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Pharmacology, Biochemistry, and Behavior Jul 2012Opiate addiction is a chronic recrudescent disorder characterized by a high rate of relapse. Levo-tetrahydropalmatine (l-THP) is an alkaloid substance extracted from...
Opiate addiction is a chronic recrudescent disorder characterized by a high rate of relapse. Levo-tetrahydropalmatine (l-THP) is an alkaloid substance extracted from Corydalis and Stephania and is contained in a number of traditional Chinese herbal preparations. Compared to other dopamine receptor antagonists, l-THP has lower affinity for D2 receptors than for D1 receptors, and a recent study showed that l-THP also binds to D3 receptors, possibly functioning as an antagonist. The unique pharmacological profile of l-THP suggests that l-THP may be effective for the treatment of opiate addiction. In this study, we investigated the effects of l-THP on heroin self-administration and reinstatement triggered by a priming injection of heroin in abstinent rats trained to stably self-administer heroin under an extinction/reinstatement protocol, and found that l-THP (2.5 and 5 mg/kg, i.p.) decreased heroin self-administration on the fixed-ratio 1 schedule and dose-dependently (1.25, 2.5 and 5 mg/kg, i.p.) inhibited heroin-induced reinstatement of heroin-seeking behavior. Importantly, l-THP (1.25 and 2.5 mg/kg, i.p.) did not affect locomotion, indicating that the observed effects of l-THP on reinstatement do not appear to be due to motor impairments. The present results demonstrated that dopamine receptor antagonist l-THP attenuates heroin self-administration and heroin-induced reinstatement.
Topics: Animals; Behavior, Addictive; Berberine Alkaloids; Dopamine Antagonists; Heroin; Male; Random Allocation; Rats; Rats, Sprague-Dawley; Reinforcement Schedule; Secondary Prevention; Self Administration
PubMed: 22741173
DOI: 10.1016/j.pbb.2012.03.014 -
CNS & Neurological Disorders Drug... 2015The identification of effective medications for the management of cocaine use disorders remains an unmet public health challenge. In view of the prominent role of... (Review)
Review
The identification of effective medications for the management of cocaine use disorders remains an unmet public health challenge. In view of the prominent role of dopaminergic mechanisms in cocaine's abuse-related effects, research has focused on the development of subtype-selective dopamine D1-4 receptor antagonists. Here, we briefly recap the current status of this research effort, with a focus on several aspects of D4 research that may be pertinent to the consideration of D4 ligands in the development of candidate medications. Additionally, we present data from self administration studies in nonhuman primates showing that intravenous cocaine-maintained behavior is moderately, though non-significantly, decreased by doses of the D4-selective partial agonist Ro10-5824 and dramatically reduced by the D4- selective receptor antagonist NGD-94-1. The effects of these D4 ligands on cocaine self-administration were consistent among subjects and occurred in the absence of comparable effects on food-maintained responding. These data suggest that available D4 receptor antagonists should be investigated further as candidate medications for the management of cocaine use disorders.
Topics: Animals; Cocaine-Related Disorders; Dopamine Antagonists; Humans; Receptors, Dopamine D4
PubMed: 26022267
DOI: 10.2174/1871527314666150529132723 -
Neuroscience and Biobehavioral Reviews 1989Animals working for any one of a variety of positive reinforcers (food, water, brain-stimulation...) produce dramatic decrements in operant performance when challenged... (Review)
Review
Animals working for any one of a variety of positive reinforcers (food, water, brain-stimulation...) produce dramatic decrements in operant performance when challenged with dopamine antagonist neuroleptic drugs. This well-established fact has generated considerable research aimed at identifying the precise nature of the drug-induced behavioral impairment. The two most oft-cited hypotheses suggest that much of the reduction in operant responding can be accounted for by either an "anhedonic" or "motoric" consequence of dopamine antagonism. Several novel behavioral paradigms are described which were devised to more clearly elucidate both the motor and reward impairing qualities of neuroleptic agents. Motor performance was assessed in a food-reinforced task in which a computer-operated force-transducer was used to obtain detailed analyses of the biophysical properties of operant responding. These studies suggested that neuroleptics impair the temporal nature (i.e., "timing") of normal operant behavior and not the physical capacity of the animals (i.e., the ability to emit "force"). This identification of a robust "slowing" effect of neuroleptic challenge, suggested that the investigation of putative "reward" impairments should best be conducted with behavioral paradigms in which the test data are collected from undrugged animals. Three such paradigms are described: a partial reinforcement extinction test, an incentive motivation test, and a conditioned place preference test. To date, our results suggest that when motor confounds are avoided, dopamine antagonist drugs can still produce patterns of operant behavior that very closely resemble those observed with actual reductions in reward magnitude. Such data provide support for the contention that central dopaminergic substrates play a role in the neurobiology of positive reinforcement.
Topics: Animals; Antipsychotic Agents; Behavior, Animal; Conditioning, Psychological; Dopamine; Dopamine Antagonists; Motivation; Reinforcement, Psychology; Self Stimulation
PubMed: 2573021
DOI: 10.1016/s0149-7634(89)80018-1 -
Clinical Neuropharmacology Dec 1995Eight Cebus apella monkeys previously treated with dopamine D1 and D2 receptor antagonists were used to elucidate the pathophysiology of acute oral dyskinesia. Five...
Dopamine receptor agonist- and antagonist-induced behaviors in primates previously treated with dopamine receptor antagonists: the pathogenetic mechanisms of acute oral dyskinesia.
Eight Cebus apella monkeys previously treated with dopamine D1 and D2 receptor antagonists were used to elucidate the pathophysiology of acute oral dyskinesia. Five monkeys had mild oral tardive dyskinesia because of previous antagonist treatment. Interactions between the dopamine (DA) D1 receptor agonist SKF 81297 and the DA D2/D3 receptor agonist quinpirole, DA D1 and D2 receptor antagonists, and the anticholinergic biperiden were investigated. SKF 81297, 0.3 mg/kg, induced acute oral dyskinesia and grooming, which were each inhibited by the DA D1 receptor antagonist NNC 756 in a dose-dependent manner. The DA D2 receptor antagonist raclopride enhanced SKF 81297-induced acute oral dyskinesia and suppressed SKF 81297-induced grooming, each with bell-shaped dose-effect curves. Quinpirole, 0.1 mg/kg, induced a hyperarousal syndrome (i.e., increased arousal, stereotypy, and locomotion). Concomitant treatment with SKF 81297 and quinpirole caused an extreme hyperarousal syndrome but antagonized acute oral dyskinesia and grooming, suggesting a synergistic effect of high-efficacy DA D1 and D2/D3 receptor agonists regarding the induction of the hyperarousal syndrome and the antagonism of acute oral dyskinesia and grooming. Biperiden, 0.25 mg/kg, antagonized both the SKF 81297-induced and raclopride-induced acute oral dyskinesia. The results suggest that oral dyskinesia and grooming are independent but most often simultaneously occurring behaviors. Grooming is induced by DA D1 receptor agonists and antagonized by D1 and D2 antagonists and D2/D3 agonists. Acute oral dyskinesia is induced by D1 agonists and lower doses of D2 antagonists, but antagonized by D1 antagonists, D2/D3 agonists, and anticholinergics. These results suggest varying interactions between dopaminergic receptor subtypes in different types of dopaminergic behaviors.
Topics: Animals; Behavior, Animal; Benzazepines; Dopamine Agonists; Dopamine Antagonists; Macaca; Male; Movement Disorders
PubMed: 8681313
DOI: 10.1097/00002826-199512000-00005 -
Acta Pharmacologica Sinica May 2019Increasing preclinical evidence demonstrates that dopamine D3 receptor (D3R) antagonists are a potential option for the treatment of drug addiction. The reinstatement of...
Increasing preclinical evidence demonstrates that dopamine D3 receptor (D3R) antagonists are a potential option for the treatment of drug addiction. The reinstatement of the addiction can be triggered by environmental stimuli that acquire motivational salience through repeated associations with the drug's effects. YQA14 is a novel D3R antagonist that has exhibited pharmacotherapeutic efficacy in reducing cocaine and amphetamine reward and relapse to drug seeking in mice. In this study we investigated the effects of YQA14 on morphine-induced context-specific locomotor sensitization in mice. We showed that repeated injection of YQA14 (6.25-25 mg/kg every day ip) prior to morphine (10 mg/kg every day sc) not only inhibited the acquisition, but also significantly attenuated the expression of morphine-induced locomotor sensitization. Furthermore, in the expression phase, one single injection of YQA14 (6.25-25 mg/kg, ip) dose-dependently inhibited the expression of morphine-induced behavioral sensitization. Moreover, YQA14 inhibited the expression of morphine-induced behavioral sensitization in wild mice (WT), but not in D3R knockout (D3R) mice in the expression phase. In addition, D3R mice also displayed the reduction in the expression phase compared with WT mice. In summary, this study demonstrates that blockade or knockout of the D3R inhibits morphine-induced behavior sensitization, suggesting that D3R plays an important role in the pathogenesis and etiology of morphine addiction, and it might be a potential target for clinical management of opioid addiction.
Topics: Animals; Benzoxazoles; Dopamine Antagonists; Drug-Seeking Behavior; Injections, Intraperitoneal; Male; Mice, Knockout; Morphine; Morphine Dependence; Motor Activity; Piperazines; Receptors, Dopamine D3
PubMed: 30224637
DOI: 10.1038/s41401-018-0153-0 -
The Journal of Pharmacology and... Oct 2021Current therapies for gastroparesis metoclopramide and domperidone carry risks of extrapyramidal symptoms and life-threatening cardiac arrhythmias. Trazpiroben, a novel,...
Current therapies for gastroparesis metoclopramide and domperidone carry risks of extrapyramidal symptoms and life-threatening cardiac arrhythmias. Trazpiroben, a novel, potent dopamine D/D receptor antagonist, has low brain permeation and very low affinity for human ether-à-go-go-related gene (hERG) channel inhibition, potentially improving on safety profiles of existing therapies. Trazpiroben demonstrated the following receptor affinities: high for D and D, moderate for D, and minimal for D and D It demonstrated moderate affinity for adrenergic 1B ( ) and 5-hydroxytryptamine (5HT) 2A receptors and low potential for off-target adverse events (AEs). Trazpiroben potently inhibited dopamine-activated D receptor activation of cognate G-proteins in human embryonic kidney 293 cell membranes and was a neutral D receptor antagonist. In vivo, trazpiroben dose-dependently increased prolactin release in orally dosed rat (0.1-1 mg/kg). Additionally, multiple oral doses in the rat (100 mg/kg) and dog (50 mg/kg) for 3 days produced robust plasma exposures and prolactin increases in both species. Trazpiroben inhibited retching/vomiting in the dog with apomorphine-induced emesis with a potency (0.1-1 mg/kg) like that of trazpiroben-mediated prolactin increases in rat. Oral trazpiroben (1, 10, and 30 mg/kg) did not affect rat rotarod performance, suggesting low brain penetration. Trazpiroben concentrations were low in cerebrospinal fluid versus plasma after multiple oral doses for 4 days in rat and dog. Trazpiroben weakly inhibited the hERG channel current (concentration causing half-maximal inhibition of control-specific binding of 15.6 µM), indicating little potential for disrupting cardiac rhythm. Overall, trazpiroben is a potent D/D receptor antagonist designed to avoid the serious potential AEs associated with current gastroparesis therapies. SIGNIFICANCE STATEMENT: Trazpiroben is a novel, potent dopamine D/D selective receptor antagonist designed to avoid adverse effects associated with the current pharmacological therapies metoclopramide and domperidone. Preclinical studies have demonstrated low brain penetration and weak affinity for the hERG channel, indicating that trazpiroben is not expected to be associated with central nervous system or cardiovascular safety issues. With these pharmacological properties, trazpiroben may represent a viable new treatment option for gastroparesis because of a potentially improved safety profile relative to existing therapies.
Topics: Animals; Antiemetics; CHO Cells; Cricetinae; Cricetulus; Dogs; Domperidone; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Female; Gastroparesis; HEK293 Cells; Humans; Male; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Receptors, Dopamine D3; Triazoles
PubMed: 34253646
DOI: 10.1124/jpet.121.000698 -
The International Journal of... Jun 2009Antipsychotic drugs produce unpleasant subjective experiences, which have been associated with high levels of dopamine D2 receptor occupancy. Aripiprazole is a partial... (Comparative Study)
Comparative Study Randomized Controlled Trial
Antipsychotic drugs produce unpleasant subjective experiences, which have been associated with high levels of dopamine D2 receptor occupancy. Aripiprazole is a partial agonist antipsychotic, which is hypothesized to produce a different subjective experience profile compared to standard D2 antagonist antipsychotics. The aim of this study was to compare the effect of D2 occupancy produced by a partial agonist antipsychotic (aripiprazole) to that of antagonist antipsychotics (risperidone or olanzapine) on the subjective well-being of patients. Subjective well-being was measured using the Subjective Well-being under Neuroleptics Scale (SWN) and was related to dopamine D2 receptor occupancy using [11C]raclopride PET. Patients that were switched to aripiprazole showed improvement in their subjective well-being from 79.80 (S.D.=16.08) to 89.90 (S.D.=15.33), an effect that was sustained for 6 months. This sustained improvement was observed despite very high levels of DA D2 occupancy (82-99%), in contrast to the effects of antagonist antipsychotics on subjective well-being.
Topics: Adult; Affect; Antipsychotic Agents; Brain; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Humans; Positron-Emission Tomography; Protein Binding; Receptors, Dopamine D2; Schizophrenia; Young Adult
PubMed: 19366489
DOI: 10.1017/S1461145709000327 -
Drugs Feb 2021Amisulpride intravenous (IV) injection (Barhemsys; hereafter referred to as IV amisulpride), a selective dopamine receptor antagonist, is approved in the USA as a single... (Review)
Review
Amisulpride intravenous (IV) injection (Barhemsys; hereafter referred to as IV amisulpride), a selective dopamine receptor antagonist, is approved in the USA as a single IV infusion for the prevention and treatment of post-operative nausea and vomiting (PONV) in adults. Results from placebo-controlled phase III trials showed that IV amisulpride is efficacious both in the prevention of PONV (used either alone or in combination with an antiemetic of a different class) and in the treatment of PONV (irrespective of prior antiemetic prophylaxis status). When administered as a single IV infusion, amisulpride had a tolerability profile that was generally similar to that of placebo, with no significant safety concerns identified. Thus, IV amisulpride is a useful additional option in the prevention and treatment of PONV in adults, particularly for patients who have failed previous antiemetic prophylaxis and for whom effective treatment options may be limited.
Topics: Amisulpride; Dopamine Antagonists; Humans; Injections, Intravenous; Postoperative Nausea and Vomiting; Vomiting
PubMed: 33656662
DOI: 10.1007/s40265-020-01462-1 -
Naunyn-Schmiedeberg's Archives of... Dec 2002LE300 (7-methyl-6,7,8,9,14,15-hexahydro-5 H-benz[d]indolo[2,3-g]azecine), a previously reported subnanomolar antagonist at rat striatal dopamine D1 receptors, and three...
LE300 (7-methyl-6,7,8,9,14,15-hexahydro-5 H-benz[d]indolo[2,3-g]azecine), a previously reported subnanomolar antagonist at rat striatal dopamine D1 receptors, and three of its azecine-N-substituted congeners combining structural elements of serotonin and dopamine were comprehensively characterised (binding and function) at recombinant human dopamine receptors. Radioligand competition experiments at D1 and D2L receptors were performed by using [(3)H]SCH23390 and [(3)H]spiperone, respectively. Functional assays included measurements of cAMP, intracellular [Ca(2+)], and [(35)S]GTPgammaS-binding. LE300 was the most potent compound with a 10- to 20-fold selectivity for D1 over D2L receptors as measured in equilibrium binding experiments [competition radioligand binding: K(i)(D1)=1.9 nM, K(i)(D2L)=44.7 nM; [(35)S]GTPgammaS-binding: K(i)(D1)=1.8 nM, K(i)(D2L)=21.5 nM]. In functional (non-equilibrium) experiments, LE300 did not reveal a D1 over D2L selectivity but retained nanomolar K(i) values at human dopamine receptors (measurement of cAMP: K(i)(D1)=25.9 nM, K(i)(D2L)=5.2 nM; measurement of intracellular [Ca(2+)]: K(i)(D1)=60.4 nM, K(i)(D2L)=19.0 nM). LE300 is currently under investigation for usefulness as positrone emission tomography ligand. In conclusion, LE300 is a novel type of a nanomolar dopamine receptor antagonist combining structural core elements of dopamine and serotonin, and may become useful as positrone emission tomography ligand.
Topics: Animals; CHO Cells; Cell Line; Cricetinae; Dopamine Antagonists; Dose-Response Relationship, Drug; Humans; Indoles; Nanotechnology; Receptors, Dopamine
PubMed: 12444495
DOI: 10.1007/s00210-002-0641-z -
Advances in Pharmacology (San Diego,... 1998
Topics: Animals; Antipsychotic Agents; Brain; Clozapine; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Humans; Imidazoles; Pyrimidines; Radioligand Assay; Rats; Receptors, Dopamine D2; Receptors, Dopamine D4; Stereotyped Behavior; Tritium
PubMed: 9327946
DOI: 10.1016/s1054-3589(08)60795-4