Developmental influences on stress response systems: Implications for psychopathology vulnerability in adolescence

The adolescent transition is marked by increases in stress exposure and significant maturation of neural and hormonal stress processing systems. Variability in the development of these systems during adolescence may influence the risk for stress-related psychopathology. This paper aims to review the developmental maturation of the HPA axis and related stress regulation systems, and demonstrate how interference in this adaptive developmental process may increase the risk for negative outcomes. We argue that the developmental maturation of the HPA axis aims to improve the regulatory capacity of the axis in order to more adaptively respond to these increases in stress reactivity. Additionally, we review evidence that sex differences in the development of the HPA and related axes may contribute to sex differences in the risk for stress-related psychopathology. Finally, we discuss how contextual factors, such as early trauma and obesity may alter the development of HPA axis during the adolescence transition and how alterations of normative development increase the risk for stress-related disorders.     

The neurocircuitry involved in oxytocin modulation of methamphetamine addiction

The role of oxytocin in attenuating the abuse of licit and illicit drugs, including the psychostimulant methamphetamine, has been examined with increased ferocity in recent years. This is largely driven by the potential application of oxytocin as a pharmacotherapy. However, the neural mechanisms by which oxytocin modulates methamphetamine abuse are not well understood. Recent research identified an important role for the accumbens core and subthalamic nucleus in this process, which likely involves an interaction with dopamine, glutamate, GABA, and vasopressin. In addition to providing an overview of methamphetamine, the endogenous oxytocin system, and the effects of exogenous oxytocin on drug abuse, we propose a neural circuit through which exogenous oxytocin modulates methamphetamine abuse, focusing on its interaction with neurochemicals within the accumbens core and subthalamic nucleus. A growing understanding of exogenous oxytocin effects at a neurochemical and neurobiological level will assist in its evaluation as a pharmacotherapy for drug addiction.     

Molecular genetics of addiction vulnerability

Classical genetic studies document strong complex genetic contributions to abuse of multiple addictive substances. to mnemonic processes that are likely to include those involved in substance dependence, and to the volumes of brain gray matter in regions that are likely to contribute to mnemonic/ cognitive and to addictive processes. The working idea that these three heritable phenotypes are likely to share some of the same complex genetic underpinnings is presented. This review contains association-based molecular genetic studies of addiction that largely derive from my laboratory and their fit with linkage data from other laboratories. These combined results now identify many of the loci and genes that contain allelic variants that are likely to provide the heritable components of human addiction vulnerability. These data are also likely to have broad implications for neurotherapeutics. Drugs with potential abuse liabilities are widely used for indications that include pain, anxiety, sleep, seizure, and attentional disorders. There is increasing nonmedical use of these prescribed substances. Increasing information about addiction vulnerability gene variants should help to improve management of risks of dependence in individuals who receive such therapeutics. In addition, since mnemonic components that correlate well with individual differences in brain regional volumes are likely to play major roles in addiction processes, many addiction vulnerability genes are also good candidates to contribute to individual differences in mnemonic processes. Recently elucidation of addiction-associated haplotypes for the “cell adhesion” Nr-CAM gene illustrate several of these points.     

"Computer addiction": a critical consideration

Problems related to intemperate Internet use are examined within the conceptual framework of addiction. It is argued that empirical support for the construct validity of computer addiction has yet to emerge, that defining the construct as a unique psychiatric disorder is therefore premature, and that, in most cases, excessive computer use may be symptomatic of other, more primary disorders. Greater caution and rigor are urged in investigating and treating problems related to intemperate computer use.     

The neural basis of addiction: a pathology of motivation and choice

OBJECTIVE: A primary behavioral pathology in drug addiction is the overpowering motivational strength and decreased ability to control the desire to obtain drugs. In this review the authors explore how advances in neurobiology are approaching an understanding of the cellular and circuitry underpinnings of addiction, and they describe the novel pharmacotherapeutic targets emerging from this understanding. METHOD: Findings from neuroimaging of addicts are integrated with cellular studies in animal models of drug seeking. RESULTS: While dopamine is critical for acute reward and initiation of addiction, end-stage addiction results primarily from cellular adaptations in anterior cingulate and orbitofrontal glutamatergic projections to the nucleus accumbens. Pathophysiological plasticity in excitatory transmission reduces the capacity of the prefrontal cortex to initiate behaviors in response to biological rewards and to provide executive control over drug seeking. Simultaneously, the prefrontal cortex is hyperresponsive to stimuli predicting drug availability, resulting in supraphysiological glutamatergic drive in the nucleus accumbens, where excitatory synapses have a reduced capacity to regulate neurotransmission. CONCLUSIONS: Cellular adaptations in prefrontal glutamatergic innervation of the accumbens promote the compulsive character of drug seeking in addicts by decreasing the value of natural rewards, diminishing cognitive control (choice), and enhancing glutamatergic drive in response to drug-associated stimuli.     

The developmental psychopathology of motivation in adolescence

Adolescence is a key period for the emergence of psychopathology, with many psychiatric disorders having their modal age-of-onset during this period. Relative to other periods of the lifespan, susceptibility to a number of psychiatric disorders is greatest during adolescence, particularly in females. In addition, disorders which emerge during adolescence appear to be more enduring and serious than those with a later onset. Although these psychiatric conditions may appear different from each other in terms of their associated behavioral signs or symptoms, this review will argue that they involve common alterations in motivational processes or disturbances in reward processing, although the direction of such changes (hypersensitivity vs. hyposensitivity to reward) and the stage of processing affected (reward anticipation vs. receipt) may differ across broader groupings of disorder. Recent behavioral, neuropsychological and neuroimaging research on reward processing in children, adolescents, and adults with these conditions will be described and evaluated. In addition, this article will consider what these studies tell us about their etiology and highlight gaps in our knowledge base. The review will also attempt to explain why adolescence is a period of elevated risk for the development of psychopathology, by discussing normative changes in reward processing in humans and animals.     

Anxiety disorders of childhood and adolescence: a critical review

The 1980s were a decade of advancement in the knowledge of anxiety disorders in children and adolescents; this sets the stage for research achievements in the 1990s. This review examines the anxiety disorders of childhood and adolescence (separation anxiety disorder, overanxious disorder, and avoidant disorder), including prevalence rates, demographic profiles, comparisons of clinical presentations in different developmental age groups, and comorbidity patterns. Fears and simple phobias, obsessive-compulsive disorder, post-traumatic stress disorder, and panic disorder in children and adolescents are also evaluated. The controversy of whether panic attacks occur in prepubertal children is addressed. A brief review of behavioral and pharmacological treatment studies is included. Future directions for research are suggested.     

Parental rearing and individual vulnerability to drug addiction: a controlled study in a Swedish sample

In a convenience sample of 81 healthy subjects vs. a group of 81 heroin addicts from the Methadone program in Stockholm, Sweden, the hypothesis of a possible link between experiences of dysfunctional parental rearing and the subsequent development of dysfunctional assumptions concerning self and others was tested. The subjects (n=162) completed the EMBU to report perceptions of parental rearing behaviour, two measures of dysfunctional assumptions and dysfunctional working models, the Dysfunctional Attitude Scale (DAS) and the DWM-S, and the Screening Drug Career Questionnaire (SDCQ) for assessing different aspects of the drug career in the sample of addicts. Four predictions were made: 1) parental emotional warmth should be negatively correlated with DAS and DWM-S scores; 2) experiences of dysfunctional parental rearing activities should be correlated with high scores on the DAS and the DWM-S; 3) there should be significant differences between the group of addicts and the control group on the EMBU first-order factors Rejection, Emotional warmth, Overprotection, and on the EMBU midparent subscale and finally 4) the results should support the hypothesis of an overprotecting mother and a rejecting father. The four predictions were supported by the results. The inter-group differences in quality of rearing shown in this study support the assumption of the impact of parental rearing on the development of dysfunctional working models of self and others. Accordingly, the presented data confirm that a parental rearing behaviour perceived both as Rejecting and Overprotective represents a link between dysfunctional parenting and the development of maladaptive psychosocial behaviour like drug addiction.     

Developmental psychopathology in adolescence: findings from a Swiss study--the NAPE Lecture 2005

Objective: Presentations of selective findings coming from the Zurich Adolescent Psychology and Psychopathology Study with two major aims: i) the study of the prevalence, course, and correlates of mental disorders in adolescence, and ii) the study of the determinants and processes of mental disorders in adolescence. Method: A representative sample of n = 1964 children and adolescents was studied in the canton of Zurich in 1994. Additional waves of data collection took place in 1997 and 2000/2001. Mean ages at these three assessments were 13, 16, and 20 years. Each wave contained a two‐stage procedure of assessment with screening by questionnaires and consecutive interviewing. The main constructs used were general and specific measures of psychopathology, life events, coping styles, self‐related cognitions, and quality of the social network. Results: Prevalence rates of any mental disorder in school‐age at the time of assessment was 22.5% fitting into a transcultural range of 18–26% based on DSM‐III‐R criteria. Furthermore, the derivation and validation of a four‐group adolescent drinker typology was demonstrated. Additionally, the prevalence and continuity of functional‐somatic symptoms from adolescence to young adulthood was shown. Another piece of the research tested for the identification of risk, compensatory, vulnerability, and protective factors influencing behaviour problems and found remarkably different frequencies across the four types of moderating factors. Conclusion: The presented findings provide further understanding of the developmental psychology and psychopathology of adolescence and the service, intervention, and prevention needs of this age‐group.     

A scale-free systems theory of motivation and addiction

Scale-free organizations, characterized by uneven distributions of linkages between nodal elements, describe the structure and function of many life-based complex systems developing under evolutionary pressures. We explore motivated behavior as a scale-free map toward a comprehensive translational theory of addiction. Motivational and behavioral repertoires are reframed as link and nodal element sets, respectively, comprising a scale-free structure. These sets are generated by semi-independent information-processing streams within cortical-striatal circuits that cooperatively provide decision-making and sequential processing functions necessary for traversing maps of motivational links connecting behavioral nodes. Dopamine modulation of cortical-striatal plasticity serves a central-hierarchical mechanism for survival-adaptive sculpting and development of motivational-behavioral repertoires by guiding a scale-free design. Drug-induced dopamine activity promotes drug taking as a highly connected behavioral hub at the expense of natural-adaptive motivational links and behavioral nodes. Conceptualizing addiction as pathological alteration of scale-free motivational-behavioral repertoires unifies neurobiological, neurocomputational and behavioral research while addressing addiction vulnerability in adolescence and psychiatric illness. This model may inform integrative research in defining more effective prevention and treatment strategies for addiction.     

The role of interoception in addiction: A critical review

Interoception refers to a collection of processes by which the state of the body is transmitted back to the brain, giving rise to awareness of the internal milieu, and motivating behavioural responses to homeostatically regulate internal state. Recent work has begun to explore the relevance of this construct to drug addiction: drugs of abuse and drug-related stimuli induce pronounced peripheral changes, and damage to a brain region known to support interoception (the insula) disrupts nicotine dependence. This article critically reviews existing accounts of addiction that suggest impaired interoception contributes to drug abuse. Conceptually, we argue that existing addiction interoception models could be usefully extended by considering (i) the multiple components of the bodily feedback system (signal, perception, and appraisal) and (ii) how individual differences in these three components impact on cognitive-affective processing in addiction. Empirically, whilst no studies have examined direct behavioural measures of interoception in addicted populations, several indirect lines of experimental work that pertain to this altered interoception hypothesis are presented. Clinical implications are discussed.     

Parental rearing and individual vulnerability to drug addiction: A controlled study in a Swedish sample

In a convenience sample of 81 healthy subjects vs. a group of 81 heroin addicts from the Methadone program in Stockholm, Sweden, the hypothesis of a possible link between experiences of dysfunctional parental rearing and the subsequent development of dysfunctional assumptions concerning self and others was tested. The subjects (n=162) completed the EMBU to report perceptions of parental rearing behaviour, two measures of dysfunctional assumptions and dysfunctional working models, the Dysfunctional Attitude Scale (DAS) and the DWM-S, and the Screening Drug Career Questionnaire (SDCQ) for assessing different aspects of the drug career in the sample of addicts. Four predictions were made: 1) parental emotional warmth should be negatively correlated with DAS and DWM-S scores; 2) experiences of dysfunctional parental rearing activities should be correlated with high scores on the DAS and the DWM-S; 3) there should be significant differences between the group of addicts and the control group on the EMBU first-order factors Rejection, Emotional warmth, Overprotection, and on the EMBU midparent subscale and finally 4) the results should support the hypothesis of an overprotecting mother and a rejecting father. The four predictions were supported by the results. The inter-group differences in quality of rearing shown in this study support the assumption of the impact of parental rearing on the development of dysfunctional working models of self and others. Accordingly, the presented data confirm that a parental rearing behaviour perceived both as Rejecting and Overprotective represents a link between dysfunctional parenting and the development of maladaptive psychosocial behaviour like drug addiction.     

Rat pup social motivation: a critical component of early psychological development

Examining the role of the offspring in early social dynamics is especially difficult. Human developmental psychology has found infant behavior to be a vital part of the early environmental setting. In the rodent model, the different ways that a rodent neonate or pup can influence social dynamics are not well known. Typically, litters of neonates or pups offer complex social interactions dominated by behavior seemingly initiated and maintained by the primary caregiver (e.g., the dam). Despite this strong role for the caregiver, the young most likely influence the litter dynamics in many powerful ways including communication signals, discrimination abilities and early approach behavior. Nelson and Panksepp (1996) developed a preference task to examine early rodent pup social motivation. We have used the same task to examine how variations in maternal care or different environmental perturbations could alter the rat pup preferences for social-related stimuli. Rat pups receiving low levels of maternal licking and grooming were impaired in maternal odor cue learning and emitted lower levels of 22 kHz ultrasounds compared to pups from the high licking and grooming cohort. Prenatal stress or early exposure to a toxicant (polychlorinated biphenyl) altered early social preferences in the rat pup in different ways indicating that diverse strategies are expressed and specific to the type of perturbation exposure. A greater focus on the offspring motivation following early ‘stressors’ will allow for more complete understanding of the dynamics in behavior during early social development.     

Loss of environmental enrichment increases vulnerability to cocaine addiction

Life experiences, especially during critical periods of maturation, such as adolescence, can dramatically affect vulnerability to diseases at adulthood. Early exposure to positive environmental conditions such as environmental enrichment (EE) has been shown to reduce the occurrence and the intensity of neurological and psychiatric disorders including drug addiction. However, whether or not exposure to EE during early stages of life would protect from addiction when, at adulthood, individuals may find themselves in non-enriched conditions has not been investigated. Here we show that switching mice from EE to non-enriched standard environments not only results in the loss of the preventive effects of EE but also increases the rewarding effects of cocaine. This enhanced vulnerability is associated with emotional distress and with increased levels in the mRNA levels of corticotropin releasing factor (CRF) in the bed nucleus of the stria terminalis (BNST), as well as with increases in CREB phosphorylation in the BNST and in the shell of the nucleus accumbens. The increased sensitivity to the rewarding effects of cocaine is completely blocked by the CRF antagonist antalarmin, confirming a major role of the CRF system in the negative consequences of this environmental switch. These results indicate that positive life conditions during early stages of life, if they are not maintained at adulthood, may have negative emotional consequences and increase the risks to develop drug addiction.     

Low startle magnitude may be a behavioral marker of vulnerability to cocaine addiction

Cocaine addicted men have low startle magnitude persisting during prolonged abstinence. Low startle rats show greater cocaine self‐administration than high startle rats. Low startle may be a marker of a vulnerability to heightened cocaine‐related behaviors in rats and similarly may be a marker of vulnerability to cocaine addiction in humans.     

Developmental trajectories during adolescence in males and females: a cross-species understanding of underlying brain changes

Adolescence is a transitional period between childhood and adulthood that encompasses vast changes within brain systems that parallel some, but not all, behavioral changes. Elevations in emotional reactivity and reward processing follow an inverted U shape in terms of onset and remission, with the peak occurring during adolescence. However, cognitive processing follows a more linear course of development. This review will focus on changes within key structures and will highlight the relationships between brain changes and behavior, with evidence spanning from functional magnetic resonance imaging (fMRI) in humans to molecular studies of receptor and signaling factors in animals. Adolescent changes in neuronal substrates will be used to understand how typical and atypical behaviors arise during adolescence. We draw upon clinical and preclinical studies to provide a neural framework for defining adolescence and its role in the transition to adulthood.