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The aim of this work was to reinvestiagte usual values of neurotransmitter catabolites (5-HIAA and HVA) in CSF, their determination being a current method for studying pathological processes and/or drug induced changes on CNS metabolism. 5-HIAA and HVA have been measured by reverse phase HPLC and electrochemical detection. Since many confounding factors have been identified to modify the concentration of both analytes in CSF, data from 1.480 patients have been revisited with strict exclusion and 323 have been selected. Age dependent variation and asymetric distributions were observed. Age-related usual values ranges were established after identification of outliers by non-parametric analysis. In a group of patients for which repeated CSF collection have been performed for the follow up of acute leukemia, wide and unpredictible individual variations (up to 400 %) of CSF 5-HIAA and HVA concentrations have been observed. These large interindividual and individual variations may explain the numerous discrepancies found in studies investigating the CNS monoamine metabolism, especially when small groups of patients are used. Such observation limits the interpretation of monoamine metabolic for diagnostic purposes without a strict selection of indication.

Pheochromocytoma and neuroblastoma are distinct tumours, but their biological diagnosis is based on secretion increase of one or several catecholamines. Assays have to be very sensible and specific for an early diagnosis. 24 hours urinary catecholamines and metabolites are currently measured, but technical improvements permit plasma metanephrine assay, an excellent indicator of pheochromocytoma. HPLC coupled to electrochemical detection represents the most efficient methodology. After a review of urinary and plasma assay methods, the authors show usual values of catecholamines, metanephrines, HVA and VMA, according to ages, and give examples of results encountered in classical or not tumours and in falsely positive cases. Urinary metanephrine assay is the most sensible and specific in biological diagnosis of pheochromocytoma, while catecholamines and VMA assays lack of sensibility. Results have to be given by 24 hours and by creatinine ratio. Metanephrine assay can be performed also in plasma and exhibits the same interest. However, in urine as in plasma, in case of renal failure, results cannot be interpreted. Neuroblastoma biological diagnosis is based classically on HVA, VMA, and dopamine assays, nowadays only in 24 hours urine (or in urinary micturition for screening), and results are also expressed as creatinine ratio. But even if several assays are advisable, 5% of the neuroblastoma cases do not produce increased catecholamine values. In some cases, metanephrine assay could be of interest. After the age of 12 months, clinical expression of neuroblastoma is dramatic in 70% of cases. So, a biological screening has been experimented in several countries including France. A French translation of the consensus conference report (1998) is appended, which shows the complexity of neuroblastoma screening. Now, there is no evidence that early tumour detection by screening lessens the mortality rate, but a weak benefit is not excluded.

According to the ICD 10 only acute psychotic disorders and transitory acute disorders are specified, whereas DSM IV index, in the same class, schizophreniform disorder, schizoaffectif disorder and atypical psychosis. State biological markers of these disorders are present during the acute episode and disappear with it. A few studies concerns trait predispositional markers of these acute psychotic disorders. In addition, several studies of acute psychotic states are indexed as a partition of usual schizophrenic disorder, as a simple occurrence of that chronic disease. From the biological point of view, dysfunctions of norepinephrine and dopaminergic metabolisms are reported within these acute schizophrenic disorganisation, especially hyperdopaminergia, causality, consequence or evidence of the state syndrome. Those kinds of data are also reported in mood disorder with delusional symptoms. A hypothetic dysregulation of the balance between oxydation and antioxydation system has been searched in these acute states of schizophrenia. From the electrophysiologic perspective, no abnormalities are found for ocular movement functions during these acute psychotic disorders. Besides the clouding of consciousness of confusional states, neuropsychological abnormalities are reported: attention disorders, lack of inhibition of non relevant informations, abnormalities of working memory. Brain imaging can substantiate a diminution of the caudate nucleus size and a possible increase of D2 receptors number. Also, in these acute psychotic states abnormalities of humoral and cellular immunologic system have been found. Lastly, street drugs can originate confusional states and depersonalization, through their serotoninergic, dopaminergic and anticholinergic properties. Ethical drugs can also create an acute psychosis disorder: individual vulnerability and somatic disease cooccurrence act as risk-factors.

Depression raises numerous questions that are pathophysiological, diagnostic and epidemiological as well as therapeutic. Amongst those questions, antidepressant drugs and their action mechanism(s) remain the subject of many studies in all fields, with a view to enhanced management of patients suffering from mood disorders. Numerous hypotheses both neurobiological and pharmacological have been advanced with respect to the neurochemical mechanisms involved in depressive disease and the neurobiological impact of antidepressants. In addition to the aminergic hypotheses which are currently the best supported, numerous arguments tend to show the value of taking into account the overall function of the brain and no longer only considering a single neuronal system. In this context, the value of a dual specific action on the main two central aminergic systems, the noradrenergic and serotoninergic systems, has now emerged.

Predicting the clinical improvement of patients with antidepressant drugs, at an early stage and in a individualistic manner, allows to choose the product which is most adapted to each case and to avoid leaving patients under an inefficient medication for several weeks. Predictability studies have multiplied. A general review of these studies is made here by examining the clinical, biological, electrophysiological, and finally the pharmacokinetic predictors. Clinical predictors have a practical use as they define certain clinical types of depression which best respond to antidepressants specific to a monoaminergic axis. It has been shown that a complete absence of symptomatic improvement after two weeks of treatment predicts the inefficacy of the treatment. Inversely, to this day, none of the biological predictors lead to a practical application during the treatment of patients, but they allow a better understanding of the antidepressants' mode of action. Finally, the elaboration of pharmacokinetic equations define for each patient the doses that allow to determine the therapeutic zones when these have been recognized.

This study was aimed at assessing monoamine catabolites plasma levels in depressed patients and healthy volunteers. Plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) of 21 control subjects and 26 depressed patients (according to DSM III-R criteria) were measured at baseline (day 0) and day 4, day 7, day 30 of prescribed antidepressant treatment. The clinical assessment, at baseline as well as during treatment, used the Hamilton depression rating scale and the BPRS. Our data show the interest of these results in predicting response. The respondent patients showed a significant decrease in plasma MHPG level at J7, contrary to non-respondent patients. Moreover, a positive correlation between plasma levels of MHPG and HVA before any prescribed antidepressants was found only with respondent patients. The lack of correlation for non-respondent patients can suggest that the relationships between this monoamine systems should be disrupted in these patients. Significant relationships appear between clinical symptoms and plasma catabolites, allowing us to consider new physiopathological aspects of the depressive picture. The 3 monoamines seemed involved in sleep disorders. Perturbations of norepinephrine and serotonin metabolism could intervene in suicidal ideation and behaviour. Motor activity was associated with a modification in dopamine and serotonin metabolism. Moreover significant correlations were observed between items referring to thought content and monoamine plasma catabolites such as MHPG and blunted affect, 5-HIAA and obsessions, HVA and guilt feelings, devalorization and without hope items.(ABSTRACT TRUNCATED AT 250 WORDS)

Dopamine (DA) and its metabolites homovanillic acid (HVA) in total, free and conjugated forms, dihydroxyphenylacetic acid (DOPAC) in total, free and conjugated forms, and 3 methoxytyramine (3 MT) levels were determined in the urine of autistic children from 2 years 8 months to 12 years of age and compared to those in normal children of identical age. Very significant group and age effects were found for DA, HVA and 3 MT. In the discussion, results are related to the hypothesis of a disorder in the maturation of the dopaminergic systems in infantile autism.

Wistar male rats received N-linoleyl dopamine (L-DA) at doses of 10, 50 or 100 mg/kg (i.p.). 2 h after these injections they were decapitated and dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), as well as the ratio DOPAC/DA, which could represent the DA turnover, were determined in the striatum, the frontal cortex or the hypothalamus, while homovanillic acid (HVA) as well as the ratio HVA/DA, which could represent the DA release, were determined in the striatum by high performance liquid chromatography (HPLC). Except a small rise of DA and DOPAC in the hypothalamus, at high L-DA doses, no significant modifications in DA, DOPAC, DOPAC/DA, HVA or HVA/DA were observed in the other brain areas studied. These results, in good agreement with the recent data obtained with other dopaminergic agonists, could show the absence of correlation between the hypomotility, on the one hand and the decreasing of the turnover or the release of the brain DA, on the other hand. Together with the data obtained recently by scandinavian and italian authors, they could raise questions about the position and the role of dopaminergic autoreceptors.

The study of 33 cerebrospinal fluids of infants victims of sudden death shows a very significant increase of the metabolites of dopamine and serotonin. These determinations, compared to a control group, indicate a failure, concerning these two neurotransmitters, which could induce a cardiorespiratory seizure. This failure has likely a multifactorial origin.

A retrospective comparison of urinary excretion of norepinephrine, epinephrine, dopamine and/or their acidic metabolites, HVA and VMA, in 36 children with neuroblastoma versus 360 hospitalized children without neuroblastoma showed a sensibility of 72% and a specificity of 98% for HVA and 80% and 97% for VMA respectively. Consequently, the sensibilities and specificities of these 2 determinations confirm their useful purpose for the biochemical diagnosis of neuroblastoma in preference to the determinations of norepinephrine, epinephrine and dopamine.

Abnormalities in brain monoamines have been implicated in the pathogenesis of several psychiatric disorders. A brief revue of biochemical studies on indolamines and catecholamines in mental disorders with special emphasis on endogenous depression will be presented. Progress in neurochemistry makes it possible to investigate the biochemical disturbances present in the major psychoses. Recent knowledge in the neuropharmacological mechanism of action of psychotropic drugs have shed some light on the basic understanding of the pharmacological treatment of psychotic disorders. The implication of biogenic amine studies in psychiatry for endocrinological research in mental disorders will also be discussed.

Studying the effects, on the isolated rat duodenum motricity, of ten compounds precursors or metabolites of catecholamines, the following results were obtained: The direct metabolites of epinephrine and norepinephrine (metanephrine, normetanephrine), are either ineffective at concentrations below 5 X 10(-6) M, or weakly inhibitory at higher concentrations. Such inhibitory effects are prevented by alpha- and beta-blockers. 3-methoxy, 4-hydroxyphenylglycol and vanylmandelic acid have no significant effect. The catecholamine precursor, dopamine, the related compounds DOPA, 3 methoxytyramine, and to a lesser extent, 3-O methyl DOPA and homovanillic acid, have excito-motor effects at concentrations ranging mainly from 10(-7) M to 10(-5) M. At higher concentrations, the same compounds frequently exhibit inhibitory effects. The excito-motor effects might be due to a serotoninergic mechanism, since they are suppressed by the serotoninergic blocking agents methysergide and cyproheptadine. Furthermore, in the case of DOPA, we were able to establish a relationship between the excito-motor effects and duodenal serotonin stores. As for the inhibitory effects, they may be prevented by using alpha and beta blocking agents. Dihydroxyphenylacetic acid has no effect on the isolated rat duodenum motricity. The fact that dopamine and related compounds may have excitomotor effects at some concentrations, correlated with some physiopathological observations in man and animal allows some considerations about the eventual role of dopamine on intestinal motricity.

Relationships between augmenting/reducing (aug/red) in auditory modality and dopaminergic metabolism were investigated in young normal adults. Auditory evoked potentials (AEP) to tones (750 Hz, 200 msec) varying from 50 to 80 sB SPL were recorded at Cz and Fz sites. Individual differences in dopaminergic metabolism were estimated by assaying homovanillic acid levels in urines (u-HVA). The slopes values of P1, N1 and P2 amplitude changes with increasing stimulus intensities were used to evaluate the relationships between aug/red and u-HVA levels. The results of this study showed significant negative correlations between the aug/red of the N1 component recorded at Fz site and the u-HVA concentrations: the higher the aug/red slopes (augmenting tendency), the lower the u-HVA levels. In fact, the main result was that this finding was in accordance with previous ones relating aug/red to HVA when assayed in cerebrospinal fluid (CSF). Our data also showed that in further studies on auditory aug/red, the interest should be focused on the N1 component at Fz site.

Several biological theories were proposed to explain symptoms of childhood autism in terms of monoamine metabolic dysfunction. Clinical, electrophysiological and biochemical markers which support the dopaminergic hypothesis will be given in this paper. A factorial analysis, performed on the 'behavior summarized evaluation' (BSE, scoring behavioral data), exhibits a first component corresponding to the autistic DSM III criteria, and also shows that the disturbances of attention and perception belonged to this component. So, as well as communication, selective attention, perception and gestures, usually considered as regulated by the dopaminergic system are deeply modified and appeared as primary symptoms in autistic syndromes. Many electrophysiological data recorded in autistic children suggest both faulty modulation of sensory input and deficiency in dealing with sensory cross-modal association which have been related to a dysfunctioning of the dopaminergic system. Elevated homovanillic acid levels, the main dopamine metabolite, have been attributed to a reduced re-uptake of dopamine related to a 'longer occupation' of the receptors which is in agreement with the electrophysiological 'sensory overload'. The relationships found between these markers are discussed. Such an approach would contribute to a better understanding of the underlying mechanism of autism.

Three cases of abdominal sympathoma, a tumor generally affecting young children, presented with clinical symptomatology differing from that observed in infants. Diagnosis is much more difficult and the prognosis constantly fatal.

Biogenic amines in pons and striatum have been dosed in twenty-four months old Wistar male rats. Choline acetyltransferase (CAT) and acetylcholine esterase (ACHesterase) activities, [3H] choline uptake by a synaptosomal preparation, [3H] quinuclidinyl benzylate (QNB) binding to muscarinic cholinergic receptors have been determined in hippocampus. Malondialdehyde (MDA) levels in plasma, in liver and in lungs and the characteristics of the skin collagen have been evaluated. Important differences are shown in comparison with three months old of the same strain animals.

Basing their study on the investigations which led to the dopaminergic theory of the psychoses, the authors studied homovanillic acid (principal derivative from dopamine) levels in the urines of 37 autistic children, and 11 normal children acting as controls. The favourable action of vitamin B6 on autism, reported by anglosaxon authors, was confirmed in 15 of the children. Furthermore, vitamin B6 reduces homovanillic acid levels in 33 autistic chilren and increases them in all the control group children.

Infantile autism is a behaviorally defined syndrome. Many investigators suggest that it is probably related to a brain dysfunctioning in which catecholamine metabolism is involved. The aim of the following paper is to study the validity of different clinical and biological markers of this syndrome: 1. clinical scores using a behavioral rating scale, 2. amplitude and variability of conditioned auditory evoked potentials, 3. urinary levels of homovanillic acid. The response of these markers in autistic children treated with vitamin B6 and magnesium have been assessed. The relationships found between clinical and biological data are discussed. It can be expected that such an approach would contribute to a better understanding of the underlying mechanism of autism.

The aim of this study was to study the relationships between conditioned AEPs and homovanillic acid (HVA) levels in autistic children (A, 9 boys, average age 6.3) compared to normal children (9 boys, average age 6.5) and to mentally retarded children (MR, 9 boys, average age 6.1) without any autistic behavior. AEPs were recorded at Cz and Oz during two sessions. The auditory stimulus (S) was first presented alone (habituation); the visual stimulus (L) was then presented 800 msec after S (conditioning). S was again presented alone (extinction). Urinary HVA dosage was performed on samples of urine taken after a 48-h tyrosine-free diet. Conditioning induced enhancement of AEPs. Latencies and amplitudes were smaller in autistic children. AEP presence was smaller in patients than in normal children and smaller in MR than in A children. Urinary HVA level was higher in patients and higher in the MR group than in the A group. A negative correlation between HVA level and Cz AEP presence was observed. Results showing higher Cz AEP variability and higher HVA level in MR than in autistic children tend to lead us to consider that both syndromes are related to common neurological dysfunctionings rather than indicating autistic syndrome behavioral specificity.

Two sporadic cases of striato-nigral degeneration were characterized by the onset at the age of 61 of an akinetic-hypertonic syndrome and of a minimal or absent rest tremor, with a pyramidal syndrome, sphincter disorders, dysphonia, difficulty in swallowing and an unfavorable development in the space of two or three years not affected by L-Dopa. In one case, total insomnia was demonstrated by means of 3 polygraphic recordings during the night, two of them consecutive, and aprobenecide test showed a definite fall in H.V.A. and 5 H.I.A.A. in the lumbar cerebrospinal fluid. Anatomical verification showed, in one case, isolated putamino-nigral degeneration, and in the other associated with lesions of the olivo-cerebellopontine system. Much of the excess pigmentation found only in the putamen was melanotic in character and resulted perhaps from the striato-nigral degeneration, making it possible to classify this more accurately among the other multisystem degenerations, especially olivo-ponto-cerebellar atrophy and Shy-Drager syndrome

In this study, the urinary H.V.A. of new borns and of older children was measured. The urinary H.V.A. titer of the new borns was found to be significantly greater than in older children. Moreover the increase is more pronounced when those infants are born prematurely. Former studies have shown that the metabolism of central nervous system catecholamine reflected by the urinary titers of H.V.A. is as accurate as titers measured in the CSF. Recently several authors have found increased titers of urinary H.V.A. in autistic children. It is therefore possible that the elevated urinary H.V.A. titers in the new born are due to an immaturity of the dopaminergic structures. Blocking these structures provokes an accelerated catecholamine turnover, thereby increasing the levels of catecholamines metabolites (most notably H.V.A.).

In a child presenting with malignant phenylketonuria due to dihydrobiopterin synthetase deficiency, the authors studied the cerebrospinal fluid (CSF) homovanillic acid and 5 hydroxyindole acetic acid levels under different circumstances: without treatment; under a treatment with tetrahydrobiopterin used alone at various doses; under a treatment associating BH4, L-dopa, 5 hydroxytryptophan and carbidopa, with increasing doses and varying administration schedules. This biological study compared with clinical evolution, shows clearly the inefficacy, regardless of the doses, of BH4 on the CSF levels of neuromediators and on the neurological status, and the excellent efficacy of neuromediator precursors provided high doses are given, divided in the nyctohemeral period.

The effect of high doses of haloperidol on the clinical status, plasma neuroleptic and prolactin concentrations as well as on CSF HVA and GABA levels was investigated in 3 paranoid schizophrenic patients over a 6 weeks period. When the study was initiated patients had been on haloperidol (10 mg a day) for 4-10 weeks. Oral doses were increased at weekly intervals from 10 (day 0) to 100 (day 7) and 200 (days 14 to 28) mg a day and then reduced to 100 (day 35) and 10 (day 42) mg/day. A linear relationship was observed between plasmatic levels and daily doses of haloperidol. In neither patient, the increase in haloperidol dosage affected paranoid symptoms. Neurological side effects were slightly increased in 2 cases and moderately reduced in one case. Prolactin plasma levels, already high at the onset of the study rose when increasing the dose to 100 mg a day but did not increase further despite increment in the haloperidol dosage. CSF levels of HVA and GABA rose from day 0 to day 7 but were back to the initial values on day 28 in 2 patients and were decreased from day 0 to day 28 in one patient. For the 3 patients a close correlation was observed between changes in CSF HVA and GABA levels. It is concluded that high doses of haloperidol, although causing biochemical changes compatible with the occurrence of dopamine target cell supersensitivity, do not lead to any clinical improvement in the 3 studied schizophrenic patients.

Forty-five patients presenting a parkinsonian syndrome, accompanied in some cases by depressive and/or confusional signs, were subjected to neurological and neurobiochemical investigation involving a probenecid test (estimate of central turnover of dopamine by determination of homovanillic acid in cerebrospinal fluid before and after an oral dose of probenecid). Patients were classified in two groups on the basis of the benefit procured by dopa therapy as estimated at least one year after treatment. The probenecid test revealed a sharp drop in turnover of dopamine in the dopasensitive group. Furthermore, in this group the dopamine turnover was not related to sex, age, duration of the parkinsonian syndrome or clinical severity. In contrast, there seemed to be a correlation between dopamine turnover and optimum dosage of l-DOPA. Lastly, the study showed that, beyond the diagnosis of dopasensitivity, the test was useful for patient follow-up. The test profile in cases of excess dopatherapy is described.

Aminergic neurotransmitters and their main metabolites concentrations are measured in four areas (posterior cortex, striatum, hippocampus, hypothalamus) of the rat brain, 24 hours after an acute ischemic injury (created by the occlusion of the four cephalic vessels). Simultaneously, spontaneous motility and neurological status are evaluated. The main results are the increase of 5 HIAA in striatum, hippocampus and cortex, associated with an increase of HVA in striatum. Motility as well as neurological scores are significantly decreased in ischemic animals when compared with controls. The conclusion is that this model of cerebral ischemia is may be useful for pharmacological assessment of drugs liable to antagonize cerebrovascular disorders.

After administration of a single and small (125 mg) dose of benserazide, 3,4-dihydroxyphenyl-alanine and 3-O-methyldopa are excreted in urine. Uturbancies last for at least 48 hours.

Serotoninergic function has been evaluated in 15 H.C. patients. Therapeutic results obtained with an inhibitor of 5 HT reuptake (Fenfluramine) were evaluated in comparison to the effects of L-5HTP, CSF-5HIAA measurements were performed is each case before and after treatment. The pathological role of 5HT impairment in H. C. can not be excluded by the behavioral effects and CSF-5HIAA modifications that were observed.

Hemispheric ischemia was induced in normothermic, artificially ventilated and anesthetized rats, by electrocauterization of the vertebral arteries and a transient occlusion of the common carotid arteries for 10 minutes. Cerebrospinal fluid (CSF) was continuously pumped out of the third cerebral ventricle for potassium, dopamine and serotonin metabolite determinations. Levels were stable until ischemia, which interrupted the CSF production. During early recirculation a marked increase in dopamine metabolites occurred. The metabolite of serotonin increased slightly with a delay. Potassium in CSF was transitorily increased following ischemia. Reserpine pretreatment prevented most of the changes such as the early increase in dopamine metabolites. A delayed increase of these metabolites was still observed. This model of short ischemia altered the neurological functioning and survival time of the animals especially 15 minutes after removal of bilateral carotid occlusion, as compared to the later periods of observation. This model is therefore applicable to the study of cerebral alterations secondary to ischemia in vivo. The presently observed alterations of metabolite levels could reflect an increased neuronal release of parents monoamines that could participate to the neurological deficit.

We have studied disturbances in dopamine metabolism by assaying HVA in urines of 44 autistic children. First a clinical study identifies the main clinical symptoms. This allows to differentiate between "pure" autistic children and autistic children with associated signs. Urinary HVA was significantly higher in autistic children and there was a relationship between severity of autism and HVA levels.

The pathways for the synthesis and degradation of the principal monoamines (dopamine, noradrenaline, serotonin, and phenylethylamine) concerned in the pathology of depression are briefly presented. Differences in the activities of the enzymes which control the amounts of monoamines or their principal metabolites in serum, urine or cerebrospinal fluid are discussed in relation to the different types of depression, as is also the role of changes in the sensitivity of neuronal receptors. The specific biochemical effects of monoamine oxidase inhibitors (MAOI's) and of the inhibitors of monoamine re-uptake are considered. MAOI's are classified as irreversible mixed inhibitors (A + B), as irreversible specific inhibitors and as reversible specific inhibitors; their mechanism of interaction with the enzyme is presented. Inhibitors of monamine re-uptake are classified according to their specificity for different monoamines. The mechanism of action of some antidepressants which have an atypical mechanism of action is outlined. Finally, the effect of chronic treatment with antidepressants on the sensitivities of the noradrenergic, serotoninergic and dopaminergic pre- and post-synaptic receptors is discussed.

The authors describe the results of biochemical analysis carried out on 28 patients with Parkinson's disease who had been treated by L-dopa. Twenty of them showed either no abnormal movements at all or very few, eight others had considerable dyskinesia. Biochemical analysis of the urinary degradation products of L-Dopa revealed the existence of a swing in the degradation of dopamine towards 4-O-methylate derivatives in dyskinetic patients (significant difference at .01). The results confirm those obtained in their initial analysis carried out in 1973. The authors express the view that abnormal movements while under L-Dopa treatment are dependent on two factors: one, the hypersensitivity of dopaminergic reception, the other, the greater or lesser preponderance of the COMT isozyme giving rise to 4-O-methylates

The sensitivity of dopamine receptors in Mouse striatum has been evaluated both behaviourally (responsiveness to apomorphine as regarviour) and biochemically (striatal level of homovanillic acid and its decrease induced by apomorphine) After a single administration of apomorphine (0.25 mg.kg-1 or 5 mg.kg-1) or piribedil, another dopamine agonist, a state of "behavioural facilitation" develops which differs from the state of hypersensitivity following blockade. This state of facilitation is characterized by a lower threshold dose of apomorphine eliciting the stereotyped behaviour, without modification of the response to higher doses. In contrast with the state of hypersensitivity, the level of homovanillic acid is not modified and the decrease of this level by a low dose of apomorphine is less important. The hypothesis is put forward that "behavioural facilitation" results from the hyposensitivity of a class of dopamine receptors, possibly autoreceptors, mediating an impaired activity of dopaminergic neurons and, consequently, inhibitory behavioural effects.

Modulation in sensitivity of dopamine receptors in the central nervous system are reviewed. Three main types differing by their behavioural and biochemical characteristics are described: -- Disuse hypersensitivity to dopamine agonists, induced by an interruption of dopaminergic transmission, seems to depend on an increased number of post-synaptic dopamine receptors; -- Hyposensitivity to dopamine agonists, induced by an overstimulation of dopamine receptors, could depend on their qualitative or quantitative modifications; -- Behavioural facilitation, elicited by a previous administration of dopaminergic agonists in low dosage, could be associated with an hyposensitivity of dopaminergic autoreceptors. They seem to constitute important parameters in adaptation of synaptic efficacy in physiological as well as pathological states.