Combined Neuropeptide S and D-Cycloserine Augmentation Prevents the Return of Fear in Extinction-Impaired Rodents: Advantage of Dual versus Single Drug Approaches

Abstract

Background:Despite its success in treating specific anxiety disorders, the effect of exposure therapy is limited by problems with tolerability, treatment resistance, and fear relapse after initial response. The identification of novel drug targets facilitating fear extinction in clinically relevant animal models may guide improved treatment strategies for these disorders in terms of efficacy, acceleration of fear extinction, and return of fear.Methods:The extinction-facilitating potential of neuropeptide S, D-cycloserine, and a benzodiazepine was investigated in extinction-impaired high anxiety HAB rats and 129S1/SvImJ mice using a classical cued fear conditioning paradigm followed by extinction training and several extinction test sessions to study fear relapse.Results:Administration of D-cycloserine improved fear extinction in extinction-limited, but not in extinction-deficient, rodents compared with controls. Preextinction neuropeptide S caused attenuated fear responses in extinction-deficient 129S1/SvImJ mice at extinction training onset and further reduced freezing during this session. While the positive effects of either D-cycloserine or neuropeptide S were not persistent in 129S1/SvImJ mice after 10 days, the combination of preextinction neuropeptide S with postextinction D-cycloserine rendered the extinction memory persistent and context independent up to 5 weeks after extinction training. This dual pharmacological adjunct to extinction learning also protected against fear reinstatement in 129S1/SvImJ mice.Conclusions:By using the potentially nonsedative anxiolytic neuropeptide S and the cognitive enhancer D-cycloserine to facilitate deficient fear extinction, we provide here the first evidence of a purported efficacy of a dual over a single drug approach. This approach may render exposure sessions less aversive and more efficacious for patients, leading to enhanced protection from fear relapse in the long term.

Corticosterone Treatment and Incubation Time After Contextual Fear Conditioning Synergistically Induce Fear Memory Generalization in Neuropeptide S Receptor-Deficient Mice

“…Injections of NPS into the cerebral ventricle or into the amygdala, the central site of the brain fear circuitry, reduce conditioned fear (e.g., Jüngling et al, 2008;Fendt et al, 2010), in line with the idea that NPS-deficient mice seem to be more anxious than wildtype mice (Liu et al, 2017). Moreover, NPS injections rescue stress-induced fear extinction deficits (Chauveau et al, 2012) and boost the beneficial effects of D-cycloserine on fear extinction (Sartori et al, 2016). Interestingly, exposure to forced swim stress induces an increase of amygdaloid NPS levels (Ebner et al, 2011).…”

Neuropeptide S precursor knockout mice display memory and arousal deficits

“…Conversely, the synthetic NPSR antagonist SHA 68 (Okamura et al ., ) was able to attenuate fear extinction (Jüngling et al ., ). Two recent studies further confirmed NPS’ role in extinction of conditioned fear in models of rats and mice with high trait anxiety as well as a mouse model of attenuated fear extinction, respectively (Slattery et al ., ; Sartori et al ., ). These observations may be attributed to a profound memory‐enhancing effect of NPS, as we have previously described that activation of central NPS signaling can promote consolidation of long‐term memory, independent of emotional content of the memory trace, by interacting with noradrenergic signaling in the brain (Okamura et al ., ), and these memory‐enhancing effects were later replicated in rats and mice (Lukas & Neumann, ; Han et al ., ).…”

Effects of systemic glutamatergic manipulations on conditioned eyeblink responses and hyperarousal in a rabbit model of post-traumatic stress disorder

“…Our findings mirror these results as we demonstrated a within-session enhancement of CR extinction with the highest d-cycloserine dose that did not develop until an excess of 20 extinction trials were presented. Importantly, these studies in rodents also demonstrated that effects of d-cycloserine did not last long-term or prevent fear renewal (Bouton et al, 2008; Sartori et al, 2016). In agreement, our results from the extinction retention test one week later in the highest dose group showed no carryover of the extinction enhancement but rather showed an increase in responding at the beginning of the retention test compared to the terminal level at the end of extinction.…”

“…Similarly, in studies in rats, d-cycloserine was only beneficial when subjects exhibited some extinction learning (Bouton et al, 2008), and enhancement could be improved if more trials were presented under the drug (Bouton et al, 2008; Lee et al, 2006). In another example, d-cycloserine treatment in mice did not facilitate extinction in an extinction-resistant strain but did in strains able to demonstrate some extinction learning (Sartori et al, 2016). Our findings mirror these results as we demonstrated a within-session enhancement of CR extinction with the highest d-cycloserine dose that did not develop until an excess of 20 extinction trials were presented.…”