|Posted on December 9, 2020 at 8:45 AM|
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Oxytocin for the treatment of drug and alcohol use disorders
Mary R. Lee and Elise M. Weerts
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There is growing interest in the use of oxytocin (OT) as a potential treatment for alcohol and other substance use disorders. OT is a neuropeptide that modulates adaptive processes associated with addiction including reward, tolerance, associative learning, memory, and stress responses. OT exerts its effects via interactions with the hypothalamic–pituitary–adrenal (HPA) axis, and multiple neurotransmitter systems including the dopamine mesolimbic reward and corticotrophin-releasing factor stress systems. Oxytocin effects on stress systems are of high interest given the strong link between stress, drug use and relapse, and known dysregulation of HPA-axis activity associated with substance use disorders. At the same time, the oxytocin system is itself altered by acute or chronic drug exposure. This review summarizes the preclinical and clinical literature on the oxytocin system, and its relevance to drug and alcohol addiction. In addition, findings from recent clinical trials conducted in participants with cocaine, cannabis or alcohol use disorder are included and evidence that oxytocin may help to normalize blunted stress responses, and attenuate withdrawal associated hypercortisolism, negative mood and withdrawal symptoms are summarized.
Keywords: Oxytocin, addiction, dependence, substance use disorder, alcoholism, treatment
Oxytocin (OT) is a 9 amino acid polypeptide hormone that acts via a specific receptor and is widely distributed in the central nervous system (CNS) and peripheral tissues (Gimpl and Fahrenholz 2001). OT is involved in the regulation and release of adenohypophyseal hormones including prolactin, adrenocorticotropin (ACTH), gonadotropins, and corticotrophin-releasing factor (CRF). Initially, OT was thought to be primarily involved in sexual behaviors, female parturition and lactation. Subsequent research has determined that OT is also involved in emotional regulation, pain and stress, and modulates response to rewarding behaviors promoted by food, sex and drugs (Meyer-Lindenberg et al. 2011; Onaka et al. 2012). The co-modulation of both stress and motivational processes is believed to be due to the important role of OT to shift salience to social, affiliative processes, both by increasing the salience itself of rewarding stimuli and/or by reducing stress, allowing for attention to social bonding (Baskerville and Douglas 2010). This is obviously relevant to addiction, where salience of drug stimuli overshadows motivation for social affiliation, and where stress may trigger drug seeking and relapse (Sinha 2008). In the current review, we will focus on the role of the oxytocin system in drug and alcohol addiction and highlight key findings to date on the use of intranasal OT to treat substance use disorders.
Oxytocin and stress
The influence of OT to dampen stress responses is important. Neuroendocrine pathways that modulate the response to stress include three interconnecting circuits, the HPA axis, the adrenomedullary system, and the extra-hypothalamic CRF system. The HPA axis releases CRF from paraventricular neurons within the hypothalamus, stimulating the synthesis and release of adrenocorticotropin (ACTH) by the anterior pituitary, which in turn stimulates the synthesis and release of corticosteroids (CORT) (cortisol in human and nonhuman primates and corticosterone in rodents) via the adrenal cortex. The sympathetic adrenomedullary system, which releases norepinephrine and epinephrine, and CRF expression in the extra-hypothalamic brain regions including limbic regions, are key substrates involved in anxiety and other stress-related behaviors. Stress, defined as any stimulus that disrupts physiological homeostasis, triggers a cascade of adaptive responses involving any or all of these pathways to return the organism to homeostasis.
There is strong evidence from the preclinical literature that stress exposure is an important contributor to relapse. In rats and monkeys, acute stress enhances alcohol preference and reward (Funk et al. 2004), and increased alcohol intake is correlated with stress-induced increases in CORT levels (Fahlke et al. 2000; Fish et al. 2008). In addition, following repeated social stress exposure (e.g., defeat, low social rank, and maternal separation), rats and monkeys subsequently show greater alcohol intake when compared to non-stressed cohorts (Fahlke et al. 2000; Cruz et al. 2008; Fish et al. 2008). Current theories suggest that CORT release induced by stress augments drug reinforcement. Indeed, in rodents, CORT increases drug reward by increasing mesolimbic dopamine transmission (Piazza and Le Moal 1996), rats self-administer CORT itself at levels similar to those elicited by stress, and intracerebroventricular infusions of CORT enhance the reinforcing effects of alcohol (Fahlke et al. 1996).
Studies in laboratory animals have demonstrated that OT has marked anti-stress effects. When administered centrally, OT decreases stress-induced increases in CORT levels (Lang et al. 1983; Windle et al. 1997; Neumann et al. 2000) and reduces stress-induced behaviors in rodent models of anxiety and depression (Arletti and Bertolini 1987; Insel and Winslow 1991; Windle, et al. 1997; Neumann et al. 2000). At the same time, the endogenous OT system appears to be sensitive to stressors. In rats, exposure to acute stress increased OT levels in blood and in hypothalamic and extra-hypothalamic brain regions (Lang et al. 1983; Neumann et al. 1998; Ebner et al. 2000; Ondrejcakova et al. 2010) and increased OT mRNA levels (Jezova et al. 1995). Thus, OT appears to play a protective role in homeostatic regulation of stress responses, and OT administration may attenuate the effects of stress on drinking/drug use and relapse (Uhart and Wand 2009; Koob et al. 2014).
Investigations in human subjects are in line with the preclinical literature. When administered via the intranasal route, OT produces changes in measures of autonomic arousal and mood (MacDonald et al. 2011), increased positive communication during couples’ conflict discussions (Ditzen et al. 2009) and improved recognition and processing of positive facial expressions (Di Simplicio et al. 2009; Marsh et al. 2010; Lischke et al. 2012). The anti-stress effects of OT have been also been investigated using the Trier Social Stress Test, a well-validated laboratory procedure for induction of stress responses in human subjects (Foley and Kirschbaum 2010). This test, which includes components of public speaking component and oral mental arithmetic, produces a robust increase in CORT and self-reported psychological stress and these effects are attenuated by OT (Heinrichs et al. 2003; Quirin et al. 2011; Simeon et al. 2011; de Oliveira et al. 2012; Kubzansky et al. 2012). Consistent with an OT anti-stress hypothesis, a recent study that measured both OT and CORT after the TSST found that salivary OT levels increased immediately following social stress exposure, prior to increases in salivary CORT (Jong et al. 2015). Taken together, these data suggest that OT treatment may be useful to normalize the HPA-axis and reduce stress-related physiological and subjective responses (e.g., anxiety, craving) that increase drug and alcohol use and trigger relapse. ......
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