Role of beta-adrenergic receptors in the ventromedial prefrontal cortex during contextual fear extinction in rats

Abstract

It has been reported that stress-related activation of the noradrenergic system strengthens the formation of aversive memories and that beta-adrenergic receptors seem to be involved in this emotional memory processing. In this study, the effects of beta-adrenergic compounds on the extinction of contextual conditioned fear responses were evaluated. Rats were trained with footshock in a conditioning box. In the 3 days following the training, the animals were re-exposed to the apparatus and received either a single or repeated intraperitoneal injections of the beta-adrenergic antagonist propranolol, the beta-adrenergic agonist isoproterenol, or saline 30 min before (acquisition of extinction) or immediately after (consolidation of extinction) the extinction sessions. A drug-free session was performed on the last day. While repeated isoproterenol treatment facilitated the consolidation of contextual fear extinction, repeated propranolol administration impaired the acquisition and the consolidation of this process. Further, the role of ventromedial prefrontal cortex (vmPFC) in the extinction of contextual conditioned fear was tested with an immunohistochemistry assay. Our results show a reduction in Fos-protein expression between the first and the last extinction session. In a follow-up experiment, intra-vmPFC microinjection of isoproterenol before the first extinction session facilitated the extinction of contextual fear. This facilitation was antagonized by pre-treatment with atenolol, suggesting that this change is mediated by beta-1-adrenergic activity. Our results reinforce the role of the vmPFC in fear extinction mechanisms, suggesting that vmPFC-beta-1-adrenergic receptor activation underlies part of the facilitation of the fear extinction processes.

The Possible Role of Medial Prefrontal Cortex Beta-1-Adrenoceptors in Morphine-Induced Amnesia

“…In agreement with our result, our previous study demonstrated that atenolol decreased memory retrieval [29]. The propranolol injection into the ventromedial prefrontal cortex impaired the acquisition and the consolidation of extinction in rats [30]. Moreover, injections of β 1 -AR antagonists into the amygdala produced memory impairment [21,31].…”

Revisiting propranolol and PTSD: Memory erasure or extinction enhancement?

“…Propranolol has been studied extensively, but with mixed results, leading many to believe it is an ineffective therapeutic option (Raskind et al, 2003; Strawn & Geracioti, 2008; Tawa & Murphy, 2013). In addition, many studies in rodents have shown that systemic propranolol prior to delayed extinction impairs long-term retention (Cain et al, 2004; Do-Monte et al, 2010; Fitzgerald et al, 2015). One possibility is that, similar to extinction learning itself, the efficacy of propranolol as a fear-reducing agent is sensitive to the timing of administration.…”

“…Nonetheless, pharmacotherapies that either dampen NE transmission, such as the α1-adrenoceptor antagonist prazosin, the α2 agonist clonidine, and the non-selective β antagonist propranolol, or enhance NE transmission such as the α2 antagonist yohimbine, have shown some success in diminishing the exaggerated fear responding associated with PTSD (Belkin & Schwartz, 2015; Morris & Bouton, 2007; Powers, Smits, Otto, Sanders, & Emmelkamp, 2009; Raskind et al, 2003; Strawn & Geracioti, 2008; Tawa & Murphy, 2013; Taylor, Freeman, & Cates, 2008; Wangelin, Powers, Smits, & Tuerk, 2013). Yohimbine, as well as the non-selective β agonist isoproterenol, can enhance extinction learning (Cain, Blouin, & Barad, 2004; Do-Monte et al, 2010; Morris & Bouton, 2007; Powers et al, 2009), as well as memory consolidation or reconsolidation (Dębiec, Bush, & LeDoux, 2011; Gazarini, Stern, Carobrez, & Bertoglio, 2013). For these reasons, there has been a resurgence of interest in using noradrenergic drugs as adjuncts to cognitive-behavioral therapies for PTSD.…”

Inhibition of β-Adrenergic Receptors Induces a Persistent Deficit in Retrieval of a Cocaine-Associated Memory Providing Protection against Reinstatement

“…Furthermore, it is well accepted that norepinephrine facilitates, rather than impedes, memory formation through b-receptor activation (McGaugh, 2000). Finally, research has demonstrated that propranolol impairs extinction learning (for review see Mueller and Cahill, 2010) in both aversive (Do-Monte et al, 2010;Merlo and Izquierdo, 1967;Mueller et al, 2008;Ouyang and Thomas, 2005) and appetitive paradigms (LaLumiere et al, 2010).…”