Persons suffering from opioid use disorder (OUD) experience long‐lasting dysphoric symptoms well into extended periods of withdrawal. This protracted withdrawal syndrome is notably characterized by heightened anxiety and hyperkatifeia. Here, we investigated if an exacerbated withdrawal model of acute morphine dependence results in lasting behavioral adaptation 6 weeks into forced abstinence in C57BL/6J mice. We found that our exacerbated morphine withdrawal paradigm produced distinct alterations in behavior in elevated plus maze (EPM), open field, and social interaction tests in male and female mice. Following protracted withdrawal male mice showed enhanced exploration of the open arms of the EPM, reduced latency to enter the corner of the OF, and a social interaction deficit. In contrast, female mice showed enhanced thigmotaxis in the OF. In both sexes, protracted withdrawal enhanced locomotor behavior in response to subsequent morphine challenge, albeit at different doses. These findings will be relevant for future investigation examining the neural mechanisms underlying these behaviors and will aid in uncovering physiological sex differences in response to opioid withdrawal.
Stress can drive adaptive changes to maintain survival during threatening stimuli. Chronic stress exposure, however, may result in pathological adaptations. A key neurotransmitter involved in stress signaling is norepinephrine. Previous studies show that stress elevates norepinephrine levels in the bed nucleus of the stria terminalis (BNST), a critical node regulating anxiety and upstream of stress responses. Here, we use mice expressing channelrhodopsin in norepinephrine neurons to selectively activate terminals in the BNST, and measure norepinephrine release with fast-scan cyclic voltammetry. Mice exposed to a single restraint session show an identical norepinephrine release profile compared to that of unexposed mice. Mice experiencing five days of restraint stress, however, show elevated norepinephrine release across multiple stimulation parameters, and reduced sensitivity to the α 2 -adrenergic receptor antagonist idazoxan. These data are the first to examine norepinephrine release in the BNST to tonic and phasic stimulation frequencies, and confirm that repeated stress alters autoreceptor sensitivity.
103)Persons suffering from opioid use disorder (OUD) experience long-lasting dysphoric symptoms well into extended periods of withdrawal. This protracted withdrawal syndrome is notably characterized by heightened anxiety. Here we investigate if an exacerbated withdrawal model of acute morphine dependence results in lasting behavioral adaptation 6 weeks into forced abstinence. We found that our exacerbated morphine withdrawal paradigm produced distinct impairments in elevated-plus maze, open field, and social interaction tests in male and female mice. These findings will be relevant for future investigation examining the neural mechanisms underlying these behaviors, and will aid in uncovering physiological sex differences in response to opioid withdrawal.
The opioid epidemic has increased dramatically over the last few decades resulting in many suffering from opioid use disorder (OUD). The prevalence of opioids and opioid overdose has been driven by the development of new synthetic opioids, increased availability of prescription opioids, and more recently, the COVID-19 pandemic. As we see increased in exposure to opioids, the United States has also seen increases in the frequency of instances of Narcan (naloxone) administration as a life saving measure for respiratory depression, and, thus, consequently, naloxone-precipitated withdrawal. Sleep dysregulation is one of the main symptoms of OUD and opioid withdrawal syndrome, and therefore should be a key facet of animal models of OUD. Here we examine the effect of precipitated and spontaneous morphine withdrawal on sleep behaviors in C57BL/6J. We find that morphine administration and withdrawal dysregulates sleep, however not equally across morphine exposure paradigms and not qualitatively the same across sexes. Furthermore, many environmental triggers promote relapse to drug seeking/taking behavior, and the stress of disrupted sleep may fall into that category. We find that sleep deprivation dysregulates sleep in mice that had previous opioid withdrawal experience. These data suggest that the 3-day precipitated withdrawal paradigm has the most profound effects on opioid induced sleep dysregulation, and that further validate the construct of the 3-day precipitated withdrawal model as a model for opioid dependence and OUD.
Opioid Use Disorder (OUD) is a chronic and relapsing psychiatric condition which is currently the leading cause of accidental death in the US. Symptoms of acute opioid withdrawal resemble a flu-like illness which is accompanied by a dysphoric state. Psychological comorbidities such as anxiety, depression, and disordered sleep can persist for months or years, well into the abstinence period. These symptoms are thought to drive further opioid intake in order to alleviate this unpleasant internal state. Many differences in OUD have been documented between male and female patients, with females at higher risk for relapse and overdose. This study sets out to characterize sex differences in symptoms and behavioral adaptations in mice during early withdrawal. Using our moderate dose, three day precipitated withdrawal paradigm, we discovered significant effects of sex, time, and drug treatment on early withdrawal behaviors, locomotor activity, and gut motility in C57BL/6J mice. Here I will discuss previous methods of condensing behavioral phenotypes into one global withdrawal score, and propose a new methodology. This method increases the ability to detect nuanced effects and allows for more accurate translation across strain, sex, paradigm, and experimental context. Classification of opioid withdrawal-induced behavioral adaptations will allow for improved behavioral analysis of pharmacological manipulations, and investigations of brain circuitry involved in opioid withdrawal, as well as future screening of compounds with potential therapeutic benefit for the treatment of OUD.
Stress can drive adaptive changes to maintain survival during threatening stimuli. Chronic stress exposure, however, may result in pathological adaptations. A key neurotransmitter involved in stress signaling is norepinephrine. Previous studies show that stress elevates norepinephrine levels in the bed nucleus of the stria terminalis (BNST), a critical node regulating anxiety and upstream of stress responses. Here, we use mice expressing channelrhodopsin in norepinephrine neurons to selectively activate terminals in the BNST, and measure norepinephrine release with fast-scan cyclic voltammetry. Mice exposed to a single restraint session show an identical norepinephrine release profile compared to that of unexposed mice. Mice experiencing five days of restraint stress, however, show elevated noradrenergic release across multiple stimulation parameters, and reduced sensitivity to the α2-adrenergic receptor antagonist idazoxan. These data are the first to examine norepinephrine release in the BNST to tonic and phasic stimulation frequencies, and confirm that repeated stress alters autoreceptor sensitivity.Stress; Norepinephrine; Fast-Scan Cyclic Voltammetry; Optogenetics; Bed Nucleus of the Stria Terminalis; Corticosterone . CC-BY-NC-ND 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/335653 doi: bioRxiv preprint first posted online May. 31, 2018; Stress is an important physiologic response to potentially harmful environmental stimuli.Under some conditions, however, such as chronic stress exposure or especially traumatic events, persistent alterations in the stress response occur, leading to abnormal and potentially maladaptive responses. Previous research has shown a central role of the catecholamine neurotransmitter norepinephrine (NE) in the physiological and behavioral stress responses 1 . NE release, in key downstream nuclei following stress has been implicated in a number of psychological disorders including addiction 2-3 , affective disorders 1 , and PTSD 4 .Noradrenergic neurons project through two primary pathways in the brain: the dorsal noradrenergic bundle and ventral noradrenergic bundle. The pontine locus coeruleus (A6) gives rise to the dorsal noradrenergic bundle sending projections throughout the cortex, thalamus, hippocampus, cerebellum, and amygdala [5][6][7] . In contrast, the ventral noradrenergic bundle mainly arises from two nuclei, A1 of the rostral ventrolateral medulla and A2 of the nucleus of the solitary tract 6 , and projects mainly to hypothalamus, parabrachial nucleus, midbrain, and bed nucleus of the stria terminalis (BNST) 3,6,8 . Of particular interest is the projection from the medullary noradrenergic nuclei (i.e. A1/A2) to the BNST because it comprises the densest region of NE terminals in the brain 9-12 and serves as a critical nucleus for processing affective state 13 .Furthermore,...
In all non-diabetic patients, blood glucose level was below the lower limit of the recommended range prior to all their FDG PET scans while this was not the case in diabetic patients. We conclude that measuring blood glucose level prior to FDG PET may be limited to diabetic patients.
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