Arthur Yuwiler

Serotonergic mechanisms promote dominance acquisition in adult male vervet monkeys

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, a first experimental, a second baseline, a second experimental, and a third baseline period. At the end of the first baseline period, the dominant male was removed from each group. In each group, one of the two remaining subordinate males was selected at random for treatment and during the first experimental period, 6 of the 12 treated males received drugs that enhanced serotonergic activity (3 were given tryptophan 40 mg/kg/day and 3 fluoxetine 2 mg/kg/day). The other 6 treated males received drugs that reduced serotonergic function (3 were given fenfluramine 2 mg/kg/day and 3 cyproheptadine 60 micrograms/kg/day). At the end of the first experimental period, the original dominant male was returned to his group and the second baseline period began. In all instances, the originally dominant male regained his dominant position. The second experimental period began with the dominant male again being removed and, the 12 treated males were given the treatment they had not received in the first experimental period. At the start of the third 12-week baseline period, the original dominant male was returned to his group and resumed his dominant status. When the 12 treated subjects received tryptophan or fluoxetine, they became dominant in all instances. When they received fenfluramine or cyproheptadine, their vehicle-treated cage mates became dominant. The sequence of the behavioral changes shown by the treated males as they acquired dominance status paralleled those seen in naturalistic conditions. These observations support the distinction between dominance and aggression and strongly suggest that when hierarchical relationships are uncertain, serotonergic mechanisms may mediate the behaviors which permit a male to attain high dominance status.

Dominant social status facilitates the behavioral effects of serotonergic agonists

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 encounters. In every group one male was clearly the dominant, or alpha male, and the other two males were subordinate. Males from 5 groups received 3 doses of the serotonin reuptake inhibitor fluoxetine (0.5, 1.0 and 2.0 mg/kg/day); those from a second set of 5 groups received 3 doses of the receptor agonist quipazine (0.25, 0.50 and 1.0 mg/kg/day); those from a third set of 5 groups received the serotonin precursor tryptophan (10, 20 and 40 mg/kg/day). The 3 drug treatments produced strikingly similar behavioral effects. Each produced dose-dependent increases in approaching, grooming, resting and eating and decreases in locomoting, avoiding, being vigilant and being solitary. Dominant males were significantly more responsive behaviorally to all 3 drugs than were subordinate males: the increase or decrease in each behavioral measure was larger in dominant than in subordinate males. In combination with previous studies, these data suggest that dominant and subordinate males differ in the drug sensitivity of their serotonergic systems.

Serotonergic influences on the social behavior of vervet monkeys (Cercopithecus aethiops sabaeus)

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 followed by concurrent PCPA and 5-HTP. Grooming, approaching, resting, and eating were increased by TRP and decreased by PCPA; TRP decreased and PCPA increased locomoting, avoiding, being solitary, and being vigilant. Grooming, being vigilant, and receiving aggression were increased by 5-HTP, and PCPA increased initiating aggression and decreased huddling. Concurrent administration of 5-HTP and PCPA reversed the effects of PCPA on approaching, grooming, and resting; augmented the PCPA effects on avoiding, being solitary, and aggression; and did not alter the PCPA effects on eating, locomoting, and huddling. Chlorgyline increased grooming, approaching, and being vigilant and decreased being solitary. No treatment significantly affected sexual behavior. These data suggest that serotonergic systems contribute relatively substantially to the mediation of grooming and approaching, participate less strongly in resting and locomoting, are implicated still more weakly in being solitary, avoiding, and being vigilant, and have little if any involvement in huddling, aggression, and sexual behavior.

Studies on 5-hydroxytryptophan decarboxylase. I. In vitro inhibition and substrate interaction☆

Abstract 1. 1. An enzyme preparation obtained from quickly frozen hog kidney by the method of Clark et al. (10) was found to decarboxylate l -5-hydroxytryptophan, l -3,4-dihydroxyphenylalanine, l - erythro -3,4-dihydroxyphenylserine, and l - threo -3,4-dihydroxyphenylserine. 2. 2. The enzymic activity toward l -5-hydroxytryptophan or l -3,4-dihydroxyphenylalanine was not affected by the addition of 5-hydroxytryptamine, α-methyltryptamine methane sulfonate, 5-(3-indol-acrylolyl)salicylic acid, 1-benzyl-2,5-dimethylserotonin, or (5-oxyindolyl-3) butenone-3 but was inhibited by 2-(3,4-dihydroxyphenyl)ethylamine, m -hydroxypropadrine, norepinephrine, epinephrine, thiosemicarbazide, β-(3-indolyl)acrylic acid, 3,4′-dihydroxy-3′-carboxychalcone and 3,4,4′-trihydroxy-3′-carboxychalcone, and 1-(5-hydroxyindolyl-3)-2-(3-carboxy-4-hydroxybenzoyl)ethylene. The inhibition by 2-(3,4-dihydroxy-phenyl)ethylamine could be reversed by addition of pyridoxal phosphate. 3. 3. Mixtures of l -5-hydroxytryptophan and l -3,4-dihydroxyphenylalanine were found to be decarboxylated at a rate intermediate between the decarboxylation rates of the separate substrates. 4. 4. The depression in the decarboxylation rate of the mixture was roughly proportional to the molar ratio of l -5-hydroxytryptophan and l -3,4-dihydroxyphenylalanine. 5. 5. The intermediate relationship between the decarboxylation rate of the mixture and the individual substrates was approximately the same whether 0 μg., 25 μg., or 20 μmoles of pyridoxal phosphate was included in the system. 6. 6. Additive stoichiometry could be obtained with substrate mixtures in the presence of excess enzyme or after relatively long periods of incubation. 7. 7. The implications of these findings are discussed with regard to the discrete nature of l -5-hydroxytryptophan and l -3,4-dihydroxyphenylalanine decarboxylases and the possible physiological significance of their interactions.

Uptake and efflux of serotonin from platelets of autistic and nonautistic children

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 environmental and dietary influences upon the results. Uptake methods were similar to those used by previous investigators. Two efflux procedures were utilized to explore the possibility that methodological factors accounted for previously reported differences between autistic and comparison groups. The results failed to indicate statistically significant differences in uptake or efflux between the autistic and the hospitalized comparison groups or the normals. Methodologic considerations which could possibly account for the failure to confirm previous findings are discussed in detail.

Maturational changes in blood serotonin levels and platelet counts

Abstract A study was carried out on a medically normal control population to assess the influence of age, sex, and menstrual cycle phasing on whole blood serotonin levels and platelet counts. Intrasubject consistency was also determined. Serotonin levels and platelet counts of age-grouped males and females did not significantly differ in mean value or in variability. Intrasubject variability of blood serotonin levels or platelet counts appeared low but intersubject variability was high between subjects within age-matched groups. Changes in both serotonin levels and platelet counts accompanied the menstraual cycle. Platelet levels decreased prior to and during menses and peaked at midcycle. Serotonin levels changed in a similar but not identical manner. Both serotonin levels and platelet counts decline from the first year of age until the midteens and thereafter remain fairly constant until age 40.

Study of fenfluramine in outpatients with the syndrome of autism

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 daily) for 8 months, followed by placebo for 2 months. Blood serotonin levels promptly fell approximately 49% regardless of baseline levels. Clinical improvement returned, and on some scales gains after 8 months exceeded those noted after only 4 months of treatment. Significant correlations emerged among the amount of clinical response, initially high verbal IQs, and low blood serotonin concentrations. Compliance was excellent, and no clinically relevant side effects or weight changes occurred. It appears that fenfluramine is effective in ameliorating specific symptoms in certain autistic patients. The extent and mechanism of its action remain to be discovered.

Studies on 5-hydroxytryptophan decarboxylase. II. Additional inhibition studies and suggestions on the nature of the enzymic site

Abstract 1. 1. The inhibition of 5-HTP decarboxylation by 3,4′-dihydroxy-3′-carboxychalcone, 3,4,4′-trihydroxy-3′-carboxychalcone and 1-(5-hydroxyindolyl-3)-2-(3-carboxy-4-hydroxybenzoyl)ethylene was found to be competitive at both pH 6.8 and pH 8.0. 2. 2. The K m for 5-HTP decarboxylation was estimated to be 4.0 × 10 −5 at pH 8.0 and 1.7 × 10 −4 at pH 6.8. 3. 3. Preincubation experiments appear to rule out the possibility that 5-HTP irreversibly combines at a DOPA site while reacting at a different site. It appears possible but unlikely that DOPA irreversibly binds at a 5-HTP site while reacting at a different site. 4. 4. These experiments would seem to strengthen the view that one enzymic site is involved in the decarboxylation of DOPA and 5-HTP.

Peripheral correlates of serotonergically-influenced behaviors in vervet monkeys (Cercopithecus aethiops sabaeus)

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 behavior. The biochemical parameters measured were whole blood serotonin, plasma free tryptophan, and plasma total tryptophan. Throughout the study period, intraindividual variability in both the behavioral and the biochemical measures was small, although there was substantial interindividual variability in both sets of measures. Free and total tryptophan correlated positively with approach, heterogroom, and eat, and inversely with avoid and be solitary. Whole blood serotonin correlated inversely with avoid and be solitary. These data are compatible with previously reported observations on the behavioral consequences of manipulating serotonergic systems in vervet monkeys and suggest that in normal, drug naive monkeys, free and total tryptophan are better correlates of the central serotonergic activity influencing behavior than is whole blood serotonin.

Effects of Light and Temperature on the Pineal Gland in Suckling Rats

Enucleated and enucleated+Harderianectomized (E+H) 12-day-old rats were exposed to an additional 5 h of light or placed in the dark at 17.00. Body temperatures were lower in both groups in the dark in