Dopamine D3 receptor-modulated neuroprotective effects of lisuride.

Dopamine (DA) contributes to the regulation of voluntary movement, and a deficiency in DAergic neurons leads to movement disorders. The objective of this study was to examine the neuroprotective effect of DA D2-like receptor agonist, lisuride, and the role of DA receptors in this protection. Treatment with lisuride alleviated loss of tyrosine hydroxylase (TH) both direct and intraperitoneal injection in 6-hydroxydopamine (6-OHDA) mouse model. Similar results were obtained in primary neuronal cultures treated with lisuride. Lisuride protected TH expression against 6-OHDA-induced cytotoxicity in a concentration-dependent manner. Then, we evaluated the role of DA D2 and D3 receptor in neuroprotective effect of lisuride. Treatment of neuronal cultures with L-741,626, a DA D2 receptor-selective antagonist, did not alter neuroprotective effect of lisuride. However, protective effect of lisuride on TH expression was abolished when cells were treated with GR103691, a D3 receptor selective antagonist. Furthermore, whether lisuride can alleviate mitochondrial damage of DAergic neurons induced by 6-OHDA, we investigated the expression of the mitochondrial regulatory protein, paraplegin, and changes in mitochondria morphology. Treatment with lisuride countered a 6-OHDA-induced reduction in paraplegin and TH expression, and co-treatment with GR103691 blocked this effect of lisuride. Transmission electron microscopy confirmed the lisuride mitigation of 6-OHDA-induced damage to the mitochondrial membrane and cristae. These results suggest that the DA D3 receptor mediates the neuroprotective effects of lisuride by preventing mitochondrial damage.

Lisuride acts at multiple sites to induce ocular hypotension and mydriasis.

Topically unilaterally applied lisuride caused dose-related lowering of intraocular pressure in ipsilateral (treated) but not in contralateral eyes of normal rabbits. The ocular hypotensive response induced by lisuride was antagonized by pretreatment with metoclopramide, a dopamine receptor antagonist, and was partially reduced by local sympathetic denervation. In contrast to the unilateral effect on intraocular pressure, lisuride caused mydriasis in both eyes. Mydriasis was of greater magnitude and more sustained in normal eyes compared to sympathetically denervated eyes. Additional in vivo experiments demonstrated that lisuride caused dose-related suppression of neuronally initiated contractions of cat nictitating membrane. In in vitro experiments lisuride caused dose-related inhibition of norepinephrine release from isolated rabbit iris-ciliary bodies. Pretreatment with Bay K 8644, a calcium channel activator, did not attenuate lisuride-induced inhibition of norepinephrine release in isolated rabbit iris-ciliary bodies. Because lisuride pretreatment caused no change in isoproterenol-stimulated cAMP accumulation in isolated iris-ciliary bodies, suppression of adenylate cyclase was unlikely. It is concluded that the ocular hypotensive effect of lisuride results, in part, from activation of prejunctional dopaminergic receptors on peripheral sympathetic nerves in the anterior segment of the eye but may also involve antagonism on peripheral postjunctional alpha1 adrenoceptors as well. Bilateral increases in pupil diameter antagonized by metoclopramide suggest a stimulatory action of lisuride on dopamine receptors in the central nervous system.

Dopaminergic and alpha 1-adrenergic properties of B-HT920 revealed in morphine-dependent rats.

B-HT920 is known to be a selective alpha 2-adrenoceptor agonist, and has been used in a study on morphine-withdrawal in rats. In accordance with other alpha 2-agonists B-HT920 was found to potentiate "jumping" and to reduce "body shakes." However, B-HT920 did not suppress body weight loss. Furthermore, it induced strong salivation and prevented ptosis (described for the alpha 1-adrenergic agonist ST-587). Rearing and locomotor activity appeared to be enhanced, an effect shared by dopamine-agonist lisurid. The effects of B-HT920 have been specified using the alpha-adrenergic antagonists yohimbine and prazosin and the dopamine antagonist haloperidol. Yohimbine could not antagonize any of the actions of B-HT920. However the increase in rearing and locomotion was blocked by haloperidol. The induction of salivation was prevented by prazosin. Pretreatment with prazosin showed a decrease in the loss of body weight caused by B-HT920, while pretreatment with yohimbine showed that B-HT920 induced an increased loss in body weight. These data suggest that B-HT920 under certain conditions exerts dopamine-agonistic actions in stimulating locomotor activity and alpha 1-adrenergic actions in inducing salivation and enhanced loss of body weight.

SCH 23390 antagonizes apomorphine- and ergot-induced hypothermia.

The reportedly specific D-1 dopamine (DA) receptor antagonist SCH 23390 significantly reduced the hypothermia elicited by various DA receptor agonists like apomorphine, pergolide and lisuride. When tested against equihypothermic doses of each agonist, SCH 23390 significantly reduced the hypothermia elicited by apomorphine (0.2 mg/kg s.c.) and by pergolide (0.1 mg/kg i.p.) at doses of 0.025 mg/kg s.c. Doses of 0.050 mg/kg s.c. of SCH 23390 were necessary to reduce the hypothermia elicited by 0.012 mg/kg s.c. of lisuride. Pretreatment with the specific D-2 antagonist (-)sulpiride (50 mg/kg i.p.) completely prevented the hypothermia elicited by lisuride (0.012 mg/kg i.p.), pergolide (0.1 mg/kg i.p.) and apomorphine (0.2 mg/kg s.c.) and shifted to the right the dose-response curve for agonist-induced hypothermia. A study of the interaction between 0.05 mg/kg s.c. of SCH 23390 with various doses of the agonists showed that the effectiveness of SCH 23390 in antagonizing the hypothermia was maximal towards apomorphine and least towards lisuride for which significant antagonism was observed only against the lowest dose tested (0.012 mg/kg s.c.). The reportedly specific D-1 receptor agonist SKF 38393 given in doses up to 20 mg/kg i.p. or intracerebroventricularly up to 100 micrograms failed to influence body temperature while it evoked intense grooming and stimulated motility.

Discriminative stimulus properties of clonidine: substitution by ergot derivatives.

Bromocriptine, lergotrile and lisuride but not apomorphine, ergonovine or lysergic acid diethylamide (LSD) mimicked clonidine in rats trained to discriminate this compound (0.02 mg/kg) from saline. BC 105, ketanserin and haloperidol failed to block the clonidine cue. Yohimbine was an effective antagonist of clonidine but not of the lisuride substitution for clonidine. Since dopamine does not appear to be involved in the stimulus effects of clonidine, the behavioral similarities between clonidine and some ergots may be related to alpha-adrenoceptor stimulation; however, the role of blood pressure changes in the stimulus effects of all of these compounds should not be overlooked.

The 5HT2 antagonist pirenperone reverses disruption of FR-40 by hallucinogenic drugs.

Indolealkylamine and phenethylamine hallucinogens disrupted responding maintained under a fixed-ratio 40 (FR-40) schedule of reinforcement. LSD, DMT, mescaline and DOM produced dose-dependent decreases in number of reinforcers and increases in 10-sec periods of non-responding (pause-intervals). The 5HT agonist quipazine, as well as the LSD congener lisuride, altered response patterns in a similar manner. The effects of these drugs were examined after pretreatment with pirenperone, an antagonist with specificity toward the 5HT2 receptor with reference to the 5HT1 receptor. The dose-response curves for the phenethylamine hallucinogens were shifted significantly to the right and to a greater degree than were those for the indolealkylamine hallucinogens. Pirenperone also antagonized the effects of quipazine to a degree similar to that observed with the phenethylamine-type hallucinogens. Pirenperone did not significantly shift the dose-response pattern to lisuride. These data suggest that the behavioral disruption induced by these hallucinogens and quipazine relates at least in part to an effect on 5HT2 receptors, while the effects of lisuride do not involve a significant interaction at the 5HT2 receptor.

Evidence for a direct dopaminergic effect of lisuride.

The discriminative stimulus properties of the clinically important ergot derivative lisuride hydrogen maleate were studied by training 2 groups of rats to discriminate 0.04 mg/kg lisuride from saline and 0.16 mg/kg apomorphine from saline. Dose-response and substitution tests between these groups showed that lisuride and apomorphine are discriminated similarly by both groups and that lisuride is 5 to 9 times more potent. The dopaminergic agonists d-amphetamine, quipazine, bromocriptine, cocaine and cathinone did not substitute for lisuride. In antagonism studies, only the dopamine receptor blocker haloperidol attenuated the lisuride cue; the serotonin receptor blockers pirenperone and BC-105 were ineffective. These data indicate that the primary central action mediating the discriminative stimulus effects of lisuride was direct activation of dopamine receptors.

Blockade of the behavioral effects of lysergic acid diethylamide, 2,5-dimethoxy-4-methylamphetamine, quipazine and lisuride by 5-hydroxytryptamine antagonists.

The effects of lysergic acid diethylamide (LSD), 2,5-dimethoxy-4-methylamphetamine (DOM), quipazine or lisuride alone and in combination with the 5-hydroxytryptamine antagonist metergoline, pizotifen and cinanserin were studied in rats responding on a fixed-ratio 40 schedule of food presentation. LSD, DOM, quipazine or lisuride produced a similar dose-dependent decrease in the number of food presentations (ED50 values: 81 micrograms/kg, 0.6 mg/kg, 1.6 mg/kg and 31 micrograms/kg, respectively) and a reciprocal increase in the number of pause intervals (IRTs = 10 sec). All three antagonists attenuated the behavioral effects of LSD and DOM for both food presentations and pause intervals. The LSD-response curve for reinforcers was shifted to the greatest degree by pizotifen (1.0 mg/kg), followed by cinanserin (20 mg/kg) and metergoline (1.0 mg/kg). The ED50 values for this effect were 334, 181 and 141 micrograms/kg, respectively. The DOM dose-response pattern for decrease in reinforcers was shifted to the greatest degree by metergoline, followed by pizotifen and cinanserin (ED50 values: 26.5, 3.2 and 1.8 mg/kg, respectively). The effect of quipazine on reinforcers was antagonized by metergoline and pizotifen (ED50 values: greater than 8.0 for both) but not by cinanserin, although all three antagonists attenuated the increase in pause intervals in the same order as they did for DOM. The decrease in reinforcers by lisuride was equally antagonized by metergoline and pizotifen (ED50 values: 58 and 57 micrograms/kg, respectively), whereas cinanserin potentiated the effect of lisuride (ED50: 16 micrograms/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of dopamine synthesis in striatal synaptosomes by lisuride: stereospecific reversal by (-)-sulpiride.

Lisuride, an ergot D2 dopamine receptor agonist inhibited dopamine synthesis in striatal synaptosomes concentration-dependently. Significant inhibition was detected at 10(-8) M, and the inhibition by 10(-4) M lisuride was 50%. The inhibitory effect of lisuride was reversed by more than 50% not only by the D1-D2 dopamine receptor blocker haloperidol but also by the D2 dopamine receptor blocker(-)-sulpiride. The effect of sulpiride was stereospecific. Under the same test conditions a similar inhibition of dopamine synthesis by apomorphine was reversed by the neuroleptics almost completely. The results suggest that there are dopamine autoreceptors controlling dopamine synthesis in synaptosomes and these receptors resemble D2 dopamine receptors according to the nomenclature of Kebabian and Calne (1979).

[General pharmacology of lisuride hydrogen maleate--actions on isolated organs, especially on smooth muscles].

Pharmacological actions of lisuride hydrogen maleate (lisuride) were studied by using isolated organs. 1) Lisuride at 2.2 microM exerted a negative chronotropic effect on guinea-pig atria, the effect being antagonized completely by 2.9 microM sulpiride. 2) alpha-Adrenolytic action of lisuride was observed in the rat vas deferens and beta-adrenolytic action in the rabbit trachea, respectively. The former (ID50 = 64 nM) was potent and equivalent to that of phentolamine, whereas the latter (ID50 = 26 microM) was only 1/30 as compared to that of propranolol. 3) Anti-5-hydroxytryptamine action (ID50 = 11 nM) was detected in the rat stomach and anti-histamine (ID50 = 15 nM) in the guinea-pig ileum, respectively. In these respective activities, lisuride was equipotent to methysergide and diphenhydramine. 4) Lisuride showed a spasmodic action, which may be categolized as an ergot alkaloid action, on the guinea-pig ileum and on rabbit renal artery. A weak positive inotropic action of lisuride was also observed in guinea-pig atria. In the rat uterus, however, no uterotonic action of lisuride was detected. It is concluded that, in addition to its known effects on the central nervous system, lisuride possesses potent peripheral anti-5-hydroxytryptamine and anti-histamine activities.

[Effects of an ergot derivative, lisuride, on the central dopaminergic system -- studies of behavioral pharmacology].

The central dopaminergic (DA) activity of lisuride hydrogen maleate (lisuride) was investigated from the view point of behavioral pharmacology in rats and mice. Lisuride exhibited a biphasic action on locomotor activity in mice and rats; with low doses lisuride caused hypomotility, whereas higher doses produced locomotor stimulation. The hypomotility induced by lisuride (0.00625 mg/kg, s.c.) was antagonized by a low dose of sulpiride (10 mg/kg, i.p.) in rats, and the lisuride (0.05 mg/kg)-induced hyperactivity was inhibited with haloperidol (0.1 mg/kg, i.p.). The stimulatory effect of lisuride on locomotion was not affected by the combined pretreatment with reserpine and alpha-methyl-p-tyrosine. The hyperactivity of mice induced by methamphetamine was inhibited by pretreatment with lisuride. In the rat lesioned unilaterally in the nigro striatal pathway by a local injection of 6-hydroxydopamine, a low dose of lisuride induced rotational behavior contralateral to the side of the lesion, and the rotational behavior was inhibited by pretreatment with haloperidol. These results indicate that lisuride at low doses effectively stimulates pre-synaptic DA receptors and the post-synaptic DA receptor under supersensitization in the mesolymbic and nigro striatal systems.

[Effects of an ergot derivative, lisuride, on the central nervous system -- stimulatory effect on local cerebral glucose utilization in the rat].

Effects of lisuride, a central dopamine and serotonin agonist of the ergot type, on local cerebral glucose utilization were studied in conscious, anesthetized, and substantia nigra-lesioned rats using the autoradiographic 2-deoxyglucose method. In the conscious rat, lisuride produced dose-dependent (0.05-0.5 mg/kg s.c.) increases of glucose utilization in the cerebellar gray structures (lobule of culmen, vermian lobule, uvula, cerebellar hemisphere) and the lateral nucleus of the thalamus. Although some other gray structures including cerebral cortex were also slightly stimulated, no change was observe in the hippocampus, hypothalamus, amygdala, mammillary body, superior colliculus, pons, and any of the white structure. The stimulatory effect of lisuride was abolished almost completely by the pretreatment with sulpiride or haloperidol. Pentobarbital and gamma-butyrolactone produced marked reduction in the glucose utilization all over the brain, and these effects were not affected by the pretreatment of lisuride. A unilateral 6-hydroxydopamine lesion at the substantia nigra caused a reduction of glucose utilization in the ipsilateral auditory cortex that was reversed by the administration of lisuride. These results indicate that lisuride modulates the motion coordination function of the cerebellum through the cerebral cortex.

The interaction of lisuride, an ergot derivative, with serotonergic and dopaminergic receptors in rabbit brain.

The interaction of lisuride (Lysenyl, Spofa), an ergot derivative, with serotonergic and dopaminergic receptors and with adenylate cyclase was studied in homogenates of rabbit brain. In frontal cortex, lisuride interacts with serotonin receptors as shown by its ability to compete with [3H]serotonin, [3H]spiroperidol and [3H]lysergic acid diethylamide for their receptor binding sites, with respective IC50 values of 14, 1.0 and 3.7 nM. The IC50 for displacement of [3H]spiroperidol by lisuride in frontal cortex was increased by the GTP analog, 5'-guanylylimidodiphosphate, indicating an agonist-like interaction. Lisuride is extraordinarily potent in stimulating serotonin-sensitive adenylate cyclase in this brain region, with maximal stimulations occurring at 0.1 nM lisuride. In caudate nucleus, lisuride interacted with both serotonergic and dopaminergic receptor sites as labeled by [3H]serotonin, [3H]lysergic acid diethylamide and [3H]2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene, with IC50 values ranging from 2.0 to 7 nM. Lisuride did not stimulate adenylate cyclase in caudate nucleus. In summary, lisuride is a very potent stimulator of serotonin-sensitive adenylate cyclase in rabbit frontal cortex and can interact with serotonin and dopamine receptor binding sites in rabbit cortex and caudate nucleus.

Stimulatory action of lisuride on dopamine-sensitive adenylate cyclase in the rat striatal homogenate.

Effect of lisuride, an ergot derivative of isolysergic structure, on dopamine-sensitive adenylate cyclase was studied in the homogenate of rat corpus striatum. Stimulatory action of lisuride, similar to the actions of dopamine and apomorphine, on striatal adenylate cyclase was potentiated significantly by guanosine triphosphate (GTP) and by guanyl-5'-yl imidodiphosphate (GMP-PNP), although with lisuride alone, there was only a slight stimulation. The maximal stimulation attained in the presence of GTP corresponded to about 1.4 times the basal rate of cyclic AMP formation in the homogenate and was abolished by an addition of haloperidol. Lisuride at a concentration about 3 microM inhibited stimulation of cyclic AMP formation by dopamine. The effect of lisuride and the extent of potentiation by the guanyl nucleotides were almost comparable to the effects of apomorphine, under corresponding conditions. Thus, lisuride, like apomorphine, acts as a partial agonist-antagonist, and has the ability to stimulate the dopamine-sensitive adenylate cyclase in the rat corpus striatum.

Bromocriptine and lisuride stimulate the accumulation of cyclic AMP in intact slices but not in homogenates of rat neostriatum.

The effects of bromocriptine and lisuride on cyclic AMP concentrations in homogenates and in intact slices of rat neostriatum were investigated. Significant increases in cyclic AMP concentration were found after a 10-min exposure to bromocriptine and lisuride in striatal intact slices. On the contrary, as previously found, the two dopaminergic ergot derivatives did not stimulate dopamine-senstiive adenylate cyclase present in striatal homogenates. The stimulatory effects observed only in intact tissues were blocked by the specific dopamine receptor blocking agent fluphenazine. It is tempting to conclude that dopaminergic ergot derivatives have a site of action different from that stimulated by classic dopamine agonists in tissue homogenates.