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

Abstract

Alcohol use disorder is a significant public health concern, further exacerbated by an increased risk of relapse due to stress. In addition, factors such as biological sex may contribute to the progression of addiction, as females are especially susceptible to stress-induced relapse. While there have been many studies surrounding potential pharmacological interventions for male stress-induced ethanol reinstatement, research regarding females is scarce. Recently, the neuropeptide oxytocin has gained interest as a possible pharmacological intervention for relapse. The present study examines how oxytocin affects yohimbine-induced reinstatement of ethanol-seeking in female rats using a self-administration paradigm. Adult female rats were trained to press a lever to access ethanol in daily self-administration sessions. Rats then underwent extinction training before a yohimbine-induced reinstatement test. Rats administered with yohimbine demonstrated significantly higher lever response indicating a reinstatement of ethanol-seeking behavior. Oxytocin administration, both systemically and directly into the central amygdala, attenuated the effect of yohimbine-induced reinstatement of ethanol-seeking behavior. The findings from this study establish that oxytocin is effective at attenuating alcohol-relapse behavior mediated by the pharmacological stressor yohimbine and that this effect is modulated by the central amygdala in females. This provides valuable insight regarding oxytocin's potential therapeutic effect in female stress-induced alcohol relapse.

Keywords: alcohol; central amygdala; females; oxytocin; reinstatement; stress; yohimbine.

Figure 1

Timeline depicting the experimental paradigm across Experiments 1 and 2. All animals underwent ethanol habituation followed by ethanol self-administration, extinction, and reinstatement testing. YOH = yohimbine; VEH = vehicle; OXT = oxytocin.

Figure 2

Anatomical depiction of terminal point of the internal cannulae injectors used for intra-central amygdala infusions. Numerical measurements indicate posterior coordinates relative to bregma. All cannulae were targeted toward the CeA (−2.4 AP; ±4.0 ML; −6.9 DV from bregma).

Figure 3

(A) Experiment 1: Active and inactive presses during ethanol self-administration across FR1 and FR3 schedules of reinforcement. (B) Active and inactive presses during extinction. (C) Systemic administration of OXT-attenuated YOH-induced reinstatement of ethanol-seeking behavior. YOH administration alone results in the reinstatement of lever-pressing behavior. Concurrent administration of YOH and OXT results in diminished active lever pressing. (D) YOH alone or concurrent YOH and OXT did not have any effect on inactive lever presses. * denotes a significant difference in active lever presses relative to EXT (avg. lever presses across the last 2 days of extinction) at p < 0.05. YOH = yohimbine; OXT = oxytocin.

Figure 4

(A) Experiment 2: Active and inactive presses during ethanol self-administration across FR1 and FR3 schedules of reinforcement. (B) Active and inactive presses during extinction. (C) Intra-CeA administration of OXT-attenuated YOH-induced reinstatement of ethanol-seeking behavior. YOH administration alone results in the reinstatement of lever-pressing behavior. Consecutive administration of YOH and OXT results in diminished active lever pressing. (D) YOH alone or concurrent YOH and OXT did not have any effect on inactive lever presses. * denotes a significant difference in active lever presses relative to EXT (avg. lever presses across the last 2 days of extinction) at p < 0.05.