A. Pletscher

Ultrastructural Localization of 5-Hydroxy-tryptamine in Blood Platelets

THE blood platelets of various animals, including man, contain 5-hydroxytryptamine (5HT) and can take up this amine from plasma and other incubation media. The amine seems to be stored by a mechanism which requires metabolic energy, because metabolic inhibitors (such as potassium cyanide and chloro-mercuribenzoate) or elimination of glucose from the incubation medium lead to a rapid loss of platelet 5HT (refs. 1 and 2). On the basis of the results of differential centrifugation experiments, as well as of electron microscope investigations, it has been postulated that platelet 5HT is localized in special sub-cellular organelles in a similar way to aromatic mono-amines in nervous tissue2–6. Some investigators think that the 5HT might be associated with the α-granules or vacuoles of the platelets4,6. 5HT storing particles have not, however, been clearly demonstrated up to now at an ultrastructural level. The present communication shows that platelet 5HT is at least partially localized in special submicroscopic organelles which are not identical with α-granules.

Increase of 3-methoxy-4-hydroxyphenylethylene glycol in rat brain by neuroleptic drugs

Abstract The potency of various neuroleptic drugs in increasing the content of endogenous 3-methoxy-4-hydroxyphenyl-ethylene glycol (MOPEG) in rat brain decreased in the order methiothepin, haloperidol, clozapine, thioridazine, chlorpromazine, pimozide. The neuroleptics, except pimozide and chlorpromazine, also caused a slight to moderate diminution of the endogenous cerebral noradrenaline (NA). Based on these and earlier findings it is concluded that (a) changes in brain NA turnover induced by neuroleptics can be estimated, in a relatively simple way, by measuring cerebral MOPEG; (b) these drugs markedly differ in their ability to activate noradrenergic neurons; and (c) the activation of noradrenergic neurons by neuroleptics does not seem to parallel that of dopaminergic neurons.

Effect of various decarboxylase inhibitors on the cerebral metabolism of dihydroxyphenylalanine

Small doses of Ro 44602 [N-(~~-seryl)-N’-(2,3,4-trihydroxybenzyl)hydrazine], an inhibitor of decarboxylase (DC), enhance the dopa-induced increase of catecholamines in the brain of rats. This was attributed to a poor penetration of the drug through the blood-brain barrier leading to a preferential inhibition of DC in extracerebral tissues like liver, heart and kidney. As a consequence, the concentration of administered dopa in plasma rose and the supply to the brain of this amino-acid was enhanced. This was followed by an increased formation of cerebral catecholamines and their metabolites, the phenolic carboxylic acids (Bartholini, Bates & others, 1967 ;. Bartholini & Pletscher, 1968 ; Bartholini, Tissot & Pletscher, 1968 ; Constantinidis, Bartholini & others, 1968). We now report the effect of some other known DC inhibitors : MK485 [~-(3,4-dihydroxyphenyl)-a-hydrazino-a-methyl propionic acid] ; NSD 101 5 (m-hydroxybenzylhydrazine) and a-methyldopa.

Isolated 5‐hydroxytryptamine organelles of rabbit blood platelets: physiological properties and drug‐induced changes

1 . In isolated 5‐hydroxytryptamine (5‐HT) organelles of rabbit platelets, the concentrations of 5‐HT, histamine and adenosinetriphosphate (ATP) respectively are about 200 times higher than in intact platelets. Organelles incubated in plasma at 37° C gradually lose endogenous 5‐HT, histamine and ATP and take up 14C‐5‐HT against a considerable concentration gradient. Liberation and uptake of 5‐HT markedly decrease with dimishing incubation temperature. 2 . Exposure to reserpine in vitro strongly counteracts the uptake of 14C‐5‐HT by isolated organelles, whereas the 14C‐5‐HT uptake of intact isolated platelets is less affected by the drug. 5‐HT organelles of platelets from reserpinized rabbits also take up very little 14C‐5‐HT. 3 . Imipramine inhibits the uptake of 14C‐5‐HT in isolated organelles less markedly than in isolated platelets. 4 . It is concluded that in the organelles 5‐HT and possibly histamine may be associated with ATP. Reserpine probably impairs the uptake of 5‐HT at the level of the organelles (possibly by interfering with the association 5‐HT/ATP), whereas imipramine seems to act preferentially on the cell membrane.

Effects of clozapine on cerebral catecholaminergic neurone systems.

1 . Clozapine, a dibenzodiazepine derivative claimed to possess antipsychotic properties in man without producing extrapyramidal disorders, greatly increased the turnover of cerebral dopamine in the rat. 2 . The drug itself was virtually devoid of cataleptigenic activity in rats; however, it antagonized prochlorperazine‐induced catalepsy. 3 . It is proposed that clozapine causes a blockade of striatal dopamine receptors which is of the surmountable type in contrast to that produced by cataleptigenic neuroleptics. In addition, clozapine may also increase the turnover of cerebral noradrenaline.

Acceleration of the cerebral dopamine turnover by chlorpromazine.

Im Stammhirn von normothermen Ratten bewirkt Chlorpromazin einen Anstieg von Homovanillinsäure (HVS), der bei Hypothermie verringert wird. Dieser Anstieg geht nicht mit einer Verminderung der Dopaminkonzentration einher und bleibt nach Hemmung der Monoaminoxydase aus. Die durch Vorbehandlung mit einem kurzwirkenden Monoaminfreisetzer (Benzochinolizinderivat Ro 4-1284) erhöhte endogene HVS zeigt nach Chlorpromazin keinen verzögerten Abfall.

On the origin of homovanillic acid in the cerebrospinal fluid

In Occipitalliquor und Gehirn von Katzen ist der Gehalt an radioaktiver Homovanillinsäure (HVS) bezogen auf Plasma nach i.v. Applikation vonl-14C-DOPA erheblich höher als nach i.v.3H-HVS.14C-HVS, welche nachl-14C-DOPA im Liquor erscheint, entsteht deshalb wahrscheinlich mindestens zum Teil im Gehirn.

Inhibition of decarboxylase of aromatic amino acids by 2,3,4-trihydroxybenzylhydrazine and its seryl derivative

N-(2,3,4-Trihydroxybenzyl)hydrazine [Ro 4-5127] and N1-(dl-seryl)-N2-(2,3,4-trihydroxybenzyl)hydrazine [Ro 4-4602] are powerful inhibitors of the decarboxylase of aromatic amino acids in vitro. Their effect is not reversible by dialysis or addition of pyridoxal-5′-phosphate. The inhibition by trihydroxybenzylhydrazine seems to be pseudo-irreversible and competitive. In vivo, i.e. after a single intraperitoneal injection of the drugs into rats, the activity of the decarboxylase is markedly reduced in kidney and to a lesser degree in brain. The seryl compound, however, causes in vivo no or only weak inhibition of other enzymes, such as monoamine oxidase, diamine oxidase, catecholamine-O-methyl transferase, transaminase of aromatic amino acids, tryptophan hydroxylase; in vitro, the seryl derivative does not affect the histidine decarboxylase or dopamine-β-oxidase either, nor does it alter the spontaneous release of C14-catecholamines in the rat heart in vivo.

Lysergic acid diethylamide: evidence for stimulation of cerebral dopamine receptors.

In the rat, lysergic acid diethylamide (LSD) decreased the striatal and retinal content of homovanillic acid. LSD did not change the level of dopamine (DA), but delayed the a-methyl-p-tyrosine-induced disappearance of this amine in the teldiencephalon. In the cat, LSD diminished the DA output into the perfusate of the caudate nucleus. Furthermore, LSD increased the activity of adenylate cyclase in striatal homogenates of rat. These and other findings indicate that in the central nervous system LSD stimulates DA receptors which may be involved in LSD-induced phychosis.

The effect of a new decarboxylase inhibitor on endogenous and exogenous monoamines

Abstract In various animal species the hydrazide Ro 4-4602, a potent irreversible inhibitor of decarboxylase of aromatic amino acids, decreases 5-hydroxytryptamine (5HT) and norepinephrine (NE) in the brain as well as NE in the heart by a maximum of about 50 per cent. The 5HT-increase in brain and heart induced by 5-hydroxytryptophan as well as the recovery of 5HT in the brain after its depletion by a monoamine releaser (Ro 4-1284) is, however, completely inhibited by the drug. The possibility is discussed that Ro 4-4602 might interfere mainly with the metabolism of “free” and relatively little with that of “stored” amines.