Effects Of Dopaminergic Agents Research Articles

Changes of Locomotor Activity by Dopamine D2, D3 Agonist Quinpirole in Mice Using Home-cage Monitoring System.

: As dopamine is closely linked to locomotor activities, animal studies on locomotor activities using dopaminergic agents were widely done. However, most of animal studies were performed for a short period that there is a lack of longitudinal study on the effects of dopaminergic agents on locomotor activities. This study aimed to examine the longterm effect of a dopamine D2, D3 agonist quinpirole on locomotor activities in mice using a home-cage monitoring system. : The locomotor activities of Institute Cancer Research mice were measured by infrared motion detectors in home-cages under the 12-hour dark and 12-hour light condition for three days after the quinpirole injection. Quinpirole was injected at a concentration of 0.5 mg/kg intraperitoneally in the beginning of the dark phase. The locomotor activities before and after the quinpirole administration were compared by the Wilcoxon signed-rank test and one-way repeated measures ANOVA. : After the quinpirole administration, the 24-hour total locomotor activity did not change (p = 0.169), but activities were significantly increased in the 12-hour dark phase sum (p = 0.013) and decreased in the 12-hour light phase sum (p = 0.009). Significant increases in the activities were observed in the dark-light difference (p = 0.005) and dark-light ratio (p = 0.005) as well. : This study suggests that quinpirole injection entrains the circadian rest-activity rhythm of locomotor activities. Therefore, quinpirole can be a drug that mediates locomotor activity as a dopamine agonist as well as a modulator of the circadian rhythms.

The effects of dopaminergic agents on the high potassium-evoked DOPA and dopamine release from PC12 cells

The effects of dopaminergic agents on the high potassium-evoked DOPA and dopamine release from PC12 cells

Beyond Metoclopramide for Gastroparesis

Beyond Metoclopramide for Gastroparesis

Dopaminergic Modulation of Sleep-Wake States.

The role of dopamine in sleep-wake regulation is considered as a wakefulness-promoting agent. For the clinical treatment of excessive daytime sleepiness, drugs have been commonly used to increase dopamine release. However, sleep disorders or lack of sleep are related to several dopaminerelated disorders. The effects of dopaminergic agents, nevertheless, are mediated by two families of dopamine receptors, D1 and D2-like receptors; the first family increases adenylyl cyclase activity and the second inhibits adenylyl cyclase. For this reason, the dopaminergic agonist effects on sleep-wake cycle are complex. Here, we review the state-of-the-art and discuss the different effects of dopaminergic agonists in sleep-wake states, and propose that these receptors account for the affinity, although not the specificity, of several effects on the sleep-wake cycle.

Effects of dopaminergic agents on progression of naturally occurring myopia in albino guinea pigs (Cavia porcellus).

Disruption of dopaminergic signaling has been implicated in the abnormalities of ocular development in albinism, and many experiments have shown that retinal dopamine is a major regulator of postnatal eye growth and myopia in animal models. Therefore, in the present study we investigated whether progressive myopia, which can occur in albino guinea pigs without experimental manipulation of visual conditions, is affected by dopaminergic agents. Two-week-old albino guinea pigs, selected for being myopic (range refractive error [RE], -2 to -10 diopters [D]), received unilateral peribulbar injections of apomorphine (nonselective dopamine receptor agonist; 0, 7.5, 25, 75, 250, 750, and 2500 ng; n = 112), SKF38393 (D1-like agonist; 0, 10, 100, 1000 ng; n = 63), SCH23390 (D1-like antagonist; 0, 2500 ng; n = 27), quinpirole (D2-like agonist; 0, 10, 100, 1000 ng; n = 58), or sulpiride (D2-like antagonist; 0, 2500 ng; n = 24) once a day for four weeks. One noninjected group (n = 19) served as untreated control. Refractive states and axial dimensions of the eyes were measured without cycloplegia or general anesthetic, using eccentric infrared photoretinoscopy and A-scan ultrasonography, respectively, before treatment, and after 2 and 4 weeks of treatment. The main drug effects were analyzed by paired t-test or 2-way repeated measures ANOVA, as required. The naturally occurring progression of myopic RE was inhibited by apomorphine at relatively high doses (250 and 750 ng), SKF38393 at 100 ng (D1-like agonist), and sulpiride at 2500 ng (D2-like antagonist), but promoted by apomorphine at a lower dose (25 ng), quinpirole at 100 ng (D2-like agonist), and SCH23390 at 2500 ng (D1-like antagonist). All drugs affected primarily vitreous chamber depth, rather than anterior segment dimensions. Our data suggest that the activation of D1-like receptors inhibits, whereas activation of D2-like receptors promotes, progressive myopia in this animal model. The robust effects of antagonists suggest that ocular dopamine receptors in these albinos may be in a chronic state of partial excitation. The precise location and identity of the receptors responsible for these effects remain to be determined.

The role of dopaminergic agents in improving quality of life in major depressive disorder

Quality of life (QOL) is greatly diminished in patients with major depressive disorder (MDD) before treatment. This deficit persists even when patients are in remission; thus, interventions are needed to improve QOL. This article reviews QOL impairment in MDD and the cost of impairment, then summarizes the empiric literature on the effects of dopaminergic agents on QOL in patients with MDD. Studies were identified through a MEDLINE search from the past 35 years (1974-2009) using key terms "quality of life," "major depression," and "major depressive disorder," and "dopaminergic," "bupropion," or "modafinil." A total of 47 studies were included in this review. A brief overview of the relationship between QOL and MDD is presented, followed by a review of dopaminergic agent chemistry, mechanism of action, use, and trials conducted to investigate agents' effects on QOL. Preliminary evidence suggests dopaminergic agents may have a positive effect on QOL for patients with MDD. Prospective, randomized, double-blind, placebo-controlled studies are needed to extend these findings.

Effects of dopaminergic agents on carrageenan hyperalgesia after intrathecal administration to rats

The present study explored the role of dopaminergic transmission in spinal cord in a model of carrageenan-induced inflammatory pain by examining the effects of selective agonists and antagonists of dopamine receptors. The results were as follows: (1) trans-(−)-4 aR-4,4 a,5,6,7,8,8 a,9-octahydro-5-propyl-1 H-pyrazolo[3,4− g] quinoline hydrochloride (LY171555), a dopamine D 2 receptor agonist, produced anti-hyperalgesia (150 and 300 nmol) or hypoalgesia (300 nmol) in the inflamed hindpaws and non-inflamed hindpaws, respectively; spiperone hydrochloride (8-[4-(4-fluorophenyl)-4-oxobutyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one hydrochloride), a dopamine D 2 receptor antagonist, decreased the pain threshold of non-inflamed hindpaws (300 nmol). (2) (±)-SKF38393 hydrochloride ((±)-1-phenyl-2,3,4,5-tetrahydro-(1 H)-3-benzazepine-7,8-diol hydrochloride), a dopamine D 1 receptor agonist, had no effect on either hindpaw, even at a higher dose (300 nmol); R(+)-7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine hydrochloride ( R(+)-SCH23390 hydrochloride), a dopamine D 1 receptor antagonist, induced anti-hyperalgesia in the inflamed hindpaws (300 nmol). The present results suggest that the dopaminergic system in the spinal cord is involved in the central modulation of inflammatory hyperalgesia, and that the different effects are probably induced by different receptors.

Dopamine and Alcohol Relapse: D1 and D2 Antagonists Increase Relapse Rates in Animal Studies and in Clinical Trials

A considerable number of animal studies on the effects of dopaminergic agents on alcohol intake behavior have been performed. Acute alcohol administration in rats induces dopamine release in the caudate nucleus and in the nucleus accumbens, an effect related among others to reinforcement. It has been repeatedly suggested that D₁ and D₂ receptor activation mediates reward. As alcohol consumption and dopaminergic transmission seem to have a close relationship, all kinds of dopaminergic agents may be regarded as putative therapeutics for preventing relapse. In a prospective European double-blind multicenter clinical trial, comparing the D₁, D₂, D₃ antagonist flupenthixol and placebo in 281 chronic alcohol-dependent patients (27.4% women), the application of the Lesch typology made an outcome differentiation possible. It could be shown in which patients flupenthixol administration was followed by a significantly higher relapse rate and in which patient groups no differences were found when compared to placebo.

Dopamine and alcohol relapse: D1 and D2 antagonists increase relapse rates in animal studies and in clinical trials

A considerable number of animal studies on the effects of dopaminergic agents on alcohol intake behavior have been performed. Acute alcohol administration in rats induces dopamine release in the caudate nucleus and in the nucleus accumbens, an effect related among others to reinforcement. It has been repeatedly suggested that D1 and D2 receptor activation mediates reward. As alcohol consumption and dopaminergic transmission seem to have a close relationship, all kinds of dopaminergic agents may be regarded as putative therapeutics for preventing relapse. In a prospective European double-blind multicenter clinical trial, comparing the D1, D2, D3 antagonist flupenthixol and placebo in 281 chronic alcohol-dependent patients (27.4% women), the application of the Lesch typology made an outcome differentiation possible. It could be shown in which patients flupenthixol administration was followed by a significantly higher relapse rate and in which patient groups no differences were found when compared to placebo.

Localization of dopaminergic markers in the human subthalamic nucleus

The potential role for dopamine in the subthalamic nucleus was investigated in human postmortem tissue sections by examining; (1) immunostaining for tyrosine hydroxylase, the rate-limiting enzyme in catecholamine synthesis; (2) binding of [(3)H]-SCH23390 (D1-like), [(3)H]-YM-09151-2 (D2-like), and [(3)H]-mazindol (dopamine uptake); and (3) expression of dopamine D1 and D2 receptor mRNAs. Immunostaining for tyrosine hydroxylase was visualized in Bouin's-fixed tissue by using a monoclonal antibody and the avidin-biotin-complex method. The cellular localization of the dopamine D1 and D2 receptor mRNAs was visualized by using a cocktail of human specific oligonucleotide probes radiolabeled with (35)S-dATP. Inspection of immunostained tissue revealed a fine network of tyrosine hydroxylase-immunostained fibers traversing the nucleus; no immunopositive cells were detected. Examination of emulsion-coated tissue sections processed for D1 and D2 receptor mRNA revealed, as expected, an abundance of D1 and D2 mRNA-positive cells in the caudate nucleus and putamen. However, no D1 or D2 receptor mRNA-expressing cells were detected in the subthalamic nucleus. Further, semiquantitative analysis of D1-like, D2-like and dopamine uptake ligand binding similarly revealed an enrichment of specific binding in the caudate nucleus and putamen but not within the subthalamic nucleus. However, a weak, albeit specific, signal for [(3)H]-SCH23390 and [(3)H]-mazindol was detected in the subthalamic nucleus, suggesting that the human subthalamic nucleus may receive a weak dopaminergic input. As weak D1-like binding is detected in the subthalamic nucleus, and subthalamic neurons do not express dopamine D1 or D2 receptor mRNAs, together these data suggest that the effects of dopaminergic agents on the activity of human subthalamic neurons may be indirect and mediated via interaction with dopamine D1-like receptors.

Effects of Dopaminergic Agents and of an NMDA Receptor Antagonist on Motor Coordination in Lurcher Mutant Mice

Lurcher mutant mice, characterized by an ataxic gait and olivocerebellar degeneration, were evaluated for motor coordination in the coat-hanger test after peripheral injections of two doses of dextromethorphan, a noncompetitive N-methyl- d-aspartate receptor antagonist, l-dopa/carbidopa, and SKF 77434, a dopamine D 1 receptor agonist. There was an improvement in the distance traveled on the suspended horizontal string after 25 and 50 mg/kg of dextromethorphan and 37.5 mg/kg of l-dopa/carbidopa, but not after SKF 77434. None of the drugs reduced movement times or increased latencies before falling. These results indicate that NMDA receptor antagonism or stimulation of some dopaminergic mechanisms partially improve genetically determined cerebellar ataxia in mice.

Psychopharmacology of conditioned reward: evidence for a rewarding signal at D1-like dopamine receptors.

A neutral stimulus can acquire conditioned rewarding properties through association with an intrinsically rewarding stimulus. The acquisition of responding for conditioned rewards requires that environmental stimuli and reward processes interact in a highly specific manner; analyses of this phenomenon may provide valuable insight into the processes that underlie reward-related learning. The effects of dopaminergic agents with different mechanisms of action in this paradigm have revealed several interesting dissociations suggesting that a rewarding signal at dopamine D1-like receptors may mediate both the acquisition of rewarding properties by neutral stimuli and their ability to control behavior. Dopamine-induced changes in responding for conditioned reward are susceptible to modulation by other neurotransmitter systems. In many cases, the molecular and cellular bases of these interactions support the notion that signaling through D1-like receptors is critical for a conditioned reward to direct responding. The model outlined in this paper reflects a comprehensive integration of the existing literature in the field, and has several implications that are readily testable by future research. Moreover, given the known biochemical coupling of D1-like receptors, this model may help in characterizing the sequence of intracellular events, from signal transduction to possible transcriptional and/or translational regulation, that give rise to the acquisition of rewarding properties by neutral stimuli.

The effects of dopaminergic agents on reaction time in rhesus monkeys.

Many CNS pathologies, including Parkinson's, Alzheimer's and Huntington's diseases, as well as AIDS dementia complex, involve some degree of movement dysfunction. Reaction time (RT) performance has been shown to be a sensitive measure of motor function for these disorders. Useful models of RT performance exist in a variety of species, but few are performed in the same manner as with humans. To facilitate species comparisons, the present RT task was developed from a human RT task. Dopaminergic drugs were then used to characterize the sensitivity of the model to CNS changes and to investigate their effects on RT performance in intact rhesus monkeys. With cumulative dosing, the selective dopamine receptor antagonists (D1) SCH 39166 and (D2) raclopride produced dose-dependent slowing of RT performance. Results following bolus administration of these drugs were consistent with the cumulative dosing procedure, although of smaller magnitude and higher variability. Amphetamine had no significant effect on group RT performance with either dosing scheme, but RT performance in individual monkeys was either speeded or slowed by d-amphetamine. The present results suggest that blockade of either D1-like or D2-like dopamine receptors can slow RT performance in rhesus monkeys and that this paradigm may be useful to study movement dysfunction in non-human primates.

Detection of mRNAs and alternatively spliced transcripts of dopamine receptors in rat peripheral sensory and sympathetic ganglia

The presence of mRNAs for dopamine receptor subtypes and dopamine transporter in rat peripheral sensory and sympathetic ganglia was investigated using polymerase chain reaction (PCR) and DNA sequencing. Dopamine D 1, D 2, D 3, D 5 receptor subtype mRNAs and dopamine transporter mRNA were detected in both superior cervical sympathetic ganglia (SCG) and dorsal root ganglia (DRG) in the rat; the expression of D 4 mRNA was only detected in DRG. While two alternatively spliced isoforms of D 2 were detected in both ganglia, the alternative splicing transcripts for D 3 and D 4 were only found in the DRG. These results are useful in further studying the roles of dopamine and the effects of dopaminergic agents in the peripheral nervous system.

Effects of Dopaminergic Agents on Reversal of Reserpine-Induced Impairment in Conditioned Avoidance Response in Rats

Male Slc:Wistar, Std:Wistar, and Slc:F344/N rats had good acquisition of the conditioned avoidance response (CAR), while that of the male Slc:Wistar/ST, Jcl:Wistar, and Crj:Wistar rats was bad. Reserpine-induced impairment (RII) in CAR was observed 2–72 h after administration of dopaminergic (DAergic) agents in male Slc:Wistar rats. Amitriptyline (5–80 mg/kg, PO), imipramine, desipramine, cis-dosulepine, and trans-dosulepine at dose of 40 mg/kg, PO showed no antagonism against RII in CAR 20–23 h after reserpine injection (1 mg/kg, SC). However, the atypical antidepressive agents sibutramine (5–10 mg/kg, PO), bupropion (40 mg/kg, PO), and nomifensine (10–40 mg/kg, PO) exhibited antagonism against RII in CAR. The calcium channel antagonists flunarizine, nimodipine, and KP-840 at dose of 10 and 100 mg/kg, PO, the cerebral improving agent indeloxazine (20–80 mg/kg, PO), the anticholinergic agent atropine (5–40 mg/kg, PO), 5-hydroxy-l-tryptophan (5-HTP) (40 mg/kg, IP), a precursor of 5-hydroxytryptamine (5-HT), and (±)-threo-dihydroxyphenylserine [(±)-threo-DOPS] (20–200 mg/kg PO), a norepinephrine (NE) precursor, showed no antagonism against RII in CAR. The DAergic agents methamphetamine (5 mg/kg, PO) and amantadine (50–250 mg/kg, PO), l-DOPA (200 mg/kg, PO), and the DAergic D 1/D 2 receptor agonist apomorphine (0.1–1 mg/kg, SC) showed marked antagonism against RII in CAR. Although the DAergic D 1-receptor agonist KF-38393 (0.3–30 mg/kg, IP) and the DAergic D 2-receptor agonist quinpirole (0.3–10 mg/kg, IP) induced only a weak recovery of RII in CAR when they were administered alone, in contrast to a potent synergistic recovery of RII in CAR, which was observed when SKF-38393 (1 mg/kg, IP) and quinpirole (1 mg/kg, IP) were administered together. These results suggest that the DAergic nervous system rather than the adrenergic or 5-HT nervous system is involved in RII in CAR, and that both the DAergic D 1- and D 2-mediated nervous systems play important roles in this process.

Acute effects of D 1- and D 2-receptor agonist and antagonist drugs on somatostatin binding, inhibition of adenylyl cyclase activity and accumulation of inositol 1,4,5-trisphosphate in the rat striatum

A recent study carried out by our group demonstrated that exogenous dopamine increases the somatostatin (SS) receptor–effector system in the rat striatum. The present study examined the participation of the D 1- and D 2-dopaminergic systems in the modulation of the rat striatal SS receptor–effector system by use of the D 1-receptor agonist and antagonist SKF 38393 and SCH 23390, respectively, and the D 2-receptor agonist and antagonist bromocriptine and raclopride, respectively. In view of the rapid onset of dopamine action, the effect of dopaminergic agents on the SS mechanism of action were studied 3 h after their administration. SKF 38393 (4 mg/kg i.p.) or bromocriptine (2 mg/kg i.p.) administered to male Wistar rats increased the number of 125I-Tyr 3-SMS receptors in the striatum (52 and 30%, respectively) without changing the affinity constant. The effect of SKF 38393 on 125I-Tyr 3-SMS binding was antagonized by the D 1-specific antagonist SCH 23390 (0.25 mg/kg i.p.) whereas the effect of bromocriptine was abolished by the D 2-specific antagonist raclopride (5 mg/kg i.p.). No change in binding was produced when SKF 38393 or bromocriptine were added directly to the incubation medium. The acute systemic administration of SCH 23390 or raclopride alone had no effect on the binding of 125I-Tyr 3-SMS to its receptors. The increase of the number of 125I-Tyr 3-SMS receptor induced by SKF 38393 or bromocriptine was accompanied by an increase in the capacity of SMS 201-995 to inhibit basal and forskolin (FK)-stimulated adenylyl cyclase (AC) activity when compared to the control groups. In addition, the effect of SMS 201-995 on the mass accumulation of inositol 1,4,5-trisphosphate (IP 3) was investigated. SKF 38393 as well as bromocriptine increased the capacity of SMS 201-995 to accumulate IP 3 in the rat striatum although this effect was only statistically significant in the case of SKF 38393. These results suggest that the activation of D 1 and D 2 receptors increases the activity of the SS receptor–effector system, the effect being greater in the case of D 1 receptors. These findings are consistent with a functional interaction between dopamine and SS in the rat striatum.

Effects of putative cognitive function-enhancing drugs and dopaminergic agents on somatostatin and neuropeptide Y in rat brain

Reduced levels of somatostatin and neuropeptide Y (NPY) have been demonstrated in the brain of patients with some organic mental disorders. We designed the present study to test whether drugs thought to be effective in improving cognitive functions in these disorders increased the levels of these two peptides. The drugs were given to normal rats for 14 days to examine chronic effects on regional brain somatostatin and NPY levels. Amantadine and bifemelane increased these peptide levels. Idebenone and indeloxazine had little effect. The effect of dopaminergic agents on peptide levels was also tested in rats. 1-Dihydroxyphenylalanine increased somatostatin levels in whole brain, and hypothalamic NPY levels, and reduced NPY levels in the cerebral cortex, hippocampus and striatum. Sulpiride increased the levels of NPY in the striatum and brainstem. 6-Hydroxydopamine decreased cortical somatostatin levels, and increased striatal NPY levels. These findings indicate that some agents used to improve cognitive function impairment in organic mental disorders may increase somatostatin and NPY content in the brain of rats. Also, it is suggest that these peptides are under different influences of the dopaminergic system in the brain.

Different effects of direct and indirect dopamine receptor agonists on immobility time in reserpine-treated mice

1. The effects of dopamine agonists on the immobility time in mice were examined. 2. Apomorphine (APO), bupropion (BUP), bromocriptine (BRC) and quinpirole but not SKF 38393 elicited anti-immobility effect. The effect of the agonists was decreased by the D-2 antagonist sulpiride but not by the D-1 antagonist SCH 23390. 3. In animals pretreated with reserpine, the anti-immobility effects of APO and quinpirole were potentiated, while the response of BPU was decreased and that of BRC was not changed. 4. It is concluded that D-2 dopamine receptors are involved in the anti-immobility effects of dopaminergic agents, D-2 dopamine receptors may become hypersensitive by reserpine and BUP exerts its response through indirect dopaminergic if mechanism.

Neuroleptic-induced catalepsy as a model of Parkinson's disease I. Effect of dopaminergic agents

Catalepsy was observed in the rat following intrastriatal injections of the dopamine antagonists sulpiride or fluphenazine and after subcutaneous administration of fluphenazine. The neuroleptic-induced catalepsy was reversed by the classical anti-parkinsonian agent L-DOPA and by agents that function through dopamine systems such as d- and methamphetamine and the direct D2 receptor agonist quinpirole. The D1 agonist SKF 38393, and the D1/D2 agonist apomorphine, were ineffective in this model. These results support limited use of the rat catalepsy model for the screening of potential anti-parkinsonian compounds and indicate that this procedure can provide valuable information concerning striatal dopamine function.

Effects of dopaminergic agents on alcohol consumption by rats in a limited access paradigm

The effects of several dopaminergic drugs on alcohol consumption were studied in free-feeding rats using a limited access paradigm. Ascending doses of amphetamine (0.1, 0.3 and 1.0 mg/kg), haloperidol (0.1, 0.3 and 1.0 mg/kg), SKF 38393 (a D1 receptor agonist - 0.3, 1.0 and 3.0 mg/kg), quinpirole (LY 171555, a D2 receptor agonist - 0.03, 0.1 and 0.3 mg/kg), SCH 23,390 (a D1 receptor blocker, 0.003, 0.01, 0.03 and 0.1 mg/kg) and spiperone (a D2 receptor blocker, 0.003, 0.01, 0.03 and 0.1 mg/kg) were administered IP to rats approximately 30 min prior to their 1-h per day access to alcohol. Each dose was administered for 5 successive days, and the effects of the drugs were compared to those of respective saline or 0.4% lactic acid solution controls. Although there was an overall significant dose effect of amphetamine on alcohol consumption, no single dose altered alcohol consumption significantly from baseline. SKF 38,393 specifically decreased alcohol consumption at the highest dose of 3 mg/kg. Quinpirole significantly increased water consumption at the highest dose but had no effect on alcohol consumption. The antagonist haloperidol decreased alcohol consumption but only at doses that also reduced water consumption. The specific antagonists SCH 23,390 and spiperone decreased water consumption at the highest doses tested without modifying alcohol consumption. Taken together, these data suggest that dopamine does not play as critical a role in mediating the reinforcing effects of alcohol (insofar as they are reflected by alcohol consumption) as it does in relation to other psychoactive drugs, particularly the psychomotor stimulants.