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PubMed1998

Behavioural pharmacology of dopamine, serotonin and putative aminergic ligands in the mushroom bodies of the honeybee (Apis mellifera).

The proboscis extension response (PER) which can be elicited in bees by stimulating one antenna with water vapour, was used to quantify the effects of dopamine, serotonin (5-HT) and putative receptor ligands in the mushroom body of the bee. The drugs were microinjected into the alpha-lobe of the mushroom body in one brain hemisphere. Injection of dopamine reduces the water vapour-elicited PER significantly. The effects of dopamine are limited to the treated side. Injection of 5-HT has similar effects to dopamine. The effects of 5-HT are apparent on the treated and partly also on the contralateral side. Significant effects for dopamine on the treated side were found when the concentration in the injected drop was 10(-7) M. For 5-HT significant effects on the treated side were apparent for concentrations of 10(-8) M. Putative dopamine and 5-HT receptor ligands were injected alone and coinjected with the amines. Two ligands with dopamine-antagonistic effects were found: buspirone > spiperone, while lisuride, sulpiride, chlorpromazine, SCH 23390, butaclamol and haloperidol had no dopamine-antagonistic effects. All tested putative 5-HT receptor ligands had significant 5-HT-antagonistic effects: butaclamol > methysergide > lisuride > cyproheptadine > SCH 23390. Good correlations between the behavioural data and in vitro radioligand binding studies were found for 5-HT receptor ligands, while there exist only partial correlations for dopamine receptor ligands.

Animals↗
PubMed1999

Specific binding of 3H-spiperone to peripheral blood cells: relevance for the interpretation of binding studies in psychiatric disorders.

1. There is an ongoing discussion regarding the elevated binding of 3H-spiperone to lymphocytes of schizophrenic patients. Several authors described an atypical binding pattern with a saturable high-affinity and a nonsaturable binding site both displaceable by (+)-butaclamol. Recent findings are still controversial (Fartacek et al., 1997; Wodarz et al., 1996), possibly due to methodological differences. The authors investigated 3H-spiperone binding to different peripheral blood cells including B- and T-lymphoblastoids. 2. B-lymphocytes (KD = 0.081 nM; Bmax = 0.46 x 10(-15) mol/10(6) cells) and macrophages (KD = 0.1-1 nM, Bmax = 2.44 x 10(-15) mol/10(6) cells) are characterized by a minor but saturable binding of 3H-spiperone in a concentration range between 0.5 and 1 nM. Above 1 nM, only non-saturable binding was measurable. Interestingly, Epstein-Barr virus (EBV) transformed lymphoblastoids (KD = 0.13 nM) have nearly the same affinity for 3H-spiperone as native B-cells, but an increased number of binding sites (Bmax = 1.76 x 10(-15) mol/10(6) cells). 3. Membranes from B-lymphoblastoids displayed a saturable binding in a concentration between 0 and 1.8 nM of 3H-spiperone (KD = 0.5 nM and Bmax = 1.72 x 10(-15) mol/mg protein). Extraction with 1% digitonin resulted in a similar binding characteristic (KD = 0.17 nM and Bmax = 1.97 x 10(-15) mol/mg protein). 4. T-cells, granulocytes and MOLT-3-cells did not show is a saturable binding even not at high concentrations of 3H-spiperone. 5. The pharmacological profile of the high-affinity 3H-spiperone binding site is clearly different from the dopamine D2 and D4, serotonin 5-HT2 histamine H1 and noradrenergic alpha1 and alpha2 receptor, respectively. 6. In summary, the results suggest that spiperone binding studies to enriched lymphocytes of psychiatric patients should be interpreted cautiously. Variable amounts of leucocytes might result in a higher proportion of nonsaturable, butaclamol displaceable spiperone binding with relevance for the calculation of KD and Bmax of the saturable high-affinity site. Interestingly, homogenous B-lymphoblastoid cell lines have the same binding characteristics as native B-lymphocytes and therefore should be recommended for characterization of 3H-spiperone binding sites.

B-Lymphocytes↗
PubMed2003

Excitation by dopamine of rat subthalamic nucleus neurones in vitro-a direct action with unconventional pharmacology.

Recent anatomical and physiological studies have pointed to a functional innervation of the subthalamic nucleus by dopamine. This nucleus has a pivotal role in basal ganglia function and voluntary movement control and the possibility that dopamine, and dopaminergic medication used in Parkinson's disease, might directly influence its activity is of considerable interest. We have evaluated electrophysiologically the action and pharmacology of dopamine on single subthalamic neurones in rat brain slices. Dopamine increased firing rate to up to a mean of 60% in 98% of the 261 neurones tested when examined using extracellular single-unit recording. This excitation was unaffected by the GABA antagonist picrotoxin, and the glutamate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione, and persisted in a low Ca(2+)/raised Mg(2+) solution, indicative of a direct action, independent of synaptic transmission. Of the 33 cells examined using whole patch-clamp recording, only 13 showed measurable increases in firing rate and/or depolarisations in response to dopamine. Dopamine-responsive cells displayed significantly greater access resistance, suggesting that an unidentified cytoplamic constituent, removed by whole-cell dialysis, was required for the response. Using extracellular recording, the D2-like dopamine receptor agonists quinpirole and bromocryptine, but not the D1-like receptor agonist 1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol, also consistently caused an excitation. This was mimicked by the catecholamine releaser amphetamine in 60% of cells tested. However, the dopamine excitation was not significantly reduced either by the D1-like receptor antagonist 7-chloro8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine or the D2-like receptor antagonists (-)-sulpiride, eticlopride and (+)-butaclamol, and the quinpirole excitation was also unaffected by (-)-sulpiride. In contrast, (-)-sulpiride, eticlopride and (+)-butaclamol all abolished the D2-like receptor-mediated inhibition by dopamine of substantia nigra pars compacta neurones. The alpha-adrenoceptor antagonist phentolamine was a weak antagonist of dopamine excitations, but not of those caused by quinpirole. Dopamine excitations also showed weak sensitivity to the 5-HT(2) antagonist ritanserin, but were unaffected by the alpha(1)-adrenoceptor antagonist prazocin and the beta-adrenoceptor antagonist propranolol. The pharmacology of this dopamine excitation is inconsistent with an action on any known catecholamine receptor. However, the effect of amphetamine indicates that an unidentified monamine--possibly dopamine--can be released within the subthalamic nucleus to cause an excitation. The anomalies of its pharmacological characterisation do not strongly support a physiologically relevant direct action of dopamine in the rat subthalamic nucleus.

Amphetamine↗
PubMed1986

Affinity chromatography of the anterior pituitary D2-dopamine receptor.

The D2-dopamine receptor from bovine anterior pituitary has been solubilized with digitonin and purified approximately 1000-fold by affinity chromatography on a new affinity support. This support consists of a (carboxymethylene)oximino derivative of the D2-selective antagonist spiperone (CMOS) covalently attached to Sepharose 4B through a long side chain. The interaction of the solubilized receptor activity with the affinity gel was biospecific. Dopaminergic drugs blocked adsorption of solubilized receptor activity to the CMOS-Sepharose with the appropriate D2-dopaminergic potency and stereoselectivity. For agonists, (-)-N-n-propylnorapomorphine greater than 2-amino-6,7-dihydroxytetrahydronaphthalene approximately equal to apomorphine greater than dopamine, whereas for antagonists (+)-butaclamol much greater than (-)-butaclamol. The same D2-dopaminergic specificity was observed for elution of receptor activity from the gel. To observe eluted receptor binding activity, reconstitution of the eluted material into phospholipid vesicles was necessary. Typically, 70-80% of the solubilized receptor was adsorbed by CMOS-Sepharose, and 40-50% of the adsorbed activity could be recovered after reconstitution of the eluted material. The overall recovery of D2-receptor activity from bovine anterior pituitary membranes was 12-15% with specific binding activity of approximately 150 pmol/mg. The reconstituted affinity-purified receptor bound ligands with the expected D2-dopaminergic specificity, stereoselectivity, and rank order of potency.

Animals↗
PubMed1991

Conformational properties of semirigid antipsychotic drugs: the pharmacophore for dopamine D-2 antagonist activity.

Conformational energy calculations using the MM2-87 program have been performed on the tetracyclic spiro amines 1 (A23887) and 2 (A31472) which have previously been shown to have considerable affinity for dopamine D-2 receptors. These compounds are important for defining the pharmacophore for D-2 antagonist activity due to their limited conformational freedom. Possible foldings of the multicyclic structure were energy minimized and the barriers for inversion and for rotation of the ammonium group were computed. The conformational properties of 1 and 2 are consistent with a pharmacophore recently proposed by Liljefors and Bøgesø. The greater affinity of (S)-octoclothepin for D-2 receptors as compared with its enantiomer was attributed to the latter having an incorrect orientation of the ammonium hydrogen despite the correct folding of the tricyclic structure. Other D-2 antagonists with limited conformational freedom such as butaclamol, isobutaclamol, loxapine, clozapine, and resolved cyproheptadine analogues were also found to be consistent with the pharmacophore. In addition, 1, 2, and their enantiomers were tested on radioligand binding assays for dopamine D-1, dopamine D-2, noradrenergic alpha-1, serotonergic 5-HT2, muscarinic, and sigma receptors. 1 and 2 have greater affinities than their enantiomers in the D-1, D-2, alpha-1, and 5-HT2 assays though there was little difference between 2 and its enantiomer in the latter two assays. In the muscarinic assays, 2 and its enantiomer, which were approximately equipotent, had greater affinity than 1 and its enantiomer. None of the compounds had substantial affinity for sigma receptors. Since the same enantiomers of 1, 2, butaclamol, and the resolved cyproheptadine analogues also have greater affinities for D-1 receptors, the conformational requirements of D-1 ligands appear to be quite similar to those of D-2 ligands.

Antipsychotic Agents↗
PubMed1996

Visualization of D1 dopamine receptors on living nucleus accumbens neurons and their colocalization with D2 receptors.

To examine the substrate for dopamine (DA) synaptic action in the nucleus accumbens (nAcc), we visualized the cellular and subcellular distribution of DA receptors on postnatal nAcc neurons in culture using fluoroprobe derivatives of DA receptor ligands. Previously, we have shown that rhodamine-N-(p-aminophenethyl)-spiperone (NAPS) (10 nM), a derivative of the D2 antagonist spiperone, labels D2-like receptors on living nAcc neurons. We now show that rhodamine-Sch-23390 (30 nM), a derivative of the D1 antagonist, labels D1-like receptors. Putative specific membrane labeling reached a plateau after about 20 min. Labeling was stereospecific, as it was unaffected by competition with (-)-butaclamol, but blocked with (+)-butaclamol. We found that 52 +/- 7% of nAcc medium-sized neurons showed D1 labeling, which extended onto the dendrites. Labeling was also seen on presynaptic terminals, often abutting D1-positive and D1-negative cell bodies, consistent with a presynaptic modulatory role for D1 receptors. Larger neurons, which may be GABAergic or cholinergic interneurons, were also labeled. By sequential labeling first with rhodamine-Sch-23390 and then rhodamine-NAPS, we found that 38 +/- 6% of medium-sized neurons express both D1- and D2-like receptors, indicating that D1-D2 interactions may occur at the level of single postsynaptic neurons.

Animals↗
PubMed1976

Dopamine receptors in human and calf brains, using [3H]apomorphine and an antipsychotic drug.

In order to develop a better dopamine receptor radioligand, [3H[apomorphine was prepared and tested for dopamine-like binding properties in both calf and human brain tissues. Specific binding of [3H]apomorphine was defined as that binding which occurred in the presence of 1 muM (-)-butaclamol (an inactive neuroleptic) minus that occurring in the presence of 1 muM (+)-butaclamol (active neuroleptic). The specific binding was saturable, the number of sites being double that of specific [3H]dopamine binding, and occurred primarily in dopamine-rich regions of postmortem human brains. The binding had a dissociation constant of 0.9 nM for human caudate (2 nM for calf caudate) and was blocked by dopamine and norepinephrine, but not by isoproterenol or (-)-propranolol, distinguishing it from a beta-adrenergic receptor. Since there was little desorption of [3H]apomorphine, the ligand permits extensive washing during routine assays for dopamine receptors, and facilitates biochemical purification of the receptor.

Affinity Labels↗
PubMed1983

Responses of pulmonary vasculature of cattle to dopamine and apomorphine.

Both dopamine and apomorphine caused concentration-dependent contractions of the bovine pulmonary artery from rest. Both of these compounds caused of the bovine pulmonary artery from rest. Both of these compounds caused relaxation of histamine-precontracted arterial and venous strips after alpha-adrenoceptor blockade. Arterial contraction elicited by dopamine was inhibited either by phentolamine (alpha-blocker) or by the dopamine-selective antagonists, spiperone and butaclamol. Apomorphine in the highest concentration (greater than 10(-5) M) inhibited dopamine-induced contractions. Dopamine- and apomorphine-induced vascular relaxations were attenuated by propranolol but not by spiperone or butaclamol. These data suggest that dopamine- and apomorphine-induced relaxation in these preparations is most likely mediated through beta-adrenergic mechanisms, whereas dopamine-induced contractions seem to involve both alpha-adrenergic and dopaminergic receptors.

Animals↗
PubMed1986

Differential effect of subchronic treatment with various neuroleptic agents on serotonin2 receptors in rat cerebral cortex.

In addition to antidepressant drugs, some neuroleptic (NL) drugs reduce serotonin2 (5-HT2) receptor binding sites after chronic administration. The present study was undertaken to characterize further this property of NL drugs. Scatchard analysis of [3H]spiperone binding in rat cerebral cortex revealed that 21-day treatment with chlorpromazine (CPZ), cis-flupenthixol, and thioridazine reduced 5-HT2 radioligand binding density by 60, 27, and 18%, respectively. The more selective dopamine-D2 antagonists haloperidol and sulpiride were totally ineffective in this regard. No reduction in 5-HT2 ligand binding sites occurred after 1 day of treatment with CPZ but 3-days of treatment was effective and this reduction persisted, although diminished, for at least 72 h after the last injection. cis-Flupenthixol and d-butaclamol were also effective after 3 days of treatment but trans-flupenthixol and l-butaclamol were not, indicating stereo-specificity of the response mechanism. Female rats showed the same response to CPZ as did male rats. Central 5,7-dihydroxytryptamine-induced lesions of 5-HT neurons demonstrated that intact 5-HT neurons were not required for the reduction of 5-HT2 receptor ligand binding by CPZ. Since CPZ has high affinity for many receptors, including alpha 1, histamine1, and muscarinic receptors, the role of these effects in producing 5-HT2 receptor down-regulation was considered by studying the effects of prazosin, atropine, and pyrilamine administration on 5-HT2 radioligand binding. Results indicate that no one of these actions appears to account for the down-regulation of 5-HT2 receptors by CPZ. Several of these effects, in combination, or some unique mechanism, may be involved.

5,7-Dihydroxytryptamine↗
PubMed1990

Expression of functional D2 dopamine receptors following differentiation of Y-79 human retinoblastoma cells.

Y-79 human retinoblastoma cells grown in serum-free medium in monolayer culture have previously been shown to undergo differentiation in response to dibutyryl cyclic AMP (Bt2cAMP). We report here that Y-79 cells treated in this manner also express very high levels of functional D2 dopamine receptors. In control Y-79 cells, cultured in suspension, D2 dopamine receptors, quantified via saturation analysis with the D2 antagonist [3H]methylspiperone, are expressed at a level of approximately 3 fmol/10(6) cells (approximately 1,800 receptor sites/cell). Differentiation is initiated by attachment of the cells to the culture dish with poly-D-lysine and fibronectin and continued culture in serum-free medium. After 8 days in serum-free culture, differentiation is further induced with continuous Bt2cAMP treatment. Using this differentiation protocol, D2 receptor levels increase up to a maximum of 30 fmol/10(6) cells (18,000 receptors/cell) on day 20, the limit of culture viability. Cultures of 15-17 days (7-9 days of Bt2cAMP treatment) expressing receptor levels of 15-20 fmol/10(6) cells are used for pharmacological and functional characterization of D2 dopamine receptors. The pharmacology of competition for [3H]methylspiperone binding to differentiated Y-79 (dY-79) cell membranes by a series of dopaminergic antagonists verifies the D2 receptor nature of this site, exhibiting appropriate affinities and the following rank order of potency: YM-09151-2 approximately spiperone greater than domperidone approximately (+)-butaclamol approximately fluphenazine greater than chlorpromazine greater than (-)-sulpiride greater than (+)-sulpiride greater than promethazine greater than (+)-SCH 23390 much greater than (-)-butaclamol.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclase Inhibitors↗
PubMed1979

Drug-induced changes in the formation, storage and metabolism of tyramine in the mouse.

1 The endogenous concentrations of p- and m-tyramine in the mouse striatum were determined by a mass spectrometric integrated ion current technique and concentrations were 21.3 and 6.1 ng/g, respectively.2 The present results further confirm that the administration of antipsychotic drugs (chlorpromazine, haloperidol, spiroperidol, alpha-flupenthixol and (+)-butaclamol) reduces p-tyramine concentrations in the mouse striatum. In contrast, striatal m-tyramine showed a tendency to increase, although only in the cases of haloperidol and (+)-butaclamol were the differences statistically significant.3 Administration of antipsychotic drugs to mice pretreated with tranylcypromine or clorgyline produced a significant reduction in striatal p-tyramine when compared with the concentrations obtained in mice given a monoamine oxidase inhibitor. These results suggest that antipsychotic drugs reduce striatal p-tyramine formation. The moderate increases produced by monoamine oxidase inhibitors on striatal m-tyramine were not significantly changed after the administration of an antipsychotic.4 Drugs that reduce dopamine turnover (apomorphine, piribedil, lergotrile, alpha-methyl-p-tyrosine) significantly increased the concentration of striatal p-tyramine. No significant changes were observed in striatal m-tyramine concentrations after apomorphine, piribedil or lergotrile; alpha-methyl-p-tyrosine produced a reduction in its concentration.5 Drugs that impair amine storage (reserpine, tetrabenazine, oxypertine) reduced striatal concentrations of p-tyramine. The m-tyramine concentrations were also reduced by reserpine or tetrabenazine.6 It is possible that striatal tyramines act as modulators, or transmitters, and control the activity of dopaminergic neurones.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1980

A dopamine-5-hydroxytryptamine link in the hypothalamic pathways which mediate heat loss in the rat.

1. Intrahypothalamic injection of either dopamine or 5-hydroxytryptamine (5-HT) in a dose volume of 1 microliters caused a fall in core temperature in lightly restrained rats maintained at an ambient temperature of 17 +/- 1 degree C. 2. Haloperidol (6.5 n-mole), a dopamine antagonist, prevented the hypothermic effect of dopamine (65 n-mole), but was ineffective against the response to either intrahypothalamic 5-HT (114 n-mole) or oxotremorine (6.0 n-mole). 3. Methysergide (14 n-mole) and cryproheptadine (17 n-mole) blocked the effect of both 5-HT and dopamine. However, these same doses failed to antagonise the effect of oxotremorine. 4. Rats placed on 0.65 m below a 250 W infra-red lamp responded to the imposed heat load vasodilation of tail skin blood vessels, as indicated by an increased tail skin temperature. 5. Rats tested 2 weeks after bilateral intrahypothalamic injection of 5,6-dihydroxytryptamine (42 n-mole in 2 microliters) showed a significant reduction in their tail skin temperature response and were less able to withstand the imposed heat load. 6. Three serial sections (0.8 mm thick) were prepared from the preoptic area of the rat brain, one anterior, one posterior and one corresponding to the previously defined dopamine-sensitive site. 7. Pretreatment with 5,6-dihydroxytryptamine significantly reduced the 5-HT concentration in the dopamine sensitive site, but had no effect on the concentration of dopamine. This pretreatment blocked dopamine but not 5-HT-induced hypothermia. 8. The 5-hydroxyindoleacetic acid (5HIAA) concentration in the hypothalamus of the normal rat exposed to a heat load was found to be significantly elevated, whereas there was no change in the 5HIAA concentration in the cortex. 9. Slices of rat preoptic hypothalamus and hippocampus were incubated with [3H]5-HT (0.2-2 microM). These slices accumulated 5-HT with properties characteristic of a neuronal uptake process. 10. Perfusion with either dopamine (greater than 50 microM) or apomorphine (greater than 200 microM) enhanced the release of [3H]5-HT from the prelabelled hypothalamic slices, but failed to stimulate release from hippocampal slices. 11. The release of [3H]5-HT from preoptic slices by dopamine and apomorphine was antagonised by the dopamine antagonists haloperidol (2 microM) and (+) isomer of butaclamol (1 microM), the (-) isomer of butaclamol was inactive. 12. These results support the hypothesis of a dopamine-5HT link in the hypothalamic thermoregulatory pathways of the rat.

Animals↗
PubMed1975

Antipsychotic drugs: direct correlation between clinical potency and presynaptic action on dopamine neurons.

Neuroleptic (antipsychotic) drugs inhibited the electrically stimulated release of [3-H] dopamine from rat striatal slices. The concentrations for 50 percent inhibition (ranging from 11.5 nanomolar for spiroperidol to 800 nanomolar for thioridazine) correlated closely with the average daily dosages of 25 neuroleptic drugs used clinically for schizophrenia. The correlation includes butyrophenones, phenothiazines, reserpine, pimozide, clozapine, and (plus)- butaclamol. Clinically inactive isomers [trans-thiothixene, trans-flupenthixol, and (minus)-butaclamol] required 20 to 1000 times higher concentrations than the active isomers to inhibit release. Compared to the inhibition of [3-H] dopamine release, much higher neuroleptic concentrations were needed to inhibit the electrically stimulated release of other neurotransmitters--[3-H] acetylcholine, [3-H-a1 (gamma-aminobutyric acid). The neuroleptic drugs may block the presynaptic coupling between impulse and neurosecretion.

Acetylcholine↗
PubMed1980

Absence of high affinity dopamine receptor in GH3 cells: a prolactin-secreting clone resistant to the inhibitory action of dopamine.

Dopamine (DA) and DA agonists bind with high affinity to anterior pituitary receptors which mediate the inhibition of PRL release. Spiperone (SPIP), a DA antagonist, has also been successfully used to characterize pituitary DA receptors with a dissociation constant (Kd) of less than 1 nM. We studied the binding of SPIP to GH3D6 cells which secrete only PRL and GH. This clone was derived from a radiation-induced tumor of the rat anterior pituitary. Equilibrium binding of [3H]SPIP to living GH3 cells showed no high affinity receptors, but a low affinity (Kd = 0.83 microM) and saturable (0.06 fmol/cell) population of sites was observed. In addition, saturable binding with a similar affinity (Kd = 0.57 microM) was noted in broken GH3 cells. The interaction was completely reversible and temperature dependent. The concentration of various ligands required to compete for half of the [3H]SPIP binding to whole cells were: chlorpromazine, 0.17 microM; haloperidol, 0.68 microM; pimozide, 0.77 microM; d-butaclamol, 1.16 microM; 1-butaclamol, 1.30 microM; SPIP, 1.49 microM; bromergocryptine, 4.98 microM; apomorphine, 13.9 microM; and DA, 100 microM. The absence of a high affinity site in GH3 cells is consistent with the decreased effectiveness of various agonists and antagonists on PRL secretion. It is possible that the low affinity interactions observed in GH3 cells are normally present in the anterior pituitary and brain and do not simply represent an alteration of receptor affinity.

Animals↗
PubMed1994

Dopamine D2 receptor gene expression and binding sites in adrenal medulla and pheochromocytoma.

To determine whether dopamine D2 receptors are present in normal and neoplastic chromaffin tissues, 10 pheochromocytomas and 5 human adrenal glands were studied. Dopamine D2 receptor messenger ribonucleic acid corresponding to a single band of approximately 2.5 kilobases was detected in both pheochromocytoma and human adrenal gland by Northern blot analysis. D2 receptor messenger ribonucleic acid levels determined by dot blot analysis were 3.1-fold lower in human adrenal medullas than in pheochromocytomas (P < 0.001). Simultaneous Scatchard analysis of [3H]spiperone binding experiments demonstrated the presence of two different binding sites in membrane preparations from bovine adrenal medullas [R1: Kd = 0.14 nmol/L; binding capacity (Bmax) = 6.2 fmol/mg protein: R2: Kd = 16 nmol/L; Bmax = 223 fmol/mg protein]. Similarly, two binding sites were present in membrane preparations from pheochromocytomas (R1: Kd = 0.39 nmol/L; R2: Kd = 61 nmol/L]. Binding capacities were greatly variable among pheochromocytomas (R1: Bmax = 12.0-372.5 fmol/mg protein; R2: Bmax = 1,000-11,586 fmol/mg protein). The relative potencies of different compounds to displace [3H]spiperone were spiperone > domperidone > (+)-butaclamol > quinpirole > SCH 23390 in bovine adrenal medulla, and spiperone >> domperidone > quinpirole > (+)-butaclamol > SCH 23390 in pheochromocytoma. We conclude that dopamine D2 receptors are synthesized in human adrenal medulla and pheochromocytoma tissues.

Adrenal Gland Neoplasms↗
PubMed2001

Selective dopamine receptor stimulation differentially affects [3H]arachidonic acid incorporation, a surrogate marker for phospholipase A2-mediated neurotransmitter signal transduction, in a rodent model of Parkinson's disease.

Our laboratory has developed a technique whereby radiolabeled long-chain fatty acids are injected intravenously in awake rats to pulse-label brain lipids, mainly phospholipids, to measure regional brain lipid metabolism by autoradiography. The brain incorporation of [(3)H]arachidonic acid ([(3)H]AA), a polyunsaturated fatty acid, may reflect regional changes in neurotransmitter signal transduction using phospholipase A(2). Using this radiotracer, we examined the brain dopamine system in rats with a chronic unilateral 6-hydroxydopamine lesion of the substantia nigra pars compacta, a model of Parkinson's disease. Four weeks after lesioning, rats received either vehicle; SKF38393 or quinpirole (LY-171,555) (D(1)- and D(2)-dopamine-like agonists, respectively); or (+)-butaclamol (D(1)/D(2) antagonist) followed by either vehicle, SKF38393, or quinpirole. They then were infused with [(3)H]AA and their brains processed for autoradiography. SKF38393 increased [(3)H]AA incorporation into the lesioned side compared with the intact side in the caudate putamen, somatosensory and motor cortices and subthalamic nucleus, but decreased incorporation in the ipsilateral ventrolateral thalamus. Quinpirole increased ipsilateral [(3)H]AA incorporation in the caudate putamen and somatosensory and motor cortices, and decreased it in the ventrolateral thalamus. (+)-Butaclamol blocked this effect. The data suggest up-regulation in basal ganglia and cortical dopamine circuits mediated by phospholipase A(2) ipsilateral to the substantia nigra lesion.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1991

Identification and characterization of two sigma-like binding sites in the mouse neuroblastoma x rat glioma hybrid cell line NG108-15.

NG108-15 cells were shown to possess high affinity binding sites for 1,3-di(2-[5-3H]tolyl)guanidine ([3H]DTG), a selective sigma ligand (Kd = 23 nM; maximal number of binding sites = 15.6 pmol/mg). The rank order of potency of drugs at this site was DTG greater than haloperidol greater than pentazocine greater than 3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [(+)-3-PPP] greater than phencyclidine (PCP) greater than metaphit greater than (-)-3-PPP greater than (-)-N-allylnormetazocine [(-)-SKF 10,047] greater than (-)-butaclamol greater than (+)-butaclamol greater than (+)-SKF 10,047 greater than dizolcipine (MK 801 [5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine- maleate]) greater than ketamine. Both, Kd value and pattern of ligand selectivity suggest a close relationship to sigma sites in rodent brain. However, in comparison to sigma sites in brain stereoselectivity for the benzomorphan, SKF 10,047 was reversed and the affinities for benzomorphans were only moderate to low. Thus, sigma binding sites in NG108-15 cells seem to correspond to recently detected sigma sites in a pheochromocytoma cell line (PC12). [3H]-1-(2-thienyl)-cyclohexyl]piperidine ([3H]TCP), a PCP receptor-selective ligand binds to NG108-15 cells with moderate affinity (Kd = 139 nM; maximal number of binding sites = 4.7 pmol/mg of protein).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

High affinity dextromethorphan binding sites in guinea pig brain. Effect of sigma ligands and other agents.

Dextromethorphan (DM), a non-narcotic antitussive, binds in the guinea pig brain to specific high- and low-affinity sites with Kd values of 57 nM and 24 microM, respectively (Musacchio et al., 1988). The antitussives carbetapentane, caramiphen, butamirate and dimethoxanate competed with the high-affinity binding of [3H]DM at pH 7.4 with nanomolar Ki values. Sigma site ligands showed high affinity for [3H]DM binding sites. The rank order of potency was: haloperidol greater than (+)-pentazocine greater than (+)-cyclazocine greater than 3-(-3-hydroxyphenyl)-N-(1-propyl)piperidine greater than (+)-N-allylnormetazocine greater than (-)-butaclamol much greater than (+)-butaclamol (-)-N-allylnormetazocine. The antipsychotic perphenazine competed with low nanomolar Ki values, whereas rimcazole was weaker. The antidepressant opipramol and the benzomorphan (+)2'methoxyphenazocine were the most effective drugs tested, with Ki values of 0.4 nM. By contrast, MK-801 and phencyclidine hydrochloride were very weak competitors for [3H]DM binding. The diphenylalkylamines were the most effective competitors of the calcium channel blocking agents: prenylamine and cinnarizine had Ki values of 17 and 22 nM, respectively. Lidoflazine and hydroxyzine were slightly less potent, but nifedipine and the benzothiazepine diltiazem were much weaker. Potassium channel blockers inhibited DM binding in pharmacologically relevant concentrations: primaquine was the most effective with a Ki of 0.5 microM. Other antimalarial potassium channel blockers tested inhibited binding in the micromolar range. 4-Aminopyridine and tetraethylammonium had Ki values of 0.76 and 1.40 mM, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗