Commentary: Improving the Effectiveness and Utility of the Helping to End Addiction Long-Term (HEAL) Prevention Cooperative: A Full Translational Framework.

The Helping to End Addiction Long-term (HEAL) Prevention Collaborative (HPC) is designed to expedite the development of programs aimed at preventing opioid misuse and opioid use disorder (OUD) in older adolescents and young adults (ages 16-30). Funded by the National Institutes of Health Office of the Director (ODP-NIH), the HPC includes ten outcome studies that focus on distinct interventions to determine their effectiveness and real-world applicability. Also included is a coordinating center at RTI International that supports the individual projects. This commentary highlights the scientific and practical significance of this cooperative and its promise for facilitating the production and implementation of successful interventions. Attributes such as novel program designs, advanced methodologies, addressing unique characteristics of diverse populations, and real-time analysis of data and costs make this cooperative highly innovative. We note, however, that papers in this Supplemental Issue did not specifically address the persistent need to obtain stronger effect sizes than those achieved to date. Existing data captured earlier in development (< 16 years of age) are uncovering interactive neurocognitive and social-contextual mechanisms underlying the phenomena we wish to prevent. HPC projects could be guided by this information to incorporate developmentally appropriate measures of mechanisms shown previously to be influential in targeted outcomes and determine how they are impacted by specific components of their interventions. This mechanistic information can provide a roadmap for constructing interventions that are more precision-based and, thus, more likely to yield greater benefits for a larger number of recipients. Furthermore, an understanding of underlying mechanism(s) promises to shed light on the sources of heterogeneity in outcomes for further intervention refinement. It is quite possible, if not probable, that meaningful measures of underlying processes will reveal subtypes-some with very high effect sizes and others that are much lower-directly enabling program refinements to more directly target mechanisms that portend and explain less favorable outcomes. Described herein is a full-spectrum translational approach which promises to significantly boost effect sizes, a key objective that should be reached prior to scaling.

Working memory and salivary brain-derived neurotrophic factor as developmental predictors of cocaine seeking in male and female rats.

Poor working memory is linked to future risk-taking behaviors. Lifelong risk of habitual drug use is highest in individuals who initiate use in early adolescence. We sought to determine in rats whether juvenile traits, specifically poor working memory and low salivary brain-derived neurotrophic factor (BDNF), are related to elevated cocaine taking and relapse in adolescence and adulthood. On postnatal day (P) 20, working memory was assessed using the novel object recognition task in male and female rats. Saliva was assayed at P20 for BDNF before cocaine self-administration on P28 [0.75 or 0.25 mg/kg/infusion for 30 days under a fixed-ratio (FR) 1 to FR5 schedule] and on P94 before relapse after 30-day abstinence in adulthood. A separate cohort of P28 male rats was assayed for object discrimination and BDNF in saliva and the medial prefrontal cortex and dorsolateral striatum. Novel object discrimination correlated positively with salivary BDNF on P20 and dorsolateral striatum levels, but negatively with medial prefrontal cortex BDNF in male rats. In female rats, P20 salivary BDNF negatively correlated with object discrimination. Salivary BDNF positively correlated across age in male rats. Male rats earned more cocaine (0.75 mg/kg) at FR5 and responded more at relapse than did female rats. These elevated relapse rates in male rats were significantly associated with P20 object discrimination and salivary BDNF. Relapse after 0.75 and 0.25 mg/kg in female rats correlated only with object discrimination. In conclusion, poor working memory and low salivary BDNF in juvenile male rats may represent biomarkers for later cocaine use. Further research is needed to identify biomarkers for risk in male rats.

Sex differences in the ontogeny of CRF receptors during adolescent development in the dorsal raphe nucleus and ventral tegmental area.

Interactions between corticotropin-releasing factor (CRF) and monoaminergic systems originating from the dorsal raphe nucleus (DR) and ventral tegmental area (VTA) have been implicated in the etiology and pathophysiology of several stress-related neuropsychiatric disorders such as depression and substance abuse. Sub-regions within the DR and VTA give rise to specific projections that have unique roles in limbic- and reward-related behaviors. Given that these disorders typically emerge during adolescence, it is surprising that few studies have examined the age-, sex-, and region-dependent expression of CRF receptors throughout multiple stages of adolescence in these stress-relevant circuits. To determine the ontogeny of CRF receptors during adolescent development, three regions of the DR (dorsal, caudal, and ventrolateral parts) and the posterior VTA were microdissected from Sprague-Dawley male and female rats on postnatal day (P) 25, P35, P42, P56, and P90. Tissue was processed and analyzed with qRT-PCR to measure CRF1 and CRF2 receptors. The serotonin and catecholamine enzymes in the DR and VTA, tryptophan hydroxylase 2 (TPH2) and tyrosine hydroxylase, respectively, were also analyzed for maturational differences. This study identified that CRF1 receptors are lower in males than females within the dorsal, ventrolateral region of the DR (DRVL), which is involved in anxiety-, stress-, and panic-related responses. Females had higher CRF2 receptors compared to males in the DRVL only. Levels of TPH2 mRNA in the DRVL were overproduced transiently in females before declining into adulthood. These fundamental studies suggest that sex differences in CRF receptors should be considered when examining stress-related neuropsychiatric disorders and their treatment.

The developmental inter-relationships between activity, novelty preferences, and delay discounting in male and female rats.

Increased locomotion, novelty-seeking, and impulsivity are risk factors associated with substance use. In this study, the inter-relationships between activity, novelty preferences, and delay discounting, a measure of impulsivity, were examined across three stages: juvenile/early adolescence (postnatal Day [P] 15, 19, and 42 for activity, novelty, and impulsivity, respectively), adolescent/late adolescent (P28, 32, 73), and adult (P90, 94, 137) in male and female rats. Our estimates of impulsive choice, where animals were trained to criterion, revealed an age × sex interaction where early adolescent females had the lowest levels of impulsivity. The relationships of activity and novelty to impulsivity significantly changed across age within each sex. Early adolescent males with high activity, but low novelty preferences, were more impulsive; however, low activity and high novelty preferences were related to high impulsivity in adult males. Female activity gradually increased across age, but did not show a strong relationship with impulsivity. Novelty preferences are moderately related to impulsivity into adulthood in females. These data show that males and females have different developmental trajectories for these behaviors. Males show greater sensation-seeking (e.g., activity) and risky behavior (e.g., novelty preferences) earlier in life, whereas these behaviors emerge during adolescence in females.

Exposure to early adversity: Points of cross-species translation that can lead to improved understanding of depression.

The relationship between developmental exposure to adversity and affective disorders is reviewed. Adversity discussed herein includes physical and sexual abuse, neglect, or loss of a caregiver in humans. While these stressors can occur at any point during development, the unique temporal relationship to specific depressive symptoms was the focus of discussion. Further influences of stress exposure during sensitive periods can vary by gender and duration of abuse as well. Data from animal studies are presented to provide greater translational and causal understanding of how sensitive periods, different types of psychosocial stressors, and sex interact to produce depressive-like behaviors. Findings from maternal separation, isolation rearing, chronic variable stress, and peer-peer rearing paradigms clarify interpretation about how various depressive behaviors are influenced by age of exposure. Depressive behaviors are broken down into the following categories: mood and affect, anhedonia, energy, working memory, sleep-wake, appetite changes, suicide, and general malaise. Cross-species evidence from humans, nonhuman primates, rats, and mice within each of these categories is discussed. In conclusion, sensitive periods for affective-related behaviors (anxiety, mood, and controllability) occur earlier in life, while other aspects of depression are associated with adversity later during adolescence.

Increasing CB2 Receptor Activity after Early Life Stress Prevents Depressive Behavior in Female Rats.

Early adversity, the loss of the inhibitory GABAergic interneuron parvalbumin, and elevated neuroinflammation are associated with depression. Individuals with a maltreatment history initiate medicinal cannabis use earlier in life than non-maltreated individuals, suggesting self-medication. Female rats underwent maternal separation (MS) between 2 and 20 days of age to model early adversity or served as colony controls. The prelimbic cortex and behavior were examined to determine whether MS alters the cannabinoid receptor 2 (CB2), which has anti-inflammatory properties. A reduction in the CB2-associated regulatory enzyme MARCH7 leading to increased NLRP3 was observed with Western immunoblots in MS females. Immunohistochemistry with stereology quantified numbers of parvalbumin-immunoreactive cells and CB2 at 25, 40, and 100 days of age, revealing that the CB2 receptor associated with PV neurons initially increases at P25 and subsequently decreases by P40 in MS animals, with no change in controls. Confocal and triple-label microscopy suggest colocalization of these CB2 receptors to microglia wrapped around the parvalbumin neuron. Depressive-like behavior in MS animals was elevated at P40 and reduced with the CB2 agonist HU-308 or a CB2-overexpressing lentivirus microinjected into the prelimbic cortex. These results suggest that increasing CB2 expression by P40 in the prelimbic cortex prevents depressive behavior in MS female rats.

Evidence for a neuroinflammatory mechanism in delayed effects of early life adversity in rats: relationship to cortical NMDA receptor expression.

Postnatal maternal separation in rats causes a reduction of GABAergic parvalbumin-containing interneurons in the prefrontal cortex that first occurs in adolescence. This parvalbumin loss can be prevented by pre-adolescent treatment with a non-steroidal anti-inflammatory drug that also protects against excitotoxicity. Therefore, the neuropsychiatric disorders associated with early life adversity and interneuron dysfunction may involve neuroinflammatory processes and/or aberrant glutamatergic activity. Here, we aimed to determine whether delayed parvalbumin loss after maternal separation was due to inflammatory activity, and whether central administration of the anti-inflammatory cytokine interleukin (IL)-10 could protect against such loss. We also investigated the effects of maternal separation and IL-10 treatment on cortical NMDA receptor expression. Male rat pups were isolated for 4h/day between postnatal days 2-20. IL-10 was administered intracerebroventricularly through an indwelling cannula between P30 and 38. Adolescent prefrontal cortices were analyzed using Western blotting and immunohistochemistry for parvalbumin and NMDA NR2A subunit expression. We demonstrate that central IL-10 administration during pre-adolescence protects maternally separated animals from parvalbumin loss in adolescence. Linear regression analyses revealed that increased circulating levels of the pro-inflammatory cytokines IL-1ß and IL-6 predicted lowered parvalbumin levels in maternally separated adolescents. Maternal separation also increases cortical expression of the NR2A NMDA receptor subunit in adolescence, which is prevented by IL-10 treatment. These data suggest that inflammatory damage to parvalbumin interneurons may occur via aberrant glutamatergic activity in the prefrontal cortex. Our findings provide a novel interactive mechanism between inflammation and neural dysfunction that helps explain deleterious effects of early life adversity on prefrontal cortex interneurons.

Depressive-like behavior in adolescents after maternal separation: sex differences, controllability, and GABA.

Exposure to adversity during development is an identified risk factor for depression later in life. In humans, early adversity accelerates the onset of depressive symptoms, which manifest during adolescence. Animal studies have used maternal separation as a model of early adversity to produce adult depressive-like behaviors, but have yet to examine these behaviors during adolescence. Moreover, the nature of depressive-like behaviors has not been well characterized in this model. Here, we used the triadic model of learned helplessness to understand controllability, helplessness, and motivational factors following maternal separation in male and female adolescent rats. We found sex-dependent changes in the effects of separation, with males demonstrating loss of controllability in an escapable shock condition, whereas females demonstrated motivational impairment in a no-shock condition. The effect, however, did not endure as adult females were no longer helpless. Reductions in parvalbumin, a GABAergic marker, in the prefrontal cortex of separated subjects relative to age-matched controls were evident and paralleled depressive-like behavior. Understanding the risk factors for depression, the nature of depressive-like behaviors, and their unique sex dependency may ultimately provide insight into improved treatments.

Neuroinflammation, Early-Life Adversity, and Brain Development.

ABSTRACT: The overarching objective is to review how early exposure to adversity interacts with inflammation to alter brain maturation. Both adversity and inflammation are significant risk factors for psychopathology. Literature relevant to the effects of adversity in children and adolescents on brain development is reviewed. These studies are supported by research in animals exposed to species-relevant stressors during development. While it is known that exposure to adversity at any age increases inflammation, the effects of inflammation are exacerbated at developmental stages when the immature brain is uniquely sensitive to experiences. Microglia play a vital role in this process, as they scavenge cellular debris and prune synapses to optimize performance. In essence, microglia modify the synapse to match environmental demands, which is necessary for someone with a history of adversity. Overall, by piecing together clinical and preclinical research areas, what emerges is a picture of how adversity uniquely sculpts the brain. Microglia interactions with the inhibitory neurotransmitter GABA (specifically, the subtype expressing parvalbumin) are discussed within contexts of development and adversity. A review of inflammation markers in individuals with a history of abuse is combined with preclinical studies to describe their effects on maturation. Inconsistencies within the literature are discussed, with a call for standardizing methodologies relating to the age of assessing adversity effects, measures to quantify stress and inflammation, and more brain-based measures of biochemistry. Preclinical studies pave the way for interventions using anti-inflammation-based agents (COX-2 inhibitors, CB2 agonists, meditation/yoga) by identifying where, when, and how the developmental trajectory goes awry.

Annual Research Review: New frontiers in developmental neuropharmacology: can long-term therapeutic effects of drugs be optimized through carefully timed early intervention?

Our aim is to present a working model that may serve as a valuable heuristic to predict enduring effects of drugs when administered during development. Our primary tenet is that a greater understanding of neurodevelopment can lead to improved treatment that intervenes early in the progression of a given disorder and prevents symptoms from manifesting. The immature brain undergoes significant changes during the transitions between childhood, adolescence, and adulthood. Such changes in innervation, neurotransmitter levels, and their respective signaling mechanisms have profound and observable changes on typical behavior, but also increase vulnerability to psychiatric disorders when the maturational process goes awry. Given the remarkable plasticity of the immature brain to adapt to its external milieu, preventive interventions may be possible. We intend for this review to initiate a discussion of how currently used psychotropic agents can influence brain development. Drug exposure during sensitive periods may have beneficial long-term effects, but harmful delayed consequences may be possible as well. Regardless of the outcome, this information needs to be used to improve or develop alternative approaches for the treatment of childhood disorders. With this framework in mind, we present what is known about the effects of stimulants, antidepressants, and antipsychotics on brain maturation (including animal studies that use more clinically-relevant dosing paradigms or relevant animal models). We endeavor to provocatively set the stage for altering treatment approaches for improving mental health in non-adult populations.

Novelty preferences and cocaine-associated cues influence regions associated with the salience network in juvenile female rats.

Preferences for novel environments (novelty-seeking) is a risk factor for addiction, with little known about its underlying circuitry. Exposure to drug cues facilitates addiction maintenance, leading us to hypothesize that exposure to a novel environment activates a shared neural circuitry. Stimulation of the D1 receptor in the prelimbic cortex increases responsivity to drug-associated environments. Here, we use D1 receptor overexpression in the prelimbic cortex to probe brain responses to novelty-preferences (in a free-choice paradigm) and cocaine-associated odors following place conditioning. These same cocaine-conditioned odors were used to study neural circuitry with Blood Oxygen Level Dependent (BOLD) activity. D1 overexpressing females had deactivated BOLD signals related to novelty-preferences within the insula cortex and amygdala and activation in the frontal cortex and dopamine cell bodies. BOLD responses to cocaine cues were also sensitive to D1. Control females demonstrated a place preference for cocaine environments with no significant BOLD response, while D1 overexpressing females demonstrated a place aversion and weak BOLD responses to cocaine-conditioned odor cues within the insula cortex. For comparison, we provide data from an earlier study with juvenile males overexpressing D1 that show a strong preference for cocaine and elevated BOLD responses. The results support the use of a pharmacological manipulation (e.g., D1 overexpression) to probe the neural circuitry downstream from the prelimbic cortex.

Stress, sensitive periods and maturational events in adolescent depression.

In this paper, we provide an overview of how the maturation of specific brain regions and stress exposure during windows of vulnerability initiate a series of events that render adolescents exceptionally susceptible to the development of depression. This stress-incubation/corticolimbic development cascade provides a means of understanding why depression emerges with such force and frequency in adolescence. The development of the prefrontal cortex, hippocampus, amygdala and ventral striatum is described from a translational perspective as they relate to stress exposure, onset, pathogenesis and gender differences in depression. Adolescent depression is a serious recurrent brain-based disorder. Understanding the genesis and neurobiological basis is important in the development of more effective intervention strategies to treat or prevent the disorder.

Pharmacologic neuroimaging of the ontogeny of dopamine receptor function.

Characterization of the ontogeny of the cerebral dopaminergic system is crucial for gaining a greater understanding of normal brain development and its alterations in response to drugs of abuse or conditions such as attention-deficit hyperactivity disorder. Pharmacological MRI (phMRI) was used to determine the response to dopamine transporter (DAT) blockers cocaine and methylphenidate (MPH), the dopamine releaser D-amphetamine (AMPH), the selective D1 agonist dihydrexidine, and the D2/D3 agonist quinpirole in young (<30 days old) and adult (>60 days old) rats. In adult rats, cocaine (0.5 mg/kg i.v.) or MPH (2 mg/kg) induced primarily positive cerebral blood volume (rCBV) changes in the dopaminergic circuitry, but negative rCBV changes in the young animals. Microdialysis measurements in the striatum showed that young rats have a smaller increase in extracellular dopamine in response to cocaine than adults. The young rats showed little rCBV response to the selective D1 agonist dihydrexidine in contrast to robust rCBV increases observed in the adults, whereas there was a similar negative rCBV response in the young and adult rats to the D2 agonist quinpirole. We also performed a meta-analysis of literature data on the development of D1 and D2 receptors and the DAT. These data suggest a predominance of D2-like over D1-like function between 20 and 30 days of age. These combined results suggested that the dopamine D1 receptor is functionally inhibited at young age.

Gene expression profiling of substantia nigra dopamine neurons: further insights into Parkinson's disease pathology.

Parkinson's disease is caused by a progressive loss of the midbrain dopamine (DA) neurons in the substantia nigra pars compacta. Although the main cause of Parkinson's disease remains unknown, there is increasing evidence that it is a complex disorder caused by a combination of genetic and environmental factors, which affect key signalling pathways in substantia nigra DA neurons. Insights into pathogenesis of Parkinson's disease stem from in vitro and in vivo models and from postmortem analyses. Recent technological developments have added a new dimension to this research by determining gene expression profiles using high throughput microarray assays. However, many of the studies reported to date were based on whole midbrain dissections, which included cells other than DA neurons. Here, we have used laser microdissection to isolate single DA neurons from the substantia nigra pars compacta of controls and subjects with idiopathic Parkinson's disease matched for age and postmortem interval followed by microarrays to analyse gene expression profiling. Our data confirm a dysregulation of several functional groups of genes involved in the Parkinson's disease pathogenesis. In particular, we found prominent down-regulation of members of the PARK gene family and dysregulation of multiple genes associated with programmed cell death and survival. In addition, genes for neurotransmitter and ion channel receptors were also deregulated, supporting the view that alterations in electrical activity might influence DA neuron function. Our data provide a 'molecular fingerprint identity' of late-stage Parkinson's disease DA neurons that will advance our understanding of the molecular pathology of this disease.

This is your teen brain on drugs: In search of biological factors unique to dependence toxicity in adolescence.

Response variability across the lifespan is an important consideration in toxicology and risk assessment, and the toxic effects of drugs and chemicals during adolescence need more research. This paper summarizes a workshop presented in March 2019, at the Society of Toxicology Annual Meeting in Baltimore, Maryland, that brought together experts in research on drug dependence and toxicity related to nicotine, cannabis, cocaine, and other illicit drugs during adolescence. The goal of the workshop was to address the following issues: (1) Do the effects of adolescent exposure differ from the same exposure in adults? (2) Are there unique biological markers of adolescent brain development? If so, what are they and how reliable are they? (3) Since multiple factors influence substance use disorder, can we disentangle risk factors for abuse and/or toxicity? What are the underlying biological susceptibilities that lead to dependence and neurotoxicity? What are the social, psychosocial and environmental factors that contribute to abuse susceptibilities? This paper reviews drug policy and national trends in adolescent substance use; the public health consequences of e-cigarettes; rat models of adolescent-onset nicotine self-administration and persisting effects of gestational nicotine; sex-dependent effects of delta-9-tetrahydrocannabinol on adolescent brain-behavior relationships; and translational approaches for identifying adolescent risk factors for transition to drug dependence. There is strong evidence that drug exposure prior to adulthood has longer lasting effects on behavior and the underlying neural circuitry. These effects, which are sex-dependent and influenced by stress, may be candidates as predictors of adolescent vulnerability. A major challenge to determining if adolescents have a unique susceptibility to dependence is whether and to what extent the human data allow distinction between the increased risk due to biological immaturity, an underlying biological susceptibility to dependence, or psychosocial and environmental factors for substance dependence. Factors important to consider for development of animal models include the timing and pattern of exposure as it relates to adolescence; age of assessment, and direct comparison with similar effects following exposures to adults to demonstrate that these effects are unique to adolescence. Here we provide a roadmap for further research into what makes adolescent brain development unique.

Transient D1 dopamine receptor expression on prefrontal cortex projection neurons: relationship to enhanced motivational salience of drug cues in adolescence.

Adolescence is a transitional period during development that is associated with a greater likelihood of addiction to drugs than any other age. In the prefrontal cortex (PFC), D(1) dopamine receptors mediate motivational salience attribution, which plays a role in addiction. Here, we investigated the relationship of age-related D(1) dopamine receptor expression in the PFC with the maturation of cocaine place conditioning. Confocal microscopy revealed that retrogradely traced cortical output neurons to the nucleus accumbens express higher levels of D(1) receptors during adolescence compared with younger and older ages. D(1) expression does not change on GABAergic interneurons across age. Adolescent differences in D(1) expression occur independently of cortical-accumbens connectivity, which proliferates through adulthood. Behaviorally, adolescent rats are more sensitive to cocaine place conditioning than younger and older rats. However, microinjections of the D(1) antagonist SCH23390 into the PFC blocked adolescent place preferences, whereas microinjections of D(1) agonists dose-dependently increased preferences for cocaine-associated environments previously not preferred by juveniles. These results suggest that the heightened expression of D(1) receptors on cortical-accumbens projections may help explain increased sensitivity to environmental events and addictive behaviors during adolescence, whereas the paucity of D(1)-expressing projections may reduce risk in juveniles.

Desperately driven and no brakes: developmental stress exposure and subsequent risk for substance abuse.

Adverse life events are associated with a wide range of psychopathology, including an increased risk for substance abuse. In this review, we focus on the inter-relationship between exposure to adversity and brain development, and relate this to enhanced windows of vulnerability. This review encompasses clinical and preclinical data, drawing evidence from epidemiological studies, morphometric and functional imaging studies, and molecular biology and genetics. The interaction of exposure during a sensitive period and maturational events produces a cascade that leads to the initiation of substance use at younger ages, and increases the likelihood of addiction by adolescence or early adulthood. A stress-incubation/corticolimbic dysfunction model is proposed based on the interplay of stress exposure, development stage, and neuromaturational events that may explain the seeking of specific classes of drugs later in life. Three main factors contribute to this age-based progression of increased drug use: (1) a sensitized stress response system; (2) sensitive periods of vulnerability; and (3) maturational processes during adolescence. Together, these factors may explain why exposure to early adversity increases risk to abuse substances during adolescence.

Juvenile methylphenidate exposure and factors that influence incentive processing.

Methylphenidate (MPH) is one of the few psychotropic agents approved for use in pediatric populations, underscoring the importance of elucidating any long-term consequences following exposure to this agent. Here, we examined the influence of several variables (i.e. age of assessment, age of exposure, sex, route of administration) on the effect of chronic low-dose MPH (2 mg/kg, twice daily) exposure on place conditioning to cocaine. Juvenile exposure to MPH, but not later exposure, resulted in aversions to cocaine-paired environments when assessed in young adult male rats, but not those entering adolescence. Juvenile MPH enhanced place preferences for cocaine-paired environments in female adolescent rats. The route of administration (i.p. injection or oral ingestion) did not produce enduring differential effects on behavior, and D-MPH was confirmed as the active enantiomer. These observations add to the growing literature on the enduring effects of MPH exposure, and highlight the need for more research in females.

Stress, sensitive periods, and substance abuse.

Research on the inter-relationship between drug abuse and social stress has primarily focused on the role of stress exposure during adulthood and more recently, adolescence. Adolescence is a time of heightened reward sensitivity, but it is also a time when earlier life experiences are expressed. Exposure to stress early in postnatal life is associated with an accelerated age of onset for drug use. Lifelong addiction is significantly greater if drug use is initiated during early adolescence. Understanding how developmental changes following stress exposure interact with sensitive periods to unfold over the course of maturation is integral to reducing their later impact on substance use. Arousal levels, gender/sex, inflammation, and the timing of stress exposure play a role in the vulnerability of these circuits. The current review focuses on how early postnatal stress impacts brain development during a sensitive period to increase externalizing and internalizing behaviors in adolescence that include social interactions (aggression; sexual activity), working memory impairment, and depression. How stress effects the developmental trajectories of brain circuits that are associated with addiction are discussed for both clinical and preclinical studies.