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PubMed1992

Optimization of a peak compression system for a remoxipride metabolite (FLA797) and its application to bioanalysis.

A peak compression system is optimized for FLA797 (I), a phenolic tertiary amine and a metabolite to the antipsychotic drug remoxipride. An application is described where this effect is used to give a 6-7-fold improvement of the quantification limit in an assay of I in plasma. The liquid chromatographic system is constructed so that the injection of I dissolved in a solution of a competing amine gives a very high and narrow analyte peak with an apparent efficiency of 1.5 x 10(6) plates/m. When the levels of I in plasma are determined, an internal standard, giving a normal isocratic peak, is added to the plasma sample before the extraction. Concentrations of I down to 0.5-1.0 nM can be determined with reasonable precision. FLA908, another phenolic remoxipride metabolite and a regioisomer to I, eluting as a normal isocratic peak, can be determined simultaneously although only at concentrations higher than 10-15 nM.

Animals↗

PubMed1995

Increased density of dopamine D2 receptors in the putamen, but not in the caudate nucleus in early Parkinson's disease: a PET study with [11C]raclopride.

Striatal dopamine D2 receptors were studied, using positron emission tomography (PET), in 10 patients with early Parkinson's disease without any antiparkinsonian medication and in 14 healthy controls. [11C]Raclopride was used as ligand and an equilibrium method was applied. The maximum count of receptors (Bmax) and their dissociation constant (Kd) were calculated according to the Scatchard principle. In parkinsonian patients, the Bmax of D2 receptors was increased in the putamen contralateral to the predominant symptoms, as compared to the opposite putamen, by 33% (p = 0.0008). In the caudate nucleus no significant side to side differences was noted. On comparison with age-matched healthy controls, Bmax values in the putamen (p = 0.0012) but not in the caudate nucleus contralateral to the side of predominant clinical symptoms were increased in PD patients. The Kd values were unchanged. The difference in putaminal Bmax values between the opposite hemispheres correlated with the difference in the severity of parkinsonian motor symptoms between the two body sides (r = 0.69, p = 0.03). The present results show that there is both a relative and absolute increase in the number of dopamine D2 receptors in the putamen, but not in the caudate nucleus in early Parkinson's disease.

Carbon Radioisotopes↗

PubMed1991

Pituitary and brain D2 receptor density measured in vitro and in vivo in EEDQ treated male rats.

The effect of the alkylating compound N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) (20 mg/kg, 24 h) on dopamine D2 receptor density in rat pituitary and brain was measured using in vitro and in vivo radioligand binding techniques. In the in vitro radioligand binding experiments EEDQ was found to reduce the density (Bmax) of [3H]-spiperone binding sites in the striatum by 86% while in the pituitary the corresponding decrease was only 37%. The affinity (KD) of the remaining striatal and pituitary D2 receptors was not different in EEDQ treated animals as compared to controls. When D2 receptor density was measured in vivo the effect of EEDQ was less pronounced. Thus, in rats given EEDQ the specific binding of either of the two D2 ligands [3H]-raclopride or [3H]-spiperone (administered in a single dose) in striatum and in the limbic forebrain was reduced by 45-62%; moreover, no significant decrease in pituitary D2 receptor density was observed. The data are discussed in relation to the finding (presented in a separate paper) that the same dose of EEDQ that failed to influence pituitary D2 receptor density as measured in vivo effectively antagonizes the prolactin decreasing effect of the partial D2 agonist (-)-3-(3-hydroxyphenyl)-N-n-propyl-piperidine [(-)-3-PPP].

4-Butyrolactone↗

PubMed1992

Opposite influence of medial preoptic D1 and D2 receptors on genital reflexes: implications for copulation.

Dopamine D1 and D2 receptors may synergize with or oppose each other's effects. We suggest that stimulation of D1 and D2 receptors in the medial preoptic area (MPOA) of male rats have opposing effects on genital reflexes. In Experiment 1 a D1 agonist injected into the MPOA increased the number of ex copula erections but decreased the number of seminal emissions. In Experiment 2 a D1 antagonist had the opposite effects (decreased erections and increased seminal emissions), as had a D2 agonist previously. We also suggest that D1 and D2 mechanisms in the MPOA have different thresholds of activation. In Experiment 3 a low dose of the mixed D1/D2 agonist apomorphine increased erections and anteroflexions, an effect blocked by the D1 antagonist. In Experiments 3 and 4 a high dose of apomorphine increased seminal emissions, an effect blocked by the D2 antagonist. Thus, low levels of dopaminergic stimulation may facilitate erections and anteroflexions (controlled by the parasympathetic system and striated muscles) via D1 receptors; higher or more prolonged stimulation may shift to seminal emission (controlled by the sympathetic system) via D2 receptors. This may explain the progression from erectile to ejaculatory mechanisms during copulation.

Animals↗

PubMed1993

Differential effects of the D2 receptor agonist quinelorane on the secretion of prolactin and alpha-melanocyte-stimulating hormone.

The purpose of the present study was to determine the effects of quinelorane, a selective D2 receptor agonist, on concentrations of prolactin and alpha-melanocyte-stimulating hormone (alpha-MSH) in plasma of male rats. Quinelorane decreased plasma concentrations of prolactin but not of alpha-MSH, whereas, the D2 receptor antagonist raclopride increased plasma concentrations of both hormones. Quinelorane reversed the effects of raclopride on circulating levels of prolactin, but not alpha-MSH. The results of this study suggest that secretion of hormones from melanotrophs and lactotrophs is regulated by different subtypes of D2 receptors.

Analysis of Variance↗

PubMed1994

The selective D2 dopamine receptor antagonist eticlopride counteracts the ejaculatio praecox induced by the selective D2 dopamine agonist SND 919 in the rat.

The selective D2 antagonist eticlopride, at a dose (0.01 mg/kg, s.c.) that fails to modify the normal behavior of rats, significantly reversed all the behavioral effects exerted by the selective D2 agonist SND 919 (0.1 mg/kg, i.p.), namely, the stimulation of stretching-yawning, penile erection and sedation and the inhibition of grooming. In the copulatory test, eticlopride at the same dose did not affect animal sexual behavior but potently counteracted the reduction in mount and intromission frequency and latency to ejaculation induced by SND 919 at 0.1 mg/kg, a behavioral pattern which might possibly be proposed as an animal model for human ejaculatio praecox.

Animals↗

PubMed1995

Is clozapine selective for the dopamine D4 receptor?

Binding of 3H-spiperone and 3H-raclopride to membranes of cells stably-transfected with a human dopamine D2 receptor clone was investigated, as was that of 3H-spiperone to those stably-transfected with a human D4 receptor clone. 3H-spiperone and 3H-raclopride labeled the same number of sites in the D2 receptor preparation. The inhibition of binding by clozapine, spiperone, (-) eticlopride, haloperidol and the novel substituted benzamide 1192U90 was also investigated. Clozapine and 1192U90 showed greater inhibition of 3H-raclopride binding than 3H-spiperone binding to the D2 receptor. Comparison with inhibition of 3H-spiperone binding to the D4 receptor revealed that clozapine and 1192U90 displayed apparent selectivity (as assessed by Ki ratios) for the D4 receptor when compared with binding of 3H-spiperone, but not 3H-raclopride, to the D2 receptor.

Binding Sites↗

PubMed1996

18F-desmethoxyfallypride: a fluorine-18 labeled radiotracer with properties similar to carbon-11 raclopride for PET imaging studies of dopamine D2 receptors.

We have developed (S)-N-[(1-allyl-2-pyrrolidinyl)methyl]-5-(3-18F-fluoropropyl)-2- methoxybenzamide (18F-desmethoxyfallypride) as a fluorine-18 radiotracer with properties analogous to that of 11C-raclopride. In vitro experiments in rat brain homogenates showed an association rate constant of 2.16 x 10(8) M(-1)min(-1) and a dissociation rate constant of 0.073 min(-1). High striatal uptake (up to 0.08% injected dose/cc) of 18F-desmethoxyfallypride in rhesus monkeys was observed in PET experiments. The radiotracer cleared from the striata with a dissociation rate of 1.80 x 10(-2) min(-1). Striatum to cerebellum ratios peaked at 3.0 in 30 min after which they decreased steadily. Intravenously administered haloperidol displaced specifically bound 18F-desmethoxyfallypride with a koff of 0.058 min(-1). Synaptic dopamine released by the treatment of the monkeys with d-amphetamine increased the dissociation rate of 18F-desmethoxyfallypride to 0.83 min(-1) thus reducing specifically bound 18F-desmethoxyfallypride by 56% over a period of 42 mins compared to a reduction of only 20% in controls during this time period. The sensitivity of 18F-desmethoxyfallypride towards competition with dopamine should make this radiotracer useful in PET studies to evaluate in vivo pharmacological effects of various agents that alter levels of endogenous dopamine.

Animals↗

PubMed1987

Dopamine turnover and glutamate decarboxylase activity in the rat brain after acute and chronic treatment with raclopride, a dopamine D2-selective antagonist.

The effect of acute and chronic (94, 141 and/or 199 days) oral treatment of rats with the dopamine D2-selective antagonist raclopride (0, 5, 15, 45 and 135 mumol/kg) upon the turnover of dopamine in the striatum and limbic system and upon the activity of glutamate decarboxylase (GAD) in the s. nigra, striatum and frontal cortex has been investigated. A dose-dependent tolerance to the effect of raclopride on the turnover of dopamine was observed after chronic treatment, although the degree of tolerance was marginal at the 5 and 15 mumol/kg doses. Acute treatment with raclopride was without effect on the activity of GAD in the s. nigra, striatum or frontal cortex, whereas chronic (199 days) treatment with 45 mumol/kg of raclopride produced an increase in the activity of GAD in the s. nigra and striatum.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1988

Synchronization of the EEG and sedation induced by neuroleptics depend upon blockade of both D1 and D2 dopamine receptors.

Blockade of dopamine (DA) receptors by neuroleptics tends to produce sedation, as shown by increased sleeping time, reduction of the arousal response to sensory stimuli and slowing of the electrical (EEG) activity of the brain. The EEG and behavioural effects of the selective compounds, SCH 23390 and raclopride, which block either D1 or D2 receptor subtypes, respectively were evaluated. Groups of rabbits were prepared for the measurement of EEG activity (neocortex and hippocampus). The EEG was analyzed visually and by spectral power analysis. Gross behaviour was also observed. The D1 antagonist, SCH 23390, by itself (0.03-0.3 mg/kg i.v.) produced small changes in the EEG and no evidence of sedation. Periods of slow waves occurred sporadically. Computerized EEG analysis showed moderate increases of total power density. The D2 receptor blocker, raclopride, alone (1-3 mg/kg i.v.) produced changes of the activity of the EEG, mostly, short periods of slow waves and slight increases of total power. No sedation was noted. Although both selective antagonists were studied at larger doses than those minimally effective, they produced slight EEG and behavioural changes which were not comparable with the marked actions produced by classical neuroleptics, such as haloperidol. However, when raclopride (1 mg/kg) was given after treatment with SCH 23390 (0.03 mg/kg) there was a marked synchronized activity in the EEG, associated with a state of sedation and diminished responsiveness to sensory stimuli. The data indicate that EEG synchronization and sedation, classically associated with treatment with neuroleptics, do not depend upon the selective blockade of either D1 or D2 receptors but, instead, require concurrent blockade of both subtypes of receptor.

Animals↗

PubMed1991

In vivo assessment of release and metabolism of dopamine in the ventrolateral striatum of awake rats following administration of dopamine D1 and D2 receptor agonists and antagonists.

The ability of specific dopamine (DA) receptor agonists and antagonists to modify the release and metabolism of DA in the ventrolateral striatum of awake rats was assessed using in vivo microdialysis. The specific DA D2 receptor antagonist, raclopride (0.1, 0.5 and 2.0 mg/kg, i.p.), dose-dependently increased release of DA and levels of the metabolites DOPAC and HVA, while the D2 receptor agonist, quinpirole (0.03, 0.1 and 0.3 mg/kg), decreased levels of DA, DOPAC and HVA. The DA D1 receptor antagonist, SCH23390 [(R + (+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl- 1H-3-benzazepin-7-ol) (0.01, 0.05 and 0.25 mg/kg), produced an increase in DA, DOPAC and HVA but of a lesser magnitude than raclopride. The D1 agonist SKF38393 (1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol) (1.0, 3.0 and 10.0 mg/kg) failed to affect the release of metabolism of DA at any dose. These results support previous findings that activation of D2 receptors has greater control over in vivo DA function, than drugs specifically affecting D1 receptors.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1992

Remoxipride and raclopride differentially alter the activity of incertohypothalamic dopaminergic neurons.

The effects of two dopaminergic (DA) antagonists, raclopride (S-(-)-3,5-dichloro-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2-hydroxy- 6-methoxybenzamide(+)-tartrate) and remoxipride (S(-)-3-bromo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2, 6-dimethoxybenzamide hydrochloride monohydrate), were compared on the DA receptor-mediated regulation of incertohypothalamic and nigrostriatal DA neurons. Both drugs produced dose- and time-related increases in concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum, which contains the terminals of the nigrostriatal DA neurons. On the other hand, raclopride but not remoxipride increased concentrations of DOPAC in the medial zona incerta and dorsomedial hypothalamic nucleus, regions that contains cell bodies and terminals, respectively, of incertohypothalamic DA neurons. These results suggest that raclopride blocks a population of DA receptors that regulates the activity of incertohypothalamic DA neurons, whereas remoxipride does not.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1993

The effects of SCH 23390 and raclopride on cocaine-induced analepsis and EEG arousal in rabbits.

The effects of the dopamine D1 and D2 receptor antagonists on cocaine-induced, cholinergically-mediated analeptic and hippocampal theta activity in anesthetized rabbits were investigated. Cocaine (2 mg/kg, i.v.) reduced by 35% the duration of loss of righting reflex produced by a 25 mg/kg dose of pentobarbital. This shortening of narcosis time was blocked by pretreating the animals with the D1 antagonist, SCH 23390 (0.1 mg/kg) but not with the D2 antagonist raclopride (1-2 mg/kg). Cocaine (5 mg/kg, i.v.) also produced a short burst of increased hippocampal theta activity in urethane-anesthetized rabbits, which was also blocked by SCH 23390 but not by raclopride. An unexpected finding was that raclopride itself, at 2 mg/kg (i.v.), produced a marked activation of theta activity that lasted for 15-20 min. When cocaine was administered after this time it produced a potentiated theta response, both in duration and in magnitude. These results suggest that in the rabbit, cocaine exerts a cholinergically-mediated behavioral and EEG arousal through a D1 dopamine mechanism. The role of the D2 system is less clear but appears to be antagonistic to the D1-mediated response.

Analysis of Variance↗

PubMed1993

Behavioural effect of pretreatment with opioid antagonists and sigma binding site ligands on the abnormal motor response produced by the kappa opioid agonist U50,488H in guinea pigs.

Dose-responsive motor activity induced by systemic injection of the kappa (kappa) preferring opioid agonist, U50,488H (1-10 mg/kg, s.c.) in guinea pigs was recently reported [Brent P. J. and Bot G. (1992) Psychopharmacology 107: 581-590], characterised at the higher doses used (5-10 mg/kg) by sustained postural abnormalities. The effects on the U50,488H-induced, abnormal, motor response of pharmacological manipulation of opioid receptors and sigma (sigma) sites was studied. The opioid antagonist naloxone, [5 and 15 mg/kg, subcutaneously (s.c.)], the kappa selective antagonist, norbinaltorphimine (NBNI), administered intracerebroventricularly (i.c.v., 20 and 50 nM) 0.5 hr before U50,488H, and the anticonvulsant phenytoin [25 and 50 mg/kg, intraperitoneally (i.p.)] given 1 hr before, attenuated the abnormal postures, whereas naloxone methobromide (15 mg/kg), a quaternary opioid which does not cross the blood-brain barrier, had no significant effect on the movements. In contrast, the drugs with varying affinity for sigma binding sites such as 1,3-di(2-tolyl)guanidine (DTG, 10 and 30 mg/kg), haloperidol (1 and 5 mg/kg, s.c.), dextromethorphan (1, 10 and 20 mg/kg, s.c.) and reduced haloperidol (1 mg/kg, s.c.), given 0.5-1 hr before U50,488H, exacerbated the severity of the abnormal motor activity in a dose-related manner by decreasing the latency to onset of maximum obtainable motor response and increasing the duration of the response. In addition, haloperidol (1 and 5 mg/kg, s.c.), dextromethorphan (10 mg/kg, s.c.) and DTG (30 mg/kg, s.c.), given in combination with U50,488H, induced behaviour characterised by marked oral activity. In contrast to the effect of haloperidol, pretreatment with the selective dopamine D-2 antagonist, raclopride (10 mg/kg, s.c.), had no significant effect on the abnormal movements induced by U50,488H, but did induce oral activity. These data indicate the possible involvement of kappa opioid receptors in the abnormal movement induced by U50,488H, and further demonstrate that there is an interaction between the kappa receptors and sigma sites which can influence the abnormal motor activity.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1993

Cocaine and dopaminergic actions in rat neostriatum.

Electrophysiological experiments were conducted in vivo to characterize the involvement of dopamine in effects of cocaine at the cellular level. L-DOPA (preceded by carbidopa) evoked excitation and depression equally at 0.25 mg/kg; however, at 0.5 and 1.0 mg/kg depression in the basal rate of discharge predominated. Cocaine evoked similar responses. At 0.25 and 0.5 mg/kg excitation and depression were elicited in about equal proportion, while at 1.0 mg/kg depression was predominant. Cocaine-induced neuronal changes were reversible by haloperidol. In experiments with specific dopamine antagonists, cocaine-induced neuronal depression was blocked with the D1 antagonist, SCH 23390 at a dose of 0.25 mg/kg. The D2 antagonist, eticlopride, did not alter cocaine-induced depression in any specific manner. Excitation, following cocaine, was not altered by intervention with SCH 23390, yet it was blocked with the D2 antagonist eticlopride at a dose of 0.25 mg/kg. The duration of these changes was consistent with the observed duration of the psychotropic actions of cocaine.

Animals↗

PubMed1995

Pharmacological evidence for the involvement of sigma sites in DTG-induced contralateral circling in rats.

The central distribution of sigma sites labelled by di-o-tolylguanidine (DTG), a compound which has specific affinity for sigma sites, and its ability to produce postural movements, are consistent with the hypothesis that sigma sites may play a functional role in the regulation of movement. The aim of the present study was to evaluate the specificity of the circling behaviour induced by unilateral intranigral injection of DTG in rats. As previously described, DTG produced dose-dependent unilateral rotations (2.5-20 nmol/rat). A similar dose-dependent circling behaviour was observed with DMTG and (+) NANM (3-40 nmol/rat), compounds which bind to both sigma and PCP sites, and with haloperidol (3-20 nmol/rat) whereas raclopride and D,L-sulpiride did not elicit any circling (10 nmol/rat). DTG-induced circling after intranigral injection (10 nmol/rat) was decreased in a dose-dependent manner by rimcazole (20-40 mg/kg, i.p.), a selective ligand for sigma sites, and by BMY 14802 (3, 10, 30 mg/kg, i.p.), ifenprodil and eliprodil (1, 3, 10 mg/kg, i.p.), non-selective sigma ligands. In contrast, naloxone (1 mg/kg, s.c.) and CGS 19755 (1, 3, 10 mg/kg, i.p.) did not change the DTG-induced circling. Eliprodil failed to inhibit circling produced by compounds devoid of any affinity for sigma sites such as APV, dizocilpine or muscimol, indicating the specificity of the inhibition observed with eliprodil on the DTG-induced circling.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Remoxipride and raclopride differ from metoclopramide by their effects on striatal dopamine release and biosynthesis in rats.

Effects of new neuroleptics remoxipride (2.4 mg/kg, i.p.) and raclopride (1.2 mg/kg, i.p.) in comparison to metoclopramide (5 mg/kg, i.p.) on the extracellular levels of DA and its metabolites using microdialysis technique in freely moving rats were studied. The effects of these drugs as well as that of cis- and trans-carbidine (25 and 1 mg/kg, i.p., respectively), sulpride (50 mg/kg, i.p.) and haloperidol (1 mg/kg, i.p.) on the DA biosynthesis rate by accumulation of L-DOPA after inhibition of L-DOPA decarboxylase (NSD-1015 model) in rat striatum were also investigated. All the drugs studied increased significantly DA biosynthesis rate. The order of potency of drugs was: metoclopramide > haloperidol > raclopride > remoxipride > sulpride > cis-carbidine > trans-carbidine. In microdialysis study metoclopramide was shown to produce much greater increase in HVA and DOPAC and only modest rise in DA levels. Meanwhile remoxipride and raclopride were found to differ from the former drug being approximately equally effective in increasing both DA and its metabolite extracellular levels. It is suggested that typical and atypical neuroleptics may differentially affect dopamine release and synthesis in rat striatum.

Animals↗

PubMed1995

Stimulation of median, but not dorsal, raphe 5-HT1A autoreceptors by the local application of 8-OH-DPAT reverses raclopride-induced catalepsy in the rat.

The local application of 8-OH-DPAT (0.5 or 2.5 micrograms/rat, 10 min) into the median, but not the dorsal, raphe nucleus resulted in a reversal of the catalepsy induced by the DA D2 receptor blocking agent raclopride (16 mg kg-1 s.c., 60 min). The local application of 8-OH-DPAT into serotonergic projection areas of the forebrain (dorso-lateral neostriatum, accumbens core; 0.5 or 2.0 micrograms/side) did not affect raclopride-induced catalepsy. Thus, the 5-HT1A autoreceptor in the median raphe nucleus is an important site of action for the reversal of DA D2 receptor antagonist-induced catalepsy by systemic administration of 5-HT1A receptor agonists, in the rat.

8-Hydroxy-2-(di-n-propylamino)tetralin↗