Social Stress Engages Opioid Regulation of Locus Coeruleus Norepinephrine Neurons and Induces a State of Cellular and Physical Opiate Dependence

Abstract

Stress is implicated in diverse psychiatric disorders including substance abuse. The locus coeruleus-norepinephrine (LC-NE) system is a major stress response system that is also a point of intersection between stress neuromediators and endogenous opioids and so may be a site at which stress can influence drug-taking behaviors. As social stress is a common stressor for humans, this study characterized the enduring impact of repeated social stress on LC neuronal activity. Rats were exposed to five daily consecutive sessions of social stress using the resident-intruder model or control manipulation. LC discharge rate recorded 2 days after the last manipulation was decreased in stressed rats compared with controls. By 10 days after the last manipulation, LC rates were comparable between groups. Systemic administration of the opiate antagonist, naloxone, robustly increased LC discharge rate in a manner suggestive of opiate withdrawal, selectively in stressed rats when administered 2 or 10 days after the last manipulation. This was accompanied by behavioral signs of mild opiate withdrawal. Western blot and electron microscopic studies indicated that repeated social stress decreased corticotropin-releasing factor type 1 receptor and increased m-opioid receptor levels in the LC. Together, the results suggest that repeated social stress engages endogenous opioid modulation of LC activity and induces signs of cellular and physical opiate dependence that endure after the stress. These cellular effects may predispose individuals with a history of repeated social stress to substance abuse behaviors.

Adolescent Social Stress Produces an Enduring Activation of the Rat Locus Coeruleus and Alters its Coherence with the Prefrontal Cortex

“…Repeated resident-intruder exposure produces enduring changes in afferent regulation of the LC that are expressed days after the last stress. Specifically, there is evidence for enhanced opioid drive to the LC in adult male rats (Chaijale et al, 2013). In contrast, LC neurons of early adolescent rats recorded in the anesthetized state 24 h after the last resident-intruder stress were tonically activated, suggesting age-related differences in stress adaptation (Bingham et al, 2011).…”

“…repeated exposure to the single prolonged stress paradigm produce LC hypoactivity in adult rats that is observed days after stressor termination (Chaijale et al, 2013;George et al, 2013). Inhibited LC discharge rate is also seen immediately after acute stress termination or after repeated trials of noise stress (Abercrombie and Jacobs, 1987;Curtis et al, 2001).…”

“…Cables connected the head stage to the data acquisition system and baseline recordings were done in the intruder's home cage. LC multiunit activity was recorded using the AlphaLab (Alpha Omega, Alpharetta, GA), as previously described (Chaijale et al, 2013). LC spontaneous activity was recorded for 300 s followed by a 200-s period of auditory stimulation (3 kHz tone, 50 ms duration, 80 db intensity, presented at 0.25 Hz, total 50 presentations).…”

“…A major stress-response system that is sensitive to social stress is the locus coeruleus-norepinephrine (LC-NE) system (Chaijale et al, 2013). Stressors activate the LC-NE system and this translates to heightened arousal and cognitive changes that are adaptive in the acute stress response (Valentino and Van Bockstaele, 2008).…”

Stress and Drug Dependence Differentially Modulate Norepinephrine Signaling in Animals with Varied HPA Axis Function

“…Interestingly, a number of psychological disorders and addictions are comorbid with stress and involve noradrenergic dysregulation (eg, posttraumatic stress disorder) (Hyman et al, 2006;Sinha, 2008). For example, exposing rats to intruder stress evokes an opiate-dependent like state and alters firing of norepinephrine neurons (Chaijale et al, 2013). Therefore, investigation of noradrenergic systems and their role in the initiation/ termination of stress is important for understanding the pathophysiology of diseases that co-express with addiction.…”