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PubMed2004

Inverse agonist properties of atypical antipsychotic drugs.

Mechanisms of action of several atypical antipsychotic drugs have been examined at the D(2) dopamine receptor expressed in CHO cells. The drugs tested were found to exhibit inverse agonist activity at the D(2) dopamine receptor based on their effects to potentiate forskolin-stimulated cyclic AMP (cAMP) accumulation. Each of the antipsychotic drugs tested (clozapine, olanzapine, quetiapine and risperidone) increased cAMP accumulation to the same extent. The increase in cAMP was also similar to that seen with typical antipsychotic drugs. Inverse agonism at the D(2) dopamine receptor seems, therefore, to be a property common to all classes of antipsychotic drugs. The effect of sodium ions on the binding of the drugs to the receptor was also assessed. Each of the atypical antipsychotic drugs tested here bound with higher affinity in the absence of sodium ions. Previous studies have shown that some antipsychotic drugs are insensitive to sodium ions and some bind with higher affinity in the presence of sodium ions. Given that all of these antipsychotic drugs are inverse agonists, it may be concluded that this sodium ion sensitivity is unrelated to mechanisms of inverse agonism.

Animals↗
PubMed1998

Are high-affinity progesterone binding site(s) from porcine liver microsomes members of the sigma receptor family?

Membrane progesterone binding sites have been purified recently from pig liver. Since progesterone is considered as an endogenous sigma (sigma) receptor ligand, these sites were characterized pharmacologically by ligands selective for sigma receptor and dopamine receptor binding sites, and by other drugs from distinct pharmacological classes. Binding studies using the radioligand [3H]progesterone were done in crude membrane preparations and solubilized fractions to determine half-maximal inhibitory concentration (IC50) values, from which inhibitory constants (Ki values) were calculated. Radioligand binding was inhibited by the sigma receptor ligands haloperidol, carbetapentane citrate, 1,3-Di(2-tolyl)guanidine (DTG), R(-)-N-(3-phenyl-1-propyl)-1-phenyl-2 aminopropane HCl (R(-)-PPAAP HCl), or sigma receptor antagonists like (+)-3-(3-hydroxyphenyl)-N-propylpiperidine HCl (R(+)-PPP HCl) and cis-9-[3-(3,5-dimethyl-1-piperazinyl)propyl]-9H-carbazole dihydrochloride (rimcazole 2HCl). The hierarchy of inhibitory action was not fully compatible with either sigma receptor class I (moderate affinity of pentazocine, diphenylhydantoin (phenytoin) insensitivity) or II sites (high affinity of carbetapentane). The data thus suggest that progesterone binding sites in porcine liver membranes are related to the sigma receptor binding site superfamily, but may represent a particular species with progesterone specificity.

Animals↗
PubMed1997

Dual actions of (-)-stepholidine on the dopamine receptor-mediated adenylate cyclase activity in rat corpus striatum.

(-)-Stepholidine (SPD) is an antagonist of normosensitive dopamine (DA) receptors, but it exhibits D1 agonistic action on rotational behaviour in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta (SNC). In the present study, agonistic and antagonistic effects of SPD on the DA receptor-mediated synaptosomal adenylate cyclase (AC) activity in rat striatum were investigated. After blockade of D2 receptors, SPD augmented AC activity dose-dependently. The EC50 value was 41.1 +/- 8.6 micromol/L. At the concentration of 10 micromol/L, SPD increased cAMP formation from a basal level (50.8 +/- 10.3 pmol/mg protein/min) to 133.7 +/- 31.8 pmol/mg protein/min. The SPD-induced stimulation of AC activity was almost completely reversed by 10 micromol/L Sch23390. These results indicate that SPD possesses an agonistic action on the D1 receptor. Forskolin-stimulated adenylate cyclase (FSAC) activity was used as a model to elucidate the effect of SPD on D2 receptors. The results indicate that DA inhibited FSAC activity dose-dependently, while SPD partially restored FSAC activity. Taken together, these results support the conclusion that SPD has dual actions on DA receptors that mediate AC activity, i.e., an agonistic action on D1 receptors and an antagonistic action on D2 receptors.

Adenylyl Cyclase Inhibitors↗
PubMed2000

Modulation of [(35)S]GTPgammaS binding to chinese hamster ovary cell membranes by D(2(short)) dopamine receptors.

Rat dopamine D(2short) expressed in Chinese hamster ovary (CHO) cells were characterized by means of activation of [(35)S]-guanosine 5'-O-(gamma-thiotriphosphate) ([(35)S]GTPgammaS) binding and inhibition of [(3)H]raclopride binding. Among 18 dopaminergic ligands studied dopamine, NPA, apomorphine and quinpirole were full agonists in activation of [(35)S]GTPgammaS binding, while seven ligands were partial agonists with efficacies from 16 to 69% of the effect of dopamine and seven ligands were antagonists having no effect on the basal level of [(35)S]GTPgammaS binding, but inhibited dopamine-dependent activation in a dose-response manner. Despite the different efficacies, the potencies of all 18 ligands to modulate [(35)S]GTPgammaS binding revealed a good correlation with their potencies to inhibit [(3)H]raclopride binding in the CHO cell membranes. This indicates that the binding of the ligand to the receptor determines its potency, but has no direct correlation with its intrinsic activity.

Animals↗
PubMed1980

Dopaminergic stimulation of prolactin release.

Prolactin (PRL) secretion from anterior pituitary is believed to be under tonic inhibitory control of dopamine (DA) released from the tubero-infundibular dopaminergic neurones into the hypophysial portal blood. Inhibition of PRL release by DA seems to be mediated by sereospecific DA receptors located in PRL cells. Apomorphine and various ergot alkaloids such as bromocryptine mimic the inhibitory effect of DA both in vivo and in vitro, presumably by a direct agonist action on these 'inhibitory' receptors. We now report that PRL secretion in primary cultures of rat pituitary cells can be stimulated by DA when concentrations a thousand times lower than those required for inhibition are used. Secretion rates above basal release can also be induced by apomorphine and bromocryptine when the 'inhibitory' receptors are blocked with certain DA receptor antagonists.

Animals↗
PubMed1994

Distribution of D1- and D2-dopamine receptors, and dopamine and its metabolites in the human brain.

Densities and distribution of D1-dopamine and D2-dopamine receptors were investigated in vitro using [3H]SCH 23390 and [3H]raclopride in receptor binding assays and autoradiography on human post mortem whole hemisphere slices to serve as anatomical correlates to PET studies using [11C]SCH 23390 and [11C]raclopride. In addition, the levels of dopamine and its metabolites were determined by HPLC in various brain regions. Both dopamine receptor subtypes, as well as dopamine, HVA and DOPAC, were primarily found in the basal ganglia. Very high densities of D1-dopamine receptors were found particularly in the medial caudate nucleus, whereas D2-dopamine receptors were evenly distributed throughout the caudate. The densities of D1- and D2-dopamine receptors were similar in the caudate nucleus and the putamen, whereas there were 4 to 7 times higher densities of the D1- than of the D2-dopamine receptors in several limbic and neocortical regions. The receptor distribution in the autoradiographic study was consistent with that demonstrated in the living human brain using [11C]SCH 23390 and [11C]raclopride.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2001

Mechanisms of inverse agonism of antipsychotic drugs at the D(2) dopamine receptor: use of a mutant D(2) dopamine receptor that adopts the activated conformation.

The antipsychotic drugs have been shown to be inverse agonists at the D(2) dopamine receptor. We have examined the mechanism of this inverse agonism by making mutations in residue T343 in the base of the sixth transmembrane spanning region of the receptor. T343R, T343S and T343K mutant D(2) dopamine receptors were made and the T343R mutant characterized in detail. The T343R mutant D(2) dopamine receptor exhibits properties of a receptor that resides more in the activated state, namely increased agonist binding affinity (independent of G-protein coupling and dependent on agonist efficacy), increased agonist potency in functional tests (adenylyl cyclase inhibition) and increased inverse agonist effects. The binding of agonists to the mutant receptor also shows sensitivity to sodium ions, unlike the native receptor, so that isomerization of the receptor to its inactive state may be driven by sodium ions. The binding of inverse agonists to the receptor is, however, unaffected by the mutation. We conclude that inverse agonism at this receptor is not achieved by the inverse agonist binding preferentially to the non-activated state of the receptor over the activated state. Rather the inverse agonist appears to bind to all forms of the receptor but then renders the receptor inactive.

1-Methyl-3-isobutylxanthine↗
PubMed1978

Multiple receptors for brain dopamine.

This study was done to obtain direct in vitro evidence for the possible existence of more than one type of dopaminergic binding site in homogenates of the caudate nucleus from calf brain. Five radioligands for dopaminergic sites were tested. The inhibitions of two agonist radioligands ([3H]dopamine, [3H]apomorphine) by haloperidol, chlorpromazine, or piflutixol were biphasic. The inhibitions of [3H]haloperidol, [3H]spiroperidol, and [3H]dihydroergocryptine binding by dopamine and (-)-norepinephrine were also biphasic. Thus, both 3H-labeled agonists and 3H-labeled antagonists were possibly binding to two high-affinity sites.

Animals↗
PubMed1981

Dopaminergic modulation of adenylate cyclase stimulation by vasoactive intestinal peptide in anterior pituitary.

The activation of adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] by vasoactive intestinal peptide (VIP) was used as a model to investigate the molecular mechanisms triggered by the occupancy of dopamine recognition sites in rat anterior pituitary. Dopamine failed to change the basal enzyme activity, but it inhibited the stimulation of adenylate cyclase elicited by VIP. Apomorphine, 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene, and 2-bromo-alpha-ergocryptine mimicked the effect of dopamine, whereas (-)-sulpiride and and classical neuroleptics antagonized it. Dopamine failed to modulate the activation of pituitary adenylate cyclase by prostaglandin E1, which does not increase prolactin secretion. From these results we infer that stimulation of D-2 (dopamine) receptors may affect pituitary secretion by inhibiting the activation of anterior pituitary adenylate cyclase by VIP or other secretagogues.

Adenylyl Cyclases↗
PubMed1981

Dopamine receptor binding in inbred mice: strain differences in mesolimbic and nigrostriatal dopamine binding sites.

Dopamine receptors were examined by Scatchard analysis in the striatal and olfactory tubercle regions of 11 inbred mouse strains. Simultaneous determinations of the binding characteristics of 3H-labeled 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (ADTN), a dopaminergic agonist, and [3H]spiroperidol, a dopaminergic antagonist, were examined. Among the 11 strains, the equilibrium dissociation constant (Kd) for agonist binding did not vary in either the striatum or the olfactory tubercle. Similarly, no strain differences were observed in the Kd for spiroperidol in either region, although the Kd for spiroperidol in the olfactory tubercle was uniformly higher than that in the striatum. Measurement of receptor concentrations revealed strain differences of up to 2-fold for both [3H]ADTN and [3H]spiroperidol binding sites. Within each brain region, the densities of agonist and antagonist binding sites correlated significantly. However, between brain regions there was no correlation in the density of agonist or antagonist binding sites, which suggests that mesolimbic and nigrostriatal dopamine neurons may be under independent genetic control. Analysis of [3H]spiroperidol displacement by clofluperol, aceperone, cinanserin, and mianserin in four inbred mouse strains revealed that 88-90% of the striatal spiroperidol sites are dopaminergic, with the remainder being serotonergic. In contrast, 53-66% of the olfactory tubercle [3H]spiroperidol binding sites are dopaminergic and 34-47% are serotonergic. These data suggest that genetic differences in serotonin receptors and dopamine receptors may exist among inbred mouse strains.

Animals↗
PubMed1989

Direct visualization and cellular localization of D1 and D2 dopamine receptors in rat forebrain by use of fluorescent ligands.

The regional and cellular localization of the two subtypes of dopamine receptors, D1 and D2, have been ascertained in rat forebrain by use of fluorescent dopaminergic antagonist ligands. (R,S)-5-(4'-aminophenyl)-8-chloro-2,3,4,5-tetrahydro-3- methyl-[1H]-3-benzazepin-7-ol, the 4'-amino derivative of the high-affinity D1-specific antagonist SCH 23390, and the D2 selective antagonist N-(p-aminophenethyl)spiperone were chemically derivatized using the fluorescent compound tetramethylrhodamine. The modification of these antagonist ligands has allowed the specific, cellular resolution of the D1 and D2 receptor binding sites in intact, highly organized regions of forebrain slices in a very rapid experimental time frame. The regional localization of receptors labeled by the fluorescent probes is in agreement with previous receptor autoradiography studies. Moreover, the specific cellular binding patterns for both receptors can now be compared and contrasted to one another in the same tissue by using these fluorescent ligands. D1 receptor sites are most evident within the striatum and exhibit regions of intense "patch" fluorescence corresponding to receptor reactivity in cells and their processes. The distribution of D1 receptor binding is highly analogous to the pattern of dopamine terminal histofluorescence in the caudate nucleus. D2 receptor sites are less prevalent overall and may be localized to a subpopulation of the D1 fluorescent neurons in the caudate nucleus and nucleus accumbens regions.

Animals↗
PubMed1996

Silencing of the constitutive activity of the dopamine D1B receptor. Reciprocal mutations between D1 receptor subtypes delineate residues underlying activation properties.

Recently, we have shown that the dopamine D1B/D5 receptor displays binding and coupling properties that are reminiscent of those of the constitutively activated G protein-coupled receptors when compared with the related D1A/D1 receptor subtype (Tiberi, M., and Caron, M. G. (1994) J. Biol. Chem. 269, 27925-27931). The carboxyl-terminal region of the third cytoplasmic loop of several G protein-coupled receptors has been demonstrated to be important for the regulation of the equilibrium between inactive and active receptor conformations. In this cytoplasmic region, the primary structure of dopamine D1A and D1B receptors differs by only two residues: Phe264/Arg266 are present in D1A receptor compared with Ile288/Lys290 in the D1B receptor. To investigate whether these structural differences could account for the distinct binding and coupling properties of these dopamine receptor subtypes, we swapped the variant residues located in the carboxyl-terminal region by site-directed mutagenesis. The exchange of the D1A receptor residue Phe264 by the D1B receptor counterpart isoleucine led to a D1A receptor mutant exhibiting D1B-like constitutive properties. In contrast, substitution of D1B receptor Ile288 by the D1A receptor counterpart phenylalanine resulted in a loss of constitutive activation of the D1B receptor with binding and coupling properties similar to the D1A receptor. The Arg/Lys substitution had no effect on the function of either receptor. These results demonstrate that the carboxyl-terminal region, and in particular residue Ile288, is a major determinant of the constitutive activity of the dopamine D1B receptor. Moreover, these results establish that not only can agonist-independent activity of a receptor be induced, but when given the appropriate mutation, it can be reversed or silenced.

Adenylyl Cyclases↗
PubMed1991

Olfactory bulb DA receptors may be located on terminals of the olfactory nerve.

The glomerular layer of the olfactory bulb contains a substantial population of dopaminergic neurons. We determined the quantity and location of D1 and D2 dopamine receptors which are the presumed targets of these neurons. Binding of the D1 selective ligand [3H]SCH23390 was slightly above background and was distributed through all layers of the bulb except the olfactory nerve layer. In contrast there were relatively high levels of [3H]spiperone binding to D2 DA receptors in the glomerular and olfactory nerve layers. The presence of relatively high concentrations of D2 DA receptors in both the nerve layer and glomerular layer suggests the novel hypothesis that these receptors may be localized on terminals of the olfactory nerve.

Animals↗