-
Journal of Psychopharmacology (Oxford,... Nov 2018
Topics: Animals; Dopamine Antagonists; Drug Development; Drug Evaluation, Preclinical; Humans; Receptors, Dopamine D1
PubMed: 30354927
DOI: 10.1177/0269881118799380 -
CNS Drug Reviews 2007As a continuation of our work with SB-277011A, we have examined the effects of another highly elective dopamine (DA) D3 receptor antagonist,... (Review)
Review
As a continuation of our work with SB-277011A, we have examined the effects of another highly elective dopamine (DA) D3 receptor antagonist, N-(4-[4-{2,3-dichlorophenyl}-1-piperazinyl]butyl)-2-fluorenylcarboxamide (NGB 2904), in animal models of addiction. Our results indicate that by systemic administration, NGB 2904 inhibits intravenous cocaine self-administration maintained under a progressive-ratio (PR) reinforcement schedule, cocaine- or cocaine cue-induced reinstatement of cocaine-seeking behavior, and cocaine- or other addictive drug-enhanced brain stimulation reward (BSR). The action of NGB 2904 on PR cocaine self-administration was long-lasting (1-2 days) after a single injection, supporting its potential use in treatment of cocaine addiction. The effects of NGB 2904 in the BSR paradigm were dose-dependent for both NGB 2904 and cocaine; that is, only lower doses of NGB 2904 were effective, and their putative antiaddiction effect could be overcome by increasing the doses of cocaine or other addictive drugs. A dopamine-dependent mechanism is proposed to explain the effects of NGB 2904 on cocaine's actions in these animal models of drug addiction. The data reviewed in this paper suggest that NGB 2904 or other D3-selective antagonists may have potential in controlling motivation for drug-taking behavior or relapse to drug-seeking behavior, but may have a limited role in antagonizing the acute rewarding effects produced by cocaine or other addictive drugs. In addition, NGB 2904 may also act as a useful tool to study the role of D3 receptors in drug addiction.
Topics: Animals; Behavior, Addictive; Disease Models, Animal; Dopamine Antagonists; Fluorenes; Piperazines; Rats; Receptors, Dopamine D3; Substance-Related Disorders
PubMed: 17627675
DOI: 10.1111/j.1527-3458.2007.00013.x -
Behavioural Brain Research Sep 2023Mitragynine (MG) is the primary active constituent of Mitragyna speciosa Korth (kratom), a psychoactive Southeast Asian plant with potential therapeutic use. Numerous...
Mitragynine (MG) is the primary active constituent of Mitragyna speciosa Korth (kratom), a psychoactive Southeast Asian plant with potential therapeutic use. Numerous studies support roles of dopaminergic system in drug reward. However, the involvement of the dopaminergic system in mediating MG reward and drug-seeking is poorly understood. Using conditioned place preference (CPP) paradigm, the present study aims to evaluate the roles of the dopamine (DA) D1 receptor in the acquisition and expression of MG-induced CPP in rats. The effects of SCH-23390, a selective DA D1 receptor antagonist, on the acquisition of MG-induced CPP were first investigated. Rats were pre-treated systemically with SCH-23390 (0, 0.1 and 0.3 mg/kg, i.p.) prior to MG (10 mg/kg) conditioning sessions. Next, we tested the effects of the DA D1 receptor antagonist on the expression of MG-induced CPP. Furthermore, the effects of a MG-priming dose (5 mg/kg) on the reinstatement of extinguished CPP were tested. The results showed that SCH-23390 dose-dependently suppressed the acquisition of a MG-induced CPP. In contrast, SCH-23390 had no effect on the expression of a MG-induced CPP. The findings of this study suggested a crucial role of the DA D1 receptor in the acquisition, but not the expression of the rewarding effects of MG in a CPP test. Furthermore, blockade of the D1-like receptor during conditioning did not prevent MG priming effects on CPP reinstatement test, suggesting no role for the DA D1 receptor in reinstatement sensitivity.
Topics: Animals; Rats; Benzazepines; Dopamine; Dopamine Antagonists; Receptors, Dopamine D1
PubMed: 37619769
DOI: 10.1016/j.bbr.2023.114638 -
Archives of Pharmacal Research Apr 2018Cancer is one of the deadliest diseases in the world. Despite extensive studies, treating metastatic cancers remains challenging. Years of research have linked a rare... (Review)
Review
Cancer is one of the deadliest diseases in the world. Despite extensive studies, treating metastatic cancers remains challenging. Years of research have linked a rare set of cells known as cancer stem cells (CSCs) to drug resistance, leading to the suggestion that eradication of CSCs might be an effective therapeutic strategy. However, few drug candidates are active against CSCs. New drug discovery is often a lengthy process. Drug screening has been advantageous in identifying drug candidates. Current understanding of cancer biology has revealed various clues to target cancer from different points of view. Many studies have found dopamine receptors (DRs) in various cancers. Therefore, DR antagonists have attracted a lot of attention in cancer research. Recently, a group of antipsychotic DR antagonists has been demonstrated to possess remarkable abilities to restrain and sensitize CSCs to existing chemotherapeutics by a process called differentiation approach. In this review, we will describe current aspects of CSC-targeting therapeutics, antipsychotic DR antagonists, and their extraordinary abilities to fight cancer.
Topics: Animals; Antipsychotic Agents; Cell Differentiation; Clinical Trials as Topic; Dopamine Antagonists; Drug Resistance, Neoplasm; Humans; Neoplasms; Neoplastic Stem Cells
PubMed: 29556831
DOI: 10.1007/s12272-018-1017-3 -
The American Journal of Drug and... Jan 2014Methamphetamine (MA) use disorders are major public health problems nationally and worldwide and treatment remains an unmet need. (Review)
Review
BACKGROUND
Methamphetamine (MA) use disorders are major public health problems nationally and worldwide and treatment remains an unmet need.
OBJECTIVES
(1) To review preclinical and clinical studies identifying the dopamine D3 receptor as a therapeutic target for substance use disorders (SUDs), including MA dependence, (2) to consider buspirone (Buspar®) as a potential medication based on its dopamine D3 receptor antagonist properties, and (3) to evaluate the safety and initial efficacy of buspirone in a pilot study of MA-dependent individuals.
METHODS
Literature on the dopamine D3 receptor as a therapeutic target and on the potential of buspirone as a novel therapy for MA dependence was reviewed. The cardiovascular and subjective effects of intravenous MA challenge were assessed in five non-treatment seeking individuals. Participants met DSM-IV criteria for MA dependence and were treated subacutely (9 days) with buspirone (60 mg daily).
RESULTS
The literature identified the dopamine D3 receptor as a therapeutic target for MA dependence, a safe and approved medication, and a valuable opportunity to re-purpose buspirone for treating MA dependence and perhaps other SUDs. Pilot data (n = 5) indicated that buspirone is safe in MA-using individuals and comparison against historical placebo data from this laboratory suggested that at least some aspects of the subjective properties of MA may be diminished during buspirone treatment.
CONCLUSION
Future studies should include a small-scale, placebo-controlled Phase IIa trial of buspirone in MA dependence.
Topics: Amphetamine-Related Disorders; Animals; Behavior, Addictive; Buspirone; Cardiovascular System; Dopamine Antagonists; Humans; Molecular Targeted Therapy; Receptors, Dopamine D3; Translational Research, Biomedical
PubMed: 24359505
DOI: 10.3109/00952990.2013.858723 -
The Journal of Pharmacology and... Sep 2015The chronic and relapsing nature of addiction presents unique challenges for ensuring the safety of a potential medication. A patient may use cocaine, for example, while...
The chronic and relapsing nature of addiction presents unique challenges for ensuring the safety of a potential medication. A patient may use cocaine, for example, while taking the medication or take more medication than prescribed. Thus, a potential medication must be safe and not exacerbate the effects of cocaine. Multiple published studies support antagonism of brain dopamine D3 receptor function as a potential mechanism of action for an anti-addiction medication. Dopamine D3 receptors are widely distributed outside the central nervous system, however; for example, dopamine D3 receptors in the kidneys are implicated in regulating blood pressure. The selective dopamine D3 receptor antagonist GSK598809 [1-(2-fluoro-4-trifluoromethyl-phenyl)-3-{3-[4-methyl-5-(4-methyl-oxazol-5-yl)-4H-[1,2,4]triazol-3-ylsulfanyl]-propyl}-3-aza-bicyclo[3.1.0]hexane] has been proposed as a medication to treat cocaine and other substance use disorders. The US Food and Drug Administration has established guidelines recommending safety studies to investigate potential undesirable pharmacodynamic effects of a substance in relation to exposure in the therapeutic range and above. Hence, we assessed the interaction between this selective dopamine D3 receptor antagonist and cocaine on hemodynamics and cardiac function in freely-moving, telemetered dogs before conducting a clinical trial. GSK598809 increased the hemodynamic effect of cocaine in this model. Thus, the increase in blood pressure after intravenous cocaine was greater in animals that had been pretreated with GSK598809 compared with vehicle. This finding suggests that GSK598809 in particular, and perhaps dopamine D3 receptor antagonists as a class, may produce unacceptable cardiovascular risks as medications to treat cocaine use disorder.
Topics: Animals; Azabicyclo Compounds; Behavior, Addictive; Blood Pressure; Cardiovascular Diseases; Cocaine; Cocaine-Related Disorders; Dogs; Dopamine Antagonists; Male; Oxazoles; Receptors, Dopamine D3
PubMed: 26177654
DOI: 10.1124/jpet.115.224121 -
Neuropharmacology Feb 2005Functional magnetic resonance imaging (fMRI), employing BOLD-contrast, was used to measure changes in regional brain activation following amphetamine administration,... (Comparative Study)
Comparative Study
Functional magnetic resonance imaging (fMRI), employing BOLD-contrast, was used to measure changes in regional brain activation following amphetamine administration, either alone or after pre-treatment with the dopamine D1 receptor antagonist SCH23390, or the dopamine D2 receptor antagonist, sulpiride, in anaesthetised rat. After obtaining baseline data, rats (n=8) were given amphetamine (3 g/kg i.v) and volume data sets collected for 90 mins. Acute amphetamine challenge caused widespread increases in BOLD signal intensity in many subcortical structures with rich dopaminergic innervation, with decreases in BOLD contrast observed in the superficial layers of the cortex. Pretreatment with SCH23390 (n=8, 0.5 mg/kg, i.v) substantially attenuated the increases in BOLD activity in response to amphetamine, with lesser effects on the amphetamine-evoked decreases in BOLD signal. In contrast, sulpiride (n=8, 50 mg/kg, i.v) predominantly blocked the decrease in BOLD signal, having a smaller effect on the increases in BOLD signal. In summary, these data are supportive of the notion that different dopamine receptor types are responsible for separate components of the full amphetamine response. Furthermore the utility of BOLD contrast fMRI as a means of characterising the mechanisms of drug action in the whole brain has been demonstrated. Such studies may be of particular use for investigation of localised action and interaction of different dopaminergic agents.
Topics: Amphetamine; Animals; Benzazepines; Dopamine Antagonists; Magnetic Resonance Imaging; Male; Rats; Rats, Sprague-Dawley; Receptors, Dopamine; Sulpiride
PubMed: 15695162
DOI: 10.1016/j.neuropharm.2004.10.006 -
The International Journal of... Aug 2022Restless legs syndrome (RLS) is a common condition that initially responds dramatically to dopaminergic therapy. Over time, however, dopaminergics cause augmentation,...
BACKGROUND
Restless legs syndrome (RLS) is a common condition that initially responds dramatically to dopaminergic therapy. Over time, however, dopaminergics cause augmentation, where symptoms occur earlier and intensify. Animal models suggest this may result from increased dopamine receptor type-1 affinity in the spinal cord. Ecopipam is a potent, specific dopamine-1/5 receptor antagonist.
METHODS
We performed a small ( = 10) exploratory placebo controlled, cross-over safety trial of ecopipam (25-100 mg/day) for patients with augmented RLS currently taking dopamine agonists.
RESULTS
Ecopipam was well tolerated with sedation being the most common adverse event in drug and placebo. Safety scales and serology data were similar to placebo. The study was not powered to demonstrate efficacy and exploratory efficacy data showed no significant improvement compared to placebo, but RLS diaries, the international RLS rating scale, and clinical global impressions all favored drug. No subject worsened on drug or demonstrated rebound worsening after drug discontinuation.
CONCLUSION
Ecopipam was safe and well tolerated in this initial study for RLS. Given the lack of alternate options, larger efficacy studies for augmented RLS, and potentially de novo RLS are justified.
Topics: Benzazepines; Cross-Over Studies; Dopamine Antagonists; Humans; Restless Legs Syndrome
PubMed: 33066723
DOI: 10.1080/00207454.2020.1838515 -
Biomedicine & Pharmacotherapy =... Jun 2021Several brain neurotransmitters, including histamine (HA), acetylcholine (ACh), and dopamine (DA) are suggested to be involved in several brain disorders including...
Several brain neurotransmitters, including histamine (HA), acetylcholine (ACh), and dopamine (DA) are suggested to be involved in several brain disorders including cognitive deficits, depression, schizophrenia, anxiety, and narcolepsy, all of which are comorbid with Autism spectrum disorder (ASD). Therefore, the ameliorative effects of the novel multiple-active compound ST-713 with high binding affinities at histamine H3 receptor (H3R), dopamine D2sR and D3R on ASD-like behaviors in male BTBR T+tf/J mice model were assessed. ST-713 (3-(2-chloro-10H-phenothiazin-10-yl)-N-methyl-N-(4-(3-(piperidin-1-yl)propoxy)benzyl)propan-1-amine; 2.5, 5, and 10 mg/kg, i.p.) ameliorated dose-dependently social deficits, and significantly alleviated the repetitive/compulsive behaviors of BTBR mice (all P < 0.05). Moreover, ST-713 modulated disturbed anxiety levels, but failed to obliterate increased hyperactivity of tested mice. Furthermore, ST-713 (5 mg/kg) attenuated the increased levels of hippocampal and cerebellar protein expressions of NF-κB p65, COX-2, and iNOS in BTBR mice (all P < 0.05). The ameliorative effects of ST-713 on social parameters were entirely reversed by co-administration of the H3R agonist (R)-α-methylhistamine or the anticholinergic drug scopolamine. The obtained results demonstrate the potential of multiple-active compounds for the therapeutic management of neuropsychiatric disorders, e.g. ASD.
Topics: Animals; Autistic Disorder; Cerebellum; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Hippocampus; Histamine Antagonists; Mice; Mice, Inbred C57BL; Mice, Transgenic; Receptors, Dopamine D2; Receptors, Dopamine D3; Receptors, Histamine H3
PubMed: 33773463
DOI: 10.1016/j.biopha.2021.111517 -
Neuropeptides Oct 2015It has been shown that dopamine antagonists suppress the ghrelin-induced increased motivation to work for food. The aim of this study was to investigate the influence of...
It has been shown that dopamine antagonists suppress the ghrelin-induced increased motivation to work for food. The aim of this study was to investigate the influence of the dopamine antagonist flupentixol on ghrelin-induced food intake. Ad libitum fed male Sprague-Dawley (SD) rats were injected intraperitoneally (ip) with vehicle plus vehicle, vehicle plus ghrelin (13 μg/kg), 0.25mg/kg or 0.5mg/kg flupentixol plus ghrelin, or 0.25mg/kg or 0.5 mg/kg flupentixol plus vehicle. In a second experiment, intracerebroventricularly (icv) cannulated rats received an ip injection of vehicle (0.15M NaCl) or flupentixol (0.25mg/kg) and 20 min later an icv injection of vehicle or ghrelin (1 μg/rat). Both experiments were performed twice: first, rats were offered only standard chow, while in the second experiment they could choose between standard chow and a palatable/preferred chow. Cumulative light phase food intake was assessed for 7h. Ip as well as icv injected ghrelin reliably increased intake of standard chow. Flupentixol did not affect ghrelin-induced intake of standard chow. Ip injected ghrelin failed to increase the intake of palatable chow, whereas icv injected ghrelin did. This effect was not blocked by ip flupentixol. In summary, ip administered ghrelin did not increase the intake of chow the rats preferred; whereas icv injected ghrelin further stimulated the intake of preferred chow suggesting a direct central mediation of this effect. Our results show that the dopamine antagonist flupentixol does not influence ghrelin-induced feeding in our choice paradigm.
Topics: Animals; Dopamine Antagonists; Dose-Response Relationship, Drug; Eating; Flupenthixol; Food Preferences; Ghrelin; Injections, Intraperitoneal; Injections, Intraventricular; Male; Periodicity; Rats; Rats, Sprague-Dawley
PubMed: 26329764
DOI: 10.1016/j.npep.2015.08.007