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Approach to a social stranger is associated with low central nervous system serotonergic responsivity in female cynomolgus monkeys (Macaca fascicularis).

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American Journal of Primatology 61:187–194 (2003)
Approach to a Social Stranger is Associated With Low
Central Nervous System Serotonergic Responsivity in
Female Cynomolgus Monkeys (Macaca fascicularis)
Behavioral Physiology Laboratory, Department of Psychology, University of Pittsburgh,
Pittsburgh, PA
Comparative Medicine Clinical Research Center, Wake Forest University School of
Medicine, Winston-Salem, NC
Department of Anthropology, Wake Forest University, Winston-Salem, NC
Neuropsychiatric Institute, University of California-Los Angeles, Los Angeles, CA
Yerkes National Primate Research Center, Emory University, Atlanta, GA
It is widely hypothesized that individual differences in central nervous
system (CNS) serotonergic activity underlie dimensional variation in
‘‘impulsive’’ vs. ‘‘inhibited’’ social behavior in both humans and nonhuman primates. To assess relative impulsivity in a social context, a
behavioral challenge involving animals’ exposure to a social stranger
(termed the ‘‘Intruder Challenge’’) was recently validated in adolescent
and adult male vervet monkeys (Cercopithecus aethiops sabaeus). Among
these animals, monkeys that quickly approached the intruder were found
to have lower cerebrospinal fluid (CSF) concentrations of the serotonin
(5-HT) metabolite, 5-hydroxyindoleacetic acid, than less impulsive
animals. In the present study we extended these observations to
determine whether approach to a social stranger, as operationalized by
the Intruder Challenge, is similarly associated with diminished CNS
serotonergic function in female cynomolgus monkeys (Macaca fascicularis). Study animals were 25 adult monkeys that had been housed for
2 years in stable social groups. In each animal, the rise in plasma
prolactin concentration induced by acute administration of the
5-HT agonist, fenfluramine, was used to assess ‘‘net’’ central serotonergic
responsivity. When exposed later to an unfamiliar female of the
same species in a catch-cage placed for 20 min within the subjects’
home enclosure, monkeys that approached to within 1 m of the intruder
(median latency to approach ¼ 3 min) were found to have significantly
smaller prolactin responses to fenfluramine (diminished serotonergic
Contract grant sponsor: NIH; Contract grant numbers: HL 40962 and HL 65137 (SBM); HL 45666
(JRK); HD 38917 (MEW).
Correspondence to: Jay R. Kaplan, Ph.D., Department of Pathology, Wake Forest University
School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157-1040.
Received 15 May 2003; revision accepted 15 August 2003
DOI 10.1002/ajp.10118
Published online in Wiley InterScience (
2003 Wiley-Liss, Inc.
188 / Manuck et al.
responsivity) compared to ‘‘inhibited’’ animals that failed to approach
the intruder (t ¼ 2.9, df ¼ 23, Po0.009; rpb ¼ –0.51). Neither approach
behavior nor the animals’ fenfluramine-induced prolactin responses
covaried significantly with nondirected expressions of arousal
(or anxiety) or with aggressive behaviors exhibited during testing. We
conclude that in female cynomolgus monkeys, social impulsivity
(vs. inhibition) correlates inversely with individual differences in
CNS serotonergic activity, as assessed by neuroendocrine challenge.
Am. J. Primatol. 61:187–194, 2003.
r 2003 Wiley-Liss, Inc.
Key words: impulsivity; serotonin; fenfluramine
People imprisoned for impulse-related crimes, or who suffer from psychiatric
disorders in which problems of impulse control figure prominently (e.g.,
borderline and antisocial personality disorders, and suicidal depression) tend to
show altered central nervous system (CNS) serotonergic activity, as indicated
(indirectly) by a low cerebrospinal fluid (CSF) concentration of the serotonin
(5-HT) metabolite, 5-hydroxyindoleacetic acid (5-HIAA), or a blunted neuroendocrine response to pharmacologic agents that enhance serotonergic neurotransmission [e.g., Coccaro et al., 1989; Linnoila et al., 1983; Mann et al., 1995;
Virkkunen et al., 1994]. Otherwise normal individuals who report on a standard
personality questionnaire that they are highly impulsive also exhibit diminished
central serotonergic responsivity, compared to persons who describe themselves
as less impulsive [Manuck et al., 1998]. Analogous findings have been reported for
nonhuman primates, in which lower cisternal CSF 5-HIAA concentrations in
rhesus monkeys (Macaca mulatta) are associated with several naturally occurring
behaviors of a putatively impulsive nature. These include such acts as leaping
long distances in the forest canopy, risking injury by escalating aggressive
encounters to fights of heightened severity, and (among adolescent males)
emigrating from natal groups at an early age, when the animals are more
susceptible to attack and predation [Higley et al., 1992, 1996, 1997; Kaplan et al.,
1995; Mehlman et al., 1994, 1995].
Although problems associated with impulsivity often occur in a social
context, standardized assessments of impulsivity rarely incorporate social cues to
elicit impulsive behavior. To address this limitation, a behavioral challenge
employing a salient social stimulus–an unfamiliar ‘‘intruder’’–was recently
developed and validated in a large sample of adolescent and adult male vervet
monkeys (Cercopithecus aethiops sabaeus) [Fairbanks, 2001]. Animals that
responded impulsively to the appearance of a strange animal (intruder), as
indexed by latency to approach and frequency of antagonistic interactions, were
also found to have lower CSF 5-HIAA levels than less impulsive monkeys
[Fairbanks et al., 2001]. Here we extend these observations to determine whether
social impulsivity (operationalized by the Intruder Challenge) is similarly
associated with diminished central serotonergic activity in female cynomolgus
monkeys (Macaca fascicularis). In the present study we employed a standard
neuropharmacologic challenge – the rise in plasma prolactin concentration
induced by acute administration of the 5-HT agonist, fenfluramine – to assess in
vivo CNS serotonergic responsivity (Botchin et al., 1993; Coccaro et al., 1989;
Yetham & Steiner, 1993).
Approach to a Stranger and Serotonin / 189
The study animals were 25 female cynomolgus monkeys that had been
imported as adults from Indonesia (Institut Pertanian Bogor, Bogor, Indonesia).
Although their exact ages were unknown, all of the animals had radiographic
evidence of epiphyseal closure and were therefore probably 49 years of age. At
the time the behavioral observations described in this report were conducted, the
monkeys had been housed for 24 months in five five-member isosexual social
groups of stable membership (these animals comprised the untreated control
condition of an experimental study designed to evaluate estrogenic effects on bone
metabolism and atherosclerosis). The animals were fed monkey chow, and groups
were housed in pens measuring 2 3.2 2.5 m (with outdoor exposure).
The animals’ social ranks were evaluated once each month. These
determinations were based on the observation of dyadic fight episodes and were
defined by the direction of fight outcomes (recorded as unambiguous fight
gestures expressed by one of the participants). The animal that defeated all others
in her social group was assigned rank 1, the animal that defeated all but the
highest-ranking monkey was assigned rank 2, and so forth. Dominance ranks
were fully transitive (as is typical of this species) and were stable over the course
of study.
Intruder Challenge
The procedures of the Intruder Challenge employed in this study were based
on the protocol described by Fairbanks et al. [2001]. At the start of each challenge,
either two animals (those of social ranks 2 and 4) or three animals (of ranks 1, 3,
and 5) were left in their home enclosure, and the remaining monkeys were
removed to an adjacent housing area. A tarp-covered catch-cage, measuring
50 43 36 cm and containing an unfamiliar female of the same species, was
then placed in the home enclosure. The tarp was removed and the behaviors of
each animal were scored (by one observer per subject) as present or absent in 1min intervals over a 20-min test session. Recorded behaviors included those
denoting ‘‘Approach’’ (sitting within 1 m of the intruder’s cage, touch, sniff) and
‘‘Aggression’’ (lunge, smack, or threaten, either as expressed toward the intruder
or redirected to a cagemate), and nondirected expressions of arousal or ‘‘Anxiety’’
(yawn, scratch, body-shake). ‘‘Latency’’ to approach the intruder was measured
as time elapsed (min) until the subject first moved within 1 m of the intruder’s
cage. Testing proceeded until all 25 monkeys were evaluated, but not more than
two challenges were conducted on a single day. Interobserver reliabilities for
behavioral observations made on this set of animals were 40.90.
Assessment of CNS Serotonergic Responsivity
Fenfluramine increases serotonergic neurotransmission by causing a release
of serotonin stores, reuptake inhibition, and possible activation of postsynaptic
serotonin receptors [Borroni et al., 1983; Coccaro et al., 1989]. Stimulation of
hypothalamic serotonin receptors promotes the pituitary release of prolactin
(PRL), so the relative increase in circulating PRL concentration induced by
fenfluramine provides an index of ‘‘net’’ serotonergic responsivity in the
hypothalamic-pituitary axis [Yetham & Steiner, 1993]. The fenfluramine
challenge employed here was based on the protocol developed by Botchin et al.
[1994] and was administered 4 months prior to the behavioral observations
190 / Manuck et al.
described above. At 0830 hr on each of 2 test days scheduled 1 week apart, all
animals in a social group were placed in a squeeze cage and given an
intramuscular (IM) injection of either sterile saline or 4 mg/kg fenfluramine
hydrochloride. The monkeys were then returned to the group home cage. One
hour later, they were returned to the squeeze cage and anesthetized with
ketamine hydrochloride (10 mg/kg, IM). Blood samples were collected by
venipuncture 10–20 min after the animals were anesthetized, and then
transferred to tubes containing EDTA and frozen at –201C for later determination of plasma PRL levels. In two of the five social groups (selected randomly),
saline was injected in the first week, followed by fenfluramine in the second week.
For the remaining groups, the order of injections was reversed. The animals were
fasted for 12 hr prior to each procedure.
PRL was measured by enzyme-linked immunoabsorbent assay (ELISA),
using a commercially available kit for the assay of human PRL (Diagnostic
Systems Laboratory, Webster, TX). The assay uses 25 ml of serum, and has a
sensitivity of 0.52 IU/dL. Serial dilution of monkey serum (6, 12, and 25 ml)
provided estimates of PRL parallel to the standard curve and, when corrected for
the dilution factor, yielded comparable estimates of PRL (32.8, 36.4, and 34.8 IU/
dL, respectively). The intra-assay coefficient of variation (CV) was 8.3% at 5.5 IU/
dL (n ¼ 10), and the interassay CVs were 14.7% (n ¼ 14) and 6.6% at 1.95 and 12.3
IU/dL, respectively. Following the administration of fenfluramine, PRL concentrations averaged 54.8 (SE ¼ 4.8) IU/dL among the 25 study animals, and reflected
a significant rise over corresponding saline-day PRL values (M ¼ 6.4 [1.8] IU/dL;
Wilcoxon T ¼ 4.3, Po0.0001). Each monkey’s PRL response to fenfluramine was
expressed as the difference in PRL concentration between the drug- and salineday injections. Across all animals, the fenfluramine-stimulated rise in PRL
(DPRL[fen]) correlated strongly with PRL levels following drug administration
(r ¼ 0.93, df ¼ 23, Po0.0001), but not with ‘‘baseline’’ (saline-day) PRL values
(r ¼ 0.26, df ¼ 23, n.s.). The mean PRL change also did not differ by order of saline
and fenfluramine injection (fenfluramine first vs. second: M ¼ 49.2 [7.2] vs. 47.8
[4.8] IU/dL; t ¼ 0.2, df ¼ 23, n.s.).
Of the 25 study animals, only 11 (44%) actually approached within 1 m of the
intruder at any time during the 20-min challenge, and those that did approach
tended to do so very quickly. Six approached within the initial 3 min, and an
additional four approached within 8 min of first being exposed to the intruder; the
median latency to approach among the 11 animals that did so was 3 min. Due to
the discontinuity of distribution in approach behavior, these data were treated on
analysis as a nominal variable; for convenience, animals that approached the
intruder were designated as ‘‘impulsive’’ and those that did not were identified as
‘‘inhibited.’’ With respect to central serotonergic activity, the fenfluramineinduced PRL responses of impulsive monkeys were significantly smaller
than those of inhibited animals (DPRL[fen]: M ¼ 37.0 [SE ¼ 6.2) and 57.2
[3.9] IU/dL, t ¼ 2.9, df ¼ 23, Po0.009). A correlation of social impulsivity
(impulsive vs. inhibited) with the animals’ PRL responses to fenfluramine yielded
a point-biserial coefficient (rpb) of –0.51 (df ¼ 23, Po0.009). PRL concentrations
following fenfluramine administration covaried similarly with social impulsivity
(rpb ¼ –0.50, df ¼ 23, Po0.01), whereas baseline (saline-day) PRL values did
not (rpb ¼ –0.22, df ¼ 23, n.s.). Lastly, animals’ PRL responses (DPRL[fen]) did not
Approach to a Stranger and Serotonin / 191
correlate significantly with approach latency (in min) among the 11 monkeys that
actually approached the intruder (rs ¼ 0.14, df ¼ 9, n.s.).
Aggressive behaviors during the Intruder Challenge also varied among
animals, but were not expressed at all in 11 of the 25 monkeys. Among the
remaining 14 animals (56%), the number of recorded aggressive acts varied from
one to 26, with a median value of 4.0. Interestingly, whether or not the monkeys
expressed any aggressive behavior during the challenge was unrelated to whether
or not they approached the intruder (w21o1, n.s.). Moreover, the PRL response to
fenfluramine in animals that exhibited aggression did not differ significantly from
that in monkeys that showed no aggressive behavior (DPRL[fen]: M ¼ 54.7 [7.7]
and 54.8 [5.3] IU/dL, t ¼ 0.01, df ¼ 23, n.s.), and among the 14 monkeys that
displayed aggression, the PRL response did not covary significantly with the
number of aggressive acts observed (rs ¼ –0.37, df ¼ 12, n.s.).
Behaviors expressive of nondirected arousal or anxiety (e.g., yawn and
scratch) were common and varied continuously from zero to 29 such acts over the
20-min challenge (M ¼ 11.6 [1.9]; median ¼ 10). These behaviors were exhibited
with equal frequency by monkeys that did or did not approach the intruder
(M ¼ 10.9 [2.8] and 12.1 [2.2], respectively, t ¼ 0.35, df ¼ 23, n.s.; rpb ¼ –0.07,
df ¼ 23, n.s.), and among those that did or did not exhibit any aggressive behavior
during the challenge (M ¼ 10.5 [2.19] and 12.9 [2.71], respectively; t ¼ 0.70,
df ¼ 23, n.s.; rpb ¼ – 0.14, df ¼ 23, n.s.). Also, anxiety did not covary with the
animals’ PRL responses to fenfluramine (r ¼ 0.11, df ¼ 23, n.s.).
Finally, social rank (ranks 1–5) did not correlate significantly with whether
or not animals approached the intruder (rpb ¼ 0.0, df ¼ 23, n.s.), displayed
aggression during the challenge (rpb ¼ –0.22, df ¼ 23, n.s.), or exhibited behaviors
indicative of anxiety (r ¼ –0.02, df ¼ 23, n.s.). Rank did not covary with the
animals’ PRL response to fenfluramine (r ¼ 0.12, df ¼ 23, ns).
Social impulsivity in response to a stranger (as assessed by the Intruder
Challenge) was found in this study to be associated with diminished CNS
serotonergic responsivity among 25 adult female cynomolgus macaques. Specifically, impulsive monkeys (those that readily approached a novel animal
(intruder)) showed a blunted PRL response to the 5-HT agonist, fenfluramine,
compared to socially ‘‘inhibited’’ animals, which failed to approach the intruder at
any time during the challenge. This finding closely parallels the observations of
Fairbanks et al. [2001], who reported that similarly assessed impulsivity in
adolescent and adult male vervet monkeys covaried inversely with cisternal CSF
5-HIAA concentrations, an alternate measure of central serotonergic activity.
Nonetheless, the monkeys observed here appeared to be more inhibited in their
approach behavior than male vervets: 450% of the animals tested by Fairbanks
et al. [2001] approached the intruder within 1 min, while only two of 25 female
cynomolgus monkeys in the current study approached that quickly. It is
noteworthy, though, that the median latency to approach among animals that
did so in this study (impulsives) was still relatively brief (3 min) and that in both
studies behaviors indicative of generalized arousal or anxiety did not correlate
significantly with either approach behavior or indices of serotonergic function.
Fairbanks et al. [2001] identified two correlated components of animals’
behavioral responses to the Intruder Challenge among vervet monkeys: latency to
approach the intruder, and aggressive interactions (threats and assertive
displays). Although the latency and aggression components both covaried
192 / Manuck et al.
inversely with serotonergic function (CSF 5-HIAA) in vervets, the association
between approach latency and the animals’ 5-HIAA concentrations remained
significant after the correlated variation in aggressive behavior was adjusted for
statistically. Moreover, because the aggression component did not similarly
predict 5-HIAA levels after adjustment for the animals’ approach behavior,
Fairbanks et al. [2001] proposed that dimensional variation in ‘‘impulsivity vs.
inhibition’’ comprises the key behavioral correlate of central serotonergic
function (at least as assessed by the Intruder Challenge). In this view,
aggressiveness (unlike impulsivity) is not a direct consequence of low serotonergic
activity, but rather a category of behavior that uninhibited, impulsive individuals
are simply more likely to express, depending on circumstance and motivation. For
instance, among the male vervets observed by Fairbanks et al. [2001], animals
approaching an intruder within 1 min (the most impulsive monkeys) were also
more likely to make threatening gestures toward the stranger, as compared to
animals that approached the intruder more hesitantly or not at all, yet over 40%
of the latter group were still characterized as highly aggressive (viz., having
aggression ‘‘scores’’ above the sample median).
Our results are consistent with those of Fairbanks et al. [2001], inasmuch as
social impulsivity covaried inversely with monkeys’ fenfluramine-induced PRL
responses and did so independently of variation in the animals’ aggressive
behavior. However, in contrast to the previous study, the likelihood that animals
would engage in any aggressive acts during the challenge was unrelated to
whether or not they approached the intruder, and was not itself associated with
diminished serotonergic responsivity. Because the current experimental animals
were female cynomolgus monkeys, and those in the previous investigation were
male vervet monkeys, it is conceivable that in the present study impulsivity was
independent of aggression, and aggressive behavior was unrelated to central
serotonergic activity due to a difference in either sex or species. Lending some
plausibility to a primary sex difference is the fact that we previously found
fenfluramine-stimulated PRL responses in male cynomolgus monkeys (n ¼ 75) to
be attenuated in animals that showed the highest rates of ‘‘overt’’ aggression
when housed socially with other monkeys [Botchin et al., 1993], and, in laboratory
testing (n ¼ 40), in monkeys that displayed the greatest number of aggressive
gestures when they viewed slides of threatening content [Kyes et al., 1995].
Although a preliminary study of eight socially-housed female cynomolgus
monkeys suggested that rates of aggressive behavior in these animals may also
correlate inversely with PRL response to fenfluramine [Shively et al., 1995], this
association was not replicated in a subsequent investigation involving a larger
number of females (n ¼ 40) [Shively, 1998] (Shively, personal communication).
Obviously, though, only a direct comparison of males and females of both species
and under identical testing conditions can adequately address whether the
covariation of approach (impulsive) and aggressive behaviors and the relationship
between aggression and serotonergic function differ significantly by sex and/or
between cynomolgus and vervet monkeys.
Finally, in agreement with Fairbanks et al. [2001], we view an uninhibited
approach to a social stranger to be indicative of social impulsivity, which in
conjunction with a blunted PRL response to fenfluramine is consistent with the
broader human literature linking CNS serotonergic activity to psychopathologies
of impulse control and normative (trait) variation in impulsivity [e.g., Coccaro
et al., 1989; Linnoila et al., 1983; Virkkunen et al., 1994; Manuck et al., 1998].
This interpretation is also consistent with naturalistic observations in
rhesus monkeys, which show low cisternal CSF 5-HIAA concentrations
Approach to a Stranger and Serotonin / 193
to be associated with impulsive acts expressed in both social and nonsocial
contexts [Higley et al., 1992, 1997; Mehlman et al., 1994]. Nonetheless, in
the absence of other, correlated indices of impulsive behavior in the present
study, alternative interpretations (such as social attraction) of an animal’s
rapid approach to a social stranger during the Intruder Challenge cannot be
fully excluded.
The authors acknowledge the valuable assistance of Dewayne Cairnes and
Melissa Ayers in collecting the data reported in this paper.
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associates, cynomolgus, fascicularis, approach, low, responsivity, system, strange, central, social, nervous, monkey, female, macaca, serotonergic
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