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PubMed1961

Effects of cocaine and antidepressant drugs on the nictitating membrane of the cat.

Cocaine, imipramine and pipradol potentiated the contractions to adrenaline and noradrenaline, but not to tyramine, on the nictitating membrane of the spinal cat. Pheniprazine and dexamphetamine potentiated the responses to adrenaline, noradrenaline and tyramine, whereas nialamide only potentiated the response to tyramine. Potentiation of the response to stimulation of either the preganglionic or the postganglionic sympathetic nerve trunks was observed with imipramine, pipradol, pheniprazine and dexamphetamine. Only dexamphetamine and pheniprazine caused substantial contractions of the membrane when the preganglionic nerve was cut (acutely decentralized), or when the superior cervical ganglion was removed (acutely denervated). Cocaine produced contractions of the innervated but not of the acutely decentralized membrane. The significance of the peripheral effects of these antidepressant drugs in relation to their central actions is discussed.

Animals↗
PubMed1969

Effects of monoamine oxidase inhibitors on the hypothermia produced in cats by halothane.

1. In cats, the effects of intraperitoneal injections of four monoamine oxidase (MAO) inhibitors, tranylcypromine, pheniprazine, pargyline, and nialamide, were examined on rectal temperature and on the hypothermia during anaesthesia produced by a 2 hr period of halothane inhalation.2. A 2 hr period of halothane inhalation produced a steady fall in temperature amounting to between 2 degrees and 3.5 degrees C. After discontinuation of halothane inhalation, temperature quickly returned to the pre-anaesthetic level but no pyrexia developed. A peculiar stiffness of the leg muscles occurred in several experiments either at the beginning of the inhalation or after its discontinuation.3. An injection of tranylcypromine (5 mg/kg) caused a rise in rectal temperature and prevented the hypothermia of halothane anaesthesia. This effect lasted for at least 4 hr; 20 hr after the injection, halothane again caused hypothermia.4. An injection of pheniprazine (10 mg/kg) usually caused a small rise in temperature which was not sustained. Pheniprazine not only prevented the hypothermia of halothane anaesthesia during the subsequent 20 hr, but during the first few hours after the injection halothane inhalation actually produced a steep rise in temperature.5. An injection of pargyline (50 mg/kg) had no effect on temperature but the hypothermia due to halothane inhalation was prevented 1 hr after the injection and attenuated after 20 hr. Injection of 200 mg/kg caused a steady rise in temperature which was accelerated when halothane was administered 1 hr later.6. An injection of nialamide (10, 25 or 50 mg/kg) had no immediate effect on temperature, but pyrexia developed overnight after the two larger doses. The effect on the hypothermia due to halothane inhalation was greater 20 hr after the injection than it was after 1 to 2 hr. Twenty hours after injection of the two larger doses, halothane no longer produced hypothermia but caused a lethal rise in temperature either during or after its inhalation.7. In rabbits, the effect on temperature of halothane inhalation varied. Either temperature rose slightly or it fell, but not as much as in cats. In one rabbit in which the inhalation had produced a transient rise, pyrexia developed 40 min after discontinuation of halothane.

Anesthesia, Inhalation↗
PubMed1970

Effects of monoamine oxidase inhibitors and amphetamine on hypothermia produced by halothane.

1. In cats, the effects of tranylcypromine and pheniprazine, two monoamine oxidase (MAO) inhibitors with strong amphetamine-like actions, of pargyline, an inhibitor without amphetamine-like actions, and of amphetamine itself, were examined on the hypothermia produced by a 2 hr period of halothane inhalation.2. The hypothermia was prevented by intraperitoneal injections of the three MAO inhibitors. Tranylcypromine and pheniprazine acted in doses of a few milligrams, pargyline in doses of over 100 mg.3. The hypothermia was prevented by injections into the cerebral ventricles of tranylcypromine and pheniprazine, in doses which were effective also on intraperitoneal injection; intraperitoneal injections were sometimes more effective. The large doses of pargyline needed to prevent the hypothermia when injected intraperitoneally were not tested by the intraventricular route, as the injections had to be made in a volume of 0.1 ml. In smaller doses intraventricular pargyline was not effective.4. The hypothermia was prevented by an intraperitoneal or intraventricular injection of amphetamine in a dose as little as 1 mg; intraperitoneal injections were sometimes more effective.5. The effects of tranylcypromine and pargyline given intraperitoneally, and of amphetamine given intraventricularly as well, were also examined on the hypothermia produced by an intraventricular injection of 200 mug noradrenaline. The two MAO inhibitors and amphetamine prevented the hypothermia, or greatly reduced it.6. It is concluded (a) that even on intraventricular injection the MAO inhibitors must first be absorbed into the blood stream before they can prevent the hypothermia of a halothane anaesthesia; (b) that their action may not be solely on the anterior hypothalamus; and (c) that they may not act only through MAO inhibition.

Amphetamine↗
PubMed1971

Bretylium potentiation of the contractor responses of isolated rabbit aortic strips to potassium and tyramine.

1. Pretreatment of rabbit aortic strips with bretylium potentiated the contractor response to potassium and tyramine but not to noradrenaline. On the other hand, such pretreatment inhibited the response to nicotine.2. Even in reserpinized or cold stored aortic strips, pretreatment with bretylium enhanced the contractor response to potassium and tyramine.3. Pretreatment of fresh, reserpinized, or cold stored aortic strips with pheniprazine potentiated the contractor response to potassium and tyramine.4. Pretreatment of aortic strips with bretylium or pheniprazine did not potentiate the response to 5-hydroxytryptamine (5-HT).5. The results indicate that both bretylium and pheniprazine potentiate the action of tyramine and potassium, not by presynaptic mechanisms, but by postsynaptic action, causing an increase in the sensitivity of the effector cells to the stimulants.

Animals↗
PubMed1999

Some peculiar aspects of monoamine oxidase inhibition.

CN- ions enhance the inhibition of monoamine oxidase by the hydrazine derivatives, phenelzine [2-phenylethylhydrazine] and pheniprazine [(1-methyl-2-phenylethyl)hydrazine]. This involves partial competitive activation of the initial noncovalent enzyme-inhibitor complex with no significant effect on the subsequent reaction to give the irreversibly inhibited species. Whereas the maximum effects on pheniprazine inhibition of rat liver MAO-B occurred at about 5 microM cyanide, concentrations of 5 mM were necessary for maximum stimulation of MAO-A inhibition. A comparison of the behaviour of rat and ox MAO revealed considerable differences in their sensitivities to pheniprazine and the potentiating effects of cyanide. Species differences were also evident in the interactions derivatives of milacemide [2-n-pentylaminoacetamide] as substrates and mechanism-based inhibitors of MAO-B. In one case there was evidence for apparently large difference in inhibitor sensitivities between human brain MAO-B from different individuals.

Animals↗
PubMed1976

Monoamine oxidase inhibition and the induction of ponto-geniculo-occipital wave activity by reserpine in the cat.

Reserpine induces ponto-geniculo-occipital wave activity similar to that seen in the cat during the rapid eye movement phase of sleep. This action of reserpine was blocked by the monoamine oxidase inhibitors, pheniprazine, harmaline and clorgyline, but not deprenyl or its demethylated analog. After a single dose (20 mg/kg) of either pheniprazine or harmaline, the time course of antagonism of the effect of reserpine was in good correspondence with inhibition of monoamine oxidase but not with restoration of the serotonin content of several regions of the brain. Harmaline had a reversible effect while that of pheniprazine persisted for weeks. Clorgyline in low doses (0.5-1.0 mg/kg), at which it is a specific inhibitor of type A monoamine oxidase, antagonized the action of reserpine for over 2 weeks. Deprenyl and its demethylated analog failed to suppress the reserpine-induced waves even at 10 times the dose of clorgyline when they should have completely inhibited type B monoamine oxidase. In contrast to antagonism of reserpine, suppression of rapid eye movement sleep by these monoamine oxidase inhibitors could be temporally dissociated from their inhibition of the enzyme. It is concluded that suppression of the induction of ponto-geniculo-occipital waves by reserpine after administration of the monoamine oxidase inhibitors is a specific effect of these drugs and is related to inhibition of type A monoamine oxidase. Suppression of rapid eye movement sleep is probably a nonspecific effect and not related to inhibition of the enzyme.

Animals↗
PubMed1980

Evidence that a preferred substrate for type B monoamine oxidase mediates stimulus properties of MAO inhibitors: a possible role for beta-phenylethylamine in the cocaine cue.

In the experiment, rats were trained to discriminate 5 mg/kg cocaine HCl from saline in a two-bar drug discrimination procedure. Stimulus generalization experiments were carried out with six inhibitor drugs of monoamine oxidase. The rank order of absolute potency of these drugs in inducing stimulus generalization with cocaine was: tranylcypromine (ED50 in mg/kg; 1.2)>pheniprazine (3.5)>deprenyl (5)>pargyline (28)>nialamide (approximately 170); at up to 40 mg/kg, clorgyline failed to produce 50% generalization. All six drugs also potentiated tryptamine in producing body tremors and clonic seizures, the rank order of potency being tranylcypromine (0.081)>clorgyline (0.14) greater than or equal to pheniprazine (0.15)>pargyline (1.97)>deprenyl (15.5)>nialamide (18.7). Tryptamine is a common substrate for both type A and type B monoamine oxidase, so that tryptamine potentiation may serve to determine the relative specificity of the doses at which the inhibitor drugs generalized with cocaine. The present data may suggest that endogenous substances which are preferred substrates for type B monoamine oxidase in rat brain can exert control of behavior by virtue of cocaine-like stimulus properties. beta-Phenylethylamine, more so than dopamine, appears to be candidate substance for mediating the discriminative stimulus properties of cocaine and, perhaps, of other central nervous system stimulants.

Animals↗
PubMed1989

Metabolism of monoamine oxidase inhibitors.

1. Despite the fact that monoamine oxidase inhibitors have been used clinically and in animal experiments for many years, much still remains unknown about their metabolism. An overview of the metabolic aspects of several monoamine oxidase inhibitors, including phenelzine, tranylcypromine, pheniprazine, pargyline and deprenyl, is presented. 2. There is still considerable controversy surrounding the role of acetylation in the metabolism of phenelzine. The possibility of ring hydroxylation as well as the formation of beta-phenylethylamine, phenylacetic acid and rho-hydroxyphenylacetic acid from phenelzine is explored. 3. Tranylcypromine has been shown to undergo acetylation and ring hydroxylation. Opening of the cyclopropyl ring is also possible, although this still remains a matter of debate. The pharmacological activity and pharmacokinetic properties of the enantiomers of tranylcypromine are discussed. Chemical substitution in the 4-position of the phenyl ring has been utilized in the design of tranylcypromine analogues with potential antidepressant activity. 4. The formation of amphetamine from pheniprazine and the metabolism of the N-propargyl drugs pargyline and deprenyl are discussed.

Animals↗
PubMed1975

Effect of age of habit on susceptibility to cycloheximide-induced amnesia in mice.

The amnesic effects of cycloheximide (CYC) on habits of different ages were investigated in a food-motivated, discrimination-reversal task. Groups of C57BL/6J mice were injected 30 min before training or immediately, 3 days, 6 days, or 9 days after training. Retention was tested 24 hr after CYC treatment. The usual amnesic effect of CYC occurred in animals injected before training. No amnesia was apparent in groups injected immediately, 3 days, or 9 days after training. However, a reliable and reproducible amnesia occurred in the group injected 6 days after training. This amnesia could be reversed by pretest treatment with a monoamine oxidase inhibitor, pheniprazine. Pheniprazine, given 7 days after training, also enhanced retrieval of memory in saline-injected mice.

Amnesia↗
PubMed1977

[Studies on monoamine oxidase. (Report 37) Effects of oxygen concentration on rat liver and brain monoamine oxidase (author's transl)].

MAO activity in rat brain mitochondria with tyramine as substrate at 100% oxygen concentration was three times as much as that at 20%. When serotonin served as substrate, difference in activities between the two oxygen concentrations was not significant. Similar results were obtained when rat liver MAO was used as the enzyme source. At 100% oxygen concentration, pargyline showed the most potent inhibition of MAO activity in liver mitochondria with tyramine as substrate, but inhibitions caused by pheniprazine and harmaline were not remarkable. At 100% oxygen concentration, harmaline showed the most potent inhibition of MAO activity in the liver when serotonin served as substrate, while inhibitions of the MAO activity by pargyline and pheniprazine were weak. At 20% oxygen concentration, harmaline showed the most potent inhibition of MAO activity in the brain when serotonin was used as substrate. These inhibitions were studied using Lineweaver-Burk plots. Pargyline revealed a noncompetitive inhibition to MAO activity in liver and brain with tyramine and serotonin as substrate, harmaline a competitive inhibition to MAO activity in liver and brain with tyramine as substrate, while noncompetitive inhibition to MAO activity in liver and brain was evident when serotonin was used as the substrate.

Animals↗
PubMed1976

Precipitation of abstinence-like syndrome in morphine-dependent mice by pargyline.

In mice rendered morphine-dependent by pellet implantation for 3 days, the administration of pargyline 6 hours after pellet removal intensified narcotic abstinence behavior, particularly the narcotic withdrawal jumping response. Pargyline, 75 mg/kg i.p., caused a 6- to 9-fold increase in the incidence of jumping in mice withdrawing from morphine 6 hours after removal of the pellet, whereas this effect was not observed: 1) 1 hour after the injection of pargyline or 2) in animals still implanted with the morphine pellet. The median effective dose (ED50) of pargyline required to elicit withdrawal jumping in mice implanted with morphine decreased with increasing physical dependence. The ED50 for 72 hours was about one-sixth that after 24 hours of implantation. Additionally, pargyline potentiated naloxone-precipitated withdrawal jumping as evidenced by a reduction of the naloxone ED50 by approximately one-half. Administration of other monoamine oxidase inhibitors such as pheniprazine, iproiazid or tranylcypromine failed to alter the indicence of jumping in dependent mice undergoind abrupt morphine with drawal. Further, dopamine receptor stimulation by amphetamine, pheniprazine or amantadine antagonized the pargyline-induced jumping response. These data suggest that the increased incidence of withdrawal jumping observed after pargyline in morphine-dependent mice is not related to monoamine oxidase inhibition but rather to a possible pargyline-induced decrease in dopaminergic activity.

Amantadine↗
PubMed1977

Unusual alpha adrenergic receptor potency of methyldopa metabolites on melanocyte function.

Catecholamines possessing alpha adrenergic receptor agonist properties induce lightening or reverse melanocyte stimulating hormone darkening of frog skin in vitro. The capacity to activate this alpha receptor by the methyldopa metabolites methyldopamine and methylnorepinephrine was compared with the capacity of the naturally occurring dopa metabolites, dopamine and norepinephrine. Melanocyte stimulating hormone-induced darkening or dispersion of the granules was reversed by each of these metabolites. Methylnorepinephrine was 10 times as potent as norepinephrine, and methyldopamine was 30- to 100-fold more potent than the naturally occurring dopamine. These inhibitory effects on melanocyte stimulating hormone could be blocked or partially impaired using the alpha adrenergic blocker, phentolamine. They were not affected by pretreatment of frogs with the monoamine oxidase inhibitor pheniprazine (Catron) nor by the application of pheniprazine, angiotensin or serotonin in vitro. This neuroendocrine model has alpha adrenergic receptor relationships analogous to those described in the central nervous system for methyldopa metabolites.

Animals↗