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Published in final edited form as: Mol Cell Neurosci. 2023 Feb 24;125:103825. doi: 10.1016/j.mcn.2023.103825

Early life adversity: Epigenetic regulation underlying drug addiction susceptibility

Julia J Winter 1, Kiara L Rodríguez-Acevedo 1, Mia Dittrich 1, Elizabeth A Heller 1
PMCID: PMC10247461  NIHMSID: NIHMS1880387  PMID: 36842544

Abstract

Drug addiction is a leading cause of disability worldwide, with more than 70,000 Americans dying from drug overdose in 2019 alone. While only a small percentage of chronic drug users escalate to drug addiction, little is understood on the precise mechanisms of this susceptibility. Early life adversity is causally relevant to adult psychiatric disease and may contribute to the risk of addiction. Here we review recent pre-clinical evidence showing that early life exposure to stress and/or drugs regulates changes in behavior, gene expression, and the epigenome that persist to adulthood. We summarize the major findings and gaps in the preclinical literature, highlighting studies that demonstrate the often profound differences between female and male subjects.

Introduction

The 2019 United States National Survey on Drug Use and Health reported that 20.8% of people aged 12 or older used an illicit drug in the past year, while only 3.0% of the respondents had an illicit drug use disorder (Substance Abuse and Mental Health Services Administration, 2020). Drug addiction can therefore be considered a disease of individual susceptibility, yet individual differences that contribute to the development of addiction remain elusive (Maldonado et al., 2021; Reed & Kreek, 2021). A wealth of research suggests that early life adversity increases susceptibility to adult psychiatric disorders, including addiction, depression and post-traumatic stress disorder in humans and animal models (Bagot et al., 2014; Birn et al., 2017; Hanson et al., 2021a; Levis et al., 2021; Novick et al., 2018; Peña et al., 2019; Silberman et al., 2016; Targum & Nemeroff, 2019). In addition to early life, adolescence is a critical period for vulnerability to addiction in adulthood (Blanco et al., 2018; Hamidullah et al., 2020; Salmanzadeh et al., 2020; Spear, 2016).

Epigenome remodeling regulates gene expression in response to environmental exposures across the lifespan and likely contributes to the relative risk of addiction in adulthood in humans (Szutorisz & Hurd, 2022). DNA modifications have recently been implicated in addiction susceptibility (Kaplan et al., 2022), but the contribution of other epigenetic mechanisms to susceptibility is yet to be uncovered. Novel approaches to study the neuronal epigenome include interrogation of three-dimensional chromatin architecture and epigenetic editing of precise genomic loci (Policarpi et al., 2021). When applied to preclinical studies of addiction, these methods reveal the interplay between environmental exposures, epigenetic modulation, neuronal function, and behavior (Anderson et al., 2019; Browne et al., 2020; Nestler & Lüscher, 2019; Shu et al., 2018; Torres-Berrío et al., 2019). We review the last five years of preclinical research that supports a causal role of early life adversity in increased susceptibility to addiction, with a focus on epigenetic regulation of gene expression in animal models.

Biological sex is a factor in the development of human addiction and in the effects of early life adversity (Becker & Chartoff, 2018; National Institute on Drug Abuse, 2020). Women report more adverse early life experiences (Petruccelli et al., 2019; Stein et al., 2017), are more vulnerable to the impacts of early life stress, and are more likely to develop severe stress disorders in adulthood compared to men. Men are more likely to initiate use of illicit substances (Levis et al., 2021) and more likely to engage in injection drug use than women (Stein et al., 2017). Although there are few preclinical models stratified by sex, recent studies find that male rodents initiate substance intake earlier than females (Castro-Zavala et al., 2020; Swalve et al., 2016), yet female rodents are more vulnerable to early life stress and exhibit more severe stress-related behaviors in adulthood than males (Goodwill et al., 2019). We recommend several excellent manuscripts for comprehensive reviews of sex differences in stress (Bangasser & Wicks, 2017) and addiction (Becker, 2016; McHugh et al., 2018; Quigley et al., 2021).

Sex-specific underpinnings of addiction likely involve epigenetic regulation of baseline behavior and reward psychopathology (Becker, 2016). Variability in sex hormones across both male and female individuals, as well as developmental and cyclical fluctuations in female sex hormones, dynamically regulate the epigenome, gene expression and chromatin organization (Becker & Tollkuhn, 2018; Jaric et al., 2019a; Kundakovic & Rocks, 2022). Because the preclinical research has historically excluded female subjects, the molecular mechanisms of sexually dimorphic reward pathophysiology remain unknown. This review highlights the inclusion of male and female data within recent studies of epigenetic regulation of early-life adversity and drug addiction susceptibility (Figure 1).

Figure 1:

Figure 1:

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Early life adversity is causally relevant to adult psychiatric disease and may contribute to the risk for addiction. Early life exposure to stress and/or drugs regulates changes in behavior, gene expression and the epigenome that persist to adulthood. The precise mechanisms of susceptibility to elevated drug-reward behavior in adulthood remains partially understood and there are still gaps in the preclinical literature, addressing the often profound differences between female and male subjects. Created with BioRender.com.

Early life stress regulates adult drug-reward behavior

Early life stress is a type of early life adversity associated with changes in behavior (Eck & Bangasser, 2020; Peña et al., 2019; Smith & Pollak, 2020), gene expression (Peña et al., 2019; Usui et al., 2021), and the epigenome (Lewis & Olive, 2014; Peter et al., 2016). In humans, early life stress in the form of childhood maltreatment, parental separation, and social poverty also produces changes in brain structure and activity that could lead to mental deficits (Dufford et al., 2020; McEwen et al., 2017; Moreno-López et al., 2020; Sheridan & McLaughlin, 2022). Adverse childhood experiences further contribute to deficits in reward processing and slower reward learning (Hanson et al., 2021).

Early life stress is modeled in rodents using variations of maternal separation that cause activation as well as attenuation of the hypothalamic-pituitary-adrenal axis (Smith & Pollak, 2020; Tschetter et al., 2022). The neurobiological effects of early life stress on reward exposure and motivation are due, in part, to changes in expression of corticotropin releasing factor (CRF) and glucocorticoid receptors (GRs) in the hypothalamic-pituitary-adrenal axis and brain reward areas (for review see Novick et al., 2018). Early life stress paradigms vary by type and duration, which differentially regulate epigenetic, transcriptional, and behavioral outcomes (Levis et al., 2021). Variations to the maternal separation paradigm include the age of pups at time of separation (typically postnatal day 1 – 15), the duration of the separation, and variations in the intensity of investigator handling. Fifteen minutes of maternal separation is considered mildly stressful whereas 180 – 360 minutes is considered severe (for review see Schmidt et al., 2011; Tschetter et al., 2022). Early life stress is also modeled using the limited nesting and bedding paradigm, in which dams have limited access to or availability of nesting and bedding materials (Hanson et al., 2021; Ordoñes Sanchez et al., 2021; Walker et al., 2017).

Rodents exposed to maternal separation exhibit sex-specific behavioral changes in adulthood and adolescence, including addiction-related behavior. Female neonatal rats exposed to maternal separation show behavioral differences in adulthood compared to standard housed rats, such as enhanced novelty seeking and risk taking, increased cocaine-induced locomotion (Tschetter et al., 2022), and increased depressive-like behavior after cocaine re-exposure during abstinence (Bis-Humbert & García-Fuster, 2021; García-Cabrerizo & García-Fuster, 2019). These behaviors may be downstream of sex-specific, maternal separation-induced changes in expression of Crf family and serotonin 1A receptor (5-HT1A) genes in reward- and stress-related brain regions, including the nucleus accumbens (NAc), ventral tegmental area (VTA), bed nucleus of the stria terminalis (BNST), and the paraventricular nucleus (PVN) of the hypothalamus (Tschetter et al., 2022). Male neonatal rats exposed to limited nesting and bedding exhibit decreased morphine self-administration in adulthood, compared to standard housed male rats and limited nesting and bedding-female rats (Ordoñes Sanchez et al., 2021). Limited nesting and bedding also leads to sex-specific gene expression changes in the NAc (Ordoñes Sanchez et al., 2021). The combination of maternal separation and early weaning increases cocaine self-administration and expression of NAc AMPA glutamate receptor subunit A1 (GluA1), cAMP response element-binding protein (CREB), and phospho-CREB in adult male mice only, while phospho-CREB increases only in adult mice female VTA (Castro-Zavala et al., 2020).

Early life stress regulates adult gene expression

Maternal separation regulation of adult gene expression may be due to epigenetic changes. For example, DNA methylation of nuclear receptor subfamily 3 group C member 1 (Nr3c1), arginine vasopressin (Avp), and nuclear receptor subfamily 4 group A member 1 (Nr4a1) responds to maternal separation in a strain- and sex-specific manner (Kember et al., 2012). Finally, maternal separation causes epigenetic changes in early life, including increased histone 3 Lysine 9 methylation (H3K9me) in male NAc and increased histone 3 Lysine 79 dimethylation (H3K79me2) in both sexes (Kronman et al., 2021). Such epigenetic changes acquired during early life stress may persist in regulating gene expression in response to subsequent drug exposure later in life.

Sensitivity to early life adversity extends beyond the postnatal period into adolescence (Bryant et al., 2020). Prolonged adolescent social isolation increases adult cocaine self-administration and c-Fos expression in NAc and basolateral amygdala (BLA) in both sexes (Fosnocht et al., 2019), increases cocaine conditioned place preference in adult male mice, and conditioned place aversion in adult female mice (Walker et al., 2020). Overall, the amygdala plays a central role in the impact of early life stress on reward-related behaviors (for review see Guadagno et al., 2021). The sexual dimorphism described above is associated with sex-specific transcription in the medial amygdala (MeA), potentially downstream of non-canonical transcription factor, crystallin mu (Crym). Several Crym-regulated genes show sexually dimorphic expression after acute saline and cocaine stimulation, including oxytocin (Oxt), vasopressin (Avp), and dopamine receptor 1 (Drd1), which may be key drivers in sexually dimorphic addiction-like behaviors (Walker et al., 2020). Neuropeptides, like OXT, are viable candidates for potential pharmacotherapy, given that early life adversity impacts OXT signaling and has debilitating effects on the regulation of social behaviors and emotion (Baracz et al., 2022). Further study of the sex-specific epigenetic changes following adolescent social isolation is necessary to determine their effect on susceptibility to addiction in adulthood and to identify potential therapeutic targets.

Preclinical studies that include sex as a biological variable are necessary to elucidate the human condition. While few preclinical studies examine the role of early-life adversity in adult addiction-like behavior in females, several studies do examine female adult stress susceptibility. For example, maternal separation followed by adolescent social isolation increases resilience to anxiety- and depressive-like behavior during adulthood, while maternal separation alone increases susceptibility (Jaric et al., 2019b), in both male and female mice. Interestingly, female-specific effects of maternal separation, such as increased anhedonic-like behavior during adulthood, resemble behavior normally associated with low estrogen levels (Jaric et al., 2019b). Further, maternal separation increases adult female expression of glucocorticoid receptor, Nr3c1, and decreases DNA methylation in the early growth response 1 (Egr1) binding motif of Nr3c1 (Jaric et al. 2019b).

Finally, exposure to early life adversity interacts with genetic vulnerability to stress disorders and/or addiction. Rodent models of stress vulnerability include Wistar-Kyoto rats (Nam et al., 2014; Rana et al., 2015) and BALB/c mice which show increased stress- and depression-like behavior at baseline relative to C57Bl/6 mice (Tsuchimine et al., 2020). Chronic restraint stress in adult male BALB/c mice causes a greater stress phenotype, measured as higher blood corticosterone and reduced sucrose preference, compared to C57Bl/6 adult male mice (Tsuchimine et al., 2020), but data on early life adversity is scant in this model. Adolescent male BALB/c mice show less sociability and increased anxious behavior at baseline than adolescent male C57Bl/6 mice as measured by three-chamber sociability and the elevated plus-maze, respectively (Russo et al., 2019). Kyoto-Wistar rats display reduced baseline exploratory activity on the elevated platform, the open field test, and during novel object recognition compared to Wistar rats (Alves et al., 2020), yet corticosterone levels in a stress-free environment are similar across strains (Jastrzȩbska et al., 2015). Following early life stress, both Kyoto-Wistar and Wistar rats exhibit greater cocaine conditioned place preference in adolescence relative to standard housed rats (Alves et al., 2020). These data suggest that the effect of early life stress on drug reward behavior is independent of the genetically defined depression vulnerability of Wistar-Kyoto rats, supporting the hypothesis that early life adversity is a greater risk factor for adolescent addiction than genetic vulnerability (Alves et al., 2020).

A complementary approach models genetic vulnerability to addiction using selectively bred high responder rats and low responder rats, which exhibit high and low baseline drug seeking behavior, respectively (Flagel et al., 2016; Stead et al., 2006). Male adolescent cocaine exposure increases cocaine locomotor sensitization, reduces repressive histone 3 Lysine 9 trimethylation (H3K9me3) and increases activating H3K9 acetylation only in high responder but not low responder rats, compared to saline-treated controls (Parsegian et al., 2022). Cocaine re-exposure in male adults low-responder rats with a history of cocaine leads to locomotor sensitization and increased H3K9 acetylation in the NAc, an effect not observed in high responder rats (Parsegian et al., 2022). Given that low responder rats are more anhedonic at baseline (Stedenfeld et al., 2011) and do not exhibit cocaine locomotor sensitization following adolescent cocaine exposure (Parsegian et al., 2022), these data suggest distinct epi/genetic regulation downstream of cocaine exposure based on genetic background. Overall, these initial studies probe the interactions between genetics, early life adversity, and persistent epigenetic changes that may determine susceptibility to addiction. Additional studies including females are needed that model the interaction between genetic and exposure-based effects on reward pathophysiology, with a focus on the gene regulatory factors that sustain effects across development.

Beyond regulation of gene expression, 95% of mammalian transcripts are regulated by alternative splicing. Alternative splicing is another outcome of early life adversity that may underlie the persistence of its effects and sex-specificity therein. For example, chronic unpredicted stress during adolescence in both male and female mice produces anxiety behaviors and memory impairment in adulthood and alters alternative splicing of Tyrosine receptor kinase B (TrkB) and Sirtuin 1 (Sirt1) only in females (Shlomi et al., 2022). The mechanism for selection of these sex-specific splicing targets after stress is yet to be uncovered, but persistence in differential alternative splicing may be regulated epigenetically. We show that chronic cocaine self-administration simultaneously alters H3K36me3 and alternative splicing genome-wide, that persists for one month after abstinence. Furthermore, enrichment of H3K36me3 by SET2 overexpression or epigenetic editing regulates global or exon-targeted alternative splicing, respectively, and drug reward behavior in adult male mice (Xu et al., 2021). Analyses of alternative splicing in addition to gene expression are needed to comprehensively define the molecular mechanism underlying the persistence of early life stress and adversity.

Early life drug exposure regulates adult reward behavior

Childhood and adolescence are critical periods for the impact of early life adversity, which is associated with early initiation of drug use and increased risk of overdose (Leza et al., 2021; Stein et al., 2017; Trujillo et al., 2019). Comparable to early life stress, early life drug exposure can greatly increase susceptibility to drug addiction (Lacy et al., 2018; Salmanzadeh et al., 2020; Williams, 2020). Preclinical models of addiction find that the effects of early life exposure are drug-, sex- and paradigm-specific with respect to both the early life exposure paradigm and the adult reward behavior paradigm (Caffino et al., 2021). This section examines the effect of early life drug exposure on adult behavior, gene expression and the epigenome for different classes and types of illicit drugs.

Early life cocaine exposure affects addiction-related behavior in both male and female rodents, including increased habit formation, perseverative operant behavior, and diminished information updating (Depoy et al., 2016; Malvaez & Wassum, 2018; Murphy & Heller, 2022). Natural variation in reward behavior affects responses to early life drug exposure. For example, during acquisition of cocaine self-administration, adolescent mice either escalate intake or exhibit stable intake across days (Depoy et al., 2016). Male adolescent mice that escalate intake exhibit habit-like behavior and are resistant to information updating in adulthood, compared to those that exhibit stable cocaine intake in adolescence. In contrast, female adolescent mice with a history of stable cocaine intake are more vulnerable to habit formation when re-exposed to cocaine during adulthood (Depoy et al., 2016). Importantly, investigator administered cocaine at escalating doses does not increase behavioral inflexibility or habit formation in either sex, indicating that motivation and operant learning are necessary for adolescent cocaine exposure to regulate adult behavior (Depoy et al., 2016). Beyond operant behavior, adolescent male rat cocaine exposure enhances negative affect following drug re-exposure in adult rats. Chronic investigator-administered cocaine during adolescence followed by cocaine re-exposure in adulthood increases immobility time in the forced swim test and reduces sucrose intake, compared to adult saline re-exposure. Interestingly, adolescent cocaine exposure has no effect on parameters of the open field test, indicating an effect on depressive-like behavior rather than anxiety-like behavior. On a molecular level, adolescent cocaine exposure reduces c-Fos expression in dorsal striatum, but only when male mice are re-exposed to cocaine in adulthood (García-Cabrerizo & García-Fuster, 2019). Adolescent Δ9-tetrahydrocannabinol (THC) exposure increases Pavlovian to instrumental transfer expression in adult male rats but does not accelerate or inhibit habit formation in adults of either sex (Orihuel et al., 2021), suggesting that the behavioral effects of adolescent drug exposure are substance specific.

While the above studies summarize the effects of exposure to adolescent and adult exposure to a single drug, early life exposure to one substance may precipitate addiction to another (McCabe et al., 2019; Veliz et al., 2022). Adolescents that practice non-medical prescription opioid use, are more likely to develop substance use disorders involving alcohol, cannabis, and heroin (McCabe et al., 2019). Drug cross-sensitization is modeled in animals when pre-exposure to one drug leads to behavioral hyperreactivity to another drug, and occurs in both sexes to varying degrees (Carr et al., 2020; Kharas et al., 2019). For example, adolescent THC exposure regulates adult cocaine self-administration in both male and female rats, with subtle differences by sex. While there is no effect of adolescent THC exposure on acquisition of adult cocaine self-administration in either sex, adult males increase cocaine intake on a progressive ratio schedule and adult females increase seeking during forced abstinence, compared to rats exposed to vehicle in adolescence (Orihuel et al., 2021).

Early life drug exposure regulates adult gene expression

The persistent effects of early life and adolescent drug exposure are likely due to underlying changes in gene expression and the epigenome. Transcriptional profiling of adult rodent NAc following adolescent THC or saline exposure identifies sex-specific differential gene expression (Orihuel et al., 2021; Zuo et al., 2022). Functional terms for synaptic activity and learning are enriched in male NAc and those for hormonal activity are enriched in female NAc (Orihuel et al., 2021). Male adolescent rat exposure to a THC analog, WIN 55,212–2, leads to cross-sensitization to cocaine, an increase in permissive H3K27 acetylation and a decrease in histone deacetylase 6 (HDAC6) in the prefrontal cortex (PFC) of adult male rats (Scherma et al., 2020). Female adolescent rat THC exposure increases NAc heterochromatic H3K9me2/3 and permissive H3K9 acetylation two and 24 hours after the last injection; these modifications are then depleted at 48 hours. Hippocampal H3K9me2/3 increases at 24 hours, with no effect at two or 48 hours, while amygdalar H3K9me2 increases at two hours and H3K9me3 increases at 24 hours, after the last THC injection (Prini et al., 2018). Taken together, these studies demonstrate that early life THC exposure affects sex- and brain-region specific gene expression and epigenetic modifications, which may regulate adult drug motivation and intake.

Adolescent drug exposure is associated with neurological and behavioral consequences including altered dopamine signaling (Areal & Blakely, 2020). Exposure to opioids during adolescence is associated with escalation in opioid use and increased likelihood of opioid addiction in adulthood (Butelman et al., 2020; Guarino et al., 2018, 2021; Windisch & Kreek, 2020). Preclinical studies support the effect of early opioid exposure in the development of reward pathophysiology. Male adolescent mouse oxycodone exposure represses expression and enriches repressive H3K27me3 of dopamine-signaling related genes in the adult VTA, including Nr4a2, tyrosine hydroxylase (Th), Cart prepropeptide (Cartpt), and dopamine transporter (Dat), compared to control adult mice exposed to vehicle in adolescence (Carpenter et al., 2021). Taken together, these results suggest that male adolescent oxycodone exposure inhibits dopamine signaling-related gene expression by maintaining repressive epigenetic modifications into adulthood. Additional preclinical studies report behavioral and epigenetic effects of adolescent-onset opioid intake (Altshuler et al., 2021; Gerra et al., 2021), but most do not include adolescent animals.

Beyond illicit substances, early life exposure to alcohol can precipitate addiction in adulthood via epigenetic mechanisms (Bohnsack et al., 2019). Moreover, epigenetic regulation is implicated in alcohol consumption in animal models (Dulman et al., 2020; Sakharkar et al., 2016). Adolescent male rats exposed to intermittent ethanol exhibit increased alcohol consumption and anxiety-like behavior in adulthood, compared to adolescent rats exposed to saline (Sakharkar et al., 2016). Adolescent alcohol exposure decreases expression and histone acetylation of activity–regulated cytoskeleton-associated protein (Arc) in adult male rat central nucleus of amygdala (CeA) (Kyzar et al., 2019). Epigenetic editing of H3K27 acetylation in the adult male central amygdala (CeA) increases Arc expression and rescues the behavioral effects of early life alcohol exposure (Bohnsack et al., 2022). Finally, intracranial delivery of HDAC inhibitors to the VTA of early life stress-exposed male rats restores histone acetylation and expression of brain derived protein factor (BDNF) (Shepard et al., 2018). These findings underscore the sex-specific nature of epigenetic reprogramming in susceptibility to early life adversity and suggest that epigenetic editing and enzymatic inhibitors can function as potential therapeutic interventions to prevent the durable effects of early life stress and drug exposure. Taken together, these findings portray a hopeful outlook for substance use disorder intervention in early life.

Future directions: Enhancers, proteomics, inheritance, and sex

Epigenetic changes following early life adversity occur genome wide, but most studies examine only gene promoters. Epigenetic changes at non-coding genomic elements, such as enhancers, in both male and female subjects are also profoundly relevant to the longitudinal effects of early life adversity. For example, human addiction is linked to a single nucleotide polymorphism in an enhancer of the cannabinoid-1 receptor (CB1R) gene, necessary to maintain high levels of CB1R in hippocampus (Hay et al., 2019). Deletion of this CB1R enhancer in mice reduces alcohol intake and cannabinoid-induced behavior in both sexes, accompanied by increased anxiety-like behavior in female and reduced anxiety-like behavior in male mice (Hay et al., 2019). Another well-characterized enhancer linked to stress-regulation is that of KF506 binding protein 5 (FKBP5). FKBP5 polymorphism decreases FKBP5 interaction with long-range enhancers and is linked to increased susceptibility to stress-related psychiatric disorders following childhood trauma (for review see Matosin et al., 2018). Finally, recent studies have identified human variants associated with cocaine dependence (Cabana-Domínguez et al., 2019), childhood environmental exposures and cocaine use disorders (for review see Fernàndez-Castillo et al., 2022). Beyond promoter-enhancer interactions, three-dimensional chromatin conformation regulates gene expression and accessibility and is just starting to be analyzed in the contexts of drug and stress exposure, with sex as a factor (Jaric, et al., 2019a; Rocks et al., 2022). Longitudinal studies of chromatin conformation are a critical next step in determining the epigenetic regulation of early life adversity and addiction susceptibility.

Sex differences in response to early life adversity could also be attributed to distinct proteomic profiles at baseline. For example, basal differences in circulating hormones and signaling factors regulate sex-specific stress and drug response (Bangasser et al., 2019; Heck & Handa, 2019). Proteomic analysis of adult male and female rat NAc shows differential protein expression, including proteins involved in neuronal signaling and reward circuitry, at baseline. After cocaine self-administration, altered proteins in male and female NAc were highly dissimilar (López et al., 2021). These studies suggest that drug exposure can greater target these differentially expressed proteins to produce divergent behavioral outcomes.

Epigenetic regulation by early life stress may fundamentally alter the pharmacodynamic effects of cocaine exposure later in life. In more detail, studies in the VTA have shown that both early life stress and early life drug exposure lead to GABAergic dysfunction in VTA dopaminergic neurons via HDAC2 mediated histone modifications (Shepard et al., 2018; Shepard & Nugent, 2020) which can contribute to changes in drug pharmacodynamics later in life. In addition to long-known histone modifications, the recently discovered dopaminylation (Lepack et al., 2020) has been shown to play a role in cocaine reward behavior. Furthermore, this modification seems to increase susceptibility to cocaine with prior drug exposure (Lepack et al., 2020), reiterating the link between early life adversity, epigenetics, and changes in cocaine pharmacodynamics.

Finally, the effects of early life adversity may be extremely long-lasting, even beyond individual lifespan. Several preclinical studies that model parental drug exposure during adolescence and adulthood report effects on immediate offspring and following generations (reviewed in Baratta et al., 2021; Brynildsen et al., 2020). Maternal and paternal rat adolescent THC exposure alters genome-wide transcription and DNA methylation of adolescent offspring of both sexes (Szutorisz et al., 2016; Watson et al., 2015), decreasing expression of glutamate ionotropic receptor NMDA type subunit 2B (Grin2B) in female offspring only, that persists into adulthood (Szutorisz et al., 2016). Adolescent female offspring also show decreased locomotor activity while males do not (Szutorisz et al., 2016). Male and female adult offspring from THC exposed parents show differentially methylated regions in comparison to offspring with parents exposed to vehicle including hypermethylation at the DLG associated protein 1 (Dlgap), brain-enriched guanylate kinase-associated protein (Begain), and Potassium Voltage-Gated Channel Subfamily A Member 5 (Kcna5) loci, and hypomethylation at Grin2A in the NAc (Watson et al., 2015). Further segregation of sex-specific methylation changes will help pinpoint potential mechanisms for alternate offspring consequences to parental adolescent drug exposure.

Maternal rat adolescent morphine exposure increases cocaine self-administration of adult male and female offspring (Vassoler et al., 2019), while paternal rat adolescent morphine exposure decreases cocaine self-administration of adult male and female offspring (Vassoler et al., 2020). Paternal adolescents exposed to morphine have increased H3 acetylation in the seminiferous tubules compared to vehicle exposed males. Moreover, paternal adolescence morphine exposure increases Bdnf expression in the PFC of male and female offspring (Vassoler et al., 2020). Adolescent male rat cannabis exposure regulates genome-wide sperm DNA methylation, compared to vehicle exposure, and increases hippocampal and NAc DNA methylation of male and female offspring (Schrott et al., 2022). While these studies of male sires suggest a parental-sex-specific mechanism of increased vulnerability to drug addiction following early life drug exposure, additional studies are needed to determine the effects of maternal drug exposure. Early life adversity in the form of chronic stress in maternal rats has been associated with sex-specific transcriptional alterations in fetal brain, including higher downregulation in synapse development genes in female than male offspring (Cissé et al., 2020). Altogether, these works exemplify the role of parental drug exposure during adolescence can lead to susceptibility in progeny and in a sex-dependent manner, and the potential of evaluating epigenetic mechanisms in transgenerational inheritance of drug susceptibility.

Conclusion

Early life adversity is a key driver of addiction susceptibility in both men and women. The effects of early life adversity on addiction susceptibility are sex-, brain-region, and exposure-specific, reflecting the specific type of early life adversity and adult drug exposure. Underlying molecular mechanisms include sex-specific regulation of genome-wide neuronal epigenetic modifications and gene expression and early life stress. Although both sex and age of exposure specify susceptibility to addiction, studies have mainly relied on adult male data. Only by including females in preclinical studies and stratifying addiction studies by sex and developmental phase will we fully elucidate the underpinnings of addiction susceptibility.

Highlights.

  • Drug addiction is a leading cause of disability worldwide.

  • Early life adversity may contribute to the risk of addiction.

  • Detailed research on the profound epigenetic and genetic differences between female and male subjects leading to addiction susceptibility is necessary.

Acknowledgements

The authors acknowledge Yuan Li for pencil artwork in Figure 1. Financial support was provided by NIH-NIDA Avenir Director’s Pioneer Award (E.A.H, DP1 DA044250), NIDA Research Project Grant (E.A.H, 1R01DA052465-01A1), and the National Science Foundation Graduate Research Fellowship under Grant No. DGE-1845298 (K.L.R.).

Footnotes

Declaration of competing interest

We declare no competing interests.

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