Bridging Species and Disciplines: Incorporating Sociological Frameworks into Animal Models of Addiction

Abstract

This chapter explores the integration of sociological concepts and frameworks into animal models of addictive behaviors, aiming to enhance cross-species validity and deepen understanding of addiction’s multifaceted biopsychosocial roots. Through an interdisciplinary approach merging sociology and behavioral neuroscience, the investigation examines how experiences of discrimination and constrained agency may contribute to addiction vulnerability. Specifically, chronic social defeat stress’s impact on drug-seeking behaviors is explored, drawing parallels between rodent models and human experiences of racial battle fatigue resulting from daily racial microaggressions. The chapter also delves into how lack of autonomy, social isolation, and perceived loss of control due to discrimination may precipitate substance use as a coping mechanism. Additionally, the influence of social hierarchies, bonding patterns, and intergenerational epigenetic effects on resilience versus susceptibility to addiction is considered. Current methodologies are critically evaluated, with a proposal to enhance ecological validity in animal experiments to better simulate nuanced sociocultural stressors associated with addiction risk. Emphasizing the urgent need for cross-disciplinary collaborations between rodent researchers and social scientists, the chapter advocates for the incorporation of relevant sociological concepts into behavioral assays. Ultimately, the integration of diverse perspectives is crucial for comprehensively addressing the psychosocial and neurobiological dynamics underlying addiction across mammalian species and for developing more effective and equitable prevention and treatment approaches.

1. Introduction

Addiction has evolved from notions of moral failing or criminal deviance into recognition as a chronic relapsing brain disease with complex biological, psychological, and sociocultural underpinnings [1]. Preclinical animal models have been invaluable for elucidating the neural circuitry governing substance use habits and identifying potential pharmacotherapeutic targets [2]. However, the external validity of current models in capturing addiction experiences in the real world remains limited [3]. This chapter proposes that incorporating sociological concepts like social defeat stress, perceived inequality, constrained agency, and cultural marginalization into animal model designs will significantly advance our understanding of addiction risk and resilience across mammals.

While cohort studies and epidemiological data reveal higher vulnerability of substance misuse among populations facing discrimination, oppression, and diminished life chances due to systemic inequities [4, 5, 6, 7], the relationship between race and substance dependence, particularly in African Americans, is complex and influenced by a multitude of factors. It is essential to explore how racial stressors, such as experiences of discrimination and cultural marginalization, interact with substance use and dependence. This exploration must consider the unique historical, social, and psychological contexts of African-American experiences, which may differ significantly from those of Caucasian populations [8]. Integrating the minority stress model with behavioral neuroscience research on social defeat stress can shed light on how experiences of racial battle fatigue resulting from daily racial microaggressions might influence substance use behaviors as a form of maladaptive coping [9]. Animal experiments simulating chronic social stress could provide insight on such pathways from social marginalization to addiction vulnerability [10].

However, the social variables modeled rarely extend beyond physical acts of aggression or brief threats [11]. Researchers must consider long-term experiences of constrained agency, lack of autonomy, and eroded perceptions of control that often accompany discrimination [12]. Through this lens, addiction represents attempts to exert control and self-medicate distress when disadvantaged groups lack economic, social, and political resources to alter broader societal conditions [13]. Incorporating concepts like relative social status, shifts in dominance hierarchies, and culturally-mediated epigenetic changes across generations could significantly enhance the ethological fidelity of animal models [14].

The potential of animal models in elucidating the mechanisms and risk factors associated with addiction is immense. These models offer a controlled environment to dissect the complex interplay of genetic, neurobiological, and environmental factors contributing to addictive behaviors [15]. For instance, rodent models have been instrumental in understanding the effects of chronic social defeat stress on substance use, including nicotine, alcohol, and opioids [16]. These models simulate aspects of human experiences, such as racial battle fatigue and microaggressions, providing insights into how stress and perceived inequality contribute to addiction [17]. Animal models also allow for the exploration of sex differences in addiction, which is crucial given the distinct patterns of substance use and vulnerability between males and females [18]. Animal models have shown sex- and gender-dependent differences in impulsivity and addiction, highlighting the need for gender-sensitive approaches in addiction research [19]. Additionally, the sociocultural context for these sex differences must be considered, as it can differentially influence the biological processes of addiction and relapse in men and women [20]. Furthermore, studies on nonhuman primates have shed light on the distribution of drinking levels in populations, guiding prevention and treatment strategies [21]. The psychobiology of drug dependence, as explored through these models, offers valuable insights for clinicians in understanding and treating addiction [22]. However, it’s important to recognize the limitations of these models. For instance, the complexity of human social environments and individual experiences cannot be fully replicated in laboratory settings. Therefore, while animal models are invaluable in addiction research, they must be complemented by human studies to fully understand the multifaceted nature of addiction [23, 24].

This chapter highlights the conceptual framework that can guide the incorporation of sociocultural variables into animal models of addiction. This framework acknowledges the intricate interplay between biological predispositions and environmental factors, including experiences of discrimination and constrained agency, in the development and perpetuation of addictive behaviors. This chapter will detail how animal models can be adapted to more accurately reflect the sociocultural realities that influence addiction. This includes examining the impact of social stressors, akin to human experiences of discrimination and marginalization, on addiction-related behaviors in animal subjects [25]. By simulating conditions of social defeat or inequality in these models, researchers can gain insights into how chronic stress and reduced agency contribute to the vulnerability to addiction [26]. This chapter will also detail the role of social structures and bonding in addiction, drawing parallels between animal social hierarchies and human societal dynamics. This comparison will help us understand how social relationships and support systems can either mitigate or exacerbate addiction risk [20].

Furthermore, the chapter will delve into the methodological challenges and opportunities in enhancing the ecological validity of animal models. This involves integrating complex sociocultural stressors, such as social isolation or perceived lack of control, into experimental designs to better mimic the human condition [27]. Finally, the need for cross-disciplinary collaboration in this endeavor will be emphasized. Bridging the gap between sociological research and behavioral neuroscience is crucial for developing animal models that not only reflect the neurobiological aspects of addiction but also its sociocultural dimensions [28].

In summary, this chapter aims to provide a comprehensive overview of how animal models can be refined to incorporate sociocultural variables, thereby enhancing our understanding of the biopsychosocial nature of addiction. This approach is vital for developing more effective and contextually relevant strategies for prevention and treatment.

2. Effects of social defeat stress on drug habits

The exploration of social defeat stress in animal models provides critical insights into the neurobiological and behavioral aspects of addiction. Chronic social defeat stress (CSDS) models, primarily utilizing rodents, have been instrumental in understanding how stress influences behavior and brain function, particularly in the context of substance use and addiction.

In these models, animals are exposed to repeated bouts of social defeat by a dominant conspecific, leading to various behavioral changes that mirror human psychopathology. These changes include increased anxiety-like behavior, social avoidance, and altered reward processing. Such models are significant as they provide a window into understanding how chronic stress can influence susceptibility to addiction, offering parallels to human experiences of social adversity and its impact on mental health.

CSDS models have been particularly effective in inducing depression-relevant phenotypes. For example, studies in male prairie voles have shown that repeated social defeat results in behaviors akin to human depression, including social withdrawal and memory impairments [29]. These findings are crucial as they establish a link between social stressors and depression-like states, which are often precursors or co-occurring conditions in substance use disorders.

The chronic vicarious social defeat stress (cVSDS) model in mice, a variation of the direct social defeat model, has been developed to explore the broader impact of stress. This model is used to investigate how indirect exposure to stressors can contribute to psychiatric disorders, including those related to anxiety, depression, and potentially addiction [30]. CSDS has also been observed to disrupt goal-directed behavior in mice, suggesting a mechanism through which chronic stress might lead to maladaptive decision-making and heightened addiction vulnerability [31]. Understanding how chronic stress affects decision-making processes is particularly relevant in addiction research, where stress is a significant contributing factor. Furthermore, these models explore the role of inflammation in stress-related disorders. Research focusing on Toll-like receptor 4 has demonstrated its influence on depressive-like behaviors induced by CSDS, highlighting the complex relationship between stress, inflammation, and depression [32].

This section further explores animal models of CSDS, which provide essential insights into the neurobiological and behavioral consequences of chronic stress. These insights are vital for comprehending the complexities of addiction and for developing effective interventions.

2.1 Neural mechanisms linking defeat to escalated drug taking

Exploring the neural mechanisms linking social defeat to escalated drug taking reveals significant insights into addiction’s neurobiology. Research indicates that exposure to social defeat stress can lead to neuroadaptations that intensify drug-seeking behaviors. For example, in response to social stress, some animals exhibit escalated cocaine reward, potentially due to changes in brain-derived neurotrophic factor (BDNF) levels and dopamine function within the brain’s reward circuits, particularly the ventral tegmental area (VTA) and the nucleus accumbens [33].

Further studies have described how different forms of stress, including social defeat, impact behaviors relevant to substance abuse. These include alterations in operant self-administration of drugs, indicative of changes in the brain’s reward system [34]. The reward system’s modulation in response to social defeat stress is critical in understanding the escalation of drug-seeking behavior.

The combination of social and sexual rewards has been shown to positively affect stress resilience during chronic social defeat stress. This resilience is potentially mediated by changes in endocannabinoids (ECs) and metabotropic glutamate receptor 5 (mGluR5) in the VTA and dorsal raphe nucleus (DRN), suggesting a neuroprotective mechanism against stress-induced changes in the brain [35]. The role of the periaqueductal gray (PAG) in modulating behavioral responses to social defeat has also been highlighted. The PAG acts as a hub influencing prosencephalic sites during the mediation of aversive responses, which could be linked to the stress-induced escalation of drug-seeking behaviors [36]. These findings underscore the complexity of the neural mechanisms involved in the link between social defeat and escalated drug taking. They highlight the intricate interplay between neurotransmitter systems, neurotrophic factors, and neural circuitry, contributing to heightened vulnerability to substance use disorders following experiences of social defeat.

2.2 Defeat stress effects on nicotine, alcohol, opioid habits

Chronic social defeat stress (CSDS) has been shown to significantly influence substance use habits, particularly with nicotine, alcohol, and opioids. The interaction between CSDS and these substances provides a model for understanding the stress-related escalation in drug use.

In terms of alcohol use, studies have demonstrated that both intermittent and continuous exposure to social stress can lead to excessive alcohol consumption in mice. This suggests that social stress and alcohol access may share common sensitizing neural mechanisms that promote increased alcohol intake [37]. This finding is crucial in understanding how environmental stressors can exacerbate substance use disorders.

Nicotine exposure has also been found to induce resilience to CSDS in a mouse model. In this context, nicotine activates BDNF signaling, which mediates the effects of social stress on social behavior [38]. This indicates that nicotine might have a complex role in modulating stress responses and could influence social behaviors under stress.

The response to CSDS can also be influenced by genetic factors involved in anxiety regulation. For example, a mouse model with cholinergic dysregulation exhibited an abnormal response to CSDS, indicating that genetic predispositions can modulate individual responses to social stressors [39]. This highlights the complex interplay between genetic, environmental, and psychosocial factors in the development of substance use disorders.

Moreover, the delta opioid receptor agonist KNT-127 has shown beneficial effects in a chronic vicarious social defeat stress mouse model. This suggests potential therapeutic avenues for stress-related substance use disorders, as KNT-127 acts over the hypothalamic-pituitary-adrenal axis and regulates neurogenesis and neuroinflammation [40].

These findings from animal models underscore the significant impact of social defeat stress on nicotine, alcohol, and opioid use habits. They provide valuable insights into the neurobiological mechanisms underlying stress-induced escalation of substance use and highlight potential targets for therapeutic intervention.

2.3 Racial battle fatigue and microaggression experiences

Incorporating sociological perspectives such as racial battle fatigue (RBF) and experiences of microaggressions into animal models can enhance our understanding of addiction’s complex biopsychosocial underpinnings. RBF, a psychological stress response to chronic racial microaggressions, results in a range of psychological, physiological, and behavioral outcomes due to constant exposure to racial discrimination [41, 42]. This concept is particularly relevant in understanding the stress and coping mechanisms in marginalized racial groups.

In animal models, simulating aspects of RBF and microaggressions can provide insights into the stress-induced behavioral changes that may lead to substance use. For example, models that mimic the chronic stress and vigilance associated with RBF can help in studying the neurobiological and psychological mechanisms that drive substance use as a coping strategy [43, 44].

Moreover, the coping mechanisms employed to navigate RBF, often involving engagement with historically constructed stereotypes, can be paralleled in animal models to study the psychological stress and its impact on substance use behaviors [45, 46]. These models can help in understanding how chronic stress and coping strategies influence addiction vulnerability and resilience.

The heightened state of vigilance and psychological stress, known as hypersurveillance, experienced due to racial microaggressions, can also be simulated in animal models. This would allow researchers to study its impact on mental health and substance use patterns, providing a broader perspective on how environmental and social stressors contribute to addiction [47, 48].

Furthermore, the application of these sociological concepts in animal models can inform the development of interventions that address the broader sociocultural factors contributing to addiction. This approach acknowledges the significance of social and environmental stressors in addiction and aims to develop more comprehensive and contextually relevant strategies for prevention and treatment [49].

2.4 Learned helplessness and perceived inequality

Learned helplessness (LH), a consequence of racial battle fatigue, is a state where an individual perceives no control over the outcome of a situation, is a critical concept in understanding the psychological underpinnings of addiction. Rodent models of LH, typically induced through uncontrollable stressors, mimic aspects of this condition and its impact on behavior [50, 51].

These models have been instrumental in studying the effects of uncontrollable stress on subsequent behavior, including the propensity for substance use. For instance, rodents exposed to inescapable shock or other stressors exhibit changes in escape performance and other behaviors indicative of a state of helplessness [52]. This parallels the human experience of perceived lack of control or inequality, which can lead to maladaptive coping mechanisms such as substance abuse.

Furthermore, the triadic design in rodent LH models, involving escapable shock, yoked-inescapable shock, and restrained control, allows for a nuanced exploration of the psychological dynamics of stress and its sequela. This design helps in quantifying the impact of psychological dynamics such as active behavioral coping versus helplessness [53].

The relevance of these models extends to understanding the relationship between LH, depression, and anhedonia—a core symptom seen in various forms of depression and addiction. By inducing LH in rodents, researchers can examine if and how this paradigm leads to anhedonia-like symptoms, which are often associated with increased substance use [54]. Rodent models also allow for the exploration of behavioral coping styles in strains that do not typically exhibit helplessness behavior, with one study revealing a repetitive and inflexible active coping, presenting as an addiction-like behavioral phenotype, in stressed LH-resistant mice [55].

In the context of addiction, LH models can shed light on how perceived inequality and lack of control influence drug-seeking behavior. The feeling of helplessness, often exacerbated in environments of inequality, can drive individuals towards substance use as a means of regaining a sense of control or escaping from the stressor. These rodent models, therefore, provide a framework for understanding the complex interplay between psychological stress, perceived control, and addiction. They offer a platform for developing interventions that address these psychological factors, potentially reducing the risk of substance use disorders.

3. Constrained agency and control

This section delves into the intricate relationship between constrained agency, control, and addiction, both in human epidemiology and animal models. The concepts of marginalization, inequality, and the resultant lack of autonomy and resources are central to understanding the development and perpetuation of addictive behaviors. These factors, often rooted in broader socioeconomic and environmental contexts, significantly influence an individual’s vulnerability to addiction. Animal models have been instrumental in mirroring these human experiences, providing insights into how constrained agency and control impact behavior and brain function. By simulating environments of social stress, inequality, and limited resources, these models offer a unique perspective on the neurobiological and psychological mechanisms underlying addiction.

In humans, experiences of marginalization and inequality often correlate with higher rates of substance use and addiction. Similarly, in animal studies, conditions of social defeat, hierarchical stress, and resource limitation have been shown to induce stress responses and behaviors akin to those observed in humans facing similar social challenges. These parallels are crucial for understanding the multifaceted nature of addiction and the role of social determinants in its development.

This section explores how animal models can enhance our understanding of the complex interplay between social factors and addiction. By examining the effects of constrained agency and control in these models, researchers can gain valuable insights into potential intervention strategies that address both the biological and social aspects of addiction. The integration of these findings with human epidemiological data can lead to more comprehensive and effective approaches to prevention and treatment, ultimately improving outcomes for individuals struggling with substance use disorders.

3.1 Low autonomy, lack of resources, and lost control

The concepts of low autonomy, lack of resources, and lost control are integral to understanding addiction, both in human epidemiology and animal models. These factors, often stemming from socioeconomic constraints, significantly influence the development and persistence of addictive behaviors. In animal models, the reduction of autonomy and control can be simulated through environmental restrictions or limited access to resources. Rodents in environments with restricted movement or access to resources exhibit stress and anxiety behaviors, often precursors to addictive behaviors. These models mirror the human experience where individuals in constrained environments may turn to substance use as a coping mechanism [56].

The lack of resources, whether social, economic, or environmental, is a significant factor in addiction risk. Animal studies show that limited access to essential resources like food, water, or social interaction leads to increased stress and can trigger drug-seeking behavior. This parallels the situation in human populations where economic hardship and social deprivation are strongly linked to higher rates of substance use and addiction [57, 58].

These parallels between animal models and human epidemiology underscore the importance of considering the broader social and environmental context in addiction research. They highlight how factors like autonomy, resource availability, and control over one’s environment play a crucial role in the risk and development of substance use disorders.

3.2 Economic and social inequality addiction risk factors

Economic and social inequality are significant risk factors for addiction, as evidenced in both human epidemiology and animal models. These factors create environments that can exacerbate stress and lead to increased vulnerability to substance use disorders.

In animal models, the effects of economic and social inequality can be studied by creating environments with varied access to resources and social hierarchies. These studies have shown that animals in lower hierarchical positions or with restricted access to resources exhibit higher levels of stress and are more prone to engage in drug-seeking behaviors. This mirrors findings in human populations, where individuals facing economic hardship and social marginalization are at a higher risk for developing addiction [59, 60].

The relationship between socioeconomic status and health outcomes, including addiction, is well-established in human epidemiology. Lower socioeconomic status is often associated with higher rates of substance use and addiction, a pattern that is reflected in animal models examining the impact of resource availability and social status on behavior [61, 62]. Furthermore, the stress of living in economically and socially disadvantaged conditions can lead to changes in brain chemistry and function, which animal models have helped to elucidate. These changes are linked to increased susceptibility to addiction, highlighting the biological underpinnings of how social and economic factors influence addiction risk [62, 63].

These insights from animal models are crucial for understanding the complex interplay between economic and social inequality and addiction. They provide a basis for developing targeted interventions that address not only the biological aspects of addiction but also the social and environmental factors that contribute to its development.

3.3 Coping substances as functional adaptations

The use of coping substances as functional adaptations to stress and trauma is a phenomenon observed both in human addiction epidemiology and animal models. This concept suggests that individuals, including animals, may use substances as a means to adapt to or mitigate the effects of stress and adverse environments.

In animal models, the administration of substances like opioids or cannabinoids has been shown to modify behaviors associated with stress and trauma. For example, studies have demonstrated that exposure to these substances can lead to changes in the mesolimbic dopamine system, which is crucial for motivation, reinforcement, and reward processing [64, 65]. This mirrors the human tendency to use substances as a way to cope with psychological distress or to adapt to challenging environments.

Functional imaging studies have identified common neurofunctional dysregulations in substance use and behavioral addictions, suggesting shared alterations across these conditions. These findings indicate that the use of substances may serve as a coping mechanism for underlying neurofunctional dysregulations [66]. Additionally, the impact of cue-reactivity in the ventral striatum has been studied in the context of heavy cannabis use. This research suggests that adaptations in the brain’s reward system may promote excessive drug use, while changes in the dorsal striatal systems engaged in habit formation may facilitate the transition to addictive use [67].

These insights from animal models are crucial for understanding the role of coping substances as functional adaptations in human addiction. They provide a basis for developing targeted interventions that address not only the biological aspects of addiction but also the psychological and environmental factors that contribute to substance use.

3.4 Relative social status, stress inequality, and drug habits

The relationship between relative social status, stress inequality, and drug habits is a critical area of study in both animal models and human epidemiology. This relationship underscores how social hierarchies and perceived inequalities can influence substance use behaviors.

In animal models, the impact of social hierarchy on stress responses and subsequent drug-seeking behavior has been extensively studied. For instance, low-ranking macaques are more prone to self-administer cocaine and have lower D2/D3 receptor availability compared to their higher-ranking counterparts [68]. This reflects the human scenario where individuals with lower social status or those experiencing social inequality are at a greater risk for substance use and addiction.

Similarly, rodent models have shown that animals subjected to social defeat or lower social status exhibit increased susceptibility to substance use, mirroring the human scenario where individuals with lower social status or those experiencing social inequality are at a greater risk for substance use and addiction. Kabbaj and colleagues investigated how social defeat impacts cocaine self-administration in rats, focusing on individual differences in drug-taking behavior [69]. They classified male Sprague-Dawley rats into high-responder and low-responder groups based on their activity in novel environments, then exposed them to social defeat scenarios. Their findings revealed that social defeat delayed cocaine self-administration in high-responders while enhancing it in low-responders, suggesting that social stress can induce status-dependent effects in drug-taking behaviors.

The concept of subjective socioeconomic status (SSES) and its relationship with health outcomes, including neuropsychological performance, provides insight into how perceived social standing influences health behaviors. Studies have shown that lower SSES is associated with poorer health outcomes, including higher rates of substance use [70]. These insights from animal models and human studies emphasize the importance of considering social status and perceived inequality as significant factors in addiction research. They provide a framework for understanding how social dynamics and individual perceptions of social standing can influence the risk and development of substance use disorders.

4. Social structures and bonding

Dominance patterns and social hierarchies are fundamental aspects of animal behavior that have significant implications for understanding addiction. In animal models, the establishment and maintenance of social hierarchies provide valuable insights into the behavioral and neurobiological mechanisms underlying addiction.

Research on various animal species, including primates and rodents, has shown that dominance hierarchies influence individual behavior and stress responses. For instance, animals in lower ranks of the social hierarchy often experience higher levels of stress, which can lead to increased vulnerability to addictive behaviors. This is particularly evident in studies where lower-ranking animals exhibit heightened drug-seeking behavior compared to their higher-ranking counterparts [71].

The formation of dominance hierarchies and their impact on individual behavior has been explored in detail in species like brown capuchin monkeys (Cebus [Sapajus] apella). These studies reveal complex social interaction patterns that are influenced by an individual’s position within the social hierarchy, providing a framework for understanding similar dynamics in human social structures [72].

Additionally, the concept of the winner-loser effect in social hierarchies has been studied in animal models. This effect implies that the outcome of social conflicts can reinforce future behaviors, with winners becoming more likely to win again and losers more likely to lose. This phenomenon has implications for understanding how social victories and defeats can shape addiction-related behaviors [73]. Furthermore, the network motif architecture of dominance hierarchies has been examined, revealing that overall patterns of dominance relations are strikingly similar across different group types. This suggests that key individuals and specific social dynamics play a crucial role in shaping social hierarchies and their associated behaviors [74].

These insights from animal models are crucial for understanding the role of social hierarchies in addiction. They highlight the importance of social status and its associated stressors in influencing addictive behaviors, providing a basis for developing interventions that consider the social aspects of addiction.

4.1 Evaluating social housing conditions: isolation vs. pairs

The impact of social housing conditions, particularly the contrast between isolation and pair housing, is a critical aspect of understanding addiction in both animal models and human epidemiology. These conditions can significantly influence stress levels, social behaviors, and susceptibility to addictive behaviors.

Studies have shown that social isolation in animal models, such as in mice and rats, can lead to increased stress responses and heightened vulnerability to addictive substances. For example, isolated animals often exhibit greater ethanol-induced behavioral sensitization, suggesting that social isolation can exacerbate the effects of addictive substances [75]. This is consistent with human studies where social isolation is linked to increased substance use and addiction.

Conversely, social housing, particularly in pairs, can mitigate some of these effects. Research indicates that animals housed with a partner or in a social environment display different behavioral and neurochemical responses to addictive substances compared to isolated animals. For instance, pair-housed animals may show reduced drug-seeking behavior, highlighting the protective role of social interaction [76].

The effects of social housing conditions on cocaine reward have also been explored. Animals subjected to intermittent social defeat and then housed in standard conditions displayed an anxious phenotype and developed conditioned place preference for cocaine. However, those housed with a familiar partner since adolescence did not develop place preference for cocaine, suggesting that positive social interactions can protect against drug-seeking behavior induced by social stress [77].

Moreover, the importance of considering social housing information in biomedical research involving nonhuman primates has been emphasized. This is crucial for interpreting research findings in the appropriate context and understanding unexplained variability in study outcomes [78].

These findings from animal models underscore the importance of social environment in addiction research. They provide insights into how social factors, such as isolation or social support, can influence the development and maintenance of addictive behaviors, offering a basis for developing targeted interventions that consider the social aspects of addiction.

4.2 Bonded mouse pairs: separation effects on drug seeking

The study of bonded mouse pairs and the effects of their separation on drug-seeking behavior offers valuable insights into the role of social bonds in addiction. This area of research in animal models reflects the importance of social relationships in human addiction epidemiology.

Research on prairie voles, a species known for forming strong social bonds, has shown that the loss of a bonded partner leads to behaviors indicative of social loss and increased motivation for reunion-seeking. This suggests that the disruption of social bonds can have profound effects on behavior and motivation, including the propensity for drug-seeking [79].

In mice, neural circuits in the hippocampus have been identified to specifically encode drug-associated contextual information for psychostimulants and opioids. The separation of bonded pairs can lead to changes in these neural circuits, potentially influencing drug-seeking behavior [80].

The involvement of glutamate transporter-1 (GLT-1) in mediating the rewarding effects of substances like pregabalin has been explored in animal models. This research provides insights into the neurobiological mechanisms underlying drug-seeking behavior following the separation of bonded pairs [81]. Additionally, the effects of chronic and acute intranasal oxytocin treatments on temporary social separation in adult titi monkeys have been studied. These findings suggest that oxytocin, a hormone associated with social bonding, can modulate the separation response, reflecting the complex interplay between social relationships and drug-seeking behavior [82].

These studies in animal models highlight the significant impact of social bonds and their disruption on drug-seeking behavior. They provide a framework for understanding how social relationships influence addiction and offer potential avenues for therapeutic interventions that address the social aspects of substance use disorders.

4.3 Early trauma, maternal behavior, and intergenerational transmission

The study of early trauma, maternal behavior, and intergenerational transmission in animal models provides crucial insights into the development of addiction and its transmission across generations. These models highlight the profound impact of early life experiences and maternal care on the behavioral and neurobiological outcomes in offspring.

Animal studies have shown that early-life adversity, such as maternal separation or exposure to stress, can lead to long-lasting changes in DNA methylation, a key epigenetic mechanism. These changes are associated with altered stress responses and increased vulnerability to addiction in later life [83]. This underscores the significance of early experiences in shaping addiction risk.

The role of epigenetic mechanisms in the intergenerational transmission of trauma effects has been extensively studied. These mechanisms may explain how individual, cultural, and societal experiences influence biology and contribute to the transmission of addiction risk across generations [84].

Research involving paternal early life stress in animal models, such as in C57Bl/6 J mice, has provided evidence of intergenerational effects on offspring behavior. This includes changes in risk-taking behaviors and brain function relevant to addiction, independent of specific gene expression [85].

The intergenerational transmission of mental health risk in refugee families has been explored, highlighting the role of maternal psychopathology and emotional availability. This research suggests that trauma exposure affects both maternal mental health and parenting behaviors, which in turn can contribute to children’s mental health problems, including addiction [86].

Additionally, studies have confirmed that maternal exposure to chronic traumatic events (CTE) and prenatal stress life events (PSLE) are independently associated with child mental health. This highlights intergenerational risk pathways for early psychopathology, including addiction [84].

Furthermore, the intergenerational transmission of risk for post-traumatic stress disorder (PTSD) symptoms in African American children has been studied, emphasizing the roles of maternal and child emotion dysregulation. Addressing these factors could be key in reducing the intergenerational transmission of trauma and addiction risk [87].

These insights from animal models are vital for understanding the complex interplay between early trauma, maternal behavior, and intergenerational transmission in addiction. They provide a foundation for developing interventions that address these early life factors to mitigate addiction risk across generations.

4.4 Cross-fostering rodent study designs to examine cultural factors

Cross-fostering study designs in rodent models provide a unique and insightful approach to investigating the influence of cultural and environmental factors on behavior, including addiction. This method involves rearing offspring with foster parents from different strains or species, thereby creating an opportunity to separate genetic influences from environmental ones. By doing so, researchers can gain a deeper understanding of how early life experiences, shaped by the caregiving environment, contribute to the development of various behaviors, including those related to addiction.

In these cross-fostering experiments, significant observations have been made regarding the behavior of offspring, which can be profoundly influenced by the environment provided by the foster parents. Studies have shown changes in stress responses, social behaviors, and susceptibility to addictive substances, highlighting the critical impact of early environmental and cultural factors [88, 89]. For instance, variations in maternal care in these cross-fostering setups have been linked to notable changes in stress reactivity and coping strategies in the offspring. This suggests that the type and quality of early life experiences play a crucial role in shaping behaviors related to addiction [90].

Moreover, cross-fostering studies have been instrumental in exploring the impact of the early social environment on the development of social behaviors and addiction. Research indicates that rodents raised in enriched environments, even if born to mothers from less enriched backgrounds, tend to exhibit enhanced cognitive abilities and a reduced susceptibility to addictive behaviors [91]. These findings from rodent models are invaluable, as they offer a comprehensive understanding of the role of cultural and environmental factors in the development of addiction. Such insights are crucial for developing interventions that address not only the biological aspects of addiction but also consider the significant influence of early life experiences and environmental factors.

4.5 Epigenetic modulation of addiction risk across generations

The epigenetic modulation of addiction risk across generations is a burgeoning area of research, bridging insights from animal models and human studies. Epigenetics, the study of heritable changes in gene expression without altering the DNA sequence, offers a framework for understanding how environmental factors can influence addiction risk across generations.

Animal models have been instrumental in demonstrating how early-life experiences can lead to epigenetic changes that affect behavior and susceptibility to addiction. For example, studies have shown that exposure to stress or drugs in early life can alter DNA methylation patterns in key brain regions involved in addiction, leading to long-lasting behavioral changes [83, 92].

In humans, research has begun to uncover how parental substance use and early-life adversity can lead to epigenetic modifications in offspring, potentially increasing their risk for addiction. This includes changes in DNA methylation and histone modifications that can alter gene expression in the brain’s reward pathways [93]. The intergenerational effects of alcohol and cannabis exposure have been examined, highlighting the importance of understanding the potential hazards of these substances on future generations. Epigenetic mechanisms are implicated in mediating these long-term effects [94]. Moreover, the concept of addiction as a developmental disorder is supported by evidence of genetic, epigenetic, and neurobiological factors interacting with experiences of adversity at key developmental stages. This perspective emphasizes the need for a multilevel approach to understanding and treating addiction [95].

These insights from both animal and human studies underscore the importance of considering the epigenetic underpinnings of addiction. They highlight the potential for early interventions and preventive measures that address not only the individual’s immediate environment but also the broader familial and societal context that can influence epigenetic programming and addiction risk across generations.

5. Enhancing ecological validity of animal models

Enhancing the ecological validity of rodent models, particularly in the context of social stress protocols, is crucial for accurately replicating human conditions and behaviors. Current models often lack the nuance and ethological fidelity necessary to fully understand the complexities of human social stress and addiction.

One critique of existing social stress models in rodents is their oversimplification of complex social interactions. For instance, many models rely on aggressive encounters as the primary or sole form of social stress, which does not fully capture the range of stressors experienced by humans [96]. This limitation can lead to an incomplete understanding of how diverse social stressors contribute to addiction.

The ecological validity of social interaction tests in rodents has been questioned, particularly regarding the balance between ecological validity and experimental control. While these tests are valuable, they may not fully represent the complexity of human social interactions and stressors [97].

Furthermore, the use of social defeat stress models, while informative, has been critiqued for its focus on physical aggression. This focus may overlook other forms of social stress, such as social isolation or hierarchical stress, which are also relevant to human addiction [98].

Non-rodent models can also offer important insights. For example, fish models, which provide faster reproduction cycles and are generally cheaper to maintain, have also provided important insights on neuroendocrine modulation of sociality and stress. These models could provide a more nuanced understanding of the relationship between social stress and addiction, applicable to both animal and human studies [99].

Additionally, the application of virtual reality in social neuroscience research has been proposed to enhance ecological validity. Virtual reality can simulate complex social environments and interactions, offering a more realistic context for studying social stress and addiction [100].

These critiques and suggestions highlight the need for more sophisticated and nuanced rodent models that better reflect the complexity of human social stress and its impact on addiction. By addressing these limitations, researchers can develop more accurate and effective models for studying addiction and its social determinants.

5.1 The limitations of aggression-based models

In enhancing the ecological validity of rodent models, addressing the limitations of stress modalities, particularly the over-reliance on physical aggression, is essential. Current models often focus on aggression as the primary form of social stress, which may not fully capture the diverse range of stressors experienced by humans.

The use of physical aggression in social defeat models, while providing valuable insights, may not encompass the subtler forms of social stress such as ostracism or hierarchical pressures that are prevalent in human societies [96]. This limitation can restrict our understanding of the full spectrum of social stressors that contribute to addiction.

Recent advancements in preclinical imaging have enabled a deeper exploration of brain function in rodent models, offering opportunities to study more nuanced aspects of social stress beyond physical aggression. These methods can help in understanding the neural underpinnings of complex social behaviors and their relation to addiction [101].

The establishment of mouse models of social avoidance induced by female-directed aggression demonstrates the need to diversify social stress paradigms. Such models can provide insights into different forms of social stress and their distinct impacts on behavior and addiction vulnerability [102]. Additionally, the development of novel stress models, such as those focusing on emotional stress without physical distress, can bridge the gap between human social stress and animal models. These models can offer a more accurate representation of the stressors contributing to mental disorders like depression and addiction [103, 104].

The comparison of chronic physical and emotional social defeat stress effects on mesocorticolimbic circuit activation and voluntary consumption of morphine highlights the importance of exploring various stress modalities. Both physical and emotional stress paradigms can be useful for investigating stress-induced changes in drug behavior [105].

By addressing these limitations and incorporating a broader range of social stressors, rodent models can achieve greater ecological validity. This approach will enhance our understanding of the complex interplay between social stress and addiction, leading to more effective prevention and treatment strategies.

5.2 Incorporate social ostracism in social stress models

To enhance the ecological validity of rodent models, it is essential to enrich protocols with experiences of social ostracism and ambiguity, which are critical aspects of human social stress. These elements can provide a more comprehensive understanding of the complex social dynamics that contribute to addiction.

Adolescent environmental enrichment in rodent models, particularly in lines with an anxious phenotype, has shown that manipulating the social environment can induce resilience and alter neural gene expression. This underscores the importance of social experiences in shaping behavior and stress responses [106]. The impact of early adverse experiences, including social ostracism, on later psychopathology has been extensively studied in rodent and primate models. These studies highlight the long-term effects of social stressors on mental health and addiction vulnerability [107].

Research comparing mouse behavior in classic versus revised social behavioral assays emphasizes the need for more ecologically valid anxiety and social interaction tests. These revised assays can better capture the nuances of social ostracism and ambiguity experiences [108].

Studies on acoustic communication in rats have demonstrated that social experiences, such as isolation during critical developmental periods, can affect socio-affective communication. This indicates that social ostracism can have profound effects on social behavior and stress responses [109]. Additionally, the differential effects of physical and social enriched environments on recovery after cerebral ischemia/reperfusion injury in rats suggest that social experiences play a significant role in health outcomes, including addiction [110].

By incorporating experiences of social ostracism and ambiguity into rodent models, researchers can gain a deeper understanding of the social factors contributing to addiction. This approach can lead to more effective prevention and treatment strategies that address the complex interplay between social environment and addiction.

5.3 Study microaggressions through subtle threat cues

Incorporating microaggressions through subtle threat cues in rodent models is a crucial step in enhancing the ecological validity of these models. This approach allows for a more accurate representation of the complex and often subtle nature of social stressors that contribute to addiction.

Research has shown that the recall of aversive memories, such as those associated with conditioned threat cues, can potentiate anxiety-like behavior in rodents. This suggests that subtle cues, reminiscent of microaggressions, can have significant impacts on behavior [111]. By incorporating these cues into rodent models, researchers can better mimic the nuanced social stressors experienced by humans.

Rodent models of early adversity, which impact developing social behavior circuitry, provide insights into how subtle social cues, including those akin to microaggressions, can influence long-term behavioral outcomes. These models highlight the importance of early social experiences in shaping vulnerability to addiction [112].

The study of racial microaggressions in healthcare settings, while focused on human experiences, underscores the detrimental impact of such subtle social stressors on well-being and mental health. Translating these findings to rodent models can enhance our understanding of the effects of microaggressions on addiction [113].

Additionally, research on outgroup threat and the emergence of cohesive groups through subtle behavioral cues offers insights into the social dynamics that can be modeled in rodents. Understanding how these cues influence group behavior and stress responses can inform addiction research [114].

In summary, incorporating microaggressions and subtle threat cues into rodent models is essential for capturing the complexity of human social stressors. This approach can lead to more accurate and effective models for studying addiction and its social determinants.

5.4 Model social inequality through resource restriction

Modeling social inequality in rodent models through resource restriction is a critical step in enhancing the ecological validity of these models [115, 116, 117, 118]. This approach allows for the simulation of socioeconomic disparities and their impact on behavior, including addiction.

Resource restriction in rodent models can be implemented by varying access to essential resources such as nesting materials and cage enrichments. This creates an environment that mimics the conditions of social inequality experienced by many humans. Although limited, some studies, such as those for models of Huntington’s disease, have shown that rodents provided enrichment exhibit significant improvements in pathology [119] and developmental rodent models indicate that cage enrichment improves developmental outcomes, such as improvements in brain structure such as increases in brain weight, more complex dendritic branching, heightened neurogenesis, and improved learning and memory [120]. Varying levels of cage enrichment will likely also affect stress responses, social behaviors, and drug-seeking behaviors in a variety of rodent models, which may be used to reflect the impact of socioeconomic status on addiction vulnerability.

In a rat relapse model, researchers demonstrate that environmental enrichment can have lasting effects on reducing cocaine craving after cocaine withdrawal, mediated by the re-silencing of previously “silent” excitatory synapses in the brain’s circuitry [121]. This re-silencing process, facilitated by in vivo long-term depression (LTD) induction, allows for the restructuring of neural pathways, ultimately leading to sustained anti-relapse effects of EE. Studies such as this complement findings that resource restriction can exacerbate stress responses that may lead to addiction, as was observed in a helplessness-resistant rodent strain, which exhibited inflexible addiction-like behaviors in response to food deprivation [55].

By modeling social inequality through resource restriction in rodent models, researchers can gain a deeper understanding of the social determinants of addiction. This approach can lead to more effective prevention and treatment strategies that address the broader social and environmental context of addiction.

6. Conclusion

In conclusion, this chapter highlights the need to enhance animal models of addiction through an interdisciplinary lens, incorporating insights across behavioral neuroscience, psychology and sociology. There is an intricate interplay between the biological aspects of addiction and the broader socio-environmental influences such as chronic stress, discrimination, inequality and lack of autonomy. By simulating these complex experiences using innovative techniques, we can develop ethologically valid rodent models that better represent the contexts driving human addictive behaviors.

Several important strands emerge from this cross-disciplinary approach. First, social defeat stress models reveal that adversity early in life or due to one’s social standing can alter critical neural pathways governing motivation, reward and drug-habit formation. However, existing paradigms must expand beyond singular acts of aggression to capture the nuances of marginalization. Second, concepts of unequal resource distribution, perceived inequality and loss of autonomy provide insights into the psychological pathways linking social disadvantage to addiction risk. Third, dominance patterns in animal social structures offer parallels to human societal dynamics in shaping addictive behaviors. Lastly, achieving higher ecological validity involves methodological innovation to recreate layers of complexity, as guided by frameworks in social ecology.

In essence, aligning insights from animal models with human epidemiology and clinical data will accelerate our understanding of addiction’s multifaceted origins. This allows for targeted and culturally-centered interventions addressing genetics, neurobiology, environment and sociocultural contexts in an integrated fashion. Collaborative approaches that unite diverse expertise across scientific disciplines represents the most promising path towards solving the complex problem of addiction.

Acknowledgments

This work was supported by National Institute of Mental Health (NIMH) grant F32MH129052. Additionally, I acknowledge partial funding support from the State of Connecticut, Department of Mental Health and Addiction Services. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the Department of Mental Health and Addiction Services, the State of Connecticut, the National Institutes of Health, or the National Institute of Mental Health. I extend my gratitude for the financial support that made this research possible.

Conflict of interest

The author declares no conflict of interest.