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PubMed1989

Pharmacological characterization of rat retinal dopamine receptors.

The dopamine (DA) D-1 and D-2 receptors coupled to adenylate cyclase in the rat retina were characterized pharmacologically. In confirmation of reports using other neural tissues, activation of D-1 receptors with DA, apomorphine or SKF 38393 resulted in activation of adenylate cyclase and enhanced accumulation of cyclic AMP (cAMP). The response to DA was blocked by SCH 23390, a D-1 receptor antagonist. D-2 receptors negatively coupled to adenylate cyclase were demonstrated by preincubating retina with SCH 23390 and then with DA or apomorphine. D-2 receptor responses were also elicited with quinpirole or bromocriptine, D-2 receptor agonists, in the absence of SCH 23390. (+)-Butaclamol, but not (-)-butaclamol, blocked the D-2 receptor-induced decrease of cAMP. Moreover, I-sulpiride was more active than d-sulpiride in reversing the DA-induced inhibition of cAMP accumulation. D-1 and D-2 receptor responses were also evident in forskolin-activated retina. The intraocular injection of pertussis toxin prevented the fall of cAMP and enhanced the rise of cAMP by DA, indirectly implicating the need for a guanine nucleotide regulatory protein in the process. Our results demonstrate that retinal tissue contains DA receptors that are similar to those found in brain and they imply that therapeutic agents that interact with the receptors in brain might interact with the receptors in retina.

Adenylyl Cyclases↗
PubMed1988

Initial identification and characterization of sigma receptors on human peripheral blood leukocytes.

Phencyclidine (PCP) has been reported to suppress a variety of immune functions in vitro. Because PCP binds with high affinity to both PCP and sigma receptors, the identity of the receptor(s) mediating the immunological effects of PCP is unknown. The aim of the present study was to identify and characterize the sites of PCP action (sigma and/or PCP receptors) in human peripheral blood leukocytes (PBL) using [3H]haloperidol or 1,3 di(2-([5-3H]tolyl)guanidine ([3H]DTG) to specifically label sigma receptors and 3,4-[3H]-(N)-[1-(2-thienyl)-cyclohexyl]-piperidine ([3H]TCP) to specifically label PCP receptors. [3H]Haloperidol binding was saturable and of high affinity with comparable KD values in human PBL (0.44 +/- 0.10 nM) and rat cerebellum (0.51 +/- 0.09 nM). Similarly, [3H]DTG binding was saturable with comparable KD values of 29.5 +/- 3.5 and 26.4 +/- 3.6 nM in rat cerebellum and human PBL, respectively. In contrast, there was a notable absence of [3H]TCP-labeled PCP receptors in human PBL and rat cerebellum. In competition studies, the pharmacologic profile of [3H]haloperidol-labeled sigma receptors in human PBL was virtually identical with that in rat cerebellum (slope, 0.87; correlation coefficient, 0.96); the rank order of potency of competing drugs was haloperidol greater than l-butaclamol = pentazocine greater than d-3-(hydroxyphenyl)-N-(1-propyl)-piperidine greater than DTG = d-butaclamol = d-SKF 10,047 greater than levallorphan greater than or equal to PCP greater than or equal to l-SKF 10,047 greater than TCP greater than MK-801.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Stimulation of adenylate cyclase in relation to dopamine-induced long-term enhancement (LTE) of muscarinic depolarization in the rabbit superior cervical ganglion.

Dopamine (DA) induction of the long-term enhancement (LTE) of the slow muscarinic depolarizing response to methacholine (MCh), equivalent to the slow EPSP (S-EPSP), was previously found to be mimicked by exogenous cyclic AMP (cAMP) in the rabbit superior cervical ganglion (SCG). DA-induced LTE of the S-EPSP was shown to be depressed by some DA antagonists. We now show that DA (15 microM), its analog, 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (ADTN), and a D2 receptor antagonist, metoclopramide, each can induce both LTE of MCh depolarization and an increase in ganglionic cAMP. Conversely, antagonists of DA-induced LTE also depress DA-induced rises in cAMP; these antagonists include haloperidol (1 microM), both (+) and (-) enantiomers of butaclamol (0.7-7 microM), flupenthixol (1 microM), and (+)-R-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-o l (SCH-23390) (7 microM). The selective D2 antagonists sulpiride (10 microM) and domperidone (10 microM) affect neither DA action. Alpha-2 adrenergic agonists (alpha-methyl-norepinephrine and clonidine) produce no LTE; alpha-antagonist dihydroergotamine (35 microM) does not affect either DA action, although it can completely block the hyperpolarizing response to DA or other catecholamines. Beta-antagonist propranolol (5 microM) partially depresses DA-induced rises in cAMP but has no effect on the DA-induced LTE. (Butaclamol and propranolol in combination can completely block the cAMP rise induced by DA.) Beta-agonist isoproterenol can induce appreciable LTE of MCh depolarization, but this LTE is not depressed by propranolol (10 microM). Isoproterenol can elicit a substantial rise in cAMP.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1986

Purification of bovine striatal dopamine D-2 receptor by affinity chromatography.

Bovine striatal dopamine D-2 receptor has been purified approximately 2000-fold by affinity chromatography. The receptor, solubilized with cholic acid and sodium chloride, was adsorbed on haloperidol-linked Sepharose CL-6B and eluted with spiroperidol. The adsorption of receptor to the affinity matrix was biospecific as preincubation of the solubilized preparation with D-2 receptor agonists or antagonists blocked retention of receptor. The process also displayed stereoselectivity with respect to (+)- and (-)-butaclamol. Nondopaminergic agents such as mianserin and propranolol failed to exhibit any effect on the adsorption process. Elution of the receptor was also biospecific, as dopaminergic drugs were most effective (spiroperidol greater than haloperidol greater than dopamine) in eluting the bound receptor; whereas other agents, e.g. propranolol, mianserin, and acetic acid, were only slightly effective. One-cycle affinity purification resulted in a recovery of 12% of the original membrane-bound dopamine D-2 receptor with a specific activity of 169,600 fmol/mg of protein as assayed with [3H]spiroperidol binding. The order of potency of D-2 agonists (N-propylnorapomorphine greater than NO434 greater than apomorphine greater than dopamine) and antagonists (spiroperidol greater than (+)-butaclamol greater than domperidone) with the purified preparation was found to be similar to that of the solubilized dopamine D-2 receptor.

Animals↗
PubMed1986

The thermodynamics of agonist and antagonist binding to dopamine D-2 receptors.

The ability of dopamine agonists and antagonists to compete with [3H]spiperone binding to rat striatal membrane preparations at 4, 15, 26, and 37 degrees varied markedly with temperature. Dopamine and the dopamine agonist 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide (ADTN) were more potent at lower temperatures. The ability of the dopamine antagonists, haloperidol, cis-flupenthixol, cis-N-(1-benzyl-1-methypyrrolidin-3-yl)-5-chloro-2-methoxy-9- methylaminobenzamide (YM 09151-2), raclopride, and clozapine, and of the agonists apomorphine and pergolide, to compete with [3H]spiperone binding was little altered by temperature. (+)-Butaclamol was more potent at higher temperatures. In contrast, the antagonists sulpiride, metoclopramide, clebopride, sultopride, tiapride, piquindone, and zetidoline were more potent at lower temperatures. The interaction of the agonists dopamine and ADTN was driven by a decrease in enthalpy, allowing an energetically unfavorable decrease in entropy. The binding of the antagonists, haloperidol, cis-flupenthixol, YM 09151-2, raclopride, (+)-butaclamol, and clozapine, and also of the agonists, apomorphine and pergolide, was entropy driven. The interaction of the antagonists sulpiride, metoclopramide, clebopride, alizapride, sultopride, tiapride, piquindone, and zetidoline differed from that of other antagonists in being enthalpy driven. The observed entropy changes correlated with the lipophilicity of the displacing drugs and not with their intrinsic activity.

Animals↗
PubMed1985

A photoaffinity ligand for dopamine D2 receptors: azidoclebopride.

In order to label D2 dopamine receptors selectively and covalently by means of a photosensitive compound, azidoclebopride was synthesized directly from clebopride. The dissociation constant (KD) of clebopride for the D2 dopamine receptor (canine brain striatum) was 1.5 nM, while that for azidoclebopride was 21 nM. The affinities of both clebopride and azidoclebopride were markedly reduced in the absence of sodium chloride. In the presence of ultraviolet light, azidoclebopride inactivated D2 dopamine receptors irreversibly, as indicated by the inability of the receptors to bind [3H]spiperone. Maximal photoinactivation of about 60% of the D2 dopamine receptors occurred at 1 microM azidoclebopride; 30% of the receptors were inactivated at 80 nM azidoclebopride (pseudo-IC50). Dopamine agonists selectively protected the D2 receptors from being inactivated by azidoclebopride, the order of potency being (-)-N-n-propylnorapomorphine greater than apomorphine greater than (+/-)-6,7-dihydroxy-2-aminotetralin greater than (+)-N-n-propylnorapomorphine greater than dopamine greater than noradrenaline greater than serotonin. Similarly, dopaminergic antagonists prevented the photoinactivation of D2 receptors by azidoclebopride with the following order of potency: spiperone greater than (+)-butaclamol greater than haloperidol greater than clebopride greater than (-)-sulpiride greater than (-)-butaclamol. The degree of D2 dopamine receptor photoinduced inactivation by azidoclebopride was not significantly affected by scavengers such as p-aminobenzoic acid and dithiothreitol. Furthermore, irradiation of striatal membranes with a concentration of azidoclebopride sufficient to inactivate dopamine D2 receptors by 60% did not significantly reduce dopamine D1, serotonin (S2), benzodiazepine, alpha 1- or beta-noradrenergic receptors. This study describes the use of a novel and selective photoaffinity ligand for brain dopamine D2 receptors. The molecule, in radiolabeled form, may aid in the molecular characterization of these receptors.

Affinity Labels↗
PubMed1980

Catecholamine modulation of enkephalin-induced electrophysiological responses in cerebral cortex.

The interaction between locally applied D-Ala2-methionine enkephalinamide (2dA) and catecholamine inputs to frontal cortex was investigated in rats. Parenteral administration of antipsychotic agents known to block catecholamines receptors, such as spiroperidol, alpha-flupenthixol and (+)-butaclamol, reversibly antagonized enkephalin-induced depressions. The biochemically inactive isomers of these antipsychotics, beta-flupenthixol and (-)-butaclamol, manifested no such activity. Unilateral lesions of the catecholaminergic projections to frontal cortex, produced by interstitial injection of 6-hydroxydopamine, resulted in an ipsilateral decrease in 2dA efficacy and in an elimination of the antagonisms of 2dA depressions by antipsychotic agents. The depressions caused by 2dA were not antagonized by iontophoretically applied Mg++. It is concluded that intact catecholaminergic transmission is required for the full expression of enkephalin-induced depressions in frontal cortex and that this mechanism probably does not involve presynaptic release. Taken together with other recently published data, these results suggest that catecholamines may act as postsynaptic modulators to augment responsiveness to enkephalins.

Action Potentials↗
PubMed1981

Interaction of D-LSD with blood platelets of rabbits: shape change and specific binding.

In blood platelets of rabbits, the shape change-inducing effect of D-lysergic acid diethylamide (D-LSD) has been compared with the D-LSD-binding. D-LSD, but not L-LSD, caused a shape change reaction (EC50 1.3 x 10(-9) M) which was inhibited by various 5-HT antagonists (methergoline and neuroleptic drugs), butaclamol showing marked stereospecificity. Strong inhibitors of 5 HT uptake were only weak in counteracting the D-LSD-induced shape change. Furthermore, D-[3H]LSD bound to platelets at a single saturable, high affinity, stereoselective site [Kd = (31.1 +/- 3.3) x 10(-9) M; Bmax = 28.9 +/- 2.7 fmols per 10(8) platelets]. This binding was strongly antagonized by D-LSD and methergoline and less by the hallucinogenic drugs, psilocin, bufotenin and N'N'-dimethyltryptamine. L-LSD an 5 HT, inhibitors of 5 HT uptake and neuroleptics, especially spiroperidol and butaclamol, had only a weak antagonistic effect. The latter showed stereospecificity. It is concluded that 1) the shape change reaction caused by D-LSD in platelets is mediated by the specific 5 HT-receptor, 2) the sites mediating the D-LSD-induced shape change reaction are not identical with those responsible for D-[3H]LSD-binding and both these sites are different from the 5 HT-transport sites and 3) with respect to D-LSD-binding sites, platelets and neurons are not exactly identical.

Animals↗
PubMed1983

Modulatory interactions between enkephalin and catecholamines: anatomical and physiological substrates.

The anatomical and electrophysiological basis of enkephalin-catecholamine interactions was studied in the central nervous system of the Sprague-Dawley rat. Sections of fetal rat brain were treated alternatively with antibodies raised against enkephalin or tyrosine hydroxylase (EC 1.14.16.2). Enkephalinergic fibers were found to innervate almost all brain areas known to contain catecholamine cell bodies or terminal fields. The possible electrophysiological correlates of such an overlap in enkephalin and catecholamine terminal fields was investigated in frontal neocortex. Parenteral administration of antipsychotic agents known to block catecholamine receptors, such as spiroperidol, alpha-flupenthixol, and (+)-butaclamol, reversibly antagonized enkephalin-induced depressions of neuronal activity. The biochemically inactive isomers of these antipsychotics, beta-flupenthixol and (-)-butaclamol, manifested no such activity. Unilateral lesions of the catecholaminergic projections to frontal cortex produced by interstitial injection of 6-hydroxydopamine resulted in an ipsilateral decrease in enkephalin efficacy and in an elimination of the antagonisms of enkephalin depressions by antipsychotic agents. It is hypothesized that catecholamines may act as modulators to augment responsiveness to peptides such as enkephalins.

Animals↗
PubMed1983

[Pharmacologic characteristics of renal dopaminergic receptors: therapeutic perspectives].

The effects of dopamine (DA) on the smooth muscle fibres of the renal vascular bed are complex. They involve the postsynaptic alpha- and beta-adrenoceptors as well as the dopamine ones. On denervated kidney, in presence of alpha- and beta-blockers, intrarenal DA perfusion provokes vasodilation, increases natriuresis and stimulates renin secretion. The vasodilator effect of DA on the renal vascular bed was studied thanks to an isolated perfused rat kidney preparation which, when high concentrations of phenoxybenzamine and sotalol were present, made it possible to measure the effect of dopaminomimetics and dopaminolytics on the renal vascular resistance of a kidney previously vasoconstricted by continuous PGF2 alpha perfusion. (+)--Butaclamol and cis-flupenthixol proved to be invaluable tools to demonstrate the specificity of the dopamino-agonists response, since both shift the dose-response curve according to the criteria for competitive antagonism at doses at which their isomers are not active (fig. 2). Thus, it was possible to calculate the apparent pA2 for the various dopaminolytics and to classify them according to their affinity for the renal vascular dopamine receptors. Table 1 gives the classification. Flupenthixol, which has only a low affinity for the alpha 2-adrenoceptors, already inhibits the vasodilator effect of DA at 10(-8) M. The low stereospecificity of the enantiomers of sulpiride allows a distinction to be drawn between the "postsynaptic" vascular dopamine receptors and the presynaptic ones. The agonists of the renal vascular dopamine receptors provoked dose-dependent renal vasodilation on our preparation when phenoxybenzamine and sotalol were present and this was stereoselectively inhibited by (+)-butaclamol. Table II shows the activity of the dopaminomimetics meeting these criteria. p-Tyramine, di-propyl-m-tyramine and RU 24926 proved to have no dopaminomimetic effect. Their lack of activity seems to be attributable to the suppression of the hydroxyl in position 4. Mesenteric, splenic or cerebral artery preparations were also used to characterize the vascular dopamine receptors : tables III and IV compare the results taken from the literature. The classification obtained tallies quite well which suggests that the dopamine receptors located in the various vascular beds are identical. We compared the characteristics of the renal vascular dopamine receptor established from isolated rat kidney, with three other pharmacological models of dopamine receptor : the activation of dopamine-sensitive adenylate cyclase, the presynaptic modulation of the transmission of the sympathetic influx, and prolactin release (Table V).(ABSTRACT TRUNCATED AT 400 WORDS)

Anesthesia↗
PubMed1983

Comparison of dopamine receptor sites labeled by [3H]-S-sulpiride and [3H]-spiperone in striatum.

Binding of the radiolabeled active isomer of the neuroleptic sulpiride, [3H]-S-sulpiride, to rat and rabbit striatal membranes was characterized. Regardless of whether the specific binding of [3H]-S-sulpiride was defined with spiperone or the active isomers of butaclamol or flupenthixol, a single homogeneous++ population of binding sites (rat: Kd = 5.6 nM, maximum binding = 590 fmol/mg of protein; rabbit: Kd = 8.3 nM, maximum binding = 540 fmol/mg of protein) was detected. The pharmacological profile of these sites was characteristic of that described for the dopaminergic D-2 receptor subtype. To determine whether [3H]-S-sulpiride and [3H]spiperone label common sites in the striatum, the binding of these two radioligands was compared under similar assay conditions. When specific binding of [3H]spiperone was defined with S-sulpiride, [3H]spiperone labeled the same number of binding sites as [3H]-S-sulpiride despite the fact that the affinity of the sites for [3H]spiperone was 80- to 90-fold higher than for [3H]-S-sulpiride. When specific binding of [3H]spiperone was defined with either (+)-butaclamol or (alpha)-flupenthixol, however, approximately 30% more sites were labeled. The predominant site labeled by [3H]spiperone also possessed the characteristics of the D-2 receptor. It is concluded that [3H]-S-sulpiride under the conditions used is a selective radioligand with which dopamine receptors of the D-2 subtype can be directly measured and localized. [3H]Spiperone can be used to detect the same sites only if specific binding is defined with S-sulpiride.

Animals↗
PubMed1984

Presynaptic dopaminergic activity of phencyclidine in rat caudate.

This study tested the hypothesis that phencyclidine (PCP) is an indirect dopamine (DA) agonist in the caudate nucleus. Single caudate neurons in rats anesthetized with urethane were recorded extracellularly with multibarrel micropipettes. Effects of drug solutions, applied by pressure microejection, were measured as changes in spontaneous and evoked neuronal activity. Caudate neurons were classified according to their latency-to-discharge in response to supramaximal cortical stimulation. PCP inhibited the spontaneous activity of 92% of neurons with latencies less than 13 msec, while DA inhibited 87%. Both drugs inhibited evoked activity significantly less than spontaneous activity (P less than .01). Neurons with latencies greater than 13 msec were excited by DA significantly more often (45%) than by PCP (13%; P less than .05). Receptor stereospecificity is suggested by the finding that the (+)-isomer of the 3-methyl piperidine derivative of PCP was significantly more potent than the (-)-isomer for inhibition of spontaneous activity. Mg++, which blocks presynaptic release of neurotransmitter, significantly antagonized inhibitory effects of PCP on spontaneous activity, which suggests a presynaptic effect of PCP. DA, which acts postsynaptically, was much less affected by Mg++. The potency of PCP was significantly less in rats treated with reserpine or 6-hydroxydopamine than in control rats, suggesting the endogenous DA is required for the action of PCP. Fluphenazine and (+)-butaclamol, potent DA-receptor antagonists, blocked the effect of PCP, but (-)-butaclamol did not. These results support the hypothesis that PCP facilitates release and/or inhibits reuptake of DA in nerve terminals and thereby acts as an indirect DA agonist in the caudate. However, there may be a subpopulation of caudate neurons in which PCP acts by a nondopaminergic mechanism.

Animals↗
PubMed1995

Cytotoxic effects of sigma ligands: sigma receptor-mediated alterations in cellular morphology and viability.

The morphological effects of several neuroleptics as well as other novel and prototypic sigma ligands were examined by addition to cultures of C6 glioma cells. Sigma ligands caused loss of processes, assumption of spherical shape, and cessation of cell division. The time course and magnitude of this effect were dependent on the concentration of sigma ligand. Continued exposure to sigma compounds ultimately resulted in cell death. However, the morphological effect was reversible when sigma ligand was removed shortly after rounding. The potency of compounds to produce these effects generally correlated with binding affinity at sigma receptors of C6 glioma cell membranes labeled with [3H](+)-pentazocine. At a concentration of 100 microM, haloperidol, reduced haloperidol, fluphenazine, perphenazine, trifluoperazine, BD737, LR172, BD1008, and SH344 produced significant effects in 3-6 hr of exposure. Other compounds, such as trifluperidol, thioridazine, and (-)-butaclamol, produced significant effects by 24 hr of exposure. Despite the requirement of micromolar concentrations of ligand (some compounds were effective at 30 microM), the effect showed a remarkable specificity for compounds exhibiting sigma receptor binding affinity. Neuroleptics lacking potent sigma affinity [e.g., (-)-sulpiride, (+)-butaclamol, and clozapine] and other compounds that lack significant sigma affinity but that are agonists or antagonists at dopamine, serotonin, adrenergic, glutamate, phencyclidine, GABA, opiate, or muscarinic cholinergic receptors were without effect on cellular morphology at concentrations up to 300 microM over a period of 72 hr. Likewise, blockers and activators of Na+, K+, and Ca2+ channels and a monoamine oxidase inhibitor devoid of sigma affinity were without effect. Interestingly, 1,3-di-o-tolylguanidine (DTG), (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [(+)-3-PPP], (+)-pentazocine, (+)-cyclazocine, and other sigma-active benzomorphans and morphinans appeared inactive in up to 72 hr of culture. However, these compounds interacted synergistically with a subeffective dose of BD737 (30 microM) to produce effects usually in 6 hr or less. Also, the pH of the culture medium had a profound effect on the activity of sigma compounds. Increasing the pH from the normal range of 7.2-7.4 to pH 8.3-8.5 shifted the dose curves (30, 100, 300 microM) for all sigma compounds to the left. Under these conditions, DTG, (+)-3-PPP, and benzomorphans produced effects in 24 hr or less.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Molecular cloning of a mammalian serotonin receptor that activates adenylate cyclase.

Serotonin modulates a wide range of physiological functions by activating multiple receptors, which are coupled to various effector systems. Using a strategy based on amino acid sequence homology between 5-hydroxytryptamine (5-HT) receptors, we have isolated from a mouse brain library a cDNA encoding a new 5-HT receptor, 5-HTx, that activates adenylate cyclase. Amino acid sequence comparisons revealed that the 5-HTx receptor was a distant relative of previously cloned 5-HT receptors, with the highest percentage of homology (42%) being with the 5-HTdro1 receptor, a Drosophila 5-HT receptor positively coupled to adenylate cyclase. In COS-7 cells transiently expressing the 5-HTx receptor, 5-HT induced an increase in cAMP levels that was dose dependent and saturable (EC50 = 45 nM). Agonists displayed the following rank order of potencies: 5-carboxamidotryptamine > 5-methoxytryptamine > 5-HT > RU 24969 > 8-hydroxy-2-(di-n-propylamino)tetralin. The most efficient antagonists in inhibiting the stimulatory effect of 5-HT were methysergide, methiothepin, mesulergine, metergoline, clozapine, ergotamine, and (+)-butaclamol. Membranes of COS-7 cells expressing the 5-HTx receptor displayed a single saturable binding site for [3H]5-HT. The order of potencies of various drugs in displacing [3H]5-HT binding was similar to the order obtained in cAMP experiments. The pharmacological profile of this receptor does not correspond to the profile of any of the classic 5-HT receptor subtypes. Expression of 5-HTx mRNA was highest in brainstem and lower in forebrain, cerebellum, intestine, and heart. The 5-HTx receptor might therefore correspond to 5-HT1-like receptors that have been shown to induce relaxation in porcine vena cava and guinea pig ileum as well as tachycardia in cat heart. The high affinity of the 5-HTx receptor for neuroleptic agents such as (+)-butaclamol and clozapine suggests also that this receptor might play a role in certain neuropsychiatric disorders.

Adenylyl Cyclases↗
PubMed1993

[3H]quinpirole binding to putative D2 and D3 dopamine receptors in rat brain and pituitary gland: a quantitative autoradiographic study.

The putative D2 dopamine receptor agonist quinpirole (LY 171,555) has been extensively used in a variety of in vivo and in vitro studies of D2 receptor-mediated effects and may have even higher affinity for the recently described D3 dopamine receptor. In the present study, conditions for autoradiographic visualization of [3H]quinpirole-labeled D2-like dopamine receptors were optimized and binding to slide-mounted sections was characterized with respect to pharmacology, guanine nucleotide sensitivity and regional distribution. The pharmacological profile of [3H]quinpirole binding in slide-mounted brain sections was: (+/-)-2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene > or = quinpirole > dopamine for putative dopamine agonists; spiperone > (+)-butaclamol > (-)-sulpiride > SCH 23390 >> cinanserin > (-)-butaclamol for antagonists. [3H]Quinpirole binding was decreased in the presence of guanine nucleotides in most brain regions except in the islands of Calleja and the molecular layer of cerebellar lobules 9 and 10. The regional distribution of [3H]quinpirole binding sites roughly paralleled the distribution of [3H]-(-)-sulpiride binding sites, with greatest densities present in the olfactory bulb glomerular layer, islands of Calleja, pituitary intermediate lobe, caudate/putamen, olfactory tubercles and nucleus accumbens. However, significantly greater densities of [3H]quinpirole binding than [3H]-(-)-sulpiride binding were observed in the molecular layer of cerebellar lobules 9 and 10, the islands of Calleja and olfactory bulb glomerular layer in concordance with the recently reported distribution of D3 receptor mRNA in these brain regions. Higher concentrations of [3H]quinpirole binding were also observed in the dorsomedial caudate and pituitary intermediate lobe. These data indicate the utility of [3H]quinpirole to label D3 as well as D2 dopamine receptors.

Animals↗
PubMed1980

Spiroperidol binding in the human caudate nucleus.

The displacement of spiroperidol binding by the optical isomers of butaclamol in synaptosomal preparations of the caudate nucleus obtained from parkinsonians and non-parkinsonians at post mortem were investigated. A group of spiroperidol binding sites found in the non-parkinsonians was less strongly expressed or absent in analogous tissue of the parkinsonian. The significance of these findings in relation to Parkinson's disease and its treatment are discussed.

Binding, Competitive↗
PubMed1987

Renal and iliac vascular effects of dopamine in the anaesthetized rat.

The renal and iliac vascular effects of dopamine were compared in pentobarbital anaesthetized rats. Local vascular resistances were calculated from simultaneous measurement of blood pressure, renal and iliac blood flow. Without pretreatment, dopamine increased renal and iliac vascular resistance. After pretreatment with prazosin, dopamine decreased the renal vascular resistance while the iliac vascular resistance was still increased. After a combination of yohimbine and prazosin pretreatment, dopamine lowered both the renal and iliac vascular resistance by 30%. These responses were not modified by the beta-adrenoceptor antagonist, sotalol, or by pretreating the rats with reserpine. The renal but not the iliac vascular response to dopamine was abolished by (+)-butaclamol, a stereoselective dopamine receptor antagonist, and by SCH 23390, the DA1-selective dopamine receptor antagonist. The decrease in iliac vascular resistance was not modified by indomethacin or the non-selective 5-HT receptor antagonist, metitepin. These results show that after blockade of alpha 1 and alpha 2-adrenoceptors, dopamine induces iliac vasodilation by a postsynaptic mechanism independent of an interaction with beta-adrenoceptors, dopamine or serotonin receptors. They also confirm in the rat in vivo the existence of renal vasodilation mediated by DA1 dopamine receptors.

Adrenergic alpha-Antagonists↗
PubMed1978

Amphetamine- type reinforcement by dopaminergic agonists in the rat.

Intravenous self-administration of d-amphetamine (0.25 mg/kg/injection) decreased in a dose-related fashion after injections of the dopaminergic agonists apomorphine and piribedil. The dopaminergic agonists appear to suppress amphetamine intake in the same way as do 'free' amphetamine injections, by extending drug satiation in a given interresponse period. Clonidine, an alpha noradrenergic agonist, did not have similar effects. Apomorphine and piribedil did not increase 14C-amphetamine levels in rat brains, nor did they retard disappearance of 14C-amphetamine; thus their amphetamine-like effects are not due to alterations of amphetamine metabolism. Rats responding for amphetamine continued to respond for apomorphine or peribedil when the latter drugs were substituted for the former. Rats experienced in amphetamine self-administration readily initiated and maintained responding for apomorphine and piribedil. The dopaminergic blocker (+)-butaclamol disrupted responding for apomorphine and piribedil, although it produced no marked increase in responding for the dopaminergic agonists, as it does for amphetamine. These data add to the evidence that actions in the dopaminergic synapse account for amphetamine's reinforcing properties.

Amphetamine↗