J. Korf

Endogenous depressions with and without disturbances in the 5-hydroxytryptamine metabolism: A biochemical classification?

The influence of i.v. administered probenecid on the 5-HIAA concentration in the CSF was studied in a group of patients with vital (“endogenous”) depression and a non-depressive control group.The average increase of the 5-HIAA concentration in the CSF after probenecid administration was smaller in the depressive group than in the control group. Moreover, the depressive group included patients with a normal as well as patients with a subnormal probenecid effect. This could mean, that the group of v tal depressions encompasses two biochemically different categories: patients with and patients without demonstrable disturbances in the metabolism of 5-HT in the brain.

Amine metabolism in the human brain: Further evaluation of the probenecid test

Summary Probenecid inhibits the release of 5-hydroxyindoleacetic acid (5-HIAA, a 5-hydroxytryptamine metabolite) and homovanillic acid (HVA, a dopamine metabolite) from the cerebrospinal fluid (CSF). The relation between probenecid levels in blood and lumbar CSF, after intravenous and oral loading of the drug, was studied. The correlation between the increase in acid levels (HVA and 5-HIAA) and the concentration of probenecid in human lumbar CSF has been determined. A method was described for determination of HVA, 5-HIAA and probenecid in 4 ml lumbar CSF. No correlation between levels of probenecid in plasma and CSF was found. A significant correlation exists between CSF levels of probenecid and the increase of HVA and 5-HIAA in lumbar CSF of patients with various psychiatric abnormalities. These findings indicate that the determination of probenecid in lumbar CSF is of importance in the study of the possible correlation between probenecid induced changes in amine metabolites in CSF and metabolism of amines in the human brain.

A pilot study of the predictive value of the probenecid test in application of 5-hydroxytryptophan as antidepressant

In depressions, varying therapeutic effects have been obtained with 5-HT precursors. This is possibly due to the fact that the group of the depressions is pathogenetically heterogeneous; that, specifically, some types do and other types do not entail disturbances in the central 5-HT metabolism; and that only the former types are “precursor-sensitive”. This hypothesis was tested in a preliminary pilot study, and confirmed. The central 5-HT consumption was assessed on the basis of the probenecid test. In this experiment, 5-HTP was for the first time given in large doses over a considerable period of time.

One brain, two selves

Having a sense of self is an explicit and high-level functional specialization of the human brain. The anatomical localization of self-awareness and the brain mechanisms involved in consciousness were investigated by functional neuroimaging different emotional mental states of core consciousness in patients with Multiple Personality Disorder (i.e., Dissociative Identity Disorder (DID)). We demonstrate specific changes in localized brain activity consistent with their ability to generate at least two distinct mental states of self-awareness, each with its own access to autobiographical trauma-related memory. Our findings reveal the existence of different regional cerebral blood flow patterns for different senses of self. We present evidence for the medial prefrontal cortex (MPFC) and the posterior associative cortices to have an integral role in conscious experience.

Retarded depression and the dopamine metabolism

It was demonstrated that the influence of i.v. administered probenecid on HVA concentration in CSF was less pronounced in a group of retarded depression than in a group of non-retarded depression and a non-depressive control group. The figures corresponded to that found in Parkinson patients.These findings suggest a decreased consumption of dopamine in the brain in retarded depression. This might be understood as an indication that, disorders of cerebral dopamine metabolism are related not so much to a specific nosological entity as to a given motor status, possibly that of hypokinesia.

On the significance of regional dopamine metabolism in the rat brain for the classification of centrally acting drugs

3,4-Dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured in the corpus striatum, nucleus accumbens and tuberculum olfactorium of the rat brain, 4 antidepressants, 4 anesthetics, dipropylacetate, ethosuximide and metoclopramide induced a rise of DOPAC and HVA levels in the 3 brain regions. No change was observed after carbamazepine, diazepam or propranolol treatment. Combined treatment with a maximally effective dose of haloperidol and morphine, oxotremorine or probenecid produced an additional rise of DOPAC and HVA levels, while no additional rise was seen with chloral hydrate, chlorimipramine, ether, halothane, metoclopramide or sulpiride. The potency of drugs to increase DA metabolism in corpus striatum relative to mesolimbic structures was estimated. Atypical neuroleptics such as sulpiride could be differentiated in this respect from classical neuroleptics such as chlorpromazine, fluphenazine and thioridazine, by their ability to produce a relatively large increase of metabolite levels in the mesolimbic regions. The heterogeneous group of 14 non-neuroleptics however produced regional changes which were very similar to those of the atypical neuroleptics. DA metabolism in mesolimbic regions, in contrast to striatal tissue, seems to respond more to atypical neuroleptics and non-neuroleptics than to typical neuroleptics.

Methylazoxymethanol acetate-induced abnormalities in the entorhinal cortex of the rat; parallels with morphological findings in schizophrenia.

It has been suggested repeatedly that the non-heritable factors in the pathogenesis of schizophrenia involve abnormalities of prenatal neurodevelopment. Furthermore, post-mortem studies show neuropathology of apparently developmental origin in the entorhinal cortex and other brain regions of schizophrenic subjects. In an attempt to model a developmental defect of the entorhinal region in the rat, cerebrocortical proliferation was briefly interrupted during its earliest stages, when the entorhinal area is thought to undergo major cell division. Specifically, the experimental set-up involved the administration of methylazoxymethanol acetate (MAM) on 1 of 4 consecutive days of embryonal development, from E9 to E12. Analysis of the forebrain in adult animals shows reduction of the entorhinal cortex in rats treated on each of these days. This effect shifts from lateral to medial divisions of the entorhinal cortex with later administration of MAM, following a known developmental gradient. Morphological consequences of MAM administration appear to be largely confined to the entorhinal cortex in the groups treated on E9 to E11, although slight reductions of the frontal and occipital neocortex were also observed in these animals. MAM treatment on E12 produces relatively more widespread damage, as reflected among other in a small reduction of brain weight. The described brain abnormalities are not accompanied by obvious phenotypical changes in any, but the E12-treated group. They, moreover, involve cortical thinning, disorganised cortical layering, and abnormal temporal asymmetries. These finding bare some similarity to observations in brains of schizophrenic subjects. The possible relevance of this approach in modeling neurodevelopmental aspects of schizophrenia is discussed.

Acute cortisol administration modulates EEG alpha asymmetry in volunteers: relevance to depression

The acute effects of cortisol (35mg) administration in 11 healthy male volunteers on resting frontal EEG asymmetry measured in the alpha band were investigated, using a within-subjects double-blind design. Results were indicative of a relative increase of right frontal activity with cortisol. This pattern of activity is similar to the deviant pattern that has been reported in patients suffering from depression, a condition often accompanied by elevated plasma cortisol levels. The significant effect on frontal asymmetry provides convergent support for our hypothesis, based upon previous results, that sustained (>30 minutes after stress termination) relative high levels of cortisol inhibit approach motivation.

Trigeminal nociception-induced, cerebral Fos expression in the conscious rat

Little is known about trigeminal nociception-induced cerebral activity and involvement of cerebral structures in pathogenesis of trigeminovascular headaches such as migraine. Neuroimaging has demonstrated cortical, hypothalamic and brainstem activation during the attack and after abolition with sumatriptan. This has led to the conclusion that the dorsal raphe and locus coeruleus may initiate events that generate migraneous headache. Using a conscious rat model of trigeminal nociception and cerebral Fos expression as histochemical markers of neuronal activity, we characterized the pattern of brain activity after noxious trigeminal stimulation with capsaicin (250 and 1000 nm). A significantly increased Fos immunoreactivity was found in the trigeminal nucleus caudalis (layers I and II), the area postrema, the nucleus of the solitary tract, the parvicellular reticular nucleus, the locus coeruleus, the parabrachial nucleus and the raphe nuclei. In addition, the ventrolateral periaqueductal grey, the intralaminar thalamic and various hypothalamic areas, showed an enhanced Fos expression after the intracisternal administration of capsaicin. Other responding areas were the amygdala, the upper lip and forelimb regions of the primary somatosensory cortex, and the insula. Many of these areas participate in (anti)-nociception, although we cannot exclude the possibility that in conscious animals the pain-associated physiological and behavioural responses that are an intrinsic and necessary part of coping with pain have generated the increased Fos expression. Trigeminal stimulation-induced locus coeruleus, dorsal raphe and hypothalamic activation are opposed to a suggested pathogenic role of these nuclei in migraine and cluster headache, respectively.

The Intravenous Probenecid Test: a Possible Aid in Evaluation of the Serotonin Hypothesis on the Pathogenesis of Depressions *

The serotonin (5-hydroxytryptamine, 5-HT) hypothesis postulates a causal relationship between mental depression and a 5t IT deficiency in the brain. The data on which this hypothesis is based largely originate : a) from the periphery, and b) f rom post-mortem brain studies following suicide (surveys in Coppen, 1967; Lapin and Oxcnbrug, 1969; van Praag, 1969, 1970). These data give little information on the cerebral turnover of 5-HT. I t is evident tha t a conclusive opinion on the 5-HT hypothesis must wait for suitable methods of obtaining information on the turnover rate of cerebral 5-HT in man. For this purpose, our group has recently used the so-called probenecid test in the s tudy of depressions (van Praag et al., 1970a). Probenccid 1 is a compound which inhibits the passage of 5-hydroxyindolcacetic acid (5-HIAA, the principal metabolite of 5-HT) from brain and CSF to the blood circulation. Neff et al. (1967) have demonstrated tha t the rate of accumulation of 5-HIAA in the rat brain under the influence of probenecid, is a reliable measure of the turnover rate of cerebral 5-HT. In dogs given probenecid, the concentration of 5-HIAA in the CSF also increases (Gnldberg et al., 1966). There are indications (only indirect so far) tha t CSF acid amine metabolites are derived from brain amines, and tha t changes in CSF acid concentrations m a y reflect the metabolism of the parent cerebral amine (Bowers and