Editorial: The behavioural pharmacology of oxytocin

doi: 10.1097/FBP.0000000000000274

Since its discovery in the 1950s, the neurohormone oxytocin has fascinated biologists, pharmacologists, psychologists and neuroscientists alike. Because of its important role in parturition, this nine amino acid peptide was named oxytocin, after the ancient Greek word for quick birth. Indeed, oxytocin is still widely used in the clinic to facilitate childbirth. It is also intimately implicated in lactation. Interestingly, because of its role in parturition and lactation it was soon suggested that oxytocin might also be involved in the formation of mother–infant bonding, and perhaps in other emotions as well. This notion was supported by the discovery that oxytocin was released not only into the bloodstream from the posterior pituitary but also into the central nervous system, likely from collaterals of the oxytocin-synthesizing neurons in the hypothalamus. Oxytocin receptors were identified in brain regions involved in emotions, such as the amygdala, septum, hippocampus and nucleus accumbens. Moreover, oxytocin was found to suppress the release of stress hormones from the pituitary and adrenals, implicating it also in emotions such as fear and anxiety. Work in the last decades has implicated oxytocin in a wide range of functions, ranging from parturition and lactation, cardiovascular and immune function, to abstract social emotions such as trust, generosity and even gloating (schadenfreude). For these reasons, oxytocin has been investigated as a possible treatment strategy in several mental disorders. Most prominent has been the research on the potentially beneficial effects of oxytocin in autism spectrum disorder, but there is also a lively interest in its use in anxiety and substance use disorders.

Since oxytocin has been implicated in emotion, cognition and behaviour, and is thought to be involved in psychiatric disorders, we reasoned that this is a topic that would be of great interest for the readers of Behavioural Pharmacology. We are therefore proud to announce this Special Issue, which covers the breadth of the recent neurobehavioural research on oxytocin in eight manuscripts. The Special Issue starts off with three review papers on oxytocin, followed by five empirical papers. Importantly, the role of oxytocin in normal, adaptive brain function and behaviour is highlighted, as well as its role – and potential use in the clinic – in mental disorders; and both human and animal studies are presented.

The first manuscript is a review by Johnson and Buisman-Pijlman that focuses on the idea that proper, adaptive oxytocin function promotes resilience to mental disorders. As such, individual differences in oxytocin function may determine the vulnerability to psychiatric disorders. Johnson and Buisman-Pijlman therefore discuss the factors and events that influence the development, maturation and plasticity of the oxytocin system throughout life, from the perinatal period to ageing. The detrimental effects of social adversity on oxytocin function, such as abuse and neglect, as well as exposure to substances of abuse, are highlighted. The paper concludes that there are several specific time periods at which the oxytocin system is vulnerable, and that interference with oxytocin function during these periods may aid in the prevention and treatment of oxytocin-related mental disorders, such as anxiety and substance use disorders.

The second review, by Parrott, discusses the role of oxytocin and cortisol in the psychobiological effects of 3,4-methylenedioxymethamphetamine (MDMA), in particular its energizing and positive subjective properties. Interestingly, although there is empirical evidence to indicate that acute MDMA use increases oxytocin secretion as well as prosocial emotions, these measures have generally not been found to correlate. Potential explanations for these findings are discussed. Parrott also presents an overview of the effects of MDMA on cortisol release: acute MDMA use is known to increase the secretion of this hormone. Evidence to support the idea that dysregulation of cortisol secretion contributes to the adverse effects of chronic MDMA use is also presented. Importantly, the effects of chronic MDMA use on oxytocin function remain to be investigated.

The third review, by Lee and Weerts, discussed the potential use of oxytocin in the treatment of substance use disorders. As oxytocin plays a role in reward, learning, memory and stress, processes that are known to be impaired in substance addiction, it is conceivable that dysregulated oxytocin function contributes to this disorder. Conversely, by dampening stress responses and increasing positive mood, oxytocin may be beneficial in the treatment of addictive disorders. Lee and Weerts provide an overview of the role of oxytocin in stress, and how the oxytocin system functionally changes after chronic exposure to substances of abuse. Next, they present studies that have investigated the effects of oxytocin on addictive behaviour in animal models, to demonstrate that this neuropeptide can reduce self-administration of opiates, psychostimulants and alcohol, and can inhibit reinstatement of extinguished responding for these substances. Last, a small number of clinical trials in human addicts are presented, which show that some of the negative emotions associated with cocaine, cannabis and alcohol addiction can be mitigated by oxytocin. Lee and Weerts rightly point out that these studies, though promising, need extension and replication.

The fourth paper in this Special Issue is an empirical study that follows the suggestion from the Lee and Weerts review, by investigating the effect of oxytocin on craving in tobacco smokers. In this within-subject, placebo-controlled pilot study, Miller et al. tested whether intranasal oxytocin influenced craving for cigarettes after overnight abstinence or by exposure to smoking-related cues. The data in this study showed that oxytocin did not alter abstinence-induced craving but did reduce cue-induced craving. Interestingly, the smoking cues also increased anxiety in the study participants, but this was not altered by oxytocin. This suggests that oxytocin may be directly acting on the mechanisms underlying the urge to smoke, rather than the alternative explanation that the effect on craving is secondary to a decrease in negative mood. At the same time, these findings do not support the notion that oxytocin may be useful in the treatment of addiction by dampening stress or anxiety.

The second empirical paper is another study in humans that focuses on the involvement of oxytocin in social behaviour. This study by Demirci et al. investigated the relationship between serum oxytocin levels and aggression and empathy in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) and in controls. Demirci et al. found reduced oxytocin levels in the ADHD youth, particularly in those of the hyperactive/impulsive ADHD subtype. Moreover, the ADHD patients showed increased aggression and reduced empathy, tested using questionnaires. In support of the notion that oxytocin is involved in prosocial functioning, serum oxytocin levels correlated positively with empathy, and correlated negatively with aggression, albeit that these correlations were most pronounced in the children and adolescents with ADHD. This suggests that disrupted oxytocin signalling is involved in dysfunctional social behaviour in ADHD, but may be less directly involved in prosocial behaviour in the healthy situation. Clearly, this interpretation requires further study.

The next empirical paper also investigated the involvement of oxytocin in social behaviour, but in animals. Here, Yu et al. studied the role of oxytocin on social investigation in mandarin voles (Microtus mandarinus). They made use of the fact that these voles display marked individual differences in sociability, as assessed in a social preference test, comparing investigation of a novel conspecific with investigation of a novel object. Importantly, Yu et al. found that infusion of an oxytocin receptor antagonist into the nucleus accumbens reduced social investigation in animals with high social preference. Conversely, oxytocin infusion into this region increased social investigation in voles with low social preference, according to an inverted U-shaped dose–response curve. These effects appeared to be behaviourally specific, as locomotion in an open field was not altered. Together, these data implicate oxytocin in the individual social makeup of mandarin voles.

The remaining two empirical papers deal with oxytocin involvement in negative emotions in animals. In the first of these, Ji et al. investigated oxytocin in relation to depression-like behaviour in rats. In this setup, rats that underwent repeated maternal separation showed increased immobility and reduced struggling in the forced swim test. In addition, they displayed decreased exploration in an open field test, and reduced levels of oxytocin in plasma, hypothalamus and hippocampus. The most important observation in this manuscript is perhaps that intranasal administration of oxytocin alleviated the depression-like phenotype. Moreover, oxytocin partially rescued the detrimental effect of maternal separation on hippocampal neurogenesis. These findings suggest that oxytocin may be useful in the treatment of depression.

The Special Issue concludes with a paper by Janezic et al. that presents work on the effect of oxytocin treatment in a rat model of post-traumatic stress disorder. Using a contextual fear-conditioning paradigm with multiple re-exposures to the shock environment, Janezic et al. demonstrate that chronic treatment with oxytocin reduces fear behaviour, whereas acute oxytocin is ineffective. It is suggested that oxytocin treatment interacts with exposure to the shock context to reduce fear, perhaps by enhancing consolidation of the ‘safe’ experience of the traumatic environment. To link fear behaviour back to social interaction, Janezic et al. also reports that singly housed animals showed higher levels of fear than did animals that were group-housed after fear conditioning.

We are pleased to see that the eight manuscripts in this Special Issue cover the diversity of processes in which oxytocin has been implicated. Research into the role of oxytocin in brain function has been very active in the last decades. Given the promising results in autism and substance addiction, and the intriguing data that are reported on the role of oxytocin in emotions, cognition and especially prosocial behaviour, we are confident that this will remain a fascinating research field, and that understanding oxytocin function will increase our understanding of mental health and illness.

Paul Willner

Jack Bergman

Louk Vanderschuren

Bart Ellenbroek

October 2016

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