1.Blockade of the Dopamine D3 Receptor Attenuates Opioids-Induced Addictive Behaviours Associated with Inhibiting the Mesolimbic Dopamine System.
Rong-Rong HU ; Meng-Die YANG ; Xiao-Yan DING ; Ning WU ; Jin LI ; Rui SONG
Neuroscience Bulletin 2023;39(11):1655-1668
Opioid use disorder (OUD) has become a considerable global public health challenge; however, potential medications for the management of OUD that are effective, safe, and nonaddictive are not available. Accumulating preclinical evidence indicates that antagonists of the dopamine D3 receptor (D3R) have effects on addiction in different animal models. We have previously reported that YQA14, a D3R antagonist, exhibits very high affinity and selectivity for D3Rs over D2Rs, and is able to inhibit cocaine- or methamphetamine-induced reinforcement and reinstatement in self-administration tests. In the present study, our results illustrated that YQA14 dose-dependently reduced infusions under the fixed-ratio 2 procedure and lowered the breakpoint under the progressive-ratio procedure in heroin self-administered rats, also attenuated heroin-induced reinstatement of drug-seeking behavior. On the other hand, YQA14 not only reduced morphine-induced expression of conditioned place preference but also facilitated the extinguishing process in mice. Moreover, we elucidated that YQA14 attenuated opioid-induced reward or reinforcement mainly by inhibiting morphine-induced up-regulation of dopaminergic neuron activity in the ventral tegmental area and decreasing dopamine release in the nucleus accumbens with a fiber photometry recording system. These findings suggest that D3R might play a very important role in opioid addiction, and YQA14 may have pharmacotherapeutic potential in attenuating opioid-induced addictive behaviors dependent on the dopamine system.
Rats
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Mice
;
Animals
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Analgesics, Opioid
;
Dopamine
;
Heroin/pharmacology*
;
Dopamine Antagonists/pharmacology*
;
Receptors, Dopamine D3/metabolism*
;
Morphine/pharmacology*
;
Behavior, Addictive/drug therapy*
;
Self Administration
2.The measurement of tyrosine hydroxylase activity in the brain of conscious rats.
Wei WANG ; De-zhong ZHAO ; Wei-xia WANG ; Bin-hui SUN
China Journal of Chinese Materia Medica 2002;27(2):132-135
OBJECTIVETo set the measuring method of tyrosine hydroxylase activity in the brain of conscious rats.
METHODBy using microdialysis and High Performance Liquid Chromatography-Electrochemical Detector system, the 3, 4-dihydrioxphenylalanine (DOPA) formation in the striatum of 6-hydroxdopamine-pretreated rats during infusion of an L-aromatic amino-acid decarboxylase inhibitor (NSD1015) was monitored.
RESULTThe absence of DOPA in dialysates of 6-hydroxdopamine-pretreated rats, the measurable DOPA and the steady decreasing of 3,4-dihydroxyphenylacetic acid(DOPAC) during infusion of NSD1015 and the disappearance of DOPA after administration of alpha-methyl-rho-tyrosine indicated that the dialyzed DOPA was derived from dopaminergic nerve terminals. After intraperitoneal administration of dopamine receptor agonist apomorphine the DOPA output was deseased. After intraperitoneal administration of dopamine recepter antagonist haloperidol, the DOPA output was increased. The study showed that twenty-four hours ofter implantation of the probe with infusion of 0.01 mmol.L-1 NSD1015, the DOPA level in the striatum of 6-hydroxdopamine-pretreated rats was 0.39 +/- 0.12 pmol/min (X +/- S, n = 5).
CONCLUSIONThe DOPA concentration in striatal dialysates could be considered as an index of tyrosion hydroxlase activity during infusion of 0.01 mM NSD1015. The method in vivo to monitor tyrosine hydroxlase activity in the brain is reliable.
Animals ; Apomorphine ; pharmacology ; Brain ; enzymology ; Dihydroxyphenylalanine ; metabolism ; Dopamine Agonists ; pharmacology ; Dopamine Antagonists ; pharmacology ; Female ; Haloperidol ; pharmacology ; Male ; Microdialysis ; Rats ; Rats, Sprague-Dawley ; Tyrosine 3-Monooxygenase ; metabolism
3.Effect of Itopride Hydrochloride on the Ileal and Colonic Motility in Guinea Pig In Vitro.
Hyun Chul LIM ; Young Gyun KIM ; Jung Hyun LIM ; Hee Sun KIM ; Hyojin PARK
Yonsei Medical Journal 2008;49(3):472-478
PURPOSE: Itopride hydrochloride (itopride) inhibits acetylcholinesterase (AChE) and antagonizes dopamine D(2) receptor, and has been used as a gastroprokinetic agent. However, its prokinetic effect on the small bowel or colon has not yet been thoroughly investigated. The aim of this study was to investigate the effects of itopride on motor functions of the ileum and colon in guinea pigs. MATERIALS AND METHODS: The distal ileum was excised and the activity of peristaltic contraction was determined by measuring the amplitude and propagation velocity of peristaltic contraction. The distal colon was removed and connected to the chamber containing Krebs-Henseleit solution (K-H solution). Artificial fecal matter was inserted into the oral side of the lumen, and moved toward the anal side by intraluminal perfusion via peristaltic pump. Colonic transit times were measured by the time required for the artificial feces to move a total length of 10cm with 2-cm intervals. RESULTS: In the ileum, itopride accelerated peristaltic velocity at higher dosage (10(-10)-10(-6)M) whereas neostigmine accelerated it only with a lower dosage (10(-10)-10(-9)M). Dopamine (10(-8)M) decelerated the velocity that was recovered by itopride infusion. Itopride and neostigmine significantly shortened colonic transit at a higher dosage (10(-10)-10(-6)M). Dopamine (10(-8)M) delayed colonic transit time that was also recovered after infusion of itopride. CONCLUSION: Itopride has prokinetic effects on both the ileum and colon, which are regulated through inhibitory effects on AChE and antagonistic effects on dopamine D(2) receptor.
Animals
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Benzamides/*pharmacology
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Benzyl Compounds/*pharmacology
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Cholinesterase Inhibitors/pharmacology
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Colon/*drug effects/physiology
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Dopamine/pharmacology
;
Dose-Response Relationship, Drug
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Gastrointestinal Motility/*drug effects
;
Guinea Pigs
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Ileum/*drug effects/physiology
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Neostigmine/pharmacology
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Receptors, Dopamine D1/antagonists & inhibitors/physiology
5.Application of pulsed Doppler ultrasound for the evaluation of small intestinal motility in dogs.
Yong Joo AN ; Heechun LEE ; Dongwoo CHANG ; Youngwon LEE ; Jai Ki SUNG ; Mincheol CHOI ; Junghee YOON
Journal of Veterinary Science 2001;2(1):71-74
The purpose of this study was to verify whether small intestinal peristalsis could be observed and quantitatively assessed using pulsed-Doppler ultrasound. Pulsed-Doppler ultrasound was used to evaluate small intestinal peristalsis after a meal in ten normal dogs and ten sedated dogs. The small intestinal peristalses were measured 0, 1, 3, 6, 9, 12, and 24 hours after a 24-hour fast and after feeding. The number of small intestinal peristalsis were 0.133/min, 0.100/min, 0.033/min, 0.167/min, 0.070/min, 0.067/min, and 0.100/min in the fasted dogs, and 1.667/ min, 0.933/min, 1.133/min, 1.234/min, 1.933/min, 1.533/ min, and 0.533/min in fed dogs, respectively. In the dogs sedated with xylazine HCl, the number of small intestinal peristalsis was significantly reduced (p<0.01). However, in the dogs treated with ketamine HCl and acepromazine, the number of small intestinal peristalsis remained unchanged. Therefore, it can be concluded that pulsed-Doppler ultrasound allows graphic visualization of the intestinal movements, which can be subjected to qualitative and quantitative analysis, and may be suitable for a non-invasive study of small intestinal motility.
Acepromazine/pharmacology
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Animals
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Dogs
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Dopamine Antagonists/pharmacology
;
Excitatory Amino Acid Antagonists/pharmacology
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*Gastrointestinal Motility/drug effects
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Intestine, Small/drug effects/*physiology/ultrasonography
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Ketamine/pharmacology
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Peristalsis/drug effects/*physiology
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Ultrasonography, Doppler, Pulsed/methods/*veterinary
6.Effects of D1 and D2 dopamine receptor agonists and antagonists on cerebral ischemia/reperfusion injury.
Xue-Mei ZONG ; Yin-Ming ZENG ; Tie XU ; Jian-Nong LÜ
Acta Physiologica Sinica 2003;55(5):565-570
Gerbil forebrain ischemia/reperfusion(I/R) injury model was used to study the effects of D(1) and D(2) receptor agonists and antagonists on neuronal apoptosis of hippocampal CA1 area. All animals were tested for habituation deficits in an open field test on the 1st, 3rd and 7th days after reperfusion. The animals were then killed, and brains underwent paraffin embedding for hematoxylin-eosin staining, in situ terminal deoxynucleotidyl transferase-mediated deoxy-UTP nick end labeling (TUNEL) staining and immunohistochemistry (bax, bcl-2). The result of open field test showed that the I/R group was significantly impaired (higher activity scores) when compared with the control group. Pretreatment with pergolide significantly reduced this habituation impairment. Forebrain ischemia for 5 min resulted in extensive CA1 apoptosis on the 3rd and 7th days after I/R injury. About 95% neurons in hippocampal CA1 area entered apoptosis and only 2%-7% pyramidal neurons stayed alive due to an inhibition of bcl-2 expression and an increase in bax expression. Pretreatment of pergolide attenuated neuronal damage caused by transient ischemia. Infusion of pergolide could induce the expression of bcl-2 and reduce the expression of bax. Pretreatment with SKF38393, SCH23390 and spiperone had no effects on these changes in this transient I/R injury model. All these results indicate that pergolide plays an important role in the protection of hippocampal neurons from apotosis through upregulating the expression of bcl-2 protein and reducing the expression of bax protein.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine
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pharmacology
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Animals
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Apoptosis
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Brain
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physiopathology
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Brain Ischemia
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physiopathology
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Dopamine Agonists
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pharmacology
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Dopamine Antagonists
;
pharmacology
;
Gerbillinae
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Hippocampus
;
physiopathology
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Ischemic Attack, Transient
;
physiopathology
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Male
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Neurons
;
physiology
;
Neuroprotective Agents
;
pharmacology
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Pergolide
;
pharmacology
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Prosencephalon
;
physiopathology
;
Proto-Oncogene Proteins
;
biosynthesis
;
genetics
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Proto-Oncogene Proteins c-bcl-2
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biosynthesis
;
genetics
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Receptors, Dopamine D1
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Receptors, Dopamine D2
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Reperfusion Injury
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physiopathology
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bcl-2-Associated X Protein
7.Haloperidol and clozapine differentially regulate signals pstream of glycogen synthase kinase 3 in the rat frontal cortex.
Myoung Sun ROH ; Myoung Suk SEO ; Yeni KIM ; Se Hyun KIM ; Won Je JEON ; Yong Min AHN ; Ung Gu KANG ; Yong Sung JUHNN ; Yong Sik KIM
Experimental & Molecular Medicine 2007;39(3):353-360
Glycogen synthase kinase 3 (GSK3) was recently suggested to be a potential target of psychotropics used in psychiatric illnesses such as schizophrenia and bipolar disorder. Relevant studies have found that antipsychotic drugs regulate GSK3 activity via an increase in either inhibitory serine phosphorylation or amount of GSK3 after acute or subchronic treatment. Recent evidence shows that GSK3 is regulated by dopaminergic or serotonergic systems implicated in the pathophysiology and treatment mechanisms of schizophrenia and bipolar disorder. Therefore, antipsychotics may regulate GSK3 via antagonizing dopaminergic or serotonergic activity. However, the signaling pathway that is involved in GSK3 regulation by dopaminergic or serotonergic systems has not been well established. Haloperidol is a typical antipsychotic with potent dopamine D(2) receptor antagonism. Clozapine is an atypical antipsychotic with potent serotonin 5HT(2) receptor antagonism. We injected rats with haloperidol or clozapine and examined the phosphorylation and amount of GSK3alpha/beta and its well-known upstream regulators Akt and Dvl in the rat frontal cortex by Western blotting. Both haloperidol and clozapine induced Ser21/9 phosphorylation of GSK3GSK3alpha/beta. Haloperidol increased the Ser473 phosphorylation of Akt transiently, whereas clozapine maintained the increase for 1 h. Haloperidol did not affect the phosphorylation and amount of Dvl, whereas clozapine increased both phosphorylation and the amount of Dvl. Our results suggest that GSK3 activity may be regulated by both typical and atypical antipsychotics and that Akt or Dvl, depending on the D(2)- or 5HT(2)- receptor antagonism properties of typical and atypical antipsychotics, mediate the regulation differently.
Adaptor Proteins, Signal Transducing/metabolism/*physiology
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Animals
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Antipsychotic Agents/*pharmacology
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Clozapine/*pharmacology
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Dopamine Antagonists/pharmacology
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Frontal Lobe/*drug effects/enzymology
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Glycogen Synthase Kinase 3/*metabolism
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Haloperidol/*pharmacology
;
Male
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Phosphoproteins/metabolism/*physiology
;
Phosphorylation
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Proto-Oncogene Proteins c-akt/metabolism/*physiology
;
Rats
;
Rats, Sprague-Dawley
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Serotonin Antagonists/pharmacology
;
Signal Transduction
8.The relationship between metoclopramide and hypothalamus-pituitary-thyroid axis and it's clinical application.
Journal of Biomedical Engineering 2004;21(1):164-168
TSH secretion is controlled by the stimulatory action of hypothalamic TRH and the inhibition via central dopaminergic and somatostatinergic mechanisms as well as by a hypothalamic inhibitory action of thyroid hormones. Metoclopramide is DA2 receptor blockade which can accelerate to elevate the concentration of serum TSH in hypothyroidism, which is accompanied by a progressive loss of dopaminergic tone as demonstrated by a progressive increase in prolaction serum levels, especially in patients with differentiated thyroid carcinoma(DTC). So the period of L-thyroxine withdrawal is contracted and the symptoms of hypothyroidism is released. It's important to monitor and treat DTC patients with radioactive iodide.
Dopamine Antagonists
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pharmacology
;
Humans
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Hyperthyroidism
;
blood
;
drug therapy
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Hypothalamo-Hypophyseal System
;
drug effects
;
physiology
;
Hypothyroidism
;
blood
;
drug therapy
;
Metoclopramide
;
chemistry
;
pharmacology
;
Thyroid Gland
;
drug effects
;
physiology
;
Thyroid Hormones
;
blood
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Thyrotropin
;
blood
9.Differential effects of dopamine on pain-related electric activities in normal rats and morphinistic rats.
Ying ZHANG ; Man-Ying XU ; Jie SU
Neuroscience Bulletin 2007;23(3):185-188
OBJECTIVETo investigate the influence of dopamine (DA) and DA receptor's antagonist on the transmission of noxious information in the central nervous system of normal rats or morphinistic rats.
METHODSThe influence of DA on the electric activity of the pain-excited neuron (PEN) in the caudate nucleus (Cd) of normal rats or morphinistic rats was recorded after the sciatic nerve was noxiously stimulated.
RESULTSDA shortened the average latency of the evoked discharge of PEN in the Cd of normal rats, indicating that DA could increase the activity of PEN and pain sensitivity in normal rats. This effect could be inhibited by Droperidol. DA increased the average latency of the evoked discharge of PEN in the Cd of morphinistic rats, indicating that DA could inhibit the activity of PEN and pain sensitivity in morphinistic rats.
CONCLUSIONThe responses to painful stimulation were completely opposite between normal rats and morphinistic rats after the intracerebroventricular injection of DA.
Action Potentials ; drug effects ; physiology ; radiation effects ; Analysis of Variance ; Animals ; Caudate Nucleus ; drug effects ; Disease Models, Animal ; Dopamine ; pharmacology ; Dopamine Antagonists ; pharmacology ; Droperidol ; pharmacology ; Drug Interactions ; Electric Stimulation ; adverse effects ; Female ; Male ; Morphine Dependence ; physiopathology ; therapy ; Neurons ; drug effects ; Pain ; drug therapy ; etiology ; physiopathology ; Pain Threshold ; drug effects ; Rats ; Rats, Wistar ; Reaction Time ; drug effects ; physiology ; radiation effects
10.Effects of glutamate and MK-801 on the metabolism of dopamine in the striatum of normal and parkinsonian rats.
Chun-Li DUAN ; Xiao-Hong SUN ; Man JI ; Hui YANG
Acta Physiologica Sinica 2005;57(1):71-76
The direct effects of glutamate and dizocilpine maleate (MK-801, non-competitive N-Methyl-D-aspartate glutamate receptor antagonist) on the metabolism of dopamine were investigated in the striatum of normal and parkinsonian rats. L-dopa, L-glutamic acid and MK-801 were administered in the striatum locally by microdialysis. 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were simultaneously sampled by microdialysis. The concentrations of DOPAC and HVA were assayed by high performance liquid chromatography with electrochemical detection (HPLC-ECD). L-dopa increased the concentrations of DOPAC and HVA in the striatum of normal and parkinsonian rats. L-glutamic acid decreased the concentrations of DOPAC and HVA in striatum of normal rats but not parkinsonian rats. MK-801 increased the concentrations of DOPAC and HVA in the striatum of normal rats but not parkinsonian rats. MK-801 prevented the L-glutamic acid-induced decrease of DOPAC and HVA in the striatum of normal rats. Our results indicate that glutamate modulates the metabolism of dopamine (DA) through NMDA receptors and that the improvement of PD by MK-801 is not through improving the metabolism of DA.
Animals
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Corpus Striatum
;
metabolism
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Dizocilpine Maleate
;
pharmacology
;
Dopamine
;
metabolism
;
Female
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Glutamic Acid
;
physiology
;
Microdialysis
;
Parkinson Disease
;
metabolism
;
physiopathology
;
Rats
;
Rats, Sprague-Dawley
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Receptors, N-Methyl-D-Aspartate
;
antagonists & inhibitors
;
physiology