhibitors and dextran. Evoked dopamine release in all tail divisions was smaller in amplitude than in the dorsolateral striatum and, importantly, regional variation was observed: dorsolateral ≈ lateral > medial > dorsal ≈ intermediate. Release amplitudes in the lateral division were 300% of that in the intermediate division, which also exhibited uniquely slow peak dopamine clearance velocity. Dopamine clearance in the intermediate division was most dependent on DAT, and no alternative dopamine transporters investigated (organic cation transporter-3, norepinephrine transporter and serotonin transporter) contributed significantly to dopamine clearance in any tail division. Our findings confirm that the tail striatum is not only a distinct dopamine domain but also that each tail division has unique dopamine transmission characteristics. This supports that the divisions are not only anatomically but also functionally distinct. How this segregation relates to the overall function of the tail striatum, particularly the processing of multisensory information, is yet to be determined.

The dopamine 3 receptor as a candidate biomarker and therapeutic for opioid use disorder.

Here, we present recent studies suggesting that specific DRD3 single nucleotide polymorphisms (SNPs, e.g. rs324029 and rs2654754) might serve as prognostic biomarkers for opioid use disorder (OUD). Additionally, preclinical studies with novel dopamine 3 receptor (D3R) partial agonists and antagonists have been evaluated as candidate OUD therapeutics and have shown a reduced risk of cardiovascular toxicity compared with the original D3R antagonist. From these findings, we argue that DRD3 SNPs could serve as a diagnostic tool for assessing OUD risk and that more research is warranted examining the D3R as a safe and effective therapeutic target for treating OUD.

No major effect of dopamine receptor 1/5 antagonist SCH-23390 on epileptic activity in the Tg2576 mouse model of amyloidosis.

The excitation-inhibition imbalance manifesting as epileptic activities in Alzheimer's disease is gaining more and more attention, and several potentially involved cellular and molecular pathways are currently under investigation. Based on in vitro studies, dopamine D1-type receptors in the anterior cingulate cortex and the hippocampus have been proposed to participate in this peculiar co-morbidity in mouse models of amyloidosis. Here, we tested the implication of dopaminergic transmission in vivo in the Tg2576 mouse model of Alzheimer's disease by monitoring epileptic activities via intracranial EEG before and after treatment with dopamine antagonists. Our results show that neither the D1-like dopamine receptor antagonist SCH23390 nor the D2-like dopamine receptor antagonist haloperidol reduces the frequency of epileptic activities. While requiring further investigation, our results indicate that on a systemic level, dopamine receptors are not significantly contributing to epilepsy observed in vivo in this mouse model of Alzheimer's disease.

Brain connectivity changes to fast versus slow dopamine increases.

The rewarding effects of stimulant drugs such as methylphenidate (MP) depend crucially on how fast they raise dopamine in the brain. Yet how the rate of drug-induced dopamine increases impacts brain network communication remains unresolved. We manipulated route of MP administration to generate fast versus slow dopamine increases. We hypothesized that fast versus slow dopamine increases would result in a differential pattern of global brain connectivity (GBC) in association with regional levels of dopamine D1 receptors, which are critical for drug reward. Twenty healthy adults received MP intravenously (0.5 mg/kg; fast dopamine increases) and orally (60 mg; slow dopamine increases) during simultaneous [11C]raclopride PET-fMRI scans (double-blind, placebo-controlled). We tested how GBC was temporally associated with slow and fast dopamine increases on a minute-to-minute basis. Connectivity patterns were strikingly different for slow versus fast dopamine increases, and whole-brain spatial patterns were negatively correlated with one another (rho = -0.54, pspin < 0.001). GBC showed "fast>slow" associations in dorsal prefrontal cortex, insula, posterior thalamus and brainstem, caudate and precuneus; and "slow>fast" associations in ventral striatum, orbitofrontal cortex, and frontopolar cortex (pFDR < 0.05). "Fast>slow" GBC patterns showed significant spatial correspondence with D1 receptor availability (estimated via normative maps of [11C]SCH23390 binding; rho = 0.22, pspin < 0.05). Further, hippocampal GBC to fast dopamine increases was significantly negatively correlated with self-reported 'high' ratings to intravenous MP across individuals (r(19) = -0.68, pbonferroni = 0.015). Different routes of MP administration produce divergent patterns of brain connectivity. Fast dopamine increases are uniquely associated with connectivity patterns that have relevance for the subjective experience of drug reward.

Nucleus accumbens core dopamine D2 receptors are required for performance of the odor span task in male rats.

RATIONALE: The nucleus accumbens (NAc) core gates motivationally relevant behavioral action sequences through afferents from cortical and subcortical brain regions. While the role of the NAc core in reward and effort-based decision making is well established, its role in working memory (WM) processes is incompletely understood. The odor span task (OST) has been proposed as a measure of non-spatial working memory capacity (WMC) as it requires rodents to select a novel odor from an increasing number of familiar odors to obtain a food reward. OBJECTIVE: To assess the role of the NAc core in the OST using (1) reversible chemical inactivation and (2) selective blockade of dopamine D1 and D2 receptors in the area. METHODS: Well-trained male rats were tested on the OST following intra-NAc core infusions of muscimol/baclofen, the D1 receptor antagonist SCH-23390 (1 µg/hemisphere) and the D2 receptor antagonist eticlopride (1 µg/hemisphere). Behavioral measurements included the average odor span, maximum odor span, choice latency, searching vigor, and patterns of responding during foraging that may relate to impulsivity. RESULTS: Chemical inactivation of the NAc core significantly decreased odor span relative to sham and vehicle conditions. Selective antagonism of D2, but not D1, receptors in the NAc core also produced deficits in odor span. We found that secondary behavioral measures of choice latency, searching vigor, and responding to the first odor stimulus encountered were largely unaffected by treatment. CONCLUSIONS: These findings suggest that D2 receptors in the NAc core are required for OST performance.

The dopamine receptor D1 inhibitor, SKF83566, suppresses GBM stemness and invasion through the DRD1-c-Myc-UHRF1 interactions.

BACKGROUND: Extensive local invasion of glioblastoma (GBM) cells within the central nervous system (CNS) is one factor that severely limits current treatments. The aim of this study was to uncover genes involved in the invasion process, which could also serve as therapeutic targets. For the isolation of invasive GBM cells from non-invasive cells, we used a three-dimensional organotypic co-culture system where glioma stem cell (GSC) spheres were confronted with brain organoids (BOs). Using ultra-low input RNA sequencing (ui-RNA Seq), an invasive gene signature was obtained that was exploited in a therapeutic context. METHODS: GFP-labeled tumor cells were sorted from invasive and non-invasive regions within co-cultures. Ui-RNA sequencing analysis was performed to find a gene cluster up-regulated in the invasive compartment. This gene cluster was further analyzed using the Connectivity MAP (CMap) database. This led to the identification of SKF83566, an antagonist of the D1 dopamine receptor (DRD1), as a candidate therapeutic molecule. Knockdown and overexpression experiments were performed to find molecular pathways responsible for the therapeutic effects of SKF83566. Finally, the effects of SKF83566 were validated in orthotopic xenograft models in vivo. RESULTS: Ui-RNA seq analysis of three GSC cell models (P3, BG5 and BG7) yielded a set of 27 differentially expressed genes between invasive and non-invasive cells. Using CMap analysis, SKF83566 was identified as a selective inhibitor targeting both DRD1 and DRD5. In vitro studies demonstrated that SKF83566 inhibited tumor cell proliferation, GSC sphere formation, and invasion. RNA sequencing analysis of SKF83566-treated P3, BG5, BG7, and control cell populations yielded a total of 32 differentially expressed genes, that were predicted to be regulated by c-Myc. Of these, the UHRF1 gene emerged as the most downregulated gene following treatment, and ChIP experiments revealed that c-Myc binds to its promoter region. Finally, SKF83566, or stable DRD1 knockdown, inhibited the growth of orthotopic GSC (BG5) derived xenografts in nude mice. CONCLUSIONS: DRD1 contributes to GBM invasion and progression by regulating c-Myc entry into the nucleus that affects the transcription of the UHRF1 gene. SKF83566 inhibits the transmembrane protein DRD1, and as such represents a candidate small therapeutic molecule for GBMs.