Adenylate Cyclase In Rat Striatum Research Articles

Dopamine enhances somatostatin receptor-mediated inhibition of adenylate cyclase in rat striatum and hippocampus.

Although there is evidence that suggests that dopamine (DA) has stimulatory effects on somatostatinergic transmission, it is unknown to date if DA increases the activity of the somatostatin (SS) receptor-effector system in the rat brain. In this study, we evaluated the effects of the administration of DA and the DA D1-like (D1, D5) receptor antagonist SCH 23390 and the D2-like (D2, D3, D4) receptor antagonist spiperone on the SS receptor-adenylate cyclase (AC) system in the Sprague-Dawley rat striatum and hippocampus. An intracerebroventricular injection of DA (0.5 microgram/rat) increased the number of SS receptors and decreased their apparent affinity in the striatum and hippocampus 15 hr after its administration. The simultaneous administration of the DA receptor antagonists SCH 23390 (0.25 mg/kg, ip) and spiperone (0.1 mg/kg, ip) before DA injection partially prevented the DA-induced increase in SS binding. The administration of SCH 23390 plus spiperone alone produced a significant decrease in the number of SS receptors in both brain areas studied at 15 hr after injection, an effect that disappeared at 24 hr. The increased number of SS receptors in the DA-treated rats was associated with an increased capacity of SS to inhibit basal and forskolin (FK)-stimulated (AC) activity in the striatum and hippocampus at 15 hr after injection. This effect had disappeared at 24 hr. By contrast, basal and FK-stimulated enzyme activities were unaltered after DA injection. No significant changes in the levels of the alpha i (alpha i1 + alpha i2) subunits were found in DA-treated rats as compared with control rats. In addition, the immunodetection of the alpha i1 or alpha i2 subunits showed no significant changes in their levels in DA-treated rats when compared with controls. DA injection also induced an increase in SS-like immunoreactive content in the rat striatum but not hippocampus at 15 hr after administration and returned to control values at 24 hr. These results provide direct evidence of a functional linkage between the dopaminergic and somatostatinergic systems at the molecular level.

Effect of chronic ethanol treatment on dopamine receptor subtypes in rat striatum

Chronic exposure to ethanol (6% in the drinking water, 25 days) reduces the responsiveness of both the dopamine-stimulated and of the dopamine-inhibited adenylate cyclase in rat striatum. The changes in the adenylate cyclase activity are paralleled by alterations in dopamine recognition sites, in fact binding studies using selective ligands indicate that the number of both D 1- and D 2-receptors is reduced in striatal membranes of treated rats.

Ontogenesis of D-1 and opiate receptors coupled to adenylate cyclase in rat striatum

Ontogenesis of D-1 and opiate receptors coupled to adenylate cyclase in rat striatum

Irradiation inactivation studies of the dopamine D1 receptor and dopamine-stimulated adenylate cyclase in rat striatum

In frozen rat striatal tissue, exposed to 10 MeV electrons from a linear accelerator, the sizes of the dopamine (DA) D1 receptor and the DA-sensitive adenylate cyclase complex were determined using target size analysis. The number of D1 receptors (labelled by [3H]SCH 23390) declined monoexponentially with increasing radiation intensity, yielding a molecular weight (mol.wt.) of 80 kDa. Also the activity of the catalytic unit (C) of the adenylate cyclase (as measured by forskolin stimulation), decreased monoexponentially, however with a mol.wt. of 145 kDa. Both basal, DA- and fluoride (F-)-stimulated activity declined in a concave-downward fashion with a limiting mol.wt. of 134, 138 and 228 kDa, respectively. It was estimated that the basal and DA-stimulated activity originated from an enzyme complex with a mol.wt. of 325 kDa, a value close to the combined size of RGs and C. These data suggest that F- stimulation of the adenylate cyclase, which occurs by a Gs activation, does not cause dissociation of Gs into the alpha s and beta gamma subunits. Further, the DA-regulated adenylate cyclase apparently exists as a complex consisting of RGs and C; the mechanism of hormonal activation is a dissociation of C from this complex.

Adenosine modulates the dopaminergic function in the nigro-striatal system by interacting with striatal dopamine dependent adenylate cyclase

Behavioral and pharmacological evidences suggest that dopaminergic mechanisms in striatum might be counteracted by adneosine or potentiated by its pharmacological antagonists methylxanthines. To test whether adenosine modulation of the dopaminergic function could be, at least in part, due to an interaction at the level of the adenylate cyclase complex, we studied the effects of the adenosine analog R-Phenyl-isopropil-adenosine (R-PIA) on basal and dopamine-sensitive adenylate cyclase in rat striatum. R-PIA, which interacts with both adenosine A 1-inhibitory and A 2-stimulatory receptors, dose-dependently inhibited the stimulation induced by dopamine, and seemed to utilize the same pool of enzyme linked to dopaminergic D 1 receptors. Two experimental approaches leading to supersensitivity of striatal dopaminergic receptors, (i.e., 6-hydroxy-dopamine injection in substantia nigra and reserpine administration) also induced upregulation of adenosine-dependent adenylate cyclase in striatum, and altered R-PIA modulation of dopamine-sensitive adenylate cyclase. Conversely, after subchronic treatment with neuroleptics such as haloperidol or sulpiride, upregulation of 3H-Spiroperidol binding in striatum was not associated with changes of R-PIA dependent adenylate cyclase in this area. It is concluded that adenosine might modulate post-synaptic responses to dopamine via adenosine receptors which functionally interact with dopaminergic D 1 receptors in striatum.

Interactions between opiate- and dopamine-induced effects on adenylate cyclase in rat striatum

In rat striatal P2 membrane preparations examined under constant experimental conditions, activation of either D2-dopamine or opiate receptors inhibited basal adenylate cyclase with a similar maximal inhibition of approximately 30%. These inhibitions were not additive. D1 dopamine receptor-mediated activation of adenylate cyclase by SKF38393 was inhibited by morphine in an additive fashion, but the opiate had minimal effects on the net activation of adenylate cyclase by dopamine which activates both D1 and D2 receptors. From these results it would appear that opiate and D1 dopamine receptor-mediated activation of adenylate cyclase summate, but that opiate and D2 dopamine receptors regulate a common pool of adenylate cyclase in striatal membranes.

The dopamine D1 receptor: biochemical and behavioral aspects.

Research on the role of dopamine (DA) in the control of behavior was initiated with the studies by Randrup and colleagues in the early 60’es (e.g., Randrup et al., 1965). However, the direct study of DA receptors began with the discovery in 1972 of DA sensitive adenylate cyclase in rat striatum (Kebabian et al., 1972). In 1975, tritiated haloperidol was introduced as a compound for direct labelling of DA receptors (Creese et al., 1975; Burt et al., 1975; Seeman et al., 1975). Comparing the pharmacological characteristics of DA stimulated adenylate cyclase and 3H-haloperidol binding, it was readily apparent that 3H-haloperidol does not label the same site as the one through which DA exerts its effects on adenylate cyclase. These discrepancies between binding data and functional data, resulted a few years later in the postulated existence by Kebabian and Calne (1979) of two types of DA receptors designated D1 and D2. The D1 receptor was defined by means of its coupling in a stimulatory fashion to the adenylate cyclase while the D2 receptor was associated in an inhibitory fashion to or uncoupled from the same effector system.

Effect of ionol on gastric lesions in rats with immobilization stress

It has been shown in experiments on mice and rats that unlike haloperidol and sulpiride, carbidine does not influence the intensity and even increases the duration of apomorphine stereotypy. However, similarly to haloperidol carbidine decreases head twitches in mice, induced by administration of 5-hydroxytryptophan. In radioligand-binding experiments in vitro and in vivo carbidine displaced 3H-spiperone but in the brain cortex without having any effect on the binding in the striatum. Carbidine did not affect the dopamine-sensitive adenylate cyclase in rat striatum. Based on these data it is suggested that in contrast to haloperidol and sulpiride, carbidine selectively inhibits serotonin receptors of the brain.

Quantitative determination of dopamine receptor subtypes not linked to activation of adenylate cyclase in rat striatum.

The binding of [3H]domperidone and [3H]spiroperidol was examined in membranes prepared from rat striatum. Scatchard analysis of the binding of [3H]domperidone resulted in curvilinear plots consistent with the presence of multiple classes of binding sites. Nonlinear regression analysis of untransformed data showed that the curvature was best explained by the presence of two populations of binding sites. Scatchard plots of the binding of [3H]spiroperidol were linear, suggesting that this radioligand binds to a single class of receptors. However, results obtained in studies of the inhibition of [3H]spiroperidol binding by a number of competing ligands were not consistent with the interaction of these agents with a single class of binding sites. Computer-assisted analysis of the Hofstee plots of six competing ligands gave the same relative proportion for two classes of sites as determined by analysis of the binding of [3H]domperidone. The two classes of receptors labeled with [3H]spiroperidol had affinities for domperidone that were similar to those of the two populations of binding sites for [3H]domperidone. Furthermore, the number of binding sites for [3H]spiroperidol was equal to the total number of binding sites for [3H]domperidone. These findings suggest that the two radioligands bind to the same two classes of binding sites. It is unlikely that either of the two classes of striatal sites are receptors for serotonin. The approach described will make it possible to assess the effects of physiological or pharmacological manipulations on the densities or properties of subtypes of dopamine receptors.

Stimulation of adenylate cyclase in rat striatum by pergolide: Influence of GTP

Pergolide stimulates adenylate cyclase activity in homogenates of rat striatum. In contrast, bromocriptine and lisuride are inactive. GTP enhances the stimulation produced by pergolide and has no effect on the other ergots tested. The stimulation produced by pergolide is inhibited by haloperidol but not by molindone. It is concluded that pergolide acts as an agonist at dopaminergic receptors coupled to adenylate cyclase in rat striatum.

Long-term effect of ovariectomy on dopamine-stimulated adenylate cyclase in rat striatum and nucleus accumbens

The long-term effects on dopamine-sensitive adenylate cyclase of deprivation of gonadal steroids resulting from ovariectomy were studied in extrahypothalamic areas of the brain, i.e. corpus striatum and nucleus accumbens. The results obtained show that in both central nervous system areas dopamine- and apomorphine-stimulated adenylate cyclase were significantly reduced, suggesting that the function of dopamine receptors in these areas was depressed.

Inhibition of dopamine-sensitive adenylate cyclase in rat striatum by neuroleptic drugs administered in vivo.

Journal of NeurochemistryVolume 31, Issue 5 p. 1335-1337 Inhibition of dopamine-sensitive adenylate cyclase in rat striatum by neuroleptic drugs administered in vivo T. Nakahara, T. Nakahara Department of Chemistry. Faculty of Science, Kyushu University. Hakozaki, Fukuoka 812. Japan:Search for more papers by this authorH. Uchimura, H. Uchimura Laboratory of Neurochemistry. Hizen National Mental Hospital. Kanzaki, Saga 842-01. JapanSearch for more papers by this authorM. Saito, M. Saito Laboratory of Neurochemistry. Hizen National Mental Hospital. Kanzaki, Saga 842-01. JapanSearch for more papers by this authorM. Hirano, M. Hirano Laboratory of Neurochemistry. Hizen National Mental Hospital. Kanzaki, Saga 842-01. JapanSearch for more papers by this authorJ. S. Kim, J. S. Kim Laboratory of Neurochemistry. Hizen National Mental Hospital. Kanzaki, Saga 842-01. JapanSearch for more papers by this authorM. Ito, M. Ito Department of Neuropsychiatry, Faculty of Medicine. Kyushu University, Katakasu, Fukuoka 812. JapanSearch for more papers by this author T. Nakahara, T. Nakahara Department of Chemistry. Faculty of Science, Kyushu University. Hakozaki, Fukuoka 812. Japan:Search for more papers by this authorH. Uchimura, H. Uchimura Laboratory of Neurochemistry. Hizen National Mental Hospital. Kanzaki, Saga 842-01. JapanSearch for more papers by this authorM. Saito, M. Saito Laboratory of Neurochemistry. Hizen National Mental Hospital. Kanzaki, Saga 842-01. JapanSearch for more papers by this authorM. Hirano, M. Hirano Laboratory of Neurochemistry. Hizen National Mental Hospital. Kanzaki, Saga 842-01. JapanSearch for more papers by this authorJ. S. Kim, J. S. Kim Laboratory of Neurochemistry. Hizen National Mental Hospital. Kanzaki, Saga 842-01. JapanSearch for more papers by this authorM. Ito, M. Ito Department of Neuropsychiatry, Faculty of Medicine. Kyushu University, Katakasu, Fukuoka 812. JapanSearch for more papers by this author First published: November 1978 https://doi.org/10.1111/j.1471-4159.1978.tb06260.xCitations: 3Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume31, Issue5November 1978Pages 1335-1337 RelatedInformation

The pharmacology of a new potent, long acting neuroleptic, piflutixol.

Piflutixol, 6-fluoro-9-[3-(4-(2-hydroxyethyl)piperidino)propylidene]-2-trifluoromethyl-thioxanthene, has been shown to have pronounced neuroleptic properties. It is a very potent inhibitor of methylphenidate-induced stereotypies in mice, amphetamine and apomorphine-induced stereotypies in rats, apomorphine-induced stereotypies and vomiting in dogs. Furthermore piflutixol causes cataleptic reaction in small doses and inhibits conditioned avoidance reaction in rats. The compound is equally potent orally and parenterally and has a prolonged effect. Piflutixol has up to the present proved to be the most potent inhibitor of dopamine-stimulated adenylate cyclase in rat striatum in vitro. Piflutixol has a stron sedative effect (inhibition of spontaneous motor activity, induction of ptosis and potentiation of barbiturate anaesthesia) and in addition inhibits reticular arousal reaction in very low doses. Thus piflutixol constitutes a unique combination of potent anti-stereotyped activity with potent sedative effects. This means that piflutixol may prove to be a low-dose basic neuroleptic with long duration of action.