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Neuropharmacology Mar 2023We recently reported that the "Dopamine Neuron Challenge Test" (DNC Test), a diagnostic method that measures the levels of dopamine metabolites in cerebrospinal fluid...
We recently reported that the "Dopamine Neuron Challenge Test" (DNC Test), a diagnostic method that measures the levels of dopamine metabolites in cerebrospinal fluid (CSF) and plasma samples after pharmacologically inducing a transient dopamine release, can detect early-stage Parkinson's disease (PD) with high sensitivity and selectivity in mouse models. The use of haloperidol in the original DNC test to challenge dopamine neurons was less than ideal, as it may cause extrapyramidal motor symptoms. Here we report an improved DNC Test, in which the original challenging agents, haloperidol and methylphenidate, are replaced by a single challenging agent, a dopamine autoreceptor preferring antagonist AJ76 or UH232. We show that the improved DNC Test can achieve the same level of sensitivity and selectivity in detecting early PD in a mouse model without causing motor side effects. These findings significantly improve the practicality of using the DNC Test as a screening or diagnostic test for detecting early-stage PD in the high-risk population in humans.
Topics: Animals; Mice; Humans; Dopamine; Parkinson Disease; Haloperidol; Homovanillic Acid; Dopamine Antagonists; 3,4-Dihydroxyphenylacetic Acid
PubMed: 36623805
DOI: 10.1016/j.neuropharm.2022.109397 -
Neuropsychopharmacology : Official... Aug 2015In Pavlovian conditioning, sign- and goal-tracking behaviors represent different approaches towards the conditioned stimulus. These behavioral patterns have been...
In Pavlovian conditioning, sign- and goal-tracking behaviors represent different approaches towards the conditioned stimulus. These behavioral patterns have been associated with predictive or incentive properties of the conditioned stimulus, with a crucial involvement of the mesolimbic dopamine system. As it is possible that sign tracking behavior is more sensitive to dopamine modulation, we evaluated the dopamine-dependence of sign- and goal-tracking behavior. We assessed responses to both a D2 agonist and an antagonist, and tested performance in a behavioral paradigm known to activate dopamine projections and in an animal model that affects mesolimbic and mesocortical function. Sign trackers displayed a greater sensitivity to a D2 agonist and smaller prepulse inhibition of the acoustic startle response than goal trackers, suggesting a reduced inhibitory ability. In addition, a neonatal ventral hippocampal lesion resulted in the loss of incentive salience of cues in sign trackers. Overall, these data indicate that sign-tracking behavior is more heavily controlled by dopamine than goal tracking.
Topics: Analysis of Variance; Animals; Animals, Newborn; Conditioning, Classical; Conditioning, Operant; Cues; Dopamine Antagonists; Goals; Male; Motivation; Prepulse Inhibition; Rats; Rats, Long-Evans; Receptors, Dopamine D2; Reflex, Startle; Salicylamides
PubMed: 25759299
DOI: 10.1038/npp.2015.68 -
Learning & Memory (Cold Spring Harbor,... Jun 2022Dopamine participates in encoding memories and could either encode rewarding/aversive value of unconditioned stimuli or act as a novelty signal triggering contextual...
Dopamine participates in encoding memories and could either encode rewarding/aversive value of unconditioned stimuli or act as a novelty signal triggering contextual learning. Here we show that intraperitoneal injection of the dopamine D1/5R antagonist SCH23390 impairs contextual fear conditioning and tone-shock association, while intrahippocampal injection only impairs contextual fear conditioning. By using the context pre-exposure facilitation effect test, we show that SCH23390 is able to block the encoding of the context during the pre-exposure phase. Thus, we provide additional evidence that dopamine is involved in encoding conjunctive representations of new contexts.
Topics: Conditioning, Classical; Dopamine; Dopamine Antagonists; Fear; Learning; Receptors, Dopamine D1
PubMed: 35577394
DOI: 10.1101/lm.053555.121 -
Brain Research. Brain Research Reviews Jul 2005The cDNA for the dopamine D3 receptor was isolated and characterized in 1990. Subsequent studies have indicated that D3 receptors, as well as D3 receptor mRNA, are... (Review)
Review
The cDNA for the dopamine D3 receptor was isolated and characterized in 1990. Subsequent studies have indicated that D3 receptors, as well as D3 receptor mRNA, are primarily localized in limbic regions in mammals. This finding led to the postulate that D3 receptors may be involved in drug dependence and addiction. However, this hypothesis has been difficult to test due to the lack of compounds with high selectivity for central D3 receptors. The interpretation of results from studies using mixed D2/D3 agonists and/or antagonists is problematic because these agents have low selectivity for D3 over D2 receptors and it is likely that their actions are primarily related to D2 receptor antagonism and possibly interaction with other neurotransmitter receptors. Currently, with the synthesis and characterization of new highly selective D3 receptor antagonists such as SB-277011-A this difficulty has been surmounted. The purpose of the present article is to review, for the first time, the effects of various putative D3 receptor selective compounds in animal models of drug dependence and addiction. The results obtained with highly selective D3 receptor antagonists such as SB-277011-A, SB-414796, and NGB-2904 indicate that central D3 receptors may play an important role in drug-induced reward, drug-taking, and cue-, drug-, and stress-induced reinstatement of drug-seeking behavior. Provided these results can be extrapolated to human drug addicts, they suggest that selective DA D3 receptor antagonists may prove effective as potential pharmacotherapeutic agents to manage drug dependence and addiction.
Topics: Animals; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Humans; Receptors, Dopamine D2; Receptors, Dopamine D3; Substance-Related Disorders
PubMed: 15960988
DOI: 10.1016/j.brainresrev.2004.12.033 -
British Journal of Pharmacology Jun 19971. The atypical antipsychotic profile of (R)-(+)-2-amino-4-(4-fluorophenyl)-5-[1-[4-(4-fluorophenyl)-4-oxobutyl] pyrrolidin-3-yl] thiazole (NRA0045), a potent dopamine...
1. The atypical antipsychotic profile of (R)-(+)-2-amino-4-(4-fluorophenyl)-5-[1-[4-(4-fluorophenyl)-4-oxobutyl] pyrrolidin-3-yl] thiazole (NRA0045), a potent dopamine D4 and 5-hydroxytryptamine (5-HT)2A receptor antagonist, was examined in rats. 2. Spontaneous locomotor activity was decreased dose-dependently with i.p. administration of clozapine (ED50 3.7 mg kg-1), haloperidol (ED50 0.1 mg kg-1) and chlorpromazine (ED50 0.9 mg kg-1), whereas inhibition of this type of behaviour induced by i.p. administration of NRA0045, at doses up to 10 mg kg-1, did not exceed 50%. 3. Locomotor hyperactivity induced by methamphetamine (MAP, 2 mg kg-1, i.p.) in rats (a model of antipsychotic activity) was dose-dependently antagonized by NRA0045 (ED50 0.4 mg kg-1, i.p., and 0.3 mg kg-1, p.o., respectively), clozapine (ED50 0.3 mg kg-1, i.p. and 0.8 mg kg-1, p.o., respectively), haloperidol (ED50 0.02 mg kg-1, i.p. and 0.1 mg kg-1, p.o., respectively), chlorpromazine (ED50 0.3 mg kg-1, i.p. and 3.3 mg kg-1, p.o., respectively). In contrast, the MAP (3 mg kg-1, i.v.)-induced stereotyped behaviour in rats (a model of extrapyramidal symptoms) was not affected by NRA0045 or clozapine, at the highest dose given (30 mg kg-1, i.p.). Haloperidol (ED50 0.3 mg kg-1, i.p.) and chlorpromazine (ED50 4.8 mg kg-1, i.p.) strongly blocked the MAP-induced stereotyped behaviour. NRA0045 and clozapine selectively blocked behaviour associated with activation of the mesolimbic/mesocortical dopamine neurones rather than nigrostriatal dopamine neurones. 4. Extracellular single-unit recording studies demonstrated that MAP (1 mg kg-1, i.v.) decreased the firing rate in the substantia nigra (A9) and ventral tegmental area (A10) dopamine neurones in anaesthetized rats. NRA0045 completely reversed the inhibitory effects of MAP on A10 dopamine neurones (ED50 0.1 mg kg-1, i.v.), whereas the inhibitory effects of MAP on A9 dopamine neurones were not affected by NRA0045, in doses up to 1 mg kg-1 (i.v.). Clozapine completely reversed the inhibitory effects of MAP on A10 dopamine neurones (ED50 1.9 mg kg-1, i.v.) and on A9 dopamine neurones (ED50 2.5 mg kg-1, i.v.). Haloperidol completely reversed the inhibitory effects of MAP on A10 (ED50 0.03 mg kg-1, i.v.) and on A9 dopamine neurones (0.02 mg kg-1, i.v.). NRA0045, like clozapine, was more potent in reversing the effects of MAP on A10 than A9 dopamine neurones. 5. Prepulse inhibition (PPI) is impaired markedly in humans with schizophrenia. The disruption of PPI in rats by apomorphine (0.5 mg kg-1, s.c.) was reversed significantly by NRA0045 (3 mg kg-1, i.p.), clozapine (3 mg kg-1, i.p.) and haloperidol (0.3 mg kg-1, i.p.). 6. Phencyclidine (PCP) elicits predominantly psychotic symptoms in normal humans and in schizophrenics. NRA0045 (0.03-0.3 mg kg-1, i.p.) and clozapine (0.1-1 mg kg-1, i.p.) significantly and dose-dependently shortened the PCP(1.25 mg kg-1, i.p.)-induced prolonged swimming latency in rats in a water maze task, whereas haloperidol (0.01-0.1 mg kg-1, i.p.) did not significantly alter swimming latency. 7. These findings suggest that NRA0045 may have unique antipsychotic activities without the liability of motor side effects typical of classical antipsychotics.
Topics: Animals; Antipsychotic Agents; Apomorphine; Clozapine; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Male; Maze Learning; Methamphetamine; Motor Activity; Pyrrolidines; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D4; Receptors, Serotonin; Serotonin Antagonists; Thiazoles
PubMed: 9179395
DOI: 10.1038/sj.bjp.0701164 -
PloS One 2019Schizophrenia and Parkinson's disease can be controlled with dopamine antagonists and agonists. In order to improve the understanding of the reaction mechanism of these...
Schizophrenia and Parkinson's disease can be controlled with dopamine antagonists and agonists. In order to improve the understanding of the reaction mechanism of these drugs, in this investigation we present a quantum chemical study of 20 antagonists and 10 agonists. Electron donor acceptor capacity and global hardness are analyzed using Density Functional Theory calculations. Following this theoretical approach, we provide new insights into the intrinsic response of these chemical species. In summary, antagonists generally prove to be better electron acceptors and worse electron donors than dopamine, whereas agonists present an electron donor-acceptor capacity similar to that of dopamine. The chemical hardness is a descriptor that captures the resistance of a chemical compound to change its number of electrons. Within this model, harder molecules are less polarizable and more stable systems. Our results show that the global hardness is similar for dopamine and agonists whilst antagonists present smaller values. Following the Hard and Soft Acid and Bases principle, it is possible to conclude that dopamine and agonists are hard bases while antagonists are soft acids, and this can be related to their activity. From the electronic point of view, we have evolved a new perspective for the classification of agonist and antagonist, which may help to analyze future results of chemical interactions triggered by these drugs.
Topics: Antipsychotic Agents; Dopamine Agonists; Dopamine Antagonists; Humans; Models, Chemical; Molecular Structure; Parkinson Disease; Quantum Theory; Schizophrenia
PubMed: 31830046
DOI: 10.1371/journal.pone.0224691 -
The Journal of Pharmacology and... May 2009Recent studies identified novel allosteric modulators of the dopamine (DA) transporter (DAT). N-(Diphenylmethyl)-2-phenyl-4-quinazolinamine (SoRI-9804),...
Recent studies identified novel allosteric modulators of the dopamine (DA) transporter (DAT). N-(Diphenylmethyl)-2-phenyl-4-quinazolinamine (SoRI-9804), N-(2,2-diphenylethyl)-2-phenyl-4-quinazolinamine (SoRI-20040), and N-(3,3-diphenylpropyl)-2-phenyl-4-quinazolinamine (SoRI-20041) partially inhibited [(125)I]3beta-(4'-iodophenyl)tropan-2beta-carboxylic acid methyl ester (RTI-55) binding, slowed the dissociation rate of [(125)I]RTI-55 from the DAT, and partially inhibited [(3)H]dopamine uptake. In the present study, we report that SoRI-9804 and SoRI-20040, at doses that do not alter release, partially inhibited d-amphetamine-induced DAT-mediated release of [(3)H]1-methyl-4-phenylpyridinium (MPP(+))or[(3)H]dopamine from striatal synaptosomes ("DAT-mediated DA release") in a dose-dependent manner. SoRI-20041, which does not alter DAT-mediated DA release measured with [(3)H]DA, reversed the effect of SoRI-20040. SoRI-20040 and SoRI-9804 also partially inhibited DAT-mediated DA release induced by DA or (+/-)-3,4-methylenedioxyamphetamine, demonstrating that the observed partial inhibition is not specific for a particular DAT substrate. SoRI-9804 and SoRI-20040 did not attenuate D-amphetamine-induced release of [(3)H]5-hydroxytryptamine from serotonergic, or [(3)H]MPP(+) from noradrenergic, nerve terminals. Kinetic experiments demonstrated that SoRI-9804, in contrast to cocaine, slowed D-amphetamine-induced release of [(3)H]MPP(+) from dopaminergic nerve terminals without altering the apparent rate constants. The two major findings of this study are 1) the identification of both "agonist" (SoRI-9804 and SoRI-20040) and "antagonist" (SoRI-20041) allosteric modulators of D-amphetamine-induced DAT-mediated DA release and 2) [(3)H]DA uptake and d-amphetamine-induced DAT-mediated efflux can be separately modulated. Such agents may have therapeutic potential for the treatment of stimulant addiction, Parkinson's disease, and other psychiatric disorders.
Topics: Allosteric Regulation; Animals; Biological Transport; Brain; Dextroamphetamine; Dopamine; Dopamine Agonists; Dopamine Antagonists; Dopamine Plasma Membrane Transport Proteins; Dose-Response Relationship, Drug; Male; Molecular Structure; Rats
PubMed: 19244097
DOI: 10.1124/jpet.108.149088 -
Psychopharmacology Apr 2018Dopamine (DA) is a neurotransmitter whose roles have been suggested in various aspects of brain functions. Recent studies in rodents have reported its roles in social...
RATIONALE
Dopamine (DA) is a neurotransmitter whose roles have been suggested in various aspects of brain functions. Recent studies in rodents have reported its roles in social function. However, how DA is involved in social information processing in primates has largely remained unclear.
OBJECTIVES
We investigated prefrontal cortical (PFC) activities associated with social vs. nonsocial visual stimulus processing.
METHODS
Near-infrared spectroscopy (NIRS) was applied to Japanese macaques, along with pharmacological manipulations of DA transmission, while they were gazing at social and nonsocial visual stimuli.
RESULTS
Oxygenated (oxy-Hb) and deoxygenated (deoxy-Hb) hemoglobin changes as well as functional connectivity based on such Hb changes within the PFC network which were distinct between social and nonsocial stimuli were observed. Administration of both D1 and D2 receptor antagonists affected the Hb changes associated with social stimuli, whereas D1, but not D2, receptor antagonist affected the Hb changes associated with nonsocial stimuli.
CONCLUSIONS
These results suggest that mesocortical DA transmission in the PFC plays significant roles in social information processing, which involves both D1 and D2 receptor activation, in nonhuman primates. However, D1 and D2 receptor signaling in the PFC mediates different aspects of social vs. nonsocial information processing.
Topics: Animals; Dopamine; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Female; Macaca; Nerve Net; Prefrontal Cortex; Receptors, Dopamine D1; Receptors, Dopamine D2; Social Behavior; Spectroscopy, Near-Infrared
PubMed: 29332256
DOI: 10.1007/s00213-018-4831-x -
Psychopharmacology Jul 2019Methamphetamine (MA) is an abused psychostimulant that causes cognitive deficits after chronic use. Neostriatal dopamine receptors play a role in MA monoamine...
RATIONALE
Methamphetamine (MA) is an abused psychostimulant that causes cognitive deficits after chronic use. Neostriatal dopamine receptors play a role in MA monoamine neurotoxicity. Blocking dopamine receptors prior to MA exposure in adult rats attenuates monoamine reductions and reactive gliosis.
OBJECTIVES
We tested whether blocking dopamine receptors protects against cognitive deficits.
METHODS
First, we determined the effects of MA alone versus MA in combination with the dopamine receptor D1 antagonist SCH-23390 or the dopamine receptor D2 antagonist sulpiride on cFos expression and monoamines at the age when rats in the cognitive experiment were to begin testing and monoamines in rats after cognitive testing.
RESULTS
SCH-23390 infused into the neostriatum prior to systemic administration of MA attenuated MA-induced cFos activation while sulpiride induced cFos activation. Two weeks after MA, rats had dopamine and serotonin reductions that were attenuated by each antagonist. Other rats treated the same way, were tested for egocentric learning and memory in the Cincinnati water maze, for navigational strategy in a star water maze, and spatial learning and memory in a Morris water maze. Pre-treatment with SCH-23390 or sulpiride attenuated the effects of MA on egocentric and spatial learning and memory. MA-treated rats showed a shift from an egocentric to a disorganized strategy in the star maze that was less disorganized in groups receiving MA and an antagonist. Post-behavior monoamine reductions remained but were attenuated by the antagonists but not identically to what was seen in rats not behaviorally tested.
CONCLUSIONS
The results show for the first time that dopamine receptors are mediators of MA-induced cognitive deficits.
Topics: Animals; Central Nervous System Stimulants; Dopamine; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Egocentrism; Injections, Intraventricular; Male; Maze Learning; Memory Disorders; Methamphetamine; Neostriatum; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1; Receptors, Dopamine D2
PubMed: 30919007
DOI: 10.1007/s00213-019-05221-3 -
The Journal of Medical Investigation :... Nov 2005It is obvious that DA is an important neurotransmitter in vivo. It is involved in a variety of physiological processes such as mental processes, motor function and... (Review)
Review
It is obvious that DA is an important neurotransmitter in vivo. It is involved in a variety of physiological processes such as mental processes, motor function and hormone regulation. In this context, it is quite understandable that a DA D2 receptor antagonist that inhibits the DA D2 receptor regardless of the state of activity of dopaminergic neurotransmission and inhibit the physiological function of DA can have a variety of adverse effects. In contrast to DA D2 antagonists, aripiprazole acts as an antagonist at the DA D2 receptor in the state of excessive dopaminergic neurotransmission, while it acts as an agonist at the DA D2 receptor in the state of low dopaminergic neurotransmission, and thus attempts to bring the state of dopaminergic neurotransmission to normal. This activity of aripiprazole to regulate dopaminergic neurotransmission is physiologically reasonable, and can be regarded as a stabilizing effect, for which aripiprazole is called a dopamine system stabilizer.
Topics: Animals; Antipsychotic Agents; Aripiprazole; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Humans; Molecular Structure; Piperazines; Quinolones; Receptors, Dopamine D2; Schizophrenia
PubMed: 16366516
DOI: 10.2152/jmi.52.284