Low Serotonergic Function Research Articles

Childhood serotonergic function and early adult outcomes in youth with ADHD: A 15-year follow-up study

Longitudinal studies have shown that clinical precursors of antisocial personality disorder (ASPD) include attention-deficit/hyperactivity disorder (ADHD) and more notably comorbid ADHD and conduct disorder (CD). Despite existing evidence for the purported role of abnormal serotonergic function in aggressive youth and adults, little evidence exists on the role of serotonin in the progression from childhood disruptive behavior disorders to adult psychopathology, including ASPD. This study examined the relation between serotonergic function in children diagnosed with ADHD and the development of ASPD in early adulthood. We hypothesized that low serotonin response to a pharmacological probe in childhood would predict the development of adult ASPD. Towards this goal we divided 40 adults (M = 37, F = 3), ages 23–26 (m-24.57, sd-2.33) diagnosed with childhood ADHD into 2 groups: participants with (n = 21) and without (n = 19) ASPD. We used logistic regression to assess whether serotonergic measures in childhood assessed via prolactin and cortisol responses to a fenfluramine challenge, would selectively predict the development of ASPD in early adulthood. Logistic regression models showed that low central serotonergic response in childhood indexed by cortisol response significantly predicted adult ASPD (Wald = 4.427, p = .035) but not ADHD diagnosis in adulthood. Adults without ASPD had the highest serotonergic response whereas adults with adolescent ASPD (i.e. early onset ASPD) had the lowest response. Thus we provide new evidence of the link between low serotonergic function in childhood and the development of ASPD in adulthood, particularly for boys with adolescent onset of ASPD. These findings are relevant for understanding the contribution of childhood neurobiology to risk for later ASPD.

Serotonin transporter polymorphism, depressive symptoms, and emotional impulsivity among advanced breast cancer patients.

This study tested a theory linking a marker of low serotonergic function to both depression and impulsivity in a sample of advanced breast cancer patients, among whom elevated depressive symptoms and difficulty regulating emotions are commonly reported. A total of 95 patients provided blood samples for serotonin transporter polymorphic region of the gene (5-HTTLPR) and completed questionnaires that measured depressive symptoms and emotional impulsivity. Structural equation modeling revealed that the s allele of 5-HTTLPR was related to greater depressive symptoms (β=.20, p<.042) but only marginally to greater emotional impulsivity (β=.19, p<.068). Depressive symptoms and emotional impulsivity were positively related (β=.33, p<.003). Further tests explored possible mediation from genotype to one psychological variable via the other. Results suggest that depressive symptoms, particularly perceived interpersonal rejection, may be a pathway linking genotype to emotional impulsivity. Findings provide the first evidence that low serotonergic function contributes to both depression and impulsivity within a clinically meaningful sample. Furthermore, the link of s allele of 5-HTTLPR to emotional impulsivity was mediated by depressive symptoms, particularly perceptions of social rejection. Findings have implications for advanced breast cancer patients' treatment decision.

Effects of fenfluramine, 8-OH-DPAT, and tryptophan-enriched diet on the high-ethanol intake by rats bred for susceptibility to stress

The swim-test susceptible (SUS) line of rats has been bred in our laboratory for the characteristic of reduced motor activity in the swim test following exposure to an acute stressor. Testing of multiple generations of SUS rats has also revealed that they consume large amounts of ethanol voluntarily. As reported for lines of rats that show a propensity for high-ethanol intake, the SUS rats show evidence of low serotonergic function. Because serotonergic function has often been shown to be involved in the regulation of alcohol consumption, here we examined the effects of manipulations of serotonin transmission on intake of ethanol by SUS rats. Fenfluramine, a serotonin-releasing drug, was injected at various doses (0.625, 1.25, 2.5, and 5.0 mg/kg) twice per day and ethanol intake was measured using a two-bottle free-choice method. The 8-OH-DPAT, a 5‑HT 1A agonist, was injected at various doses (0.03125, 0.0625, 0.125, 0.25, 0.5, and 1.0 mg/kg) before a 1-h session of exposure to ethanol (single-bottle test, water available the other 23 h per day). A diet enriched with 3% tryptophan (TRP), the amino acid precursor for serotonin synthesis, was administered in a restricted feeding schedule (5 h per day) with ethanol intake measured the last 4 h. Fenfluramine decreased ethanol intake at all doses tested. The 8-OH-DPAT increased ethanol intake at lower doses, presumably acting at autoreceptors, which inhibit serotonergic neurons, and decreased intake at higher doses, presumably acting at postsynaptic 5-HT 1A receptors. TRP-enriched diet also significantly decreased ethanol intake. Food and water intake were less or unaffected by these three manipulations. With all three manipulations, ethanol intake remained suppressed one or more days after the day of tests that decreased ethanol intake. These data suggest that SUS rats, like many other lines/strains of rodents that consume large amounts of alcohol, show an inverse relationship between serotonin transmission and voluntary intake of ethanol.

FC04-03 - Serotonin, trauma and violence in attempted suicide

IntroductionSerotonin is implicated in impaired impulse control, aggression and suicidal behaviour. Low cerebrospinal fluid (CSF) concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) have been found in violent suicide attempters, suicide victims and in violent offenders. CSF 5-HIAA concentrations have both genetic and environmental determinants. Childhood trauma may have an effect on central monoamine function as an adult.AimsThe aim of this study was to assess the relationship of CSF 5-HIAA and the exposure to and the expression of violence in childhood and during adult life measured with the Karolinska Interpersonal Violence Scale (KIVS).Methods42 medication free suicide attempters underwent lumbar puncture and were assessed with the Karolinska Interpersonal Violence Scale (KIVS) to assess history of childhood exposure to violence and lifetime expressed violent behaviour.ResultsIn women CSF 5-HIAA showed a significant negative correlation to exposure to violence during childhood. Furthermore, suicide attempters with low CSF 5-HIAA were more prone to commit violent acts as an adult if exposed to violence as a child compared to suicide attempters with high CSF 5-HIAA. In the non-traumatized group, CSF 5-HIAA showed a significant negative correlation to expressed violent behaviour in childhood.ConclusionsAlthough central serotonergic function has important genetic determinants, exposure to childhood trauma may also affect serotonergic function. Low serotonergic function may facilitate aggression dyscontrol in traumatized suicide attempters.

CSF 5-HIAA and exposure to and expression of interpersonal violence in suicide attempters

Serotonin is implicated in impaired impulse control, aggression and suicidal behaviour. Low cerebrospinal fluid (CSF) concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) have been found in violent suicide attempters, suicide victims and in violent offenders. CSF 5-HIAA concentrations have both genetic and environmental determinants. Childhood trauma may have an effect on central monoamine function as an adult. The aim of this study was to assess the relationship of CSF 5-HIAA and the exposure to and the expression of violence in childhood and during adult life measured with the Karolinska Interpersonal Violence Scale (KIVS). 42 medication free suicide attempters underwent lumbar puncture and were assessed with the Karolinska Interpersonal Violence Scale (KIVS) to assess history of childhood exposure to violence and lifetime expressed violent behaviour. In women, but not in men, CSF 5-HIAA showed a significant negative correlation to exposure to violence during childhood. Furthermore, suicide attempters with low CSF 5-HIAA were more prone to commit violent acts as an adult if exposed to violence as a child compared to suicide attempters with high CSF 5-HIAA. In the non-traumatized group, CSF 5-HIAA showed a significant negative correlation to expressed violent behaviour in childhood. Although central serotonergic function has important genetic determinants, exposure to childhood trauma may also affect serotonergic function. Low serotonergic function may facilitate impaired aggression control in traumatized suicide attempters.

Low Serotonergic Function and Its Normalization by Treatment With Sertraline in Obsessive-Compulsive Disorder-An Auditory Evoked Potential Study

Mavorgiorgou, Paraskevi MD1; Gohle, Doris PhD2; Winter, Christine MD3; Rujescu, Dan MD, PhD2; Pogarell, Oliver MD2; Mulert, Christoph MD, PhD2; Bär, Karl-Jürgen MD, PhD4; Zaudig, Michael MD, PhD5; Hegerl, Ulrich MD, PhD6; Juckel, Georg MD, PhD7 Author Information

Suicidal Risk in a Patient Receiving Tamoxifen Treatment for Breast Cancer

To the Editor: Tamoxifen is a first-generation selective estrogen response modulator widely used in breast cancer. We have found no reported case of suicide linked to tamoxifen. We report a case of a 53-year-old woman who made a dramatic suicide attempt following a breast cancer treatment with tamoxifen. Case report. Ms A, a 53-year-old mother of 3 children with no psychiatric antecedents, was diagnosed in November 2006 with estrogen receptor–positive breast cancer. She quickly underwent a partial mastectomy followed by radiotherapy. She was not particularly worried following the discovery of her cancer, as it had been discovered at an early stage. Tamoxifen was started in February 2007. After tamoxifen treatment was begun, she progressively developed insomnia, hot flushes, unusual sweating, urinary infections, buzzing in the ears, memory and concentration problems, and an overwhelming fatigue. She also lost her appetite and was unable to taste salt as before. She lost 10 kg in 6 months. Several of these symptoms are typical of estrogen suppression therapy. Her fatigue, loss of appetite, and depressive mood seemed to justify the introduction of antidepressants: venlafaxine was started at 75 mg/d and continued for 15 days but was stopped due to a worsening of excessive sweating. It was followed by escitalopram at 10 mg/d titrated to 20 mg/d after 15 days. In July 2007, she experienced hemorrhoidal thrombosis and vaginal discharge, side effects also commonly seen with estrogen suppression therapy. At that time, tamoxifen was stopped. In August, escitalopram, which was given for 2 months without results, was replaced by mirtazapine at 30 mg/d by her general practitioner. She was then feeling hopeless and exhausted, and she considered herself to be such a burden on her husband and children that she shot herself in the belly with her husband's shotgun 2 days after this change of treatment. She survived but had to undergo right nephrectomy and gall bladder exeresis. Her mood gradually improved, and she regained weight rapidly despite her life-rescuing intervention. She decided to stop mirtazapine by herself after 2 months of treatment. Her condition continued to improve: the overwhelming fatigue totally subsided, her taste for food returned completely, and her memory and concentration returned to normal levels. However, she abruptly relapsed in March 2008, showing marked psychomotor retardation and concentration problems. Bupropion 150 mg/d and mirtazapine 30 mg/d were introduced; no improvement was seen after 1 month. As her family, and her general practitioner, reported that her mood and energy level were somewhat above normal after her first depressive episode, and in fact reflected her usual self, the possibility of a mood disorder belonging to the spectrum of bipolar disorder type II1 was evoked and lamotrigine was introduced. Her mood totally returned to its usual state after 2 months. Bupropion and mirtazapine were both stopped by the patient another 2 months afterward. Her mood has remained stable ever since with continual treatment with lamotrigine 200 mg/d. Depression and anxiety are frequent in breast cancer due to psychological adaptation difficulties and to consequences of treatment procedures.2 Depression was seen largely after cancer diagnosis and treatment in our patient. Improvement of her first episode followed tamoxifen suppression. The second episode did not follow any observable cause. Its beginning was abrupt, and it was characterized by psychomotor retardation and contrasted markedly with the usual mood of the patient, which both before and between depressive episodes was characterized by elated mood and unusually high activity and energy level. As no depressive episode was observed before her 53rd year, we suggest that tamoxifen could have precipitated the onset of a mood disorder, which appears to be stabilized with the use of lamotrigine. Reported rates of tamoxifen-induced depression vary from 1% to 17%.3 As noted, we have found no reported case of suicide linked to tamoxifen. The relationship between estrogen and mood is well known. Estradiol increases serotonin receptor density and increases urinary excretion of serotonin metabolite, reflecting an increase in production. Tamoxifen crosses the blood-brain barrier, and its antagonist properties could block the antidepressant effects normally produced by estrogen. Tamoxifen has recently been proposed as a treatment of mania, further suggesting a possible role in mood regulation.4 Suicidal behaviors have been linked to low serotonergic function in women with genetic predisposition.5 Some women could be at risk to show suicidal impulses if treated with estrogen suppression therapy, depending on the constitutional polymorphism of their serotonergic system. Depressive symptoms should be carefully monitored after tamoxifen treatment induction, as some women might be particularly sensitive to estrogen-suppression effects on mood, which could lead to a possible suicidal outcome.

Two-Mode Models of Self-Regulation as a Tool for Conceptualizing Effects of the Serotonin System in Normal Behavior and Diverse Disorders

The serotonin system is a collection of neural pathways whose overall level of functioning (from low to high) relates to diverse kinds of psychological and behavioral variability. Individual differences in serotonergic function are important both in personality and in vulnerability to psychological disorders. These disorders range widely-from impulsive aggression to depression. One way to understand such diverse reflections of differences in serotonergic function is by viewing serotonergic function through the lens of two-mode (or dual-process) models of self-regulation. Such theories posit a lower-order system that responds quickly to associative cues of the moment and a higher-order system that responds reflectively and planfully. Low serotonergic function appears to enhance influence of the lower-order system. This often yields impulsive reactivity. Why, then, does low serotonergic function also relate to depression, which is characterized by lethargy and unresponsiveness? The answer must be that ascendance of the lower system interacts with other factors. One hypothesis is that low serotonergic function plus high sensitivity to incentives yields vulnerability to impulsive approach, whereas low serotonergic function plus low incentive sensitivity yields vulnerability to depression. Conceptualizing serotonergic function this way helps integrate information pertaining to very different disorders into a coherent picture.

Serotonin, social status and sex change in the bluebanded goby Lythrypnus dalli

In a variety of vertebrates, highly aggressive individuals tend to have high social status and low serotonergic function. In the sex changing fish Lythrypnus dalli, serotonin (5-HT) may be involved as a mediator between the social environment and the reproductive system because social status is a critical cue in regulating sex change. Subordination inhibits sex change in L. dalli, and it is associated with higher serotonergic activity in other species. We tested the hypothesis that high serotonergic activity has an inhibitory effect on sex change. In a social situation permissive to sex change, we administered to the dominant female implants containing the serotonin precursor 5-hydroxytryptophan (5-HTP). In a social situation not conducive to sex change, we administered either the serotonin synthesis inhibitor p-chlorophenylalanine (PCPA) or the 5-HT 1A receptor antagonist p-MPPI. After three weeks we used HPLC to measure brain levels of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA). We also performed PCPA, p-MPPI and fluoxetine injections in size-matched pairs of females to assess its effect on dominance status. Males and newly sex changed fish showed a trend for higher levels of 5-HIAA and 5-HT/5-HIAA ratio than females. The different implants treatments did not affect the probability of sex change. Interestingly, this species does not seem to fit the pattern seen in other vertebrates where dominant individuals have lower serotonergic activity than subordinates.

Serotonergic function, two-mode models of self-regulation, and vulnerability to depression: What depression has in common with impulsive aggression.

Evidence from diverse literatures supports the viewpoint that two modes of self-regulation exist, a lower-order system that responds quickly to associative cues of the moment and a higher-order system that responds more reflectively and planfully; that low serotonergic function is linked to relative dominance of the lower-order system; that how dominance of the lower-order system is manifested depends on additional variables; and that low serotonergic function therefore can promote behavioral patterns as divergent as impulsive aggression and lethargic depression. Literatures reviewed include work on two-mode models; studies of brain function supporting the biological plausibility of the two-mode view and the involvement of serotonergic pathways in functions pertaining to it; and studies relating low serotonergic function to impulsiveness, aggression (including extreme violence), aspects of personality, and depression vulnerability. Substantial differences between depression and other phenomena reviewed are interpreted by proposing that depression reflects both low serotonergic function and low reward sensitivity. The article closes with brief consideration of the idea that low serotonergic function relates to even more diverse phenomena, whose natures depend in part on sensitivities of other systems.

Low plasma tryptophan in carcinoid patients is associated with increased urinary cortisol excretion

Previously we observed in patients suffering from a metastatic carcinoid tumor that irritability, aggression and lack of impulse control are associated with low levels of plasma tryptophan and presumably with low brain serotonin function. In rats we showed that a diet of low tryptophan resulted in higher stress responses and higher corticosterone production. Here we tested in carcinoid patients whether tryptophan depletion due to tumor 5-HT overproduction is associated with high cortisol production. Urinary excretion of cortisol, serotonin, 5-hydroxyindole acetic acid (the main metabolite of serotonin a marker of tumor activity), plasma levels of tryptophan and platelet content of serotonin (index of peripheral serotonin synthesis) were determined in metastatic midgut carcinoid patients. Patients (N = 25) were divided into two groups based on their plasma tryptophan levels (< or = 25 micromol/l, n = 12 and > or = 49 micromol/l, n = 13). Carcinoid patients with low plasma tryptophan levels had significantly higher urinary excretion of free cortisol (p < 0.01), independent of tumor activity. The inter-individual differences in the low tryptophan group, however, were substantial. In a subgroup of the patients suffering from metastatic carcinoid disease the cerebral access of plasma tryptophan is impaired, thus rendering cerebral serotonin neurotransmission suboptimal and leading to hypercortisolism. The present study provides further support to the idea that low serotonergic function is a risk for developing stress-associated psychopathology.

Migraine prevention trials and optimized acute therapy: Translating lessons learned into clinical practice

Different classes of drugs, discovered by serendipity, have been used successfully for migraine prevention for more than 40 years. The progressive knowledge of migraine pathophysiology, brain hyperexcitability, and the specific neurotransmitter systems involved in pain perception has driven the attempts at targeting two crucial mechanisms: the restoration of nociceptive dysmodulation and the inhibition of cortical hyperexcitability. The success of modern research trials with preventive migraine agents (mainly neuromodulators) and optimized treatment of acute attacks with drug combinations aimed at low serotonergic function, neurogenic inflammation, and central sensitization has translated into better outcomes for patients and physicians. Trials combining preventive migraine agents with nonpharmacologic behavioral headache management have yielded additional benefits over either approach alone. With the clinical application of this updated information from clinical trials, migraine impact on productivity, quality of life, and suffering will certainly be diminished. We hope that these achievements will create a stable path of management to benefit our patients, without interruption, into the foreseeable future.

Rats with different profiles of impulsive choice behavior exhibit differences in responses to caffeine and d-amphetamine and in medial prefrontal cortex 5-HT utilization

This study investigated if sub-populations of rats characterized by their basal level of impulsivity (BLI) in a delayed-reinforcement task, displayed differences in the functioning of neurotransmitter systems modulating impulsive choice behavior. For this, the effects of various doses of caffeine and d-amphetamine were investigated in three sub-populations of rats displaying pronounced differences in their impulsive choice behavior and their post-mortem serotonergic and dopaminergic functions were assessed. Caffeine and d-amphetamine reduce impulsive choice behavior only in the Medium BLI sub-population. Dopamine utilization was similar in the three sub-populations, but serotonin utilization was lower in the prefrontal cortex of the Medium and Very high BLI sub-populations as compared to the low BLI one. These results suggest that anti-impulsive effects of caffeine and d-amphetamine are dependent on the BLI of rats and that a low serotonergic function in the prefrontal cortex may be a trait marker of impulsivity evaluated by impulsive choice behavior.

The Psychobiology of Burnout: Are There Two Different Syndromes?

Background: Plasma prolactin levels are sensitive to dopamine and serotonin function, and fatigue. Low cortisol, dopamine and/or serotonin may be involved in burnout and detachment. Methods: In this double-blind within-subject study, we treated 9 female burnout subjects and 9 controls with 35 mg cortisol and placebo orally. We measured state affect and plasma prolactin, oxytocin, cortisol and adrenocorticotropic hormone levels, and administered an attachment questionnaire. Results: The burnout subjects displayed an extreme distribution of basal prolactin levels, displaying higher or lower levels compared to the controls. The low prolactin burnouts had profoundly low attachment scores and tended to have low oxytocin levels. The high prolactin burnout subjects tended to show cortisol-induced decreased prolactin and fatigue, and increased vigor. Conclusion: Results are consistent with the hypothesis that burnout subjects are either characterized by low serotonergic function or by low dopaminergic function, and that the latter group benefits from cortisol replacement. These preliminary results suggest that differentiating between two syndromes may resolve inconsistencies in research on burnout, and be necessary for selecting the right treatment strategy.

Platelet 5-HT 2A receptor binding and tryptophan availability in depression are not associated with recent history of suicide attempts but with personality traits characteristic for suicidal behavior

Background Abnormalities in the serotonergic (5-HT) system have been implicated in the pathogenesis of suicidal behavior. Studies on peripheral serotonergic parameters as a measure for central serotonergic function in suicidal patients appear to be promising, yet failed to show a clear association with suicidality. The objective of this study was to elucidate the role of serotonergic blood parameters in depressed suicidal patients and to examine their usefulness as a potential biological marker for suicidality. A number of personality traits were assessed in order to provide a basis for a psychobiological model of suicidal behavior. Methods Depressed patients with a recent suicide attempt (SA; n = 59) were compared to those without history of suicide attempts (NSA; n = 28). 5-HT 2A receptor binding in platelets and tryptophan/amino acid ratio in plasma were measured. Acute psychopathology and personality traits as well as characteristics of suicide attempts were assessed. Results There was no significant difference between SA and NSA in terms of peripheral serotonergic parameters as well as personality traits. However, the whole sample showed associations between certain personality traits and serotonergic platelet parameters. Furthermore, we observed a relation between suicidal ideation, lethality of suicide attempts and peripheral serotonergic markers. Limitations The number of cases with data on peripheral markers is relatively low. The potential influence of antidepressant medication previous to study inclusion has to be taken into account. The study focussed on depressed patients only. Conclusions Low serotonergic function is involved in the pathogenesis of suicidality, whereas the use of platelet 5-HT 2A receptor activity and tryptophan availability as biological markers for suicidality in depressed patients could not be proven an appropriate tool. Alterations in the serotonergic system are associated with trait aggression and other character dimensions.

Early maternal rejection affects the development of monoaminergic systems and adult abusive parenting in rhesus macaques (Macaca mulatta).

This study investigated the effects of early exposure to variable parenting style and infant abuse on cerebrospinal fluid (CSF) concentrations of monoamine metabolites and examined the role of monoaminergic function in the intergenerational transmission of infant abuse in rhesus monkeys (Macaca mulatta). Forty-three infants reared by their biological mothers and 15 infants that were cross-fostered at birth and reared by unrelated mothers were followed longitudinally through their first 3 years of life or longer. Approximately half of the infants were reared by abusive mothers and half by nonabusive controls. Abused infants did not differ from controls in CSF concentrations of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), or 3-methoxy-4-hydroxyphenylgycol (MHPG). Abused infants, however, were exposed to higher rates of maternal rejection, and highly rejected infants had lower CSF 5-HIAA and HVA than low-rejection infants. The abused females who became abusive mothers in adulthood had lower CSF 5-HIAA than the abused females who did not. A similar trend was also observed among the cross-fostered females, suggesting that low serotonergic function resulting from early exposure to high rates of maternal rejection plays a role in the intergenerational transmission of infant abuse.

Identifying psychiatric patients with serotonergic dysfunctions by event-related potentials

Summary: The increasing knowledge concerning anatomical structures and cellular processes underlying event-related potentials (ERP) as well as methodological advances in ERP data analysis (e.g. dipole source analysis) is beginning to bridge the gap between ERP and neurochemkal aspects. Reliable indicators of the serotonin system are urgently needed because of its role in pathophysiology and as target of pharma-cotherapeutic interventions in psychiatric disorders. Converging arguments from preclinical and clinical studies support the hypothesis that the loudness dependence of the auditory evoked Nl/P2-response (LDAEP) is regulated by the level of central serotonergic neurotransmission. Dipole source analysis represents an important methodological advance in this context, because the two Nl/P2-subcomponents, generated by the primary and secondary auditory cortex known to be differentially innervated by serotonergic fibres, can be separated. A pronounced LDAEP of primary auditory cortices is supposed to reflect low central serotonergic neurotransmission, and vice versa. LDAEP is a parameter with potential clinical value since subgroups of patients with a serotonergic dysfunction can be identified and can be treated more specifically. In depressed patients, a significant relationship between strong LDAEP, indicating low serotonergic function, and a favourable response to SSRI has been found. Additionally, there is evidence from several studies with patients with affective disorders that a strong LDAEP predicts favourable response to a preventive lithium treatment.

Overt Behavior Problems and Serotonergic Function in Middle Childhood Among Male and Female Offspring of Alcoholic Fathers

A large body of literature indicates that the serotonergic system is involved in behavioral regulation, as evidenced by the inverse relationship between impulsive aggression and serotonergic function found in adult alcoholics and nonalcoholics. However, studies of this relationship among child and adolescent offspring of alcoholics (COAs) have not previously been done. This study examines the potentially parallel relationship between behavioral dysregulation and low serotonergic function in young COAs. The relationship is of potential interest as a phenotypic marker of biological vulnerability to aggressiveness, which itself has been hypothesized to be a risk factor for later antisocial alcoholism. The present work is part of an ongoing prospective study of the development of risk for alcohol abuse/dependence and other problematic outcomes in a sample of families subtyped by the fathers' alcoholism classification. We examined the relationship between overt behavior problems in middle childhood (mean age = 10.5 +/- 1.7 years) and whole blood serotonin (5-HT) in a subsample of the offspring (N = 32 boys and 12 girls). Using a Child Behavior Checklist (CBCL) index of behavioral undercontrol, we obtained results indicating that high total behavior problem (TBP) children had lower levels of whole blood 5-HT than did low-TBP children (p < 0.01). These results support the hypothesis that there is an inverse relationship between whole blood serotonin levels and behavior problems in young male and female COAs. A father's alcoholism status was not significantly related to his child's 5-HT level, i.e., the child's phenotypic expression of behavioral dysregulation was more reliably connected to serotonergic function than was paternal alcoholism.