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The present study explored the usefulness of plasma amino acid concentrations in discriminating a subgroup of patients with transient acute polymorphic psychoses characterized by psychosensory symptoms (APP+ patients). Levels of amino acids in the plasma of APP+ patients were compared with levels in psychiatric patients with other types of psychotic symptomatology and a healthy control group. Both the APP+ patients and patients with bipolar affective disorder had significantly lower plasma concentrations of serine compared with concentrations in the other groups studied. Since the plasma concentrations of taurine and methionine were also different in the APP+ patients, the ratio of taurine to the product of serine and methionine (the TSM ratio) was used in an attempt to increase the sensitivity in discriminating these patients. The TSM ratio in the APP+ patients was significantly higher than those in the other groups studied, except for the patients with bipolar affective disorder. It appears that the determination of serine and the TSM ratio in the plasma of psychotic patients may be a useful diagnostic validator in a group of patients with acute polymorphic psychoses. more...

Addition of serum, obtained from patients suffering from an acute psychosis characterized by dysperceptions, to the culture media of fibroblasts altered the amino acid metabolism in these cells. After subculturing of fibroblasts in the presence of serum obtained from these patients, the concentrations of both serine and methionine were decreased in the medium as well as in the fibroblasts. Moreover, the concentration of taurine in the fibroblasts was increased. The specific activities of serine hydroxymethyltransferase and cystathionine beta-synthase were also measured in the fibroblasts. It was found that both enzyme activities were significantly higher after subculturing with patients' serum as compared with serum obtained from healthy controls. It is concluded that a factor, present in the serum of these acute psychotic patients, is responsible for the observed changes in serine, taurine, and methionine concentrations in the fibroblasts as well as for the increased enzyme activities mentioned. more...

It was investigated whether an increased demand for glycine, as postulated to occur in patients who have suffered from episodic psychoses accompanied by multiple perceptual distortions, could evoke psychotic reactions. Catalepsy was used as a measure for psychosis and was observed after injection of serine or glycine in porphyric rats. Catalepsy was was shown to occur after serine as well as glycine administration in 2-allyl-2-isopropylacetamide (AIA) pretreated rats, while in lead (Pb) + phenobarbital pretreated rats only glycine was effective. Administration of AIA to rats resulted in a strongly enhanced excretion of porphobilinogen (PBG) in urine, while Pb + phenobarbital pretreated rats showed increased excretion of delta-aminolevulinic acid (delta-ALA). The Pb + phenobarbital pretreated animals showed elevated serine plasma levels and lowered glycine plasma levels 18 hours after injection, while no significant differences in plasma levels of these amino acids were found 24 hours after AIA administration. In AIA or saline pretreated animals, but not in those pretreated with Pb + phenobarbital, glycine formation from serine was elevated. It is concluded that the present animal model can be used to investigate episodic psychoses. more...

Summary Quasi-morphine abstinence behaviour induced by di-n-propylacetate (DPA) in rats is thought to be caused by an increased GABAergic activity in the CNS. Behavioural responses after intracerebral injections of DPA were studied to gain insight into the brain sites involved in this quasi-abstinence syndrome. Injection of DPA into the centre median-parafascicularis (Cm-Pf) resulted in a large number of body shakes and greater locomotor activity when compared to other brain areas. Injection of DPA into the central amygdala (Ac) resulted in an enhanced number of chewing episodes. Administration of bicuculline methiodide (BMI) into the Cm-Pf, 5 min after intraperitoneal administration of DPA, suppressed body shakes but had only minor effects on horizontal activity, whereas injection of morphine into the same structure suppressed both behavioural symptoms. It is concluded that GABAergic and opioid mechanisms in the Cm-Pf are involved in the DPA-induced behaviour. Injection of BMI into the central amygdala shortly after i.p. injection of DPA resulted in an increase in the number of body shakes, whereas no effect was observed on activity. Morphine applied to this structure slightly potentiated the locomotor activity, but had no effect on the body shakes induced by DPA. The present results suggest a facilitatory role for a GABAergic system in the Cm-Pf on body shakes, while in the central amygdala a GABAergic system exerts an inhibitory influence on this symptom of abstinence. more...

Porphyria was induced in adult male Wistar rats starved for 24 hr by SC injection of 400 mg/kg allylisopropylacetamide (AIA). The presence of porphyria was shown by measuring excretion of delta-aminolevulinic acid (delta-ALA) and porphobilinogen (PBG) into the urine during 24 hr after AIA administration. Plasma levels of glycine, serine and of a number of other amino acids were decreased in porphyric rats as compared to controls. Intraperitoneal injection of 2 mmol/kg serine 24 hr after AIA administration was used as an animal model for an acute psychosis, by measuring catalepsy scores 30 min after serine injection. The concentration of 5 different beta-carbolines in platelet rich plasma (PRP) was measured using an HPLC-fluorometric method. An increase in the concentration of norharman (NH) in PRP, ranging from 0.57 nmoles/l in control rats to 1.88 nmoles/l in serine treated porphyric rats was found. The catalepsy duration was exponentially correlated with the NH concentrations in PRP. It is concluded that an elevated conversion of serine into glycine via serine hydroxymethyltransferase (SHMT) may be responsible for the enhanced NH biosynthesis. more...

Di-n-propylacetate (DPA) induces a behavioral syndrome in rats resembling morphine abstinence behavior. The inhibitory action of DPA on GABA degradation, resulting in an enhanced release of GABA, is probably responsible for this behavioral effect, since GABA antagonists, like bicuculline and picrotoxin, have been shown to suppress this behavior. However, the time-course of the DPA-induced behavior is much shorter than that of the DPA-induced increase of GABA concentrations. Therefore, we have studied the influence of enhanced GABA levels caused by a first injection of DPA and the behavior evoked by a second injection of DPA at different time intervals after the first injection. The results indicate that GABA fulfills a role in both the initiation and termination of DPA-induced behavior. The mechanism responsible for this dual action of GABA is ascribed to a differential sensitivity to DPA of the nerve terminal and glial metabolic compartments of GABA in the brain. The increase of GABA in the nerve terminal caused by DPA is probably responsible for the initiation of the quasi-abstinence behavior, whereas the overflow of GABA into the synaptic cleft may be responsible for the suppression of this behavior via stimulation of presynaptic autoreceptors. Another mechanism responsible for the rapid termination of the DPA-evoked behavior could be the formation of DPA metabolites which antagonize this behavior. From the results of experiments using some primary metabolites of DPA, a role for these metabolites in the termination of the DPA-induced behavior seems unlikely. more...

Intraperitoneal administration of n-dipropylacetate (DPA) to naive rats produced abstinence behaviour including shaking, digging, hunchback posture, piloerection and ptosis during 15 min and increased motor activity considerably. Treatment with a subconvulsive dose of the GABA antagonist bicuculline suppressed this DPA-induced abstinence behaviour, indicating that GABA was increased at receptor sites. Also morphine in a low dose of 1 mg/kg suppressed this behaviour, while administration of naloxone after morphine treatment could release the abstinence behaviour. Simultaneous treatment with morphine and naloxone or naloxone alone were without effect. The administration to DPA treated rats of doses higher than 1 mg/kg morphine resulted in a severe depression of motor activity. It is concluded that an increased availability of GABA at its receptor sites plays an important role in the behaviour observed after DPA administration. The experiments with morphine and naloxone suggest that morphine receptors are involved in DPA-induced abstinence behaviour. more...

An increase in GABA-ergic activity has been implicated in the initiation of quasi-morphine abstinence behavior by di-n-propylacetate (DPA). Two structural analogues of DPA, namely, the branched-chain-fatty acid 2-methyl, 2-ethylcaproic acid and 2,2-dimethylvaleric acid have now been used to study this relationship between behavioral and biochemical effects. A correlation appeared to exist between the K1 of these compounds for succinic semi-aldehyde dehydrogenase, the second enzyme in the degradation of GABA, and the doses exerting a maximum effect on behavior. On the other hand concurrent inhibition of GABA-transaminase seemed to suppress the behavioral effects of the fatty acids. This apparent paradox can possibly be explained by supposing a different action of the fatty acids in distinct compartments of the brain, suggesting an important role for increased GABA-ergic activity in the neuronal compartment in the initiation of the quasi-morphine abstinence behavior. more...

1. 1. When morphine (20 mg/kg i.p.) was administered to rats 30 min. after treatment with an inhibitor of dopamine biosynthesis (α-methyl-paratyro-sine), it induced strong catalepsy. 2. 2. No effect on the decline of dopamine was observed in the striatum under these conditions. If morphine catalepsy is caused at the level of the striatum only dopamine receptor blockade is compatible with these results. 3. 3. Under this experimental condition, morphine does increase the decline of dopamine in the frontal cortex. 4. 4. The results suggest, that mesolimbic dopaminergic systems might be involved in the generation of morphine catalepsy. more...

A disturbance of serine-glycine metabolism in a group of patients who became psychotic after oral intake of serine may be due to any serine-related enzyme abnormality. In order to elucidate this problem, we studied several enzymes in fibroblasts obtained from these patients. First, the enzyme serine hydroxymethyltransferase was investigated. The apparent Km values for serine, L-tetrahydrofolate (H4folate), and pyridoxal 5'-phosphate, as well as the maximal velocities of the forward and backward reactions measured in fibroblasts obtained from patients, were not different from those in the cells from controls. We also measured the activities of another three enzymes of the folic acid cycle, viz., 5,10-methylene-H4folate dehydrogenase, 10-formyl-H4folate synthetase, and 5,10-methenyl-H4folate cyclohydrolase, as well as the enzyme cystathionine beta-synthase. Again, no differences were found among these enzymes in fibroblasts from patients and controls. It can be concluded that the psychotic symptoms occurring after the administration of serine are not the result of any malfunctioning of the enzymes investigated. more...

Four patients with an intermittent psychosis closely resembling hallucinogenic drug-induced states were suspected of having a porphyric disease and were investigated for a possible relation between the metabolic dysfunctions of porphyria and the psychotic syndrome. Theoretically the link could be in a disturbance of serine and glycine metabolism. This theory was supported by disturbances in serine and glycine excretion found in all patients during psychotic episodes. In addition, loading with one low oral dose of serine produced psychotic symptoms 5 h later which lasted 3-6 h. One patient reacted to glycine in the same way. These findings suggest that disturbed serine-glycine metabolism may have a key role in certain schizophreniform psychotic syndromes. more...

The role of the noradrenergic system in quasi-morphine abstinence behaviour induced by di- n -propylacetate (DPA) in rats has been studied. Depletion of noradrenaline (NA), by treatment with FLA-63, decreased the number of body shakes and the extent of horizontal activity evoked by DPA. Almost total suppression of these symptoms was obtained by injection of 20 ng morphine bilaterally into the locus coeruleus (LC). Destruction of the LC system by electrolytic lesion of the LC or by injection of 6-hyrodroxy-dopamine into the dorsal bundle revealed that degeneration of the NA system by at least 80% appears to be necessary to decrease the number of body shakes. It is concluded that the noradrenergic LC system fulfills a modulatory role in quasi-morphine abstinence behaviour induced by DPA. more...

Cyproheptadine, a 5HT 2 receptor antagonist with prominent anti-muscarinic and anti-histaminic properties, was shown to have an anti-conflict effect in rats using a modified Geller-Seifter test and also enhanced extinction of conflict behaviour. The selective 5HT 2 receptor antagonist ritanserin, however, had neither an anti-conflict effect nor an effect on extinction of conflict behaviour. The muscarinic receptor antagonist scopolamine, on the other hand, was active in both paradigms. The effect of cyproheptadine on extinction of conflict behaviour was decreased by co-administration of physostigmine, an acetylcholinesterase inhibitor, but not affected by the concomitant administration of the muscarine receptor agonist oxotremorine. The results suggest that the anti-conflict effect of cyproheptadine has to be ascribed to its anti-muscarinic activity and is not due to its 5HT 2 antagonism. more...

The so-called cycloid or degeneration psychoses form a subgroup of the vaguely defined schizoaffective psychotic disorders, or according to the DSM III criteria: "Psychotic Disorders Not Elswhere Classified" (295.40; 298.80; 295.70; 298.90). Recovery from these acute psychoses is always complete, though episodic recurrence is commonly observed. The clinical syndrome is characterized by a kaleidoscopic, polymorphous clinical picture, e.g. sudden mood swings, motility disturbances, states of pananxiety and ecstasy with visionary experiences, perfunctory delusional ideas and visual hallucinations. At the onset of the psychoses many patients experienced psychedelic phenomena. It was postulated that these patients suffered from an abnormality in one-carbon metabolism resulting in the formation of beta-carbolines which were held responsible for evoking the psychotic symptoms. Since serine is the principle donor for one-carbon units, serine was administered to nonsymptomatic patients. Two to three hours after the administration patients became psychotic again. Analysis of blood samples from these patients showed a decreased fasting plasma concentration of serine and an increased fasting plasma level of taurine. In addition a decreased formation of serine from glycine was found. These findings are in agreement with the postulated derangement of one-carbon metabolism. Moreover, the beta-carboline norharman was present in blood obtained during acute psychotic episodes and was not present in blood of nonsymptomatic patients nor in blood of healthy controls. No abnormal activities of enzymes were found in skin fibroblasts from these patients.(ABSTRACT TRUNCATED AT 250 WORDS) more...

Baclofen and oxazepam enhance extinction of conflict behaviour in the Geller-Seifter test while baclofen and diazepam release punished behaviour in Vogel's conflict test. In order to investigate the possibility that the effect of the selective GABA-B receptor agonist baclofen is mediated indirectly via the GABA-A/benzodiazepine receptor complex, the effect of pretreatment of rats with baclofen on [3H]-diazepam binding to washed and unwashed cortical and cerebellar membranes of rats has been studied. Baclofen pretreatment increased Bmax in washed cerebellar membranes when bicuculline was present in the incubation mixture. No effect was seen in cortical membranes. The present results render it unlikely that the effect of baclofen on extinction of conflict behaviour and punished drinking is mediated via the GABA-A/benzodiazepine receptor complex. more...

The conversion of succinic semialdehyde into gamma-aminobutyric acid (GABA) by GABA-transaminase was measured in rat brain homogenate in the presence of different concentrations of the cosubstrate glutamate. The calculated kinetic parameters of succinic semialdehyde for GABA-transaminase were a limiting Km value of 168 microM and a limiting Vmax value of 38 mumol g-1 h-1. Combination with previously obtained data for the conversion of GABA into succinic semialdehyde revealed a kEq value of 0.04, indicating that equilibrium of GABA-transaminase is biased toward the formation of GABA. The increased formation of GABA in the presence of succinic semialdehyde was not due to an increased conversion of glutamate into GABA by glutamic acid decarboxylase. Therefore these results indicate that succinic semialdehyde can act as a precursor for GABA synthesis. more...

A model of transient acute hepatic failure has been developed in the pig. Three days after a functional end-to-side protacaval shunt was introduced, 15 ambulant animals underwent total liver ischemia for 4 to 6 h by the closure of a mechanical clamp surrounding the hepatic artery. Four of the eight animals subjected to 4 hr of ischemia survived. All but one of the animals undergoing 6 hr of hepatic ischemia developed grade 4 encephalopathy after 24 to 30 hr and died within 50 hr. Quantitative estimation of liver cell necrosis revealed less than 40% necrosis in the survivors, and approximately 62% (range 49–75%) in animals who died of hepatic coma. As far as the putative toxins are concerned, significant differences were found between animals undergoing 4 and those undergoing 6 hr of ischemia, especially in the plasma ammonia levels and the plasma ratios for tyrosine and phenylalanine. Plasma arginine levels had fallen to zero in both groups at 24 hr and only rose to preischemic values in animals who survived. This large animal model fulfills the accepted criteria of potential reversibility, reproducibility, and death due to hepatic failure. more...

Inhibition of dopamine synthesis by a single injection of α-methyl-para-tyrosine (200 mg/kg, i.p.) was complete from 30 to at least 300 min after administration. When morphine (20 mg/kg) was given intraperitonealy 30 min after α-MpT treatment an enhanced decline of dopamine was observed in frontal parts of the cortex but not in the striatum. These results indicate that morphine affects dopaminergic neurons in frontal parts of the cortex in a way differently from those in the striatum of the rat. This may be caused either by a difference in the properties of dopaminergic nerve endings in both structures or by an effect of morphine on the input to the cortical system which is lacking in the striatum. more...

Haloperidol (1 mg/kg) was administered to rats pretreated with α-methyl-para-tyrosine-methylester. HCl (αMpT) and the levels of dopamine (DA) as well as HVA and DOPAC were measured in the striatum. While the release of DA was stimulated by haloperidol for at least 60 min, HVA and DOPAC levels were markedly increased only at 30 min, but not at 60, 90, or 120 min, after haloperidol administration. In rats not pretreated with αMpT, on the other hand, a strong increase in metabolite levels was observed between 60 and 120 min after haloperidol administration. It is concluded that a direct relation between DA release and metabolite levels does not exist in the present experiments. DA biosynthesis and processes involved with the clearance of metabolites appear to be important factors in the haloperidol-induced increase in metabolite levels. The relative importance of these three processes remains to be clarified. more...

The idea that disease entities might exist in psychiatry can be strongly supported by demonstrating that the disease is linked with a specific pathochemical marker. In general, pathochemical markers comprise the presence or (relative) absence of a biological substance, such as an enzyme, which is only found in latently or manifestly afflicted subjects. With respect to the present findings we wish to extend this narrow definition to include a specific reaction of a patient to an administered substance. Such a procedure can be compared to skin reactions of allergic subjects to hypodermically injected substances, or perhaps more appropriately to the panic reactions of patients with anxiety neurosis to infusions of lactate (Appleby et al. 1981). Demonstrating that the administered substance is pathogenetically related to the diseased state may greatly improve the understanding of the biological basis of the disease, while the specific reaction of the subject to the substance makes a more homogeneous classification of this disorder possible. more...

From the present analysis it is concluded that alterations in DA metabolite concentrations after administration of haloperidol do not reflect alterations in DA release, but may be more closely related to alterations in DA biosynthesis. more...

The striking potency of substances from exogenous sources — like hashish, mescaline or LSD — to evoke mental states similar to certain phenomena observed in psychotics, made many researchers speculate about the origin of psychoses. In this respect most at­tention was focussed on altered sensory perception of surroundings, distances, time, body, colours etc. and on subjective experiences of feelings of oneness and understand­ing of the universe. These so-called psychedelic experiences (1) have been noted in a variety of psychotic disorders including schizophrenia. more...