Oxytocin Signaling as a Target to Block Social Defeat-Induced Increases in Drug Abuse Reward

Abstract

There is huge scientific interest in the neuropeptide oxytocin (OXT) due to its putative capacity to modulate a wide spectrum of physiological and cognitive processes including motivation, learning, emotion, and the stress response. The present review seeks to increase the understanding of the role of OXT in an individual's vulnerability or resilience with regard to developing a substance use disorder. It places specific attention on the role of social stress as a risk factor of addiction, and explores the hypothesis that OXT constitutes a homeostatic response to stress that buffers against its negative impact. For this purpose, the review summarizes preclinical and clinical literature regarding the effects of OXT in different stages of the addiction cycle. The current literature affirms that a well-functioning oxytocinergic system has protective effects such as the modulation of the initial response to drugs of abuse, the attenuation of the development of dependence, the blunting of drug reinstatement and a general anti-stress effect. However, this system is dysregulated if there is continuous drug use or chronic exposure to stress. In this context, OXT is emerging as a promising pharmacotherapy to restore its natural beneficial effects in the organism and to help rebalance the functions of the addicted brain.

Keywords: animal models; corticotropin-releasing factor; drug addiction; human research; neuroinflammation; oxytocin; reward system; social stress.

Figure 1

Oxytocin modulates the addiction cycle. Clinical and preclinical studies show that oxytocin has protective effects during all stages of the addiction cycle: (1) In early drug experiences, it diminishes the reinforcing and general effects of drugs. (2) It can prevent progression from initial drug experimentation to dependence and drug escalation. (3) In drug cessation, it can prevent relapse induced by cues, drug primes, and stress.

Figure 2

Oxytocin modulates the inflammatory response induced by stress. The effects of stress are depicted in blue, and those of oxytocin in pink. Stress activates the hypothalamic–pituitary–adrenal (HPA) axis and promotes the release of glucocorticoids that turn peripheral immune cells into a primed state. The activation of stress-primed immune cells can induce an exaggerated inflammatory response that eventually reaches the brain and promotes the activation of resident immune cells (neuroinflammation). Activated microglia within the brain release inflammatory cytokines that activate the HPA. Oxytocin counteracts the effects of stress in all the stages of this loop.