Search

Drosophila melanogaster is sensitive to a variety of psychotropic and neurotropic drugs that alter neurotransmitter metabolism in humans. For many drugs the activity is a function of the stage of development of the organism. An example is the convulsant allylglycine (2-amino 4-pentenoic acid). Larvae were unaffected by a dose of allylglycine that was lethal for adults. Larvae that had been exposed to the drug continuously through three instars were able to pupate. In the pupae, which were no longer exposed to the drug, the pharate adults appeared to mature normally but subsequently died, usually before emerging from the puparium case. Allylglycine is known to inhibit mammalian glutamate decarboxylase. This enzyme is present in homogenates of Drosophila. Larvae possess a much smaller amount of glutamate decarboxylase than do adults. Allylglycine has a minimal effect on glutamate decarboxylase in vivo or in vitro. Several drug-resistant strains have been isolated.

—The effect of different qualities of ionizing radiation on the activity of brain enzymes involved in the metabolism of neurotransmitters in specific regions of the brain of rats was investigated. Groups of Sprague-Dawley adult male rats were exposed to approx. 18,000 rads of radiation either rich in neutrons or rich in gamma rays. It was found that, when the animals were exposed to radiation rich in neutrons, monoamine oxidase (MAO) activity was markedly decreased in all brain areas studied. In contrast, a very marked increase in the activity of this enzyme was observed when the animals received the same dose of radiation rich in gamma rays. Relatively minor changes were observed in the activity of choline acetyl transferase (ChAc). Acetylcholinesterase (AChE) activity did not change appreciably.

Attempts to find biochemical changes related to mental events are well known from the literature concerning manic-depressive psychosis. The most studied areas are probably carbohydrate, electrolyte, and neurotransmitter metabolism. Normal physiological connections, which exist between different metabolic reactions belonging to these areas, are reviewed, and it is concluded that many different metabolic disturbances possibly might lead to the same mental disorders. It is also emphasized that lithium influences several of the reactions, which might be involved in these metabolic disturbances.

Tyrosine hydroxylase activity was measured in high speed supernatants obtained from full thickness segments of aganglionic and ganglionic colon of three children with Hirschsprung's disease. Tyrosine hydroxylase activity expressed as pmole DOPA/mg protein/min was 0.93 ± 0.16 in ganglionic and 2.67 ± 0.21 in aganglionic colon. Tyrosine hydroxylase activity in ganglionic colon rose to 2.29 ± 0.11 following calcium stimulation (100 μM ) but could not be further increased in aganglionic colon. Addition of norepinephrine (2 × 10 −4 M ) to tissue homogenates inhibited tyrosine hydroxylase activity in ganglionic colon by 57 ± 8% but only by 14 ± 3% in aganglionic colon, suggesting that the enzyme present in aganglionic colon is insensitive to feedback inhibition by endogenous norepinephrine. The elevation of tyrosine hydroxylase activity in aganglionic colon and its insensitivity to calcium stimulation and norepinephrine inhibition is further evidence of sympathetic overactivity in the aganglionic colon and suggests a basic enzymatic abnormality in the pathogenesis of Hirschsprung's disease.

Major inhalational anesthetics cause inhibition in the electron transport chain in the region of Complex I resulting in decreased oxygen utilization, inhibition of metabolism of NAD-linked substrates, but not of succinate, inhibition of mitochondrial calcium uptake, and depression of synaptic transmission because of postulated changes in ACh sensitivity or GABA inhibition. Many cellular metabolic effects in CNS and other tissues are secondary to the above. Many metabolic changes noted with anesthetics occur subsequent to activation of the sympathetic nervous system either directly by the anesthetic or by surgical stimulation in the presence of light anesthesia. Many important studies remain to be done.

Lithium salts are used in the treatment and prophylaxis of ‘Affective disorders’. They have a strong therapeutic action in the manic phase of the disease, a weak action in the depressive phase and when given prophylactically they attenuate the recurrence of both manic and depressive phases. The mechanism of action is still completely unknown despite a host of observations on the effects of lithium on neurotransmitter metabolism, body electrolytes and various other biological systems (for a recent review see Schou, 1973). The situation is complicated because at first sight many of the reports seem to contradict each other. This is partially explained by the fact that the in vivo effects of lithium on some systems, for example, amine metabolism, are quite different depending on whether one considers the `acute effects’ (occurring during the first 4 days of lithium administration) or those occurring after prolonged administration (Shaw, 1973). The reason for this is not clear but two points are probably significant in this context.

The processes which initiate the elevation of blood pressure in most patients with hypertension are unknown. Considered here is whether neurogenic influences, especially those related to the sympathetic nervous system, are pathogenic in primary hypertension. Reviewed are the observations of autonomic function in normotensive and hypertensive man, especially those related to adrenergic neurotransmitter metabolism; altered catecholamine metabolism in hypertensive patients, and the correlations with the status of their cardiovascular and renin-angiotensin system; abnormal catecholamine metabolism in tissues of animal models with hypertension; and tissue catecholamine metabolism in man with increased and normal blood pressure. The term neurogenic, as used herein, refers to the central and peripheral aspects of the sympathetic nervous system. For other aspects of neurogenic hypertension, the reader is referred to the excellent text by Dickinson [1].

Sprague-Dawley adult male rats were exposed to incapacitating doses (20,000 rads) of mixed gamma-neutron radiation in a single pulse from the AFRRI- TRIGA reactor. The activities of the enzymes choline acetyl transferase, acetylcholinesterase, monoamine oxidase and RNA polymerase were determined in the cerebral cortex, cerebellum and hippocampus. It was found that as early as four minutes after irradiation of the animal the activity of monoamine oxidase was markedly decreased in all three brain areas investigated. Choline acetyl transferase and RNA polymerase activities were also decreased but to a lesser extent. No appreciable changes in the activity of acetylcholinesterase were observed.

The abdominal and pedal-pleural ganglia of Aplysia californica were maintained in organ culture for periods up to 45 days. Neurophysiological examination of abdominal ganglia indicated that synaptic activity could be evoked in ganglia cultured for 21 days and action potentials and spontaneous postsynaptic potentials persisted for 45 days. The effects of long-term culture on neurotransmitter metabolism were studied by measuring the activities of ChAc, AChE, AAD, and COMT in both cultured abdominal and pedal-pleural ganglia. G-6-PD and CarnAc activities were also measured. In general, the stabilities of the enzymes in abdominal ganglia to in vitro conditions were similar to those in pedal-pleural ganglia. None of the enzymes studied were markedly affected by culture conditions for at least fourteen days. After this time, enzymes involved in neurotransmitter synthesis, AAD and ChAc, exhibited fairly abrupt decreases in activity. The degradative enzymes studied, AChE and COMT, showed more gradual decreases in activity. The changes occurring in the neurotransmitter metabolizing enzymes after prolonged periods of time in culture are discussed in relation to the neurophysiological changes which were observed.

• A leading hypothesis concerning a biological basis of the affectove disorders is that altered metabolism of brain amines may underlie the cause or pathophysiology of these conditions. Features of affective illnesses supporting biological hypotheses include the somatic symptoms, diurnal rhythm, and apparent "endogenicity" of many severe depressions, and evidence of a genetic basis of manic-depressive illness. Development and preclinical study of medical therapies for the disorders substantially supported a relationship between mood-disturbances and neurotransmitters and stimulated considerable advances in the physiology and pharmacology of central synaptic neurotransmission. Unfortunately, studies of amine metabolism in patients have not provided consistent support for the amine hypotheses. Moreover, these hypotheses have not led to a coherent biological theory of abnormal behavior, to an objective basis for differential diagnosis, or to the rational development of treatments more effective or safer than those known.

Sprague-Dawley adult male rats were exposed to incapacitating doses of mixed gamma-neutron radiation in a single pulse from the AFRRI-TRIGA reactor. The activities of the enzymes choline acetyltransferase (ChAc), acetylcholinesterase (AChE), monoamine oxidase (MAO) and RNA polymerase (RNAp) were determined in the cerebral cortex, cerebellum and hippocampus. It was found that as early as 4 min after irradiation of the animal the activity of MAO was markedly decreased in all 3 brain areas investigated. ChAc and RNAp activities were also decreased but to a lesser extent. No appreciable changes in the activity of AChE were observed.