Male-selective effects of oxytocin agonism on alcohol intake: behavioral assessment in socially housed prairie voles and involvement of RAGE

Abstract

Targeting the oxytocin (OXT) peptide system has emerged as a promising new approach for the treatment of alcohol use disorder (AUD). However, further advancements in this development depend on properly modeling various complex social aspects of AUD and its treatment. Here we examined behavioral and molecular underpinnings of OXT receptor (OXTR) agonism in prairie voles, a rodent species with demonstrated translational validity for neurobiological mechanisms regulating social affiliations. To further improve translational validity of these studies, we examined effects of intranasal (IN) OXT administration in male and female prairie voles socially housed in the presence of untreated cagemates. IN OXT selectively inhibited alcohol drinking in male, but not female, animals. Further, we confirmed that exogenously administered OXT penetrates the prairie vole brain and showed that Receptor for Advanced Glycation End-products assists this penetration after IN, but not intraperitoneal (IP), OXT administration. Finally, we demonstrated that IP administration of LIT-001, a small-molecule OXTR agonist, inhibits alcohol intake in male, but not female, prairie voles socially housed in the presence of untreated cagemates. Taken together, results of this study support the promise of selectively targeting OXTR for individualized treatment of AUD.

Oxytocin Attenuates Yohimbine-Induced Reinstatement of Alcohol-Seeking in Female Rats via the Central Amygdala

“…Previous studies have found that the OXT system may interact differently with alcohol usage in males versus females. A decrease in OXT and an increase in OXTR binding sites were found in male alcohol-dependent rats and male alcohol-dependent patients compared to healthy controls, but no change was found in female subjects [57]; additionally, intranasal and intraperitoneal OXT administration both selectively inhibited alcohol-seeking in male, but not female, prairie voles [58]. In humans, the OXTR rs53576 polymorphism, which is suggested to decrease oxytocinergic functioning, was associated with increased alcohol use in males but not females [59].…”

Intranasal oxytocin does not change partner preference in female titi monkeys (Plecturocebus cupreus), but intranasal vasopressin decreases it

“…Intranasal treatments are a noninvasive method that allows nasal administration of pharmacological compound in a solution, which is meant to be delivered to the central nervous system through the olfactory and trigeminal nerves, ultimately crossing the BBB thanks to RAGE (receptor for advanced glycation end‐products) receptors 62 . Recent studies have found that RAGE transports OT across the BBB in sufficient quantity to affect behavior, 63 a process specific to IN (rather than intraperitoneal) administration 64 . While it is likely that these treatments do penetrate the BBB, they also likely lead to high peripheral concentrations 41 .…”

“…62 Recent studies have found that RAGE transports OT across the BBB in sufficient quantity to affect behavior, 63 a process specific to IN (rather than intraperitoneal) administration. 64 While it is likely that these treatments do penetrate the BBB, they also likely lead to high peripheral concentrations. 41 Peripheral effects of AVP, for example, would include higher blood pressure, 65 and it is perhaps significant that the high dose of AVP increased locomotion in our study.…”

The ReCoDe addiction research consortium: Losing and regaining control over drug intake—Findings and future perspectives

“…We will investigate the role of oxytocin in social alcohol consumption behaviour and the underlying mechanisms. Oxytocin is a prime candidate for impairment of social drinking behaviour, 64 and intranasal use in at‐risk social drinkers is a viable clinical development process. Another pharmacological intervention that is being developed preclinically is the use of psychedelic medications to treat AUD and SUDs.…”