Introduction

Opioid use disorder (OUD) is a growing epidemic in the United States and globally. To mitigate the rise in opioid-related morbidity and mortality, effective strategies are urgently needed to prevent the onset of opioid addiction by identifying individuals at high risk for developing OUD. Notably, OUD often occurs with psychiatric comorbidities such as depression, bipolar disorder, and schizophrenia (Brooner et al., 1997), all of which involve dysfunctional reward processing. Therefore, studying the basis for this disruption will provide greater understanding and insight into treating both OUD and its comorbidities.

The risk factors for OUD are numerous and complex, and genetics (Kreek et al., 2012; Crist et al., 2019; Jiang et al., 2019), drug availability (Volkow et al., 2011; Wright et al., 2014), and environmental factors such as early life adversity (ELA; Dube et al., 2003; Sinha, 2008; Kreek et al., 2012) all play a role. ELA related to poverty, trauma and chaotic environment affects over 30% of children in the U.S. (American Psychological Association, 2018). ELA is linked to numerous long-term negative health consequences including obesity, heart disease, respiratory illnesses, as well as cognitive and emotional problems (Felitti et al., 1998), and it is associated with several affective problems that indicate dysfunction of the brain’s reward circuitry (Kessler et al., 1997, 2010; Anda et al., 2006; Green et al., 2010; Pechtel and Pizzagalli, 2011; Novick et al., 2018). While a variety of the physical and mental health outcomes following ELA may lead to enhanced risk for OUD and its many comorbidities, here we focus on the effects of ELA on reward-related behaviors and underlying circuitry and propose that disrupted reward processing is a common developmental mechanism by which OUD and its comorbidities may arise following ELA. We also highlight the contribution of biological sex to the range of outcomes related to ELA-induced aberrations in reward circuitry.

Normal Reward Circuit Development Involves An Early-Life Sensitive Period

Reward circuitry in the brain is a network comprised of cortical and subcortical forebrain structures that regulate reward seeking. This circuitry is evolutionarily adapted to drive the acquisition of natural rewards, such as food, water, and reproduction. However, the maladaptive function of this circuitry can also lead to psychiatric manifestations such as mood disorders and addiction.

Whereas the reward circuitry has been extensively studied in the adolescent and mature brain, its function and developmental trajectory in infancy and early childhood are less well-known. The ventral tegmental area (VTA), nucleus accumbens (NAc), and amygdala, major nodes of the reward circuit, begin to appear in the first trimester in humans and around the second week of gestation in rodents, and continue to undergo significant maturation postnatally (Birnie et al., 2020). Behavioral manifestations of the reward function, such as responsivity to sucrose (Desor et al., 1973; Vigorito and Sclafani, 1988) and appetitive learning (Johanson and Hall, 1979; Hayne et al., 1986), emerge within the first months of life in humans and within the first postnatal days in rodents. These developmental timelines suggest that reward circuitry in a rodent in its first week of life might approximate that of a human neonate (Birnie et al., 2020).

The development of these circuits that occurs early in postnatal life suggests a possible sensitive period during which time aberrant environmental signals, such as parental abuse or neglect, may shape their developmental trajectories (Baram et al., 2012; Glynn and Baram, 2019; Luby et al., 2020). Analogous influences of critical environmental signals on network maturation are known for other circuits, including the visual and auditory (Zhang et al., 2001; Li et al., 2006). Just as these systems require predictable sensory inputs at specific times during development to mature properly, parental signals may provide important stimuli for the maturing reward system (Hane and Fox, 2016; Davis et al., 2017; Andersen, 2018; Glynn and Baram, 2019). Thus, understanding how the early environment alters reward circuitry will be critical for developing future interventions against OUD and other mental health problems.

Dysfunction of Reward Circuits: A Common Thread for Oud and Its Comorbidities?

The high prevalence of multiple diagnoses in patients with OUD (Kessler, 2004) supports shared or overlapping underlying processes and has led to searches for common genetic mechanisms (Carey et al., 2016). OUD is often diagnosed in patients who have other mental health problems (Brooner et al., 1997; Conway et al., 2006; Farrugia et al., 2011; Danovitch, 2016). Dysfunction of reward circuitry has been implicated in many of these other mental health diagnoses, such as depression and bipolar disorder (Russo and Nestler, 2013; Pizzagalli, 2014; Whitton et al., 2015), post-traumatic stress disorder (PTSD; Nawijn et al., 2015), personality disorders (Lawrence et al., 2010; Murray et al., 2018), and schizophrenia or psychosis (Kapur et al., 2005; Radua et al., 2015; Whitton et al., 2015). The specific comorbidities present with OUD also appear to be mediated by gender (Brooner et al., 1997; Conway et al., 2006). While women with OUD are more likely to also have a diagnosis of mood, anxiety, and eating disorders, men are more likely to have a diagnosed personality disorder (Brooner et al., 1997).

Notably, the prevalence of dual diagnoses is particularly high among patients who have experienced ELA, suggesting that ELA may impact a shared substrate involved in OUD and its comorbidities. In a study of patients admitted for chemical dependency treatment, those who reported a history of childhood abuse were also more likely to show symptoms of other reward-related comorbidities such as depression, bipolar, and anxiety disorders (Ellason et al., 1996). Another study found a very high co-incidence of PTSD and opioid abuse among women that was explained by a history of childhood trauma (Najavits et al., 1997). The risk for schizophrenia and psychosis is also increased by ELA (van Os et al., 2010; Bentall et al., 2014), which are highly comorbid with substance use disorder (Schmidt L. M. et al., 2011; Li et al., 2020). Palatable food cravings and disordered eating are strongly associated with ELA (Halmi, 2009; Dallman, 2014; Osadchiy et al., 2019), and these cravings are commonly observed in individuals with OUD (Morabia et al., 1989; Pelchat, 2002; Mysels and Sullivan, 2010; Canan et al., 2017; McDonald and Laurent, 2019; Nolan, 2019). This high co-incidence of multiple reward-related problems suggests a common underlying mechanism by which disruption of reward circuitry may lead to a variety of poor mental health outcomes.

Developmental Origins: Ela Leads to Poor Neuropsychiatric Health Outcomes

Numerous studies have linked ELA to poor cognitive (Lupien et al., 2009; Pechtel and Pizzagalli, 2011; Chen and Baram, 2016; Short and Baram, 2019) and emotional health (Heim and Nemeroff, 2001; Anda et al., 2006; Smyke et al., 2007; Maccari et al., 2014; Callaghan and Tottenham, 2016; Hane and Fox, 2016; Krugers et al., 2016; Strathearn et al., 2020). For example, ELA is associated with lower educational achievement (Shonkoff et al., 2012) and poorer executive functioning abilities (McDermott et al., 2012). Evidence from clinical and epidemiological literature demonstrate links between adverse childhood experiences and increased risk for depression, anxiety, PTSD, eating disorders, and psychosis (Felitti et al., 1998; Chapman et al., 2004; Whitfield et al., 2005; Anda et al., 2006; Bale et al., 2010). The specific psychiatric outcomes resulting from ELA also vary by gender (Humphreys et al., 2015), with women more frequently diagnosed with anxiety and depression (Hammen et al., 2000; Heim and Nemeroff, 2001; Davis and Pfaff, 2014), whereas men are more likely to be diagnosed with personality disorders after ELA (Anda et al., 2006), the same pattern seen among those with comorbid OUD (Brooner et al., 1997).

Adverse childhood experiences are also robustly associated with later-life substance addiction (Nurco et al., 1996; Simpson and Miller, 2002; Dube et al., 2003; Widom et al., 2006; Gershon et al., 2008; Sinha, 2008; Enoch, 2011; Shand et al., 2011; Stein et al., 2017; Marsh et al., 2018). Results from the Adverse Childhood Experiences study show that ELA can increase the risk for injection drug use up to 11-fold (Anda et al., 2006) and that ELA increases the likelihood of early initiation of drug use independent of availability or changes in social attitudes towards drugs (Dube et al., 2003), suggesting a specific effect of adverse experiences on addiction liability. Additionally, individuals with a history of ELA are more likely to be prescribed opioid pain medications (Anda et al., 2008). This effect was mediated by an increased likelihood to experience other health and psychosocial problems, which highlights the interplay among the numerous physical and mental health problems associated with ELA, and the challenges in discerning causal mechanisms.

Interestingly, women appear to be particularly predisposed to OUD following ELA (Gershon et al., 2008; Lansford et al., 2010; Shand et al., 2011; Marsh et al., 2018). For example, although men have higher rates of overall substance dependence diagnoses, women who have experienced ELA are overrepresented among heroin and nonmedical prescription opioid users (Shand et al., 2011; Marsh et al., 2018). Women diagnosed with OUD are also two to three times more likely to have a history of PTSD related to ELA than men with OUD (Najavits et al., 1997). While this could be accounted for by the fact that girls tend to experience more childhood trauma than boys (Felitti et al., 1998), the magnitude of difference suggests a mediating role of sex. The type of adversity experienced may also interact with biological sex to affect outcomes. For example, Shand et al. (2011) found that emotional neglect during childhood predicted drug dependence in women, whereas PTSD predicted drug-related diagnoses for men. Again, the presence of other comorbidities varied by sex; men were more likely to display antisocial behaviors, whereas women were more likely to be diagnosed with anxiety and depression. These differences suggest divergent mechanisms by which ELA may alter reward circuit development between sexes, resulting in psychiatric outcomes that differ between men and women.

Anhedonia and Oud, Each Manifestations of Reward Circuit Dysfunction, Arise After Ela

The paragraphs above suggest a strong association between ELA and malfunction of the reward circuit, which can manifest as OUD or other problems in reward-related behaviors. Many of these are common across several mental illnesses and may share common biological substrates. Anhedonia defined broadly as an inability to experience pleasure is a feature of substance use disorder in some individuals (Ahmed and Koob, 1998; Koob and Moal, 2001; Janiri et al., 2005; Hatzigiakoumis et al., 2011; Sussman and Leventhal, 2014; Kiluk et al., 2019; Brenner et al., 2020) and of other psychiatric diagnoses that are comorbid with addiction (Gorwood, 2008), such as depression (Loas, 1996; Blanchard et al., 2001; Pizzagalli et al., 2008; Martinotti et al., 2012), schizophrenia and psychosis (Andreasen and Olsen, 1982; Blanchard et al., 2001; Martinotti et al., 2012), PTSD (Risbrough et al., 2018), eating disorders (Davis and Woodside, 2002; Halmi, 2009), and other “high-risk” behaviors (Franken et al., 2006).

Indeed, the concept of anhedonia serves as a distinct useful transdiagnostic construct for understanding the role of altered reward processing in the etiology of psychiatric conditions (Bedwell et al., 2014; Lake et al., 2017). In line with the Research Domain Criteria (RDoC) framework put forth by the NIH, the ability to define a neurobiological basis of anhedonia, along with empirical behavioral measures both in humans and animal models, makes anhedonia a useful translational construct for studying reward circuit dysfunction and related behavioral disorders such as those seen after ELA (Cuthbert and Insel, 2013). Furthermore, the ubiquity of anhedonia as a feature of many of the psychiatric outcomes of ELA provides evidence that a mechanism by which ELA may impact cognitive and emotional health outcomes is through disruption of reward circuit development (Birnie et al., 2020). There are multiple domains of anhedonic behaviors that can be measured in humans and animal models which may have distinct neural processes (Der-Avakian and Markou, 2012; Shankman et al., 2014; Zald and Treadway, 2017). For example, anhedonia may represent a deficit in either anticipatory or consummatory reward, motivation, can be manifest for some reinforcers but not others (e.g., social vs. food rewards), and is also described as a feature of flat affect (for review, see Shankman et al., 2014). The neural substrates that govern these different forms of anhedonia have been explored (Gorwood, 2008; Der-Avakian and Markou, 2012; Treadway and Zald, 2013; Pizzagalli, 2014), and the specific effects of ELA on distinct types of anhedonic behaviors as well as their potentially dissociable neural substrates is an important area of continued investigation.

How Does Ela Provoke Anhedonia, Oud, and Comorbidities? A Need for Animal Studies

While studies in humans offer important insights into the effects of ELA on reward circuitry, one cannot dissociate the influence of early-life experiences on reward circuitry function from other genetic and environmental variables that may mediate the links between ELA, OUD, and other comorbidities. Animal models provide a method for investigating the effects of these environmental factors in isolation.

In animal studies, several different models of ELA have been used to isolate the effects of adversity on brain development from other genetic and environmental variables. These methods, such as maternal separation (MS), limited bedding and nesting (LBN), fostering by abusive caregivers, and others, have been extensively described elsewhere (Molet et al., 2014; Doherty et al., 2017; Walker et al., 2017; Wakeford et al., 2018; Brenhouse and Bath, 2019). In rodents and non-human primates, numerous studies have demonstrated that ELA results in behavioral phenotypes that suggest underlying dysfunction in reward-related brain regions (Molet et al., 2014; Andersen, 2015, 2018; Wakeford et al., 2018; Bonapersona et al., 2019; Birnie et al., 2020). The particular behavioral outcomes of ELA in animal models can vary depending on the type, timing, and duration of the paradigm, the species and strain of animal, and the timing and type of behavioral assays (Schmidt M. V. et al., 2011; Molet et al., 2014; Andersen, 2015; Walker et al., 2017; Brenhouse and Bath, 2019; Demaestri et al., 2020; Lundberg et al., 2020), as well as sex (Kundakovic et al., 2013; Bath, 2020). While this poses a challenge for interpreting this vast literature, the variability also mirrors human experience; indeed, ELA in humans can take many different forms, such as poverty, trauma, physical or sexual abuse, and neglect, and these, in combination with other environmental and biological factors, likely contribute to individual differences in clinical outcomes (Shand et al., 2011; Daskalakis et al., 2013; Sheridan and McLaughlin, 2014; Strathearn et al., 2020), highlighting the sensitivity of the brain to different types of stressors during these developmental periods.

Given that anhedonia has been associated clinically with many of the psychiatric outcomes of ELA, establishing whether ELA can actually cause anhedonia seems useful for determining neurobiological mechanisms that may ultimately underlie ELA-associated OUD and its comorbidities. Thus, we will highlight some animal studies that have focused specifically on anhedonia. The expression of anhedonia in animal models appears to be mediated by interactions between the ELA paradigm, biological sex, and testing parameters (Matthews and Robbins, 2003; Rüedi-Bettschen et al., 2005; Der-Avakian and Markou, 2010; Leussis et al., 2012; Lukkes et al., 2017; Di Segni et al., 2019). For example, in male rodents, ELA imposed via rearing for 1 week (P2-P9) in cages with limited bedding and nesting materials (LBN) leads to enduring anhedonia for both natural and drug rewards. This includes blunted sucrose and palatable food preference, reduced interest in social play, and decreased low-effort cocaine consumption (Molet et al., 2016; Bolton et al., 2018a, b). In contrast, such anhedonia is not observed in female rats after LBN (Levis et al., 2019). Yet, others have identified an age-dependent reduction of sucrose preference and depressive-like behaviors in female mice (Goodwill et al., 2019). Using a MS model of ELA, both male and female rats have reduced sucrose preference later in life (Matthews et al., 1996; Leventopoulos et al., 2009; Coccurello et al., 2014). Anhedonia has been reported also in nonhuman primates exposed to maternal deprivation and maltreatment (Rosenblum and Paully, 1987; Paul et al., 2000; Pryce et al., 2004; Kaufman et al., 2007; Glynn and Baram, 2019), such as reduced sucrose preference (Paul et al., 2000) or interest in social interaction (Coplan et al., 1996). However, others have found increased sucrose drinking in juvenile males (Nelson et al., 2009).

In contrast to natural reward anhedonia, other studies have demonstrated increased sensitivity to drug-related rewards (Andersen, 2018) as well as addiction-related behavioral traits (Hynes et al., 2018) after ELA. Although this may appear contradictory, these findings support the notion that the behavioral expression of altered reward circuitry by ELA depends on reward type and testing paradigm; thus, anhedonia and reward-seeking are not necessarily mutually exclusive.

While effects of ELA on increased alcohol and cocaine-seeking have been extensively studied and reviewed (Andersen, 2018), considerably less work has been done to model the effects of ELA specifically on opioid addiction vulnerability. Some evidence exists that MS increases morphine seeking in both male and female adult rats (Abad et al., 2016; Mohammadian et al., 2019) while others observed morphine preference only in MS males (Kalinichev et al., 2002; Vazquez et al., 2005, 2006; Michaels and Holtzman, 2008; Vey et al., 2016). Holtzman and colleagues show that male rats that have experienced MS demonstrate a greater place preference for morphine than their control counterparts (Michaels and Holtzman, 2008) and increased locomotor sensitization to repeated morphine, a measure of the psychoactive properties of the drug (Kalinichev et al., 2002). However, others have found attenuated sensitivity to the rewarding properties of heroin in MS females (Matthews and Robbins, 2003). Using the LBN model of ELA, we have demonstrated that, while males develop anhedonia for natural rewards like social play, palatable food, and sucrose (Molet et al., 2016; Bolton et al., 2018a, b), females developed a strikingly different phenotype (Figure 1). LBN females exhibit a marked increase in addiction-like seeking for opioid drugs (Levis et al., 2019). These rats were resistant to the extinction of opioid-seeking behavior, had stronger cue-induced and heroin-primed reinstatement responses, and increased motivation to self-administer the opioid remifentanil in a translationally relevant task measuring economic demand (Treadway et al., 2009; Bentzley et al., 2013; Bickel et al., 2014), demonstrating a motivation to obtain the drug even at a very high cost. Motivation for consuming palatable food was also significantly higher in LBN females, concurrent with the marked increase in addiction-like seeking for opioid drugs. Notably, this same phenomenon has been observed among patients seeking treatment for OUD (McDonald and Laurent, 2019).

Figure 1. Early life adversity (ELA) augments opioid-seeking behaviors and increases the demand for opioid drugs and highly palatable food.

Together, the findings in rodents and non-human primates suggest that ELA disrupts the maturation of reward circuits, and the resulting behavioral manifestations may vary by the timing, duration, and nature of the ELA and be further modulated by sex. Whereas deficits in reward-seeking behaviors are observed in males, such deficits are not commonly found in females. Rather, in females, the prevailing phenotype includes the enhanced consumption of opioids (and other drugs of abuse) and palatable food. The mechanisms underlying this phenotype are poorly understood and may involve ELA-induced changes in both reward and stress circuits. Support for this notion is provided by studies showing that female rats that have experienced stress tend to engage in more pro-hedonic consumption of palatable food (Dallman et al., 2003, 2005; Pecoraro et al., 2004; Jahng, 2011, 2014; Tomiyama et al., 2011; Machado et al., 2013; Kim et al., 2015), and that this may be specifically associated with anhedonia (Jahng et al., 2012; Jahng, 2014). Much information is needed to gain insight into the bases of palatable food craving as sex-dependent comorbidity of OUD.

Furthermore, the variable consequences of ELA on distinct assays of reward-seeking behaviors in animal models demonstrate that reward processing is not a singular phenomenon; rather, individuals may express different and dissociable phenotypes that suggest potentially discrete mechanisms of reward circuit disruption. Thus, further investigation into how ELA alters specific aspects of reward processing and underlying neural substrates will be critical for understanding the biological processes that contribute to the risk for OUD and comorbid disorders.

How Might Ela Lead to Oud and Related Disorders? Evidence from Clinical Imaging Studies

Evidence from human imaging studies suggests impaired development of specific reward-related brain regions and circuits after ELA that impose a risk for substance abuse and related comorbidities. Many studies have demonstrated functional and neuroanatomical effects of ELA on brain regions involved with reward and reward-learning, such as the hippocampus, amygdala, medial prefrontal cortex, and striatal areas including nucleus accumbens (Bremner, 2003; Hackman and Farah, 2009; Rao et al., 2010; Pechtel and Pizzagalli, 2011; Gee et al., 2013; Boecker et al., 2014; Callaghan and Tottenham, 2016; Teicher et al., 2016; Miguel et al., 2019; Herzberg and Gunnar, 2020). Childhood maltreatment is associated with blunted activation of these brain regions during reward processing tasks (Dillon et al., 2009; Mehta et al., 2010; Goff et al., 2013; Novick et al., 2018), a potential functional mechanism explaining the presence of anhedonia among individuals who have experienced ELA. Of these, the striatum appears to be especially important in mediating the link between reduced reward reactivity and ELA (Dillon et al., 2009; Goff et al., 2013; Goff and Tottenham, 2015; Egerton et al., 2016; Kamkar et al., 2017; Dennison et al., 2019). The ventral striatum in particular seems to be a key mediator between ELA, anhedonia, and substance abuse. Corral-Frías et al. (2015) report that reduced reward reactivity in the ventral striatum predicts ELA-associated anhedonia and structural equation modeling revealed that this relationship also predicts substance-related coping behaviors, such as self-medication. This finding highlights a possible common mechanism by which ELA can lead to OUD and its comorbidities. The type of adversity experienced may also mediate the striatal response to reward (Dennison et al., 2019; Herzberg and Gunnar, 2020), as ELA in the form of childhood poverty, specifically, is associated with increased reactivity to reward in the striatum (Gonzalez et al., 2016), especially in girls (Romens et al., 2015). These sex- and experience-dependent differences are consistent with the observed variability of mental health outcomes in humans and behavioral phenotypes in animals.

Ela Causes Functional and Anatomical Changes in Reward-Related Brain Regions: Evidence from Animal Models

Building on clinical evidence, studies using animal models provide tools for identifying mechanisms that underlie disruptions in reward circuitry after ELA. In analogy to human literature, these outcomes appear to be partially mediated by sex. In males, our group has previously shown that anhedonia after LBN is associated with altered functional connectivity between the amygdala and mPFC in rats that may be mediated by CRH expression in the amygdala (Bolton et al., 2018a). This is supported by evidence that depressive-like behaviors and natural reward anhedonia following LBN are associated with disrupted amygdala-PFC and PFC-striatal functional connectivity (Yan et al., 2017). Additionally, Walker et al. (2017) have observed morphological and functional changes in the basolateral amygdala (BLA) and reduced functional connectivity between BLA and PFC in LBN-exposed male rats (Guadagno et al., 2018a, b). MS-induced ELA alters the development of PFC→NAc projections and dopamine (DA) signaling within the pathway in male rats (Brenhouse et al., 2013). In females, MS induces early maturation of the BLA-PFC circuit (Honeycutt et al., 2020), and early life social stress alters resting-state functional connectivity in NAc, hippocampus, and PFC (Nephew et al., 2017). In nonhuman primates, maltreatment during infancy leads to increased amygdala volume (Howell et al., 2014) and altered connectivity in regions implicated in mood disorders (Howell et al., 2013). c-Fos mapping studies measuring neuronal activity further suggest specific ELA-induced alterations in reward circuit function (Rincón-Cortés and Sullivan, 2016; Bolton et al., 2018a, b; Di Segni et al., 2019). Specifically, ELA leads to reduced NAc c-Fos activation in response to typically-rewarding stimuli like a social interaction (Rincón-Cortés and Sullivan, 2016), or aberrant over-activation of other regions associated with stress and reward (Bolton et al., 2018a, b).

Molecular mechanisms mediating the effects of ELA on OUD and related comorbidities may involve alterations in neurotransmitter and neuromodulator systems. Whereas a comprehensive discussion of this important topic is beyond the scope of this review article, a few salient points are mentioned: A vast literature documents the role of DA signaling in motivated and reward-seeking behaviors. Altered DA signaling is an important mediator of drug-seeking (Koob, 1992) as well as other psychiatric problems associated with ELA such as mood disorders (Diehl and Gershon, 1992) and psychosis (Kapur et al., 2005) and has been implicated in the expression of anhedonia (Willner et al., 1992; Pizzagalli, 2014). ELA has been extensively linked to dysfunction of the DA system in rodents, especially in the striatum (for a comprehensive review of this literature, see Bonapersona et al., 2018), and this may be mediated by alterations in other stress and reward-related transmitter systems (Forster et al., 2018). Additionally, the effects of early life experiences on DA signaling may be more pronounced in females (Camp et al., 1984; Chocyk et al., 2011). It is therefore tempting to speculate about the role of ELA-provoked deficits in DA signaling as involved in ELA-related OUD and its comorbidities.

Endogenous opioids play an important role in mediating hedonic processes (Smith and Berridge, 2007; Mahler and Berridge, 2009, 2012; Mitchell et al., 2018) as well as social attachment early in life (Panksepp et al., 1980), so the endogenous opioid system might also represent an important link between ELA and reward-related outcomes later in life. Alterations in opioid receptor mRNA have been observed in both males and females after ELA, although differentially between the sexes. Chang et al. (2019) show female-specific increases in NAc mu and delta-opioid receptor mRNA levels in mice after early life predator odor exposure. Nylander and colleagues have found long-term alterations in endogenous opioid peptides and opioid and DA receptor expression in reward-associated areas that vary both by sex and by the duration of MS (Ploj et al., 1999, 2001, 2003a,b; Ploj and Nylander, 2003; Gustafsson et al., 2008). Opioid receptors are known to modulate striatal DA signaling (Mulder et al., 1984; Johnson and North, 1992), an effect that may be potentiated by ELA (Karkhanis et al., 2016). Thus, disturbances in endogenous opioids might also mediate ELA-induced alterations of striatal DA signaling leading to aberrant reward-related behaviors. These ELA-induced opioids and DA-related disruptions suggest a mechanism by which ELA may lead simultaneously or in parallel to psychiatric disorders and enhanced consumption of opioids (Khantzian, 1987; Dallman et al., 2005; Kim et al., 2015; Lovallo et al., 2018).

Together with evidence from human subjects, these findings demonstrate that ELA alters important reward-related circuit nodes to provoke vulnerability to poor psychiatric outcomes. Establishing causality between network- and molecular-level changes induced by ELA and resulting reward-related deficits remains an important area of investigation to cure OUD and its psychiatric comorbidities.

Conclusion

Evidence across species suggests that ELA during sensitive developmental periods alters the developmental trajectory of reward circuitry. The precise nature of ELA, the potentially disparate consequences of different types of ELA, and the mechanisms underlying the aberrant maturation of reward circuits remain topics of much-needed investigation. The resulting maladaptive reward processing is likely a mechanism common to OUD and its comorbidities. As both animal and human studies demonstrate, the manifestations of this aberrant reward circuit function are varied and depend on the type and extent of adversity, biological sex, and later life experiences. However, functional, anatomical, and molecular disruptions in reward-related brain regions such as the medial PFC, striatum, and amygdala have been described across multiple paradigms and several species, suggesting a common developmental origin. Likewise, anhedonia may be an important behavioral biomarker of disturbed reward processing that links ELA, OUD, and other mental health problems. Further investigation into the neurobiological basis for ELA-induced reward circuit disruptions will provide key insights into the origins of OUD and its comorbidities and may uncover new interventions that will be successful in treating both.

Introduction

Opioid use disorder (OUD) is a growing problem. Better ways are needed to stop it from starting, especially by finding people at high risk. OUD often appears with other mental health conditions like depression, bipolar disorder, and schizophrenia. These conditions all involve problems with how the brain processes rewards. Understanding these problems will help treat both OUD and its related conditions.

Many factors contribute to OUD, including genetics, how available drugs are, and environmental issues like early life adversity (ELA). ELA, which includes poverty, trauma, and unstable home environments, affects many children. It is linked to long-term health problems, mental health issues, and problems with the brain's reward system. This discussion focuses on how ELA affects reward behaviors and brain circuits. It suggests that problems with reward processing are a common way OUD and its related conditions develop after ELA. The role of biological sex in these outcomes is also important.

Normal Reward Circuit Development Involves an Early-Life Sensitive Period

The brain's reward system is a network of structures that controls how people seek rewards. This system naturally helps individuals get basic needs like food and water. However, if this system does not work correctly, it can lead to mental health problems like mood disorders and addiction.

While the reward system in teen and adult brains is well-studied, less is known about how it works and develops in babies and young children. Key parts of this system, such as the ventral tegmental area, nucleus accumbens, and amygdala, start forming early in development and continue to mature after birth. Signs of reward function, like reacting to sweet tastes or learning through rewards, appear in the first months of life in humans and days in rodents. This timeline suggests that a week-old rodent's reward system is similar to a human newborn's.

The early development of these circuits suggests a sensitive time when harmful environmental factors, like abuse or neglect from parents, can change how they develop. Similar effects of environment on other brain networks, like vision and hearing, are well-known. Just as these systems need specific sensory inputs to develop correctly, parental interactions may be important for the maturing reward system. Therefore, understanding how the early environment affects the reward system is key to creating treatments for OUD and other mental health issues.

Dysfunction of Reward Circuits: A Common Thread for OUD and Its Comorbidities?

Many people with OUD also have other mental health diagnoses, suggesting shared biological causes. These conditions include depression, bipolar disorder, PTSD, personality disorders, and schizophrenia, all of which may involve problems with the brain's reward system. The specific mental health conditions seen with OUD can differ between sexes. Women with OUD more often have mood, anxiety, and eating disorders, while men are more likely to have personality disorders.

People who have experienced ELA are especially likely to have multiple diagnoses, suggesting ELA affects a common pathway linking OUD and other conditions. Studies show that individuals treated for addiction who reported childhood abuse were more likely to have depression, bipolar, and anxiety disorders. Women with both PTSD and opioid abuse often share a history of childhood trauma. ELA also increases the risk for schizophrenia and psychosis, which often occur with substance use disorders. Strong cravings for tasty foods and disordered eating are also linked to ELA and are common in people with OUD. This strong connection among various reward-related problems points to a single way that problems with the reward system can lead to different negative mental health outcomes.

Developmental Origins: ELA Leads to Poor Neuropsychiatric Health Outcomes

Many studies show that ELA is linked to poorer thinking skills and emotional well-being. For example, ELA is associated with lower educational success and weaker executive functions. Research also connects adverse childhood experiences to a higher risk for depression, anxiety, PTSD, eating disorders, and psychosis. The specific mental health problems from ELA can differ by sex. Women are more often diagnosed with anxiety and depression, while men are more likely to develop personality disorders after ELA. This pattern is similar to what is observed in individuals with OUD and co-occurring conditions.

ELA is also strongly linked to substance addiction later in life. Studies indicate that ELA can increase the risk for injection drug use and makes people more likely to start using drugs early, regardless of drug availability or social views. This suggests that adverse experiences directly affect addiction risk. Additionally, those with a history of ELA are more likely to receive opioid pain prescriptions. This connection occurs because ELA increases the chances of other health and social problems, showing how various issues related to ELA combine, making it hard to identify exact causes.

Women seem especially vulnerable to OUD after ELA. Even though men generally have higher rates of substance dependence, women with ELA are disproportionately represented among users of heroin and non-prescribed opioids. Women with OUD are also two to three times more likely than men with OUD to have PTSD linked to ELA. While girls often experience more childhood trauma, the large difference suggests sex plays a key role. The specific type of adversity can also influence how the striatum responds to reward. For instance, emotional neglect in childhood was linked to drug dependence in women, while PTSD predicted drug issues in men. Other co-occurring conditions also differed by sex: men often showed antisocial behaviors, while women were more frequently diagnosed with anxiety and depression. These variations suggest that ELA may affect reward circuit development differently in men and women, leading to varied mental health outcomes.

Anhedonia and OUD, Each Manifestations of Reward Circuit Dysfunction, Arise After ELA

The previous sections indicate a strong link between ELA and problems with the reward system. These problems can show up as OUD or other issues with reward behaviors. Many of these issues are common across several mental illnesses and may have similar biological roots. Anhedonia, which is the inability to feel pleasure, is a symptom in some individuals with substance use disorder and other mental health conditions often seen with addiction, including depression, schizophrenia, psychosis, PTSD, eating disorders, and other risky behaviors.

Anhedonia is a valuable concept for understanding how changes in reward processing contribute to mental health conditions. Because its biological basis can be studied with both human and animal measures, anhedonia is useful for researching reward system problems and related behavioral disorders that appear after ELA. Anhedonia is a common symptom of many mental health problems caused by ELA, which suggests that ELA affects mental well-being by disrupting how the reward system develops. Anhedonic behaviors can be measured in different ways in humans and animals, and these behaviors may involve different brain processes. For example, anhedonia can involve problems with anticipating or experiencing pleasure, or with motivation. It can also appear for certain rewards but not others, like social versus food rewards, and can manifest as a lack of emotional expression. Researchers are studying the brain systems that control these various forms of anhedonia and how ELA specifically affects different types of anhedonic behaviors and their underlying brain systems.

How Does ELA Provoke Anhedonia, OUD, and Comorbidities? A Need for Animal Studies

Human studies provide valuable information about how ELA affects the brain's reward system. However, in humans, it is hard to separate the effects of early life experiences from other genetic and environmental factors that link ELA, OUD, and related conditions. Animal models allow researchers to study the effects of these environmental factors by themselves.

Animal studies use various ELA models, such as maternal separation or limited nesting, to examine how adversity affects brain development, separate from other factors. Research in rodents and primates shows that ELA leads to behaviors indicating problems in reward-related brain areas. The specific behavioral effects of ELA in animals can differ based on the type, timing, and length of the adversity, the animal species, and the tests used, as well as the animal's sex. While this variability makes the research complex, it reflects human experience; ELA in humans also comes in many forms, like poverty or abuse. These factors, combined with other biological elements, likely contribute to why people have different outcomes, showing how sensitive the brain is to different types of stress during development.

Since anhedonia is linked to many mental health problems caused by ELA, studying if ELA directly causes anhedonia can help identify brain mechanisms behind OUD and its related conditions. Animal studies focusing on anhedonia show that its presence depends on the specific ELA method, biological sex, and testing conditions. For example, male rodents exposed to limited nesting early in life show lasting anhedonia for natural and drug rewards, including less interest in sweets, tasty foods, and social play, and reduced cocaine use. However, female rats exposed to the same conditions do not show this type of anhedonia, although some studies report reduced sweet preference and depressive behaviors in female mice at different ages. In maternal separation models, both male and female rats show less preference for sweets later in life. Non-human primates that experienced maternal deprivation or maltreatment also display anhedonia, such as reduced interest in sweets or social interaction, though some studies have found increased sweet consumption in young males. Interestingly, some studies show that after ELA, there is increased sensitivity to drug rewards and behaviors linked to addiction, which seems to contradict the idea of anhedonia for natural rewards. However, these findings suggest that how ELA affects the reward system depends on the type of reward and the way it is tested. This means that feeling less pleasure (anhedonia) and seeking out rewards more strongly are not always opposites.

While the impact of ELA on alcohol and cocaine seeking is well-researched, less is known about its specific effects on opioid addiction risk. Some studies indicate that maternal separation increases morphine seeking in both male and female adult rats, while others only observe this in males. Research also shows that male rats exposed to maternal separation prefer places associated with morphine more than control rats and show increased sensitivity to the drug's effects after repeated use. However, other studies found that maternal-separated females were less sensitive to heroin's rewarding properties. Using the limited nesting model of ELA, researchers found that while males developed anhedonia for natural rewards like social play and sweets, females showed a very different outcome. Females exposed to limited nesting displayed a significant increase in opioid-seeking behaviors similar to addiction. These rats were harder to deter from seeking opioids, responded more strongly to cues that triggered opioid use, and were highly motivated to self-administer the opioid remifentanil, even when it required significant effort. Their motivation for tasty food was also much higher, alongside their increased opioid-seeking. This pattern has also been seen in human patients seeking OUD treatment.

In summary, studies in rodents and primates suggest that ELA interferes with the development of reward circuits. The behavioral effects depend on when, how long, and what type of ELA occurred, and are also influenced by sex. Males often show problems with reward-seeking behaviors, but females typically do not. Instead, females often show increased consumption of opioids, other drugs, and tasty food. The reasons for these differences are not well understood but may involve changes in both reward and stress systems due to ELA. Research indicates that stressed female rats tend to eat more palatable food for pleasure, and this can be linked to anhedonia. More research is needed to understand why cravings for tasty food are a sex-dependent co-occurring condition with OUD. The varied effects of ELA on different reward-seeking behaviors in animal models show that reward processing is not a single process. Instead, individuals may show different behaviors, suggesting distinct ways in which the reward circuit can be disrupted. Therefore, further study into how ELA changes specific parts of reward processing and their underlying brain systems is vital to understand the biological factors that contribute to OUD risk and related disorders.

How Might ELA Lead to OUD and Related Disorders? Evidence from Clinical Imaging Studies

Human brain imaging studies show that ELA can hinder the development of specific brain regions and circuits involved in reward, increasing the risk for substance use and related mental health issues. Many studies have found that ELA affects the function and structure of brain areas important for reward and learning, such as the hippocampus, amygdala, medial prefrontal cortex, and striatum (including the nucleus accumbens). Childhood maltreatment is linked to reduced activity in these brain regions during reward tasks, which could explain why individuals with ELA experience anhedonia. The striatum appears especially important in connecting ELA to reduced reward response. Specifically, the ventral striatum seems to be a key link among ELA, anhedonia, and substance use. Research indicates that less reward activity in the ventral striatum predicts anhedonia linked to ELA, and this relationship also predicts using substances to cope. This suggests a common way ELA can lead to OUD and its related conditions. The specific type of adversity can also influence how the striatum responds to reward; for example, childhood poverty is linked to increased reward reactivity in the striatum, particularly in girls. These differences, based on sex and experience, match the varied mental health outcomes observed in humans and animal behaviors.

ELA Causes Functional and Anatomical Changes in Reward-Related Brain Regions: Evidence from Animal Models

Building on human research, animal studies help identify the mechanisms behind problems in the reward system after ELA. Like in humans, these outcomes seem partly influenced by sex. In male rats, anhedonia after limited nesting is linked to altered communication between the amygdala and the medial prefrontal cortex, possibly due to changes in stress hormones in the amygdala. Depressive behaviors and anhedonia for natural rewards after limited nesting are also associated with disrupted connections between the amygdala-prefrontal cortex and prefrontal cortex-striatum. Studies have also noted structural and functional changes in the basolateral amygdala and reduced connections between it and the prefrontal cortex in male rats exposed to limited nesting. Maternal separation-induced ELA changes how connections from the prefrontal cortex to the nucleus accumbens develop and affects dopamine signaling in this pathway in male rats. In females, maternal separation causes the basolateral amygdala-prefrontal cortex circuit to mature early, and early social stress changes resting brain connections in the nucleus accumbens, hippocampus, and prefrontal cortex. In non-human primates, maltreatment during infancy leads to a larger amygdala and altered connections in areas linked to mood disorders. Studies measuring brain cell activity also point to specific changes in reward circuit function caused by ELA. Specifically, ELA leads to less activity in the nucleus accumbens in response to rewarding social interactions, or unusual over-activity in other regions linked to stress and reward.

The effects of ELA on OUD and related conditions may involve changes in brain chemicals called neurotransmitters and neuromodulators. While a full discussion is beyond this scope, it is important to note that dopamine (DA) signaling plays a large role in motivation and reward-seeking. Changes in DA signaling are crucial for drug-seeking, as well as for mental health issues related to ELA like mood disorders and psychosis, and have been linked to anhedonia. ELA has been extensively connected to problems with the DA system in rodents, particularly in the striatum. This may be influenced by changes in other brain chemical systems related to stress and reward. Also, the effects of early life experiences on DA signaling might be stronger in females. This suggests that DA signaling problems caused by ELA could be involved in OUD and its related conditions.

Natural opioids in the body are important for experiencing pleasure and for social bonding early in life. Thus, the body's opioid system might be a key link between ELA and later reward-related issues. Changes in opioid receptor levels have been seen in both males and females after ELA, but they differ by sex. For instance, female mice showed increases in certain opioid receptor levels in the nucleus accumbens after early life stress. Other research has found long-term changes in natural opioid chemicals and in opioid and dopamine receptor levels in reward areas, with these changes differing by sex and the length of maternal separation. Opioid receptors are known to affect dopamine signaling in the striatum, and ELA may strengthen this effect. Therefore, problems with natural opioids could also explain how ELA changes dopamine signaling in the striatum, leading to unusual reward behaviors. These disruptions in both opioid and dopamine systems caused by ELA suggest a way that ELA can simultaneously lead to mental health disorders and increased opioid use.

Combined with human evidence, these findings show that ELA changes key parts of the reward system, making individuals more vulnerable to negative mental health outcomes. Establishing a direct causal link between the brain network and molecular changes caused by ELA and the resulting reward problems is a crucial area of ongoing research to treat OUD and its co-occurring mental health conditions.

Conclusion

Research from various species shows that ELA during key developmental periods changes how the brain's reward system develops. More study is needed to understand the exact nature of ELA, how different types of ELA lead to different outcomes, and the specific ways reward circuits mature abnormally. The resulting problems with reward processing are likely a common cause for OUD and its related mental health conditions. Both animal and human studies show that these problems with reward circuits appear in various ways, depending on the type and severity of adversity, biological sex, and later life experiences. However, consistent problems with the function, structure, and molecular makeup of reward-related brain areas, such as the medial prefrontal cortex, striatum, and amygdala, have been observed across many studies and species, suggesting a common starting point. Anhedonia may also be a key behavioral sign of disturbed reward processing that connects ELA, OUD, and other mental health issues. Further research into the brain's biological basis for ELA-induced reward circuit problems will offer crucial insights into the origins of OUD and its co-occurring conditions, potentially leading to new, effective treatments.

Introduction

Opioid use disorder (OUD) is a growing problem worldwide. Individuals with OUD often experience other mental health conditions, such as depression or bipolar disorder, which frequently involve issues with how the brain processes rewards. Understanding the reasons for these disruptions could improve treatment for both OUD and its related conditions. Many factors contribute to the risk of developing OUD, including genetics, drug availability, and early life adversity (ELA). ELA, which affects a significant number of children, encompasses experiences like poverty, trauma, and chaotic environments. It is linked to numerous long-term health problems, including difficulties with thinking and emotions. This suggests that ELA can disrupt the brain’s reward system. The focus here is on how ELA impacts reward-related behaviors and the brain circuits involved, suggesting this disruption is a common way OUD and its related mental health issues can develop, with biological sex playing an important role in these outcomes.

Early Development and Mental Health Risks

The brain's reward system is a network that drives the pursuit of natural rewards like food and water. However, if this system functions poorly, it can lead to mental health problems such as mood disorders and addiction. This reward circuitry develops significantly in early life, suggesting a sensitive period during which environmental factors, such as parental abuse or neglect, can profoundly influence its development. Just as other brain systems need specific sensory inputs to mature correctly, parental signals might be crucial for the developing reward system. ELA is strongly associated with poor cognitive and emotional health, including lower academic achievement and higher risks for depression, anxiety, post-traumatic stress disorder (PTSD), and psychosis. These mental health outcomes, including those co-occurring with OUD, often differ between men and women. For instance, women are more likely to experience anxiety and depression after ELA, while men may be more prone to personality disorders. Crucially, ELA substantially increases the risk for substance addiction, including opioid use, and the likelihood of needing opioid pain medication.

Anhedonia: A Central Symptom

The high rate of co-occurring mental health conditions in people with OUD suggests shared underlying processes, often linked to problems in the reward circuits. A key symptom that bridges OUD and many other mental health disorders like depression, schizophrenia, and PTSD is anhedonia—the inability to experience pleasure. Anhedonia is considered a valuable concept for understanding how altered reward processing contributes to various psychiatric conditions, especially after ELA. It can manifest in different ways, such as deficits in anticipating rewards or in experiencing pleasure from them, and can be specific to certain types of rewards (e.g., social versus food). The widespread presence of anhedonia across many mental health problems resulting from ELA suggests that a disruption in the development of reward circuits is a common mechanism through which ELA impacts overall mental and emotional well-being.

Insights from Animal and Imaging Studies

While human studies offer important insights, animal models allow researchers to isolate the effects of ELA on brain development from other variables. Studies in animals using various ELA models show that early adversity leads to behaviors indicative of reward circuit dysfunction. The specific behavioral outcomes can depend on the type, timing, and duration of ELA, as well as the animal's biological sex. For example, some studies show that male animals exposed to ELA develop anhedonia for natural rewards, while female animals may show a significantly increased drive for opioid drugs and palatable food. This suggests that ELA disrupts reward circuits in sex-specific ways. Human brain imaging studies further support these findings, showing that ELA affects the development of key reward-related brain regions, such as the striatum, hippocampus, amygdala, and prefrontal cortex. ELA is often associated with reduced activity in these areas during reward processing, which could explain anhedonia. Animal models have also revealed that ELA causes functional and anatomical changes in these brain regions and alters critical neurotransmitter systems, including dopamine and endogenous opioids, which are vital for reward and motivation.

Conclusion

Evidence from both human and animal research indicates that early life adversity during sensitive developmental periods alters the normal development of the brain's reward circuitry. This leads to impaired reward processing, which appears to be a common underlying cause for opioid use disorder and its many co-occurring mental health conditions. The specific ways these problems manifest are varied, influenced by the nature and extent of the adversity, an individual's biological sex, and later life experiences. However, consistent functional, anatomical, and molecular disruptions have been observed in key brain regions like the prefrontal cortex, striatum, and amygdala across different study models and species. Anhedonia stands out as an important behavioral indicator of disturbed reward processing that links ELA to OUD and other mental health challenges. Continued research into the neurobiological foundations of ELA-induced reward circuit disruptions is essential to better understand the origins of OUD and its related conditions and to develop effective new treatments.

Opioid Use Disorder and Early Life Adversity

Opioid use disorder (OUD), also known as opioid addiction, is a growing problem globally. To reduce the number of illnesses and deaths related to opioids, it is important to find effective ways to prevent addiction. This involves identifying people at high risk for developing OUD. Often, OUD occurs alongside other mental health conditions like depression, bipolar disorder, and schizophrenia. These conditions all involve problems with how the brain processes rewards. Studying these brain disruptions can help better understand and treat both OUD and its related mental health issues.

Many factors contribute to the risk of OUD. These include genetics, the availability of drugs, and environmental factors such as difficult experiences early in life (ELA). ELA includes poverty, trauma, and unstable home environments, affecting a significant number of children. ELA is linked to various long-term health problems, including physical illnesses and cognitive and emotional difficulties. It is also associated with emotional issues that suggest problems with the brain’s reward system. This discussion focuses on how ELA affects reward-related behaviors and the brain circuits involved. It proposes that problems with reward processing are a common way OUD and other mental health conditions can develop after ELA. The role of biological sex in these outcomes is also highlighted.

How Reward Circuits Develop Early in Life

The brain’s reward circuit is a network of structures that control how people seek out rewards. This circuit naturally drives us to seek essential rewards like food, water, and opportunities for reproduction. However, if this circuit doesn't function correctly, it can lead to mental health issues like mood disorders and addiction.

While much is known about the reward circuit in older brains, less is understood about its development in infants and young children. Key parts of this circuit, such as the ventral tegmental area, nucleus accumbens, and amygdala, begin forming early in development and continue to mature significantly after birth. Behaviors related to reward, like enjoying sweet tastes and learning from rewards, appear within the first few months of life in humans. This suggests that the early development of these circuits might be a "sensitive period." During this time, negative experiences, such as abuse or neglect, could significantly impact how these circuits develop. Just as other senses need specific inputs to develop correctly, parental signals may be crucial for the maturing reward system. Understanding how early environments change the reward circuit is therefore vital for developing future treatments for OUD and other mental health problems.

Is Reward Circuit Dysfunction a Link Between OUD and Other Conditions?

Many people with OUD also have other mental health problems, which suggests there might be shared underlying causes. Problems with the brain's reward circuits have been found in many of these other conditions, including depression, bipolar disorder, post-traumatic stress disorder (PTSD), personality disorders, and schizophrenia. The specific mental health problems that occur with OUD can also differ between men and women. For instance, women with OUD are more likely to also have mood, anxiety, and eating disorders, while men are more prone to personality disorders.

The rate of co-occurring diagnoses is especially high among patients who have experienced early life adversity (ELA). This suggests that ELA might affect a common brain system involved in both OUD and its related conditions. Studies show that patients with a history of childhood abuse are more likely to have symptoms of other reward-related issues like depression, bipolar, and anxiety disorders. A strong link has also been found between PTSD and opioid abuse in women, often explained by childhood trauma. ELA also increases the risk for schizophrenia and psychosis, which are highly connected with substance use disorders. Additionally, strong cravings for tasty foods and disordered eating are common after ELA and are frequently seen in individuals with OUD. This strong co-occurrence of various reward-related problems points to a common underlying mechanism where problems in the reward circuit can lead to a range of poor mental health outcomes.

Early Life Adversity Leads to Poor Mental and Brain Health

Many studies have connected early life adversity (ELA) to difficulties with thinking skills and emotional health. For example, ELA is linked to lower educational success and poorer abilities in planning and decision-making. Clinical research consistently shows that adverse childhood experiences increase the risk for depression, anxiety, PTSD, eating disorders, and psychosis. The specific mental health problems that arise from ELA also vary by biological sex. Women are more often diagnosed with anxiety and depression, while men are more likely to receive a diagnosis of personality disorder after ELA. This pattern is similar to what is seen in individuals with OUD who have other co-occurring conditions.

Adverse childhood experiences are also strongly linked to substance addiction later in life. Research indicates that ELA can significantly increase the risk for drug use, even making people start using drugs earlier, regardless of drug availability or social attitudes. This suggests a specific impact of ELA on the likelihood of addiction. Furthermore, individuals with a history of ELA are more likely to be prescribed opioid pain medications. This is partly because they are more likely to experience other health and social problems, highlighting how various physical and mental health issues associated with ELA are interconnected.

Interestingly, women appear to be particularly vulnerable to OUD after experiencing ELA. Although men generally have higher rates of substance dependence, women who have experienced ELA are overrepresented among those using heroin and non-prescribed opioids. Women diagnosed with OUD are also much more likely than men with OUD to have a history of PTSD related to early life trauma. While girls might experience more childhood trauma than boys, the extent of this difference suggests that biological sex plays a significant role. The specific type of adversity experienced can also interact with sex to affect outcomes. For example, emotional neglect during childhood was found to predict drug dependence in women, while PTSD predicted drug-related diagnoses for men. These differences suggest that ELA may alter reward circuit development differently in men and women, leading to different mental health outcomes.

Anhedonia and OUD: Signs of Reward Circuit Problems After ELA

The information above suggests a strong connection between early life adversity (ELA) and problems in the brain's reward circuit. These problems can show up as opioid use disorder (OUD) or other difficulties with reward-related behaviors. Many of these issues are common across several mental illnesses and might share similar biological underpinnings. Anhedonia, broadly defined as the inability to experience pleasure, is a feature of substance use disorder in some individuals. It is also found in other mental health diagnoses that often occur with addiction, such as depression, schizophrenia, PTSD, and eating disorders.

Anhedonia is a useful concept for understanding how altered reward processing contributes to the causes of various mental health conditions. By identifying the brain-based reasons for anhedonia and measuring it in both humans and animal models, it becomes a valuable concept for studying reward circuit problems and related behavioral disorders that appear after ELA. The widespread presence of anhedonia in many of the mental health outcomes of ELA suggests that a key way ELA impacts cognitive and emotional health is by disrupting the development of the reward circuit. Anhedonia can show up in different ways, such as problems with anticipating pleasure or experiencing pleasure in the moment, or for certain types of rewards (like social vs. food). Further research into how ELA affects these different forms of anhedonia and their specific brain mechanisms is an important area of study.

Animal Studies: How ELA Causes Anhedonia, OUD, and Related Conditions

While studies in humans offer important insights into how early life adversity (ELA) affects reward circuits, it is hard to separate the effects of early life experiences from other genetic and environmental factors. Animal models allow researchers to study the effects of these environmental factors in isolation.

In animal studies, different models of ELA are used to study how adversity affects brain development without other variables. These methods, such as separating newborns from their mothers or limiting bedding and nesting materials, have shown that ELA leads to behaviors that suggest problems in reward-related brain regions. The specific behavioral outcomes in animals can vary depending on the type, timing, and length of the adversity, the animal species, and even its biological sex. This variability reflects the human experience, where ELA can take many forms (poverty, abuse, neglect) and combine with other factors to influence individual outcomes, highlighting how sensitive the brain is to different stressors during development.

Since anhedonia (the inability to feel pleasure) is linked to many mental health issues caused by ELA, studying whether ELA can actually cause anhedonia is useful for understanding the brain mechanisms behind ELA-related OUD and other conditions. Some animal studies focus on anhedonia, showing that its appearance can be influenced by the ELA model, biological sex, and how it is tested. For example, in male rodents, a specific type of ELA can lead to long-lasting anhedonia for natural rewards (like sweet foods and social interaction) and drug rewards. However, this anhedonia is not always seen in female rats after the same type of ELA. Other studies using different ELA models have found reduced pleasure in both male and female rats later in life. Anhedonia has also been reported in non-human primates that experienced maternal separation or maltreatment, showing reduced interest in sweet tastes or social interaction.

In contrast to anhedonia for natural rewards, some studies show increased sensitivity to drug-related rewards and addiction-like behaviors after ELA. While this might seem contradictory, it supports the idea that how altered reward circuits are expressed depends on the type of reward and the testing method. Thus, anhedonia and seeking rewards are not always mutually exclusive. While the effects of ELA on increased alcohol and cocaine seeking have been well-studied, less work has focused specifically on how ELA affects vulnerability to opioid addiction. Some evidence suggests that early maternal separation increases opioid seeking in both male and female adult rats, though some studies find this preference only in males. Other research has shown that males who experienced maternal separation show a greater preference for morphine and increased sensitivity to its effects. However, some studies found reduced sensitivity to heroin's rewarding properties in females who experienced maternal separation. Our research using a limited bedding and nesting model of ELA showed that while males developed anhedonia for natural rewards, females developed a very different pattern. Females exposed to this ELA showed a significant increase in addiction-like seeking for opioid drugs. These rats found it harder to stop seeking opioids, were more likely to relapse when exposed to cues or the drug itself, and were more motivated to get opioids even at a high cost. Their motivation for tasty food was also higher, similar to what is seen in patients seeking treatment for OUD.

Overall, findings from rodents and non-human primates suggest that ELA disrupts the development of reward circuits. The resulting behavioral problems can vary depending on the timing, length, and nature of the ELA, and are further influenced by biological sex. While males often show deficits in reward-seeking behaviors, females do not commonly show such deficits. Instead, females often show increased consumption of opioids and other drugs of abuse, as well as tasty foods. The reasons behind these differences are not well understood but may involve ELA-induced changes in both reward and stress circuits. Further research is needed to understand the causes of tasty food cravings as a sex-dependent co-occurring condition with OUD. The varied consequences of ELA on different measures of reward-seeking behaviors in animal models show that reward processing is complex. Individuals can express different and distinct problems, suggesting that ELA might disrupt reward circuits in various ways. Investigating how ELA alters specific aspects of reward processing and the underlying brain mechanisms will be crucial for understanding the biological factors that contribute to the risk of OUD and related disorders.

ELA's Link to OUD and Related Disorders: Insights from Human Brain Scans

Evidence from human brain imaging studies indicates that early life adversity (ELA) can impair the development of specific reward-related brain regions and circuits, increasing the risk for substance use and related mental health conditions. Many studies have shown that ELA affects the structure and function of brain areas involved in reward and reward-learning, such as the hippocampus, amygdala, prefrontal cortex, and striatum. Childhood maltreatment is linked to reduced activity in these brain regions during reward processing tasks, which might explain why anhedonia is present in individuals who have experienced ELA. Among these areas, the striatum appears especially important in connecting reduced reward responsiveness with ELA. The ventral striatum, in particular, seems to be a key link between ELA, anhedonia, and using substances to cope. This finding highlights a possible common mechanism through which ELA can lead to OUD and its related conditions. The specific type of adversity experienced may also influence the striatal response to reward. For example, childhood poverty is associated with increased reactivity to reward in the striatum, especially in girls. These differences based on sex and experience are consistent with the observed variety of mental health outcomes in humans and behaviors in animals.

ELA Causes Brain Changes in Reward Areas: Evidence from Animal Models

Building on human clinical evidence, animal studies provide tools to identify the specific mechanisms underlying disruptions in reward circuits after early life adversity (ELA). These outcomes also appear to be partly influenced by biological sex. In male rats, anhedonia after a specific type of ELA is linked to altered communication between the amygdala and a part of the prefrontal cortex, which might involve levels of a stress hormone. This is supported by findings that depression-like behaviors and anhedonia for natural rewards after ELA are associated with disrupted functional connections between these brain areas. Other studies have observed changes in the structure and function of parts of the amygdala and reduced communication between the amygdala and prefrontal cortex in male rats exposed to ELA. ELA caused by maternal separation in male rats alters the development of connections and dopamine signaling in pathways related to the prefrontal cortex and nucleus accumbens. In females, maternal separation leads to early maturation of specific brain circuits, and early life social stress alters how various brain regions, including the nucleus accumbens, hippocampus, and prefrontal cortex, communicate when at rest. In non-human primates, maltreatment during infancy leads to an increased amygdala size and altered connections in regions linked to mood disorders. Studies measuring brain cell activity also suggest that ELA causes specific changes in how reward circuits function. Specifically, ELA leads to reduced activity in a brain region called the nucleus accumbens in response to typical rewards like social interaction, or abnormal over-activity in other regions related to stress and reward.

Molecular mechanisms that contribute to ELA's effects on OUD and related conditions may involve changes in brain chemical systems, such as neurotransmitters and neuromodulators. Dopamine signaling plays a crucial role in motivated and reward-seeking behaviors. Altered dopamine signaling is an important factor in drug seeking as well as other mental health problems associated with ELA, such as mood disorders and psychosis, and has been linked to anhedonia. ELA has been extensively connected to problems with the dopamine system in rodents, especially in a brain region called the striatum. These problems might be influenced by changes in other stress and reward-related chemical systems. Additionally, the effects of early life experiences on dopamine signaling may be more pronounced in females. It is therefore suggested that ELA-provoked problems in dopamine signaling could be involved in ELA-related OUD and its co-occurring conditions.

Natural opioids in the body also play an important role in pleasure and social bonding early in life. So, the body's natural opioid system might also be a key link between ELA and later reward-related outcomes. Changes in opioid receptor levels have been observed in both male and female animals after ELA, though they differ between the sexes. For example, female mice showed increases in specific opioid receptor levels after early life stress. Other studies have found long-term changes in natural opioid chemicals and the expression of opioid and dopamine receptors in reward-associated brain areas, which vary by sex and the duration of early life stress. Opioid receptors are known to affect dopamine signaling in the striatum, an effect that may be strengthened by ELA. Thus, disturbances in the body's natural opioid system might also contribute to ELA-induced changes in striatal dopamine signaling, leading to abnormal reward-related behaviors. These ELA-induced disruptions in opioid and dopamine systems suggest a mechanism by which ELA might simultaneously or in parallel lead to mental health disorders and increased consumption of opioids.

Together with human research, these findings demonstrate that ELA alters important connections in the reward circuit, making individuals vulnerable to poor mental health outcomes. Establishing clear cause-and-effect relationships between ELA-induced changes at the network and molecular levels and the resulting reward-related problems remains an important area of research to find cures for OUD and its co-occurring mental health conditions.

Conclusion

Evidence from different species suggests that early life adversity (ELA) during sensitive developmental periods changes how the brain's reward circuits develop. The exact nature of ELA, the potentially different results from various types of ELA, and the specific mechanisms behind these abnormal changes in reward circuits still require much investigation. The resulting unhealthy reward processing is likely a common mechanism underlying both opioid use disorder (OUD) and its related mental health problems. As shown in both animal and human studies, the ways this abnormal reward circuit function appears are varied and depend on the type and extent of adversity, biological sex, and later life experiences. However, disruptions in the function, structure, and molecular makeup of reward-related brain regions—such as the medial prefrontal cortex, striatum, and amygdala—have been observed across many research settings and species, suggesting a common origin from early development. Likewise, anhedonia (the inability to feel pleasure) may be an important behavioral sign of disturbed reward processing that connects ELA, OUD, and other mental health problems. Further research into the brain-based reasons for ELA-induced disruptions in reward circuits will provide key insights into the origins of OUD and its co-occurring conditions and may uncover new, successful treatments.

Introduction

Opioid use disorder (OUD) is a serious problem for many people. To stop this problem from getting worse, it is important to find people who are at high risk of developing OUD. Often, people with OUD also have other mental health problems like sadness or mood swings. These problems involve how the brain handles rewards and pleasure. Learning more about this can help treat both OUD and other mental health issues.

Many things can raise the risk for OUD, such as a person's genes, how easy it is to get drugs, and hard times in childhood. These hard times, like poverty, trauma, or a chaotic home, affect many children. Such experiences are linked to long-term health problems and emotional difficulties. They are also connected to how the brain's reward system does not work properly. This information explains how hard times in childhood can lead to problems with the reward system, which can then cause OUD and other related mental health issues. It also looks at how a person's sex can play a role.

Normal Reward Circuit Development Involves An Early-Life Sensitive Period

The brain's reward system is a group of areas that control our desire for good things like food, water, and connection with others. If this system does not work correctly, it can lead to problems like mood disorders and addiction.

Scientists have studied the reward system a lot in teens and adults, but less so in babies and very young children. Key parts of this system begin to form even before birth and continue to grow a lot after a baby is born. Behaviors related to rewards, such as liking sweet tastes or learning to want things, start in the first few months of life. This early time in life is very important because bad experiences, like abuse or neglect, can change how these brain parts grow. This is similar to how eyes and ears need normal signals to grow properly. Signals from parents may be important for the growing reward system. So, understanding how early life experiences change the reward system is key to finding ways to prevent OUD and other mental health problems.

Dysfunction of Reward Circuits: A Common Thread for Oud and Its Comorbidities?

Many people who have OUD also have other mental health issues. This suggests that OUD and these other problems might have similar causes in the brain. OUD is often found alongside issues like sadness, mood swings, extreme fear after trauma, personality problems, and seeing or hearing things that are not real. Problems with the reward system in the brain are linked to many of these other mental health diagnoses. The specific mental health problems that occur with OUD can also be different for men and women. For example, women with OUD are more likely to also have mood, anxiety, and eating disorders, while men are more likely to have personality disorders.

Having both OUD and other mental health problems is especially common for people who went through hard times in childhood. This suggests that early life hardship might affect a shared brain system that leads to both OUD and these other issues. Studies show that people who were treated for drug problems and reported childhood abuse also often showed signs of depression, mood swings, and anxiety disorders. Another study found a strong link between extreme fear after trauma and opioid abuse in women, which was explained by childhood trauma. The risk for seeing or hearing things that are not real is also higher after early life hardship, and these conditions often occur with drug use problems. Strong cravings for tasty food and problems with eating are also closely linked to hard times in childhood and are often seen in people with OUD. All these common problems suggest that when the brain's reward system is disrupted, it can lead to a variety of mental health difficulties.

Developmental Origins: Ela Leads to Poor Neuropsychiatric Health Outcomes

Many studies connect hard times in childhood to poor thinking skills and emotional health. For example, early life hardship is linked to less success in school and poorer ability to plan and focus. Research shows that difficult childhood experiences increase the risk for sadness, anxiety, extreme fear after trauma, eating disorders, and seeing or hearing things that are not real. The specific mental health problems that result from early life hardship also differ between men and women. Women are more often diagnosed with anxiety and sadness, while men are more likely to be diagnosed with personality disorders after early life hardship. This pattern is similar to what is seen in people with OUD and other problems.

Hard childhood experiences are also strongly linked to drug addiction later in life. Studies show that early life hardship can greatly increase the risk for injecting drugs. It also makes it more likely for a person to start using drugs early, no matter how easy drugs are to get or how society feels about drugs. This suggests that bad experiences specifically affect how likely a person is to become addicted. Additionally, people who had difficult early lives are more likely to be given opioid pain medications. This happens because they are more likely to have other health and life problems, which shows how different physical and mental health issues related to early life hardship are connected.

It appears that women are especially likely to develop OUD after hard times in childhood. Even though men are diagnosed with drug dependence more often overall, women who experienced early life hardship make up a larger group of those who use heroin and prescription opioids without medical need. Women diagnosed with OUD are also two to three times more likely to have a history of extreme fear after trauma related to early life hardship than men with OUD. While girls tend to experience more childhood trauma than boys, the size of this difference suggests that a person's sex plays a special role. The type of hardship experienced can also interact with a person's sex to affect the outcomes. For example, emotional neglect during childhood predicted drug dependence in women, while extreme fear after trauma predicted drug-related diagnoses for men. Again, other problems differed by sex; men were more likely to show antisocial behaviors, while women were more likely to be diagnosed with anxiety and sadness. These differences suggest that early life hardship may change how the reward system develops in different ways for men and women, leading to different mental health outcomes.

Anhedonia and Oud, Each Manifestations of Reward Circuit Dysfunction, Arise After Ela

The information above suggests a strong link between hard times in childhood and problems with the brain's reward system. These problems can show up as OUD or other difficulties related to how rewards are processed. Many of these issues are common across several mental illnesses and may share similar root causes in the brain. Anhedonia, which means not being able to feel pleasure, is a feature of drug use problems in some people, and also of other mental health diagnoses that often occur with addiction. These include sadness, seeing or hearing things that are not real, extreme fear after trauma, and eating disorders.

The idea of anhedonia is helpful for understanding how changes in the brain's reward system contribute to mental health problems. Because anhedonia can be defined by brain biology and measured in both people and animals, it is a useful concept for studying problems with the reward system that happen after early life hardship. The fact that anhedonia is so common in many mental health problems resulting from early life hardship suggests that these difficult experiences hurt the development of the reward system. There are different types of anhedonia, which can be measured in people and animal studies, and these types may involve different brain processes. For example, anhedonia might mean a problem with wanting a reward in the future, or with enjoying a reward in the moment. It can also be for some rewards, like social time, but not others, like food. How early life hardship affects these different types of anhedonia and the brain parts involved is an important area of ongoing study.

How Does Ela Provoke Anhedonia, Oud, and Comorbidities? A Need for Animal Studies

Studies in people give us important information about how hard times in childhood affect the brain's reward system. However, it is hard to separate these effects from other factors like a person's genes or other life experiences. Animal studies help scientists look at the effects of hard times in childhood on brain development by themselves.

In animal studies, different ways to create early life hardship have been used to study how bad experiences affect the brain. Many studies in rats and monkeys have shown that early life hardship leads to behaviors that suggest problems in brain areas related to rewards. The exact behaviors seen can change depending on the type, timing, and length of the hardship, the animal's species, and when and how the behaviors are tested. This variety also happens in people, where early life hardship can take many forms like poverty, trauma, or neglect. This shows how sensitive the brain is to different kinds of stress during its development. Since not feeling pleasure (anhedonia) is linked to many mental health problems caused by early life hardship, finding out if early life hardship actually causes anhedonia helps us understand the brain mechanisms involved. This could ultimately help explain OUD and other problems linked to early life hardship.

How anhedonia shows up in animal models depends on the specific early life hardship, the animal's sex, and the testing conditions. For example, in male rats, being raised for a week with limited nesting materials led to lasting anhedonia for natural rewards like sweets, tasty food, and playing with others. These males also showed less interest in using cocaine. However, female rats did not show this type of anhedonia after the same hardship. Yet, other studies found less liking for sugar and behaviors like sadness in female mice. Another model of early life hardship (separating babies from their mothers) showed reduced sugar liking in both male and female rats later in life. Anhedonia has also been reported in monkeys that experienced early neglect, showing less interest in sugar or social interaction. However, some studies found more sugar drinking in young male monkeys.

Other studies have shown that early life hardship can lead to more sensitivity to drug-related rewards and behaviors linked to addiction. This might seem to contradict the idea of anhedonia, but it suggests that how early life hardship changes the reward system depends on the type of reward and how it is tested. So, not feeling pleasure for natural things and wanting drugs more are not always separate. While the effects of early life hardship on increased alcohol and cocaine seeking have been widely studied, less work has been done on its effects specifically on opioid addiction. Some evidence shows that early stress increases morphine seeking in both male and female adult rats, while other studies observed morphine seeking only in stressed males. One group found that male rats with early stress showed a stronger preference for morphine and reacted more strongly to it. However, other researchers found that stressed female rats were less sensitive to the rewarding effects of heroin.

Our group has shown that while male rats with early life hardship lost interest in natural rewards, female rats developed a very different outcome. These female rats showed a strong increase in wanting opioid drugs. They were hard to stop from seeking opioids, had stronger reactions to drug cues, and were much more motivated to get the opioid, even when it was very difficult. Their motivation for tasty food was also significantly higher, which is also seen in people seeking treatment for OUD.

Overall, findings in animals suggest that early life hardship changes how reward systems grow. The results can vary based on the timing, length, and type of hardship, and are also affected by sex. While males may show less interest in rewards, females often show an increased desire for opioids and tasty food. The reasons for this are not well understood, but may involve changes in both reward and stress systems. For example, stressed female rats tend to eat more tasty food, and this might be linked to not feeling pleasure. More research is needed to understand why cravings for tasty food are a common problem with OUD in women. The different effects of early life hardship on reward-seeking behaviors in animals show that processing rewards is complex. Individuals can show different problems, suggesting that different parts of the reward system may be disrupted. Further study into how early life hardship changes specific parts of reward processing and the brain parts involved will be crucial for understanding the biological reasons that increase the risk for OUD and related disorders.

How Might Ela Lead to Oud and Related Disorders? Evidence from Clinical Imaging Studies

Brain scans of people suggest that hard times in childhood cause problems in the development of specific brain areas and pathways related to rewards. This can increase the risk for drug abuse and other mental health problems. Many studies have shown that early life hardship affects brain areas important for rewards and learning about them, such as the hippocampus, amygdala, and areas in the front and middle of the brain. Childhood mistreatment is linked to these brain regions being less active during tasks involving rewards, which could explain why people who have experienced early life hardship often do not feel pleasure.

Among these areas, the striatum seems especially important in linking early life hardship, reduced feelings of reward, and substance use. A specific part called the ventral striatum appears to be a key link between early life hardship, not feeling pleasure, and drug abuse. One study found that less reward reaction in the ventral striatum predicted not feeling pleasure caused by early life hardship. This also predicted using drugs to cope, like self-medication. This finding points to a possible common way that early life hardship can lead to OUD and its related problems. The type of hardship experienced can also affect how the striatum responds to rewards. For instance, childhood poverty, specifically, is linked to more reaction to reward in the striatum, especially in girls. These differences based on sex and experience match the variety of mental health outcomes seen in people and the behaviors observed in animals.

Ela Causes Functional and Anatomical Changes in Reward-Related Brain Regions: Evidence from Animal Models

Building on findings from human studies, animal studies offer ways to find out the exact mechanisms behind problems in the reward system after hard times in childhood. Similar to humans, these outcomes seem to be partly affected by sex. In male rats, not feeling pleasure after early life hardship is linked to changed connections between the amygdala and another part of the brain. Other studies support this by showing that early stress changes how different brain parts connect. Additionally, early life stress changes how certain brain pathways and dopamine signals work in male rats. In female rats, early stress causes a specific brain circuit to mature earlier. Early life social stress also changes how brain areas like the NAc, hippocampus, and front part of the brain function. In monkeys, mistreatment during infancy leads to a larger amygdala and changed connections in areas linked to mood problems. Studies that measure brain cell activity also point to specific changes in how the reward system works after early life hardship. For example, early life hardship leads to less activity in the NAc in response to a social interaction, which is usually rewarding. Or it can cause too much activity in other brain regions linked to stress and reward.

Changes in brain chemicals may explain how early life hardship affects OUD and other related problems. Dopamine is very important for motivation and wanting rewards. Changes in dopamine signals are a key factor in drug seeking, as well as other mental health problems linked to early life hardship, such as mood issues and seeing or hearing things that are not real. Dopamine problems are also connected to not feeling pleasure. Early life hardship has been widely linked to problems with the dopamine system in animals, especially in the striatum. This might be caused by changes in other chemical systems related to stress and reward. Also, the effects of early life experiences on dopamine signals may be stronger in females. So, it is possible that problems with dopamine caused by early life hardship are involved in OUD and its related mental health issues.

Natural opioids in the body also play a big role in feeling pleasure and in forming social bonds early in life. So, the body's natural opioid system might also be an important link between early life hardship and reward-related problems later on. Changes in the levels of opioid receptors have been seen in both males and females after early life hardship, though in different ways. For example, one study showed increases in certain opioid receptor levels in the NAc of female mice after early life stress from a predator smell. Other studies have found long-term changes in natural opioid chemicals and opioid and dopamine receptor levels in reward-related areas, which vary by both sex and how long the early life stress lasted. Opioid receptors are known to affect dopamine signals in the striatum, and early life hardship might make this effect stronger. Thus, problems with natural opioids and dopamine caused by early life hardship could lead to mental health disorders and increased use of opioids at the same time.

Along with evidence from human studies, these findings show that early life hardship changes important areas of the reward system. This makes people more likely to develop mental health problems. More study is needed to prove how these changes in the brain caused by early life hardship lead to reward-related problems. This will be crucial for finding cures for OUD and its related mental health issues.

Conclusion

Studies in both animals and humans suggest that hard times during important growing periods in childhood change how the brain's reward system develops. We still need much more research to understand the exact nature of these difficult experiences, how different types of hardship can have different effects, and the processes behind the abnormal growth of reward circuits. The resulting problems in how rewards are processed are likely a common reason for OUD and its related mental health issues. As both animal and human studies show, how these problems in the reward system appear can vary. It depends on the type and amount of hardship, a person's sex, and experiences later in life. However, problems with how key brain areas function and are built, such as the front part of the brain, the striatum, and the amygdala, have been described in many studies and across different animal species. This suggests a common cause linked to early life development. Similarly, not feeling pleasure (anhedonia) may be an important sign of a disturbed reward system that connects early life hardship, OUD, and other mental health problems. Further research into the brain biology behind reward system problems caused by early life hardship will give us important insights into where OUD and its related problems come from. This research may also lead to new and successful treatments.