Alcohol Use Disorder and Posttraumatic Stress Disorder: A Relationship Unbonded by Oxytocin Blockade

The increase in alcohol misuse and alcohol use disorder (AUD) in recent decades is concerning (1). Stress-induced disorders, such as posttraumatic stress disorder (PTSD), are highly comorbid with AUD (50% of cases) and alcohol misuse (60% of cases) (2). Although there are 3 effective medications for AUD approved by the U.S. Food and Drug Administration (3), none of them target specifically overlapping mechanisms that are related to both AUD and PTSD. As such, the development of novel treatments that may be beneficial for patients with comorbid AUD and PTSD is highly important. The neuropeptide oxytocin and its receptor may be targets for such a potential novel pharmacotherapeutic approach. Preclinical studies and initial clinical studies suggest a role for oxytocin in both PTSD and AUD [for reviews, see (4,5)]. Nonetheless, the potential dual therapeutic role of oxytocin in treating AUD/PTSD comorbidity remains to be determined.

In their elegant study in the current issue of Biological Psychiatry, Becker et al. (6) introduce a novel mouse model that combines critical features of PTSD with sensitization to stress-induced alcohol relapse–like behavior. They found that repeated (5-day) exposure to multimodal stress, a pharmacological stressor (the α₂-adrenergic receptor antagonist yohimbine) combined with a predator odor, produced long-lasting (≥60 days) sensitization to subsequent predator odor stress–induced alcohol relapse–like behavior. In addition, exposure to cues that were associated with this combined stress exposure resulted in sensitized stress–induced alcohol relapse–like behavior. This highlights the translational value of this model for PTSD in the context of AUD and alcohol misuse that involves alcohol self-administration, extinction, and stress/cue-induced alcohol relapse–like behavior.

Neuroendocrine (corticosterone) and other physiological (defecation) responses to the combined stress exposure conferred validity to this model of chronic stress induction. This combined stressor was associated with long-lasting transcriptional changes in the hypothalamic oxytocin system, namely significantly lower oxytocin messenger RNA (mRNA) expression and significantly higher oxytocin receptor mRNA expression. Systemic oxytocin administration blocked stress-induced alcohol relapse–like behavior, including in mice that received the combined stress exposure.

PTSD and AUD/alcohol misuse are highly comorbid (2) and associated with significant mortality and morbidity. There may be shared susceptibility factors for these two disorders, and each disorder amplifies the severity of the clinical course of the other. The clinical progression of PTSD and AUD/alcohol misuse comorbidity involves alcohol misuse and exposure to traumatic events and depends on the temporal relationship between the two. Alcohol intoxication and withdrawal may increase the susceptibility to PTSD, and AUD/alcohol misuse may be a coping mechanism (i.e., self-medication) for negative affect that is associated with PTSD. The model that is presented by Becker et al. (6) mirrors the latter scenario and has relevance to reverse translation from observations in clinical practice. Consistent with observations in people with comorbid PTSD and AUD/alcohol misuse, this novel mouse model recapitulates a key feature of PTSD, stress cue reactivity, that promoted alcohol relapse susceptibility in addition to stress itself. In their model, mice were trained to self-administer alcohol before chronic/combined stress exposure, so what remains unclear is how alcohol and stress interact to impact subsequent relapse to alcohol seeking and behavioral responsiveness to traumatic cues. Similarly, as noted by Becker et al., it is unclear how stress and alcohol consumption interact to impact oxytocin and oxytocin receptor expression in the hypothalamus and other brain regions that are associated with stress, such as the amygdala.

Becker et al. (6) targeted oxytocin as a potential novel pharmacotherapy for comorbid AUD/PTSD. The justification for testing oxytocin is strong, given the robust and accumulating preclinical and clinical evidence of its role in both stress-related disorders and addictive behaviors [for reviews, see (4,5)], but there is a paucity of studies that have investigated the role of oxytocin specifically in AUD/PTSD comorbidity. Exogenous, systemically administered oxytocin was not specific for reducing stress-induced, relapse-like behavior in this model—it reduced relapse-like behavior in mice both with and without prior stress exposure. This work is timely when considering the growing interest in oxytocin as a treatment for neuropsychiatric disorders. The results of the study by Becker et al. may be rapidly translated to clinical studies in individuals with AUD/PTSD and eventually clinical practice.

Somewhat surprising in Becker et al. (6) was the lack of sex differences in their model of chronic multimodal stress exposure. The authors did not observe sex differences in alcohol relapse–like behavior, in the effects of oxytocin in blocking sensitized stress–induced alcohol relapse–like behavior, or in changes in oxytocin mRNA and oxytocin receptor mRNA expression in the hypothalamus. Indeed, as noted by the authors, previous studies suggest sex differences in the crosstalk between oxytocin and both stress and alcohol exposure. Further work is warranted to investigate these discrepancies.

The findings of Becker et al. (6) advance knowledge in the field and represent a critical foundation for future studies. For example, a follow-up question is whether intranasal oxytocin administration may be effective in this model. This is translationally relevant, given that oxytocin is typically administered intranasally in humans. Moreover, the intranasal route may lead to lower exposure to oxytocin in the periphery, thereby mitigating potential side effects. Intranasally administered oxytocin reaches the brain, possibly via a privileged nose-to-brain pathway (7). Both systemic and intranasal oxytocin administration have been shown to block the escalation of alcohol drinking and motivation for alcohol in alcohol-dependent rats, likely via central mechanisms (8).

Another interesting finding in Becker et al. (6) was that the mice exhibited relapse-like behavior to stress-related cues/contexts weeks after stress exposure, indicating the formation of long-lasting stress-related memories. Remaining to be determined is whether exposure to stress-related cues/contexts in the presence of oxytocin reduces the incentive value of cues/contexts and blocks alcohol relapse–like behavior. Although oxytocin administration during trauma and stress exposure may increase intrusive memories, oxytocin has been shown to facilitate the extinction of conditioned fear in humans (9). Another topic of further investigation is whether chronic treatment with oxytocin and/or the blockade of other systems that play a role in stress and AUD (10) normalizes dysregulation of the oxytocin system in the hypothalamus and blocks alcohol relapse–like behavior.

In conclusion, as shown in Figure 1, Becker et al. (6) report novel, comprehensive, translationally important, and clinically relevant findings that improve our understanding of the strong link between stress and alcohol drinking and the high comorbidity of PTSD and AUD/alcohol misuse. Their findings highlight oxytocin and its receptor as potential novel pharmacotherapeutic targets for this comorbidity.

Figure 1.

Chronic stress exposure (“trauma”) led to enduring (i.e., during protracted abstinence) sensitization to subsequent stress-induced and stress-related cue-induced relapse to alcohol-seeking behavior, effects that were accompanied by changes in the hypothalamic oxytocin system. Systemic oxytocin administration blocked the sensitized relapse to stress-induced alcohol-seeking behavior.