Pharmacological modulation of metabotropic glutamate receptor subtype 5 and 7 impairs extinction of social fear in a time-point-dependent manner

Highlights

• We use social fear conditioning to specifically induce social fear in naive mice.

• AMN082 and MPEP do not alter acquisition of social fear.

• AMN082 and MPEP impair extinction of social fear.

• Modulation of mGluR5 and mGluR7 delays social fear extinction processes.

Abstract

Pharmacological modulation of metabotropic glutamate receptor subtype 5 (mGluR5) and 7 (mGluR7) was shown to attenuate the acquisition and to facilitate the extinction of cued and contextual, non-social, fear. Using the allosteric mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and the allosteric mGluR7 agonist N,N’-dibenzyhydryl-ethane-1,2-diamine dihydrochloride (AMN082), we aimed to study how pharmacological blockade of mGluR5 and activation of mGluR7 influence acquisition and extinction of social fear in mice. We could show that when administered before social fear conditioning, neither MPEP nor AMN082 affected acquisition and extinction of social fear, suggesting that mGluR5 inactivation and mGluR7 activation do not alter social fear. However, when administered before social fear extinction, both MPEP and AMN082 impaired social fear extinction and extinction recall. These findings suggest that mGluR5 inactivation and mGluR7 activation are unlikely to prevent the formation of traumatic social memories. Furthermore, medication strategies aimed at augmenting exposure-based therapies for psychiatric disorders associated with social deficits via modulation of mGluR5 and mGluR7 must be pursued cautiously because of their potential to delay social fear extinction processes.

Introduction

Several psychiatric disorders, such as posttraumatic stress disorder (PTSD), panic disorder, specific phobias and social anxiety disorder (SAD) involve learned components. Memories triggered by trauma-associated cues induce fear and anxiety and contribute to the development and maintenance of symptoms. Such traumatic memories can also be induced experimentally by repeatedly pairing initially neutral cues (e.g. odors, tones, visual stimuli, social stimuli) with an unconditioned stimulus (e.g. physical punishment or onset of drug effect). Consequently, the neutral cue acquires the ability to elicit conditioned responses, such as fear and anxiety. Therapeutic approaches aimed at reducing the impact of trauma-associated cues in eliciting maladaptive fear and anxiety responses in psychiatric disorders are likely to be beneficial. The most efficient way to reduce conditioned responses is through the process of extinction, which usually involves repeated exposures to the conditioned stimulus in the absence of the adverse event it once predicted [1], [2].

Research on the role of glutamate and its ionotropic and metabotropic (mGluR) receptors in extinction have led to the development of pharmacotherapies which enhance the efficacy of extinction-based protocols in clinical populations [2]. For example, augmentation of exposure therapy with d-cycloserine, a ionotropic N-methyl-d-aspartate (NMDA) receptor agonist, was shown to improve some anxiety symptoms in SAD [3], [4], PTSD [5], [6], panic disorder [7], and acrophobia [8]. Studies on the contribution of mGluRs to fear extinction have only appeared recently, and knowledge at this time is still limited. Preclinical research suggested that mGluRs may represent promising candidates for pharmacologically improving the outcome of exposure-based therapy. As such, negative allosteric modulation of mGluR5 with 2-methyl-6-(phenylethynyl)-pyridine (MPEP) demonstrated effects against acquisition and retention of conditioned fear [9], [10], [11], [12]. Similarly, allosteric activation of the mGluR7 subtype with N,N’-dibenzyhydryl-ethane-1,2-diamine dihydrochloride (AMN082) blocked acquisition of conditioned fear, but also facilitated extinction of conditioned aversion and fear in two amygdala-dependent paradigms (i.e. conditioned taste aversion and fear-potentiated startle) [13], [14]. However, it is unclear, whether pharmacological modulation of mGluR5 and mGluR7 might also alter coping with, and recovery from, a traumatic social experience. Only a few studies investigated the effects of MPEP on social behaviors and most of these reported that MPEP has the potential to normalize deficits in social interaction. As such, MPEP decreased inter-male aggression and increased social investigation in highly aggressive OF1 mice [15]. It also increased social investigation in Balb/c mice [16], and mice lacking the excitatory synaptic signaling scaffold IRSp53 [17], which were shown to have deficits in social interaction and communication. However, MPEP did not improve social interaction deficits in autistic-like BTBR mice [18] and even decreased social investigation in Swiss Webster mice, which show normal social interaction [16]. So far, only one study investigated the effects of AMN082 on social behavior. In more detail, Navarro et al. [19] have shown that AMN082 decreased inter-male aggression without affecting social investigation in highly aggressive OF1 mice.

In the present study, we aimed to investigate whether pharmacological modulation of mGluR5 and mGluR7 affects acquisition and extinction of conditioned social fear in CD1 mice, which otherwise show normal social interaction [20], [21], [22]. In order to induce social fear, we used the social fear conditioning (SFC) paradigm, which was established to mimic the major behavioral symptoms of SAD, i.e. reduced social investigation and avoidance of con-specifics, as indicative of social fear [23], [24]. In this model, social fear is induced by administration of mild electric foot shocks during the investigation of a con-specific. Importantly, treatment of socially fear-conditioned (SFC⁺) mice with medication used for SAD patients, such as diazepam and paroxetine, reversed social fear, providing predictive validity to the SFC model [23]. Repeated exposure of the SFC⁺ mice to unknown con-specifics leads to a gradual decline in the fear response, a process termed social fear extinction. MPEP or AMN082 were administered either prior to SFC (also referred to as acquisition) or social fear extinction in order to determine whether the drugs affected acquisition or extinction of social fear.