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PubMed1986

Dopamine antagonists reduce spontaneous electrical activity in cultured mammalian neurons from ventral mesencephalon.

Mammalian neurons from ventral mesencephalon (VM) were grown in primary dissociated cell (PDC) culture. These neurons are predominantly non-dopaminergic. Many of these non-dopaminergic neurons have dopamine agonist and antagonist binding sites. Intracellular recordings were obtained from these neurons. When bathed in phosphate-buffered saline (PBS) solution they generated action potentials spontaneously. However, in the presence of haloperidol dissolved in PBS solution, the percentage of neurons which generated action potentials spontaneously was reduced in a dose-dependent manner (1-10 microM). This response was also obtained with (+) butaclamol (1 microM) but not with (-) butaclamol (1 microM). This neuroleptic inhibition of spontaneously generated action potentials was specific for neurons in PDC cultures of VM since neurons in PDC cultures of spinal cord did not demonstrate this phenomenon.

Action Potentials↗
PubMed1986

125I-LSD autoradiography confirms the preferential localization of caudate-putamen S2 receptors to the caudal (peripallidal) region.

The in vitro binding of 125I-lysergic acid diethylamide (LSD) to horizontal sections of rat brain was quantified with computer-assisted autoradiography. Specific binding of 125I-LSD to D2 and S2 sites, defined with 5 microM (+)-butaclamol, was 65-94% of the total binding. Identification of S2 sites with 50 nM ketanserin showed that over 90% of the butaclamol-displaced 125I-LSD binding in the frontal, cingulate and parietal neocortex was to S2 sites (22-55 fmol/mg protein). 125I-LSD also labeled a dense population of S2 sites (16 fmol/mg protein) in the caudal caudate-putamen at the level of the globus pallidus which exceeded by 5-fold the concentration of S2 sites (3 fmol/mg protein) in more rostral portions of the caudate-putamen. The peripallidal distribution of S2 sites was identical to that observed previously with the less selective S2 label, [3H]spiperone. The dense concentration of S2 sites in the caudal caudate-putamen and their overlap with D2 binding sites indicates that the peripallidal neostriatum may play an important role in interactions between dopamine and serotonin.

Animals↗
PubMed1982

Vasodilator effects of dopaminomimetics in the perfused rat kidney.

The renal vascular effects of dopaminomimetics were studied in the isolated perfused rat kidney after pretreatment with 10(-5) M phenoxybenzamine and 10(-5) M sotalol and after contraction of the vascular bed with prostaglandin F2 alpha (10(-7) to 3 x 10(-6) M). Under these conditions, our criterion for vascular dopaminomimetic activity was renal vasodilation, competitively inhibited by d-butaclamol (10(-8) M) but not by 1-butaclamol (3 x 10(-8) M). Dopamine is active at micromolar concentrations (ED50 = 2.53 +/- 0.34 x 10(-6) M). The N-alkylated analogues of dopamine preserve this activity if the alkyl group is a methyl group (epinine) or two n-propyl groups (di-n-propyl-dopamine). The catechol nucleus appears essential for renal vascular dopaminomimetic activity (SK&F 38393, active; p-tyramine, di-n-propyl-m-tyramine and RU 24926, inactive). Bromocriptine reproduces renal dopaminergic vasodilation with an ED50 of 1.3 +/- 0.14 x 10(-6) M. The study of structure-activity relationships of dopaminomimetics relates the vascular dopamine receptor, associated with renal vasodilation, to the dopamine receptor, associated with stimulation of dopamine-sensitive adenylate cyclase.

Animals↗
PubMed1988

Thermodynamic analysis of antagonist and agonist interactions with dopamine receptors.

The binding of [3H]spiperone to dopamine D-2 receptors and its inhibition by antagonists and agonists were examined in microsomes derived from the sheep caudate nucleus, at temperatures between 37 and 1 degree C, and the thermodynamic parameters of the binding were evaluated. The affinity of the receptor for the antagonists, spiperone and (+)-butaclamol, decreased as the incubation temperature decreased; the affinity for haloperidol did not further decrease at temperatures below 15 degrees C. The binding of the antagonists was associated with very large increases in entropy, as expected for hydrophobic interactions. The enthalpy and entropy changes associated with haloperidol binding were dependent on temperature, in contrast to those associated with spiperone and (+)-butaclamol. The magnitude of the entropy increase associated with the specific binding of the antagonists did not correlate with the degree of lipophilicity of these drugs. The data suggest that, in addition to hydrophobic forces, other forces are also involved in the antagonist-dopamine receptor interactions, and that a conformational change of the receptor could occur when the antagonist binds. Agonist binding data are consistent with a two-state model of the receptor, a high-affinity state (RH) and a low-affinity state (RL). The affinity of dopamine binding to the RH decreased with decreasing temperatures below 20 degrees C, whereas the affinity for the RL increased at low temperatures. In contrast, the affinity of apomorphine for both states of receptor decreased as the temperature decreased from 30 to 8 degrees C. A clear distinction between the energetics of high-affinity and low-affinity agonist binding was observed. The formation of the high-affinity complex was associated with larger increases in enthalpy and entropy than the interaction with the low-affinity state was. The results suggest that the interaction of the receptor with the G-proteins, induced or stabilized by the binding of agonist, leads to an increase in entropy and to negative heat capacity changes in the system.

Animals↗
PubMed1985

Amphetamine stimulation of glutaminase is blocked by neuroleptics.

The ability of several classes of neuroleptics to inhibit the activity of phosphate-activated glutaminase was studied in several brain regions. These agents decreased glutaminase activity only in the amygdala. Amphetamine elevated glutaminase activity in this region. This stimulation was not blocked by (-) butaclamol, but was blocked by (+) butaclamol, haloperidol, chlorpromazine or clozapine.

Amphetamine↗
PubMed1985

Lack of functional evidence for the involvement of sigma opiate receptors in the actions of the 3-PPP enantiomers on central dopaminergic systems: discrepancies between in vitro and in vivo observations.

In vitro radioligand binding and autoradiographic distribution studies have suggested the possible involvement of central sigma-opiate sites in the effects of several purportedly dopaminergic agents. Specifically, Largent et al. (Proc. Nat. Acad. Sci. 81, 4983, 1984) proposed that "actions of 3-PPP at sigma receptors may account for the effect of the drug on behavior and dopaminergic nerve function". Using the sigma-opiate- and dopamine (DA)-preferring (-)- and (+)-enantiomer, respectively, of butaclamol, and the two enantiomers of 3-PPP, the present study was undertaken to address the in vivo functional significance of this proposal. To this end we investigated various biological responses considered to reflect drug interactions with DA cell body and terminal autoreceptors and with presumed non-synaptic and postsynaptic DA receptors in the rat CNS. (+)- but not (-)-butaclamol antagonized the 3-PPP (either enantiomer)-induced DA synthesis and prolactin decreases in GBL-treated rats, the (+)-3-PPP-induced inhibition of substantia nigra DA cell firing and the (+)-3-PPP-induced reversal of reserpine akinesia. Taken together with previous findings available data suggest that DA rather than sigma-opiate receptors mediate the neurochemical, electrophysiological, behavioral and other physiological (prolactin, body temperature) effects of 3-PPP and its enantiomers. The in vivo pharmacological relevance of the claimed non-dopaminergic, proposedly sigma-opiatergic, radioligand binding demonstrated in vitro (with e.g. (+)-3-PPP) thus remains to be established.

Animals↗
PubMed2004

Pharmacological characterisation of the thermogenic effect of bupropion.

The pharmacological mechanism of bupropion's thermogenic effect has been investigated in female Wistar rats by measuring oxygen consumption at thermoneutrality (29 degrees C). Bupropion (30 mg/kg) rapidly increased oxygen consumption (VO2) with a maximum effect at 30 min, and VO2 remained elevated throughout the 4-h experimental period. The nonselective 5-hydroxytryptamine (5-HT or serotonin) receptor antagonist, metergoline (1 mg/kg), and the alpha1-adrenoceptor antagonist, prazosin (1 mg/kg), had no effect on the VO2 response to bupropion, whereas the alpha2-adrenoceptor antagonist, RS79948 [(8aR, 12aS, 13aS)-5,8,8a,9,10,11,12,12a,13,13a-decahydro-3-methoxy-12-(ethylsulphonyl)-6H-isoquino[2,1-g][1,6]-naphthyridine hydrochloride] (1 mg/kg), potentiated the response. The VO2 response to bupropion during the first 60 min was significantly inhibited by a high dose of the nonselective beta-adrenoceptor antagonist, propranolol (20 mg/kg), but it had no effect at a low dose (1 mg/kg). Pretreatment with the dopamine D2/D1 receptor antagonist, (+)butaclamol (200 microg/kg), caused a partial, but significant, inhibition (P<0.01) of the VO2 response to bupropion during the first 60 min, and this antagonist abolished the effect of bupropion between 90 and 240 min. Pretreatment with a combination of a high dose of propranolol (20 mg/kg) and (+)butaclamol (200 microg/kg) prevented any increase in VO2 induced by bupropion. It is concluded that the beta3-adrenoceptor subtype, as well as dopamine D2/D1 receptors, is responsible for the increase in oxygen consumption induced by bupropion. We have previously demonstrated that bupropion did not significantly reduce food intake in rats. Hence, in this species, its weight-reducing action predominantly results from thermogenesis mediated via activation of beta3-adrenergic and dopamine D2/D1 receptors. Because bupropion has also been reported not to alter food intake in the clinic, thermogenesis may also contribute to its antiobesity effect in man.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1988

Immuno-photoaffinity labeling of the D2-dopamine receptor.

Azido-haloperidol was synthesized and applied as a photoaffinity ligand for the D2-dopamine receptor. In bovine striatal membranes, azido-haloperidol bound reversibly to the receptor (KD = 15 nM), and when exposed to light, it bound to the receptor irreversibly. This irreversible inactivation was prevented by the dopaminergic agonist N-propylnorapomorphine or the dopaminergic antagonists haloperidol and (+)-butaclamol. The photoaffinity labeled D2-receptor was probed with anti-haloperidol antibodies following gel electrophoresis and transfer to nitrocellulose. A major polypeptide of 94 kDa reacted with the anti-haloperidol antibodies. This polypeptide band was not observed when the photoaffinity labeling was performed in the presence of (+)-butaclamol or spiperone.

Affinity Labels↗
PubMed2001

Real-time analysis of dopamine: antagonist interactions at recombinant human D2long receptor upon modulation of its activation state.

1. Antipsychotic drugs may mediate their therapeutic effects not only by preventing the binding of dopamine but also by decreasing the propensity of the dopamine receptor to assume an active R* state. Ligand-mediated activation and blockade of the recombinant human D(2long) receptor was investigated in CHO-K1 cells upon modulation of its R* state. 2. Both the Ala(371)Lys (A371K) and Thr(372)Arg (T372R) D2long receptor mutants could be activated in a ligand-dependent manner via a chimeric G(alphaq/o) protein, and more efficaciously so than with the promiscuous G(alpha15) protein. 3. Dopamine and partial agonists (E(max): lisuride >> (+)-UH 232 approximately bromerguride) displayed dissimilar Ca(2+) kinetic properties at wild-type and mutant receptors. A371K and T372R D2long receptor mutants demonstrated an attenuated and enhanced maximal response to these partial agonists, respectively. 4. Dopamine antagonists were unable to block the transient high-magnitude Ca(2+) phase at the wild-type D2long receptor upon simultaneous exposure to antagonist and dopamine, while full blockade of the low-magnitude Ca(2+) phase did occur at a later time (onset-time: haloperidol < bromerguride < (+)-butaclamol). A similar, though more efficacious, antagonist profile was also found at the A371K mutant receptor. Conversely, the blockade of the low-magnitude Ca(2+) phase was attenuated (haloperidol) or almost absent [(+)-butaclamol and bromerguride] at the T372R mutant receptor. 5. In conclusion, mutagenesis of the Ala(371) and Thr(372) positions affects in an opposite way the ligand-dependent activation and blockade of the D2long receptor. The observed attenuation of dopamine-mediated Ca(2+) signal generation with different decay-times may underlie distinct properties of the dopaminergic ligands.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2005

Dopamine receptor oligomerization visualized in living cells.

G protein-coupled receptors occur as dimers within arrays of oligomers. We visualized ensembles of dopamine receptor oligomers in living cells and evaluated the contributions of receptor conformation to the dynamics of oligomer association and dissociation, using a strategy of trafficking a receptor to another cellular compartment. We incorporated a nuclear localization sequence into the D1 dopamine receptor, which translocated from the cell surface to the nucleus. Receptor inverse agonists blocked this translocation, retaining the modified receptor, D1-nuclear localization signal (NLS), at the cell surface. D1 co-translocated with D1-NLS to the nucleus, indicating formation of homooligomers. (+)-Butaclamol retained both receptors at the cell surface, and removal of the drug allowed translocation of both receptors to the nucleus. Agonist-nonbinding D1(S198A/S199A)-NLS, containing two substituted serine residues in transmembrane 5 also oligomerized with D1, and both were retained on the cell surface by (+)-butaclamol. Drug removal disrupted these oligomerized receptors so that D1 remained at the cell surface while D1(S198A/S199A)-NLS trafficked to the nucleus. Thus, receptor conformational differences permitted oligomer disruption and showed that ligand-binding pocket occupancy by the inverse agonist induced a conformational change. We demonstrated robust heterooligomerization between the D2 dopamine receptor and the D1 receptor. The heterooligomers could not be disrupted by inverse agonists targeting either one of the receptor constituents. However, D2 did not heterooligomerize with the structurally modified D1(S198A/S199A), indicating an impaired interface for their interaction. Thus, we describe a novel method showing that a homogeneous receptor conformation maintains the structural integrity of oligomers, whereas conformational heterogeneity disrupts it.

Butaclamol↗
PubMed1985

Dopamine D2 receptors in the anterior pituitary: a single population without reciprocal antagonist/agonist states.

Although dopamine agonists can recognize two states of the D2 dopamine receptor in the anterior pituitary (D2high and D2low), we examined whether the dopamine antagonists such as [3H]spiperone could recognize these two sites with different affinities. Using up to 30 concentrations of [3H]spiperone, however, we could only detect a single population of binding sites (porcine anterior pituitary homogenates) with a dissociation constant (KD) of 130 pM. When specific [3H]spiperone binding was defined by a low concentration of (+)-butaclamol (100 nM), the apparent density was low. When defined by a high concentration of (+)-butaclamol (10 microM), nonspecific sites became detectable, thus revealing two apparent populations of sites for [3H]spiperone, only one of which was specific for dopamine. Sodium chloride reduced the KD of the single population of specific D2 sites to 64 pM. Guanine nucleotide by itself had no effect on the KD, but enhanced the density by 25%. Since the density-enhancement could be eliminated by extensive washing of membranes, and could be restored by preincubation with dopamine, the nucleotide-induced elevation of D2 density appeared to be a result of the release of tightly bound endogenous dopamine. Thus, monovalent cations and guanine nucleotides appear to have separate regulatory effects on the anterior pituitary D2 receptor that modulate antagonist-receptor interactions. Several maneuvers were used to test whether [3H]spiperone could differentiate between the two agonist-detected subpopulations of sites. Twentyfold different concentrations of [3H]spiperone (47 pM and 1000 pM) were found to label identical proportions of receptors in the D2high and D2low states as detected by the agonist 6,7-dihydroxyaminotetralin (ADTN), suggesting that spiperone labelled equal proportions of D2high and D2low sites without differential affinity for them. In addition, competition of spiperone for D2high sites selectively labelled by the agonist [3H]n-propylnorapomorphine (NPA) had a virtually identical KD for spiperone as did the total D2 receptor population as determined by direct binding studies (75 pM versus 64 pM). [3H]Spiperone also bound to a uniform population of D2low sites induced by preincubation with guanine nucleotide with identical affinity as to the total D2 population. Thus, these data do not support a "reciprocal model" for the D2 receptor (i.e., antagonist having low affinity for D2high and high affinity for D2low in a manner reciprocal to agonists).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

Dopamine receptors on adrenal chromaffin cells modulate calcium uptake and catecholamine release.

The presence of dopamine-containing cells in sympathetic ganglia, i.e., small, intensely fluorescent cells, has been known for some time. However, the role of dopamine as a peripheral neurotransmitter and its mechanism of action are not well understood. Previous studies have demonstrated the presence of D2 dopamine receptors on the surface of bovine adrenal chromaffin cells using radioligand binding methods and dopamine receptor inhibition of catecholamine release from perfused adrenal glands. In the present study, we provide evidence confirming a role of dopamine receptors as inhibitory modulators of adrenal catecholamine release from bovine chromaffin cell cultures and further show that the mechanism of modulation involves inhibition of stimulated calcium uptake. Apomorphine gave a dose-dependent inhibition (IC50 = 1 microM) of 45Ca2+ uptake stimulated by either nicotine (10 microM) or membrane depolarization with an elevated K+ level (60 mM). This inhibition was reversed by a series of specific (including stereospecific) dopamine receptor antagonists: haloperidol, spiperone, sulpiride, and (+)-butaclamol, but not (-)-butaclamol. In addition, the calcium channel agonist Bay K 8644 was used to stimulate uptake of 45Ca2+ into chromaffin cells, and this uptake was also inhibited by the dopamine receptor agonist apomorphine. The combined results suggest that dopamine receptors on adrenal chromaffin cells alter Ca2+ channel conductance, which, in turn, modulates catecholamine release.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1991

D1 dopamine receptors of NS20Y neuroblastoma cells are functionally similar to rat striatal D1 receptors.

Dopamine or agonists with D1 receptor potency stimulated cyclic AMP (cAMP) accumulation in whole cell preparations of NS20Y neuroblastoma cells. The accumulation of cAMP after D1 stimulation was rapid and linear for 3 min. Both dopamine and the novel D1 receptor agonist dihydrexidine stimulated cAMP accumulation two- to three-fold over baseline. The pseudo-Km for dopamine was approximately 2 microM, whereas for dihydrexidine it was approximately 30 nM. The effects of both drugs were blocked by either the D1-selective antagonist SCH23390 (Ki, 0.3 nM) or the nonselective antagonist (+)-butaclamol (Ki, 5 nM). Both (-)-butaclamol and the D2-selective antagonist (-)-sulpiride were ineffective (Ki greater than 3 microM). Forskolin (10 microM), prostaglandin E1 (1 microM), and adenosine (10 microM) also stimulated cAMP accumulation, but none were antagonized by SCH23390 (1 microM). Finally, muscarinic receptor stimulation (100 microM carbachol) inhibited both D1- and forskolin-stimulated increases in cAMP accumulation by 80%. The present results indicate that NS20Y neuroblastoma cells have D1 receptors that are coupled to adenylate cyclase, and that these receptors have a pharmacological profile similar to that of the D1 receptor(s) found in rat striatum.

Benzazepines↗
PubMed1978

The binding of haloperidol to human blood platelets and interactions with 5-hydroxytryptamine and dopamine.

1 The binding of [3H]-5-hydroxytryptamine ([3H]-5-HT), [3H]-haloperidol and [3H]-dopamine to human blood platelets was investigated and the effects of unlabelled haloperidol on [3H]-5-HT binding and (+)- and (-)-butaclamol on [3H]-haloperidol were studied. 2 Scatchard analysis did not show any specific binding of [3H]-haloperidol or [3H]-dopamine to platelets, but two binding sites were identified for binding of [3H]-5-HT. 3 Unlabelled haloperidol reduced the binding of 5-HT in concentrations comparable to those inhibigint 5-HT-induced platelet aggregation; (+)- and (-)-butaclamol did not affect the binding of [3H]-haloperidol. 4 It is concluded that haloperidol binding represents saturation of the platelet membrane, and that the platelet is not a suitable model for investigation of dopamine-drug interactions.

Adult↗
PubMed1981

Stimulation of prolactin secretion by neuroleptics in rats with medial basal hypothalamic lesions.

The ability of dopamine receptor antagonists to stimulate prolactin release in rats with medial basal hypothalamic lesions was investigated. Starting levels of prolactin were elevated to approximately 400 ng/ml in animals in which the tuberoinfundibular dopaminergic neurons were completely destroyed by the lesion. In lesioned animals, chlorpromazine administration at doses of 0.1 and 5 mg/kg induced a further 2- to 3-fold significant increase in plasma prolactin levels. the incubation of anterior pituitaries from lesioned animals with 10(6) M chlorpromazine had no effect on prolactin secretion, thereby eliminating the possibility that chlorpromazine itself stimulates prolactin release from the anterior pituitary. A similar increase in plasma prolactin in lesioned rats was also observed with the potent dopamine antagonist d-butaclamol (1 mg/kg). The effect was stereospecific since the inactive isomer l-butaclamol did not produce any change in the circulating levels of prolactin. Pimozide, another dopaminergic antagonist, was ineffective in inducing a further increase in prolactin in lesioned rats when 0.63 mg/kg was used. However, at a 10-fold lower concentration (0.63 mg/kg), pimozide stimulated a significant increase in prolactin in lesioned rats. The involvement of an alpha-adrenergic mechanism was ruled out by the inability of phentolamine (2.5 mg/kg) to increase prolactin secretion. These data suggest that dopaminergic antagonists can further increase prolactin levels in medial basal hypothalamus-lesioned rats possibly by blocking the inhibitory action of dopamine from nonhypothalamic sources, or by releasing a substance which possesses prolactin-releasing activity.

Animals↗
PubMed1980

Decreased responsiveness of GH3 cells to the dopaminergic inhibition of prolactin.

The inhibitory regulation of PRL secretion by dopamine (DA) or the dopaminergic agonists bromergocryptine (CB-154) and apomorphine was studied in cultured GH3 cells, an established rat anterior pituitary cell line which produces both PRL and GH. The basal release of PRL from GH3 cells was unaffected when incubated for 6 h with DA concentrations as high as 10(-4) M. The inability of DA to suppress PRL secretion could not be explained by the catabolism of DA or the presence of unknown inhibitors (e.g. estradiol) in the fetal calf serum present in the incubation media. Apomorphine and CB-154 were only partially effective in suppressing PRL release at high concentrations of 10(-4) and 10(-5) M, respectively. Various concentrations of the dopaminergic antagonist d-butaclamol did not reverse the inhibitory action of 10(-5) M CB-154, while equal concentrations (10(-5) M) of both d- and l-butaclamol significantly suppressed PRL release. The greatly lowered responsiveness of GH3 cells to dopaminergic inhibition of PRL is suggestive of some impairment of DA receptors. This hypothesis is supported by radioligand binding studies in which high affinity dopaminergic binding sites are absent in the same cell line used in this study.

Animals↗
PubMed1990

Growth of cultured human cerebral meningiomas is inhibited by dopaminergic agents. Presence of high affinity dopamine-D1 receptors.

We have found that microM concentrations of the dopamine agonist bromocriptine significantly decrease the proliferation rate of human meningioma cells in culture (25-56% inhibition). This effect was also seen with direct application of dopamine, as well as the dopamine-D1 agonist (+)-SKF-38393 (both applied in microM concentrations) to meningioma cell cultures. Receptor studies with the dopamine-D1 ligand (125I)SCH-23982 (dopamine-D1 antagonist) indicated that dopamine-D1 binding sites were present in the membranes of meningioma tissue. The mean dissociation constant (Kd) was 325 ( +/- 74.5 SEM) pM and the receptor density (Bmax) was 25.4 ( +/- 1.5 SEM) fmol/mg pellet protein in 5 human meningiomas. The pharmacological specificity was proven by (+)-SKF-38393, ( +/-SKF-83566 or (+)-butaclamol and their inactive isomers (-)-SKF-38393 and (-)-butaclamol in a 1000 fold excess. These results provide evidence that human meningiomas possess high affinity dopamine-D1 receptors and that dopamine agonists have an antiproliferative effect on these tumors in culture. We conclude that the proliferation of cerebral meningiomas may be under dopaminergic control and that dopamine agonists may have a role in the medical treatment of patients with meningiomas.

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