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ELife Mar 2022Some theories of human cultural evolution posit that humans have social-specific learning mechanisms that are adaptive specialisations moulded by natural selection to...
Some theories of human cultural evolution posit that humans have social-specific learning mechanisms that are adaptive specialisations moulded by natural selection to cope with the pressures of group living. However, the existence of neurochemical pathways that are specialised for learning from social information and individual experience is widely debated. Cognitive neuroscientific studies present mixed evidence for social-specific learning mechanisms: some studies find dissociable neural correlates for social and individual learning, whereas others find the same brain areas and, dopamine-mediated, computations involved in both. Here, we demonstrate that, like individual learning, social learning is modulated by the dopamine D2 receptor antagonist haloperidol when social information is the primary learning source, but not when it comprises a secondary, additional element. Two groups (total N = 43) completed a decision-making task which required primary learning, from own experience, and secondary learning from an additional source. For one group, the primary source was social, and secondary was individual; for the other group this was reversed. Haloperidol affected primary learning irrespective of social/individual nature, with no effect on learning from the secondary source. Thus, we illustrate that dopaminergic mechanisms underpinning learning can be dissociated along a primary-secondary but not a social-individual axis. These results resolve conflict in the literature and support an expanding field showing that, rather than being specialised for particular inputs, neurochemical pathways in the human brain can process both social and non-social cues and arbitrate between the two depending upon which cue is primarily relevant for the task at hand.
Topics: Cues; Dopamine; Dopamine D2 Receptor Antagonists; Haloperidol; Humans; Receptors, Dopamine D2; Reward
PubMed: 35289748
DOI: 10.7554/eLife.74893 -
The Journal of Neuroscience : the... Feb 2017Learning to optimally predict rewards requires agents to account for fluctuations in reward value. Recent work suggests that individuals can efficiently learn about... (Randomized Controlled Trial)
Randomized Controlled Trial
Learning to optimally predict rewards requires agents to account for fluctuations in reward value. Recent work suggests that individuals can efficiently learn about variable rewards through adaptation of the learning rate, and coding of prediction errors relative to reward variability. Such adaptive coding has been linked to midbrain dopamine neurons in nonhuman primates, and evidence in support for a similar role of the dopaminergic system in humans is emerging from fMRI data. Here, we sought to investigate the effect of dopaminergic perturbations on adaptive prediction error coding in humans, using a between-subject, placebo-controlled pharmacological fMRI study with a dopaminergic agonist (bromocriptine) and antagonist (sulpiride). Participants performed a previously validated task in which they predicted the magnitude of upcoming rewards drawn from distributions with varying SDs. After each prediction, participants received a reward, yielding trial-by-trial prediction errors. Under placebo, we replicated previous observations of adaptive coding in the midbrain and ventral striatum. Treatment with sulpiride attenuated adaptive coding in both midbrain and ventral striatum, and was associated with a decrease in performance, whereas bromocriptine did not have a significant impact. Although we observed no differential effect of SD on performance between the groups, computational modeling suggested decreased behavioral adaptation in the sulpiride group. These results suggest that normal dopaminergic function is critical for adaptive prediction error coding, a key property of the brain thought to facilitate efficient learning in variable environments. Crucially, these results also offer potential insights for understanding the impact of disrupted dopamine function in mental illness. To choose optimally, we have to learn what to expect. Humans dampen learning when there is a great deal of variability in reward outcome, and two brain regions that are modulated by the brain chemical dopamine are sensitive to reward variability. Here, we aimed to directly relate dopamine to learning about variable rewards, and the neural encoding of associated teaching signals. We perturbed dopamine in healthy individuals using dopaminergic medication and asked them to predict variable rewards while we made brain scans. Dopamine perturbations impaired learning and the neural encoding of reward variability, thus establishing a direct link between dopamine and adaptation to reward variability. These results aid our understanding of clinical conditions associated with dopaminergic dysfunction, such as psychosis.
Topics: Adaptation, Physiological; Adult; Bromocriptine; Computer Simulation; Corpus Striatum; Dopamine Agonists; Dopamine Antagonists; Double-Blind Method; Female; Genetic Testing; Healthy Volunteers; Humans; Image Processing, Computer-Assisted; Male; Mesencephalon; Motivation; Oxygen; Reward; Sulpiride; Young Adult
PubMed: 28202786
DOI: 10.1523/JNEUROSCI.1979-16.2016 -
Analytical Chemistry Sep 2018The fruit fly, Drosophila melanogaster, is a popular model organism for studying neurological processes and diseases due to the availability of sophisticated genetic...
The fruit fly, Drosophila melanogaster, is a popular model organism for studying neurological processes and diseases due to the availability of sophisticated genetic tools. While endogenous neurotransmitter release has been characterized in Drosophila larvae, here, we measured endogenous dopamine release in isolated adult Drosophila brains for the first time. Dopamine was measured with fast-scan cyclic voltammetry (FSCV), and acetylcholine or nicotine were used as the stimulus, as both interact with nicotinic acetylcholine receptors (nAChRs) to evoke endogenous dopamine release. Stimulations with 10 pmol of acetylcholine elicited 0.26 ± 0.05 μM dopamine, while 70 fmol nicotine stimulations evoked 0.29 ± 0.03 μM in the central complex. Nicotine-stimulated dopamine release lasted much longer than acetylcholine-stimulated release. Dopamine release is reduced in the presence of nAChR antagonist α-bungarotoxin and the sodium channel blocker tetrodotoxin, indicating release is mediated by nAChRs and exocytosis. The identity of dopamine was confirmed by using 3-iodotyrosine, a dopamine synthesis inhibitor, and by confirming that release was not changed in octopamine synthesis mutant flies, Tdc2 . Additionally, the half-decay time ( t) in fumin (67 ± 15 s), dopamine transporter mutant flies, was larger than in wild-type flies (16 ± 3.7 s) further proving that acetylcholine stimulation evokes dopamine release. This study demonstrates that stimulation of nAChRs can be used to elicit endogenous dopamine release in adult fly brains, which will be a useful technique for future studies probing dopamine changes during aging or in neurodegenerative diseases.
Topics: Acetylcholine; Animals; Brain; Bungarotoxins; Dopamine; Dopamine Antagonists; Drosophila melanogaster; Electrochemical Techniques; Exocytosis; Monoiodotyrosine; Nicotine; Nicotinic Antagonists; Octopamine; Receptors, Nicotinic; Reproducibility of Results; Sodium Channel Blockers; Tetrodotoxin
PubMed: 30073836
DOI: 10.1021/acs.analchem.8b02114 -
PloS One 2024Obesity leads to insulin resistance (IR) and type 2 diabetes. In humans, low levels of the hormone prolactin (PRL) correlate with IR, adipose tissue (AT) dysfunction,...
Obesity leads to insulin resistance (IR) and type 2 diabetes. In humans, low levels of the hormone prolactin (PRL) correlate with IR, adipose tissue (AT) dysfunction, and increased prevalence of T2D. In obese rats, PRL treatment promotes insulin sensitivity and reduces visceral AT adipocyte hypertrophy. Here, we tested whether elevating PRL levels with the prokinetic and antipsychotic drug sulpiride, an antagonist of dopamine D2 receptors, improves metabolism in high fat diet (HFD)-induced obese male mice. Sulpiride treatment (30 days) reduced hyperglycemia, IR, and the serum and pancreatic levels of triglycerides in obese mice, reduced visceral and subcutaneous AT adipocyte hypertrophy, normalized markers of visceral AT function (PRL receptor, Glut4, insulin receptor and Hif-1α), and increased glycogen stores in skeletal muscle. However, the effects of sulpiride reducing hyperglycemia were also observed in obese prolactin receptor null mice. We conclude that sulpiride reduces obesity-induced hyperglycemia by mechanisms that are independent of prolactin/prolactin receptor activity. These findings support the therapeutic potential of sulpiride against metabolic dysfunction in obesity.
Topics: Humans; Mice; Male; Rats; Animals; Insulin Resistance; Mice, Obese; Dopamine D2 Receptor Antagonists; Prolactin; Receptors, Prolactin; Diabetes Mellitus, Type 2; Sulpiride; Obesity; Diet, High-Fat; Hyperglycemia; Hypertrophy; Insulin
PubMed: 38635745
DOI: 10.1371/journal.pone.0301496 -
Nihon Eiseigaku Zasshi. Japanese... 2018Relatively high doses of psychostimulants induce neurotoxicity on the dopaminergic system and self-injurious behavior (SIB) in rodents. However the underlying neuronal... (Review)
Review
Relatively high doses of psychostimulants induce neurotoxicity on the dopaminergic system and self-injurious behavior (SIB) in rodents. However the underlying neuronal mechanisms of SIB remains unclear. Dopamine receptor antagonists, N-methyl-D-aspartic acid (NMDA) receptor antagonists, Nitric Oxide Synthase (NOS) inhibitors and free radical scavengers significantly attenuate methamphetamine-induced SIB. These findings indicate that activation of dopamine as well as NMDA receptors followed by radical formation and oxidative stress, especially when mediated by NOS activation, is associated with methamphetamine-induced SIB. On the other hand, an increase in the incidence of polydrug abuse is a major problem worldwide. Coadministered methamphetamine and morphine induced lethality in more than 80% in mice, accompanied by an increase in the number of poly (ADP-ribose) polymerase (PARP)-immunoreactive cells in the heart, kidney and liver. The lethal effect and the increase in the incidence of rupture or PARP-immunoreactive cells induced by the coadministration of methamphetamine and morphine were significantly attenuated by pretreatment with a phospholipase A2 inhibitor or a radical scavenger, or by cooling of body from 30 to 90 min after drug administration. These results suggest that free radicals play an important role in the increased lethality induced by the coadministration of methamphetamine and morphine. Therefore, free radical scavengers and cooling are beneficial for preventing death that is induced by the coadministration of methamphetamine and morphine. These findings may help us better understand for masochistic behavior, which is a clinical phenomenon on SIB, as well as polydrug-abuse-induced acute toxicity.
Topics: Animals; Central Nervous System Stimulants; Dopamine Antagonists; Dopaminergic Neurons; Dose-Response Relationship, Drug; Drug Interactions; Free Radical Scavengers; Free Radicals; Humans; Lethal Dose 50; Methamphetamine; Morphine; Receptors, N-Methyl-D-Aspartate; Self-Injurious Behavior; Substance-Related Disorders
PubMed: 29386447
DOI: 10.1265/jjh.73.51 -
Neuropsychopharmacology : Official... Jul 2019Prescription opioids such as oxycodone are highly effective analgesics for clinical pain management, but their misuse and abuse have led to the current opioid epidemic...
Prescription opioids such as oxycodone are highly effective analgesics for clinical pain management, but their misuse and abuse have led to the current opioid epidemic in the United States. In order to ameliorate this public health crisis, the development of effective pharmacotherapies for the prevention and treatment of opioid abuse and addiction is essential and urgently required. In this study, we evaluated-in laboratory rats-the potential utility of VK4-116, a novel and highly selective dopamine D3 receptor (D3R) antagonist, for the prevention and treatment of prescription opioid use disorders. Pretreatment with VK4-116 (5-25 mg/kg, i.p.) dose-dependently inhibited the acquisition and maintenance of oxycodone self-administration. VK4-116 also lowered the break-point (BP) for oxycodone self-administration under a progressive-ratio schedule of reinforcement, shifted the oxycodone dose-response curve downward, and inhibited oxycodone extinction responding and reinstatement of oxycodone-seeking behavior. In addition, VK4-116 pretreatment dose-dependently enhanced the antinociceptive effects of oxycodone and reduced naloxone-precipitated conditioned place aversion in rats chronically treated with oxycodone. In contrast, VK4-116 had little effect on oral sucrose self-administration. Taken together, these findings indicate a central role for D3Rs in opioid reward and support further development of VK4-116 as an effective agent for mitigating the development of opioid addiction, reducing the severity of withdrawal and preventing relapse.
Topics: Analgesics; Animals; Conditioning, Psychological; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Interactions; Extinction, Psychological; Indoles; Male; Oxycodone; Pain Measurement; Piperazines; Rats; Reinforcement Schedule; Self Administration; Sucrose
PubMed: 30555159
DOI: 10.1038/s41386-018-0284-5 -
Bioorganic & Medicinal Chemistry Letters Apr 2022The dopamine receptor 4 (DR) is highly expressed in both motor, associative and limbic subdivisions of the cortico-basal ganglia network. Due to the distribution in the...
The dopamine receptor 4 (DR) is highly expressed in both motor, associative and limbic subdivisions of the cortico-basal ganglia network. Due to the distribution in the brain, there is mounting evidence pointing to a role for the DR in the modulation of this network and its subsequent involvement in l-DOPA induced dyskinesias in Parkinson's disease. As part of our continued effort in the discovery of novel DR antagonists, we report the discovery and characterization of a new 3- or 4-benzyloxypiperidine scaffold as DR antagonists. We report several DR selective compounds (>30-fold vs. other dopamine receptor subtypes) with improved in vitro and in vivo stability over previously reported DR antagonists.
Topics: Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Discovery; Humans; Molecular Structure; Piperidines; Receptors, Dopamine D4; Structure-Activity Relationship
PubMed: 35151866
DOI: 10.1016/j.bmcl.2022.128615 -
Minerva Medica Jun 2021
Topics: Animals; Biomarkers, Tumor; Disease Models, Animal; Dopamine Antagonists; Forecasting; Humans; Neuroendocrine Tumors; Precision Medicine; Protein Kinase Inhibitors; Receptors, Somatostatin
PubMed: 33616378
DOI: 10.23736/S0026-4806.21.07450-4 -
Journal of Medicinal Chemistry Sep 2022To better understand the role of dopamine D receptor (DR) in glioblastoma (GBM), in the present paper, new ligands endowed with high affinity and selectivity for DR were...
To better understand the role of dopamine D receptor (DR) in glioblastoma (GBM), in the present paper, new ligands endowed with high affinity and selectivity for DR were discovered starting from the brain penetrant and DR selective lead compound 1-(3-(4-phenylpiperazin-1-yl)propyl)-3,4-dihydroquinolin-2(1)-one (). In particular, the DR antagonist , showing the highest affinity and selectivity over DR and DR within the series (D/D = 8318, D/D = 3715), and the biased ligand , partially activating DR G-/G-protein and blocking β-arrestin recruitment, emerged as the most interesting compounds. These compounds, evaluated for their GBM antitumor activity, induced a decreased viability of GBM cell lines and primary GBM stem cells (GSC#83), with the maximal efficacy being reached at a concentration of 10 μM. Interestingly, the treatment with both compounds and induced an increased effect in reducing the cell viability with respect to temozolomide, which is the first-choice chemotherapeutic drug in GBM.
Topics: Dopamine Antagonists; Glioblastoma; Humans; Ligands; Receptors, Dopamine D4; Temozolomide; beta-Arrestins
PubMed: 36098685
DOI: 10.1021/acs.jmedchem.2c00840 -
Neuropsychopharmacology : Official... May 2018Positron Emission Tomography (PET) imaging allows the estimation of multiple aspects of dopamine function including dopamine synthesis capacity, dopamine release, and...
Positron Emission Tomography (PET) imaging allows the estimation of multiple aspects of dopamine function including dopamine synthesis capacity, dopamine release, and D2/3 receptor binding. Though dopaminergic dysregulation characterizes a number of neuropsychiatric disorders including schizophrenia and addiction, there has been relatively little investigation into the nature of relationships across dopamine markers within healthy individuals. Here we used PET imaging in 40 healthy adults to compare, within individuals, the estimates of dopamine synthesis capacity (K) using 6-[F]fluoro-l-m-tyrosine ([F]FMT; a substrate for aromatic amino acid decarboxylase), baseline D2/3 receptor-binding potential using [C]raclopride (a weak competitive D2/3 receptor antagonist), and dopamine release using [C]raclopride paired with oral methylphenidate administration. Methylphenidate increases synaptic dopamine by blocking the dopamine transporter. We estimated dopamine release by contrasting baseline D2/3 receptor binding and D2/3 receptor binding following methylphenidate. Analysis of relationships among the three measurements within striatal regions of interest revealed a positive correlation between [F]FMT K and the baseline (placebo) [C]raclopride measure, such that participants with greater synthesis capacity showed higher D2/3 receptor-binding potential. In contrast, there was no relationship between [F]FMT and methylphenidate-induced [C]raclopride displacement. These findings shed light on the nature of regulation between pre- and postsynaptic dopamine function in healthy adults, which may serve as a template from which to identify and describe alteration with disease.
Topics: Adolescent; Adult; Aromatic-L-Amino-Acid Decarboxylases; Brain Mapping; Corpus Striatum; Dopamine; Dopamine Antagonists; Dopamine Uptake Inhibitors; Female; Humans; Male; Methylphenidate; Positron-Emission Tomography; Protein Binding; Raclopride; Radiopharmaceuticals; Receptors, Dopamine D2; Receptors, Dopamine D3; Young Adult
PubMed: 28816243
DOI: 10.1038/npp.2017.180