D-1 and D-2 dopamine receptor blockade: interactive effects in vitro and in vivo

Haloperidol, at low concentrations that block D-2 dopamine (DA) receptors but not D-1 DA receptors (less than 10 microM), potentiated the enhancement of adenylate cyclase activity produced by the D-1 agonist SKF 38393. Low concentrations of haloperidol (less than or equal to 5 microM) also potentiated the K+-evoked release of [3H]acetylcholine from superfused striatal tissue slices. Both of these effects of haloperidol were blocked by nanomolar concentrations of SCH 23390, a D-1 receptor antagonist. In addition, SCH 23390 reduced the ability of haloperidol to antagonize the inhibition of [3H]acetylcholine release produced by the DA agonist apomorphine. By itself, SCH 23390 did not alter either basal adenylate cyclase activity or the K+-evoked release of [3H]acetylcholine. These findings suggest that SCH 23390 can attenuate in vitro responses to D-2 receptor blockade. Likewise, in vivo, very low doses (less than 1 microgram/kg) of SCH 23390 reduced the ability of haloperidol to elevate striatal DA metabolite concentrations and plasma prolactin concentrations. Thus, D-1 receptor blockade may attenuate the effects of D-2 DA receptor blockade both in vitro and in vivo.     

Pharmacological characterization of rat renal medulla dopamine-sensitive cyclic adenosine monophosphate generating system

The dopamine (DA) DA-1 and DA-2 receptors coupled to 3'-5'-cyclic adenosine monophosphate (cAMP) generating system were characterized in membrane particles of the rat kidney medulla. In confirmation of reports using central and other peripheral tissues, activation of DA-1 receptors with DA, apomorphine or SKF 82526 induced accumulation of cAMP. This effect was blocked by the DA-1 receptors antagonist SCH 23390 and by the other DA-2 receptor antagonists fluphenazine and haloperidol. DA-2 receptor responses coupled negatively to the cAMP generating system were obtained by incubating renal medulla membrane particles with DA or SKF 82526 together with SCH 23390. DA-2 receptor responses were also elicited with the receptor agonists quinpirole and bromocriptine in the absence of SCH 23390. These inhibitory effects on cAMP generation were abolished by the DA-2 receptor antagonist l-sulpiride. Our findings suggest that rat renal medulla contains DA DA-1 and DA-2 receptors similar to those found in brain and in other peripheral tissues. The physiological significance of these receptors, if any, should be established in future studies.     

Pharmacological and biochemical characterization of the D-1 dopamine receptor mediating acetylcholine release in rabbit retina

Superfusion with dopamine (0.1 microM-10 mM) evokes calcium-dependent [3H]acetylcholine release from rabbit retina labeled in vitro with [3H]choline. This effect is antagonized by the D-1 dopamine receptor antagonist SCH 23390. Activation or blockade of D-2 dopamine, alpha-2 or beta receptors did not stimulate or attenuate the release of [3H]acetylcholine from rabbit retina. Dopamine receptor agonists evoke the release of [3H]acetylcholine with the following order of potency: apomorphine greater than or equal to SKF(R)82526 greater than SKF 85174 greater than SKF(R)38393 greater than or equal to pergolide greater than or equal to dopamine (EC50 = 4.5 microM) greater than SKF(S)82526 greater than or equal to SKF(S)38393. Dopamine receptor antagonists inhibited the dopamine-evoked release of [3H]acetylcholine: SCH 23390 (IC50 = 1 nM) greater than (+)-butaclamol greater than or equal to cis-flupenthixol greater than fluphenazine greater than perphenazine greater than trans-flupenthixol greater than R-sulpiride. The potencies of dopamine receptor agonists and antagonists at the dopamine receptor mediating [3H]acetylcholine release is characteristic of the D-1 dopamine receptor. These potencies were correlated with the potencies of dopamine receptor agonists and antagonists at the D-1 dopamine receptor in rabbit retina as labeled by [3H]SCH 23390, or as determined by adenylate cyclase activity. [3H]SCH 23390 binding in rabbit retinal membranes was stable, saturable and reversible. Scatchard analysis of [3H]SCH 23390 saturation data revealed a single high affinity binding site (Kd = 0.175 +/- 0.002 nM) with a maximum binding of 482 +/- 12 fmol/mg of protein. The potencies of dopamine receptor agonists to stimulate [3H]acetylcholine release were correlated with their potencies to stimulate adenylate cyclase (r = 0.784, P less than .05, n = 7) and with their affinities at [3H]SCH 23390 binding sites (r = 0.755, P greater than .05, n = 8). The potencies of antagonists to inhibit dopamine-evoked [3H]acetylcholine release were correlated with their potencies to inhibit the dopamine-stimulated adenylate cyclase (r = 0.759, P less than .05, n = 5) and with their affinities at [3H]SCH 23390 binding sites (r = 0.998, P less than .01, n = 7). We conclude that in rabbit retina dopamine evokes calcium-dependent [3H]acetylcholine release through activation of a site with the pharmacological characteristics of a D-1 dopamine receptor.     

Stimulation of a dopamine D1 receptor enhances inositol phosphates formation in rat brain

Accumulation of inositol phosphates was determined in rat brain slices prelabeled with 2-[3H]inositol and incubated with various drugs. In the striatum, micromolar concentrations of dopamine, apomorphine and SKF38393 induced significant accumulations of inositol phosphates in a dose-dependent manner, whereas quinpirole lacked effect. The EC50 values for the accumulation of inositol monophosphate induced by dopamine, apomorphine and SKF38393 were, respectively, 148, 159 and 129 microM. SKF 38393 effect was time-dependent on the accumulation of all three inositol phosphates, with peak effects occurring 64-128 min after drug addition. The action of the dopamine D1 receptor agonist, SKF38393, was blocked by SCH23390 (D1-selective antagonist), but not by sulpiride (D2-selective antagonist), atropine (muscarinic antagonist), prazosin (alpha-1 adrenoceptor antagonist) or methiotepin and methysergide (serotonergic antagonists), indicating that the observed effects of dopaminergic agonists were selectively mediated through the D1 dopamine receptor. On examining the effect of SKF38393 in several brain regions, the highest dopaminergic stimulation of inositol phosphates formation was obtained in the amygdala, followed by the hippocampus and then the striatum and frontal cortex. The finding of an SKF38393-stimulated PI hydrolysis in amygdala, a brain region that is enriched in SCH23390 and SKF38393 binding sites but devoid of dopamine-stimulated adenylate cyclase, suggests that the D1 receptor that is linked to PI metabolism is independent of the D1 receptor which stimulates cyclic AMP formation.     

Effect of dopamine receptor activation on ganglionic transmission and cyclic AMP levels in the stellate ganglia and renal arteries of the dog

By using selective dopamine (DA) receptor agonists and antagonists, we have demonstrated previously the presence of DA-2- and DA-1-like DA receptors in the stellate ganglia of the dog. Activation of either DA-2- or DA-1-like receptors by quinpirole or fenoldopam, respectively, leads to inhibition of ganglionic transmission. In the present study we have examined the involvement of DA receptor subtypes in the action of DA on ganglionic transmission. Inasmuch as stimulation of DA receptors is linked to the activation (DA-1) or inhibition (DA-2) of the enzyme adenylate cyclase, we have also measured the accumulation of cyclic AMP (cAMP) for biochemical characterization of ganglionic DA receptors. In isolated stellate ganglia treated with phentolamine and propranolol, DA caused concentration-dependent inhibition of ganglionic transmission as evidenced by reductions in the amplitude of the evoked postganglionic compound action potentials. The inhibitory effect of DA on ganglionic transmission was antagonized by both the DA-1 receptor antagonist, R-sulpiride, and the DA-2 receptor antagonist, S-sulpiride. However, the more potent and selective DA-1 receptor antagonist, SCH-23390, failed to antagonize the DA-induced inhibition of ganglionic transmission. Isolated stellate ganglia were also utilized for the measurement of cAMP. Neither DA nor the selective DA-1 receptor agonist, fenoldopam, caused any significant changes in cAMP, suggesting the lack of an adenylate cyclase-linked DA-1 receptor in the ganglia. On the other hand, beta adrenoceptor activation by isoproterenol produced a 3-fold increase in cAMP content of the stellate ganglia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Chronic treatment with SCH 23390 and haloperidol: effects on dopaminergic and serotonergic mechanisms in rat brain

Effects of chronic administration (18 days) with SCH 23390 (0.1 or 0.5 mg/kg/day s.c.) and haloperidol (1 mg/kg/day s.c.) on dopamine and serotonin synthesis and metabolism in discrete dopaminergic and serotonergic nuclei of rat brain were studied. Additionally, the effects of these treatments on dopamine D-1 and D-2 receptor characteristics in rat caudate-putamen were investigated. Chronic administration with both dose regimens of SCH 23390 decreased DA metabolism significantly (basal homovanillic acid concentrations) in nucleus caudatus. In another set of experiments dopamine synthesis (rate of accumulation of 3,4-dihydroxyphenylalanine after 3,4-dihydroxyphenylalanine-decarboxylase inhibition) was reduced significantly only in nucleus accumbens after the higher SCH 23390 dose regimen. In turn, chronic administration with haloperidol decreased basal dopamine metabolism and synthesis in nucleus caudatus and nucleus accumbens. Chronic haloperidol, but not SCH 23390, treatment induced a clear-cut increase in [3H]spiperone binding in caudate-putamen. Interestingly, neither SCH 23390 nor haloperidol treatments affected [3H]SCH 23390 binding in caudate-putamen. SCH 23390 and haloperidol had no significant effects on serotonin synthesis and metabolism in serotonergic and dopaminergic areas. In conclusion, the classical antipsychotic drug, haloperidol, clearly decreases dopamine turnover in nigrostriatal and mesolimbic dopaminergic systems. The D-1 antagonist, SCH 23390, also decreases dopaminergic activity in nigrostriatal and mesolimbic systems although DA synthesis and metabolism are affected to different degrees in nucleus caudatus and nucleus accumbens. Therefore, we suggest that if D-1 antagonists such as SCH 23390 show antipsychotic activity in clinical studies, they may not be free of extrapyramidal side-effects.     

SCH23390 effects on apomorphine-induced responses of nigral dopaminergic neurons

SCH23390 is a dopamine antagonist which has a high affinity for D1-like dopaminergic receptors. Receptor binding studies demonstrated significant levels of specific SCH23390 binding within nigral tissue. Therefore, electrophysiological experiments were conducted to determine if this antagonist influenced apomorphine-induced suppressions of unit firing recorded from dopaminergic cells of the substantia nigra zona compacta. Results presented in this report indicate that the autoreceptors located on dendrites and cell bodies of dopamine-containing neurons are not directly acted upon by SCH23390. This conclusion is drawn because: doses of SCH23390 known to block behaviors caused by dopamine agonists were ineffective in blocking rate reductions produced by apomorphine and pretreatment with 0.1 mg/kg of SCH23390 did not change the apomorphine dose-response curve for inhibition of dopaminergic neurons. Consistent with this finding, microinjections of SCH23390 into the zona compacta did not alter apomorphine-induced behaviors which are known to be blocked by haloperidol (a D2-like antagonist) intranigral injections. However, when only the larger apomorphine doses (64 and 128 micrograms/kg i.v.) are considered, SCH23390 pretreatment did attenuate the maximum response to apomorphine in some nigral cells. Because larger apomorphine concentrations alter striatal activity, such results may be reflective of alterations in a subpopulation of nigral neurons which are postsynaptic to neurons containing D1-like receptors and located elsewhere in the brain (e.g., in striatum). Collectively, these results agree with previous studies which suggest that dopamine receptors located on dopamine-containing neurons of the substantia nigra zona compacta are likely not of the D1-type.     

Do D-1 dopamine receptors mediate dopamine-induced pancreatic exocrine secretion in anesthetized dogs?

Characterization of dopamine (DA) receptor subtypes was examined on the canine exocrine pancreas using selective DA receptor agonists and antagonists in the isolated and blood-perfused pancreas of anesthetized dogs. Each drug was injected i.a. in a single bolus fashion. Graded doses of DA (0.01-3 mumol) produced dose-dependent increases in the secretory rate of pancreatic juice, with a maximum effect at approximately 1 mumol. SCH23390 (3-30 nmol), a selective D-1 DA receptor antagonist, caused a progressive parallel shift to the right in the dose-response curve for DA-induced pancreatic secretion without changes in the maximal response. High doses of RS-sulpiride (0.3-3 mumol) or haloperidol (1-3 mumol), a mixed D-1/D-2 DA receptor antagonist, also caused a rightward shift in the DA dose-response curve. However, domperidone (3 mumol), a selective D-2 DA receptor antagonist, did not antagonize the DA-induced pancreatic exocrine secretion. A modified Schild analysis of the data indicates that SCH23390 is approximately 2 and 3 orders of magnitude more potent than RS-sulpiride and haloperidol, respectively. In addition, the stimulatory effects of DA (0.01-3 mumol), SKF38393 (0.1-10 mumol, a selective D-1 DA receptor agonist) and LY171555 (1-10 mumol, a selective D-2 DA receptor agonist) on pancreatic secretion were demonstrated. The rank order of agonist potency was DA greater than SKF38393 greater than LY171555. The secretory response to LY171555 was inhibited completely by pretreatment with SCH23390 (30 nmol).(ABSTRACT TRUNCATED AT 250 WORDS)     

Fenoldopam is a partial agonist at dopamine-1 (DA1) receptors in LLC-PK1 cells.

Fenoldopam [6-chloro-7,8-dihydroxy-1-(4'-hydroxyphenyl)-2, 3,4,5-tetrahydro-(1H)-3-benzazepine] is a selective dopamine-1 (DA1) agonist with natriuretic/diuretic properties. A component of the natriuretic response to fenoldopam may involve direct DA1 receptor-mediated effects on proximal tubule sodium reabsorption, possibly through stimulation of adenylyl cyclase. Here, we compared the effects of fenoldopam and DA in stimulating cyclic AMP (cAMP) synthesis in LLC-PK1 cells, a renal epithelial cell line that has proximal tubule-like properties and expresses a DA1 receptor linked to stimulation of adenylyl cyclase. Fenoldopam stimulated cAMP accumulation in LLC-PK1 cells in a dose-dependent manner, an effect which could be blocked by the DA1-selective antagonist Sch 23390. Although fenoldopam was more potent than DA (EC50 55.5 +/- 7.75 nM vs. 1.65 +/- 0.64 microM) in stimulating cAMP accumulation in LLC-PK1 cells, the maximum stimulation obtained by fenoldopam was only 37% of the maximum stimulation obtained by DA(Emax 13.0 +/- 2.95 pmol/mg of protein vs. 35.6 +/- 10.19 pmol/mg of protein). Simultaneous incubation of DA and fenoldopam resulted in lower cAMP levels than with DA alone. Incubation of DA with increasing concentrations of fenoldopam produced parallel rightward shifts in the DA dose-response curves. Schild analysis further indicated that fenoldopam acted as a competitive antagonist in the presence of DA, with a pA2 value of 7.38 and a slope of unity. These results indicate that fenoldopam is a partial agonist with low efficacy at DA1 receptors linked to cAMP generation in the LLC-PK1 cells.     

Effects of chronic SCH23390 treatment on the biochemical and behavioral properties of D1 and D2 dopamine receptors: potentiated behavioral responses to a D2 dopamine agonist after selective D1 dopamine receptor upregulation

Chronic treatment of rats with SCH23390 (0.5 mg/kg/day s.c.), a D1 dopamine receptor antagonist, for 21 days resulted in an increase in D1 dopamine receptors but produced no change in D2 dopamine receptors. During habituation to locomotor activity cages the rats treated chronically with SCH23390 showed significantly higher locomotor activity than controls treated chronically with saline. When injected with the selective D1 dopamine receptor agonist SKF38393 (3 mg/kg), rats treated chronically with SCH23390 showed significantly greater stereotypy and locomotor activity responses. Surprisingly, rats treated chronically with SCH23390 also showed significantly higher locomotor activity and stereotypy responses when treated with the selective D2 dopamine receptor agonist, quinpirole (LY171555) (0.3 mg/kg). These results indicate that a selective increase in D1 receptors may not be necessary, but is sufficient, to lead to an enhanced behavioral response to either selective D1 or D2 dopamine receptor agonists. If, indeed, an enhanced stereotypy and locomotor activity response to dopaminergic agonists in rats after a brief chronic treatment with a neuroleptic drug is predictive of tardive dyskinesia potential in the clinical setting, these results can suggest that SCH23390 may also induce tardive dyskinesia in humans. Adenylate cyclase activity stimulated by guanine nucleotides, forskolin or dopamine was enhanced after chronic treatment with SCH23390. However, dopamine-stimulated adenylate cyclase activity was not potentiated detectably by the increase in receptor number over the more general increase in guanine nucleotide-stimulated cyclic AMP production. Additionally, no change was observed in dopamine competition for [3H]SCH23390 binding, with dopamine's RH/RL ratio remaining unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)     

D-2 dopamine receptors inhibit release of aspartate and glutamate in rat retina.

Release of endogenous Asp, Glu and gamma-aminobutyric acid (GABA) has been investigated using synaptosomes prepared from rat retina. Exposure in superfusion to a depolarizing concentration of KCl (30 mM) evoked overflow of Asp and Glu, which were almost entirely Ca-dependent. However, 70% of the GABA release was Ca-independent. Dopamine (DA) almost completely inhibited the K(+)-evoked release of Asp and Glu in a concentration-dependent manner, but the release of GABA was only partly inhibited. The potencies of DA (IC50) to Asp and Glu release were 12 and 30 nM, respectively. A selective D-2 receptor antagonist, S-sulpiride, counteracted the DA-induced inhibition of Asp and Glu release, but a selective D-1 antagonist, SCH 23390, showed no effect. The data suggest that D-2 dopamine receptors located on the Asp and Glu neurons in rat retina may inhibit the release of these excitatory amino acids.     

Castration blocks chronic sulpiride-induced desensitization of striatal D1 receptor-stimulated adenylate cyclase activity in male rats

Gonadal hormones have been shown to modulate adaptive responses of the mesostriatal dopaminergic system to antipsychotic challenge. We examined the role of endogenous gonadal steroids in the regulation of D1 receptor function after chronic treatment with sulpiride, a D2 specific antagonist. Chronic sulpiride treatment induced a desensitization of striatal D1 receptor-simulated adenylate cyclase activity in intact male rats with no change in the number of D1 or D2 receptors. This desensitization of D1-stimulated adenylate cyclase activity was expressed as a decrease in Vmax with no change in the activation constant. Castration of male rats blocked the chronic sulpiride-induced desensitization of D1 receptor function. Castration of male rats also resulted in a decrease in the number of D1 receptors as measured by [3H]SCH23390 binding. Ovariectomy of female rats had no effect on striatal D1 receptor-stimulated adenylate cyclase activity. Preliminary studies showed no effect of chronic sulpiride treatment on D1 receptor function in intact or ovariectomized female rats. We conclude that testicular hormones have a permissive effect on the expression of the chronic sulpiride-induced desensitization of D1 receptor function.     

Dopamine selectively inhibits angiotensin II-induced aldosterone secretion by interacting with D-2 receptors

Aldosterone secretion is subject to both stimulatory and inhibitory controls. Angiotensin II (AII) is the primary stimulator of aldosterone production and an inhibitory role of dopamine (DA) has been suggested recently. In this study we investigated the interactions between DA and AII in the intracellular events leading to aldosterone secretion. By measuring aldosterone secretion and cyclic AMP (cAMP) formation in intact adrenal glomerulosa cells we show that AII induced a sustained stimulation of aldosterone secretion (EC50, 0.41 nM) and a rapid and transient increase in intracellular cAMP content (EC50, 4 nM). DA inhibited both aldosterone secretion (IC50, 300 nM) and cAMP formation (IC50, 100 nM) elicited by submaximal concentrations of AII; in contrast, DA did not attenuate either basal or adrenocorticotropic hormone-stimulated cell activity. The pharmacological characterization of DA effects with dopaminergic agonists and antagonists strongly indicated an involvement of D-2 receptors. Indeed, selective D-2 agonists were more effective than DA in inhibiting the glomerulosa cell responses to AII; in addition, the effects of DA on both aldosterone secretion and cAMP formation were prevented by D-2 antagonists, such as (-)-sulpiride and domperidone, but not by the selective D-1 antagonist SCH 23390. These data suggest a specific functional interaction between D-2 receptors apparently associated with inhibition of cAMP formation and AII in the regulation of aldosterone production.     

Antagonism by pimozide of olanzapine-induced hypothermia

The atypical antipsychotic olanzapine (2.5-20 mg/kg) produced hypothermia in rats. The decrease in rectal temperature caused by olanzapine (2.5-20 mg/kg) was blocked by the selective dopamine D2 receptor antagonist pimozide (0.5 and 1 mg/kg) but not by the dopamine D1 receptor antagonist SCH 23390 (0.5 and 1 mg/kg). The dopamine D1/D2 receptor agonist apomorphine (3 mg/kg) and the selective dopamine D2 receptor agonist talipexole (0.5 mg/kg) produced hypothermia in rats. Olanzapine (10 and 20 mg/kg) significantly blocked hypothermia produced by both apomorphine and talipexole while the lower doses (2.5 and 5 mg/kg) of olanzapine failed to block it. The present results demonstrate that olanzapine behaves as a partial agonist at brain DA D2 receptor populations involved in thermoregulation in the rat.     

3H]SCH 23390 labels both dopamine-1 and 5-hydroxytryptamine1c receptors in the choroid plexus

[3H]SCH 23390 has been used to label the D-1 subtype of dopamine receptors. Quantitative autoradiographic studies with [3H]SCH 23390 have revealed high levels of binding in many regions of rat brain including the caudate-putamen, nucleus accumbens, substantia nigra and choroid plexus. The selectivity of the binding of [3H]SCH 23390 was characterized further in studies using homogenates of canine choroid plexus. Scatchard analysis of the binding of increasing concentrations of [3H]SCH 23390 resulted in a curvilinear plot when (+)-butaclamol was used to define specific binding. Nonlinear regression analysis of untransformed data was consistent with the presence of two distinct classes of binding sites. The high-affinity site (Kd, 0.4 nM) was present at low density (maximum binding sites, 30 fmol/mg of protein) and had the pharmacological properties expected of a D-1 receptor. The low-affinity site (Kd, 24 nM) was present at a much greater density (maximum binding sites, 350 fmol/mg of protein) and had the pharmacological properties expected of a 5-hydroxytryptamine1c receptor. Quantitative autoradiographic studies of the binding of [3H]SCH 23390 to sections of rat brain also suggested that 5-hydroxytroptamine1c receptors in the choroid plexus are labeled by [3H]SCH 23390. It is possible that [3H]SCH 23390 labels 5-hydroxytryptamine1c receptors in other brain regions as well.     

Presynaptic dopamine receptors involved in the inhibition of noradrenaline and dopamine release in the human gastric and uterine arteries

Electrical stimulation-induced depolarization releases both dopamine (DA) and noradrenaline (NA) from sympathetic neurones of the human gastric and uterine arteries. The overflow of catecholamines elicited by electrical stimulation was measured by using high performance liquid chromatography with electrochemical detection. The addition of yohimbine (0.01-10 microM), an alpha2-adrenoceptor antagonist, to the perfusion fluid increased, in a concentration-dependent manner, the electrically-evoked DA and NA overflow from gastric and uterine arteries. In the presence of sulpiride (0.01-10 microM), a dopamine D2-type receptor antagonist, the overflow of both amines was found to be increased in the uterine artery, but not in the gastric artery. Apomorphine (0.1-10 microM), a dopamine receptor agonist, produced a dose-dependent inhibition in the amount of DA and NA released from gastric and uterine arteries. SCH 23390 (0.1-10 microM), a dopamine D1 receptor antagonist, had no effect on the release of both amines in both preparations. The inhibitory effect of apomorphine was blocked by sulpiride in the gastric and uterine arteries but not by SCH 23390. The results presented suggest the existence of dopamine D2-type receptors in the human gastric and uterine arteries. They seem to have, in each artery, a different physiological importance.     

FCE 23884, substrate-dependent interaction with the dopaminergic system. II. Preclinical biochemical studies.

The effects of FCE 23884 [4-(9,10-didehydro-6-methylergolin-8 beta-yl) methyl-piperazine-2,6-dione] were examined using a variety of biochemical methods. In vitro assays showed that FCE 23884 bound to D-2, alpha-2 and 5-hydroxytryptamine1A sites with Ki values of 6.5, 4.0 and 4.0 nM, respectively. The affinity for D-1 and S-2 receptors was moderate (submicromolar range) and slight or negligible for alpha-1, cholinergic and sigma receptors. In normal rats, FCE 23884 accelerated markedly dopamine (DA) turnover in the neostriatum and nucleus accumbens as indicated by the increased ratios of dihydroxphenyl acetic acid/DA and homovanillic acid/DA. The compound enhanced DA synthesis and utilization rate. After gamma-butyrolactone treatment, a model to study DA autoreceptors function, FCE 23884 almost antagonized completely the gamma-butyrolactone reversal induced by apomorphine on l-dihydroxyphenylalanine accumulation in the two brain areas. In addition, FCE 23884 induced a rapid 20-fold increase of serum prolactin confirming its DA antagonistic profile in normal rats. In contrast with these antidopaminergic properties, FCE 23884 consistently stimulated basal adenylate cyclase activity in vitro (ED50 = 0.6 microM) and elicited a rapid increase of cyclic AMP formation in the neostriatum of normal (35%) and reserpinized (82%) rats in vivo. Furthermore in this last condition both the DA turnover and synthesis rate in the neostriatum and nucleus accumbens decreased after treatment with FCE 23884. These neurochemical data support the behavioral studies indicating that FCE 23884 possesses mixed DA antagonist and agonist properties depending on the experimental conditions, the distinguishing factor being presence or absence of DA.(ABSTRACT TRUNCATED AT 250 WORDS)     

Aspartate-releasing nerve terminals in rat striatum possess D-2 dopamine receptors mediating inhibition of release

The release of endogenous aspartic acid has been investigated using synaptosomes from rat corpus striatum. Exposure in superfusion to a depolarizing concentration of KCl (15 mM) evoked an overflow of aspartate which was almost entirely calcium-dependent. When added to the superfusion medium, dopamine (DA) and the selective DA D-2 receptor agonists quinpirole (LY-171555) and pergolide inhibited the K+ -evoked aspartate release in a concentration-dependent manner. The natural agonist DA was very potent (IC50 = 1 nM). The selective D-1 receptor agonist SK&F 38393 had no effect on the release of aspartate. The selective D-2 receptor antagonist S-sulpiride, but not the R-enantiomer, antagonized the DA-induced inhibition of aspartate release. The DA effect was unaltered by SCH 23390, a selective dopamine D-1 receptor antagonist. The findings that 1) the release of endogenous aspartate evoked by depolarization was calcium-dependent and 2) the release of aspartate was potently modulated through D-2 receptors are compatible with the idea that aspartate is released as a transmitter from striatal axon terminals. The possibility that aspartate and glutamate are coreleased from these terminals is discussed.     

Pharmacological characterization and autoradiographic localization of dopamine receptors in human epicardial arteries.

The pharmacological properties and the anatomical localization of dopamine (DA) D1 and D2 receptor sites were studied in normal samples of the human right coronary and anterior interventricular arteries by assessing the effect of DA on the cyclic AMP generating system and by using combined radioreceptor binding and autoradiographic techniques. DA caused a concentration-dependent accumulation of cyclic AMP in membranes of right and anterior interventricular coronary arteries. This effect was antagonized by the selective D1 receptor antagonist SCH 23390 and by other DA receptor antagonists. D2 receptor responses negatively coupled to cyclic AMP generation were obtained by incubating membranes of coronary arteries with DA together with SCH 23390 or with D2 receptor agonists. This D2 effect was abolished by the selective D2 receptor antagonist (-)-sulpiride. [3H]SCH 23390 was bound to sections of the coronary arteries in a manner consistent with the labeling of D1 sites. Light microscope autoradiography revealed the localization of D1 sites in the medial layer of the coronary arteries. [3H]Spiroperidol, in the presence of ketanserin, was bound to sections of the coronary arteries in a manner consistent with the labeling of D2 sites. D2 receptor sites were located within the adventitia and the adventitial-medial border of the two arteries, and are probably prejunctional in nature. These findings indicate the existence of both D1 and D2 receptor sites in human right and anterior interventricular arteries. Moreover, they suggest that coronary vasodilation induced by DA or DA receptor agonists may be the result of a direct coronary vasodilatory activity.     

Pharmacological differences between the D-2 autoreceptor and the D-1 dopamine receptor in rabbit retina

The effect of dopamine receptor agonists and antagonists was studied on the calcium-dependent release of [3H]dopamine elicited by field stimulation at 3 Hz for a duration of 1 min (20 mA, 2 msec) from the rabbit retina in vitro and on adenylate cyclase activity in homogenates of rabbit retina. The relative order of potency of dopamine receptor agonists to inhibit the stimulation-evoked [3H]dopamine release was pergolide greater than bromocriptine greater than apomorphine greater than LY 141865 greater than N,N-di-n-propyldopamine greater than or equal to dopamine. The relative order of potencies of dopamine receptor antagonists to increase [3H]dopamine release was: S-sulpiride greater than or equal to domperidone greater than or equal to spiroperidol greater than metoclopramide greater than fluphenazine greater than or equal to R-sulpiride. alpha-Flupenthixol (0.01-1 microM) and (+)-butaclamol (0.01-1 microM) did not increase [3H]dopamine overflow when added alone, but they antagonized the concentration-dependent inhibitory effect of apomorphine (0.1-10 microM). These results suggest that the dopamine inhibitory autoreceptor involved in the modulation of dopamine release from the rabbit retina possesses the pharmacological characteristics of a D-2 dopamine receptor. Maximal stimulation by 30 microM dopamine resulted in a 3-fold increase in adenylate cyclase activity with half-maximal stimulation occurring at a concentration of 2.46 microM. Apomorphine and pergolide elicited a partial stimulation of adenylate cyclase activity. However, at low concentrations both compounds were more potent than dopamine. N,N-di-n-Propyl-dopamine was 30 times less potent than dopamine, and bromocriptine was unable to stimulate adenylate cyclase activity.(ABSTRACT TRUNCATED AT 250 WORDS)