Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A culture of dispersed rat anterior pituitary cells was used to test the ability of pimozide and sulpiride to affect the basal gonadotropin release and their effects on the response to Gn-RH. Sulpiride did not alter either the basal or the Gn-RH-induced release of LH, and the lowest dose (500 ng/ml) seemed to potentiate the Gn-RH-induced FSH release. On the other hand, both doses of pimozide (100 ng/ml and 10 microgram/ml) significantly inhibited the release of FSH and LH induced by Gn-RH but did not affect the basal release of the two gonadotropins. From these results it is evident that pimozide, at the doses used, is a powerful inhibitor of the pituitary response to Gn-RH in vitro. Sulpiride on the other hand had no effect on the pituitary response to Gn-RH in vitro, except on FSH release, using the lower dose.
Mol Cell Endocrinol 1978 Apr
PMID:Effect of pimozide and sulpiride on the release of LH and FSH by pituitary cells in culture. 65 87

In the presence of SCH 23390, a potent blocker of D1 dopamine receptors, dopamine inhibits adenylate cyclase activity of synaptic plasma membranes isolated from rat striatum. Maximal inhibition corresponds to a 20-25% decrease of basal enzyme activity and is reached with 100 microM dopamine. The apparent IC50 of dopamine is 2.5 microM. The inhibitory effect of dopamine is mimicked by various dopamine receptor agonists with the following rank order of potency: (-)-propylnorapomorphine greater than or equal to bromocriptine greater than (+/-)-2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene = (-)-apomorphine greater than dopamine greater than LY 171555 greater than l-noradrenaline greater than l-phenylephrine. Clonidine and l-isoproterenol are inactive at 100 microM. Bromocriptine and LY 171555, two agents which stimulate selectively D2 receptors, inhibit striatal adenylate cyclase activity in the absence of SCH 23390. However, bromocriptine behaves like a partial agonist. A variety of neuroleptic drugs antagonize the dopamine inhibition with a rank order of potency which qualitatively correlates with their relative affinity for D2 receptors. l-Sulpiride (EC50 = 210 nM) and (+)-butaclamol (EC50 = 130 nM) are severalfold more potent than d-sulpiride (EC50 = 5 microM) and (-)-butaclamol (EC50 = 10 microM). The inhibitory effect of dopamine on striatal adenylate cyclase activity is dependent on the presence of GTP, with half-maximal inhibition occurring at 1 microM GTP. In the absence of SCH 23390, dopamine stimulates adenylate cyclase activity, reaching a maximum at 1 microM GTP. At higher concentrations of the nucleotide, the dopamine-stimulated enzyme activity decreases, and this decline is antagonized by the D2 receptor blocker l-sulpiride. Guanyl-5'-yl imidodiphosphate, a stable analogue of GTP, has a biphasic effect on the striatal adenylate cyclase activity, inhibiting at low concentration (from 1 to 100 nM) and stimulating at higher concentrations. Selective activation of D2 receptors by LY 171555 does not increase the extent of enzyme inhibition elicited by guanyl-5'-yl imidodiphosphate. Sodium chloride amplifies the inhibition of striatal adenylate cyclase activity by LY 171555 and reduces the potency of the D2 agonist by a factor of 4. The dopamine-inhibited enzyme activity is lost following intrastriatal injection of kainic acid. The results indicate that in rat striatum dopamine inhibits adenylate cyclase activity by acting on postsynaptic dopamine receptors with pharmacological properties of D2 type.
Mol Pharmacol 1985 Aug
PMID:Characterization of dopamine receptors mediating inhibition of adenylate cyclase activity in rat striatum. 241 Jul 69

Ca-dependent, K-stimulated 86Rb efflux, a measure of Ca-activated K conductance in rat brain synaptosomes, was blocked by phenothiazines and haloperidol. Micromolar concentrations of the phenothiazines, fluphenazine and trifluoperazine, and haloperidol, a non-phenothiazine antipsychotic and calmodulin antagonist, selectively inhibited the Ca-activated K channels. The IC50 values of all three agents for inhibition of the Ca-activated K channels was on the order of 0.5-1 microM. Measurements of K-stimulated 45Ca uptake indicated that the effects of these agents on Ca-activated K channels was not due to inhibition of Ca influx through voltage-gated Ca channels. Sulpiride, a potent antipsychotic with weak anti-calmodulin activity, was a relatively weak inhibitor of Ca-activated K channels. Calmidazolium (compound R-24571) and W7, two non-phenothiazine calmodulin antagonists, did not selectively inhibit Ca-activated K channels. Biphasic dose response curves for inhibition of the Ca-dependent, K-stimulated 86Rb efflux by the phenothiazines raise the possibility that there may be two kinds of Ca-activated K channels in rat brain presynaptic terminals, with different sensitivities to the phenothiazines. These results demonstrate that two phenothiazines and haloperidol are potent and relatively selective inhibitors of Ca-activated K channels in nerve endings. This inhibition does not appear to be mediated by calmodulin or by dopamine receptors.
Mol Pharmacol 1988 Feb
PMID:Phenothiazines and haloperidol block Ca-activated K channels in rat forebrain synaptosomes. 244

Dopamine (DA) regulation of intracellular cyclic AMP formation in purified, intact striatal neurons in primary culture was examined. DA (EC50, 3 microM) and vasoactive intestinal polypeptide (VIP; EC50, 10 nM) stimulated cyclic AMP formation by 2- and 5-fold, respectively. In the presence of 0.1 microM forskolin (which was virtually ineffective alone), neurohormone efficacy was augmented; potency was unaffected. In the presence of 0.1 microM SCH 23390, a selective D1 antagonist, the DA dose-response curve was shifted rightward in a competitive manner. At low concentrations (0.01-1.0 microM), however, DA inhibited basal cyclic AMP formation. The inhibitory effect, but not the shift of the dose-response curve, was blocked by 5 microM l-sulpiride, a selective D2 antagonist. At saturating concentrations of VIP (0.1-1.0 microM), no other neurohormone can further augment cyclic AMP formation. Under these conditions, increasing concentrations of DA resulted in a dose-dependent (IC50, 0.5 microM) inhibition of VIP-stimulated cyclic AMP synthesis. This effect was augmented in the presence of 0.1 microM SCH 23390 and blocked by 5 microM l-sulpiride. Sulpiride antagonism was stereospecific, with the l-isomer being 30-fold more potent than the d-isomer. The rank order of potency for a series of dopaminergic agonists and antagonists at the receptor mediating attenuation of cyclic AMP formation suggests that it is of the D2 type. Furthermore, both DA and Met-enkephalin inhibition of cyclic AMP formation is lost after exposure of striatal neurons to islet activator protein. These findings suggest that a D2 receptor mediates the inhibition of intracellular cyclic AMP formation by DA in striatal neurons in primary culture, and may do so by an interaction with the inhibitory guanine nucleotide regulatory protein of adenylate cyclase.
Mol Pharmacol 1985 Jun
PMID:D2-dopamine receptor-mediated inhibition of cyclic AMP formation in striatal neurons in primary culture. 298 58

In male and female rat anterior pituitary homogenates dopamine inhibited basal adenylate cyclase by 30% and 50%, respectively. Dopamine also inhibited vasoactive intestinal peptide-stimulated adenylate cyclase by 50% in both sexes. Sulpiride, a specific D2 antagonist, stereospecifically blocked with high affinity the dopamine inhibition in both males and females. RU 24926, a specific, non-catechol, non-ergot D2 agonist, also inhibited basal adenylate cyclase of female pituitary with a higher apparent affinity than dopamine (KDapp 20 nM and 450 nM, respectively). This effect was also stereospecifically antagonized by sulpiride. Apomorphine was also more potent (KDapp 100 nM) than dopamine, whereas norepinephrine and SKF 38393, a specific D1 agonist, were poorly active; isoproterenol and clonidine were inactive. Ergots derivatives such as CB 154, LY 14865, pergolide, and lergotrile were potent agonists. alpha-Dihydroergocryptine was a partial agonist of the dopamine receptor negatively coupled with an adenylate cyclase. Because of the slow association kinetics of this drug with the dopamine receptor, its KDapp (0.7 nM) for adenylate cyclase inhibition could be correctly determined only after a 30-min incubation period. All classical dopaminergic antagonists blocked dopamine inhibition of pituitary adenylate cyclase, pimozide (KI 1 nM) and spiperone (KI 0.8 nM) being the more potent. There were good correlations between the affinities of large series of agonists and antagonists for the anterior pituitary dopamine receptors negatively coupled with an adenylate cyclase on one hand, and for either D2 dopamine receptors labeled with [3H] dihydroergocryptine or [3H]spiroperidol in both pituitary and striatum, or D2 pituitary receptors involved in prolactin secretion on the other hand. It is concluded that the pituitary dopamine receptors negatively coupled with an adenylate cyclase are the classical D2 receptors involved in prolactin secretion.
Mol Pharmacol 1983 May
PMID:Pharmacological characterization of the D2 dopamine receptor negatively coupled with adenylate cyclase in rat anterior pituitary. 630 29

Changes in the activity of DNA polymerase and [3H]thymidine incorporation into the DNA of the anterior pituitary gland were studied in oestrogenized male and pregnant rats. The activities of DNA polymerases alpha and beta, extracted in Tris--HCl or in sodium phosphate buffer were characterized according to their optimum pH and sensitivity to N-ethyl-maleimide. In the Tris-soluble fraction DNA polymerase activity is almost exclusively alpha, while in the phosphate soluble fraction it is a mixture of alpha and beta. The administration of oestrogens to male rats increases [3H]thymidine incorporation and enhances the activity of DNA polymerases in the Tris-soluble fraction, while the activity of the phosphate-soluble enzyme does not change. Sulpiride administration results in a further increment of [3H]thymidine incorporation and of DNA polymerase activity in the Tris-soluble fraction. In pregnant rats sulpiride also produces an increment of DNA polymerase activity only in the Tris-soluble fraction. Thus, the activity of the Tris-soluble fraction from APG behaves as DNA polymerase alpha. This activity changes in parallel with [3H]thymidine incorporation into DNA which is an indication of cell proliferation in the gland. This is discussed with respect to a negative feedback mechanism between intracellular prolactin concentration and DNA synthesis in the APG.
Mol Cell Endocrinol 1980 Jun
PMID:DNA polymerases in the rat pituitary gland. Effect of oestrogens and sulpiride. 739 1

Human D2, D3, D4 and dopamine receptors were individually coexpressed in Xenopus oocytes with a G protein-regulated inwardly rectifying potassium channel (GIRK1). At -100 mV in 96 mM potassium, dopamine (0.1-100 nM) evoked an inward current; the current showed inward rectification, reversed polarity at 0 mV, and was blocked by barium (50% inhibition by 10 microM). The concentrations of dopamine activating 50% of the maximal current (EC50) were not different (2-4 nM) for D2, D3, and D4 receptors, but the maximal current was 3-fold larger for D2 and D4 than for D3 receptors. Dopamine evoked reproducible inward currents at D2 and D4 receptors when applied repeatedly, but second responses could not be observed in oocytes expressing D3 receptors. 7-Hydroxy-N,N-di-n-propyl-2-aminotetralin mimicked the effect of dopamine (EC50 of approximately 2, approximately 3, and approximately 19 nM at D2, D3, and D4, respectively). (-) Sulpiride reversibly blocked the dopamine-induced current with IC50 values of 5, 300, and 2000 nM for D2, D3, and D4 receptors, respectively. Dopamine was ineffective in oocytes injected 2 hr previously with pertussis toxin. We concluded that all three D2-like dopamine receptors share the potential to activate inwardly rectifying potassium channels.
Mol Pharmacol 1996 Apr
PMID:D2, D3, and D4 dopamine receptors couple to G protein-regulated potassium channels in Xenopus oocytes. 860 93

Sulpiride (SUL, 20 mg kg-1 day-1) induces weight gain, hyperphagia, hyperprolactinemia, hypogonadism, and perhaps increased insulin sensitivity in rats. Leptin seems to signal the brain about the size of body fat stores and nutrient metabolism. We evaluated the basal serum leptin levels in rats after acute (1 h) or prolonged SUL or vehicle administration (10, 20 and 30 days). At days 10 and 30 leptin was also assessed during a glucose overload test. As the maximal weight gain during SUL administration is observed at days 10-15 of treatment, leptin was measured in a comparison group of insulin-treated rats (5 IU day-1 for 10 days). SUL-treated rats significantly gained weight. However, leptin levels were not significantly increased at any time-point of treatment. SUL did not affect insulin levels either. By contrast, leptin levels were significantly elevated after insulin administration, along with weight gain and hyperinsulinemia. An opposite correlation was also observed at day 10: leptin and insulin correlated negatively in the SUL group and positively in the insulin group. In addition, leptin and the magnitude of weight gain tended to correlate positively after SUL treatment, but negatively after insulin administration. SUL-treated rats, thus, appear to exhibit an unusual type of weight gain, characterized by normal circulating leptin and insulin levels. Such a particular leptin profile may be related to hyperprolactinemia, hypogonadism or lack of hyperinsulinemia. Molecular Psychiatry (2000) 5, 70-76.
Mol Psychiatry 2000 Jan
PMID:Antipsychotic drug-induced obesity in rats: correlation between leptin, insulin and body weight during sulpiride treatment. 1067 71

Psychotic symptoms in different neuropsychiatric disorders are treated by neuroleptic drugs. Neuroleptics are known to block dopamine (DA) neurotransmission, however, cell types mediating their actions have not been determined. Recently, astrocytes have been demonstrated to express D1- and D2-DA receptors, whose activation leads to transient increases in intracellular calcium concentration. We show here that DA-sensitivity of cortical and striatal rat astroglial cultures, as monitored by calcium imaging, is reduced by a 12-h exposure to the atypical antipsychotic agents Clozapine (>1 nmol/liter), Olanzapine (>100 nmol/liter), and Risperidone (>1 nmol/liter), but not by classical neuroleptics Haloperidol and Sulpiride. These effects could not be reverted by the receptor-specific antagonists SCH23390, Sulpiride, L745 870, Ergotamine, and Propranolol. In addition, RT-PCR and Western blot analyses concerning the effects of Clozapine, Olanzapine, and Risperidone on DA receptor expression in cortical and striatal astroglial cells revealed no alterations in mRNAs and immunoreactive protein of D1- and D2-DA receptor subtypes. These results provide the first evidence that atypical but not classical neuroleptic drugs reduce astroglial DA-sensitivity, a mechanism that may be important for a better understanding of differences in effects and side effects between atypical and classical neuroleptic drugs.
Mol Cell Neurosci 2001 Aug
PMID:Atypical neuroleptic drugs downregulate dopamine sensitivity in rat cortical and striatal astrocytes. 1152 Jan 80

Typical neuroleptic therapy often results in extrapyramidal symptoms (EPS) and tardive dyskinesia (TD). Recent reports reveal neurotoxic activity in some neuroleptics. We hypothesized that neurotoxicity might be implicated in EPS. This study aims to evaluate the neurotoxic activity of typical and atypical neuroleptics and to determine the possible role of neurotoxicity in neuroleptic-induced EPS. Perphenazine, haloperidol, clozapine, sulpiride, and risperidone (10-100 microM) were administered, either alone or combined with dopamine, to primary mouse neuronal or intact brain culture and to a human neuroblastoma (NB) cell line (SK-N-SH). Cell viability (measured by neutral red and alamar blue), DNA fragmentation (flow cytometry-NB) were determined. Neuroblastoma: perphenazine, clozapine, and haloperidol (100 microM) decreased viability by 87, 43, and 34% respectively. Sulpiride and risperidone were not toxic. At 10 microM, toxicity decreased markedly. Dopamine (125 microM) potentiated the perphenazine-induced toxicity. Flow cytometry of NB cells treated with perphenazine (2.5-40 microM) showed an increase (perphenazine 20 microM, 40 microM, 48 h) in fragmented DNA (74.7% and 95.0% vs. 8.7% in controls). Lower concentrations increased the G1 phase and decreased S phase in the cell cycle. In primary neurons, perphenazine, haloperidol, and clozapine, but not risperidone and sulpiride, induced a significant neurotoxic effect, which, in intact brain culture, was absent (haloperidol and clozapine) or lowered (perphenazine). Dopamine (0.5 mM) did not modify the effect of the drugs in the primary cultures. Neuroleptics possess differential neurotoxic activity with higher sensitivity of neoplasm tissue (NB compared to primary cultures). The order of toxicity was perphenazine > haloperidol = clozapine:sulpiride and risperidone were not toxic. Neurotoxicity is independent of dopamine and is associated with cell cycle arrest and apoptosis. With the exception of clozapine, neurotoxicity seems relevant to neuroleptic-induced EPS and TD.
Cell Mol Neurobiol 2001 Dec
PMID:Evaluation of the neurotoxic activity of typical and atypical neuroleptics: relevance to iatrogenic extrapyramidal symptoms. 1204 43


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