Neuroscience and Biobehavioral Reviews 35 (2011) 1771–1778

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Neuroscience and Biobehavioral Reviews

journal homepage: www.elsevier.com/locate/neubiorev

Review

Adverse childhood experiences (ACEs), genetic polymorphisms and

neurochemical correlates in experimentation with psychotropic drugs among
adolescents夽
L. Somaini a,∗ , C. Donnini b , M. Manfredini b , M.A. Raggi c , M.A. Saracino c ,
M.L. Gerra d , M. Amore d , C. Leonardi e , G. Serpelloni f , G. Gerra g
a
Addiction Treatment Centre, Local Health Unit, Biella, Italy
b
Dipartimento di Genetica, Biologia dei Microrganismi, Antropologia, Evoluzione, University of Parma, Parma, Italy
c
Department of Pharmaceutical Sciences, University of Bologna, Bologna, Italy
d
Division of Psychiatry, Department of Neuroscience, University of Parma, Parma, Italy
e
District Unit for the Prevention and Treatment of Drug Dependence and Alcoholism, Drug Addiction Centre D/XI-ASL Rome C, Rome, Italy
f
Dipartimento Dipendenze, Local Health Unit, Verona, Italy
g
Drug Prevention and Health Branch, Division for Operations, United Nations Office on Drugs and Crime Vienna, Austria

a r t i c l e i n f o a b s t r a c t

Article history: Epidemiological and clinical data show frequent associations between adverse childhood experiences
Received 13 May 2010 (ACEs) and substance abuse susceptibility particularly in adolescents. A large body of evidences sug-
Received in revised form 7 October 2010 gests that the possible dysregulation of neuroendocrine responses as well as neurotransmitters function
Accepted 9 November 2010
induced by childhood traumatic experiences and emotional neglect could constitute one of the essen-
tial biological changes implementing substance abuse vulnerability. Moreover, genotype variables
Keywords:
and its environment interactions have been associated with an increased risk for early onset sub-
Adverse childhood experiences (ACEs)
stance abuse. In this paper we present several data that support the hypothesis of the involvement of
Adolescent
Substance abuse
hypothalamus–pituitary–adrenal (HPA) axis in mediating the combined effect of early adverse experi-
Susceptibility ences and gene variants affecting neurotransmission. The presented data also confirm the relationship
between basal plasma levels of cortisol and ACTH, on the one hand, and retrospective measures of neglect
during childhood on the other hand: the higher the mother and father neglect (CECA-Q) scores are, the
higher the plasma levels of the two HPA hormones are. Furthermore, such positive relationship has been
proved to be particularly effective and important when associated with the “S” promoter polymorphism
of the gene encoding the 5-HTT transporter, both in homozygote and heterozygote individuals.
© 2010 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1772
2. Gene variants and substance abuse susceptibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1772
2.1. Serotonin transporters gene polymorphism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1772
2.2. Dopamine transporter gene polymorphism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1773
3. Neurochemical correlates in abuse susceptibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1774
3.1. Dopamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1774
3.2. Serotonin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1774
3.3. HPA axis and stress system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1775
4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1775
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1776

夽 The views expressed herein are those of the author(s) and do not necessarily reflect the views of the United Nations.
∗ Corresponding author.
E-mail address: lorenzo.somaini@aslbi.piemonte.it (L. Somaini).

0149-7634/$ – see front matter © 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.neubiorev.2010.11.008
1772 L. Somaini et al. / Neuroscience and Biobehavioral Reviews 35 (2011) 1771–1778
1. Introduction
Epidemiological and clinical data show frequent associations
between adverse childhood experiences (ACEs) and substance
abuse susceptibility particularly in adolescents. In the present
paper we review the possible interactions.
ACEs have been demonstrated to play a significant negative
role in development. Numerous studies have in fact evidenced that
abuse, neglect and other childhood trauma can contribute to an
array of negative outcomes and behaviours, including mental dis-
ease and substance abuse susceptibility among both adolescents
and adults (Van der kolk et al., 1991; Mullen et al., 1993; Osofsky,
1999). Furthermore, chronic and acute stress often associated with
ACEs has been reported as major factor not only in the development
of substance abuse and dependence, but also in increasing vulner-
ability for escalation from abuse to dependence and for relapse
(Brady and Sinha, 2005).
Interestingly, different forms of ACEs have been also found to
increase the susceptibility for a variety of diseases such as obesity
and cardiovascular diseases, and other behavioural or health risk
conditions (McEwen, 2000).
Negative childhood events such as loss of parent, physical vio-
lence and abuse, neglect and isolation and social status have all
been related with a high risk of exposure to illicit drugs during
early adolescence (Gerra et al., 2009; Morgan et al., 2002; Widom
et al., 2006). Reports from ACEs study have established that forms of
ACEs and household dysfunction tend frequently to co-occur (Felitti
et al., 1998; Anda et al., 1999) and the effects of these develop-
mentally disruptive childhood experiences have been shown to be
strong and cumulative (Dube et al., 2001, 2002).
There is considerable evidence from numerous clinical studies
supporting a positive relationship between genetic polymorphism
and early ACEs that exerts long-term effects on the developing brain
and leads to neurobiological alterations, behavioural changes and
mental disorders as well as addiction phenomena (Kendler et al.,
2003; Sinha, 2008). To increase the level of complexity in this field, a
significant association of substance use disorder susceptibility and
psychiatric disorders has been found; in turn, dependence from
gene variant and adverse childhood experiences has been also evi-
denced. Acute and chronic stress, related to ACEs may induce a
variety of neurobiological events that can alter the brain devel-
opment and increase the risk of developing psychiatric disorders
such as depression, symptoms of attention-deficit/hypo reactivity
(ADHD), borderline personality and dissociative identity disorders
which in turn represent risk factors for the development of sub-
stance abuse disorder (Teicher et al., 2002).
The way, by which gene and environment interactions affect
behaviour increasing vulnerability for substance abuse, is still
unclear. Nevertheless the importance of these interactions derived
also from preclinical studies have evidenced that separation from
the mother in non-human primates was found to tend to be
fearful, to be more aggressive with a reduction of exploration
behaviour and increase the proneness to the excessive drinking
of alcohol. These behavioural alterations were present particularly
in animals carrying the 5-HTT S-allele with elevated adrenorti-
cotropic hormone (ACTH) levels during separation in association
with both trauma and genotype (Ichise et al., 2006). Although
this vulnerability has been primarily attributed to gene variants,
previous studies suggest that also ACEs may influence neuro-
transmission, affecting in particular brain catecolaminergic system
and possibly concurring to the development of behavioural disor-
ders.
The possible dysregulation of neuroendocrine responses as
well as neurotransmitters function consequence of ACEs has been
previously reported (Heim et al., 2002; Shea et al., 2005; Gerra
et al., 2008). An alteration of the turnover of dopamine, with
both excessive reuptake and decrease intra synaptic monoamine
concentration, have been hypothesized in the individuals with
externalizing behaviour, such as attention deficit hyperactivity
disorder (ADHD) and conduct disorders (Volkow and Fowler,
2000). Taking into account this evidence, a possible neurobiolog-
ical derangement as a consequence of chronic exposure to stress
during childhood, involving both different neurotransmitters func-
tion and hypothalamic–pituitary–adrenal (HPA) axis function may
implement substance abuse susceptibility in humans (Oswald et al.,
2005; Duval et al., 2006). Higher cortisol plasma level through the
day was found in subjects who had experienced parental loss if
compared to whom who had experienced neither loss nor separa-
tion, indicating that the affective deprivation during childhood may
have lasting effects on HPA axis, even in the absence of concomi-
tant psychopathology (Nicolson, 2004). In line with this evidence,
different studies indicate that the alteration of HPA axis func-
tion and stress system are crucial for the transition from casual
use of substance to the inability to stop the chronic use: this
last one is a key feature of addiction disorders. Particularly, these
neurobiological changes have been found to be associated with a
childhood history of adverse experiences and low perception of
parental care among both cocaine and heroin addicts. The inverse
relationship evidenced in our previous study (Gerra et al., 2007b)
between homovanillic acid (HVA) plasma concentration and mater-
nal neglect/antipathy measures (CECA-Q) in dependent patients
seems to support the hypothesis by other authors suggesting the
role of early environmental factors in modulating brain transmis-
sion during adulthood. In particular, retrospective evaluation on
abstinent cocaine-abusing adults showed that ACEs scores, and par-
ticularly poor child–parent relationships, appeared to negatively
influence personality development, with an inverse correlation
between emotional neglect during infancy and cerebro-spinal fluid
(CSF) metabolites of serotonin and dopamine (Roy et al., 2007).
Considering all these evidences, ACEs may be responsible for a
complex and long-lasting neurobiological dysregulation/alteration
which is responsible for increasing the susceptibility to addictive
and affective disorders.
2. Gene variants and substance abuse susceptibility
2.1. Serotonin transporters gene polymorphism
Personality and behavioural traits may be in relationship with
brain monoamines changes (Blum et al., 2000; Young et al., 2002;
Gerra et al., 2000), and particularly with a dysfunction of serotonin
transmission (Coccaro et al., 1996; Tiihonen et al., 1997; Virkkunen
and Linnoila, 1990; Gerra et al., 1995).
Heredity also accounts for a portion of individual differences
in neurobiological dysregulation/alteration. The use of molecular
genetic techniques allowed to identify some of the specific involved
genes. The polymorphism in the promoter region of the human
serotonin transporter (5-HTT) gene SLC6A4 has been found associ-
ated with behavioural disinhibition and negative affect in children
of alcoholics (Twitchell et al., 2001) and interactive with child abuse
to contribute to risk for depression in children (Kaufman et al.,
2006; Nederhof et al., 2010). Moreover, a decreased expression of
the gene encoding the 5-HTT, due to “S” promoter polymorphism,
seems to raise 12- to 14-fold the risk of high alcohol intoxication
in adolescents with family relationships being “neutral” or “bad,”
respectively (Nilsson et al., 2005) and the same gene variant was
found overrepresented in cocaine addicts with a perception of low
parental care (Gerra et al., 2007a). Similarly, serotonin transporter
promoter gene (5-HTTLPR) S-allele was reported in association
with increased drinking and drug use among college students who
have experienced multiple negative life events. The S-allele carriers
 L. Somaini et al. / Neuroscience and Biobehavioral Reviews 35 (2011) 1771–1778
appear to be at the risk of a variety of adverse behavioural outcomes
in response to stress (Covault et al., 2007).
The frequency of short (“S”) allele 5-HTT promoter polymor-
phism seems to be higher in male individuals with conduct
disorder, aggressiveness, and ADHD (Cadoret et al., 2003). SS
genotype has been also reported in association with openness per-
sonality trait measured by the NEO-Five Factor Inventory of Costa
and MacCrae (1992) (Stoltenberg et al., 2002), being openness
changes found in relationship with obsessive compulsive disorder
(Rector et al., 2002) or attitudes to increased emotional expression
(Nightingale and Williams, 2000).
For these reasons we decided to test the hypothesis that the fre-
quency of the S allele and the SS genotype may be higher in the
adolescents who were available to experiment psychotropic ille-
gal drugs, when compared with abstinent peers, and particularly
in the subjects who showed substance use disorders antecedents,
such as novelty seeking (NS)/aggressive traits and school under-
achievements. The aim of the study was to investigate whether
early exposure to drugs among minimal experimenters, commonly
considered as casual, “recreational” use under the influence of peer
pressure and social environment, was related to individual person-
ality traits.
We first evaluated the possible association between 5-HTTLPR
genotype and the availability to experiment illegal drugs among
adolescents, in relationship with psychological characteristics,
determining NS and Buss Durkee Hostility Inventory (BDHI) aggres-
siveness scores (Gerra et al., 2005a). The frequency for Long–Long
(LL), Long–Short (LS) and Short–Short (SS) for the total group of
adolescents are 37.7%, 50.5% and 11.8%, respectively. The pro-
portion of the SS genotype was significantly more consistent in
illegal drugs experimenters sample, in comparison with absti-
nent adolescents. Moreover, SS subjects scored significantly higher
both on direct aggressiveness BDHI subscale and on NS subscale
at Tridimensional Personality Questionnaire (TPQ) for personality
characteristics than LL subjects, when evaluated on the entire sam-
ple. Experimenters scored significantly higher on BDHI subscale
and on NS subscale at TPQ in comparison with abstinent adoles-
cents independently from genotype subgroups.
Our data suggest that a decreased expression of the gene encod-
ing the 5-HTT, due to the “S” promoter polymorphism, may be
associated with an increased availability to experiment illegal
drugs among adolescents, particularly in the subjects with more
consistent aggressiveness and NS temperament.
The involvement of serotonin system function in the suscep-
tibility to nicotine dependence has been also hypothesized, being
brain serotonin secretion increased by nicotine, and reduced during
nicotine withdrawal (Ribeiro et al., 1993; Mihailescu et al., 1998).
To this purpose, smoking, in particular severe nicotine depen-
dence, was found related with decreased density of platelet 5-HTT
sites in African–Americans, again suggesting a possible relationship
between 5-HT transmission and nicotine addiction vulnerability
(Patkar et al., 2003).
We also evaluated among adolescents the possible association
between 5-HTTLPR genotype and smoking behaviour (Gerra et al.,
2005b). The proportion of the SS genotype was significantly more
consistent in the smokers’ sample (23.4%). The frequency of the
SS genotype was significantly higher in heavy smoking/early onset
subjects (daily use of 10 cigarettes or more), than in individuals
with late onset smoking and moderate nicotine use (infrequent use
or less than 10 cigarettes).
The association between low activity serotonin transporter pro-
moter genotype and early onset alcoholism with habitual impulsive
violent behaviour was previously demonstrated (Hallikainen et al.,
1999). A decreased expression of the gene encoding the 5-HTT
due to “S” promoter polymorphism may be associated with an
increased risk of substance use disorders, particularly in the
1773
subjects with more consistent aggressiveness and impulsiveness
was also demonstrated (Gerra et al., 2004). The SS genotype
frequency was significantly higher among heroin dependent indi-
viduals compared with control subjects. The SS genotype frequency
was significantly higher among violent heroin dependent indi-
viduals compared with addicted individuals without aggressive
behaviour. BDHI mean total scores and suspiciousness and nega-
tivism subscales scores were significantly higher in SS individuals,
in comparison with LL subjects, among heroin addicts. No associa-
tion was found between SS genotype and suicide history.
Parents care perception, aggressive personality traits and geno-
type 5-HTTLPR have been investigated in cocaine users and
healthy control subjects (Gerra et al., 2007a). The association
between 5-HTT polymorphism and psycho-stimulant use seems
to be mediated by mother–child relationship and parental attach-
ment perception, being both environmental and genetic factors
involved in the proneness to substance use disorders, particularly in
aggressive-antisocial individuals. The SS genotype frequency was
significantly higher among cocaine users compared with control
subjects. Logistic regression proves that persons bearing the SS
genotype have a risk of becoming cocaine users almost three times
higher than those ones having the LL genotype. Estimations of the
effects of other factors potentially affecting the risk of being cocaine
addicted clearly prove the significant impact of aggressiveness: the
highest the score is, the highest the risk is of becoming cocaine user.
Paternal and maternal care perception, measured through PBI,
affects, as well, the likelihood of becoming cocaine user by yield-
ing a significant 12% and 10% decrease of the risk, respectively, for
paternal and maternal care, for each unit increase in PBI. Interest-
ingly, once controlled PBI score, the relative risk associated with the
SS genotype drops strikingly and becomes no longer statistically
significant.
The hypotheses of (1) gene × environment interaction in the
susceptibility to experiment with drugs and (2) HPA axis involve-
ment in mediating the effects of early adverse experiences and
gene variants affecting serotonin function on substance abuse vul-
nerability were tested by investigating in healthy adolescents the
possible relevance of 5-HTT “S” polymorphism, childhood parental
neglect reported retrospectively and HPA axis function to the sus-
ceptibility to experiment with illicit drugs (Gerra et al., 2010). A
higher frequency of the 5-HTT SS genotype confirms the associ-
ation with an increased susceptibility to use illegal psychotropic
drugs among the adolescents. At the same time, reduced maternal
care perception was found to represent a intermediate key factor
of the association between SS polymorphism and drug use, sug-
gesting that genetic factors and parental behaviour concur to drug
use susceptibility. The relationship between basal plasma levels of
cortisol and ACTH, on the one hand, and retrospective measures of
neglect during childhood on the other hand was also confirmed:
the higher the CECA-Q scores are, the higher the plasma levels of
the two HPA hormones are. Such positive relationship has been
proved to be particularly effective and important when associated
with the S allele, both in homozygote and heterozygote individ-
uals. However, when tested together with genotype and parental
neglect, the effect of HPA hormones such as cortisol and ACTH was
not found to improve significantly the explanatory power of the
risk model.
2.2. Dopamine transporter gene polymorphism
Previous genetic studies have suggested that also dopamine
metabolism was related to the heritable vulnerability for substance
abuse (Saxon et al., 2005).
A number of studies suggest a possible association between
dopamine transporter (DAT) gene variants and attention-deficit-
hyperactivity disorder (Barr et al., 2001; Kirley et al., 2002),
1774 L. Somaini et al. / Neuroscience and Biobehavioral Reviews 35 (2011) 1771–1778
oppositional defiant and conduct disorder (Comings et al., 1996),
that were widely reported as antecedents of substance use disor-
ders (Moffitt et al., 1998; Wills et al., 1996; Poikolainen, 2002). DAT
gene variants was found associated with cocaine-induced paranoia,
the frequency of allele 9 being significantly higher for those ones
with a history of paranoid experiences, in comparison with cocaine
addicts without paranoid symptoms (Gelernter et al., 1994). More-
over, DAT gene variants appeared to implement vulnerability to
alcoholism (Ueno et al., 1999), to the severity of alcohol with-
drawal symptoms (Wernicke et al., 2002; Gorwood et al., 2003)
and to cigarette smoking (the 10-copy allele being more frequent
in never-smokers) (Vandenbergh et al., 2002). In addition, early
development of alcohol dependence and acute alcoholic psychosis
were found associated with the 9-repeat allele variant, supporting
the hypothesis that DAT polymorphism may be involved in type
2 alcoholism, with early onset and heavy behavioural problems
(Galeeva et al., 2001). Dopamine transporter polymorphism was
also associated with conduct disorders in children (Young et al.,
2002).
For these reasons we decided to analyze variable number of
tandem repeats (VNTR) polymorphism in the 3 un-translated
region of DAT in male Caucasian heroin-addicted individuals and
(matched for ethnic origin) healthy subjects (Gerra et al., 2005c).
We also evaluated behavioural and personality traits, DSM diag-
noses and psychometric measures of aggressiveness. Our findings
suggested that the 9-repeat allele of the DAT polymorphism con-
ferred increased susceptibility to antisocial-violent behaviour and
aggressiveness, rather than drug dependence per se in heroin-
dependent males.
Recently, dopamine receptor (D2) TaqI A polymorphisms have
been also associated with specific patterns of NS temperamen-
tal nature and frontal executive function (Han et al., 2008). In
this study, the methamphetamine (MA)-dependent patients with
DRD2-TaqI A1 allele have significantly greater NS scores and lower
frontal executive function with a trend level than those ones
without suggesting that MA-dependent patients may have the pos-
sibility of genetic and biogenic vulnerability to MA.
3. Neurochemical correlates in abuse susceptibility
Neurochemical correlates of adverse childhood experiences
include the alterations of neurotransmitter systems (i.e. dopamin-
ergic and serotoninergic systems) also involved in the reward and
addiction processes as well as the dysfunction of HPA system with
altered stress responsivity. Thus, early stressors can cause long-
term changes in multiple brain circuits and systems (Bremner,
2003; Anda et al., 2006) and a persistent sensitization of central ner-
vous system (CNS) circuits may represent the biological basis of an
increased susceptibility to subsequent stress such as the substance
addiction process (Heim and Nemeroff, 2001).
3.1. Dopamine
The deleterious effects of early life stress, child maltreat-
ment and accumulated adversity are related to alterations on
the corticostriatal-limbic motivational, learning, and adaptation
systems that also include mesolimbic dopamine. Central cate-
cholamines, particularly noradrenaline and dopamine, are involved
in modulating brain motivational pathways (including the ven-
tral tegmental area, nucleus accumbens and the medial prefrontal
regions) that are crucial in exerting cognitive and behavioural con-
trol (Meaney et al., 2002). Thus, the brain motivational pathways
are key targets of brain stressors and provide a weak point by
which stress affects addiction susceptibility and other maladap-
tive behaviours (Sinha, 2008). It is well known that the positive
reinforcement of drugs involves the activation of the mesolimbic
dopaminergic pathways that, in turn, are also involved in assigning
salience to stimuli, in reward processing, in learning and adapta-
tion. Human brain imaging studies also support the role of this
system in drug reward and such activity has been associated with
the ratings of euphoria and craving (Ross and Peselow, 2009).
It has been reported that early stress exposure, chronic stress
and increased levels of glucocorticoids (GC) enhance dopamine
release in the nucleus accumbens (Kalivas and Duffy, 1995), but
chronic exposure to GC inhibits both dopamine synthesis and
turnover, thus suggesting that alterations in the HPA axis can signif-
icantly affect dopaminergic function (Pacak et al., 2002). Although
derived from both central and peripheral sources, the plasma con-
centrations of HVA, the main dopamine metabolite, have been
repeatedly reported to significant mirror brain dopamine function
(Sumiyoshi et al., 2000; Nagy et al., 2007). It has also been hypothe-
sized that HVA concentration negatively correlated with childhood
neglect and abuse scores, indicating a possible role of environ-
mental factors interacting with gene variants in modulating brain
dopamine activity and individual vulnerability (Gerra et al., 2007b).
In a recent study (Oswald et al., 2007) examined by Positron
Emission Tomography imaging the effects of chronic stress and
impulsivity on mesolimbic dopamine release: high trait impul-
sivity was associated with blunted dopamine release, but with
low/moderate stress, dopamine release was greater in low impul-
sive individuals than in high ones, and with high stress, both groups
showed low dopamine release. This study suggests the important
effects of stress and impulsivity on mesolimbic dopamine transmis-
sion and highlights the fact that both factors need to be carefully
considered to fully understand the role of stress and impulsivity on
addiction susceptibility.
3.2. Serotonin
Serotonin represents an important neurotransmitter, involved
in the elaboration of adapted response of the central nervous sys-
tem to external media. It stabilizes information processing within
frontal brain structure, controlling behavioural and affective reac-
tions. Alterations in serotonergic system can contribute to deficits
in social attachment and regulation of mood and affect following
early stress events such as abuse or neglect. The exact mechanism
by which serotonin influences aggressive or impulsive behaviour
is not yet understood, although decreased serotonergic function is
thought to increase disruptive behaviour disorder associated with
a host of negative outcomes in adulthood such as substance abuse
and dependence (Spoont, 1992).
The research suggests that stress in the family and relationship
problems between the parents, resulting in the affective neglect
of the child, are involved in childhood-onset antisocial behaviour
(van Goozen and Fairchild, 2006). Given that a high proportion
of children with serious conduct problems have been abused and
neglected at an early age, the relationship between serotonin levels
and conduct or behavioural problems among children and adoles-
cents has been widely investigated in several studies. It has been
suggested that a deficit in serotonin availability and/or turnover is
mainly associated with impulsive forms of aggression: two stud-
ies report that the levels of the main metabolite of serotonin
(5-hydroxyindolacetic acid, 5-HIAA) in liquor of children were
inversely correlated with ratings of aggressive behaviour (Kruesi
et al., 1990, 1992), while Castellanós et al. (1994) found in their
study of 29 boys with attention-deficit/hyperactivity attention that
liquor 5-HIAA levels were positively correlated with measures of
aggression and impulsivity. Studies of aggressive children using
whole blood to measure peripheral serotonin have obtained mixed
results: some authors reported a negative correlation with aggres-
sion (Hanna et al., 1995); others found positive relationships (Unis
 L. Somaini et al. / Neuroscience and Biobehavioral Reviews 35 (2011) 1771–1778
et al., 1997) or no differences in comparison with controls (Hughes
et al., 1996; Cook et al., 1995; Rogeness et al., 1982). The inconsis-
tency across these studies may be attributed to the co morbidity
within samples of children with behavioural problems, being also
diagnosed with internalizing disorders such as anxiety and fear
(Cappadocia et al., 2009).
It should be noted that HPA and serotonin systems interact at
several levels. It appears that cortisol reactivity is impaired when
serotonin neurotransmission is disrupted and it is possible that
these interactions play a key role in the aetiology of antisocial
behaviour in children with early trauma events and also in the
potential substance abuse susceptibility.
3.3. HPA axis and stress system
The HPA axis represents a major part of the neuroendocrine
system that plays a crucial role in the stress reactions and reg-
ulates many body processes, throughout feedback interactions
between hippocampus, pituitary gland and adrenal glands cul-
minating in secretion of glucocorticoids (GCs). In adults the HPA
axis shows a circadian rhythmicity with a peak around the time
of waking and a trough during the quiescent time of the activity
cycle. Briefly, corticotrophin-releasing factor (CRF), released from
the paraventricular nucleus of the hypothalamus, stimulates the
release of ACTH from the anterior pituitary; ACTH, in turn, stim-
ulates the release of GCs (cortisol in primates) from the adrenal
cortex (Herman et al., 2003). GCs mobilize energy substrates dur-
ing stress and regulate activity of the HPA axis via negative feedback
at different levels. Emerging evidence suggests that HPA axis dys-
function, evidenced by hyper- or hypo-secretion of the cortisol, may
play a key role in the association between adverse childhood expe-
riences and psychopathology (Gunnar and Quevedo, 2007) as well
as substance abuse susceptibility (Gerra et al., 2010). However, the
direction of the association between early life stressors and corti-
sol dysfunction has been conflicted across several studies, probably
depending by limitations in human risk model.
On one hand, there is large evidence that some adverse child-
hood events cause long-term increases in GCs responses to stress
(Sanchez, 2006) as well as decreased genetic expression of cortisol
receptors in the hippocampus and increased genetic expression of
CRF in the hypothalamus, both of which may contribute to dysreg-
ulation of the HPA system (Ladd et al., 1996). It is reported that
reduced mother or father care was found in a positive relationship
between cortisol and ACTH levels and retrospective neglect scores
during childhood (Gerra et al., 2010); moreover abstinent heroin
or cocaine dependent patients showed significantly higher neglect
and depression scores and ACTH-cortisol plasma levels compared
to control subjects (Gerra et al., 2008, 2009). Pfeffer et al. (2007)
reported that children who were traumatized in consequence of
parent loss in the 9/11, 2001 New York City terrorist attack exhib-
ited significantly higher basal cortisol levels than to non-bereaved
children.
Conversely, some authors showed results in which an inverse
correlation was found between early adverse events and HPA activ-
ity. In particular, in one study, involving 76 university students
(age range = 18–22 years) with both negative and positive rela-
tionship in the family of origin and engaged in a challenging role
play task, those ones from negative families exhibited significant
lower salivary cortisol than controls (Luecken et al., 2009). More-
over, in another paper a meta-analysis was conducted on 147
children (age range = 3–16 years) in a 20-year study (1988–2009);
saliva aliquots were used to test HPA activity and results together
with monitoring of growth, co-morbidity and social factors did
not support the hypothesis that early traumatic stress causes per-
manent elevation in cortisol levels (Flinn, 2009). Some studies
on adults who experienced adverse events during childhood also
1775
show mixed results. For example increased cortisol responses have
been reported (Nicolson, 2004; Tyrka et al., 2008) in adults who
experienced early parental loss; whereas others found effects of
parental loss on cortisol only in interaction with other factors such
as substance abuse or concurrent psychological disorder (Breier
et al., 1988; Luecken and Appelhans, 2006). It is noteworthy that
studies in which saliva was used for the cortisol analysis showed
an inversely correlation between HPA activity and early stressors
(Flinn, 2009; Luecken and Appelhans, 2006; Luecken et al., 2009),
probably due to more problematic matrice (saliva vs. blood) used
to measure cortisol levels and challenges in the timing of corti-
sol assays. A recent research (Hagan et al., 2010) indicates that a
great number of post-bereavement negative events correlate sig-
nificantly with lower levels of cortisol 6 years later in a longitudinal
sample of parentally bereaved youth, and this association remained
significant after controlling recent externalizing symptoms. This
study makes a significant contribution to the literature by demon-
strating a prospective relation of exposure to negative life events
and cortisol activity several years later after an adverse childhood
event such as the loss of a parent, even if a limitation of this study
is the lack of a previous measurement of cortisol (prior to or imme-
diately after parental death).
In any case changes in the HPA system due to adverse childhood
experiences contribute to addiction vulnerability later in life and
the dysregulation of the stress system plays a key role in engaging
the transition from substance abuse to dependence and maintain-
ing dependence once it is initiated (Koob, 2010). Thus, the measure
of its activity has an important role in understanding the shift from
positive to negative reinforcement associated with the develop-
ment of motivational aspects of substance dependence.
4. Conclusions
Disturbance in brain transmission has been repeatedly reported
in association with a variety of behavioural disorders, psy-
chopathologies and substance use disorders. Psychological and
biological approaches offer distinct types of data of potentially
equal relevance for understanding of the phenomena (Miller and
Keller, 2000). From a biological point of view, a critical step in
exploring the implicated mechanisms is the identification of all the
potential gene products/polymorphism that could be involved. In
fact, genetic and environmental factors interact contributing to the
etiology of the disturbance. The involvement of some functional
polymorphism was assessed.
Higher frequency of the 5-HTT SS genotype seems to be asso-
ciated with an increased susceptibility to use illegal psychotropic
drugs among the adolescents indicating that the low activity S allele
may influence behavioural traits and substance abuse suscepti-
bility (Gerra et al., 2005a), probably provoking an impairment of
brain serotonin transmission (Blier et al., 1987; Aghajanian, 1978;
Coccaro et al., 1996).
At the same time, reduced maternal care perception (high
neglect scores) seems to represent a intermediate key factor of
the association between SS polymorphism and drug use, suggest-
ing a complex relationship between genetic factors and parental
behaviour, probably both concurring to drug use susceptibility. In
particular, data here presented favour the idea of a decisive role
played by individual perception of mother neglect in infancy and
childhood, whose positive impact on the risk of drug use was sig-
nificantly far higher than the corresponding effect of father neglect.
In agreement with our findings, other studies suggest mal-
treatment, poor mother–child relations and 5-HTTLPR genotype
as genetic and environmental predictors of early alcohol use
(Kaufman et al., 2007). Accordingly, childhood trauma was reported
to interact with low expressing 5-HTTLPR genotypes to increase the
1776 L. Somaini et al. / Neuroscience and Biobehavioral Reviews 35 (2011) 1771–1778
risk of suicidal behaviour among patients with substance depen-
dence (Roy et al., 2007) and among bulimic women, previously
abused carriers of the 5-HTTLPR S allele showed special propen-
sities towards novelty seeking, impulsivity and dissocial behaviour
(Steiger et al., 2008), all contributing to substance abuse suscepti-
bility.
The presented data also favour a relationship between basal
plasma levels of cortisol and ACTH, on the one hand, and retro-
spective measures of neglect during childhood on the other: the
higher the CECA-Q scores are, the higher the plasma levels of the
two HPA hormones are. Furthermore, such positive relationship
has been proved to be particularly effective and important when
associated with the S allele, both in homozygote and heterozygote
individuals.
The contribution of early adverse stress to alterations in
mesolimbic dopamine, serotonergic and HPA system activity and
its association with substance abuse vulnerability needs to be stud-
ied in depth. Clinical goals should include the development of new
assessment procedures and biomarkers analyses that will be use-
ful to identify subjects who are at particular risk of stress-related
relapse and substance vulnerability. Further studies appear to be
necessary to better investigate these complex interactions that
could support evidence-based interventions of selective-indicated
prevention of substance abuse and trajectory of children at risk.
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