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)     

Pharmacological characterization of the receptor mediating electrophysiological responses to dopamine in the rat medial prefrontal cortex: a microiontophoretic study

The pharmacological profile of the receptor mediating inhibitory effects of dopamine (DA) in the rat medial prefrontal cortex (PFC) was characterized using extracellular single unit recording and microiontophoretic techniques. Iontophoretic application of DA inhibited 65% of spontaneously active cells in the deep layers of the PFC, while producing little effect on cells in superficial laminae. The D2 selective antagonist, sulpiride, specifically attenuated DA-induced inhibition of deep layer PFC neurons, without blocking the inhibitory effects of gamma-aminobutyric acid (GABA) or serotonin (5-HT). Surprisingly, sulpiride antagonism did not appear to be stereospecific, as both its (-)- and (+)-isomers proved equally effective at blocking the inhibitory effects of DA. In contrast to sulpiride, the D1 selective antagonist, SCH23390, was much less effective at attenuating inhibitory responses to DA. The effects of selective agonists also were examined on DA-sensitive PFC neurons. The D2 selective agonist, LY171555, and the D1 selective agonist, SKF38393, produced inhibitory effects on a small number of DA-sensitive PFC neurons. However, the majority of cells tested were inhibited only by DA and not by LY171555 or SKF38393. In addition, coiontophoresis of LY171555 and SKF38393. In addition, coiontophoresis of LY171555 and SKF38393 failed to inhibit the majority of DA-sensitive PFC cells tested. LY171555, but not SKF38393, significantly attenuated DA-induced inhibition when applied simultaneously, suggesting that the D2 selective agonist might possess partial agonist/weak antagonist activity at this receptor. These results indicate that the receptor mediating the inhibitory effects of DA in the medial PFC has the pharmacological characteristics of a D2 subtype. However, this receptor may not be identical to D2 sites in other brain regions.     

Interactions of D1 and D2 dopamine receptors on the ipsilateral vs. contralateral side in rats with unilateral lesions of the dopaminergic nigrostriatal pathway

In rats with a unilateral lesion of the nigrostriatal dopaminergic pathway, the ipsilateral rotation produced by the enhanced actions of endogenous dopamine (DA) on the nonlesioned side, induced by either the DA-releasing drug amphetamine or the DA uptake inhibitor GBR 13069, was blocked effectively by pretreatment with either the selective D1 DA receptor antagonist, SCH 23390, or the D2 selective antagonist, haloperidol. In contrast, contralateral rotation produced by apomorphine or I-dihydroxyphenylalanine, which lead to the preferential activation of D1 and D2 receptors on the lesioned side, was effectively prevented only when both receptor subtypes were inhibited. The results of these experiments demonstrate that the interaction between D1 and D2 receptors in the lesioned side differs from that in the nonlesioned side. Whereas the simultaneous stimulation of both DA receptor subtypes in the normally innervated basal ganglia is required for the production of turning behavior, the stimulation of either subtype alone in the dopaminergic denervated side can produce rotation. However, the concurrent administration of the D1 agonist, SKF 38393, with the D2 agonist, LY 171555, produced a synergistic effect on contralateral rotation. These results suggest that there is preservation of at least some functional interaction between D1 and D2 receptors in the lesioned basal ganglia but that there may be in addition a mechanism by which the two receptor subtypes can function independently of each other. The unilaterally lesioned rat appears to be a very good model in which to study the interaction between D1 and D2 receptors under conditions of both normal innervation and of DA denervation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibitory influence of the mesocortical dopaminergic neurons on their target cells: electrophysiological and pharmacological characterization

Both dopaminergic (DA) and noradrenergic (NA) systems exert an inhibitory influence on the activity of prefrontal cortical neurons (PFC). As NA-containing fibers run close to the dorsal ventral tegmental area (VTA), electrical stimulation of the VTA might coactivate both DA and NA systems. In the present study extracellular recordings and microiontophoresis were used in anesthetized rats to analyze first whether the inhibitory cortical responses to VTA stimulation and DA application were mediated by DA or adrenergic receptors. Inhibitory responses elicited by DA application or VTA stimulation were observed in PFC output neurons identified by antidromic activation from subcortical structures. Both types of inhibitory effects were reversed by the DA antagonist sulpiride, but not by the adrenergic antagonists prazosin (alpha-1), yohimbine (alpha-2) or propranolol (beta). NA and the beta agonist isoproterenol inhibited the activity of PFC cells and these effects were antagonized by propranolol, but neither by prazosin and yohimbine nor by the DA antagonist sulpiride. Thus, the inhibitory influence of the mesocortical DA system in the PFC involves DA, but not NA, recognition sites. The DA receptor subtype mediating the inhibitory effects of VTA stimulation and DA application in the PFC was analyzed further. VTA- and DA-evoked inhibitory responses were antagonized by the D2 selective antagonists (-)-sulpiride, LUR 2366 and RIV 2093, but not by the D1 selective antagonist SCH23390. In addition, the DA-induced inhibitory response was mimicked by the selective D2 agonist LY 171555 but not by the selective D1 agonist SKF 38393. Surprisingly, haloperidol, which is also a potent D2 antagonist, failed to consistently block DA- and VTA-induced inhibitory effects. The present results indicate that the inhibition of PFC cells by mesocortical DA neurons is mediated via a subtype of DA receptors which is particularly sensitive to benzamides.     

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.     

D1 receptor stimulation inhibits dopamine cell activity after reserpine treatment but not after chronic SCH 23390: an effect blocked by N-methyl-D-aspartate antagonists.

Single unit recordings were conducted to examine the effects of systemic D1 agonist SKF 38393 on the firing rate of substantia nigra pars compacta dopamine (DA) neurons in rats pretreated subchronically with reserpine or chronically with a D1 antagonist. The effect of N-methyl-D-aspartate receptor antagonists on these processes was also investigated. An i.v. injection of SKF 38393 (10 mg/kg) significantly inhibited DA cell activity by approximately 70% in rats pretreated with reserpine (1 mg/kg, s.c.) for 6 days and studied under conditions of local anesthesia. SKF 38393 exerted no effect in reserpinized rats anesthetized with chloral hydrate. The SKF 38393-induced inhibition was reversed by the D1 antagonist SCH 23390, but not by the preferential D2 antagonist haloperidol. This effect of SKF 38393 was observed in 60% of the rats as early as 3 to 8 hr after the first reserpine injection, and the inhibition remained significant 5 to 15 days (averaging 64 and 58%) after termination of the 6-day reserpine treatment. The N-methyl-D-aspartate antagonists ketamine, at anesthetic doses (100 mg/kg, i.p.), and MK 801, at a nonanesthetic dose (0.15 mg/kg, i.v.), completely blocked the inhibitory effect of SKF 38393. In contrast, DA cells recorded in rats pretreated with SCH 23390 for 7 to 21 days, followed by a 4-day washout period, failed to respond to SKF 38393. Because nigrostriatal DA neurons do not appear to express D1 receptors, these results suggest that D1 receptors can exert an indirect inhibitory effect on the activity of nigral DA neurons, presumably through striatonigral neuronal pathways.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacological analysis of the actions of SKF 82526 on cardiovascular dopamine receptors

We have performed experiments with SKF 82526, a selective dopamine (DA1) receptor agonist to determine whether this compound would activate either ganglionic and/or central DA receptors. Bilateral hindlimb perfusion was carried out at controlled flow rates and changes in hindlimb perfusion pressure were recorded to evaluate the action of SKF 82526 on vascular resistance in anesthetized dogs. Intracisternal administration of SKF 82526 (10 and 40 micrograms/kg) did not produce any changes in blood pressure, heart rate or hindlimb vascular resistance. When the same doses were administered i.v., SKF 82526 produced hypotension and a decrease in perfusion pressure in the innervated limb, whereas perfusion pressure in the denervated limb was not altered. Intravenous SKF 82526 did not produce any changes in heart rate. When given into the lower abdominal aorta, SKF 82526 caused a dose-dependent decrease in perfusion pressure only in the innervated hindlimb, no significant changes in perfusion pressure occurred in the denervated limb. The hypotensive and the hindlimb vasodilatory actions of SKF 82526 could be antagonized by RS-sulpiride. It was discovered that SCH 23390, a selective DA1 receptor antagonist was most potent in blocking the hypotensive action of i.v. SKF 82526; however, it did not influence the neurogenic hindlimb vasodilation produced by intra-aortic SKF 82526. On the other hand, R-sulpiride, another selective DA1 receptor antagonist significantly antagonized the hypotensive as well as hindlimb vasodilatory actions of SKF 82526. S-sulpiride, a selective DA2 receptor antagonist, was least effective in blocking hypotension and did not influence the hindlimb vasodilatory action.(ABSTRACT TRUNCATED AT 250 WORDS)     

Roles of central and peripheral mu, delta and kappa opioid receptors in the mediation of gastric acid secretory effects in the rat

The opioid receptors involved in the mediation of gastric acid secretory effects were studied in the pylorus-ligated rat. The effects of i.c.v. and i.v. administration of morphine and mu ([D-Ala2, NMePhe4, Gly5-ol]enkephalin and Tyr-Pro-NMePheD-Pro-NH2)-, delta ([D-Pen2,D-Pen5]enkephalin)- and kappa-selective [trans-3,4-dichloro-N-methyl-N-[2-91-pyrrolidinyl)-cyclohexyl]- benzeneacetamide methanesulfonate (U-50,488H), dynorphin-(1-9), dynorphin-(1-17), nalorphine, alpha-neoendorphin and ethyl-ketocyclazocine) opioid receptor agonists on gastric volume and acid output were examined. Morphine, [D-Ala2, NMePhe4, Gly5-ol]enkephalin and Tyr-Pro-NMePhe-D-Pro-NH2 decreased gastric acid secretion more potently after i.c.v. than after i.v. administration. The inhibitory effect of i.v. administered morphine on gastric acid secretion was not blocked by the quaternary opioid antagonist naltrexone methylbromide when given s.c. However, when naltrexone methylbromide was administered i.c.v., it blocked completely the effects of i.c.v. morphine and partially antagonized the effects of i.v. morphine, indicating a central site of action for morphine. The delta-selective agonist [D-Pen2,D-Pen5]enkephalin did not alter gastric acid secretion after i.c.v. or i.v. administration. The kappa-selective opioid agonist U-50,488H produced a dose-dependent increase in gastric acid secretion after i.v. but not i.c.v. administration. The other kappa-selective agonists tested did not produce a significant increase in gastric acid secretion after i.c.v. or i.v. administration. The increase in gastric acid secretion produced by U-40,488H was blocked by pretreatment with the opioid receptor antagonist naloxone, the nonselective muscarinic receptor antagonist atropine and the M1 selective muscarinic receptor antagonist pirenzepine.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

D2 dopamine receptors modulate calcium channel currents and catecholamine secretion in bovine adrenal chromaffin cells

Although dopamine is known to be present in sympathetic ganglia, its role and mode of action as a peripheral neurotransmitter are still poorly understood. Dopaminergic agonists have been shown to inhibit adrenal catecholamine release and calcium uptake. However, the specific dopamine receptor subtype mediating these effects and the receptor transduction mechanism remain unknown. We now provide evidence demonstrating 1) that slowly inactivating, voltage-gated calcium channels serve as a target site for dopaminergic modulation of chromaffin cell function and 2) that it is the D2 receptor subtype which mediates dopaminergic inhibitory effects on catecholamine secretion, 45Ca uptake and voltage-gated calcium currents. Whole cell patch clamp electrophysiological techniques were used to monitor directly voltage-gated Ca++ channels. The D2 agonist apomorphine but not the D1 agonist SKF 38393 reduced reversibly a slowly inactivating, voltage-gated calcium current in cultured chromaffin cells and this effect was blocked by the D2 receptor antagonist haloperidol. The presence of D2 but not D1 dopamine receptors on chromaffin cell membranes was demonstrated by radioligand binding methods, using the specific D1 and D2 receptor radioligands, [3H]SCH23390 and [3H]N-methylspiperone, respectively. Nicotine- and KCl (60 mM)-evoked catecholamine secretion and 45Ca uptake were inhibited by the D2 agonist, apomorphine, but not by the D1 agonist, SKF 38393. These inhibitory effects were prevented by the D2 antagonist, sulpiride, but not by the D1 antagonist, SCH 23390. D2 dopamine receptors appear to function as inhibitory modulators of adrenal catecholamine secretion with a mode of action involving inhibition of calcium channel currents.     

Effects induced by chronic treatment with selective D1 or D2 antagonists on open-field behavior and colonic temperature

We have studied the behavioral responses in open-field and the changes in body temperature induced after chronic treatment with a selective D1 antagonist, SCH 23390, a selective D2+ antagonist, sulpiride, or a non specific but preferential D2 antagonist, haloperidol. After chronic treatment with SCH 23390 or sulpiride, rats were challenged with SKF 38393, selective D1 agonist, or LY 171555, selective D2 agonist, in order to study the responses of D1 and D2 stimulation. After chronic SCH 23390, an increase of the locomotion and of the number of rears were observed whereas, no changes were induced by chronic sulpiride or haloperidol. Acute treatment with sulpiride blocked the hyperlocomotion induced by chronic SCH 23390. In naive rats acute administration of SKF 38393 or LY 171555 did not produce any change in locomotion or rearing. In rats treated chronically with SCH 23390 this acute administration of LY 171555 induced an increase of the number of squares and of the number of rears. In these animals, acute administration of SKF 38393 also augmented the number of squares crossed. In contrast, chronic sulpiride did not modify behavioral responses obtained after acute SKF 38393 or LY 171555. Colonic temperature was not changed after acute SKF 38393 while acute LY 171555 induced a hypothermia. Chronic sulpiride did not modify the responses of SKF 38393 or LY 171555, but an increase in body temperature was observed after acute SKF 38393 in animals chronically treated with SCH 23390. The present results support a different behavioral expression of D1 and D2 supersensitivity in rats. Furthermore, chronic treatment with a D1 antagonist induced facilitatory effects on D2 behavioral responses; however, these D1-D2 interactions were not observed in body temperature responses.     

Intravenous self-administration of dopamine receptor agonists by rhesus monkeys

Pharmacological studies have provided important information relevant to the behavioral role of central nervous system (CNS) dopamine (DA) as well as the existence of multiple DA receptors in the CNS. In the present experiment, the i.v. self-administration of several compounds that are direct DA receptor agonists was evaluated in rhesus monkeys. Apomorphine, piribedil, propylbutyldopamine and bromocriptine were self-administered by at least half of the animals tested, whereas SKF 38393 failed to maintain self-administration. Each of the compounds that was self-administered is an agonist at the DA2 receptor that has been demonstrated in the periphery, whereas SKF 38393 is principally a DA1 agonist. The results suggest that a DA receptor that is similar to the DA2 receptor is involved in this behavioral effect. In addition, the results are consistent with the hypothesis that CNS DA is involved in the reinforcing properties of psychomotor stimulants.     

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.     

Activation of DA1 receptors by dopamine or fenoldopam increases cyclic AMP levels in the renal artery but not in the superior cervical ganglion of the rat

In the isolated superior cervical ganglion of the rat, activation of either DA1 or DA2 receptors leads to inhibition of ganglionic transmission. Using dopamine as well as relatively selective dopamine receptor agonists and antagonists we have performed electrophysiological as well as biochemical experiments to study the nature of dopamine receptors in this sympathetic ganglion. Fenoldopam, a selective DA1 receptor agonist caused marked inhibition of the compound postganglionic action potential evoked by stimulation of preganglionic nerve. The inhibitory effect of fenoldopam was antagonized by the DA1 receptor antagonist R-sulpiride but not by the DA2 receptor antagonist S-sulpiride. However, the more potent and selective DA1 receptor antagonist SCH-23390 failed to antagonize ganglion blocking effect of fenoldopam indicating that DA1 receptor in sympathetic ganglia is different from that in blood vessels. The superior cervical ganglion also contains DA2 receptors inasmuch as quinpirole, a DA2 receptor agonist, caused inhibition of ganglionic transmission which was antagonized by S-sulpiride but not by R-sulpiride. The existence of both subtypes of dopamine receptor in the superior cervical ganglion was ascertained further as dopamine itself caused inhibition of ganglionic transmission which was antagonized by either S- or R-sulpiride. Again, however, the DA1 receptor antagonist SCH-23390 failed to antagonize the ganglion blocking effect of dopamine. To characterize further the ganglionic DA1 receptor we sought to demonstrate whether or not ganglionic DA1 receptor is linked to the enzyme adenylate cyclase as is known to be the case for peripheral DA1 or central D1 dopamine receptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Actions of nizatidine, a selective histamine H2-receptor antagonist, on gastric acid secretion in dogs, rats and frogs

Nizatidine (LY139037), a selective histamine H2-receptor antagonist, is a potent inhibitor of gastric acid secretion. It was 17.8 times as active as cimetidine on histamine (10(-5) M)-induced secretion from the isolated gastric mucosa of the bullfrog. Nizatidine was 8.9 times as active as cimetidine on basal acid secretion of the chronic gastric fistula rats after s.c. administration. Against acid secretion from the vagally innervated gastric fistula and Heidenhain pouch of dogs stimulated with submaximal doses of histamine, methacholine and gastrin, nizatidine was, respectively, 6.5, 5 and 4.7 times as active as cimetidine by i.v. administration. Nizatidine was very well absorbed from the gut and was 5 to 10 times as active as cimetidine on gastric acid secretion of dogs induced by submaximal and maximal doses of histamine when given p.o. Equal molar doses of nizatidine showed equal peak effects when given i.v., s.c. or i.m. Pharmacological data indicate that nizatidine is safe and effective as an agent for the control of excessive gastric acid secretion.     

Effect of continuous exposure to selective D1 and D2 dopaminergic agonists on rotational behavior in supersensitive mice

The effects of continuous exposure to selective dopaminergic agonists were examined in mice with unilateral 6-hydroxydopamine-induced lesions of the corpus striatum. Continuously infusing the D1 agonists, SKF 38393, SKF 75670 and Cy 208-243 with the use of implanted Alzet minipumps initially produced rotational behavior, but this effect decreased during the first 2 days and then stopped completely during days 3 to 7 of drug infusion. Infusion of the D2 agonists quinpirole and N-0437 also produced rotational behavior but, in contrast to the results seen with the D1 agonists, the rotational response remained present throughout the 7 days of drug exposure. The desensitization produced by continuous exposure to SKF 38393 was selective for the D1 system, as animals exposed continuously to SKF 38393 failed to rotate to an acute challenge dose of SKF 38393 but had a normal rotational response to quinpirole. SKF 75670 and CY 208-243 were less selective than SKF 38393; continuous exposure to SKF 75670 and CY 208-243 decreased the response to an acute injection of D1-agonists by 98 and 95%, respectively, and to that of D2-agonists by 64 and 38%, respectively. Infusing the peripherally acting D1 agonist, fenoldopam, or the inactive isomer (-)-SKF 38393 failed to produce desensitization, suggesting that SKF 38393-induced desensitization is produced by an action at D1 receptors within the central nervous system. These results demonstrate that the D1 system can be desensitized independently from the D2 system and that there are different mechanisms for the long term regulation of D1 and D2 dopaminergic systems.     

Effects of (+)-4-propyl-9-hydroxynaphthoxazine on midbrain dopamine neurons: an electrophysiological study

(+)-4-Propyl-9-hydroxynaphthoxazine (PHNO) is a highly potent, D2-selective dopamine (DA) receptor agonist. In the present study, we have examined the electrophysiological effects of PHNO on identified nigrostriatal DA (NSDA), mesoaccumbens DA (MADA) and Type I caudate neurons. Intravenous PHNO dose-dependently inhibited the firing rate of NSDA and MADA neurons in both chloral hydrate (CH)-anesthetized rats (ED50 values = 21.2 +/- 1.2 and 26.5 +/- 1.4 ng/kg, respectively) and locally anesthetized, paralyzed rats (ED50 values = 105.0 +/- 1.4 and 109.1 +/- 1.4 ng/kg, respectively). PHNO was significantly more potent in the CH-anesthetized rats. There was a significant, positive correlation between basal firing rate and log ED50 for NSDA neurons in both preparations and for MADA cells only in CH-anesthetized animals. Neither pretreatment with the D1 receptor agonist SKF 38393 nor hemitransection of the forebrain altered the rate-dependent nature of PHNO-induced inhibition of NSDA neurons. Likewise, depletions of serotonin with either p-chlorophenylalanine or 5,7-dihydroxytryptamine failed to alter the rate-dependent PHNO-induced inhibition of NSDA neurons. Iontophoretically applied PHNO inhibited both NSDA and MADA neurons to a similar degree as either DA or the D2 agonist quinpirole. In contrast, the similar effects of PHNO and quinpirole on Type I caudate neurons were significantly different than those of DA. These results suggest that PHNO inhibits midbrain DA neurons via stimulation of somatodendritic autoreceptors and that PHNO exhibits an electrophysiological profile characteristic of D2 agonists. In contrast to quinpirole, however, the rate-dependent nature of PHNO-induced inhibition of these cells was resistant to modulation.     

D1 receptors function to inhibit the activation of tuberoinfundibular dopamine neurons

The effects of the D1 dopamine agonists SKF 38393 and CY 208-243 on the activity of tyrosine hydroxylase within tuberoinfundibular dopamine neurons were studied by measuring the accumulation of dihydroxyphenylalanine (DOPA) in the median eminence in vivo after inhibition of DOPA decarboxylase. SKF 38393 (5-20 mg/kg) and CY 208-243 (5-20 mg/kg) alone did not alter the accumulation of DOPA in the median eminence of male rats. However, the haloperidol-, reserpine- and neurotensin-induced increases in DOPA formation in the median eminence were antagonized dose-dependently by SKF 38393 (5-20 mg/kg i.p.) and/or CY 208-243 (5-20 mg/kg i.p.). Treatment of rats with SCH 23390 (0.5 mg/kg i.p.), a selective D1 antagonist, or loxapine (5 mg/kg i.p.), a dopamine antagonist with high affinity for D1 receptors, prevented the inhibitory effect of CY 208-243 on the haloperidol-induced activation of tyrosine hydroxylase in the median eminence. SKF 38393 did not inhibit the basal activity or the haloperidol-induced increase in activity of tyrosine hydroxylase in the striatum or nucleus accumbens. It is concluded that D1 receptor activation results in little or no effect on the basal rate of dopamine synthesis within tuberoinfundibular dopamine neurons, but under conditions in which the activity of tyrosine hydroxylase is increased D1 receptor stimulation results in a marked inhibition of the rate of dopamine synthesis within these neurons.     

Opposite effects of NMDA receptor blockade on dopaminergic D1- and D2-mediated behavior in the 6-hydroxydopamine model of turning: relationship with c-fos expression.

In rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal dopaminergic pathway, I-dihydroxyphenylalanine (L-DOPA) induces contralateral turning through activation of denervated D1 and D2 receptors. Blockade of N-methyl-D-aspartate (NMDA) receptors by the noncompetitive antagonist (+)MK-801 (0.1 mg/kg, i.p.), potentiated L-DOPA-induced contralateral turning. In 6-OHDA lesioned rats, selective agonists of D1 (SKF 38393, CY 208-243) or D2 (LY 171555) receptors also induce contralateral turning; however, (+)MK-801 pretreatment, although markedly potentiating D1, almost completely inhibited D2-mediated turning. The potentiation of SKF 38393-induced contralateral turning by MK-801 was stereospecific and was observed also with the noncompetitive NMDA antagonist phencyclidine, and with the competitive antagonist CPP. Administration of the D1 antagonist SCH 23390 (0.1 mg/kg s.c.) blocked (+)MK-801-induced potentiation of L-DOPA contralateral turning, confirming the D1 nature of the effects observed. Expression of the early gene c-fos in the caudate-putamen (CPu) is known to be activated by stimulation of supersensitive D1 receptors. Immunohistochemical studies on c-fos revealed sparse c-fos positive nuclei in the lesioned CPu after 1.5 mg/kg of SKF 38393, whereas after combined administration of (+)MK-801 and SKF 38393, dense labeling of nuclei was obtained in the dorso-lateral aspect of the CPu. Therefore, blockade of NMDA receptors acts synergistically with D1 and antagonistically with D2 receptor stimulation in the 6-OHDA model of turning, suggesting that different neuronal pathways are involved in the mediation of D1 and D2 responses.     

Therapeutic potential of 1-methylnicotinamide against acute gastric lesions induced by stress: role of endogenous prostacyclin and sensory nerves

1-Methylnicotinamide (MNA) is one of the major derivatives of nicotinamide, which was recently shown to exhibit antithrombotic and antiinflammatory actions. However, it is not yet known whether MNA affects gastric mucosal defense. The effects of exogenous MNA were studied on gastric secretion and gastric lesions induced in rats by 3.5 h of water immersion and water restraint stress (WRS) or in rats administered 75% ethanol. MNA [6.25-100 mg/kg intragastrically (i.g.)] led to a dose-dependent rise in the plasma MNA level, inhibited gastric acid secretion, and attenuated these gastric lesions induced by WRS or ethanol. The gastroprotective effect of MNA was accompanied by an increase in the gastric mucosal blood flow and plasma calcitonin gene-related peptide (CGRP) levels, the preservation of prostacyclin (PGI(2)) generation (measured as 6-keto-PGF1alpha), and an overexpression of mRNAs for cyclooxygenase (COX)-2 and CGRP in the gastric mucosa. R-3-(4-Fluoro-phenyl)-2-[5-(4-fluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-propionic acid (RO 324479), which is the selective antagonist of IP/PGI(2) receptors, reversed the effects of MNA on gastric lesions and GBF. MNA-induced gastroprotection was attenuated by suppression of COX-1 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole; SC-560] and COX-2 [4-(4-methylsulfonylphenyl)-3-phenyl-5H-furan-2-one; rofecoxib] activity, capsaicin denervation, and by the pretreatment with CGRP(8-37) or capsazepine. Addition of exogenous PGI(2) or CGRP restored the MNA-induced gastroprotection in rats treated with COX-1 and COX-2 inhibitors or in those with capsaicin denervation. WRS enhanced MDA content while decreasing superoxide dismutase (SOD) activity in the gastric mucosa, but pretreatment with MNA reversed these changes. MNA exerts potent gastroprotection against WRS damage via mechanisms involving cooperative action of PGI(2) and CGRP in preservation of microvascular flow, antioxidizing enzyme SOD activity, and reduction in lipid peroxidation.