Sydney Spector

Association of behavoural effects of pargyline, a non-hydrazide mao inhibitor with increase in brain norepinephrine

Abstract Pargyline (MO 911) a non-hydrazide MAO inhibitor administered to rabbits in repeated doses causes a rise in brain 5HT and NE and a pronounced increase in reactivity to environmental change. On discontinuance of the drug, effects disappear when the NE decreases, although 5HT is still maximally elevated. Further evidence that central stimulation after MAO blockade is associated with free NE, and not with 5HT or dopamine was shown by giving MO 911 to rabbits which have been depleted of amine stores by reserpine; free 5HT in brain and dopamine in caudate nucleus rise rapidly, become maximal within 1 hr when remain constant for about 7 hr with animals still deeply sedated. Only in about 12 hr when there is a small but definite rise in NE are the effects of reserpine counteracted. The results indicate that MAO plays a different role than O-methyltransferase and has the important role of regulating the NE content of nerve endings. MO 911 acts differently in various species. The drug causes rapid elevation of brain levels of NE and excitation in mice and rats and causes a slow elevation in NE and excitation in rabbits; in contrast it does not elevate brain NE or cause excitation in dogs and cats. In all these species it causes a marked rise in brain 5HT. Possible pitfalls that should be avoided in relating changes in behaviour to brain amines are discussed.

INTERACTION OF MONOAMINE OXIDASE INHIBITORS WITH PHYSIOLOGICAL AND BIOCHEMICAL MECHANISMS IN BRAIN

Accumulating evidence indicates that monoamine oxidase (MAO) is important in the metabolism of serotonin (5-HT) and norepinephrine (NE). Since these amines are substances of high biological activity and have been implicated in brain function, it becomes of great interest to see whether the antidepressant effects elicited by MA0 inhibitors are related to changes in the brain levels of these amine~.’-~ The effect of a single dose of iproniazid (Mardid)* (100 mg./kg.) on the brain amines is shown in FIGURE l:, The level of 5-HT rises over a period of 6 hours until it reaches a plateau about twice normal. The level of N E rises more slowly and to a somewhat lesser degree. No obvious pharmacological signs result from a single dose of the drug. Daily doses of 25 mg. of iproniazid/kg. also elevate 5-HT levels, which reach a plateau 2 to 3 times normal in 2 days, while N E again rises more slowly but finally, by the fourth day reaches a maximum level (TABLE l), which is somewhat higher than that obtained from the single large dose. At this time, the rabbits show definite sympathomimetic signs, including mydriasis, constriction of the blood vessels in the ear, and an increased motor activity. These effects disappear when the N E levels decline on cessation of drug administration, even though the 5-HT levels are still elevated. FIGURE 2 shows the effect of a single dose (2 mg./kg.) of the potent MA0 inhibitor JB-516 (phenylisopropylhydrazine).6* The 5-HT rises more rapidly than after iproniazid, reaching its maximum level in about 1 hour; the N E levels again rise more slowly and to a lesser degree. Here, too, no pharmacological effects are evident. The administration of JB-516 in daily doses of 2 mg./kg. elevates the 5-HT levels no higher than does the single dose but, by the fourth day, it elicits appreciably higher NE levels (TABLE 2). The animals now exhibit the same sympathomimetic signs as seen after repeated doses of iproniazid. When the drug administration is terminated the excitation again disappears when the N E levels decline, although the 5-HT levels are still elevated. The same pattern of response is seen with JB-835 (phenylisobutylhydrazine), another potent MA0 inhibitor that has activity comparable to that of JB-516 (FIGURE 3, TABLE 3). These results suggest that the rise in 5-HT is not the important factor in the excitation caused by MA0 inhibitors, but that N E might be. Further evidence of this is found in the failure of MA0 inhibitors to produce psychomotor activity in cats even after daily administration of the drugs for a period of 7 days. In this species the inhibitors induce a pronounced increase in brain

Synthesis and Turnover of Norepinephrine in the Heart of the Spontaneously Hypertensive Rat

The kinetics of norepinephrine (NE) metabolism in the heart was studied in genetically hypertensive and normotensive control Wistar rats. Concentrations of endogenous NE were similar in the two groups. However, rates of synthesis of NE were reduced in these hypertensive rats, whether calculated from the rate of decline (fractional turnover rate) of cardiac tritiated NE (3H-NE) after intravenous injection, or estimated from levels of 14C-NE in the heart after injection of the precursor14C-L-tyrosine. In experiments with 3H-NE the synthesis rate of NE was 30.2 ng/hour/g heart in control and 18.2 ng/hour/g heart in hypertensive rats. The levels of 14C-NE found in the heart of normotensive rats given 14C-tyrosine were up to 1.4 times those found in hypertensive rats. These findings indicate a reduced rate of release of NE in this form of hypertension and, rather than implicating NE as a primary factor, suggest a secondary, compensatory mechanism.

Role for Ganglionic Norepinephrine in Sympathetic Synaptic Transmission

Transmission of nerve impulses in superior cervical sympathetic ganglia of cats and rabbits is markedly enhanced after reserpine-induced depletion of ganglionic norepinephrine. Transmission is also enhanced by administration of adrenergic blocking agents. In contrast, reserpine-induced release of ganglionic norepinephrine in animals pretreated with a monoamine oxidase inhibitor results in a pronounced depression of ganglionic transmission, which lasts until the ganglionic norepinephrine disappears. These results support the concept that norepinephrine in ganglia modulates the action of acetylcholine.

MONOAMINE OXIDASE IN CONTROL OF BRAIN SEROTONIN AND NOREPINEPHRINE CONTENT

Interest in the role of monoamine oxidase (MAO) in the metabolism of brain norepinephrine (NE) and serotonin (5HT) has been stimulated by the findings that inhibitors of this enzyme can elevate the brain levels of both amines.l.2 The problem arises whether the behavioral effects produced after blockade of MA0 are limited to an increase in brain amines and whether they can be related to a particular amine. Our previous studies with hydrazides have indicated that the stimulation produced by M A 0 inhibitors is associated with the rise in brain NE and the consequent overspill of the amine onto receptor sites? It might well be argued that since hydrazides have a high chemical reactivity, the association is fortuitous and unrelated to blockade of MAO. Pargyline ( M0911),* a non-hydrazide and potent M A 0 inhibitor which also has the advantage of being devoid of amphetamine-like properties was used to show the relationship between the central excitatory effect of MO 911 and the increase in brain NE.

NORADRENALINE IN THE HEART OF THE SPONTANEOUSLY HYPERTENSIVE RAT

Abstract Studies of the fate of intravenously administered [ 3 H]-noradrenaline in normal and spontaneously hypertensive (S.H.) rats revealed an increased 24-hour accumulation in the heart of the S.H. animal. This increased accumulation was associated with a normal 5-minute uptake of [ 3 H]-noradrenaline and normal endogenous levels of cardiac noradrenaline. It is suggested that the increased accumulation reflects a reduced rate of noradrenaline release. These changes in noradrenaline metabolism do not explain the hypertension but rather appear to be secondary to the hypertension.

The effects of blockade of monoamine storage processes upon limbic system excitability and behaviour in the cat

Summary The effects of α-methyl-meta-tyrosine (MMT), reserpine, and a benzoquinolizine derivative, Ro 4-1284 upon hippocampal evoked potentials, behaviour and processes that store 5HT and NE in brain were studied in the cat. Reserpine and Ro 4-1284 blocked the storage of 5HT and NE, facilitated the amygdalo-hippocampal evoked potential and produced hypokinesis, hyporeactivity, increased parasympathetic activity and other CNS effects. MMT, which specifically blocks NE storage did not facilitate the potential nor did it mimic reserpine in any other way. Pretreatment with MMT did not affect the actions of reserpine and Ro 4-1284. These results indicate that blockade of NE storage, with consequent loss of brain NE, was not responsible for the central effects of reserpine and Ro 4-1284. A causal relationship between blockage of 5 HT storage and the neurobiological effects of reserpine is possible but not proven.

Antihypertensive and noradrenaline-depleting effects of α-methyl-5-hydroxytryptophan in the rat

Abstract Known for several years as a decarboxylase inhibitor and catecholamine depletor and more recently as tyrosine hydroxylase inhibitor, α-methyl-5-hydroxytryptophan (α-methyl-5HTP) was studied further because it became newly-available in an orally-effective ester form. Single doses (200 mg/kg) of α-methyl-5HTP ethyl ester produced an average decrease of 50 mm Hg in the systolic blood pressure of spontaneously hypertensive rats with a maximum effect at 1 to 5 hr and persistence for 10 to 20 hr. There was a concomitant decrease in noradrenaline levels in heart and brain. Pretreatment with a decarboxylase-inhibiting drug, RO 4-4602, prevented the antihypertensive effect and partially blocked the noradrenaline-depleting effect. Up to 25 mg/kg of α-methyl-serotonin intraperitoneally markedly reduced heart and spleen noradrenaline content but failed to alter brain noradrenaline or blood pressure. While the acute antihypertensive effects of α-methyl-5HTP appear to be related to decarboxylation, other properties of the compound will undoubtedly contribute the effect of chronic administration of the drug.

RESTORATION OF TYRAMINE PRESSOR RESPONSES IN RESERPINE-TREATED ANIMALS BY METHYLDOPA AND ITS AMINE METABOLITES.

Summary Administration of methyldopa (L-a-methyldopa) to reserpine-treated dogs and rabbits results in restoration of pressor responses to tyramine. The amine metabolites of methyldopa, α-methyldopamine and α-methylnorepinephrine, cause similar but more prompt enhancement of tyramine responses with the latter compound showing maximum potency and more prompt onset of effect. That the effects of methyldopa are due to its amine metabolites is also indicated by the fact that D-α-methyldopa, which is not decarboxylated, is inactive. Present evidence favors α-methylnorepinephrine as the mediator responsible for the blood pressure lowering produced by methyldopa in man, as well as the preservation and restoration of tyramine responses following administration of the parent drug.

Reduction of tissue norepinephrine and blood pressure by 3,5-dihydroxy-4-methoxy-phenylalanine

Abstract 3, 5-Dihydroxy-4-methoxyphenylalanine (DHMPA) has been shown to be an effective depletor of norepinephrine content of the heart, brain and spleen in mouse and rat. Significant antihypertensive effects of the drug were observed in spontaneously hypertensive rats. This action of the drug appears related to the catecholamine depletion and a possible false transmitter mechanism.