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At least 955 records · Page 53Linked to original sources
PubMed1993

Binding characteristics of remoxipride and its metabolites to dopamine D2 and D3 receptors.

The substituted benzamide, remoxipride, is a new atypical antipsychotic agent with good clinical efficacy and low extrapyramidal side-effect potential. In the present study, the in vitro receptor binding properties of remoxipride and several of its metabolites to rat striatal dopamine D2 and cloned human dopamine D2A and D3 receptors were investigated. Remoxipride bound to [3H]raclopride-labelled dopamine D2 receptors in rat striatum with an affinity (Ki) of 113 nM. The significantly lower affinities of remoxipride reported when [3H]spiperone was used as a radioligand are suggested to be due to methodological problems associated with the use of very high-affinity radioligands. Some of the phenolic metabolites of remoxipride found mainly in rat exhibited considerably higher affinities to dopamine D2 and D3 receptors than remoxipride itself. The pyrrolidone metabolites found mainly in the human had very low dopamine D2 and D3 affinities. The present in vitro results suggest that the behavioural effects of remoxipride in rats may reflect the effect of remoxipride and some of its high-affinity metabolites.

Animals↗
PubMed1993

The C-terminal neurotensin-(8-13) fragment potently modulates rat neostriatal dopamine D2 receptors.

The effects of neurotensin fragments and of neurotensin itself on the characteristics of neostriatal dopamine D2 agonist binding were studied in competition experiments with dopamine using the D2 antagonist, [3H]raclopride. The biologically active neurotensin-(8-13) fragment, but not the inactive neurotensin-(1-7) fragment, caused a concentration-related increase in the KH and KL values of dopamine with a maximal increase by 110 and 97%, respectively, at 1 nM, while neurotensin-(1-13) only induced such changes at 10 nM. In view of the higher potency and the increased ability of neurotensin-(8-13) versus neurotensin (1-13) to reduce the affinities of the high- and low-affinity states of the neostriatal D2 receptors, the C-terminal neurotensin fragments may be among the endogenous ligands of the neostriatal neurotensin receptors.

Animals↗
PubMed1993

Low dose raclopride spares the extrapyramidal system in rat brain from metabolic effects.

The effect of a highly selective dopamine D2 receptor antagonist, raclopride ((-)-(S)-3,5-dichloro-N-(1-ethyl-2-pyrrolidinyl) methyl-6-methoxysalicylamide tartrate), on regional cerebral glucose metabolism in rat brain was determined using [14C]2-deoxyglucose autoradiography, and compared to a typical neuroleptic, haloperidol. Based on preclinical biochemistry and early clinical trial reports, it was hypothesized that raclopride would fail to functionally affect brain regions putatively involved with motor function, while altering psychosis-related regions. Raclopride at a low dose (1.5 mg/kg) significantly reduced regional cerebral glucose metabolism in neocortical areas. It showed a trend toward a similar reduction in limbic structures. But the drug did not have an effect in the extrapyramidal system at this dose. While, at a higher dose, raclopride (10.0 mg/kg), significantly reduced regional glucose metabolism throughout the susceptible grey matter areas of the brain including extrapyramidal regions, an effect similar to haloperidol. Based on approximate antipsychotic dose equivalence between haloperidol and raclopride, the clinically relevant low dose used in this study, failed to functionally alter metabolism in motor regions of brain while exerting a haloperidol-like effect in other areas traditionally linked to cognitive and affective behaviors. This suggests that a low dose of raclopride can exert regionally selective actions. The high dose of raclopride is metabolically active in all brain areas, and, therefore, in clinical application might produce involuntary motor syndromes, like parkinsonism and late onset dyskinesias, along with its antipsychotic effects.

Animals↗
PubMed1993

Opposite effects of NMDA and AMPA receptor blockade on catalepsy induced by dopamine receptor antagonists.

Excitatory amino acid antagonists have been proposed as novel therapeutic agents for Parkinson's disease due to their ability to reverse akinesia in animal models of this disorder. To further evaluate this therapeutic potential, we examined the effects of a N-methyl-D-aspartate (NMDA) and an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist on catalepsy produced by dopamine D1 or D2 receptor antagonists in rats. Male Sprague-Dawley rats were injected with dizocilpine (MK-801 0.025, 0.05 or 0.1 mg/kg i.p.), 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX 12.5 mg/kg i.p.) or saline prior to administration of either raclopride (2.5 mg/kg i.p.) or SCH 23390 (0.5 mg/kg i.p.). Catalepsy was evaluated with both grid and bar tests every 20 min for 2.7 h. MK-801 (0.1 mg/kg) reversed the catalepsy produced by either raclopride or SCH 23390 but did not stimulate locomotion when given alone at this dose. At 0.05 mg/kg, MK-801 markedly decreased SCH 23390-induced catalepsy, but did not affect the catalepsy produced by raclopride. In contrast, NBQX increased raclopride-induced catalepsy, but had no effect on catalepsy elicited by SCH 23390. These findings suggest that blockade of NMDA receptors, but not non-NMDA receptors, may reverse the catalepsy produced by dopamine receptor antagonists.

Animals↗
PubMed1993

Comparison of the effect of substituted benzamides on midbrain dopamine neurones after treatment of rats for 21 days.

We have tested five different substituted benzamides (nemonapride, D,L-sulpiride, remoxipride, raclopride and zacopride) for their potential to decrease the number of spontaneously active dopamine neurones in the rat midbrain after treatment for 21 days. Nemonapride, D,L-sulpiride, and remoxipride significantly reduced the number of spontaneously active dopamine neurones in the ventral tegmental area, indicating an antipsychotic potential, while raclopride and zacopride induced but minor effects. The number of active dopamine neurones in the substantia nigra pars compacta was reduced by nemonapride at higher doses which should indicate the propensity for developing extrapyramidal side-effects. In conclusion, several of the substituted benzamides showed an antipsychotic profile in this test model. In addition, some of the benzamides also showed a propensity for extrapyramidal side-effects and these results are in accordance with the profile reported from clinical trials. However, the results obtained with this model indicate that raclopride neither has antipsychotic potential nor induces extrapyramidal side-effects. The reason for this discrepancy is at present not known.

Animals↗
PubMed1993

Isomeric selectivity at dopamine D3 receptors.

Racemic 7-hydroxy-N,N-dipropylaminotetralin (7-OH-DPAT) shows greater affinity for limbic-selective dopamine D3 receptors than for more ubiquitous dopamine D2 receptors. R(+)-7-OH-DPAT was prepared and evaluated in radioreceptor assays using membranes of fibroblasts expressing the human dopamine D3 receptor as well as rat striatal membranes containing dopamine D2 receptors. This enantiomer had 2-fold greater D3 affinity than the racemate and similarly greater D3 vs. D2 selectivity (64-fold). The results may facilitate development of D3 selective agents and evaluation of functions of these receptors.

Animals↗
PubMed1995

Discriminative stimulus effects of esteratic local anesthetics in squirrel monkeys.

A number of esteratic local anesthetics serve as positive reinforcers and produce cocaine-like discriminative stimulus effects in animals. It has been suggested that the affinity of these compounds for a site on the dopamine transporter, and not their local anesthetic actions, is responsible for these abuse-related behavioral effects. In the present study, three local anesthetics previously shown to be self-administered in animals were examined in squirrel monkeys trained to discriminate cocaine (0.3 mg/kg) from saline in a two-lever, food-reinforced procedure. Dimethocaine (0.1-3.0 mg/kg) fully and dose-dependently substituted for cocaine. Doses of dimethocaine (1.7 mg/kg) and cocaine (0.3 mg/kg) which produced full (> 80%) substitution for cocaine were administered in combination with the dopamine D1 receptor antagonist SCH 39166 ((-)-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5H -benzo [d]naphtho-(2,1-b)azepine) and the dopamine D2 receptor antagonist raclopride (both at 0.003-0.03 mg/kg). SCH 39166 fully blocked the cocaine-like discriminative stimulus effects of dimethocaine and cocaine, but raclopride produced only partial antagonism of cocaine-lever selection. In addition, there was some evidence that raclopride blocked cocaine-lever responding produced by a lower dose of dimethocaine. In substitution studies, neither procaine (1-10 mg/kg) nor chloroprocaine (1-30 mg/kg) produced cocaine-like effects. These results support a role for dopamine in the behavioral effects of some local anesthetics.

Aminobenzoates↗
PubMed1995

Dopamine receptor antagonists prevent expression, but not development, of morphine sensitization.

The present experiments determined the effects of selective dopamine receptor antagonists on the initiation and expression of sensitization to the locomotor-stimulating effects of morphine in rats. Although both the dopamine D1 receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzaz epine hydrochloride (SCH 23390, 0.25 mg/kg) and the dopamine D2 receptor antagonist eticlopride (0.1 mg/kg) suppressed the ability of morphine (10 mg/kg) to elicit sensitized locomotor activity during the course of a 12 day treatment schedule, subsequent tests with morphine alone revealed significant sensitization. Sensitization in the SCH 23390 + morphine group could not be attributed to dopamine D1 receptor supersensitivity caused by repeated SCH 23390 administration because electrophysiological recordings indicated that nucleus accumbens neurons in SCH 23390-treated rats were not more sensitive to the inhibitory effects of either dopamine or a dopamine D1 receptor-selective agonist. Thus, dopamine receptor stimulation may be involved in expression, but not development, of morphine sensitization.

Animals↗
PubMed1994

Dopamine receptor antagonist properties of S 14506, 8-OH-DPAT, raclopride and clozapine in rodents.

S 14506 (1-[-(4-fluorobenzoylamino)ethyl]-4-(7-methoxynaphthyl)piper azine hydrochloride), 8-OH-DPAT ((+/-)-8-hydroxydipropylaminotetralin hydrobromide), clozapine and raclopride were compared in some behavioural models able to characterize dopamine antagonist properties. In mice treated with apomorphine (0.75 mg/kg, s.c.), stereotyped climbing and sniffing were dose dependently antagonized by S 14506, by clozapine and by raclopride, but were virtually not modified by 8-OH-DPAT. Stereotyped climbing and sniffing induced by (+)-amphetamine (1.25 mg/kg, s.c.) in mice treated with L-DOPA (L-3,4-dihydroxyphenylalanine 75 mg/kg, associated with benserazide, i.p.) were also dose dependently antagonized by S 14506 and by raclopride, but were only partially antagonized by clozapine and unaffected by 8-OH-DPAT. Grooming behaviour induced by SK&F 38393 ((+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride, 1.87 mg/kg, s.c.) in mice was inhibited by low doses of S 14506 and of clozapine, and by relatively high doses of 8-OH-DPAT and of raclopride. The decreased grooming behaviour observed in apomorphine-treated mice was partly antagonized by high dose of raclopride but was significantly potentiated by S 14506, 8-OH-DPAT and clozapine. Raclopride produced the same effect in mice treated with (+)-amphetamine and L-DOPA. In rats treated with apomorphine (0.6 mg/kg, s.c.), sniffing was dose dependently antagonized by S 14506, by raclopride and by clozapine, but not by 8-OH-DPAT. Again, whereas increasing doses of raclopride allowed grooming to reappear in apomorphine (0.6 mg/kg)-treated rats, S 14506, 8-OH-DPAT and clozapine did not. Raclopride induced catalepsy in rats, whereas like clozapine, S 14506 was virtually ineffective. All the tested compounds inhibited in vitro [3H]raclopride binding in rat striatum (raclopride > S 14506 > clozapine > 8-OH-DPAT), whereas only clozapine inhibited [3H]SCH 23390 binding. Finally, S 14506 inhibited the in vivo binding of [3H]raclopride in striatum and olfactory bulbs, but did not affect the striatal in vivo binding of [3H]SCH 23390. From these data, it appears that like raclopride, S 14506 displays dopamine antagonist properties by blocking dopamine D2 receptors. However, the psychopharmacological profile of S 14506 is closer to that of clozapine than to that of raclopride, probably as a result of its actions at 5-HT receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1994

Intracerebral infusion of (+)-AJ76 and (+)-UH232: effects on dopamine release and metabolism in vivo.

The dopamine D3- and autoreceptor preferring antagonists (+)-AJ76 and (+)-UH232 were administered locally in the striatum and the nucleus accumbens. Their effects on dialysate dopamine and 3,4-di-hydroxyphenylacetic acid (DOPAC) were measured and compared with the effects of raclopride. (+)-AJ76 and (+)-UH232 but not raclopride seem to interact primarily with dopamine receptors in the terminal regions of the A9 and A10 dopaminergic fibers to exert their maximal effect on dopamine release in vivo. Thus, (+)-AJ76 and (+)-UH232 seem to recruit different dopamine receptor populations as compared to raclopride. Though the dopamine receptor antagonist-induced effects on dopamine release seem to be mediated mainly by dopamine receptors in the terminal areas, the effects on DOPAC by the different antagonists seem to be mediated mainly via effects elsewhere, presumably at the somatodendritic autoreceptors. Thus, it is suggested that the regulation of extracellular dopamine and DOPAC after treatment with dopamine receptor antagonists are subjected to different control mechanisms.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1994

Dopamine D1 and D2 receptor antagonism differentially modulates stimulation of striatal neurotransmitter levels by N-methyl-D-aspartic acid.

The effects of local perfusion with the dopamine D1 receptor antagonist SCH 23390 and the dopamine D2 receptor antagonist raclopride on basal and N-methyl-D-aspartate (NMDA) stimulated dopamine, gamma-aminobutyric acid (GABA) and glutamate levels in the dorsolateral striatum were monitored using in vivo microdialysis in the halothane anaesthetized rat. Local perfusion (90 min) with SCH 23390 and raclopride (1 and 10 microM) dose dependently increased basal striatal dopamine release whereas GABA and glutamate dialysate levels were unaffected. Local perfusion (10 min) with the 1 mM concentration of NMDA increased striatal dopamine, GABA and glutamate outflow. However, when perfused together with SCH 23390 (1 microM) NMDA inhibited glutamate efflux. Moreover, in the presence of SCH 23390 (10 microM) the NMDA induced rise in dopamine and GABA levels was partly prevented. On the other hand, raclopride 1 microM enhanced the NMDA stimulated GABA efflux while at 10 microM it partly counteracted the NMDA induced dopamine release. These data demonstrate that NMDA induced changes in striatal neurotransmitter outflow are effectively modified by dopamine D1 and D2 receptor blockade.

Animals↗
PubMed1994

Antagonism by SCH 23390 of clozapine-induced hypothermia in the rat.

Clozapine (7.5-30.0 mumol kg-1 s.c.) produced a decrease in core temperature in the rat. The temperature decrease caused by clozapine (7.5 mumol kg-1 s.c.) was fully antagonized by the selective dopamine D1 receptor antagonist SCH 23390 (0.3 mumol kg-1) s.c.) and a partial antagonism was obtained by the selective dopamine D2 receptor antagonist raclopride (1.6 mumol kg-1 s.c.). On the other hand, the hypothermia was not antagonized by alpha-adrenoceptor antagonists (idazoxan and prazosin), 5-HT receptor antagonists ((-)-pindolol and ritanserin) or by the muscarinic M1 receptor antagonist scopolamine. The hyperthermia produced by the 5-HT1C/2 receptor agonist DOI (0.75 mumol kg-1) was blocked by clozapine (3.0 mumol kg-1 s.c.). Clozapine did not antagonize hypothermia produced by selective dopamine D1 and D2 receptor agonists (A 68930 and quinpirole), the alpha 2-adrenoceptor agonist clonidine, the 5-HT1A receptor agonist 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin) or the muscarinic M1 receptor agonist oxotremorine. The present results suggest that clozapine may be a partial agonist at brain dopamine D1 receptors.

Amphetamines↗
PubMed1994

Performance on a lever-release, conditioned avoidance response task involves both dopamine D1 and D2 receptors.

SCH-23390 (0.01 and 0.05 mg/kg s.c.), a dopamine D1 receptor antagonist, or eticlopride (0.01 and 0.05 mg/kg s.c.), a dopamine D2 receptor antagonist, dose-dependently impaired performance on a lever-release conditioned avoidance response (CAR) task by decreasing percent avoidance responses and increasing avoidance latency. When combined, these drugs impaired CAR performance in an additive fashion. Lever-release CAR performance, therefore, requires activation of both dopamine D1 and D2 receptors.

Animals↗
PubMed1995

Effects of antipsychotics on cognitive behaviour in rats using the delayed non-match to position paradigm.

The acute effects of the dopamine D1 receptor antagonist SCH 23390 [(R)-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepi n-7-ol d hemimaleat, the dopamine D2 receptor antagonists raclopride and haloperidol, the compounds with mixed receptor profiles clozapine, risperidone and sertindole, the alpha 1-adrenoceptor antagonist prazosin and scopolamine were investigated in a delay-response task, a test for working memory, for rats. SCH 23390 induced a delay-dependent impairment of the performance. Raclopride, haloperidol, clozapine, and risperidone induced a delay-independent impairment. Sertindole was without effect. The specific (delay-dependent) and unspecific (delay-independent) effects on working memory of the dopamine D1 and D2 receptor antagonists, respectively, were associated with the dominance of dopamine D1 receptors in the prefrontal cortex and of dopamine D2 receptors in the basal structures of the brain. Prazosin did not affect working memory; however, a reduction in intertrial responses was found. Scopolamine induced a delay-independent impairment. It is concluded that the compounds have different activity profiles in this cognitive task. This finding may have important implications for the development of antipsychotics with a lower propensity for cognitive side effects.

Animals↗
PubMed1995

Antagonism by the 5-HT2A/C receptor agonist DOI of raclopride-induced catalepsy in the rat.

It has been shown that the administration of 5-hydroxytryptamine (5-HT)1A receptor agonists will antagonize the catalepsy induced by dopamine D1 or D2 receptor blocking agents. In the present study, administration of the 5-HT2A/C receptor agonist, 1-(2,5-dimethoxy-4-iodo)-2-aminopropane (DOI) (1 mg kg-1 s.c.), counteracted the catalepsy produced by the dopamine D2 receptor antagonist, raclopride (16 mg kg-1 s.c.), but not by the dopamine D1 receptor antagonist (R)-(+)-8-chloro-2,3,4,5-tetra-hydro-3-methyl-5-phenyl-1H-3-benzazepine (SCH 23390) (0.2 mg kg-1 s.c.). The effects of DOI on raclopride-induced catalepsy were fully antagonized by pretreatment with the 5-HT2A/C receptor antagonist, ritanserin (2 mg kg-1 s.c.). The 5-HT precursor, 5-hydroxytryptophan (5-HTP) (6.25-25.0 mg kg-1 i.p.), in combination with the peripheral 5-HTP decarboxylase inhibitor, benserazide (25 mg kg-1 i.p.), and the selective serotonin reuptake inhibitor, zimeldine (10 mg kg-1 s.c.), enhanced the catalepsy produced by a low dose of raclopride (4 mg kg-1 s.c.). It is concluded that stimulation of (postsynaptic) 5-HT2 receptors results in antagonism of the catalepsy induced by treatment with a dopamine D2, but not a D1, receptor antagonist. The fact that 5-HTP, in the presence of benserazide and zimeldine, enhanced raclopride-induced catalepsy suggests the possibility of postsynaptic 5-HT receptors acting in opposition to the 5-HT1 and 5-HT2 receptors, as regards extrapyramidal motor functions in the rat.

5-Hydroxytryptophan↗
PubMed1996

Effects of cannabinoid receptor stimulation and blockade on catalepsy produced by dopamine receptor antagonists.

The ability of cannabinoid receptor stimulation or blockade to alter catalepsy produced by dopamine D1 and D2 receptor antagonists was studied in rats. The cannabinoid receptor antagonist SR 141716A (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1H- pyrazole-3-carboxamidehydrochloride) (0.5 and 2.5 mg/kg) reduced catalepsy elicited by the cannabinoid receptor agonist CP 55,940 (1 alpha,2-(R)-5-(1,1-dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl ) cyclohexyl-phenol) (0.5 mg/kg). However, SR 141716A (0.5 and 2.5 mg/kg) did not decrease catalepsy produced by the dopamine D1 receptor antagonist SCH 23390 (R-(+)-7chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5- tetrahydro-1-H-3-benzazepine) (0.5 mg/kg) or the dopamine D2 receptor antagonist raclopride (S(-)-3,5-dichloro-N-(1-ethyl-2-pyrrolidinyl)-methyl-6-methoxysalicylami de) (2.5 mg/kg), suggesting that, under these conditions, endogenous cannabinoid ligands do not modulate the cataleptic effects of dopamine D1 or D2 receptor antagonists. In contrast, CP 55,940 (0.025 and 0.1 mg/kg), at doses which do not produce catalepsy when administered alone, enhanced catalepsy produced by SCH 23390 and raclopride. These results suggest that stimulation, but not blockade, of brain cannabinoid receptors modifies catalepsy behavior produced by selective dopamine D1 and D2 receptor blockade.

Animals↗
PubMed1996

Brain sigma receptors labelled by [3H]nemonapride.

Binding of [3H]nemonapride and [3H]raclopride was examined in the brain areas of three species (rat, cow and human). The results indicated that [3H]nemonapride binding is inhibited by selective sigma receptor ligands in frontal cortex, striatum and cerebellum. Only the striatum showed significant dopaminergic sites as defined by sulpiride. Use of the subtraction method of [3H]nemonapride minus [3H]raclopride binding as a measure of D4 dopamine receptor binding may, therefore, also include a sigma receptor component.

Animals↗
PubMed1996

Critical reevaluation of spiperone and benzamide binding to dopamine D2 receptors: evidence for identical binding sites.

There are several inconsistencies in the literature as regards the characteristics of benzamide and butyrophenone binding to dopamine D2-like receptors. The variations observed in Bmax, Kd and Ki values have led to hypotheses, such as the existence of a specific "benzamide binding site' and that dopamine D2 receptors exist in a monomer-dimer equilibrium, where benzamides are supposed to bind receptor monomers and butyrophenones receptor dimers. We have previously suggested that the discrepant results may instead be related to methodological difficulties associated with the use of very high-affinity radioligands (e.g. ligand depletion and failure to achieve equilibrium). The present study was designed to reinvestigate and critically reevaluate the binding characteristics of [3H]spiperone, [3H]nemonapride, [125I](S)-3-iodo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5,6- dimethylsalicylamide ([125I]NCQ-298) and [3H]raclopride to cloned human dopamine D2A and rat striatal dopamine D2 receptors in order to establish whether they label the same receptor population. We found that the Kd values of [3H]spiperone, [125I]NCQ-298 and [3H]nemonapride were about 20 pM and that of [3H]raclopride about 1 nM. We did not find any significant differences between the Bmax values determined with the various radioligands. Furthermore, the Ki values of spiperone and NCQ-298 (derived from cross-competition studies) for dopamine D2 receptors labelled with either [3H]spiperone or [125I]NCQ-298 were in good agreement with the corresponding Kd values. In conclusion, our results clearly demonstrate that when studied under correct experimental conditions, all four radioligands label an identical receptor population.

Animals↗