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PubMed1984

Mapping brain neuroleptic receptors in the live baboon.

An experimental strategy for external detection of specific neuroleptic receptors in living brain using positron emission transaxial tomography (PETT) and [11C]spiroperidol was applied to the mapping of brain neuroleptic receptors in the live baboon. A double injection of [11C]spiroperidol with an intervening time interval for carbon-11 decay and an intervening dose of (+)-butaclamol to block specific neuroleptic receptors produced two sets of PETT scans which were subtracted to produce a three-dimensional map of relative regional binding of neuroleptic receptors in the baboon brain. Sixty-five percent of the total radioactivity in the striatum was bound to neuroleptic receptors at 65 min after injection.

Animals↗
PubMed1981

Antipsychotic drug effects on dopamine and serotonin receptors: in vitro binding and in vivo turnover studies.

The stereospecific binding sites of [3H]spiroperidol in frontal cortical regions of the rat brain have a higher affinity for serotonin than they do for dopamine, although the reverse relative affinity is observed in the caudate nucleus and in mesolimbic regions. The antipsychotic butyrophenones haloperidol and butaclamol compete with comparably high affinities for [3H]spiroperidol binding sites in all of the above brain regions. Both butyrophenones accelerated dopamine turnover in these three brain regions without altering serotonin turnover. A chronic treatment regimen with fluphenazine which induced tolerance to the metabolic effects of haloperidol in all three brain regions also induced tolerance to its behavioral effects. The number of binding sites of [3H]spiroperidol were increased in the caudate nucleus and mesolimbic regions but not in the frontal cortex of tolerant animals. These results are consistent with the hypothesis that [3H]spiroperidol interacts with a serotonergic site in the frontal cortex. However, the in vitro interaction of antipsychotic drugs with this receptor does not seem to be related to their acute or chronic effects on neurotransmitter function in the frontal cortex in vivo.

Animals↗
PubMed1982

Buspirone: chemical profile of a new class of anxioselective agents.

Buspirone is a lipophilic, dibasic heterocyclic with no structural resemblance to other anxiolytic or antipsychotic agents. Neurochemical binding studies suggest that buspirone has both dopamine agonist and antagonist properties. Structural comparisons with (+)-butaclamol indicate that buspirone possesses features required for binding at the postsynaptic dopamine receptor site. This is consonant with the drug's biologic properties, but does not define a mechanism for its anxioselective action. The transient antipsychotic effect associated with peak blood levels of buspirone in rats was consistent with such an effect, predicted by [3H]spiperone binding studies. The low (20 mg) anxioselective dose, acting in concert with extensive metabolism in humans, produces low blood levels of the parent drug, suggesting that buspirone's effect is exerted through interactions with a high-affinity, low-threshold receptor system.

Animals↗
PubMed1978

Yohimbine-induced stimulus control in the rat.

Rats were first trained in a 2-lever operant test chamber using a fixed ratio 10 schedule of water reinforcement. Discrimination training was then begun. In sessions following the injection (i.p.) of yohimbine . HC1 (3 mg/kg), responses on 1 of the 2 levers were reinforced. In sessions following the injection of saline, responses on the remaining lever were reinforced. The distribution of responses between the 2 levers prior to reinforcement provided an index of discrimination. The criterion for stimulus control was set at 80% correct responses in each of five consecutive sessions. In a group of six rats, criterion performance was begun after a mean of 33 sessions. Cross tests were conducted in yohimbine-trained subjects with d-amphetamine, harmaline, and LSD. Each test drug yielded intermediate results, i.e., response distribution was significantly different from both the yohimbine and the saline training conditions. No significant antagonism of yohimbine-induced stimulus control was achieved with BC-105, phentolamine, or butaclamol, purported antagonists at serotonergic, alpha-adrenergic, and dopaminergic receptor sites, respectively.

Animals↗
PubMed1994

The sigma receptor ligand (+/-)-BMY 14802 prevents methamphetamine-induced dopaminergic neurotoxicity via interactions at dopamine receptors.

The possibility that compounds which interact with the putative sigma receptor might influence the dopaminergic neuropathology produced by the administration of methamphetamine (METH) to mice was investigated. (+/-)-BMY 14802 [alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanol hydrochloride] attenuated METH-induced dopaminergic neuropathology whereas several other sigma-acting compounds such as R-(+)-3-(3-hydroxyphenyl)-N-propylpiperidine hydrochloride, 1,3-di-o-tolyl-guanidine, rimcazole, clorgyline or (-)-butaclamol did not alter neurotoxicity produced by this central nervous system stimulant. (-)-BMY 14802, which has a lower affinity for the sigma site than (+)-BMY 14802, was more potent than (+)-BMY 14802 in antagonizing METH-induced neuropathology. In addition, the ketone metabolite (BMY 14786; alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanone hydrochloride), which is a major metabolite formed from (-)-BMY 14802, also attenuated the METH-induced effects. (+/-)-BMY 14802 pretreatment of mice prevented the reduction in D1 and D2 dopamine receptor number produced by the systemic administration of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline and demonstrates that (+/-)-BMY 14802 and/or its metabolites interact with the dopamine receptor subtypes. Taken together, these findings suggest that the protective effect of (+/-)-BMY 14802 against METH-induced neuropathology is mediated, at least in part, through dopamine receptor antagonism. Furthermore, the failure of other sigma-acting compounds to alter METH-induced neurotoxicity indicates that the putative sigma receptor is unlikely to be an important mediator in this type of neuropathology.

Animals↗
PubMed1997

Agonist-induced morphologic decrease in cellular D1A dopamine receptor staining.

The distribution of D1A dopamine (DA) receptor proteins was assessed by using subtype specific antireceptor antisera after acute DA exposure. The immunofluorescent staining of D1A DA receptor protein expression was examined in (1) stably transfected Chinese hamster ovary (CHO) cells, (2) primary striatal cell cultures, and (3) rat striatal brain slices. After agonist exposure as brief as 2 min and as long as 60 min, profound loss of immunofluorescent D1A receptor protein staining occurred in each paradigm. Additionally in the tissue slice, immunofluorescent neuropil staining for the receptor protein also was attenuated. The DA-induced alteration in receptor protein staining was blocked by the antagonist (+)-butaclamol and by the selective D1-family antagonist SCH 23390. Receptor staining patterns reverted back to the control immunofluorescent distribution within 15 min after removing the agonist from the bath. Immunofluorescence for the second-messenger cyclic AMP increased at all DA exposure times in the three experimental paradigms, was blocked by D1-family antagonists, and decreased to basal staining after brief recovery periods. This demonstrated the functional integrity of the D1A receptor in target cells. Pretreatment with the mitogenic plant lectin concanavalin A blocked the immunofluorescent decrease in receptor staining but not the elevation of the second messenger, indicating a morphologic distinction in these two events, parallel to other biochemical reports. The data suggested that a morphologic basis of acute homologous D1A DA receptor desensitization may be transposition of membrane-surface receptors to a transiently unavailable, intracellular compartment. This finding is supported by specific fluorescence incorporation of FM1-43, used as a marker of endocytosis, in CHO cells treated with DA.

Animals↗
PubMed2001

Dopamine interacts directly with its D3 and D2 receptors on normal human T cells, and activates beta1 integrin function.

Dopamine by itself has not up to now been reported to activate T cell function. We show here that dopamine interacts directly with dopaminergic receptors on normal human T cells and triggers beta1 integrin-mediated T cell adhesion to a major extracellular matrix component, fibronectin (FN). Such adhesion is a characteristic feature of activated T cells, and is critical for trafficking and extravasation of T cells across blood vessels and tissue barriers. Seven dopamine D2/D3 receptor agonists and antagonists were used to identify the receptor subtypes with which dopamine specifically interacts to activate T cells. The D3 dopamine receptor agonist, 7-hydroxy-DPAT (DPAT), mimics the effects of dopamine, and the effects of both dopamine and DPAT are blocked by a specific D3 receptor antagonist, U-maleate. The dopamine receptor agonists bromocriptine and pergolide mimic the direct effect of dopamine on the beta1 integrin function, while the dopamine receptor antagonists butaclamol and haloperidol suppress it, suggesting additional signaling via the dopamine D2 receptor subtype. Our study shows, for the first time, that dopamine can directly activate T cells via ist specific receptors and suggests a possible role for dopamine in integrin-mediated cellular trafficking and extravasation of T cells in the central nervous system and possibly also in the periphery. Finally, we suggest that the reported changes in the D3 and D2 receptor RNA levels in peripheral blood lymphocytes of individuals with schizophrenia, Parkinson's disease, Alzheimer's disease and migraine can serve not only as a 'passive' diagnostic marker, but primarily reflect the dynamic functional dopamine-T cell interactions in these diseases.

Cell Adhesion↗
PubMed2005

Competitive MS binding assays for dopamine D2 receptors employing spiperone as a native marker.

A competitive MS binding assay employing spiperone as a native marker and a porcine striatal membrane fraction as a source for dopamine D2 receptors in a nonvolatile buffer has been established. Binding of the test compounds to the target was monitored by mass-spectrometric quantification of the nonbound marker, spiperone, in the supernatant of the binding samples obtained by centrifugation. A solid-phase extraction procedure was used for separating spiperone from ESI-MS-incompatible supernatant matrix components. Subsequently, the marker was reliably quantified by LC-ESI-MS-MS by using haloperidol as an internal standard. The affinities of the test compounds, the dopamine receptor antagonists (+)-butaclamol, chlorpromazine and (S)-sulpiride obtained from the competitive MS binding assay were verified by corresponding radioligand binding experiments with [3H]spiperone. The results of this study demonstrate that competitive MS binding assays represent a universally applicable alternative to conventional radioligand binding assays.

Animals↗
PubMed2004

Modulation of adenyl cyclase activity in the gills of Tapes philippinarum.

Adenyl cyclase (AC) plays a pivotal role in cell signaling. The AC system of bivalves has received little attention so far, and our study has been addressed to the characterization of AC properties in the gills of T. philippinarum. The enzyme showed a Km value of 0.77 mM for ATP in the presence of 5 mM Mg2+; in the absence of agonists, it was poorly affected by GTP, while it was stimulated by GTPgammaS and GppNHp up to 14-fold and 4-fold, respectively. Similarly to other invertebrates, the enzyme activity was scarcely stimulated by forskolin. The receptor agonist serotonin (5-HT) significantly stimulated the AC activity, and the pharmacological profile of the 5-HT receptor/s was as follows: (+)butaclamol > dihydroergocryptine > methysergide > prazosin > yohimbine. The AC activity was assessed in vitro in the presence of tributyltin chloride and HgCl2, which reduced the AC activity only at the highest dose tested (10-100 microM). Our data indicate the presence of a membrane-bound AC in gill membranes of T. philippinarum, coupled to Gs proteins and to a specific class of 5-HT receptors. Such receptors show a pharmacological profile slightly different from that reported for 5-HT invertebrate receptors cloned so far.

Adenylyl Cyclases↗
PubMed1983

[3H]spiperone binding sites in rat primary glial cultures, C6 glioma, and B104 neuroblastoma.

Binding sites for [3H]spiperone were detected on membranes from primary glial cultures from neonatal rat cortex and striatum and from the C6 glioma cells. [3H]Spiperone binding was displaceable by d-butaclamol. However, competition studies suggest that [3H]spiperone binding to primary glial cultures was mainly to serotonergic sites, and binding to the C6 glioma was alpha-adrenergic. No specific binding was detected to membranes from B104 neuroblastoma cells. Although [3H]spiperone binding to glial sites on whole striatum under generally used conditions is small (about 10%), the striatal glial hyperactivity that is often associated with neuronal degeneration could lead to an overestimation of presumed neuronal binding sites for dopaminergic ligands.

Animals↗
PubMed1987

Dopamine receptors and the dopamine hypothesis of schizophrenia.

The discovery of neuroleptic drugs in 1952 provided a new strategy for seeking a biological basis of schizophrenia. This entailed a search for a primary site of neuroleptic action. The Parkinsonian effects caused by neuroleptics suggested that dopamine transmission may be disrupted by these drugs. In 1963 it was proposed that neuroleptics blocked "monoamine receptors" or impeded the release of monoamine metabolites. The neuroleptic concentration in plasma water or cerebrospinal fluid was of the order of 2 nM for haloperidol in clinical therapy. A systematic research was made between 1963 and 1974 for a primary site of neuroleptic action which would be sensitive to 2 nM haloperidol and stereoselective for (+)-butaclamol. Direct evidence that neuroleptics selectively blocked dopamine receptors occurred in 1974 with the finding that nanomolar concentrations of these drugs stereoselectively inhibited the binding of [3H]-dopamine or [3H]-haloperidol. These binding sites, now termed D2 dopamine receptors (which inhibit adenylate cyclase), are blocked by neuroleptics in direct relation to the antipsychotic potencies of the neuroleptics. No such correlation exists for D1 receptors (which stimulate adenylate cyclase). Based on the fact that dopamine-mimetic drugs elicited hallucinations, and that neuroleptics caused rigidity, Van Rossum in 1966 had suggested a hypothesis that dopamine pathways may be overactive in schizophrenia. The D2-selective blockade by all neuroleptics (except the monoamine-depleting reserpine) provided strong support for the dopamine hypothesis. Further support now comes from postmortem data and in vivo positron tomographic data, both of which indicate that the density of D2 receptors are elevated in the schizophrenic brain. The postmortem data indicate a bimodal pattern with half the schizophrenics having striatal D2 densities of 14 pmol/g (control is 13 pmol/g) and the other half having 26 pmol/g. Current positron tomographic data indicate D2 densities of 14 pmol/g in control subjects, but values of 34 pmol/g in drug-naive schizophrenics. Future tests of the dopamine hypothesis of schizophrenia may entail an examination of the amino acid composition and genes for D2 receptors in schizophrenic tissue, an examination of the ability of the D2 receptor to become phosphorylated and to desensitize into the low-affinity state, and an examination of the interaction of D2 receptors with D1 receptors or other neurotransmitters.

Antipsychotic Agents↗
PubMed1992

Acute effects of sigma ligands on the electrophysiological activity of rat nigrostriatal and mesoaccumbal dopaminergic neurons.

The effects of acute i.v. administration of several sigma ligands on the single-unit activity of nigrostriatal and mesoaccumbal dopaminergic (DA) neurons were evaluated in chloral hydrate-anesthetized rats. DTG (1,3-di(o-tolyl)guanidine) did not alter DA neuronal activity at nontoxic doses and JO 1784 [(+)-N-cyclopropylmethyl-N-methyl-1,4-diphenyl-1-ethylbut-3-en-1-+ ++ylamine] was inactive. (+)-Pentazocine was more effective in increasing mesoaccumbal vs. nigrostriatal DA cell firing rates. BMY 14802(alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-but anol) dose-dependently increased DA cell firing rate in both populations. The inhibition of nigrostriatal DA cell firing rate by (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [(+)-3-PPP] was reversed by (-)-eticlopride and (+)-but not (-)-butaclamol, which supports previous evidence that (+)-3-PPP-induced inhibition is due to the DA agonist properties of the drug. From what is known of the pharmacological properties of these compounds, it is concluded that acute sigma receptor occupation does not markedly alter the firing rate of DA neurons. The dose-response curve for inhibition of nigrostriatal DA neuronal activity by the D2 DA agonist, quinpirole, was shifted to the right tenfold by BMY 14802 pretreatment (8 mg/kg, i.v.) and twofold by (+)-pentazocine (8 mg/kg, i.v.), but was not changed by DTG (2 mg/kg, i.v.). It is concluded that the marked effects of certain sigma ligands on DA cell electrophysiology are likely due to their non-sigma properties.

Animals↗
PubMed1988

3- and 4-O-sulfoconjugated and methylated dopamine: highly reduced binding affinity to dopamine D2 receptors in rat striatal membranes.

The binding properties of 3- and 4-O-sulfo-conjugated dopamine (DA-3-O-S, DA-4-O-S) as well as 3-O-methylated dopamine (MT) to rat striatal dopamine D2 receptors were investigated. 3H-spiperone was used as a radioligand in the binding studies. In saturation binding experiments (+)butaclamol, which has been reported to bind to dopaminergic D2 and serotoninergic 5HT2 receptors, was used in conjunction with ketanserin and sulpiride, which preferentially label 5HT2 and D2 receptors, respectively, in order to discriminate between 3H-spiperone binding to D2 and to 5HT2 receptors. Under our particular membrane preparation and assay conditions, 3H-spiperone binds to D2 and 5HT2 receptors with a maximal binding capacity (Bmax) of 340 fmol/mg protein in proportions of about 75%:25% with similar dissociation constants KD (35 pmol/l; 43 pmol/l). This result was verified by the biphasic competition curve of ketanserin, which revealed about 20% high (KD = 24 nmol/l) and 80% low (KD = 420 nmol/l) affinity binding sites corresponding to 5HT2 and D2 receptors, respectively. Therefore, all further competition experiments at a tracer concentration of 50 pmol/l were performed in the presence of 0.1 mumol/l ketanserin to mask the 5HT2 receptors. DA competition curves were best fitted assuming two binding sites, with high (KH = 0.12 mumol/l) and low (KL = 18 mumol/l) affinity, present in a ratio of 3:1. The high affinity binding sites were interconvertible by 100 mumol/l guanyl-5-yl imidodiphosphate [Gpp(NH)p], resulting in a homogenous affinity state of DA receptors (KD = 2.8 mumol/l).2+ off

Animals↗
PubMed1987

Further in vitro and in vivo studies with the putative presynaptic dopamine agonist N,N-dipropyl-7-hydroxy-2-aminotetralin.

The in vitro binding of the putative dopamine autoreceptor agonist [3H]DP-7-ATN to rat striatal membrane homogenates was investigated. The maximum number of binding sites Bmax was 497.5 +/- 50.2 fmol/mg protein and the affinity constant KD was 8.3 +/- 1.5 nM using 10 microM (+) butaclamol to define non-specific binding. Lesion of the left medium forebrain bundle by 6-hydroxydopamine resulted in an almost complete loss of dopamine in the striatum but did not affect the binding of [3H]DP-7-ATN. The binding of [3H]DP-7-ATN to the homogenates of the dopaminergic cell bodies in the substantia nigra revealed a Bmax of 542.4 +/- 40.1 fmol/mg protein and a KD of 11.1 +/- 1.3 nM. The pharmacological profile of the binding was characterized as being to D-2 receptors. No direct in vitro evidence could be found for a selective binding to DA autoreceptors. The dopamine uptake inhibitor GBR 12909 interacted in a noncompetitive manner with the in vitro binding of [3H]DP-7-ATN and the latter compounds uptake into isolated synaptosomes was not through the specific dopamine uptake system but rather through diffusion. GBR 12909 failed to reveal any agonistic or antagonistic activity in the GBL model but was able to antagonize the hypomotility in rats induced by 0.25 mg/kg DP-7-ATN. The inhibitory effect of DP-7-ATN on DA release was also demonstrated using in vivo brain dialysis in conscious rats. Based on the above results, the possibility is discussed that the release regulating DA autoreceptors, which might be coupled to the reuptake complex, and the DA biosynthesis regulating autoreceptors, are different entities.

4-Butyrolactone↗
PubMed1986

Response decrement patterns after neuroleptic and non-neuroleptic drugs.

Previous work has shown that administration of pimozide and other neuroleptic drugs can produce within-session response decrement patterns of appetitively-reinforced behaviour. This phenomenon has been described as an extinction-like pattern of responding and used as evidence for the hypothesis that these drugs attenuate the rewarding properties of food, water and electrical stimulation of the brain. The present study was carried out to investigate within-session patterns of responding maintained by food presentation or shock avoidance after administration of a variety of neuroleptic and non-neuroleptic drugs. Haloperidol, metoclopramide, pimozide and butaclamol produced within-session response decrements of both food-reinforced lever pressing and one-way shock avoidance. The atypical antipsychotic drug clozapine did not consistently produce similar effects nor did the alpha-adrenoceptor agonist clonidine, the opiate agonist morphine, the benzodiazepine anxiolytic chlordiazepoxide and the muscle relaxant methocarbamol, although all these drugs were tested up to doses which markedly disrupted responding. Thus, within-session response decrement patterns are a characteristic effect of dopamine-blocking neuroleptic drugs. However, because of the generally similar effects of these drugs on appetitively- and aversively-motivated behaviour, these effects are probably best interpreted as actions on motor, rather than motivational, mechanisms.

Animals↗
PubMed1981

The stimulus properties of gamma-hydroxybutyrate.

Fourteen rats were trained to discriminate the effects of gamma-hydroxybutyrate (GHB) (sodium salt, 200 mg/kg) and saline in a two-lever choice task using a fixed ratio 10 schedule of water reinforcement. Intermediate responding, i.e., responding not fully appropriate for either training condition was observed in tests following morphine, lysergic acid diethylamide, chlordiazepoxide, and the presumed GABA-mimetics muscimol, gamma-butyrolactone, baclofen, and 3-aminopropane sulfonic acid. Naloxone blocked the intermediate results following morphine, but had no effect on GBH-induced stimulus control. The GABA antagonist bicuculline partially blocked GHB, but pizotyline, phentolamine, and butaclamol were without effect. It is concluded that the compound stimulus produced by GHB is most closely associated with GABAergic systems, but that minor opiate and serotonergic components are present as well.

Animals↗
PubMed1980

Supersensitivity to apomorphine in experimentally induced hypokinesia and drug-induced modifications of the apomorphine response.

The development and degree of supersensitivity to the locomotor stimulant effect of apomorphine were studied in rats which had been rendered hypokinetic by bilateral injections of 6-hydroxydopamine into the anterolateral hypothalamus. Up to 2 days after surgery the effect of apomorphine was comparable in lesioned and normal rats, indicating that dopaminergic supersensitivity did not develop over this short period. As the duration between the 6-hydroxydopamine injections and time of testing with apomorphine increased, the animals became progressively more sensitive to the stimulant effects of apomorphine. Pretreatment with butaclamol reduced the effect of apomorphine in a dose-dependent manner. A high dose of clozapine also antagonized the effect of apomorphine, but a low dose potentiated it. No inhibition was observed following administration of the alpha-adrenergic antagonist, phenoxybenzamine, or the beta-adrenergic antagonist, propranolol. The 5HT antagonist methysergide and the anticholinergic drug, scopolamine potentiated the effects of apomorphine.l These studies suggest that the apomorphine-induced ambulation in hypokinetic rats is primarily mediated through dopaminergic mechanisms but both serotonergic and cholinergic mechanisms exert modulating influences.

Animals↗
PubMed1981

Binding of antiparkinsonian ergot derivatives to the dopamine receptor.

The effects of bromocriptine, lisuride and apomorphine on specific binding of 3H-spiroperidol to homogenates of rat caudate nucleus were studied. (+)-Butaclamol was used to define specific binding. Bromocriptine and lisuride inhibited binding markedly, in vitro and also 30 min after in vivo injection. Bromocriptine continued to inhibit binding 24h after a single injection and also after 4 days of drug administration. Lisuride did not affect net specific binding at these periods. Apomorphine produced a mild reduction in binding after 30 min but none after 4 days. It appears that the ergot alkaloids inhibit binding of 3H-spiroperidol by binding strongly to the dopamine receptor.

Animals↗