G. Bartholini

Differential effect of neuroleptic drugs on dopamine turnover in the extrapyramidal and limbic system.

In gallamine‐immobilized cats, the caudate nucleus and the nucleus accumbens septi were perfused by means of a push‐pull cannula and dopamine was measured in the perfusate. Chlorpromazine (10 mg kg−1) and clozapine (20 mg kg−1), administered intravenously, enhanced the release of dopamine. The effect of chlorpromazine was similar in both regions whereas that of clozapine was more pronounced in the nucleus accumbens than in the caudate nucleus. Furthermore, in the rat, sulpiride, clozapine and thioridazine increased the homovanillic acid concentration in striatum and limbic system to a similar extent. However, following probenecid administration, the net effect of these drugs on homovanillic acid accumulation was more marked in the limbic system than in the striatum whereas haloperidol and chlorpromazine had a similar effect in the two regions. It is concluded that, in contrast to haloperidol and chlorpromazine, sulpiride, clozapine and thioridazine may preferentially affect the limbic dopaminergic transmission. This possibly accounts for the fact that sulpiride, clozapine and thioridazine display an antipsychotic action and yet cause less extrapyramidal side effects than haloperidol and chlorpromazine.

Cortical modulation of striatal function

The effect of bilateral section of the corticostriatal projections or of selective bilateral ablation of the frontal cortex on behavioral and biochemical parameters related to striatal function were investigated in the rat. Either lesion almost completely prevented the cataleptogenic action of haloperidol: this effect was observed as soon as 3 days and lasted for at least 3 months after surgery, paralleling a reduction in striatal glutamate uptake. Also, such lesions enhanced the apomorphine-induced stereotyped behavior (as measured 21 days after surgery). In the striatum, dopamine, dihydroxyphenylacetic acid, acetylcholine and substance P levels as well as choline acetyltransferase and glutamic acid decarboxylase activities were unaffected 10 or 21 days after either type of lesion. In the substantia nigra, substance P levels were unchanged 10 days following suction of the frontal cortex, but glutamic acid decarboxylase was reduced at 21 days postsurgery. Cortical lesions only partially prevented the reduction in striatal acetylcholine concentrations and did not affect the increase in striatal dihydroxyphenylacetic acid caused by haloperidol. Finally, lesions of the corticostriatal pathways failed to affect the apomorphine-induced increase in striatal acetylcholine levels, reduction of the potassium (20 mM) evoked [3H]acetylcholine release in striatal slices preloaded with [3H]choline and decrease of striatal dihydroxyphenylacetic acid concentrations. These findings indicate that the frontal cortex influences extrapyramidal function by a mechanism which--in behavioral terms--is antagonistic to dopamine-mediated events. As indicated by the biochemical data, this mechanism does not involve changes in striatal dopaminergic and cholinergic neuron activity. This mechanism may utilize: (1) corticostriatal glutamatergic neurons as suggested by the reduction in striatal glutamate uptake following lesions; and (2) GABAergic pathways as suggested by the reduction of nigral glutamic acid decarboxylase activity as well as by the finding that GABA receptor agonists reinstate haloperidol-induced catalepsy.

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.

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.

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.

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.

Dissociation between biochemical and ultrastructural effects of 6-hydroxydopamine in rat brain

Im Gehirn von Ratten bewirkt einmalige intraventrikuläre Injektion von 200 μg 6-Hydroxydopamin nach 2 und 5 Tagen eine deutliche Verminderung von Noradrenalin und Dopamin, während 5-Hydroxytryptamin nur geringfügig herabgesetzt wird. Elektronenmikroskopisch sind keine strukturellen Veränderungen festzustellen. Zweimalige Injektion von 200 μg 6-Hydroxydopamin führt dagegen zu schweren spezifischen Degenerationen im Bereich des Nucleus caudatus und Hypothalamus. Daraus wird geschlossen, dass niedrige Dosen 6-Hydroxydopamin die cerebralen Catecholamine vermindern können, ohne ultrastrukturelle Schädigungen des Gehirns zu verursachen.

Formation of monoamines from various amino acids in the brain after inhibition of extracerebral decarboxylase

Abstract The effect of an inhibitor of extracerebral decarboxylase (Ro 4-4602) on the formation of cerebral monoamines from various amino acids has been investigated in rats by biochemical and histochemical methods. Pretreatment with Ro 4-4602 markedly increases the l -3,4-dihydroxyphenylalanine (DOPA)-induced formation of dopamine (DA), slightly enhances the DL-5-hydroxytryptophan (5HTP)-induced elevation of 5-hydroxytryptamine (5HT) and diminishes the DL-threo-3,4-dihydroxyphenylserine (DOPS)-induced rise of norepinephrine (NE) in the brain. Correspondingly, Ro 4-4602 abolishes the typical fluorescence caused by the amines within the walls of brain capillaries but markedly increases the parenchymal fluorescence after DOPA, and slightly that after 5HTP. The DOPS-induced weak parenchymal fluorescence is not modified by the inhibitor. It is concluded that a) the effect of Ro 4-4602 varies according to differences in the affinity of the amino acids for the decarboxylase and possibly in their penetration through the blood-brain barrier, and b) the cerebral norepinephrine formed after administration of DOPS is mainly localized in the capillaries of the brain.

Accumulation of dopamine in the parenchyma after decarboxylase inhibition in the capillaries of brain.

Im Pallium und im Nucleus caudatus des Rattenhirns verstärkt der Decarboxylasehemmer Ro 4-4602 den durch Dopa bedingten Anstieg von Dopamin. Mit einer fluoreszenzmikroskopischen Methode wird gezeigt, dass Dopamin wahrscheinlich im Parenchym und nicht in den Kapillaren des Gehirns akkumuliert.