Oxytocin in the prelimbic medial prefrontal cortex reduces anxiety-like behavior in female and male rats

Abstract

The neuropeptide oxytocin (OT) has anxiolytic effects in rodents and humans. However, the specific brain regions where OT acts to regulate anxiety requires further investigation. The medial prefrontal cortex (mPFC) has been shown to play a role in the modulation of anxiety-related behavior. In addition, the mPFC contains OT-sensitive neurons, expresses OT receptors, and receives long range axonal projections from OT-producing neurons in the hypothalamus, suggesting that the mPFC may be a target where OT acts to diminish anxiety. To investigate this possibility, females rats were administered OT bilaterally into the prelimbic (PL) region of the mPFC and anxiety-like behavior assessed. In addition, to determine if the effects of OT on anxiety-like behavior are sex dependent and to evaluate the specificity of OT, male and female anxiety-like behavior was tested following delivery of either OT or the closely related neuropeptide arginine vasopressin (AVP) into the PL mPFC. Finally, the importance of endogenous OT in the regulation of anxiety-like behavior was examined in male and female rats that received PL infusions of an OT receptor antagonist (OTR-A). Overall, even though males and females showed some differences in their baseline levels of anxiety-like behavior, OT in the PL region of the mPFC decreased anxiety regardless of sex. In contrast, neither AVP nor an OTR-A affected anxiety-like behavior in males or females. Together, these findings suggest that although endogenous OT in the PL region of the mPFC does not influence anxiety, the PL mPFC is a site where exogenous OT may act to attenuate anxiety-related behavior independent of sex.

Oxytocin in the medial prefrontal cortex attenuates anxiety: Anatomical and receptor specificity and mechanism of action

“…The injector was left in place for an additional 1 min before withdrawal. Testing for anxiety-related behavior was done 15 min after the OT or saline infusion which is consistent with other studies examining the behavioral effects of OT (Bale et al, 2001; Lukas et al, 2011; Sabihi et al, 2014b). Because of the short half-life of brain OT (approximately 30 min), all behavioral testing was completed within 30 min of infusion (Gimpl and Fahrenholz, 2001).…”

“…OT was dissolved in 0.5 µl saline at a dose of 0.1 µg (Cg1: n = 6; PL: n = 6; IL: n = 9) or 1.0 µg (Cg1: n = 6; PL: n = 6; IL n = 10). Doses were selected based on prior studies of anxiety-like behavior using site specific administration of OT (Ayers et al, 2011; Bale et al, 2001; Lee et al, 2005; Sabihi et al, 2014b). Control rats received a 0.5 µl infusion of saline (Cg1: n = 7; PL: n = 6; IL: n = 8).…”

“…In rats and mice, exogenous OT has repeatedly been shown to attenuate anxiety-like behavior when administered peripherally or centrally (Ayers et al, 2011; Bale et al, 2001; Blume et al, 2008; Mak et al, 2012; McCarthy et al, 1996; Ring et al, 2006; Sabihi et al, 2014b; Slattery and Neumann, 2010; Uvnas-Moberg et al, 1994; Windle et al, 1997). The anxiolytic effect of OT in rodents translates to humans with several studies demonstrating that intranasal administration of OT suppresses anxiety responses in healthy individuals as well as patients with anxiety disorders (de Oliveira et al, 2012; Feifel et al, 2011; Guastella et al, 2009; Heinrichs et al, 2003; MacDonald and Feifel, 2014).…”

“…Numerous brain regions have been identified as sites of action for the anxiolytic effect of OT, including the hypothalamic paraventricular nucleus (Blume et al, 2008; Smith et al, 2016), amygdala (Bale et al, 2001; Neumann, 2002), raphe nucleus (Yoshida et al, 2009), and most recently, the prelimbic (PL) region of the medial prefrontal cortex (mPFC) (Sabihi et al, 2014a; Sabihi et al, 2014b). In addition to the PL region, the mPFC of the rodent brain also includes the infralimbic (IL) and anterior cingulate (Cg1) cortices.…”

Oxytocin in General Anxiety and Social Fear: A Translational Approach

“…Relatively simple pharmacologic approaches using intracerebroventricular (icv) or local (PVN, central amygdala, prefrontal cortex) administration of an OXT-R agonist or antagonist have consistently shown an anxiolytic effect of synthetic or endogenous OXT in male and female rodents (53)(54)(55)(56)(57)(58). Particularly intriguing is the anxiolytic effect of endogenous brain OXT during periods of robust activation and increased central release, including lactation (51,57,59) and sexual activity in both male and female rodents (60)(61)(62).…”