Distribution of serotonin-immunoreactivity in the central nervous system of the rat-cell bodies and terminals.

Deficiency in monoamine oxidase A (MAOA), an enzyme that degrades serotonin and norepinephrine, has recently been shown to be associated with aggressive behavior in men of a Dutch family. A line of transgenic mice was isolated in which transgene integration caused a deletion in the gene encoding MAOA, providing an animal model of MAOA deficiency. In pup brains, serotonin concentrations were increased up to ninefold, and serotonin-like immunoreactivity was present in catecholaminergic neurons. In pup and adult brains, norepinephrine concentrations were increased up to twofold, and cytoarchitectural changes were observed in the somatosensory cortex. Pup behavioral alterations, including trembling, difficulty in righting, and fearfulness were reversed by the serotonin synthesis inhibitor parachlorophenylalanine. Adults manifested a distinct behavioral syndrome, including enhanced aggression in males.

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Aggressive Behavior and Altered Amounts of Brain Serotonin and Norepinephrine in Mice Lacking MAOA

2. Evidence for A m i n o Acids as T ransmi t t e r s . . . . . . . . . . . . . . . . . . . . 99 2.1. Synthesis and Storage . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 2.2. Synapt ic Release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 2.3. Postsynapt ic Act ion . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 2.4. Postsynapt ic An tagon i s t s . . . . . . . . . . . . . . . . . . . . . . . . . 103 2.5. Inac t iva t ion and R e m o v a l . . . . . . . . . . . . . . . . . . . . . . . . . 104

Amino acid transmitters in the mammalian central nervous system

The role of monoamines and acetylcholine-containing neurons in the regulation of the sleep-waking cycle

Do some nerve cells release more than one transmitter

A fluorometric micromethod for the simultaneous determination of serotonin, noradrenaline and dopamine in milligram amounts of brain tissue

Uptake of 5‐hydroxytryptamine and 5‐hydroxytryptophan by neurons of the central nervous system normally containing catecholamines *

The uptake of norepinephrine (NE), epinephrine (E), dopamine (DA) and 3,4-dihydroxyphenylalanine (dopa) into the mouse brain has been studied by means of the histochemical fluorescence method of Falck. Prior to the intraperitoneal administration of one of the catecholamines or of dopa, the amine stores were depleted by reserpine and monoamine oxidase was inhibited by Nialamide. In addition, azapetine was given shortly before high doses of NE or E. The animals were killed 5 hr after reserpine, when no green fluorescence (indicating the presence of a catecholamine) was observed in the controls. The uptake of NE administered in high doses was found to be limited to nerve cell bodies in the nucleus arcuatus, with axons descending to the external layer of the median eminence, nucleus periventricularis anterior and posterior hypothalami, area retrochiasmatica, area postrema and bulbus olfactorius and nerve endings in the median eminence. After smaller doses of NE the fluorescence intensity decreased accordingly. After DA and E, only a weak green fluorescence developed in these neurons even if high doses were given. The existence of a catecholamine-containing arcuatoinfundibular neuron is indicated by the demonstration of green fluorescent axons which connect green fluorescent nerve cell bodies in the arcuate nucleus with their nerve endings in the median eminence. In both regions, green fluorescent nerve cells and nerve endings respectively are also found in normal, untreated animals. The nerve endings are situated in the region of the primary plexus of the hypophyseal portal system.

Uptake of exogenous catecholamines by monoamine-containing neurons of the central nervous system: uptake of catecholamines by arcuato-infundibular neurons

GLUTAMIC acid decarboxylase in brain was first described by ROBERTS and FRANKEL (1951). LOWE, ROBINS and EYERMAN (1958) using a fluorimetric method, and ALBERS and BRADY (1959) estimating ['*C]O, by means of a microradiometric method, found marked differences in the activity of the enyme in various parts of the brain of the monkey. The results of the two groups, however, are not in agreement for all the different parts investigated. The figures of LOWE et al. are in general somewhat higher than those of ALRERS and BRADY. Neither group was able to correlate the distribution of the enzyme activity with any of the functional systems of the central nervous system. LANGEMANN and ACKERMANN (1961), using a manometric method reported very low values in human brain, which did not show a characteristic distribution of the enzyme. However, using the fluorimetric method of LOWE et nl. (1958) we have now been able to do so. M E T H O D According to LDWE et af. (1958) 7-aminobutyric acid (GABA) formed enzymically from glutamic acid during incubation can be detected fluorimetrically. 7-Aminobutyric acid in amounts as low as 0.1 can be estimated with an accuracy of about 5 \"/. In the present work the brain parts uscd wcre cut out in the autopsy room of the Department of Pathology, University of Zurich, by courtesy of Prof. E. UEHLINGER. They were either immediately assayed or stored at -25\" until used (not longer than 4 days). Careful selection ensured that the material was taken from persons below 55 years of age (average 39 years) within 17 hr of death (average 14 hr). Cases treated before death by thiourea and sulphonlyurea derivatives or by tuberculostatic and cytostatic drugs were excluded as wcrc also cases of diabetes, or of renal or hepatic insufficiency. We investigated cases of sudden death following myocardial infarction or malformation of blood vessels, or of death during surgical operation or traffic accidents. The procedure followed that of LOWE et al. (1958). About 300 mg of tissue were homogenized with 2 ml of 0.1 M-sodium phosphate buffer, pH 6.5. The homogenate was centrifuged at 25,000 g for 15 min and 0.5 ml of the supernatant liquid contaiaing 8-40 pmoles of nitrogen were incubated at 37\" for 60 min. The final concentrations of ~-glutamic acid and pyridoxal phosphate were 2.5 x M, respectively. The fluorexencc was measured in a Zeiss PMQ I1 spectrophotometer at an excitation wavelength of 405 mp and an emission wavelength of 469 mp. The enzyme activity is expressed as pmoles of y-aminobutyric acid/m-mole N/60 min. We are indebted to Prof. A. PLETSSCHER, Hoffmann-La Roche A. G., Basle, for gifts of ~-glutamic acid, 7-aminobutyric acid and pyridoxal phosphate. M and 5 x

Heinrich Langemann

Papers

A fluorometric micromethod for the simultaneous determination of serotonin, noradrenaline and dopamine in milligram amounts of brain tissue

Uptake of 5‐hydroxytryptamine and 5‐hydroxytryptophan by neurons of the central nervous system normally containing catecholamines *

Uptake of exogenous catecholamines by monoamine-containing neurons of the central nervous system: uptake of catecholamines by arcuato-infundibular neurons

Distribution of glutamic acid decarboxylase activity in human brain.

Standardized excision of small areas of rat and mouse brain with topographical control.