Arthur Yuwiler's research while affiliated with University of California, Los Angeles and other places

Publications (141)

Article
Full-text available
An empirically based 78 question self-rating scale based on DSM-IV-TR and ICD-10 criteria was developed to assist clinicians' diagnosis of adults with autism and Asperger's Disorder-the Ritvo Autism and Asperger's Diagnostic Scale (RAADS). It was standardized on 17 autistic and 20 Asperger's Disorder and 57 comparison subjects. Both autistic and As...
Article
Inhibitors of monoamine oxidase A (MAO-A) but not MAO-B stimulate the activity of pineal serotonin N-acetyltransferase (AANAT) in the adult rat pineal leading to increased formation of N-acetyl serotonin (NAS) and melatonin (MEL). The pineal gland of the neonatal rat has AANAT activity, but the second enzyme in melatonin biosynthesis, HIOMT (hydrox...
Article
Full-text available
The present study on overnight urinary melatonin was conducted on the most geographically dispersed population to date, over a 1 year period, also covering a broad age range (18-62 years). An inverse relationship between melatonin and age, as well as between melatonin and weight was observed for both genders. Females as a whole, had higher melatoni...
Article
Full-text available
Overnight urines were collected each month for 12-16 months from 321 normal subjects at 19 medical centers in 14 countries distributed on 5 continents at latitudes from 31 01 South to 77 00 North. Mean melatonin concentration was found to negatively correlate with age, weight, and height. When the sexes were considered separately melatonin only cor...
Article
Rats were treated with daily oral doses of 1, 4, and 6 mg/kg risperidone (RSP) and its metabolite, 9-hydroxy-risperidone (9-OH-RSP), for 15 consecutive days. Concentrations of RSP and 9-OH-RSP were measured in plasma, brain, liver, kidney, lungs and fat tissue by high-performance liquid chromatography with electrochemical detection. Non-specific di...
Article
Clinical and animal studies suggest that brain serotonergic systems may regulate aggressive behavior; however, the serotonin/violence hypothesis has not been assessed at the epidemiological level. For study of an epidemiological sample we examined blood serotonin, because certain physiological and behavioral findings suggested that it might serve a...
Chapter
Clinical and animal studies suggest that brain serotonergic systems may regulate aggressive behavior. However, the serotonin/violence relation has not been assessed at the epidemiological level. For study of an epidemiological sample we examined blood serotonin; certain physiological and behavioral data suggested that it might serve as an analogue...
Article
Rats were given 5, 10, or 20 mg/kg oral doses of fluphenazine (FLU) dihydrochloride daily for 15 days. FLU and its sulfoxide (FL-SO), 7-hydroxy (7-OH-FLU) and N4'-oxide (FLU-NO) metabolites were assayed in plasma, liver, kidney, fat, whole brain, and brain regions by specific and sensitive radioimmunoassays (RIA). All metabolites were detected in t...
Article
The 27 amino acid peptide, pituitary adenylate cyclase-activating polypeptide (PACAP-27), and its 38 amino acid analogue, PACAP-38, stimulate serotonin-N-acetyltransferase (NAT) activity and N-acetylserotonin (NAS) and melatonin content of pineal glands from adult rats. Maximal stimulation of rat pineal NAT by PACAP-38 is not increased further sign...
Article
Pineals from neonatal rats born to alcohol-fed mothers had lower unstimulated serotonin-N-acetyltransferase activity (NAT) and responded less to isoproterenol, vasoactive intestinal polypeptide, or desmethylimipramine challenge than did pineals from pups born to normal or pair-fed mothers. Group differences disappeared after the first week of life....
Article
The study was conducted with children and adolescents with obsessive-compulsive disorder (OCD) to assess the relationship of whole blood serotonin (5-HT) content to a concurrent diagnosis of a disruptive behavior disorder (DBD) and to severity ratings of aggressive behavior. Eighteen children and adolescents who met DSM-III-R criteria for OCD were...
Article
The chronopharmacological hypothesis of the mechanism of the antidepressant effect of MAO-A inhibitors predicts that clinical efficacy depends upon the time of the day at which the drugs are administered. In the present study moclobemide (10 mg/kg, s.c.) injected at the end of the light phase advanced the onset of the nighttime increase of the rat...
Article
Six months of administration of the selective MAO-B inhibitor, selegiline (l-deprenyl 0.25 mg/kg, s.c.) to aged female Fisher 344N rats suppressed MAO-A as well as MAO-B activity and increased serotonin (substrate for melatonin biosynthesis) and N-acetylserotonin (immediate melatonin precursor) levels in pineal glands taken from the animals during...
Article
Total suppression of righting reflex in frogs (Rana pipiens, 25-35 mg b.w.) was observed after combined administration of melatonin (12.5 mg/kg) and selective inhibitors of MAO-A: clorgyline (2.5 mg/kg) and moclobemide (50 mg/kg) but not MAO-B: selegiline (25 mg/kg) and Ro-19-6327 (50 mg/kg). None of these drugs alone affected the righting reflex....
Article
The bioprecursor amino acid MDL 72394 is decarboxylated by aromatic L-amino acid decarboxylase (AADC) to liberate MDL 72392, an irreversible selective MAO-A inhibitor. Pretreatment with the AADC inhibitor carbidopa, which does not penetrate the brain-blood barrier, prevents the liberation of the MAO-A inhibitor outside the brain and results in excl...
Chapter
While norepinephrine is regarded as the primary regulator of melatonin biosynthesis, an increasing number of “classical” transmitters and neuropeptides have been implicated as modulating pineal function. The anatomical and functional bases for these suggestions is briefly reviewed. In addition, some of the similarities and differences between the e...
Chapter
This chapter reviews the influence of age, sex, height, weight, urine volume, and latitude on melatonin concentrations in urine from normal subjects. Because melatonin formation involves the stimulated metabolism of one monoamine by the transmitter actions of another in accordance with the coupling between an endogenous, free-running pacemaker and...
Article
Full-text available
Whole-blood serotonin (5-HT) concentration was assessed in 15 children and adolescents with obsessive-compulsive disorder (OCD) before and during treatment with clomipramine (CMI). Pretreatment blood 5-HT content had no correlation with clinical improvement during drug therapy. CMI administration produced a marked reduction in blood 5-HT content du...
Article
Exposure of adult rat pineal glands in organ culture to the polypeptides vasoactive intestinal polypeptide (VIP), and peptide N-terminal histidine C-terminal isoleucine (PHI) increases pineal serotonin N-acetyltransferase (NAT) activity and melatonin synthesis. The following research results are taken to indicate that VIP and PHI share common compo...
Article
Concentrations of melatonin in overnight and first-voiding urine samples from 10 people with autism, 15 parents, 1 grandparent, 9 sibs without autism, and 10 healthy, unrelated volunteers, were measured by radioimmunoassay. Those with autism had significantly higher melatonin concentrations in the first voiding samples than controls. Groups did not...
Article
We examined the effects of gender, age, weight, length, body shape (ectomorphy), and matrilineal influences on cisternal cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF 5-HIAA) and homovanillic acid (HVA) in 78 socially living adult and adolescent vervet monkeys. CSF 5-HIAA and the 5-HIAA:HVA ratio were higher (by 27% and 18%, respectively) in...
Article
Full-text available
Two normal control populations, separated by 8,000 miles and 24 degrees of latitude, had similar six-month mean values for overnight urinary melatonin concentrations. These values were significantly higher than six-month values for depressed subjects and abstinent alcoholic subjects, while the means for the two clinical populations were similar. Ag...
Article
Full-text available
The case of a female patient showing aggressive, compulsive, destructive behaviour, ritualistic faecal smearing, and hyperactivity is presented. The behaviour is long standing, therapy-resistant, and its aetiology is unknown, although it is seemingly associated with chromosomal abnormalities secondary to abnormal plasma factors.
Article
DL-Fenfluramine (20 mg/kg) releasing serotonin and amphetamine (2 mg/kg) releasing dopamine were given to adult rats trained to bar press for electrical stimulation to the medial forebrain bundle. Amphetamine treatment enhanced lever-pressing for 1-2 h. A single fenfluramine treatment rapidly suppressed self-stimulation with slow recovery in 5-7 da...
Article
Many investigations in humans indicate that epinephrine, norepinephrine and their ratio may correlate with such traits as social competence, academic achievement, and aggression. However, the socioeconomic, dietary, and environmental confounds accompanying most human studies complicate their interpretation. Social status, aggression, and other soci...
Article
Full-text available
This study examined the linkage between elevated blood serotonin in autism and the presence of circulating autoantibodies agianst the serotonin 5HT1A receptor. Information was also obtained on the diagnostic and receptor specificity of these autoantibodies. Blood serotonin was measured as was inhibition of serotonin binding to human cortical membra...
Article
Chronic fenfluramine treatment reduced whole blood serotonin and CSF 5-hydroxyindoleacetic acid, but increased aggressive and locomotor behavior, in adult male vervet monkeys (Cercopithecus aethiops sabaeus). Following a drug-free washout period to monitor the drug recovery course, we initiated a second period of fenfluramine treatment in the same...
Article
In a counter-balanced, cross-over study, we examined the contributions of serotonergic systems to the acquisition of social dominance in adult male vervet monkeys. Subjects were members of 12 social groups, each containing 3 adult males, at least 3 adult females, and their offspring. Animals were observed in 5 intervals including a first baseline,...
Article
The present study examined the effects of "peripheral," "central," and "mixed" benzodiazepine agonists and antagonists on the nocturnal rise in rat pineal NAT activity in vivo and the isoproterenol-stimulated NAT activity of pineals in organ culture. Administration of the central agonist clonazepam or the mixed agonist-antagonist diazepam, 4 hr aft...
Article
Whole blood serotonin (5-HT) concentration was assessed in 16 children and adolescents with severe obsessive-compulsive disorder (OCD) and in 14 normal adolescent controls. There was no difference in blood 5-HT content between the OCD patients and the normal controls. However, the OCD patients with a family history of OCD had significantly higher b...
Article
Moderate concentrations (10 microM) of cocaine increased melatonin content and N-acetylserotonin and serotonin-N-acetyltransferase activity in rat pineal glands freshly placed in organ culture. Pineals cultured for 48 hours or taken from ganglionectomized animals did not respond to cocaine. Both procedures markedly reduced pineal noradrenalin (NA)....
Article
It has been reported that selective MAO-A inhibitors, clorgyline and brofaromine, but not the MAO-B inhibitors, deprenyl and pargyline, stimulated rat pineal melatonin synthesis in humans and animals. Recent studies, however, found no eflect of moclobemide, a selective MAO-A inhibitor, on human plasma melatonin levels. Present study found that in v...
Article
Isatin (Tribulin) produced a dose-dependent inhibition of both MAO A and MAO B in broken cell preparations from rat brain and pineal. However, isatin administered in vivo (80-160 mg/kg) to the intact animal significantly increased brain, but not pineal, serotonin and did not affect 5HIAA or other indoles in either brain or pineal. Further, in vivo...
Article
It has been suggested that the HIV virus binds to VIP recognition sites which can be blocked by the octapeptide, peptide T. Stimulation of VIP receptors on pinealocytes activates adenylate cyclase and increases the activity of the enzyme serotonin N-acetyltransferase (NAT). We examined whether peptide T or D-Ala peptide T amide affected this induct...
Article
Treatment of neonatal, but not adult, rats with glucocorticoids decreases the rise in pineal serotonin N-acetyltransferase activity upon stimulation with beta agonists. Pineals in organ culture and exposed to steroids also show a dose-dependent decrement in response to beta agonists which increases with steroid exposure time. Pineals from neonatal...
Article
Platelet volumes were measured in 19 autistic, 26 normal, and 6 schizophrenic children with similar blood serotonin concentrations. The groups did not significantly differ in platelet volumes, nor did platelet volumes and blood serotonin concentrations correlate. These results do not support the hypothesis that the hyperserotoninemia in some autist...
Article
Freshly cultured pineal glands respond to the monoamine oxidase A (MAO A) inhibitor clorgyline and to high concentrations of the MAO B inhibitor, deprenyl, with an increase in serotonin N-acetyltransferase activity and N-acetylated indoles and a fall in 5-hydroxylated serotonin degradation products. Glands cultured for 48 hours before challenge res...
Article
Brain serotonin has been hypothesized to be involved in the modulation of psychotic symptoms in at least some forms of schizophrenia. We examined the effects of the serotonin precursor L-5-hydroxytryptophan (5HTP) on D-amphetamine induction of acute psychotic symptoms in schizophrenic patients. Preadministration with 5HTP significantly antagonized...
Article
The alpha-adrenergic agonists phenylephrine and methoxamine, at concentrations that have little effect on pineal N-acetyltransferase activity, markedly enhance stimulation of this enzyme by vasoactive intestinal polypeptide (VIP). This augmentation can be blocked by the alpha 1-adrenergic antagonists phenoxybenzamine and prazosin and, at 10 but not...
Article
Day and nighttime melatonin and dopamine-beta-hydroxylase activity were measured in blood from 10 Jewish and 9 non-Jewish dystonics and from 22 nondystonic family members. Groups did not significantly differ on either of these measures. These results do not support a generalized abnormality of noradrenergic release in dystonia.
Article
The irritants used by some organisms to discourage predators have been adapted by nature as a chemical nudge by which one cell can communicate with its neighbor. A nervous system is merely a group of long skinny cells interconnected and communicating with each other by the release of, and response to, such irritants, which are then termed neurotran...
Article
Several recent studies have described the benefits of fenfluramine for the symptomatic treatment of infantile autism. No large surveys of side effects of this drug have been reported in autistic children. To evaluate the untoward effects of fenfluramine in children with autism, 12 subjects were systematically studied. Medication was administered in...
Article
The effects of long term (70 days) fenfluramine treatment on selected physiological and behavioral measures were examined in four adult male vervet monkeys (Cercopithecus aethiops sabaeus). Relative to pretreatment baseline values, whole blood serotonin (WBS) and cerebrospinal fluid 5-hydroxyindole acetic acid (5-HIAA) were reduced, cerebrospinal f...
Article
The effects of dominance rank on the behavioral responses to drugs that enhance central serotonergic function were examined in 45 adult male vervet monkeys living in 15 stable social groups. Each group contained 3 adult males, 3 adult females, and their immature offspring. Dominance rank was assessed by measuring success in intermale agonistic enco...
Article
6-Methoxy-2-benzoxazolinone (6-MBOA) at concentrations greater than 20 microM stimulates serotonin N-acetyltransferase (NAT) activity of rat pineal glands in 48-hr organ culture as well as of glands freshly cultured, indicating that 6-MBOA acts postsynaptically. The effects of 6-MBOA on NAT activity can be blocked by propranolol but not by prazosin...
Article
Hydrocortisone acetate given to the neonatal rat diminishes subsequent elevations in pineal serotonin N-acetyltransferase (acetyl-coenzyme A:arylamine N-acetyltransferase; EC 2.3.1.5; NAT) activity produced by administration of catecholamines to the intact animal or to pineals in organ culture. The time required for development of this decrease in...
Article
The relative roles of norepinephrine (NE) and dopamine (DA) in sustaining neonatal hyperactivity were assessed in rats given 6-hydroxydopamine (6-OHDA) neonatally into the lateral ventricles after pargyline (P) or desmethylimipramine (DMI) pretreatment. On day 5 after birth, male and female rat pups were pretreated with P (50 mg/kg IP) or DMI (25 m...
Chapter
Like many contemporary clinical designations, the term early infantile autism refers to a clinical syndrome and not an etiologically homogeneous disease. This is a distinction of some importance in evaluating the existing literature on the syndrome and in devising strategies for its biochemical elucidation. The term was coined by Kanner1 in 1944 to...
Article
Fenfluramine was administered to 14 outpatient children with the syndrome of autism to determine whether previously produced decreases in blood serotonin concentrations and clinical improvements could be reinstituted. A double-blind medication-placebo crossover design was used. Each patient received fenfluramine 1.5 mg/kg daily (0.75 mg/kg twice da...
Article
Dominant male adult vervet monkeys have whole-blood serotonin concentrations approximately twice those of subordinate adult males. We examined the effects of spontaneous and induced changes in social status, temporary isolation from the social group, and membership in single male groups on whole-blood serotonin concentrations. We found that in male...
Article
Fenfluramine was administered to 14 outpatients with the syndrome of autism in a double blind crossover study (ABA design) to determine its effects on blood serotonin concentrations, platelet counts, and symptomatic behaviors. Blood serotonin concentrations decreased an average of 51% after 1 month on medication and returned to baseline levels with...
Article
Vasoactive intestinal polypeptide (VIP) stimulates basal serotonin-N-acetyltransferase (NAT) activity in pineals in organ culture and enhances the effects of catecholamines in inducing the enzyme. VIP appears to act postsynaptically; its action is independent of the beta receptor and is dependent upon protein synthesis. Its effects may be mediated...
Article
Vasoactive intestinal polypeptide stimulated serotonin N-acetyltransferase activity in rat pineal glands in organ culture by a postsynaptic action that was independent of the beta-receptor. The magnitude of stimulation could be altered by environmental lighting conditions and by prior exposure to the agonist. Such up- and down-regulation, well know...
Article
In vivo tryptophan 2,3-dioxygenase (TPO) activity in male rats was estimated from the rate of production of 14CO2 after intragastric administration of [14C-2]tryptophan. The synthetic glucocorticoids hydrocortisone-21-sodium succinate or Triamcinolone acetonide were injected to elevate hepatic TPO activity on an acute (1-6 hr) or chronic (24 hr) ba...
Article
Probenecid inhibits the transport of the small monocarboxylic acids lactate and propionate from blood to brain but does not affect the transport of 5HIAA or HVA. Neither lactate, 5HIAA, HVA, nor probenecid itself inhibits probenecid uptake into brain from blood and neither lactate nor 5HIAA itself inhibits 5HIAA uptake. These results indicate first...
Article
It is now generally agreed that a subgroup of autistic persons (perhaps as many as 40 per cent) have elevated blood serotonin, as compared with normal persons of the same age and sex. The authors have hypothesized that central-nervous-system serotonin may also be elevated in this subgroup, and that this abnormality may be related to certain clinica...
Article
The circadian release of norepinephrine from nerve terminals in the pineal gland drives acetyl-CoA:serotonin N-acetyltransferase (NAT; EC 2.3.1.5) activity in the adult pineal from a daytime low to a nighttime high. In the newborn, enzyme activity is intermediate between the adult's daily extremes and has only a small circadian fluctuation. With ag...
Article
Single and repetitive tryptophan loads were consumed by normal, adult male volunteers, and blood concentrations of tryptophan, serotonin, and kynurenine, their time courses, and their distributions within blood were measured. Repeated measures of basal and tryptophan-induced changes in tryptophan and serotonin blood concentrations were characterist...
Article
The possible roles of monoamine neurotransmitters in the regulation of the hypothalamic-pituitary-thyroid axis were examined in the rat. Rats were treated acutely and repeatedly with drugs which are presumed to alter neutransmitter functional activity. These drugs include neurotransmitter precursors (tryptophan and L-DOPA), synthesis inhibitors (p-...
Article
Neonatal exposure of rats to cortisol acetate was found to alter pituitary-adrenal feedback regulation at 20-25 days of age. Plasma levels of adrenocorticotrophin (ACTH) after ether stress were reduced in cortisol-treated rats pre-treated with 100 microgram corticosterone/100 g body weight, while rats given vehicle neonatally did not show suppressi...
Article
The associations among twelve behaviors and three potential peripheral markers of central serotonergic activity were investigated in vervet monkeys (Cercopithecus aethiops sabaeus). The behaviors monitored included approach, heterogroom, rest, eat, avoid, be solitary, be vigilant, huddle, initiate aggress, receive aggress, and engage in sexual beha...
Article
Four patients had high serum thyroxine (T4) concentrations during periods of heavy amphetamine abuse. After amphetamine was withdrawn, serum T4 returned to normal. Administration of amphetamine to monkeys induced a rise in serum T4; in this model the high T4 level appeared to be caused by increased serum thyrotropin. The mechanism of this effect is...
Article
Vervet monkeys were pharmacologically treated acutely and with repeated dose loading to alter serotonergic systems to assess the role of serotonin in the regulation of the hypothalamus-pituitary-thyroid axis. Acute L-tryptophan administration failed to alter basal levels of thyroid hormones but did decrease the TRH-induced TSH response. Repeated do...
Article
The behavioral effects of altering serotonin neurotransmission by chronic drug treatments in socially living vervet monkeys (Cercopithecus aethiops sabaeus) were examined. Animals received tryptophan (TRP, 20 mg/kg/day), parachlorophenylalanine (PCPA, 80 mg/kg/day), 5-hydroxytryptophan (5-HTP, 40 mg/kg/day), chlorgyline (10 mg/kg/day), or PCPA foll...
Article
Tryptophan transport through the blood-brain barrier of lithium-treated animals did not differ from transport by controls. Lithium ion, itself, did not appear to alter such transport, nor did lithium treatment alter serum constituents so as to modify tryptophan passage through the blood-brain barrier. These results suggest that the accumulation of...
Article
We examined in the rat several possible relationships between the pineal gland and the hypothalamus-pituitary-thyroid axis. The pineal gland, the retina, and the hypothalamus exhibited a diurnal rhythm in thyrotropin-releasing hormone (TRH) content with peak values occurring around 1200 h. This rhythm in the hypothalamus was abolished by constant l...
Article
Administration of corticosteroids to rat pups within the first several days of life results in retardation of several behavioral, neurophysiological, and biochemical developmental patterns. At 25 days of age, animals treated neonatally with 1.0, 0.5, or 0.1 mg hydrocortisone acetate showed dose-dependent decreases in plasma ACTH following 2.5 min c...
Article
Glucocorticoid administration to newborn rats leads to the premature induction of hepatic tryptophan oxygenase. This is accompanied by a retardation of the developmental increase in brain serotinin both in regions of serotoninergic cell bodies and in terminal projection areas. The magnitude of the fall in serotonin is relatively small. This appears...
Chapter
Biological studies of psychiatric disease generally rely on examination of cerebrospinal fluid, blood, urine, or other tissues far removed from the brain. Indeed, metabolism in the brain is frequently so rapid that even autopsied brains, when available, shed little light on any but the most gross psychiatric or neurological disorders. Cerebrospinal...
Article
The activity of pineal N-acetyltransferase in the neonatal rat does not exhibit the large daily rhythm seen in the adult and is intermediate between the low day and high night adult values. These intermediate values appear to result from adrenergic stimulation. Blockade of adrenergic receptors or of catecholamine synthesis results in a decrease in...
Article
— In the present study we examine the influence of pH, palmitate, and neutral amino acids on the passage of tryptophan from blood into brain during a single capillary pass, and on the partitioning of tryptophan between free and albumin-bound forms. The results show that a considerable fraction of albumin-bound tryptophan is stripped from albumin si...
Article
Subcutaneous administration of hydrocortisone acetate to the newborn rat produces a premature induction of hepatic tryptophan oxygenase consisting of a transient rise in activity 6-8 h after treatment, followed by a second sustained rise beginning 40 h later, which plateaus at 10 days of age. Cycloheximide treatment at the midpoint of this second e...
Article
Neonatal rats were given s.c. injections of 1 mg of hydrocortisone acetate, and the effect on the subsequent development of the pituitary-adrenal response to ether stress and the development of the circadian rhythm in adrenal and serum corticosterone (B) was investigated. Following exposure to ether, adrenal steroids were elevated in 11-day-old con...
Article
This study examined, in vitro, the uptake and efflux of serotonin by platelets from autistic children, nonautistic hospitalized comparison cases, and normal children. The autistic patients were carefully selected according to previously established diagnostic criteria. The hospitalized comparison children were utilized to assess possible environmen...
Article
Implants of hydrocortisone acetate (HCA), cholesterol or empty tubing were placed in the hypothalamus of rats. Corticoid implants elevated serotonin levels in the basomedial hypothalamus compared to the other two groups, but norepinephrine levels were unchanged. Adrenal and serum cortcosterone, as well as adrenal weight, were lower in animals with...
Article
Ovariectomy of adult female rats significantly decreased the porphyrin content of the Harderian glands compared with intact control rats. Treatment of ovariectomized rats for 5 days with testosterone propionate, progesterone or oestradiol did not alter porphyrin content or concentration; however, administration of oestradiol plus progesterone signi...
Article
This chapter presents a study investigating beta-adrenergic regulation of indole metabolism in the pineal gland. Pineal glands contain about 250 pmol of serotonin after 24 h of organ culture in medium containing 0.2 mM tryptophan. Treatment with L-norepinephrine for 6 h results in a reduction of serotonin to about 40% of control values. This effect...