We evaluated the in vivo kinetics, distribution, and pharmacology of N-(4-[F] fluorornethylbenzyl)spiperone ([F]FMBS), a newly developed derivative of spiperone, as a potentially more selective #radiotrar.er for the dopamine (DA) Dz receptors. Mice received 1.9-3.7 MBq (1.8-3.6 nmol/kg) of [F]FMBS by tail vein injectivn. The time course and regional distribution of the tracer in brain were assessed. Blocking studies were carried out by intravenously preinjecting DA Dp receptor blockers (spiperone, butaclamol) as well as drugs with high affinity for DA Dr lSCH 23390), DA transporter (GBR 12909), and serotonin Sp (5-HTz) (ketanserin) sites. After injection of the tracer, the radioactivity in striatum increased steadily over time, resulting in a striatal-to-cerebellar ratio of 4.8 at 120 min postinjection. By contrast, the radioactivity in cerebellum, frontal cortex, and remaining cortex washed out rapidly. Preinjection of unlabe1ed FMBS (1 rng/kg) and spiperone (1 mg/kg) reduced [F] FMBS striatal-to-cerebellar ratio by 41Zo and 80Ya, respectively. (+)-Butaclamol(1 mg/kg) blocked 80Yo of the striatal [F]FMBS binding, while (-)-butaclamol (1 rng/kg) did not. Preinjection of SCH 23390 (1 mg/kg) and GBR 12909 (5 mg/kg) had no significant effect. On [""F]FMBS binding. Ketanserin (1 mg/kg), a ligand for the 5-H1g receptors, did not cause significant inhibition either in striatum, in frontal cortex, or the remaining cortex. The results demonstrate that [F]FMEtS labels DA Dz receptors selectively in vivo in the mouse brain. It may hold promise as a selective radiotracer for studying DA Dz receptors in vivo by PET.
Animals ; Brain ; Cerebellum ; Dopamine* ; Ketanserin ; Kinetics ; Mice ; Pharmacology ; Radioactivity ; Receptors, Dopamine D2* ; Serotonin ; Spiperone* ; Veins

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 ; Mice ; Animals ; Analgesics, Opioid ; Dopamine ; Heroin/pharmacology* ; Dopamine Antagonists/pharmacology* ; Receptors, Dopamine D3/metabolism* ; Morphine/pharmacology* ; Behavior, Addictive/drug therapy* ; Self Administration

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

OBJECTIVETo investigate the mechanism of the apoptosis-inducing effects of dopamine on K562 leukemia cells.

METHODSK562 cells were treated with DP2785, the dopamine receptors were detected with fluorescence spectrophotometer, UV spectrophotometer and fluorescence microscope; the contents of cAMP in K562 cells were measured; and the subtypes of dopamine receptor on K562 cells were analyzed by receptor blocking.

RESULTThe existence of dopamine receptors in K562 cells was demonstrated by fluorescence microscopy, UV spectrophotometer and fluorescence spectrophotometer. Dopamine enhanced the contents of cAMP in K562 cells. Dopamine receptors were blocked by both D1 and D2 antagonists.

CONCLUSIOND1 and D2 dopamine receptors may be involved in dopamine-induced apoptosis of K562 cells, and dopamine can also increase the contents of cAMP in K562 cells.

Apoptosis ; drug effects ; Cyclic AMP ; metabolism ; Dopamine ; pharmacology ; Humans ; K562 Cells ; Microscopy, Fluorescence ; Receptors, Dopamine D1 ; metabolism ; Receptors, Dopamine D2 ; metabolism ; Spectrometry, Fluorescence ; Spectrophotometry, Ultraviolet

A series of nitrogen-containing benzoheterocyclic derivatives were synthesized and tested for their antipsychotic activities. Their structures were confirmed by 1H NMR and HR-MS. Preliminary in vitro pharmacological trials showed that most of the target compounds have high affinity with D2 and 5-HT(2A) receptors. Among the tested compounds, 20 exhibited the highest affinity and D2 partial agonist activity. In vivo studies showed 20 has potent antipsychotic activities on apomorphine mice model, which is a chance to find a better precursor of D2 partial agonist for further optimization.
Animals ; Antipsychotic Agents ; chemical synthesis ; pharmacology ; Dopamine Agonists ; chemical synthesis ; pharmacology ; Drug Design ; Isoquinolines ; chemical synthesis ; pharmacology ; Mice ; Receptors, Dopamine D2 ; Structure-Activity Relationship

OBJECTIVETo investigate the role of dopamine-1 receptor in the modulation of basic respiration rhythm.

METHODSNewborn SD rat (0-3 days, n=20) brain stem slices containing the medial region of the nucleus retrofacialis (mNRF) were prepared with the hypoglossal nerve roots retained. The respiratory rhythmical discharge activity (RRDA) of the hypoglossal nerve was recorded using suction electrodes on these preparations, and the effects of dopamine-1 receptor on RRDA were investigated by application of the specific agonist of dopamine-1 receptor A68930 at different concentrations (0, 1, 2, and 5 micromol/L) in the perfusion solution.

RESULTSThe respiratory cycles (RC) and the expiratory time (TE) decreased progressively with gradual increment of the integrated amplitude (IA) after A68930 administration, and their changes were the most conspicuous at 5 min after the administration. A68930 at the concentrations of 2 and 5 micromol/L resulted in the most obvious changes in RC, TE, and IA (P<0.05), but IA exhibited no significant variation at 1 min after perfusion with 2 micromol/L A68930 (P>0.05). RC and TE were gradually shortened after treatment with increasing concentrations of A68930, which also caused gradual increment of IA, and at the concentration of 5 micromol/L, RC, TE, and IA all showed the most obvious changes (P<0.01).

CONCLUSIONSDopamine-1 receptor plays a role in the modulation of RRDA in isolated neonatal rat brainstem slice. A68930 may increase the frequency of respiration by shortening TE and enhance the respiratory activity by increasing the amplitude of inspiratory discharge of the respiratory neurons.

Animals ; Animals, Newborn ; Cell Separation ; Chromans ; pharmacology ; Dopamine Agonists ; pharmacology ; In Vitro Techniques ; Medulla Oblongata ; cytology ; physiology ; Neurons ; cytology ; Rats ; Rats, Sprague-Dawley ; Receptors, Dopamine ; physiology ; Respiration ; drug effects

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 ; Benzamides/*pharmacology ; Benzyl Compounds/*pharmacology ; Cholinesterase Inhibitors/pharmacology ; Colon/*drug effects/physiology ; Dopamine/pharmacology ; Dose-Response Relationship, Drug ; Gastrointestinal Motility/*drug effects ; Guinea Pigs ; Ileum/*drug effects/physiology ; Neostigmine/pharmacology ; Receptors, Dopamine D1/antagonists & inhibitors/physiology

Serum dopamine-beta-hydroxylase (DBH) inhibition has been reported in lead workers treated with CaNa2EDTA and in alcoholic patients repeatedly treated with the alcohol aversive drug Disulfiram. The mechanism of inhibition involves Cu++ chelation at the active site of DBH. The effect of CaNa2EDTA and Disulfiram on serum DBH has been compared to the effect of dithiocarbamate pesticides in vitro for the possible use of serum DBH determination for the biological monitoring of workers exposed to these pesticides. Most dithiocarbamates inhibit human serum DBH at micromolar concentrations (range of I50, 0.027-1.6 mumol/L). The inhibitory potency increased from methyl- and dimethyl dithiocarbamates to diethyl dithiocarbamates up to the most potent ethylene bisdithiocarbamates. The I50 of CaNa2EDTA was 3.8 mumol/L, higher than those of dithiocarbamates. Copper addition to the test system reactivated at stoichiometric concentrations dithiocarbamate-inhibited DBH indicating that both base line values and percent of inhibition can be calculated in a single blood sample. Results suggest that serum DBH determination could be useful in case of acute poisoning involving high doses of dithiocarbamate pesticides.
Alcohol Deterrents ; pharmacology ; Biomarkers ; blood ; Chelating Agents ; pharmacology ; Disulfiram ; pharmacology ; Ditiocarb ; pharmacology ; Dopamine beta-Hydroxylase ; blood ; drug effects ; Edetic Acid ; pharmacology ; Female ; Humans ; Male ; Pesticides ; blood

Quetiapine is an atypical or second-generation antipsychotic agent and has been a subject of a series of case report and suggested to have the potential for misuse or abuse. However, it is not a controlled substance and is not generally considered addictive. In this study, we examined quetiapine's dependence potential and abuse liability through animal behavioral tests using rodents to study the mechanism of quetiapine. Molecular biology techniques were also used to find out the action mechanisms of the drug. In the animal behavioral tests, quetiapine did not show any positive effect on the experimental animals in the climbing, jumping, and conditioned place preference tests. However, in the head twitch and self-administration tests, the experimental animals showed significant positive responses. In addition, the action mechanism of quetiapine was found being related to dopamine and serotonin release. These results demonstrate that quetiapine affects the neurological systems related to abuse liability and has the potential to lead psychological dependence, as well.
Animals ; Behavior, Animal ; Dopamine ; Head ; Molecular Biology ; Pharmacology* ; Rodentia* ; Serotonin ; Substance-Related Disorders ; Quetiapine Fumarate

Animals ; Aorta, Thoracic ; physiology ; Dopamine ; pharmacology ; Hydrogen-Ion Concentration ; In Vitro Techniques ; Rats ; Vasoconstriction ; drug effects