Oxytocinergic manipulations in corticolimbic circuit differentially affect fear acquisition and extinction.

The oxytocinergic system promotes social behavior and reduces anxiety. The significant roles and functional interactions of the medial prefrontal cortex and the amygdala in the regulation of fear provide a unique experimental setting to examine the effects of oxytocin on extinction of fear. In this study we manipulated the oxytocin system at different time points in either the infralimbic region of the medial prefrontal cortex (IL-mPFC), the basolateral amygadala (BLA) or in the central amygdala (CeA). Manipulations of the oxytocin following retrieval of fear in the IL-mPFC resulted in facilitation of subsequent extinction. In contrast, in the BLA, manipulating the oxytocinergic system after the retrieval of fear was associated with contrasting effects; whereas the microinjection of exogenous synthetic oxytocin was associated with impaired extinction, the microinfusion of WAY-267474 facilitated extinction. In contrast, intra-BLA microinfusion of the selective agonist TGOT did not affect freezing. Oxytocin manipulations in the CeA had no effect on subsequent extinction. Contrasting effects were also found when the drugs were injected before conditioning. Whereas oxytocin manipulations in the BLA enhanced fear and impaired extinction, in the CeA the microinfusion of the selective agonists (WAY-267474 and TGOT), but not synthetic oxytocin, resulted in reduced freezing levels. These results show that in the rat, the oxytocinergic system differentially regulated fear and extinction in region and temporal-dependent manners and further join data to show that contrary to the prevailing belief that oxytocin is solely involved in reducing fear, oxytocin can also act as an enhancer of fear responses.