J. Gerald Young

Central Biogenic Amine Metabolism in Children with the Syndrome of Chronic Multiple Tics of Gilles de la Tourette: Norepinephrine, Serotonin, and Dopamine

Abstract Central nervous system metabolism in children with the syndrome of Gilles de la Tourette (TS) and contrasting pediatric patients was assessed by measuring the cerebrospinal fluid (CSF) metabolites of dopamine (homovanillic acid, HVA) and serotonin (5-hydroxyindoleacetic acid, 5-HIAA) with and without the administration of probenecid. Reduced accumulation of CSF HVA and 5-HIAA was found in TS. This may represent a primary decrease in brain turnover of dopamine and serotonin or a long-term adaptation to overactivity in these systems, perhaps as a result of changes in receptor sensitivity. In the CSF of a child with profound TS, an elevated level of the major metabolite of norepine.

Clinical neurochemistry of autism and associated disorders

Advances in information concerning brain function in animals and advances in analytical neurochemical methods for determining extremely low levels of compounds in physiological fluids have opened great opportunities for clinical neurochemical studies of autism. Nevertheless, the behavioral deficits in autistic individuals are major obstacles to clarification of the relations between symptoms and biochemical dysfunction in the brain. The fundamental preclinical and clinical studies of serotonin, dopamine, and norepinephrine metabolism related to infantile autism are reviewed, and new studies are suggested, as examples of the productive strategies that will illuminate features of the autistic syndrome in the next decade.

Dopaminergic but not noradrenergic mediation of hyperactivity and performance deficits in the developing rat pup

The relative contribution of dopamine (DA) and norepinephrine (NE) in behavioral arousal was examined in developing rat pups using intracisternal 6-hydroxydopamine (6-OHDA) either alone or following pretreatment with desmethylimipramine (DMI). Such treatments were designed to examine the effects of preferential reduction of DA (DA depletion), NE (NE depletion), or both catecholamines (CA depletion) in the development of motor activity and escape performance. General motor activity increased with age and, over all ages, DA-depleted pups tended to exhibit greater activity. This was most apparent at 15 days of age, where DA-depleted pups were significantly more active than controls, NE-depleted, or CA-depleted pups. DA-depleted pups failed to exhibit the steep decline in activity over time (habituation of activity) demonstrated by the control and NE-depleted pups, while pups depleted of both CA fell into an intermediate position in habituation. Escape latency in a T-maze at 20 days and shuttle box at 26 days of age indicated comparable performance to controls for NE-depleted pups, while those animals in DA-depleted and CA-depleted groups appeared unable to perform the task. Brain CA concentrations (determined by a radioenzymatic assay) indicated preferential reduction of DA in the DA-depleted group to concentrations 25% of controls, reduction of NE to 62% of controls in the NE-depleted group, and reductions of DA to 42% and NE to 60% in the CA-depleted group. These results suggest that preferential reduction of brain DA in the developing rat pup increases motor activity and impairs habituation of activity during the stage of behavioral arousal in week 3 of postnatal life. A theory incorporating both NE facilitory mechanisms and pre- and postsynaptic dopaminergic mechanisms in the mesolimbic-dopaminergic pathway is proposed.

Neurochemistry and child psychiatry.

Abstract Normal brain function depends on the integration of the synthesis, storage, release, and inactivation of neurotransmitters localized in different brain structures and pathways. Neurotransmitters, such as dopamine, serotonin, and acetylcholine, are implicated in various neurological and psychiatric diseases and in a broad range of normal physiological processes. Neurotransmitters, metabolites, and enzymes can be measured in cerebrospinal fluid, blood, and urine, permitting clinical researchers to study correlations between metabolic and behavioral dimensions. There are serious methodological problems which must be considered in interpreting biological research in child psychiatry. However, studies of neurotransmitter metabolism in conjunction with other types of research strategies offer promise for clarifying the basis for some serious developmental disturbances of childhood and the impact of psychoactive medication.

Determination of indoles in human and rat pineal

Tryptophan, serotonin, N-acetylserotonin, melatonin, 5-hydroxyindoleacetic acid and 5-hydroxytryptophol have been determined in rat and human pineal glands. The compounds were measured by directly injecting centrifuged tissue homogenates into a liquid chromatographic-fluorometric system. Normal ranges are reported for these compounds and upper limits established for several other indoles.

Determination of indoles and catechols in rat brain and pineal using liquid chromatography with fluorometric and amperometric detection.

Tryptophan, serotonin, 5-hydroxyindoleacetic acid, and homovanillic acid were determined in rat brain by the direct injection of a centrifuged tissue homogenate into a liquid chromatographic-fluorometric/amperometric system. The above indoles, along with melatonin, were also determined in single rat pineal glands. The utility of the system in determining several additional catechols and idoles in brain was examined.

Platelet monoamine oxidase activity in children and adolescents

Abstract Platelet monoamine oxidase activity has been measured in a group of preadolescent, adolescent, and post-adolescent individuals. The platelet oxidase activity was highest in the female in all three populations examined. Children diagnosed as having primary autism did not display differences in their platelet oxidase activity as compared to children of similar age and sex.

Applications of liquid chromatographic-fluorometric systems in neurochemistry

Abstract The coupling of high-performance liquid chromatography (HPLC) with on-line fluorometric detection has resulted in powerful, yet simple, analytical systems capable of great sensitivity and selectivity. We review the application of liquid chromatographic-fluorometric (LC-F) systems to the determination of catecholamine and indoleamine neurotransmitters and metabolites in physiological samples. The determinations using LC-F systems are compared most thoroughly to alternative liquid chromatographic-electrochemical (LC-EC) methods in terms of practicality, selectivity, and sensitivity.

Monoamine oxidase and catechol-o-methyltransferase activities in cultured fibroblasts and blood cells from children with autism and the Gilles de la Tourette syndrome

Monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) activities were measured in cells from children with autism (n = 5) and the Gilles de la Tourette syndrome (n = 5). Monoamine oxidase activities in cultured skin fibroblasts (type A) and platelets (type B) from the same individual were not correlated. COMT activities in fibroblasts and red blood cells showed a negative but not significant correlation (r = -0.42). Fibroblast MAO and COMT activities from patients were similar to values from controls matched for age, race, and sex. Increasing clinical severity of illness in both disorders, however, correlated significantly with higher fibroblast MAE activity. Cultured fibroblasts provide a means of measuring enzyme activities independently of the individuals current physiological and psychological state.

Decreased Urinary Free Catecholamines in Childhood Autism

Abstract Urinary free catecholamines were reduced in a group of boys with childhood autism when compared to normal boys of similar age. This may reflect a difference in brain and peripheral noradrenergic activity in autistic children, and is a possible correlate of altered modulation of attention, arousal, and anxiety.