Adverse childhood experiences (ACEs), genetic polymorphisms and neurochemical correlates in experimentation with psychotropic drugs among adolescents

Adverse childhood experiences (ACEs), genetic polymorphisms and neurochemical correlates in experimentation with psychotropic drugs among adolescents

Neuroscience and Biobehavioral Reviews 35 (2011) 1771–1778 Contents lists available at ScienceDirect Neuroscience and Biobehavioral Reviews journal ...

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Neuroscience and Biobehavioral Reviews 35 (2011) 1771–1778

Contents lists available at ScienceDirect

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 Dipartimento di Genetica, Biologia dei Microrganismi, Antropologia, Evoluzione, University of Parma, Parma, Italy 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 b c

a r t i c l e

i n f o

Article history: Received 13 May 2010 Received in revised form 7 October 2010 Accepted 9 November 2010 Keywords: Adverse childhood experiences (ACEs) Adolescent Substance abuse Susceptibility

a b s t r a c t Epidemiological and clinical data show frequent associations between adverse childhood experiences (ACEs) and substance abuse susceptibility particularly in adolescents. A large body of evidences suggests that the possible dysregulation of neuroendocrine responses as well as neurotransmitters function induced by childhood traumatic experiences and emotional neglect could constitute one of the essential biological changes implementing substance abuse vulnerability. Moreover, genotype variables and its environment interactions have been associated with an increased risk for early onset substance abuse. In this paper we present several data that support the hypothesis of the involvement of hypothalamus–pituitary–adrenal (HPA) axis in mediating the combined effect of early adverse experiences 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. 2.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gene variants and substance abuse susceptibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Serotonin transporters gene polymorphism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Dopamine transporter gene polymorphism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Neurochemical correlates in abuse susceptibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Dopamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Serotonin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. HPA axis and stress system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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: [email protected] (L. Somaini). 0149-7634/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.neubiorev.2010.11.008

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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 disease 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 vulnerability 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 violence 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 developmentally 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 evidenced. Acute and chronic stress, related to ACEs may induce a variety of neurobiological events that can alter the brain development 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 substance 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 adrenorticotropic 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 neurotransmission, affecting in particular brain catecolaminergic system and possibly concurring to the development of behavioural disorders. 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 neurobiological derangement as a consequence of chronic exposure to stress during childhood, involving both different neurotransmitters function 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 separation, indicating that the affective deprivation during childhood may have lasting effects on HPA axis, even in the absence of concomitant psychopathology (Nicolson, 2004). In line with this evidence, different studies indicate that the alteration of HPA axis function 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 maternal 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 transmission during adulthood. In particular, retrospective evaluation on abstinent cocaine-abusing adults showed that ACEs scores, and particularly 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 associated 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

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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 polymorphism 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 personality 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 frequency of the S allele and the SS genotype may be higher in the adolescents who were available to experiment psychotropic illegal 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 underachievements. 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 personality 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) aggressiveness 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 proportion of the SS genotype was significantly more consistent in illegal drugs experimenters sample, in comparison with abstinent 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 sample. Experimenters scored significantly higher on BDHI subscale and on NS subscale at TPQ in comparison with abstinent adolescents independently from genotype subgroups. Our data suggest that a decreased expression of the gene encoding 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 susceptibility 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 dependence, 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 promoter 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

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subjects with more consistent aggressiveness and impulsiveness was also demonstrated (Gerra et al., 2004). The SS genotype frequency was significantly higher among heroin dependent individuals compared with control subjects. The SS genotype frequency was significantly higher among violent heroin dependent individuals compared with addicted individuals without aggressive behaviour. BDHI mean total scores and suspiciousness and negativism subscales scores were significantly higher in SS individuals, in comparison with LL subjects, among heroin addicts. No association was found between SS genotype and suicide history. Parents care perception, aggressive personality traits and genotype 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 attachment 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 yielding a significant 12% and 10% decrease of the risk, respectively, for paternal and maternal care, for each unit increase in PBI. Interestingly, 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 involvement in mediating the effects of early adverse experiences and gene variants affecting serotonin function on substance abuse vulnerability 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 susceptibility to experiment with illicit drugs (Gerra et al., 2010). A higher frequency of the 5-HTT SS genotype confirms the association 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, suggesting 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 individuals. 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-deficithyperactivity disorder (Barr et al., 2001; Kirley et al., 2002),

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oppositional defiant and conduct disorder (Comings et al., 1996), that were widely reported as antecedents of substance use disorders (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). Moreover, DAT gene variants appeared to implement vulnerability to alcoholism (Ueno et al., 1999), to the severity of alcohol withdrawal 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 diagnoses and psychometric measures of aggressiveness. Our findings suggested that the 9-repeat allele of the DAT polymorphism conferred increased susceptibility to antisocial-violent behaviour and aggressiveness, rather than drug dependence per se in heroindependent males. Recently, dopamine receptor (D2) TaqI A polymorphisms have been also associated with specific patterns of NS temperamental 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 possibility 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. dopaminergic 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 longterm changes in multiple brain circuits and systems (Bremner, 2003; Anda et al., 2006) and a persistent sensitization of central nervous 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 maltreatment and accumulated adversity are related to alterations on the corticostriatal-limbic motivational, learning, and adaptation systems that also include mesolimbic dopamine. Central catecholamines, particularly noradrenaline and dopamine, are involved in modulating brain motivational pathways (including the ventral tegmental area, nucleus accumbens and the medial prefrontal regions) that are crucial in exerting cognitive and behavioural control (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 maladaptive 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 adaptation. 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 significantly affect dopaminergic function (Pacak et al., 2002). Although derived from both central and peripheral sources, the plasma concentrations 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 hypothesized that HVA concentration negatively correlated with childhood neglect and abuse scores, indicating a possible role of environmental 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 impulsivity was associated with blunted dopamine release, but with low/moderate stress, dopamine release was greater in low impulsive 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 transmission 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 system to external media. It stabilizes information processing within frontal brain structure, controlling behavioural and affective reactions. 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 adolescents 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 studies 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 aggression (Hanna et al., 1995); others found positive relationships (Unis

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et al., 1997) or no differences in comparison with controls (Hughes et al., 1996; Cook et al., 1995; Rogeness et al., 1982). The inconsistency 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 regulates many body processes, throughout feedback interactions between hippocampus, pituitary gland and adrenal glands culminating 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, stimulates the release of GCs (cortisol in primates) from the adrenal cortex (Herman et al., 2003). GCs mobilize energy substrates during stress and regulate activity of the HPA axis via negative feedback at different levels. Emerging evidence suggests that HPA axis dysfunction, evidenced by hyper- or hypo-secretion of the cortisol, may play a key role in the association between adverse childhood experiences 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 cortisol 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 childhood 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 dysregulation 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 exhibited 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 activity. In particular, in one study, involving 76 university students (age range = 18–22 years) with both negative and positive relationship 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). Moreover, 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 permanent elevation in cortisol levels (Flinn, 2009). Some studies on adults who experienced adverse events during childhood also

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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 cortisol assays. A recent research (Hagan et al., 2010) indicates that a great number of post-bereavement negative events correlate significantly 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 demonstrating 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 immediately 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 maintaining 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 development of motivational aspects of substance dependence.

4. Conclusions Disturbance in brain transmission has been repeatedly reported in association with a variety of behavioural disorders, psychopathologies 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 associated 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 susceptibility (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, suggesting 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 significantly far higher than the corresponding effect of father neglect. In agreement with our findings, other studies suggest maltreatment, 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

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risk of suicidal behaviour among patients with substance dependence (Roy et al., 2007) and among bulimic women, previously abused carriers of the 5-HTTLPR S allele showed special propensities towards novelty seeking, impulsivity and dissocial behaviour (Steiger et al., 2008), all contributing to substance abuse susceptibility. The presented data also favour a relationship between basal plasma levels of cortisol and ACTH, on the one hand, and retrospective 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 studied in depth. Clinical goals should include the development of new assessment procedures and biomarkers analyses that will be useful 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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