Michael J. Raleigh

Effects of chronic fenfluramine on blood serotonin cerebrospinal fluid metabolites and behavior in monkeys

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 fluid homovanillic acid (HVA) was unaltered, and aggressive and locomotor behavior were increased. Both physiological and behavioral effects were reversible: all measures returned to baseline values in the 35 day post-treatment period, with WBS resuming pretreatment values more rapidly than CSF 5-HIAA. At the relatively low doses (1–4 mg/kg/day) employed in the present study fenfluramine produced behavioral effects similar to those resulting from PCPA and opposite to those following tryptophan administration. Thus the behavioral effects of long-term fenfluramine may involve reductions in serotonergic transmission.

6-[18F]fluoro-L-DOPA-PETstudies show partial reversibility of long-term effects of chronic amphetamine in monkeys

The acute and long‐term effects of chronic amphetamine administration on the striatal dopamine system in monkeys were assessed with 6‐[18F]fluoro‐L‐DOPA (FDOPA) and positron emission tomography (PET). Vervet monkeys (Cerecopithecus aethiops) were administered amphetamine doses, i.m., that increased from 4 mg/kg/d to 18 mg/kg/d over a 10 day period. Post‐amphetamine FDOPA‐PET scans at 1–2, 3–4, and 6 week time points in individual subjects showed persistent decrements in dopamine synthesis capacity as reflected by FDOPA influx rate constant (Ki) values being ∼30% that of pre‐drug assessment. In other animals that were administered the same drug regimen, biochemical analysis of striatal regions at 1–2 weeks post‐drug indicated that dopamine concentrations were decreased by ∼95% throughout caudate and putamen regions, while the homovanillic acid/dopamine level ratio was increased 3–10‐fold. Post‐drug FDOPA‐PET Ki values remained consistently low up to 6 weeks; however, at the 5–6 month time point, relative increases in FDOPA‐Ki values (∼53% of pre‐drug values) were observed for all subjects, indicative of partial recovery of striatal dopamine synthesis capacity.

Mitochondrial content of choroid plexus epithelium

Abstract The objective of the present study was to examine the apparent work capacity of one of the two separate membrane systems (the blood-cerebrospinal fluid barrier) that isolate the mammalian brain extracellular fluid (and cerebrospinal fluid, CSF) from plasma. Digitized analyses of electron-microscopic images provided estimates of mitochondrial volumes, which were expressed as a percentage of the cell cytoplasm. We recorded a high mitochondrial content of 12–15% in the cuboidal epithelium of primate choroid plexus, which was consistent in vervet, rhesus, and squirrel monkeys, as well as in baboons. Similarly high mitochondrial contents were observed in the rabbit, rat, and mouse choroid plexus. It has been postulated that the high mitochondrial content of brain endothelium is associated with maintaining the ionic gradients within the central nervous system. We observed that the mitochondrial content of the choroid plexus (where CSF is produced) was slightly higher than in (prior measurements of) the blood-brain barrier (BBB). In addition, surface areas at the apical borders of the choroid plexus epithelia (where the Na+K+ATPase activity has been localized) were increased 7- to 13-fold over the basal borders, in the primate species examined. The observation of high mitochondrial volumes in choroid plexus cells is consistent with the suggestion that increased mitochondrial densities seen in choroidal epithelia and BBB capillaries provide a metabolic work capability for both secretory activities and maintaining ionic gradients across blood-CSF barriers.

Differential behavioral effects of tryptophan and 5-hydroxytryptophan in vervet monkeys: influence of catecholaminergic systems.

In previous studies tryptophan and 5-hydroxytryptophan (5-HTP) treatments produced opposite effects on aggression and vigilance and differing effects on eating and locomoting in vervet monkeys. This study examined the effects of the serotonin reuptake inhibitor fluoxetine, and the catecholamine reuptake inhibitor desmethylimipramine (DMI) on tryptophan and 5-HTP induced behavioral changes. Thirty-two adult males from 16 different social groups were studied. Tryptophan (10, 20, and 40 mg/kg/day) produced dose-dependent reductions in aggression, vigilance, and locomotion and increases in eating. In contrast, 5-HTP (20, 40, and 80 mg/kg/day) increased aggression and vigilance and did not affect locomotion or eating. Fluoxetine (0.5, 1.0, and 2.0 mg/kg/day) produced effects identical to tryptophan while DMI (1.5, 3.0, and 6.0 mg/kg/day) resulted in dose-dependent increases in aggression, vigilance, and locomotion, and decrements in eating. When combined with tryptophan, fluoxetine augmented and DMI diminished the effects of tryptophan on all behaviors. Fluoxetine decreased and DMI increased the effects of 5-HTP on aggression and vigilance. Thus concurrent DMI enhanced and concurrent fluoxetine reduced the differences between 5-HTP and tryptophan. These results suggest that 5-HTPs effects on catecholaminergic systems may underlie the differing behavioral effects of tryptophan and 5-HTP on behavior in a species closely related to humans.

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.

Menstrual cycle and social behavior in vervet monkeys.

We assessed the relationship between social behavior and the menstrual cycle in 11 adult female vervet monkeys (Cercopithecus aethiops sabaeus) living in an established, stable social group. The findings indicated that fluctuations in ovarian steroids are accompanied by behavioral changes in vervet monkeys. A significant increase in aggressive action, avoidance of social overtures, and retreats from threat occurred during the late luteal phase. However, the social environment can greatly affect behavior independent of the phase of the menstrual cycle. The 10 nondominant (or subordinate) individuals not only exhibited behavioral changes across their own menstrual cycles, but also were responsive to the dominant females cycle. During the dominant females late luteal phase, subordinate females significantly increased aggression and decreased social activity. Some of behavioral patterns in female vervet monkeys are therefore relatively independent of direct hormonal modulation and support the contention of the dominant female as the driving force for behavioral changes related to aggression and social interaction. The differential effect of hormones and social status and other environmental factors on behavior has not been critically evaluated in human studies of the premenstrual syndrome. The present study suggests that it is important to assess which behavioral patterns in women are hormonally mediated and which are dependent on the environment.

Whole Blood Serotonin and Family Background Relate to Male Violence

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 marker for brain serotonergic function. Whole blood serotonin was measured in a representative birth cohort of 781 21-year-old women (48%) and men (52%). Violence was measured using cumulative court conviction records and participant’s self-reports. Potential intervening factors addressed were: gender, age, diurnal variation, diet, psychiatric medications, illicit drug history, season of phlebotomy, plasma tryptophan, platelet count, body mass, suicide attempts, psychiatric diagnoses, alcohol and tobacco dependence, socio-economic status, IQ, and overall criminal offending. Whole blood serotonin related to violence among men but not women. Violent men’s mean serotonin level was .56 SD above the mean of nonviolent men. The finding was specific to violence, as opposed to general crime, and it was robust across two different methods of measuring violence. Together, the intervening variables accounted for 25% of the relation between serotonin and violence. Developmental context interacted significantly with serotonin; serotonin was linked to violence primarily among men who grew up in families with little cohesion and much conflict. To our knowledge, this is the first demonstration that altered blood serotonin concentration is related to violence in the general population, and that the relation may depend on family origins.

Ethological and 6-[18F]fluoro-L-DOPA-PET profiles of long-term vulnerability to chronic amphetamine.

A chronic 10-day amphetamine (Amp) protocol was used to induce significant long-term decrements of the striatal [18F]fluoro-L-DOPA influx rate constant (FDOPA Ki) in the vervet monkey. Longitudinal FDOPA-positron emission tomography (PET) assessment in Amp-treated subjects subsequently revealed a gradual recovery of striatal dopamine function: FDOPA Ki values were decreased by approximately 70% at 1 month, approximately 45% at 6 months, approximately 20% at 12 months and were similar to pre-Amp values at 24 months. Motoric and social behavioral measures were obtained on all subjects within a species-typical group setting. Behavioral observations were conducted during both basal and stressor-challenge conditions, the latter being created by placing a potential intruder-animal in an individual cage adjacent to the subjects group enclosure. During basal conditions, post-Amp stereotypies were present at 2 weeks and locomotor behaviors were increased throughout 1 month; both alterations occurred while FDOPA Ki values were significantly decreased. Social behaviors were also significantly affected; affiliative behavior was decreased up to 6 months while aggressive behavior was increased for 12 months. However, a different pattern of behavioral changes emerged under stressor-challenge conditions. Motoric and social changes were of greater magnitude and persisted longer than in basal settings while aggressive behavior remained elevated at 24 months. These results indicate that chronic Amp-induced decreases in FDOPA Ki values and behavioral alterations are reversible. Changes in striatal dopamine function as indexed with FDOPA-PET are not correlated with post-Amp alterations in behaviors and moreover, expression of those behaviors is context-dependent.

Sex differences in behavior among juvenile vervet monkeys (Cercopithecus aethiops sabaeus)

Sex differences in the behavior of juvenile vervet monkeys (Cercopithecus aethiops sabaeus) were investigated. Five male and five female juvenile (aged 24 to 30 months) members of a captive group were observed. Behaviors monitored included playing, aggressing, submitting, approaching, grooming, mounting, genital inspecting, caretaking, huddling, exploring, locomoting, eating, and being solitary. Juvenile males played more, ate more, and were solitary more. Females groomed and were groomed more, approached more, and engaged in more caretaking. There were no sex differences in the other behaviors. These data indicate that juvenile vervet monkeys do not manifest many of the sex differences in behavior reported to occur in other species of Old World monkeys. The data also indicate that juvenile sex differences in behavior are not necessarily predictive of adult differences.

Serotonergic and catecholaminergic influence on thyroid function in the vervet monkey

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 dose loading of tryptophan or 5-hydroxytryptophan increased blood serotonin and plasma T3 and decreased plasma TSH. The tryptophan hydroxylase inhibitor p-chlorophenylalanine yielded decreased blood serotonin, but did not affect plasma TSH, T4 or T3. The monoamine oxidase inhibitor chlorgyline also resulted in increased blood serotonin, but increased plasma TSH and T4 and decreased T3. These data may be explained by a unitary hypothesis involving central catecholaminergic, rather than serotonergic, control of TRH release. Chlorgyline may produce its effects predominantly by facilitating catecholaminergic stimulation of TRH release resulting in increased TSH and a consequent increase in T4. It is suggested that the effects of tryptophan and 5-hydroxytryptophan result from increases in serotonin levels in the thyroid gland to produce an increase in T3 with a compensatory decrease in TSH via negative feedback. The differences observed between the acute and repeated dose loading studies stress the need for both types of studies before drawing conclusions about the effects of pharmacological manipulations on hormonal levels.