Malcolm B. Bowers

CSF monoamine metabolites in children with minimal brain dysfunction: Evidence for alteration of brain dopamine: A preliminary report

Epidemiologic and pharmacologic evidence suggests that abnormalities of catecholaminergic systems in the brain play a role in the pathogenesis of minimal brain dysfunction, but previous attempts to document a neurochemical abnormality have been unsuccessful. To better define central nervous system mechanisms in children with MBD, we have utilized the probenecid loading technique to determine the concentrations of metabolites in the CSF of a clinically homogeneous group of children with MBD. CSF concentrations of homovanillic acid, the principal metabolite of dopamine, correlated directly with CSF probenecid in 26 control subjects (r = 0.05, p less than 0.01) and in six children with MBD (r = 0.91, p less than 0.05). Concentration of HVA (ng/ml) per unit of probenecid (mug/ml) was found to be significantly lower in children with MBD (9.8 +/- 1.5, mean +/- SEM) compared to those in control subjects (16.5 +/- 1.5), suggesting reduced turnover of brain dopamine in the MBD group. CSF concentrations of 5-hydroxyindoleacetic acid (5-HIAA), the principle metabolite of serotonin, did not differ significantly between the groups. Our findings indicate that there may be a neurochemical abnormality in MBD.

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.

Mesolimbic and mesocortical dopamine activation induced by phencyclidine: contrasting pattern to striatal response

The effects of acute administration of phencyclidine, an indirect dopamine agonist, on biochemical indices of dopaminergic activation were examined in mesocortical, mesolimbic and nigrostriatal regions of the rat. High doses (10 mg/kg) of phencyclidine resulted in a marked increase in levels of the dopamine metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid in all mesolimbic and mesocortical sites examined, as well as in the ventral tegmental area, source of the dopaminergic innervation of mesolimbic/cortical sites. In contrast, levels of both metabolites decreased in the striatum and tended to decrease in the substantia nigra, source of the striatal dopaminergic innervation. The metabolite response to phencyclidine was dose-related. These data indicate that the mesolimbic and mesocortical dopaminergic neurons are activated by phencyclidine. Since the firing rate of both A10 (ventral tegmental area) and A9 (substantia nigra) dopamine neurons has previously been shown to be increased by phencyclidine, these data suggest that phencyclidine results in a differential regulation of presynaptic release of dopamine in mesolimbic/cortical as opposed to nigrostriatal dopaminergic regions.

REM sleep and central monoamine oxidase inhibition.

Our preliminary observations on the relationship of sleep and lumbar CSF acid monoamine metabolite levels suggested a greater decrease in lumbar CSF HVA as compared to 5HIAA following clinical doses of phenelzine in the presence of virtually total REM suppression. This report on nine psychiatric patients confirms these findings in a larger sample and thus supports an inhibitory role for dopamine or other catecholamines in REM sleep mechanisms. The drug-withdrawal results indicate that the four patients with REM rebound showed increases in HVA levels compared to treatment levels, while the single patient with no REM rebound also had no increase in HVA levels.

Brain homovanillic acid: Regional changes over time with antipsychotic drugs

Acute administration of equivalent doses of either chlorpromazine, thioridazine, or clozapine, respectively, produced progressively smaller increases in brain homovanillic acid (HVA) in the rabbit; however, changes in HVA in three brain regions were of equal magnitude for a single dose of a given drug. Chronic administration of fluphenazine enanthate resulted in a decrease in HVA relative to acute treatment in caudate more than limbic regions. No differences between caudate and limbic regions were observed during daily chlorpromazine administration for 3 ro 8 days. Tolerance appeared to develop in approximately 1 week. Chronic treatment with clozapine produced no tolerance at one week but suggestive evidence of tolerance in caudate and limbic regions at two weeks. No tolerance was observed in the hypothalamus during chronic treatment with any drug used. Cisternal CSF HVA paralleled caudate HVA during acute and chronic treatments.

Early neuroleptic response in psychotic men and women: correlation with plasma HVA and MHPG.

Abstract We measured fasting free plasma HVA and MHPG prior to neuroleptic treatment in 47 psychotic inpatients. Early neuroleptic response (ten days) was significantly related to plasma homovanillic acid (HVA) in both sexes, plasma methoxyhydroxyphenylethylene glycol (MHPG) in women, and length of hospital stay in both men and women. Drug dose did not determine early response. As a group, women were more depressed on admission, received lower neuroleptic doses, and were discharged sooner than men. Plasma catecholamine metabolites deserve further study as correlates of neuroleptic treatment in psychotic disorders.

Regional brain homovanillic acid followingδ9-tetrahydrocannabinol and cocaine

Abstract δ 9 -Tetrahydrocannabinol (10 mg/kg) increased homobanillic acid in rat prefrontal cortex and olfactory tubercle. This dose did not affect homobanillic acid in the caudate. Higher doses increased homobanillic acid in all 3 regions. Cocaine (20, 30, or 50 mg/kg) did not affect homobanillic acid in any of these brain regions.

Thioridazine: Central dopamine turnover and clinical effects of antipsychotic drugs

Thioridazine was administered to 14 patients diagnosed as within the “schizophrenic spectrum” with the result that substantial improvement in psychotic symptoms was achieved while significant extrapyramidal side effects occurred in only 1 patient. Under these conditions lumbar cerebrospinal fluid homo vanillic acid following probenecid was significantly elevated (48%). Cerebrospinal fluid probenecid and 5‐hydroxyindoleacetic acid declined significantly during treatment with thioridazine. Taken in conjunction with the results of other studies, it appears that cerebrospinal fluid homo vanillic acid can be moderately elevated in man during successful treatment with antipsychotic drugs when extrapyramidal side effects are virtually absent. Possible interpretations of these results are discussed with regard to the clinical effects of antipsychotic drugs as they relate to central dopaminergic activity.

Recent life stressors and biological markers in newly admitted psychotic patients

The association of recent life stressor severity to putative biological markers of stress was examined in 34 newly admitted patients with acute psychosis. Of the biological variables examined, only pretreatment admission serum cortisol was correlated with stressor severity. Pretreatment serum prolactin, plasma homovanillic acid (HVA), and methoxyhydroxyphen-ethylglycol were not associated with severity of recent life stressors. We controlled for clinical and psychosocial variables that might affect the relationship of stressor severity to biological markers, and found that duration of psychotic symptoms was negatively correlated with stressor severity; however, when both cortisol and duration were entered in a stepwise multiple regression analysis, only pretreatment admission cortisol remained significantly and positively correlated with stressor severity. These findings suggest that serum cortisol may be a useful biological marker when investigating the relationship of life stress to episode onset. In addition, pretreatment HVA was correlated with early neuroleptic response but not with stressor severity, suggesting that HVA has value as a predictor of response independent of recent life stressors.

Cerebrospinal Fluid Monoamine Metabolites in Neuropsychiatric Disorders of Childhood

The severe neuropsychiatric disorders of childhood, phenotypically and genotypically diverse behavioral syndromes apparent during the first years of life, affect up to 3% of all children. Organically definable causes include structural malformations of the brain, chromosomal abnormalities, inborn errors of metabolism, anoxia, infection, head trauma, and numerous other types of inborn and acquired pathological influences on central nervous system (CNS) maturation. When such medically explicable disorders are excluded, the neuropsychiatric disorders consist of a broad range of syndromes of unknown etiology involving the normal unfolding of linguistic, cognitive, and social competence. In their most severe forms, such as primary childhood autism, all spheres of development may be disturbed pervasively; in less severe syndromes, one or another facet of development is more prominently involved (such as expressive and receptive language in the developmental aphasias or the regulation of attention and motor activity in attention-deficit syndromes).13,15,18,58,59