Casein kinase 1‐epsilon deletion increases mu opioid receptor‐dependent behaviors and binge eating1

Abstract

Genetic and pharmacological studies indicate that casein kinase-1 epsilon (Csnk1e) contributes to psychostimulant, opioid, and ethanol motivated behaviors. We previously used pharmacological inhibition to demonstrate that Csnk1e negatively regulates the locomotor stimulant properties of opioids and psychostimulants. Here, we tested the hypothesis that Csnk1e negatively regulates opioid and psychostimulant reward using genetic inhibition and the conditioned place preference assay in Csnk1e knockout mice. Similar to pharmacological inhibition, Csnk1e knockout mice showed enhanced opioid-induced locomotor activity with the mu opioid receptor agonist fentanyl (0.2 mg/kg i.p.) as well as enhanced sensitivity to low-dose fentanyl reward (0.05 mg/kg). Interestingly, female knockout mice also showed a markedly greater escalation in consumption of sweetened palatable food – a behavioral pattern consistent with binge eating that also depends on mu opioid receptor activation. No difference was observed in fentanyl analgesia in the 52.5°C hot plate assay (0–0.4 mg/kg), naloxone conditioned place aversion (4 mg/kg), or methamphetamine conditioned place preference (0–4 mg/kg). To identify molecular adaptations associated with increased drug and food behaviors in knockout mice, we completed transcriptome analysis via mRNA sequencing of the striatum. Enrichment analysis identified terms associated with myelination and axon guidance and pathway analysis identified a differentially expressed gene set predicted to be regulated by the Wnt signaling transcription factor, Tcf7l2. To summarize, Csnk1e deletion increased mu opioid receptor-dependent behaviors, supporting previous studies indicating an endogenous negative regulatory role of Csnk1e in opioid behavior.

Genetic differences in the behavioral organization of binge eating, conditioned food reward, and compulsive-like eating in C57BL/6J and DBA/2J strains

“…We identified robust strain differences in BE, with the D2J strain but not the B6J strain exhibiting a dramatic escalation in PF consumption along with compulsive-like eating in the light-dark test (Figs.1-3). Consistent with our previous studies of BE in B6J mice [18] or WT littermates on a B6J background [25], B6J mice showed little evidence of BE in our intermittent, limited access paradigm of sweetened PF and correspondingly, showed no conditioned PF reward or compulsive-like eating (Figs.1,2). In examining the behavioral organization of BE and other behavioral measures in the parental strains, for the BE-resistant B6J strain, ingestive behaviors (yellow: #1, #2, #6) loaded onto a separate factor from light/dark activity (red; #14, #15, #16; Fig.7A).…”

“…Post hoc one-or two-way ANOVA and Welch's unequal variances t tests (p < 0.05, Bonferroni-corrected) were also conducted to determine effects on individual days. Slope analysis of normalized food intake across the food training days was conducted to quantify escalation [18,25,41,42]. Due to a video recording failure caused by insufficient computer storage space, non-ingestive behaviors (time on, number of visits to, and mean visit time on the light side) on D23 were not obtained in 8 of the 16 PF-trained F 1 mice.…”

“…To facilitate the long-term goal of conducting genetic mapping studies in additional crosses and panels, in the present study, we assessed strain differences in BE of sweetened palatable food (PF) and concomitant behaviors between the BE-resistant B6J strain [18,25] and the D2J strain which has previously been shown to exhibit either less or more consumption of sweetened solutions relative to the B6J strain, depending on the duration of access and the D16, and D18, mice were restricted to the right side of the apparatus (pointed floor texture) and…”

Fentanyl-induced antinociception, reward, reinforcement, and withdrawal in Hnrnph1 mutant mice

“…On Days 3-5, mice received a fentanyl injection (0.2 mg/kg) and locomotor activity was recorded for 30 min each day. The dose of fentanyl was chosen based on previous studies indicating a robust increase in locomotor activity in C57BL/6J mice (Bryant et al 2009a(Bryant et al , 2009c(Bryant et al , 2012Goldberg et al 2017). Mice were recorded with infrared security cameras (Swann Communications, U.S.A., Inc., Santa Fe Springs, CA USA) mounted above the Plexiglas chambers [40 cm long x 20 cm wide by 45 cm high (Yazdani et al 2015)].…”

“…Genetic loci and genetically engineered mutations can exert pleiotropic behavioral effects on multiple classes of drugs of abuse (Tammimäki & Männistö 2011), including psychostimulants and opioids (Bryant et al 2009b(Bryant et al , 2009a(Bryant et al , 2012Goldberg et al 2017). Thus, in the present study, we examined OUD-related traits in Hnrnph1 mutant mice that display deficits in methamphetamine-induced locomotor activity, reward, reinforcement, and dopamine release (Ruan et al 2020a).…”