Pharmacological enhancement of mGluR5 facilitates contextual fear memory extinction

Abstract

Behavioral exposure therapy, which involves extinction of the previously acquired fear, has been used to treat anxiety-related symptoms such as post-traumatic stress disorder. It has been hypothesized that proextinction pharmacotherapeutics may enhance the efficacy of exposure therapy. Systemic administration of the metabotropic glutamate receptor 5 (mGluR5)-positive allosteric modulator 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) facilitated the extinction of contextual fear memory. Notably, CDPPB also enhanced the initial fear memory formation, and had no effect on memory retrieval. Our data suggest that positive regulation of mGluR5 may offer a new method to enhance exposure therapy through facilitating extinction without adversely affecting other aspects of memory process.

Acute inhibition of mGluR5 disrupts behavioral flexibility

“…We found that the mGluR5 inhibitor MPEP disrupted both the initial contextual fear learning and the inhibitory learning during the extinction sessions. This is consistent with the recent finding showing that enhancement of mGluR5 function facilitates both initial learning and extinction learning of contextual fear memory [(Sethna and Wang, 2014) but also see (Xu, Zhu, Kraniotis, He, Marshall, Nomura, Stauffer, Lindsley, Conn, and Contractor, 2013)]. Interestingly, the mouse model of Fragile X syndrome shows abnormal hyperfunction of mGluR5 (Huber, Gallagher, Warren, and Bear, 2002) along with faster extinction of passive avoidance memory (Dolen, Osterweil, Rao, Smith, Auerbach, Chattarji, and Bear, 2007).…”

Gadd45α modulates aversive learning through post‐transcriptional regulation of memory‐related mRNA s

“…Similar alterations were found for other Gadd45a-regulated targets, such as Grin2b (ionotropic glutamate receptor, subunit epsilon 2), Kcnq3 (potassium voltage-gated channel, subfamily Q, member 3), and Grm5 (metabotropic glutamate receptor 5) (Appendix Fig S3A-F). Of note, these genes have been previously implicated in memory formation and synaptic plasticity [28][29][30][31][32][33][34].…”

The divergent effects of CDPPB and cannabidiol on fear extinction and anxiety in a predator scent stress model of PTSD in rats.

“…was suspended in 10% Tween 80 (Sigma-Aldrich) in phosphate-buffered saline (PBS) to a final concentration of 30 mg/ml and injected subcutaneously (s.c.). The dose of CDPPB was based on previous studies indicating an effect on fear extinction (Sethna & Wang, 2014). Cannabidiol (CBD, 5 mg/kg) was provided by the NIDA controlled substances program (RTI, Research Triangle, NC) and dissolved in a mixture of 100% ethanol, Cremophor, and 0.9% NaCl to 5 mg/ml and injected intraperitoneally (i.p.).…”

“…Last, we examined the effects CDPPB and CBD on anxiety in the light-dark box test. Previous studies have found that CDPPB produces either no effect or a moderate anxiogenic effect in previously unstressed rodents (Sethna & Wang, 2014;Lee et al, 2018). As CDPPB enhances extinction of fear, and drugs in this class of mGlu5…”

“…Pharmacological and genetic inhibition of mGlu5 function impairs extinction of both cues and contexts paired with footshock in rodents (Sethna & Wang, 2016;Fontanez-Nuin, 2010;Sepulveda-Orengo et al, 2013;Xu et al, 2009), while administration of of mGlu5 positive allosteric modulators (PAM) enhances extinction of footshock-associated contexts (e.g. Sethna & Wang, 2014). While mGlu5 antagonists inhibit fear extinction, they also produce anxiolytic effects (Rahman et al, 2017;Porter et al, 2005).…”