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Neuroscience Sep 2022Dopamine facilitates approach to reward via its actions on dopamine receptors in the nucleus accumbens. For example, blocking either D1 or D2 dopamine receptors in the...
Dopamine facilitates approach to reward via its actions on dopamine receptors in the nucleus accumbens. For example, blocking either D1 or D2 dopamine receptors in the accumbens reduces the proportion of reward-predictive cues to which rats respond with cued approach. Recent evidence indicates that accumbens dopamine also promotes wakefulness and arousal, but the relationship between dopamine's roles in arousal and reward seeking remains unexplored. Here, we show that the ability of systemic or intra-accumbens injections of the D1 antagonist SCH23390 to reduce cued approach to reward depends on the animal's state of arousal. Handling the animal, a manipulation known to increase arousal, was sufficient to reverse the behavioral effects of the antagonist. In addition, SCH23390 reduced spontaneous locomotion and increased time spent in sleep postures, both consistent with reduced arousal, but also increased time spent immobile in postures inconsistent with sleep. In contrast, the ability of the D2 antagonist haloperidol to reduce cued approach was not reversible by handling. Haloperidol reduced spontaneous locomotion but did not increase sleep postures, instead increasing immobility in non-sleep postures. We place these results in the context of the extensive literature on dopamine's contributions to behavior, and propose the arousal-motor hypothesis. This novel synthesis, which proposes that two main functions of dopamine are to promote arousal and facilitate motor behavior, accounts both for our findings and many previous behavioral observations that have led to disparate and conflicting conclusions.
Topics: Animals; Arousal; Dopamine; Dopamine Antagonists; Haloperidol; Nucleus Accumbens; Rats; Receptors, Dopamine D1; Reward
PubMed: 35853563
DOI: 10.1016/j.neuroscience.2022.07.008 -
Psychopharmacology Mar 2015(-)-Stepholidine is a tetrahydroberberine alkaloid that is known to interact with dopamine receptors and has also been proposed as a novel antipsychotic agent. Its...
RATIONALE
(-)-Stepholidine is a tetrahydroberberine alkaloid that is known to interact with dopamine receptors and has also been proposed as a novel antipsychotic agent. Its suggested novelty lies in the fact that it has been proposed to have D1-like receptor agonist and D2-like receptor antagonist properties. Thus, it might be effective in treating both positive and negative (cognition) symptoms of schizophrenia. However, its activity on specific dopamine receptor subtypes has not been clarified, especially with respect to its ability to activate D1-like receptors.
OBJECTIVES
We wished to examine the affinity and functional activity of (-)-stepholidine at each of the human dopamine receptor subtypes expressed in a defined cellular environment.
METHODS
D1-D5 dopamine receptors were stably expressed in cell lines and their interactions with (-)-stepholidine were examined using radioligand binding and various functional signaling assays. Radioligand binding assays were also performed using bovine striatal membranes.
RESULTS
(-)-Stepholidine exhibited high (nM) affinity for D1 and D5 receptors, somewhat lower (two- to four-fold) affinity for D2 and D3 receptors, and low micromolar affinity for D4 receptors. Functionally, (-)-stepholidine was ineffective in activating G protein-mediated signaling of D1-like and D2 receptors and was also ineffective in stimulating β-arrestin recruitment to any dopamine receptor subtype. It did, however, antagonize all of these responses. It also antagonized D1-D2 heteromer-mediated Ca(2+) mobilization. Radioligand binding assays of D1-like receptors in brain membranes also indicated that (-)-stepholidine binds to the D1 receptor with antagonist-like properties.
CONCLUSIONS
(-)-Stepholidine is a pan-dopamine receptor antagonist and its in vivo effects are largely mediated through dopamine receptor blockade with potential cross-talk to other receptors or signaling proteins.
Topics: Animals; Arrestins; Berberine; Brain; CHO Cells; Cricetulus; Dopamine Antagonists; GTP-Binding Proteins; HEK293 Cells; Humans; Receptors, Dopamine; Receptors, Dopamine D5; Signal Transduction; beta-Arrestins
PubMed: 25231919
DOI: 10.1007/s00213-014-3726-8 -
European Journal of Pharmacology Jul 2018Long-term treatment with antipsychotic drugs in patients with schizophrenia can lead to dopamine supersensitivity psychosis. It is reported that repeated administration...
Long-term treatment with antipsychotic drugs in patients with schizophrenia can lead to dopamine supersensitivity psychosis. It is reported that repeated administration of haloperidol caused dopamine supersensitivity in rats. Blonanserin is an atypical antipsychotic drug with high affinity for dopamine D, D and serotonin receptors. In this study, we investigated whether chronic administration of blonanserin leads to dopamine supersensitivity. Following oral treatment with blonanserin (0.78 mg/kg) or haloperidol (1.1 mg/kg) twice daily for 28 days, the dopamine D agonist quinpirole-induced hyperlocomotion test and a dopamine D receptor binding assay were conducted. We found that haloperidol significantly enhanced both quinpirole-induced hyperlocomotion and striatal dopamine D receptor density in rats. On the other hand, repeated administration of blonanserin had no effect on either locomotor activity or striatal dopamine D receptor density. Further, our results show that mRNA levels of dopamine D and D receptors in several brain regions were unaffected by repeated administration of both agents. In addition, we examined the effect of the dopamine D receptor antagonist PG-01037 on development of dopamine supersensitivity induced by chronic haloperidol treatment and showed that PG-01037 prevents the development of supersensitivity to quinpirole in chronic haloperidol-treated rats. Given the higher affinity of blonanserin at dopamine D receptors than haloperidol, antagonism of blonanserin at dopamine D receptors may play a role in lack of dopamine supersensitivity after chronic administration. The present findings suggest long-term treatment with antipsychotic dose of blonanserin may be unlikely to lead to dopamine supersensitivity.
Topics: Animals; Antipsychotic Agents; Benzamides; Brain; Dopamine; Dopamine Agonists; Dopamine Antagonists; Haloperidol; Locomotion; Male; Methamphetamine; Piperazines; Piperidines; Pyridines; Quinpirole; RNA, Messenger; Rats, Wistar; Receptors, Dopamine D2; Receptors, Dopamine D3
PubMed: 29684390
DOI: 10.1016/j.ejphar.2018.04.014 -
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 -
Psychopharmacology Aug 2023Dopaminergic dysfunction is implicated in disorders of impulsivity and inattention. The rodent continuous performance test (rCPT) has been used to quantify changes in...
Assessing attention and impulsivity in the variable stimulus duration and variable intertrial interval rodent continuous performance test schedules using dopamine receptor antagonists in female C57BL/6JRj mice.
RATIONALE
Dopaminergic dysfunction is implicated in disorders of impulsivity and inattention. The rodent continuous performance test (rCPT) has been used to quantify changes in attention and impulsivity.
OBJECTIVE
To examine the roles of dopamine receptors in attention and impulsivity behaviours measured in the rCPT variable stimulus duration (vSD) and the variable intertrial interval schedules (vITI) using DA receptor antagonists.
METHODS
Two cohorts of 35 and 36 female C57BL/6JRj mice were examined separately in the rCPT, vSD, and vITI schedules, respectively. Both cohorts received antagonists of the following receptors: D (SCH23390, SCH: 0.01, 0.02, 0.04 mg/kg) and D (raclopride, RAC 0.03, 0.10, 0.30 mg/kg) in consecutive balanced Latin square designs with flanking reference measurements. The antagonists were subsequently examined for effects on locomotor activity.
RESULTS
SCH showed similar effects in both schedules, and the effects were reference-dependent in the vITI schedule. SCH reduced responding, but improved response accuracy, impulsivity, discriminability, and locomotor activity. RAC showed mixed effects on responsivity, but improved accuracy and discriminability. The discriminability improvement was driven by an increase in hit rate in the vITI schedule and a reduction in false alarm rate in the vSD schedule. RAC also decreased locomotor activity.
CONCLUSION
Both D and D receptor antagonism reduced responding, but the outcome on discriminability differed, stemming from individual effects on hit and false alarm rate, and the weight of omissions within the calculation. The effects of SCH and RAC suggest that endogenous DA increases responding and impulsivity, but reduces accuracy and shows mixed effects on discriminability.
Topics: Mice; Animals; Female; Dopamine Antagonists; Rodentia; Mice, Inbred C57BL; Receptors, Dopamine D1; Attention; Impulsive Behavior; Dopamine D2 Receptor Antagonists; Benzazepines; Dose-Response Relationship, Drug
PubMed: 37378887
DOI: 10.1007/s00213-023-06387-7 -
Acta Pharmacologica Sinica Sep 2022Major depressive disorder is a global mental illness associated with severe mortality and disability. The dopaminergic system is involved in both the etiology and...
Major depressive disorder is a global mental illness associated with severe mortality and disability. The dopaminergic system is involved in both the etiology and therapeutics of depression. Distinct functions of dopamine D and D receptor subtypes have attracted considerable research interest, and their roles in the pathogenesis of depression and interaction with antidepressants need to be comprehensively elucidated. Herein, we investigated the antidepressant effects of a candidate antidepressant from a cinnamamide derivative, M2, and examined underlying neural mechanisms. We observed that a single dose of M2 (30 mg/kg, ip) produced rapid antidepressant-like effects in mice subjected to the forced swim and tail suspension tests. Using whole-cell recordings in mouse coronal brain slices, we found that application of M2 (10-150 μM) concentration-dependently increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) of the pyramidal neurons in the medial prefrontal cortex (mPFC). Furthermore, M2-induced enhancement of sEPSC frequency was abolished by sulpiride (10 µM), a dopamine D2 receptor antagonist, but not by the dopamine receptor D antagonist, SCH23390 (10 μM). In addition, M2 administration significantly increased expression levels of synaptogenesis-related proteins, including p-mTOR and p-TrkB, in the mPFC at 30 min, and increased postsynaptic protein PSD-95 at 24 h. Our results demonstrated that M2 produces rapid antidepressant actions through a novel mechanism via dopamine D receptor-mediated enhancement of mPFC neurotransmission.
Topics: Animals; Antidepressive Agents; Cinnamates; Depressive Disorder, Major; Dopamine; Dopamine Antagonists; Mice; Prefrontal Cortex; Receptors, Dopamine D1; Receptors, Dopamine D2
PubMed: 35079131
DOI: 10.1038/s41401-021-00854-7 -
Scientific Reports Jan 2020Dopamine is a neurotransmitter of great physiological relevance. Disorders in dopaminergic signal transduction are associated with psychiatric and neurological...
Dopamine is a neurotransmitter of great physiological relevance. Disorders in dopaminergic signal transduction are associated with psychiatric and neurological pathologies such as Parkinson's disease, schizophrenia and substance abuse. Therefore, a detailed understanding of dopaminergic neurotransmission may provide access to novel therapeutic strategies for the treatment of these diseases. Caged compounds with photoremovable groups represent molecular tools to investigate a biological target with high spatiotemporal resolution. Based on the crystal structure of the D receptor in complex with eticlopride, we have developed caged D/D receptor ligands by rational design. We initially found that eticlopride, a widely used D/D receptor antagonist, was photolabile and therefore is not suitable for caging. Subtle structural modification of the pharmacophore led us to the photostable antagonist dechloroeticlopride, which was chemically transformed into caged ligands. Among those, the 2-nitrobenzyl derivative 4 (MG307) showed excellent photochemical stability, pharmacological behavior and decaging properties when interacting with dopamine receptor-expressing cells.
Topics: Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Drug Design; Drug Development; Drug Stability; Humans; Ligands; Molecular Conformation; Parkinson Disease; Photochemical Processes; Receptors, Dopamine D2; Receptors, Dopamine D3
PubMed: 31965029
DOI: 10.1038/s41598-020-57770-9 -
Psychopharmacology Jun 2024Evidence 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)... (Review)
Review
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.
Topics: Dopamine; Animals; Humans; Receptors, Dopamine D1; Receptors, Dopamine D2; Time Factors; Dopamine Antagonists; Reward; Eating; Drinking Behavior; Dopamine D2 Receptor Antagonists
PubMed: 38702473
DOI: 10.1007/s00213-024-06600-1 -
Journal of Dairy Science Nov 2015In previous studies, our team showed that the inhibition of prolactin (PRL) secretion by the dopamine agonist quinagolide reduces milk production in dairy cows. The...
In previous studies, our team showed that the inhibition of prolactin (PRL) secretion by the dopamine agonist quinagolide reduces milk production in dairy cows. The objective of this study was to determine the effects of administration of a dopamine antagonist on basal and milking-induced PRL concentrations in blood and on milk production during positive energy balance and feed restriction in dairy cows. Eighteen mid-lactation Holstein cows received daily s.c. injections of either domperidone (300 mg, DOMP, n=9) or the vehicle, canola oil (CTL, n=9), for 5 wk. During wk 5, all cows were fed at 65% of their dry matter intake in the previous week. Blood and milk samples were collected before (for blood) and during (for milk) the a.m. milking thrice weekly from d -9 to 41 (8d after the last injection). In addition, blood samples were collected during the a.m. milking on d -1 (before the first injection), and on d 1, 28, and 34. Basal PRL concentration was similar in both groups before the start of the treatments. Domperidone injections caused a gradual increase in basal PRL concentration. Feed restriction reduced basal PRL concentration in both the CTL and DOMP cows, but PRL concentration remained higher in the DOMP cows. Prolactin concentration remained elevated in the DOMP cows 7d after the last injection. The milk concentration of PRL increased during the DOMP treatment, but the increase was smaller than that observed in serum. In the CTL cows, the milking-induced PRL release above the premilking concentration was similar on d -1, 1, and 28 but was reduced during feed restriction. In the DOMP cows, the milking-induced PRL release was similar on d -1 and 1 but was reduced on d 28 and 34. Milk production was similar for both groups before the treatments started but was greater in the DOMP cows during the treatment period, at 2.9 ± 0.6 and 2.4 ± 0.6 kg/d greater during wk 3 and 4 of treatment, respectively. Milk production declined in both groups during feed restriction but remained higher in the DOMP cows. Milk production became similar again for both groups after the last injection. In addition, dry matter intake was increased by DOMP. These results support the hypothesis that PRL is galactopoietic in dairy cattle.
Topics: Animal Feed; Animals; Cattle; Diet; Domperidone; Dopamine Antagonists; Energy Metabolism; Female; Food Deprivation; Lactation; Milk; Prolactin
PubMed: 26298751
DOI: 10.3168/jds.2015-9865 -
Journal of Physiology and Pharmacology... Dec 2020Chronic epigastric pain syndrome (CEPS) is an important diagnostic problem, especially in patients without macroscopic and microscopic changes in gastric mucosa. The... (Comparative Study)
Comparative Study Randomized Controlled Trial
Chronic epigastric pain syndrome (CEPS) is an important diagnostic problem, especially in patients without macroscopic and microscopic changes in gastric mucosa. The cause of this ailment is unclear. The aim of this study was the assessment of coexistence between symptoms of this syndrome and secretion level of dopamine (DA), as well as the efficacy of peripheral and central D2 receptors antagonist. Sixty depressive patients with CEPS occurring independently of the diet and with no Helicobacter pylori infection and 30 healthy subjects were enrolled in this study. Plasma DA and urinary homovanilic acid (HVA) concentration were measured by ELISA, and the mRNA expression of dopa decarboxylase (DDC) in gastric mucosa was evaluated by RT-PCR in 30 patients with CEPS and 30 controls. Severity of epigastric pain before and after 12 weeks 2 x 50 mg itopride or sulpiride treatment was evaluated using the modified 10-point Visual Analogue Scale. Higher average levels of plasma DA and urinary HVA levels in CEPS patients than controls 129.5 ± 22.0 versus 109.1 ± 18.4 pg/ml (p < 0.001) and 6.82 ± 1.55 versus 5.39 ± 1.04 mg/24 h, respectively were obtained. Moreover, the expression of DDC in gastric mucosa of CEPS patients was higher than in healthy subjects (p < 0.01). Sulpiride subsided epigastric pain in 73.3%, but itopride reduced it only in 6.6% of CEPS patients. We concluded that altered dopamine signalling may affect locally-and-centrally mediated chronic epigastric pain.
Topics: Abdominal Pain; Adult; Benzamides; Benzyl Compounds; Case-Control Studies; Chronic Pain; Depression; Dopamine; Dopamine Antagonists; Female; Gastric Mucosa; Homovanillic Acid; Humans; Male; Middle Aged; Pain Measurement; Signal Transduction; Sulpiride
PubMed: 33727428
DOI: 10.26402/jpp.2020.6.05