Central Dopamine Research Articles

D4 and D5 dopamine receptor mRNA expression in human peripheral blood lymphocytes among cooccurring opioid and amphetamine-type stimulants use disorder undergoing methadone maintenance therapy

Introduction: Opioid and amphetamine type stimulant (ATS) exert their rewarding effects by stimulating the dopaminergic system in the mesolimbic area. It has been suggested that dopamine system in peripheral blood lymphocytes reflect the central dopamine system’s activity and pathology, especially in neuropsychiatric diseases including drug addiction. The present study aimed to assess the effect of co-occurring opioid and ATS (COATS) addiction towards mRNA expression of dopamine receptors DRD4 and DRD5 in peripheral blood lymphocytes (PBLs) of drug dependent subjects (n=36) undergoing methadone maintenance therapy in comparison to control subjects (n=36).
 Materials and methods: Ten mL blood were obtained from the subjects followed by lymphocyte isolation, RNA extraction and reverse transcription. DRD4 and DRD5 mRNA expression in peripheral lymphocytes was assessed using real-time PCR. The DRD4 mRNA expression but not DRD5 was significantly reduced in the peripheral lymphocytes of COATS subjects.
 Results: Mean expression value for DRD4 was 14.0+0.24 among patients and 13.3+0.25 among control subjects. For DRD5 it was 12.87 + 0.75 among patients and 12.59 + 1.24 among controls.
 Conclusion: Inconclusion, co-occurring opioid and ATS addiction was associated with persistent deficiency of DRD4 but not DRD5 in PBLs.
 Bangladesh Journal of Medical Science Vol.20(3) 2021 p.563-568

New therapeutic agents marketed in 2020: Part 2

New therapeutic agents marketed in 2020: Part 2

Acute depletion of dopamine precursors in the human brain: effects on functional connectivity and alcohol attentional bias.

Individuals who abuse alcohol often show exaggerated attentional bias (AB) towards alcohol-related cues, which is thought to reflect reward conditioning processes. Rodent studies indicate that dopaminergic pathways play a key role in conditioned responses to reward- and alcohol-associated cues. However, investigation of the dopaminergic circuitry mediating this process in humans remains limited. We hypothesized that depletion of central dopamine levels in adult alcohol drinkers would attenuate AB and that these effects would be mediated by altered function in frontolimbic circuitry. Thirty-four male participants (22-38 years, including both social and heavy drinkers) underwent a two-session, placebo-controlled, double-blind dopamine precursor depletion procedure. At each visit, participants consumed either a balanced amino acid (control) beverage or an amino acid beverage lacking dopamine precursors (order counterbalanced), underwent resting-state fMRI, and completed behavioral testing on three AB tasks: an alcohol dot-probe task, an alcohol attentional blink task, and a task measuring AB to a reward-conditioned cue. Dopamine depletion significantly diminished AB in each behavioral task, with larger effects among subjects reporting higher levels of binge drinking. The depletion procedure significantly decreased resting-state functional connectivity among ventral tegmental area, striatum, amygdala, and prefrontal regions. Beverage-related AB decreases were mediated by decreases in functional connectivity between the fronto-insular cortex and striatum and, for alcohol AB only, between anterior cingulate cortex and amygdala. The results support a substantial role for dopamine in AB, and suggest specific dopamine-modulated functional connections between frontal, limbic, striatal, and brainstem regions mediate general reward AB versus alcohol AB.

Dopaminergic Modulation of Forced Running Performance in Adolescent Rats: Role of Striatal D1 and Extra-striatal D2 Dopamine Receptors

Improving exercise capacity during adolescence impacts positively on cognitive and motor functions. However, the neural mechanisms contributing to enhance physical performance during this sensitive period remain poorly understood. Such knowledge could help to optimize exercise programs and promote a healthy physical and cognitive development in youth athletes. The central dopamine system is of great interest because of its role in regulating motor behavior through the activation of D1 and D2 receptors. Thus, the aim of the present study is to determine whether D1 or D2 receptor signaling contributes to modulate the exercise capacity during adolescence and if this modulation takes place through the striatum. To test this, we used a rodent model of forced running wheel that we implemented recently to assess the exercise capacity. Briefly, rats were exposed to an 8-day period of habituation in the running wheel before assessing their locomotor performance in response to an incremental exercise test, in which the speed was gradually increased until exhaustion. We found that systemic administration of D1-like (SCH23390) and/or D2-like (raclopride) receptor antagonists prior to the incremental test reduced the duration of forced running in a dose-dependent manner. Similarly, locomotor activity in the open field was decreased by the dopamine antagonists. Interestingly, this was not the case following intrastriatal infusion of an effective dose of SCH23390, which decreased motor performance during the incremental test without disrupting the behavioral response in the open field. Surprisingly, intrastriatal delivery of raclopride failed to impact the duration of forced running. Altogether, these results indicate that the level of locomotor response to incremental loads of forced running in adolescent rats is dopamine dependent and mechanistically linked to the activation of striatal D1 and extra-striatal D2 receptors.

Does positive feeling lead to more impulsiveness? - Implication of previous rewarded experience on location-dependent motoric impulsivity.

Positive feeling or rewarding experience is crucial for individuals to operative their cognitive activities via an outcome evaluation of incentive reinforcement. For a long time, rewarding process or outcome evaluation is assumed greatly influenced by neuronal construct that holds individuals' impulsiveness, a capacity to inhibit unwanted behaviors provoked in a given situation. In the present study, we proposed that the outcome evaluation or rewarding experience can influence the occurrence of impulsiveness too. We hypothesized that animals would be more likely to deliver impulsive action in the place where it was previously associated with reinforcing process, in which central dopamine may play an important role. By employing five-choice serial reaction time task (5-CSRTT), we examined whether one of the five holes where rats made a correct response to get the reward would gain a higher probability to deliver premature or perseverative activities than other holes in the next trial of 5-CSRTT under baseline or longer waiting period condition. The effects of D1 receptor antagonist SCH23390 were also evaluated in the above paradigm. We demonstrated that (i) the influence on motoric impulsive response from previous rewarded experience can be described in a behavioral paradigm such as the 5-CSRTT, (ii) both prematures and perseverations at the hole associated with previous rewarding were about one-fifth of probability, however were statistically not correlated unless the interventions of inter-trial interval = 7 plus SCH23390, and (iii) the hole associated with the positive reinforcement of the 5-CSRTT appears more likely for rats to carry out an intuitive impetus under SCH23390 in a longer waiting condition. Our results may shed some insight toward the role of rewarding process in impulsive behavior.

Participation of dopaminergic system in the dynamics of behavioral reactions of aging rats of both sexes under daily testing in the open field

Under daily testing of aging rats of both sexes in the open field a slow lowering of motion activity is observed: by the 6th day of the experiment the passed distance of male rats reduces by 41% (р≤0.01), and of female rats – by 46% (р≤0.05) in comparison to the background values. The blockade of monoamine oxidase-B (МАО-В) by selegiline (intraperitoneal Introduction of 5 mg/kg one hour before testing) does not significantly change the orientation and intensity of this process, but probably contribute to the formation of a more comfortable psycho-emotional state of the animals. Consequently, the central dopamine cannot prevent from the motion activity lowering process of aging rats under daily testing, at least, in the frames of the experiment method used in this research. We obtained the evidence in favor of the fact that the suppression of the motion activity under daily testing is rather connected with the animals’ loss of motivation for research than with the growing anxiety.

Dopamine genetic risk score predicts impulse control behaviors in Parkinson’s disease

IntroductionUp to 40% of Parkinson’s disease patients taking dopamine agonist medication develop impulse control behaviors which can have severe negative consequences. The current study aimed to utilize dopamine genetics to identify patients most at risk of developing these behaviors. MethodsDemographic, clinical, and genetic data were obtained from the Parkinson’s Progression Markers Initiative for de novo patients (n = 327), patients taking dopamine agonists (n = 146), and healthy controls (n = 160). Impulsive behaviors were identified using the Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease. A dopamine genetic risk score was calculated for each patient according to polymorphisms in genes coding for dopamine D1, D2 and D3 receptors, and catechol-O-methyltransferase. A higher score reflected higher central dopamine neurotransmission. ResultsPatients on agonists with a low dopamine genetic risk score were over 18 times more likely to have an impulsive behavior compared to higher scores (p = 0.04). The 38% of patients taking agonists who had at least one impulsive behavior were more likely to be male and report higher Unified Parkinson’s Disease Rating Scale I&II scores. With increasing time on dopamine agonists (range 92–2283 days, mean 798 ± 565 standard deviation), only patients with a high dopamine genetic risk score showed an increase in number of impulsive behaviors (p = 0.033). Predictive effects of the gene score were not present in de novo or healthy control. ConclusionsA dopamine genetic risk score can identify patients most at risk of developing impulsive behaviors on dopamine agonist medication and predict how these behaviors may worsen over time.

Preliminary evidence for an association between intake of high-fat high-sugar diet, variations in peripheral dopamine precursor availability and dopamine-dependent cognition in humans.

Obesity is associated with alterations in dopaminergic transmission and cognitive function. Rodent studies suggest that diets rich in saturated fat and refined sugars (HFS), as opposed to diets diets low in saturated fat and refined sugars (LFS), change the dopamine system independent of excessive body weight. However, the impact of HFS on the human brain has not been investigated. Here, we compared the effect of dietary dopamine depletion on dopamine-dependent cognitive task performance between two groups differing in habitual intake of dietary fat and sugar. Specifically, we used a double-blind within-subject cross-over design to compare the effect of acute phenylalanine/tyrosine depletion on a reinforcement learning and a working memory task, in two groups that are on opposite ends of the spectrum of self-reported HFS intake (low vs high intake: LFS vs HFS group). We tested 31 healthy young women matched for body mass index (mostly normal weight to overweight) and IQ. Depletion of peripheral precursors of dopamine reduced the working memory specific performance on the operation span task in the LFS, but not in the HFS group (P=0.016). Learning from positive- and negative-reinforcement (probabilistic selection task) was increased in both diet groups after dopamine depletion (P=0.049). As a secondary exploratory research question, we measured peripheral dopamine precursor availability (pDAP) at baseline as an estimate for central dopamine levels. The HFS group had a significantly higher pDAP at baseline compared to the LFS group (P=0.025). Our data provide the first evidence indicating that the intake of HFS is associated with changes in dopamine precursor availability, which is suggestive of changes in central dopamine levels in humans. The observed associations are present in a sample of normal to overweight participants (ie, in the absence of obesity), suggesting that the consumption of a HFS might already be associated with altered behaviours. Alternatively, the effects of HFS diet and obesity might be independent.

Central dopamine D2 receptors regulate plasma glucose levels in mice through autonomic nerves

Recent evidence suggests that the central nervous system (CNS) regulates plasma glucose levels, but the underlying mechanism is unclear. The present study investigated the role of dopaminergic function in the CNS in regulation of plasma glucose levels in mice. I.c.v. injection of neither the dopamine D1 receptor agonist SKF 38393 nor the antagonist SCH 23390 influenced plasma glucose levels. In contrast, i.c.v. injection of both the dopamine D2 receptor agonist quinpirole and the antagonist l-sulpiride increased plasma glucose levels. Hyperglycemia induced by quinpirole and l-sulpiride was absent in dopamine D2 receptor knockout mice. I.c.v. injection of quinpirole and l-sulpiride each increased mRNA levels of hepatic glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, which are the key enzymes for hepatic gluconeogenesis. Systemic injection of the β2 adrenoceptor antagonist ICI 118,551 inhibited hyperglycemia induced by l-sulpiride, but not by quinpirole. In contrast, hyperglycemia induced by quinpirole, but not by l-sulpiride, was inhibited by hepatic vagotomy. These results suggest that stimulation of central dopamine D2 receptors increases plasma glucose level by increasing hepatic glucose production through parasympathetic nerves, whereas inhibition of central dopamine D2 receptors increases plasma glucose level by increasing hepatic glucose production through sympathetic nerves.

Binding of Dopamine D1 Receptor and Noradrenaline Transporter in Individuals with Autism Spectrum Disorder: A PET Study.

Although previous studies have suggested the involvement of dopamine (DA) and noradrenaline (NA) neurotransmissions in the autism spectrum disorder (ASD) pathophysiology, few studies have examined these neurotransmissions in individuals with ASD in vivo. Here, we investigated DA D1 receptor (D1R) and noradrenaline transporter (NAT) binding in adults with ASD (n = 18) and neurotypical controls (n = 20) by utilizing two different PET radioligands, [11C]SCH23390 and (S,S)-[18F]FMeNER-D2, respectively. We found no significant group differences in DA D1R (striatum, anterior cingulate cortex, and temporal cortex) or NAT (thalamus and pons) binding. However, in the ASD group, there were significant negative correlations between DA D1R binding (striatum, anterior cingulate cortex and temporal cortex) and the "attention to detail" subscale score of the Autism Spectrum Quotient. Further, there was a significant positive correlation between DA D1R binding (temporal cortex) and emotion perception ability assessed by the neurocognitive battery. Associations of NAT binding with empathic abilities and executive function were found in controls, but were absent in the ASD group. Although a lack of significant group differences in binding might be partly due to the heterogeneity of ASD, our results indicate that central DA and NA function might play certain roles in the clinical characteristics of ASD.

Breathing and its stimulatory responses in parkinsonism: repercussions for physiotherapy

This study addresses respiratory and motor impairments in an experimental reserpine-induced model of parkinsonism in rats. The role of chronic hypoxia due to diminished ventilation in the development and course of neurodegeneration is addressed. An attempt was made to distinguish between central and peripheral dopamine pathways in the mechanisms of neurodegeneration. A dissociation of putative mechanisms of respiratory and motor impairments is tackled as well. Although this purely experimental study cannot be directly extrapolated to human pathophysiology, the corollaries have been drawn concerning the potential repercussions of the respiratory and motor impairments for the physiotherapeutic procedures in the management of chronic neurodegeneration.

Breathing and its stimulatory responses in parkinsonism: repercussions for physiotherapy

This study addresses respiratory and motor impairments in an experimental reserpine-induced model of parkinsonism in rats. The role of chronic hypoxia due to diminished ventilation in the development and course of neurodegeneration is addressed. An attempt was made to distinguish between central and peripheral dopamine pathways in themechanisms of neurodegeneration. A dissociation of putative mechanisms of respiratory and motor impairments istackled as well. Although this purely experimental study cannot be directly extrapolated to human pathophysiology,the corollaries have been drawn concerning the potential repercussions of the respiratory and motor impairments forthe physiotherapeutic procedures in the management of chronic neurodegeneration.

Dissociation in Pharmacokinetic Attenuation Between Central Dopamine D2 Receptor Occupancy and Peripheral Blood Concentration of Antipsychotics: A Systematic Review.

The objective of this study was to examine the extent of possible dissociation in pharmacokinetic decay between central dopamine D₂ receptor occupancy with antipsychotics and their peripheral blood concentrations. MEDLINE and Embase were searched using the following keywords: (positron emission tomography OR PET OR single-photon emission computed tomography OR SPECT) AND (dopamine OR D2) AND (receptor* OR occupanc*) AND antipsychotic*, with a limitation of English language (last search: December 14, 2019). The search identified 18 studies that met the following criteria: (1) including patients with schizophrenia spectrum disorders and/or healthy subjects, (2) using positron emission tomography or single-photon emission computed tomography, and (3) examining the time courses of D₂ occupancy with antipsychotics and their blood concentrations. The ratios of D₂ occupancy reduction rate (%) from peak to blood concentration reduction rate (%) from peak (relative attenuation ratio) were calculated. Among the studies, oral risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, perospirone, haloperidol, sulpiride, and clozapine and long-acting injectable risperidone and haloperidol were included. Relative attenuation ratios were less than 1, indicating a slower central versus peripheral attenuation, across the time points for all antipsychotic types and doses with only a few exceptions. The ratio decreased in a dose-dependent as well as a peak D₂ occupancy-dependent fashion. It contrarily increased in a time-dependent manner. The findings indicate pharmacokinetic attenuation of antipsychotics was generally slower at the central versus the peripheral level and pose a critical challenge to the current dosing strategy that primarily relies on peripheral pharmacokinetics of antipsychotics.

Development of an in situ injectable hydrogel containing hyaluronic acid for neural regeneration

In this work, a novel enzymatically crosslinked injectable hydrogel comprising hyaluronic acid (HyA), dopamine (DA), and 3-(4-hydroxyphenyl) propionic acid (HPA) conjugates was successfully developed. To the best of our knowledge, it is the first time that HPA is conjugated to a HyA-based backbone. In situ hydrogelation of HyA-DA-HPA occurred in the presence of hydrogen peroxide (H2O2) as an oxidant and horseradish peroxidase (HRP) as a catalyst. Proton nuclear magnetic resonance and Fourier transform infrared spectroscopy were used to characterize the chemical reactions between HyA, DA, and HPA. Gel formation completed between 3 s to 5 min depending on the concentrations of polymer, HRP, and H2O2. Crosslinked HyA-DA-HPA gels acquired storage moduli ranging from ∼100 Pa to ∼20 000 Pa (at f = 2000 rad s−1). Biocompatibility of the hydrogels was examined with human mesenchymal stem cells (hMSCs) and human induced pluripotent stem cell-derived neural stem cells. The hydrogels made of 2.0 w/v% HyA-DA-HPA hydrogels, 0.24 U ml−1 HRP and ≤ 0.5 µmol ml−1 H2O2 were found biocompatible with hMSCs cultured on and encapsulated within the hydrogels. Since HyA serves as a backbone of the extracellular matrix in the central nervous system (CNS) and DA acquires the ability to restore dopaminergic neurons, use of this injectable HyA-DA-HPA hydrogel for stem cell transplantation is a potential treatment strategy for CNS repair and regeneration.

Lorcaserin Alters Serotonin and Noradrenaline Tissue Content and Their Interaction With Dopamine in the Rat Brain.

Lorcaserin is a preferential serotonin2C receptor (5-HT2CR) agonist effective to treat obesity that has also recently been proposed to treat addiction and epilepsy. Central dopamine (DA) mechanisms are likely involved in the lorcaserin mechanism of action, but other monoamines 5-HT and noradrenaline (NA) contents or their interaction with DA might account for its effects. Here we showed that lorcaserin at 3, but not 0.3 mg/kg enhanced 5-HT content in the insular cortex, the core of the nucleus accumbens, and ventral hypothalamus. Without affecting the metabolite 5-hydroxy indole acetic acid, lorcaserin reduced the indirect index of 5-HT turnover in the hippocampus, substantia nigra, and habenula. Lorcaserin at 3 mg/kg increased NA content in the orbitofrontal cortex, the central amygdala (also at 0.3 mg/kg), the ventral hypothalamus, and the shell of the nucleus accumbens. A correlative analysis of the tissue contents between pairs of brain regions revealed that 0.3 mg/kg lorcaserin enhanced the number of correlations for 5-HT, its metabolism, and NA to a lower extent. The correlation profiles were very different between saline, 0.3 and 3 mg/kg lorcaserin. Lorcaserin enhanced the correlations established between NA or 5-HT at 0.3 and 3 mg/kg and reduced the number of correlations established between the index of the turnover for DA and 5-HT. These results show that lorcaserin modulates the biochemistry of NA and 5-HT systems in a subset of brain regions. Qualitatively, they reveal, oppositely to the DA changes, that lorcaserin at 0.3, but not 3 mg/kg, enhanced the number of correlations of 5-HT content between brain regions.

Potential Biomarkers of Peripheral and Central Fatigue in High-Intensity Trained Athletes at High-Temperature: A Pilot Study with Momordica charantia (Bitter Melon).

Among potent dietary supplements, Momordica charantia, commonly called bitter melon, has various biological effects, such as antioxidant and anti-inflammatory effects, and improves energy metabolism and fatigue recovery. However, it is unknown whether Momordica charantia extract (MCE) induces antifatigue effects during exercise training in high-temperature environments. This study aimed at investigating the efficacy of MCE by examining 10 male tennis players consuming 100 mL MCE/dose (6 times a day over 4 weeks) during the summer training season. Peripheral (ammonia and uric acid) and central (serotonin, dopamine, and prolactin) fatigue parameters were measured before and after MCE consumption; before, during, and after exercise; and the next morning. After consuming MCE supplements, ammonia levels were higher during and after exercise and recovered the next morning, whereas uric acid levels did not change at any time point. Serotonin levels were lower during exercise. Dopamine levels were higher, especially during exercise. Prolactin levels were lower at all time points, especially during and after exercise. Although high-intensity training in a hot environment causes accumulation of fatigue-related metabolites, our results indicate that 4 weeks of MCE intake positively influenced fatigue parameters, suggesting that MCE can efficiently combat fatigue.

The role of dopaminergic and serotonergic transmission in the processing of primary and monetary reward.

Natural rewards such as erotic stimuli activate common neural pathways with monetary rewards. In human studies, the manipulation of dopamine and serotonin play an important role in the processing of monetary rewards with less understood on its role on erotic stimuli. In this study, we investigate the neuromodulatory effects of dopaminergic and serotonergic transmission in the processing of erotic versus monetary visual stimuli. We scanned one hundred and two (N = 102) healthy volunteers using functional magnetic resonance imaging while performing a modified version of the well-validated monetary incentive delay task consisting of erotic, monetary and neutral visual stimuli. We show a role for enhanced central dopamine and lowered central serotonin levels in increasing activity in the right caudate and left anterior insula during anticipation of erotic relative to monetary rewards in healthy controls. We further show differential activation in the anticipation of natural versus monetary rewards with the former associated with ventromesial and dorsomesial activity and the latter with dorsal cingulate, striatal and anterior insular activity. These findings are consistent with preclinical and clinical findings of a role for dopaminergic and serotonergic mechanisms in the processing of natural rewards. Our study provides further insights into the neural substrates underlying reward processing for natural primary erotic rewards and yields importance for the neurochemical systems of addictive disorders including gambling disorder.

Dopamine-Related Measurements From Both IPSC-Derived Dopaminergic Neurons and [18F]-FDOPA PET in Patients With Gaucher Disease With and Without Parkinsonism

Derivation of dopaminergic neurons from patients' induced pluripotent stem-cells (iPSCs) can enhance our understanding of the biology of dopamine-related illnesses, such as schizophrenia and Parkinson disease (PD), and provide transformative information for biological psychiatry research. However, whether dopaminergic properties of these neurons capture interindividual variation in central dopamine functioning is unknown. [18F]-FDOPA PET measures presynaptic dopamine synthesis capacity and vesicular storage, identifying hallmark diminished striatal dopaminergic content in idiopathic PD. Since mutations in GBA1, the gene implicated in Gaucher disease (GD), are an important risk factor for parkinsonism, we evaluated individuals with both GD and a family history of PD, testing for correspondence between dopamine-related measurements from both iPSC-derived neurons and molecular neuroimaging of the living brain.

Altered Sexual Behavior in Dopamine Transporter (DAT) Knockout Male Rats: A Behavioral, Neurochemical and Intracerebral Microdialysis Study.

Central dopamine plays a key role in sexual behavior. Recently, a Dopamine Transporter knockout (DAT KO) rat has been developed, which displays several behavioral dysfunctions that have been related to increased extracellular dopamine levels and altered dopamine turnover secondary to DAT gene silencing. This prompted us to characterize the sexual behavior of these DAT KO rats and their heterozygote (HET) and wild type (WT) counterparts in classical copulatory tests with a sexually receptive female rat and to verify if and how the acquisition of sexual experience changes along five copulatory tests in these rat lines. Extracellular dopamine and glutamic acid concentrations were also measured in the dialysate obtained by intracerebral microdialysis from the nucleus accumbens (Acb) shell of DAT KO, HET and WT rats, which underwent five copulatory tests, when put in the presence of an inaccessible sexually receptive female rat and when copulation was allowed. Markers of neurotropism (BDNF, trkB), neural activation (Δ-FosB), functional (Arc and PSA-NCAM) and structural synaptic plasticity (synaptophysin, syntaxin-3, PSD-95) were also measured in the ventral tegmental area (VTA), Acb (shell and core) and medial prefrontal cortex (mPFC) by Western Blot assays. The results indicate that the sexual behavior of DAT KO vs. HET and WT rats shows peculiar differences, mainly due to a more rapid acquisition of stable sexual activity levels and to higher levels of sexual motivation and activity. These differences occurred with differential changes in dopamine and glutamic acid concentrations in Acb dialysates during sexual behavior, with lower increases of dopamine and glutamic acid in DAT KO vs. WT and HET rats, and a lower expression of the markers investigated, mainly in the mPFC, in DAT KO vs. WT rats. Together these findings confirm a key role of dopamine in sexual behavior and provide evidence that the permanently high levels of dopamine triggered by DAT gene silencing cause alterations in both the frontocortical glutamatergic neurons projecting to the Acb and VTA and in the mesolimbic dopaminergic neurons, leading to specific brain regional changes in trophic support and neuroplastic processes, which may have a role in the sexual behavior differences found among the three rat genotypes.

TAK‐906, a Dopamine D2/D3 Receptor Antagonist with Minimal Brain Penetration for Gastrointestinal Disorders

IntroductionMetoclopramide and domperidone are dopamine receptor antagonists utilized for the symptomatic treatment of gastrointestinal disorders such as gastroparesis. Metoclopramide is labeled only for acute use due to the potential for extrapyramidal side‐effects elicited through the blockade of central dopamine D2 receptors, while domperidone is a peripherally selective antagonist but therapy is limited due to the potential for cardiac arrhythmias. TAK‐906 is a dopamine receptor antagonist with minimal CNS penetration and minimal potential for cardiac QTc prolongation/arrhythmia.Methods and ResultsThese studies examined the concentration of TAK‐906 in the cerebral spinal fluid (CSF) compared to plasma in rat or dog. Rat: Concentrations of TAK‐906 in plasma and CSF were assessed in five male and five female Sprague Dawley rats dosed daily via PO gavage for four consecutive days. TAK‐906 was in 5% (v/v) DMSO, 40% (v/v) PEG 400 and 55% (v/v) 0.9% sodium chloride for injection. Blood was collected from jugular vein via syringe on Study Days 1 and 3 at predose and at 1, 6 and 24 hours (hrs) post‐dose. On Study Day 4, blood was collected via cardiac puncture. CSF was collected from the cisterna magna of each animal via syringe. TAK‐906 was detected in CSF samples in limited concentrations relative to concurrent plasma concentrations. The ratio of mean plasma to mean CSF concentrations of TAK‐906 at 1 hr post dose on Day 4 in male or female rats was ~700:1. Prior in vitro studies demonstrated ~90% plasma protein binding of TAK‐906 in rat plasma. Assuming 90% plasma protein binding and zero protein binding in CSF, the ratio of plasma to CSF concentrations of free TAK‐906 was ~70:1 or 98.6% in plasma and 1.4% in CSF. Dog: Five male and five female non‐naïve beagles were administered TAK‐906 as five oral capsules daily for four consecutive days at 50 mg/kg. Blood was collected from a jugular vein on Study Days 1 and 3 at predose and at 1, 6 and 24 hrs and on Study Day 4 at 1 and 3 hrs post dose. For CSF determination, animals were anesthetized, and CSF was collected from the cisterna magna of each animal via syringe and needle at 1 and 3 hrs post dose on Day 4. TAK‐906 was rapidly absorbed following single and repeat PO dose administration to dogs, with high plasma concentrations observed. TAK‐906 CSF concentrations on Day 4 (1 and 3 hrs post dose) was measurable at concentrations that ranged from 1.35–9.79 ng/mL. The ratio of mean plasma to mean CSF concentrations of total TAK‐906 at 1 hr post dose on Day 4 was ~700:1. Prior in vitro studies demonstrated ~90% plasma protein binding of TAK‐906 in dog plasma. Assuming 90% plasma protein binding and zero protein binding in CSF, the ratio of plasma to CSF concentrations of free TAK‐906 was ~70:1 or 98.6% in plasma and 1.4% in CSF. At 3 hrs post dose, TAK‐906 ranged from 1.72–13.2 ng/mL. The ratio of mean plasma to mean CSF concentrations of total TAK‐906 at 3 hrs post dose on Day 4 was ~250:1. This predicts a ratio of plasma to CSF concentrations of free TAK‐906 of ~25:1 or 96% in plasma and 4% in CSF.ConclusionsSingle and repeat dose administration of TAK‐906 to rats or dogs yielded robust plasma exposures with minimal brain/CSF exposures. TAK‐906 has a preclinical profile that provides potential clinical benefits with minimal effect on brain dopaminergic receptors.Support or Funding InformationStudy was sponsored by Altos Therapeutics, LLC.