Zur Pharmakologie von Psilocybin,einem Wirkstoff ausPsilocybe mexicana Heim

Summary The active principle ofPsilocybe mexicana Heim, Psilocybin, is without marked effects on the isolated organs (seminal vesicle, intestine and auricle of the guinea pig; rat uterus) but exerts an actionin vivo which resembles a slight sympathetic stimulation. In unanaesthetized rabbits it produces mydriasis, tachycardia, tachypnea, hyperthermia and hyperglycemia, in unanaesthetized mice mydriasis and piloerection. The EEG (curarized rabbits) after 1–2 mg/kg Psilocybin shows an alerting pattern (disappearance of spindle activity and of slow waves). Spinal reflexes of the cat are predominantly enhanced. However, the motor activity of mice, rabbits and monkeys is unaffected or even slightly depressed. In anaesthetized cats and dogs Psilocybin affects blood pressure and heart rate, the effect depending on dosage and species.     

Dopamine-induced relaxation in human pulmonary arteries

Dose-dependent relaxations were induced by dopamine in human pulmonary arteries that had been contracted with prostaglandin F2 alpha without alpha-adrenergic blocking agents. The dopamine-induced relaxation was inhibited by haloperidol and fluphenazine, but not by domperidone, suggesting that this relaxation was mediated via DA1 receptors.     

Dopamine regulation of testicular activity in intact and hypophysectomized frogs,Rana esculenta

In intact frogs, both GnRHA and L-dopa were able to increase testicular and plasma androgen levels and to induce spermiation. The dopamine antagonist pimozide inhibited both the effects of L-dopa but not those of GnRHa. Hypophysectomy reduced androgen levels, but spermiation was still induced by both GnRHa and L-dopa, suggesting that these agents can directly influence the testis through a route not involving the pars distalis. Again, pimozide antagonised spermiation induced by L-dopa but not that induced by GnRHa.This work was supported (40% and 60%) by the Italian Ministry of Education and the C.N.R. Special Project.     

Suppression of paradoxal sleep by clonidine in man]

The administration of clonidine (300 mug) suppresses REM sleep or strikingly diminishes its duration in Man. The statistical difference with placebo given in a double blind trial is highly significant. This suppression of REM sleep may depend on the stimulation of alpha-adrenergic receptors.     

Neuronal accumulation and metabolism of3H-1-norepinephrine in rat portal vein: Evidence in relation to possible uneven alpha receptor distribution

Summary The rate of accumulation and metabolism of³H-1-norepinephrine in the neuronal plexus of rat portal vein produces a small transmitter concentration gradient across the longitudinal smooth muscle layer which cannot account for the prejunctional supersensitivity observed and suggests localization of the alpha-adrenergic receptors adjacent to the nerve plexus.Acknowledgment. This work was supported by USPHS grant HE 8359 (JAB) and USPHS grant MH 23839 (AKC).     

In vitro characterization of adrenergic receptors mediating extrusion of preformed sebum from preputial gland of rat

Extrusion of preformed sebum from the preputial glands of rat after phenylephrine and adrenaline treatment, and its inhibition by alpha-receptor blocking agents under in vitro conditions, shows that secretory response of the glands is influenced by alpha-adrenergic receptors, and isoproterenol--a beta-agonist--is not effective in elicitation of exudation of secretion from the preputial gland.     

Catecholamine-sensitive adenylate cyclase of human fat cell ghosts. Inhibition of catecholamine stimulation by phenylephrine

Summary The alpha-adrenergic agonist phenylephrine (up to 1 mM) did not affect basal and NaF-stimulated adenylate cyclase activities of human fat cell ghosts, but caused a dose-dependent inhibition of cAMP formation in the presence of catecholamines.     

Fluorimetric assay of 3-o-methyldopamine and 4-0-methyldopamine in rat urine and o-methylation of dopamine]

A new method for the isolation and determination of 3-O-methyldopamine (3 MD) and 4-O-methyldopamine (4 MD) in the urine of Rat has been described. The administration of L-dopa enabled us to detect 4 MD in the urine with a molar ratio 4 MD/3 MD = 0.07. This ratio decreased with the simultaneous treatment of S-adenosylmethionine (SAM). This result might explain the therapeutic L-dopa+SAM in the treatment of parkinsonism, 4 MD being neurotoxic. The low level of 4 MD compared with the level of isovanillic acid, found by other authors, seems to indicate that the 4-O-methylation pathway takes place via dihydroxyphenylacetic acid.     

Alpha adrenergic control of growth hormone in adult male rats.

Intravenous injection of 0.1 mg/kg clonidine into rats under urethane anaesthesia induced a prompt and long-lasting release of growth hormone, estimated by radioimmunoassay (IRGH), which could be abolished by 0.2 mg/kg phentolamine given into the 3rd ventricle. Injection of 3 mug/kg clonidine into the 3rd ventricle stimulated also the release of IRGH significantly. Intravenous administration of 0.32 mg/kg phenylephrine caused a small and transient release of IRGH only. These results provide evidence that central alpha-adrenergic stimulation resulting in an increased GH secretion is one important mechanism in the regulation of this hormone in the rat.     

Ethanol influence on insulin secretion from isolated rat islets

This study was done to delineate the role of alpha- and beta-adrenergic receptors and cyclic AMP in the mechanism of ethanol effects on insulin release from isolated islets. Rats were given an alpha-adrenergic blocker, phentolamine, or a beta-adrenergic blocker, propranolol. In addition, ethanol 1 g/kg was given intragastrically 1 h prior to sacrifice. Glucose mediated insulin release from isolated islets was enhanced by phentolamine and decreased by propranolol. Ethanol treatment inhibited glucose-induced insulin release from isolated islets of control rats as well as those given phentolamine and/or propranolol. Insulin release from isolated islets in response to dibutyryl-cyclic AMP was attenuated by ethanol. Theophylline enhanced glucose mediated insulin release from control islets but ethanol treatment produced a significant inhibition of insulin response. The data suggest that the site of action of the deleterious effects of ethanol on insulin release from isolated islets in rat does not involve adrenergic system and cyclic AMP.     

Melatonin receptors limit dopamine reuptake by regulating dopamine transporter cell-surface exposure

Melatonin, a neuro-hormone released by the pineal gland, has multiple effects in the central nervous system including the regulation of dopamine (DA) levels, but how melatonin accomplishes this task is not clear. Here, we show that melatonin MT₁ and MT₂ receptors co-immunoprecipitate with the DA transporter (DAT) in mouse striatal synaptosomes. Increased DA re-uptake and decreased amphetamine-induced locomotor activity were observed in the striatum of mice with targeted deletion of MT₁ or MT₂ receptors. In vitro experiments confirmed the interactions and recapitulated the inhibitory effect of melatonin receptors on DA re-uptake. Melatonin receptors retained DAT in the endoplasmic reticulum in its immature non-glycosylated form. In conclusion, we reveal one of the first molecular complexes between G protein-coupled receptors (MT₁ and MT₂) and transporters (DAT) in which melatonin receptors regulate the availability of DAT at the plasma membrane, thus limiting the striatal DA re-uptake capacity in mice.     

Narcotic antagonism of seizures induced by a dopamine-derived tetrahydroisoquinoline alkaloid

This paper describes experiments designed to evaluate whether the narcotic antagonist naloxone significantly interferes with seizures induced by tetrahydroisoquinolines (TIQs). In these experiments we found that naloxone significantly reduced seizure scores induced by intra-cranially infusing mice with 50 micrograms of the dopamine-derived tetrahydroisoquinoline (TIQ) alkaloid, 6,7-dihydroxy TIQ. These findings support an opioid involvement in the actions of TIQs and may lead to further understanding of opioid-mediated novel excitatory receptors.     

Vitamin D receptors in heart: effects on atrial natriuretic factor.

We report that receptors for vitamin D exist in distinct regions of the heart in female and male mice, predominantly in the right atrium where most of the cardial atrial natriuretic peptide (ANF) is produced. Tritiated 1,25-dihydroxyvitamin D3 (1,25-D3, vitamin D, soltriol) and ANF are colocalized in nuclei and cytoplasm respectively in identical cardiomyocytes. Changes of ANF tissue and blood levels under dietary deficiency and treatment with 1,25-D3 suggest direct genomic actions of vitamin D on myoendocrine cells of the atrium for the regulation of ANF manufacture and secretion. These results were obtained by combining thaw-mount autoradiography with immunocytochemistry using tritiated 1,25-D3 and an antibody against rat ANF. This antibody was also used in a radioimmunoassay to determine atrial natriuretic factor in plasma, atria and ventricles of normal or vitamin D-deficient mice.     

Zentrale vegetative LSD-Effekte

Summary d-Lysergic acid diethylamide (LSD 25) produces in rabbits a syndrome consisting of hyperthermia, hyperglycemia, mydriasis, pilomotor activation, cardiac acceleration etc. Analysis of these effects leads to the assumption of an increased sympathetic discharge induced by the central nervous action of LSD 25. Comparison of LSD 25 and reserpine shows opposite characteristics of these two drugs not only in the field of vegetative pharmacology but also concerning influence on psychic functions in man. The possibility should, therefore, be considered that an increased excitatory state of sympathetic centres by LSD 25 is a main factor in the pathogenesis of the well-known psychic disturbances produced by this amide in man.     

Modification by levo-propranolol of tremors induced by harmine in mice

Summary It has been recently reported that the levo isomer of propranolol possesses anti-serotonin properties in animals. Since harmine-induced behavioural changes in mice are reported to be mediated through central serotonergic receptors, an attempt was made to test whether 1-propranolol would also modify harmine-induced responses by virtue of its antiserotonergic or anti-adrenergic property. The results indicated that 1- and dl-propranolol inhibited central serotonin receptor mediated responses to harmine in mice, a finding that is analogous to other recent observations.     

Morphine eye-drops reduce homatropine induced mydriasis in man

Summary In 7 healthy volunteers 4% morphine eye-drops, when administered to one eye, caused a miosis limited to that eye. In 7 other healthy volunteers morphine was administered into one eye after bilateral instillation of 0.5% homatropine opthalmic drops; the eye treated with morphine and homatropine showed a mydriasis less intense than the other eye treated only with homatropine. It is suggested that topical morphine locally affects sympathetic function by inhibiting noradrenaline release into the iris neuromuscular junction.This work was partly supported by the CNR study group Pain Control. The authors wish to thank Dr Tendi of the Pharmacy of St. Maria Nuova Hospital, Florence, for the preparation of the eye-drops.     

Virus-mediated inhibition of natural cytotoxicity receptor recognition

Natural killer (NK) cells are a part of the innate immune system that functions mainly to kill transformed and infected cells. Their activity is controlled by signals derived from a panel of activating and inhibitory receptors. The natural cytotoxicity receptors (NCRs): NKp30, NKp44, and NKp46 (NCR1 in mice) are prominent among the activating NK cell receptors and they are, notably, the only NK-activating receptors that are able to recognize pathogen-derived ligands. In addition, the NCRs also recognize cellular ligands, the identity of which remains largely unknown. In this review, we summarize the current knowledge regarding viruses that are recognized by the NCRs, focusing on the diverse immune-evasion mechanisms employed by viruses to escape this detection. We also discuss the unique role the NCRs have in regulating NK cell activity with particular emphasis on the in vivo function of NKp46/NCR1.     

A postsynaptic alpha 2-receptor: the alpha-adrenergic receptor of hamster white fat cells

The effects of selected alpha-agonists and alpha-antagonists on theophylline-induces lipolysis were investigate in isolated hamster white fat cells, alpha 2-Agonists (tramazoline, clonidine) inhibited theophylline-induced lipolysis while in alpha 1-agonist (methoxamine) was without any effect. The inhibitory effect of alpha 2-agonists was suppressed by yohimbine (alpha 2-antagonist), whereas alpha 1-antagonists were inefficient. This result implies that the alpha-adrenergic receptor of hamster fat cells is of the alpha 2-type, although postsynaptically.     

Vitamin D receptors in heart: Effects on atrial natiuretic factor

We report that receptors for vitamin D exist in distinct regions of the heart in female and male mice, predominantly in the right atrium where most of the cardial atrial natriuretic peptide (ANF) is produced. Tritiated 1,25-dihydroxyvitamin D₃ (1,25-D₃, vitamin D, soltriol) and ANF are colocalized in nuclei and cytoplasm respectively in identical cardiomyocytes. Changes of ANF tissue and blood levels under dietary deficiency and treatment with 1,25-D₃ suggest direct genomic actions of vitamin D on myoendocrine cells of the atrium for the regulation of ANF manufacture and secretion. These results were obtained by combining thaw-mount autoradiography with immunocytochemistry using tritiated 1,25-D₃ and an antibody against rat ANF. This antibody was also used in a radioimmunoassay to determine atrial natriuretic factor in plasma, atria and ventricles of normal or vitamin D-deficient mice.