Increased opioid dependence in a mouse model of panic disorder

Abstract

Panic disorder is a highly prevalent neuropsychiatric disorder that shows co-occurrence with substance abuse. Here, we demonstrate that TrkC, the high-affinity receptor for neurotrophin-3, is a key molecule involved in panic disorder and opiate dependence, using a transgenic mouse model (TgNTRK3). Constitutive TrkC overexpression in TgNTRK3 mice dramatically alters spontaneous firing rates of locus coeruleus (LC) neurons and the response of the noradrenergic system to chronic opiate exposure, possibly related to the altered regulation of neurotrophic peptides observed. Notably, TgNTRK3 LC neurons showed an increased firing rate in saline-treated conditions and profound abnormalities in their response to met5-enkephalin. Behaviorally, chronic morphine administration induced a significantly increased withdrawal syndrome in TgNTRK3 mice. In conclusion, we show here that the NT-3/TrkC system is an important regulator of neuronal firing in LC and could contribute to the adaptations of the noradrenergic system in response to chronic opiate exposure. Moreover, our results indicate that TrkC is involved in the molecular and cellular changes in noradrenergic neurons underlying both panic attacks and opiate dependence and support a functional endogenous opioid deficit in panic disorder patients.

Ketamine Blocks Morphine-Induced Conditioned Place Preference and Anxiety-Like Behaviors in Mice

“…The observed anxiety-like behaviors following morphine conditioning in a three-chamber apparatus (Figure 1F) may suggest that animals seek the drug-paired chamber as a consequence of negative reinforcement to alleviate aversive affective states facilitated by opioid abstinence. Importantly, our injection regimen of morphine 10 mg/kg once a day for 5 consecutive days does not induce signs of somatic withdrawal in mice including jumping, wet dog shakes, teeth chattering, rearing, tremor, diarrhea, or mastication (Gallego et al, 2010). This coincides with the lack of observed somatic withdrawal symptoms following a more prolonged injection regimen of five daily morphine (10 mg/kg, i.p.)…”

Biological sex influences sleep phenotype in mice experiencing spontaneous opioid withdrawal

“…In our study, we utilized a 5‐day treatment paradigm to induce opioid withdrawal, whereas OUD is normally associated with longer term opioid abuse, lasting years or decades (He et al, 2020). In the preclinical literature, animals are usually treated with injection protocols typically ranging from 4 to 14 days (Gallego et al, 2010; McGregor et al, 2022; Pinelli et al, 1997). As such, physiological changes occurring as the result of longer‐term opioid use may not be fully recapitulated in these animal models.…”

“…Somatic symptoms of spontaneous withdrawal are infrequent, varying over the light/dark cycle, and are often subtle and difficult to quantify. These issues have led previous studies to focus on naloxone‐precipitated withdrawal, which triggers pronounced and frequent somatic withdrawal symptoms, and allows measurement of withdrawal intensity over an acute period (Gallego et al, 2010). In contrast, we suggest that measures of sleep, activity and/or T sc provide quantifiable physiological parameters during spontaneously‐occurring withdrawal, which can occur over a prolonged time period.…”

The Clinical Implications of Mouse Models of Enhanced Anxiety

“…Thereby, intense collaborations between researchers from both the clinical and preclinical sides will be pivotal in order to improve the bidirectional characterization of patients and mouse models of enhanced anxiety. In the (near) future this may result in a better classification of anxiety disorders and may guide the development of mouse models of anxiety disorder subcategories (see initial attempts for post-traumatic stress disorder [70] or panic disorder [330,331]). Second, the mouse models described so far mostly reflect either genetic or environmental manipulations rather than mimicking the interaction of these two risk factors, though such interaction seems to be critical in the clinical manifestation of anxiety disorders [7,159].…”