Year: 2019
Type: article
Abstract: For many psychiatric disorders, such as anxiety, depression, and addiction, sex is a critical biological variable and women represent a particularly vulnerable population (Piccinelli and Wilkinson, 2000; Becker et al., 2017). While sex differences in the pervasiveness and prognosis of these disorders have long been known to exist, there are few instances where approaches to pharmacological treatment of these disorders differ between the sexes, which likely contributes to ineffective treatments in women. In substance use disorder (SUD) women exhibit increased propensity to use drugs, a faster transition to addiction from first use, greater problems maintaining abstinence, and relapse at a higher rate than men (Randall et al., 1999; Zilberman et al., 2004; Becker and Hu, 2008). In regard to alcohol use disorder (AUD), women comprise half of the individuals suffering with AUD; however, the vast majority of clinical and preclinical research on developing treatments has focused on male subjects (Beery and Zucker, 2011). With the recent mandate to include female subjects in federally funded research in the United States, there is emerging evidence highlighting that biological sex itself is not a behavioral determinant, but rather is a complex variable interacting with environmental factors and experience to drive behavior (Figure 1A; Cahill, 2006; Kiraly et al., 2018). While research exploring sex differences in AUD has traditionally focused on differential effects of alcohol, it is important to consider that differences in fundamental behavioral strategies, which can be observed outside of the context of alcohol, may underlie the behaviors that eventually emerge after long-term alcohol exposure and may influence the severity of AUD (Figure 1B). Together, fundamental differences in basic behavioral strategies between the sexes—specifically in regard to the balance of positive and negative outcomes—point to critical factors that may promote the development of AUD specifically in women (Becker et al., 2012). Interaction of sex differences, environment, and alcohol on maladapative behaviors and development of alcohol use disorder. (A). Sex, prior experience, comorbidities, and alcohol interact to affect behavioral strategies that can ultimately lead to substance/alcohol use disorders. These behavioral strategies are a balance between maximizing positive outcomes and minimizing negative outcomes. While females may be inherently biased towards minimizing negative outcomes, a number of factors (environmental, previous experience) can interact to alter behavioral strategy and how one values positive vs aversive outcomes. (B).i. A wide range of preclinical models of behavior are utilized to understand underlying sex differences driving behavioral and environmental factors that interact to drive addictive phenotypes. Illustrated here, left to right, reward seeking, social factors that influence drinking behaviors, and drinking despite an aversive consequence (compulsive use). ii. Emerging evidence suggests that females are more vulnerable to AUD due to inherent differences in value-based decision making that alters the balance between positive and negative outcomes and promotes drinking behavior. One of the major factors to consider in SUD/AUD is why individuals start taking drug initially. Behavioral drive to avoid aversive outcomes—i.e. negative reinforcement—is a potent determinant of behavior in many contexts. This process is specifically important in AUD as alcohol has anxiolytic properties, which means differences in drive to avoid feelings of anxiety could be reflected in drinking for anxiolytic effects. Accordingly, emotional factors tend to play a sex-specific role in why women start taking drug (Kuntsche and Müller, 2012). The reports in this issue of Alcohol and Alcoholism suggest that female subjects are particularly sensitive to alcohol’s anxiolytic effects and the drive to avoid this negative internal state may be a major contributor of both why women start drinking initially and continue drinking later. Indeed, women are more likely to take drugs as self-medication to reduce stress/alleviate depression, which may in turn explain why women spiral into addiction faster (Becker et al., 2012). Conversely, men engage in more risky behaviors than women, including experimenting with drugs of abuse (Becker et al., 2012)—suggesting that seeking reward, not avoiding negative consequences, is a greater factor in males. Further highlighting this idea, a higher percentage of males engage in pre-drinking (‘pre-gaming’), or drinking in a domestic setting before going to a licensed setting, as compared to females (Ferris et al., 2019). Similarly, for natural rewards female subjects value avoiding negative outcomes over reward seeking, thus speaking to fundamental sex differences in how information is valued to guide decisions. Because the initial drive to take drug may be different, fundamentally different processes may promote addiction and how alcohol interacts with these processes to drive AUD even when the behavioral outcome looks the same. Sex-differences also emerge when looking at how aversive internal states or social interactions drive and influence the maintenance and levels of alcohol consumption. These factors can be internal—like with depression or anxiety—or external such as with social factors. Women with AUD also show distinct emotion processing deficits, which may perpetuate drug-taking (Lewis et al., 2019). Women also show higher rates of both depression and anxiety than men among those with alcoholic cardiomyopathy (ACM) (Mogos et al., 2019). Depression and anxiety could stem from alcohol use or be a factor that promotes it, further highlighting the complex interaction between sex and other factors that drive and sustain alcohol use. In addition to internal negative states, female subjects are more influenced by the social environment and may drink in order to minimize social stress. For example, in preclinical studies female prairie voles consumed more alcohol only when their male partner also consumed alcohol, but not if the male consumed water (Walcott and Ryabinin, 2019). Similarly, women with the highest rate of involvement in the Greek life system made up a larger percentage of women categorized as experiencing high rates of ‘blackouts’ and also showed increased alcohol consumption and prescription drug misuse. This was associated with higher rates of negative peer influence, further highlighting the critical role of social interactions in problematic drug use in women (Bonar et al., 2019). While women appear to preferentially value avoiding negative outcomes (relative to obtaining positive outcomes) which leads to initial consumption of alcohol, how they value aversive outcomes once they have consumed alcohol seems to shift to further increase vulnerability (Figure 1B). While many preclinical models focus on how much drug animals will consume as the dependent measure, these paradigms often present the reward/drug in isolation. In practical contexts, rewards are generally tied to negative consequences and require consideration of the value of a reward and of the associated potential aversive outcome. Consumption, motivation, and responding in the face of negative consequences are controlled by different neural circuits and can change independently of one another - and contribute to AUD in different ways -, highlighting the importance of studying a wide-range of complex behaviors in order to establish the breadth of sex differences. The differences between these processes, and how sex differences can emerge is highlighted by Fulenwider et al., where ethanol consumption in a two-bottle choice paradigm is not different between sexes (or different over the estrous cycle); however, when quinine—a bitter tastant—was introduced into the ethanol, females were resistant to quinine punishment and continued high levels of drinking, even in the face of this salient negative consequence (Fulenwider et al., 2019). This example highlights another important point; the amount of drug consumed does not predict the behavioral responses when the drug is presented concurrently with other environmental stimuli—such as negative outcomes or alternative reinforcers (Townsend et al., 2019). Thus, sex differences in specific contexts when individuals are making decisions about balancing rewarding and aversive outcomes are completely independent from the presence or absence of sex differences in consummatory drive. Finally, there are sex differences in the amount of harm induced by drinking that are likely driven by a shift in the perceived value of aversive outcomes during ongoing alcohol consumption between men and women. Balance of aversive outcomes and reward information can be discrete—like a punisher introduced into a behavioral paradigm discussed above (Fulenwider et al., 2019)—or more diffuse, such as behavior that potentially increases risk and can lead to harm. There are also robust sex differences in this process, with women presenting as the more vulnerable population. Women that drink heavily, irrespective of the frequency, are at higher risk for injury than males for all causes other than traffic accidents (Cherpitel et al., 2019). This could reflect how negative outcomes are valued but may also speak to a greater vulnerability to negative consequences in women. Although it is important to note some male-specific factors are reported, such as cardiovascular disease resulting from long-term drinking (Mogos et al., 2019). Together, research into sex differences not only better informs our understanding of motivation and value in driving addictive behaviors but is also critical in effectively treating SUD and in mitigating the serious consequences of unregulated alcohol consumption. Females are biased towards avoiding negative consequences, however, once they are exposed to alcohol, females value these negative consequences in different ways; thus, both preexisting factors and alcohol-induced adaptations contribute to AUD vulnerability and prognosis. Moving forward, it is important to comprehensively understand how a wide range of factors influence sex-specific behavioral responses, how they ultimately contribute to AUD vulnerability, and to use this understanding to develop new behavioral models that elucidate female-specific factors that underlie AUD. Importantly, inherent differences in behavioral strategies outside of the context of alcohol may underlie the behaviors that eventually emerge after long-term alcohol exposure and may influence the severity of AUD. The manuscripts within this issue highlight the dangers of making general conclusions based on simple behavioral procedures and demonstrate the importance of studying drug effects across multiple environmental conditions in order to establish how sex differences are expressed in preclinical and clinical models. J.E.Z, E.S.C conceptualized commentary. J.E.Z, E.S.C., A.R.J. wrote the manuscript. J.E.Z and E.S.C. made figures. This work was supported by NIH grants DA042111 to E.S.C., MH065215 and DA047777 to (A.R.J) and GM07628 (J.E.Z.) as well as by funds from the Brain and Behavior Research Foundation to E.S.C and the Whitehall Foundation to E.S.C., and the Edward Mallincrodt Jr. Foundation to E.S.C.
Source: Alcohol and Alcoholism
Institutions: Vanderbilt University, Vanderbilt University Medical Center
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2949227232