Discrimination of idiopathic pain syndromes from neurogenic pain syndromes and healthy volunteers by means of clinical rating,personality traits,monoamine metabolites in CSF,serum cortisol,platelet MAO and urinary melatonin

Summary The aim of the present study was to investigate the discriminative power of a series of variables (including determination of depressive symptomatology by means of a visual analogue scale, determination of personality traits by means of the Karolinska Scales of Personality, determination of monoamine metabolites in CSF, platelet MAO activities, serum cortisol before and after dexamethasone suppression and urinary melatonin) in differentiating (a) chronic pain patients from healthy subjects, and (b) patients with idiopathic pain syndromes from patients with neurogenic pain syndromes. Separately each of the measures gave a significant but often low contribution to the discrimination, while a combination of several measures gave a complete discrimination both between healthy subjects and patients with chronic pain syndromes and between patients with idiopathic and neurogenic pain syndromes, respectively.Supported in part by grants from the Swedish Medical Research Council (grants no. 3371, 4145 and 5740) and by a grant from Stiftelsen Söderström-Königska Sjukhemmet     

Pathophysiology of idiopathic dystonia: findings from genetic animal models

Dystonia is a common movement disorder which is thought to represent a disease of the basal ganglia. However, the pathogenesis of the idiopathic dystonias, i.e. the neuroanatomic and neurochemical basis, is still a mystery. Research in dystonia is complicated by the existence of various phenotypic and genotypic subtypes of idiopathic dystonia, probably related to heterogeneous dysfunctions.In neurological diseases in which no obvious neuronal degeneration can be found, such as in idiopathic dystonia, the identification of a primary defect is difficult, because of the large number of chemically distinct, but functionally interrelated, neurotransmitter systems in the brain.The variable response to pharmacological agents in patients with idiopathic dystonia supports the notion that the underlying biochemical dysfunctions vary in the subtypes of idiopathic dystonia. Hence, in basic research it is important to clearly define the involved type of dystonia.Animal models of dystonias were described as limited. However, over the last years, there has been considerable progress in the evaluation of animal models for different types of dystonia.Apart from animal models of symptomatic dystonia, genetic animal models with inherited dystonia which occurs in the absence of pathomorphological alterations in brain and spinal cord are described.This review will focus mainly on genetic animal models of different idiopathic dystonias and pathophysiological findings. In particular, in the case of the mutant dystonic (dt) rat, a model of generalized dystonia, and in the case of the genetically dystonic hamster (dt^sz), a model of paroxysmal dystonic choreoathetosis has been used, as these show great promise in contributing to the identification of underlying mechanisms in idiopathic dystonias, although even a proper animal model will probably never be equivalent to a human disease.Several pathophysiological findings from animal models are in line with clinical observations in dystonic patients, indicating abnormalities not only in the basal ganglia and thalamic nuclei, but also in the cerebellum and brainstem. Through clinical studies and neurochemical data several similarities were found in the genetic animal models, although the current data indicates different defects in dystonic animals which is consistent with the notion that dystonia is a heterogenous disorder.Different supraspinal dysfunctions appear to lead to manifestation of dystonic movements and postures. In addition to increasing our understanding of the pathophysiology of idiopathic dystonia, animal models may help to improve therapeutic strategies for this movement disorder.     

Monoamine acid metabolites in ventricular CSF of patients with brain tumours

Summary Homovanillic acid (HVA) and 5-hydroxyindolacetic acid (5-HIAA) in ventricular CSF were determined in 19 patients (12 female 7 male) with brain tumours. No relationship was found between ventricular fluid pressure (VFP) and levels of HVA and 5-HIAA. A relationship was observed between ventricular CSF, HVA concentrations and tumour induced alterations in CSF dynamics. HVA concentrations were very high in patients whose tumours involved the third ventricle, the aqueduct, or the fourth ventricle, producing marked alterations in CSF flow. HVA concentrations significantly lower than in controls were observed in cases where tumours involved the lateral ventricles. Concentrations of acid metabolites in patients with little or no alteration in CSF dynamics corresponded with those in patients with other neurosurgical disorders.     

Catatonia: short-term response to lorazepam and dopaminergic metabolism

Therapeutic response to lorazepam and dopaminergic metabolism were investigated in 18 neuroleptically naive acute catatonic patients. They were diagnosed as catatonic according to criteria by Lohr and Rosebush and treated exclusively with lorazepam (2–4 mg) during the first 24 h. Dopaminergic metabolism (plasma HVA, plasma MHPG), anxiety (HAM-A) and parkinsonic/dyskinetic movements (SEPS, AIMS) were measured under standard conditions before initial treatment with lorazepam (day 0) and 24 h after initial treatment (day 1). On day 0 responders to lorazepam treatment (complete remission of catatonic syndrome after 24 h according to Rosebush and Lohr) showed significantly higher (P=0.004) plasma HVA (130.4±51.2 pmol/ml; means ± SD) than non-responders (no remission of catatonic syndrome after 24 h; 73.2±40.5 pmol/ml; means ± SD). On day 1 plasma HVA did not differ any more significantly between both groups Clinically, responders showed significantly higher HAM-A (P=0.025) and AIMS (P=0.022) scores as well as significantly lower SEPS (P=0.049) scores than non-responders on day 0. Hence catatonic short-term responders and non-responders to lorazepam can be distinguished with regard to plasma HVA, anxiety and dyskinetic/parkinsonic movements.     

The relative role of dopamine and norepinephrine receptor blockade in the action of antipsychotic drugs: Metoclopramide,thiethylperazine, and molindone as pharmacological tools

The aim of the present studies was to further delineate the role of striatal and limbic dopaminergic versus limbic noradrenergic blockade in the pharmacologic and perhaps therapeutic action of antipsychotic drugs. Metoclopramide shares many properties of antipsychotic neuroleptic drugs, including the production of extrapyramidal side effects, but is not an efficacious antipsychotic agent. This drug was a potent blocker of dopamine (DA) receptors in both striatum and limbic forebrain (comparable in potency to that of chlorpromazine) as evidenced from the increase in homovanillic acid in both brain structures. In contrast, metoclopramide was a weak inhibitor of the norepinephrine (NE) receptor-coupled adenylate cyclase system in the limbic forebrain. Molindone, which is reported not to block DA-sensitive adenylate cyclase, was a potent in vivo blocker of DA receptors in both striatum and limbic forebrain and also inhibited markedly the cyclic AMP response to NE in the limbic forebrain. The phenothiazine derivative, thiethylperazine, was also a potent blocker of DA receptors in both brain areas and displayed an IC₅₀ for NE blockade in the limbic forebrain comparable to that of chlorpromazine. The present results support the view that the ability and potency of drugs to block DA receptors parallels their ability and potency to cause extrapyramidal symptoms in man. Moreover, these results suggest that the blockade of NE receptor-coupled adenylate cyclase systems in brain may be relevant to both the pharmacologic and therapeutic activity of antipsychotic drugs.     

The 4-O-methyl metabolites of catecholamines. Homo-iso-vanillin acid in rat urine and brain; urinary iso-vanyl compounds after intraperitoneal administration of dopamine and of dopamine precursors and derivatives

Homo-iso-vanillic acid (3-hydroxy, 4-methoxyphenylacetic acid, iso-HVA was detected in rat urine and brain, with a molar ratio of iso-HVA to HVA of 0·07 in urine and about 0·35 in brain. The free urinary iso-vanyl and vanyl phenolcarboxylic acids were studied after intraperitoneal loads with the following compounds: l-dopa, $\text{l}\text{-3-O-}\text{methyldopa}\text{,}\text{l}\text{-4-O-}\text{methyldopa}$, dopamine, 3-O-methyldopamine, 4-O-methyldopamine and 3,4-dihydroxyphenylacetic acid. The results suggest the following conclusions. (1) The molar ratio iso-HVA/HVA is not constant. After dopa as well as dopamine loads it rises with the increase of the dose of precursor administered, showing that, in vivo, the 4-O-methylation process depends, to some extent, on the substrate concentration. (2) In contrast with the other catechols (dopamine and 3,4-dihydroxyphenylacetic acid), l-dopa itself does not seem to be para-O-methylated. It is therefore unlikely that 4-O-methyldopa would be a metabolite of l-dopa in vivo. (3) Distinct urinary metabolites from $\text{l}\text{-3-O-}\text{methyldopa}$ (vanylmandelic and vanillic acids) on one hand and from l-4-O-methyldopa (unknown iso-vanyl phenolcarboxylic acid) on the other, support evidence that some of the metabolic transformations of the side-chain of the O-methyl-catecholamines are different according to whether the methyl group is bound on the meta or on the para position. (4) The high level of cerebral iso-HVA might be due to either a lower iso-HVA than HVA transport outside the brain, or to the existence, in addition to the dopamine source, of a second cerebral metabolic pathway for the production of iso-HVA.     

3,4-Dihydroxyphenylacetic acid and homovanillic acid in rat plasma: possible indicators of central dopaminergic activity.

The concentrations of dopamine (DA) metabolites (free and conjugated) was measured in plasma and brain regions of rats by the mass spectrometric method of selected ion monitoring. Experimental treatments which altered the function of central dopamine neurons also induced concomitant changes in plasma 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). Stimulation of the nigrostriatal pathway increased plasma DOPAC and HVA whereas lesion of the pathway decreased plasma metabolites. Several drug treatments induced parallel changes in brain and plasma concentrations of DA metabolites. It is suggested that changes in the concentration of DOPAC and HVA in rat brain are reflected by parallel changes in plasma. No conjugated forms of DOPAC and HVA were found in plasma and brain tissue of vervet monkeys (Cercopithecus aethiops).     

Blockade of the central effects of d-amphetamine sulfate by amantadine hydrochloride

Amantadine hydrochloride, unexpectedly, was found to block certain effects of d-amphetamine sulfate. In mice pretreated with amantadine, 150 mg/kg, d-amphetamine, 2 mg/kg or 5 mg/kg, failed to produce hyperactivity. This pretreatment also protected aggregated mice from the lethal effects of d-amphetamine, 30 mg/kg. Both d-amphetamine, 15 mg/kg, and chlorpromazine hydrochloride, 10 mg/kg, caused elevations in the homovanillic acid (HVA) concentrations in the caudate nucleus of mice, and amantadine pretreatment blocked this response to d-amphetamine but not that to chlorpromazine. Due to the many similarities in the pharmacological, behavioral, biochemical and clinical effects of amantadine and d-amphetamine, they may act at the same receptor and the observed antagonism may be due to a competitive blockade so that d-amphetamine fails to reach its site of action.