Individual Vulnerability to Stress Is Associated With Increased Demand for Intravenous Heroin Self-administration in Rats

Abstract

Opioid use is a widespread epidemic, and traumatic stress exposure is a critical risk factor in opioid use and relapse. There is a significant gap in our understanding of how stress contributes to heroin use, and there are limited studies investigating individual differences underlying stress reactivity and subsequent stress-induced heroin self-administration. We hypothesized that greater individual vulnerability to stress would predict higher demand for heroin self-administration in a within-subjects rodent model of stress and heroin use comorbidity. Male rats were exposed to inescapable intermittent swim stress (ISS) and individual biological (corticosterone) or behavioral [open field, social exploration, and forced swim tests (FSTs)] measures were assessed before and after the stress episode. Individual demand for self-administered heroin (0.05 mg/kg/infusion; 12-h sessions) was assessed using a behavioral economics approach followed by extinction and reinstatement tests triggered by stress re-exposure, non-contingent cue presentations, and yohimbine (0, 1.0, or 2.5 mg/kg). We found that behavioral, biological, and a combination of behavioral and biological markers sampled prior to and after the stress episode that occurred weeks before the access to heroin self-administration predicted the magnitude of individual demand for heroin. Non-contingent presentation of cues, that were previously associated with heroin, reinstated heroin seeking in extinction. For the first time, we show that individual biological response to an ecologically relevant stressor in combination with associated behavioral markers can be used to predict subsequent economic demand for heroin.

Early Life Stress and Risks for Opioid Misuse: Review of Data Supporting Neurobiological Underpinnings

“…Stress has been independently associated with opioid sensitivity, with several studies observing evidence of greater OUD risk (e.g., increased opioid self-administration and drug reinstatement) [52][53][54] among animals exposed to stress from restraint [55], footshock [52,56], and intermittent swim [57] assays. Stressful stimuli have also been shown to produce a hyporesponsive state of the endogenous opioid system in animals [58], and corticosterone release following a stressful stimulus has been causally and independently linked to increased opioid self-administration [57]. Early life stress appears to be particularly destructive because it produces enduring conformational changes in the endogenous opioid system that impact drug use behavior [59,60].…”

Changes in fentanyl demand following naltrexone, morphine, and buprenorphine in male rats

“…Although recent preclinical studies have characterized economic demand for opioids (Fragale et al, 2019;Lacy et al, 2019;Porter-Stransky et al, 2017;Stafford et al, 2019), previous research examining the effect of various drug pretreatments on opioid selfadministration has been conducted with simple FR schedules. With FR schedules, selective antagonists such as naloxone or naltrexone produce a biphasic dose effect, with low doses increasing and high doses decreasing heroin self-administration (Hemby et al, 1996;Koob et al, 1984).…”

Psycho-Behavioural Changes in Dogs Treated with Corticosteroids: A Clinical Behaviour Perspective

“…The differential responses of these two hormonal systems depend on the type and intensity of the stressor and how it is perceived and interpreted by the animal. Several studies have shown that there is an individual vulnerability to stress [ 3 , 4 , 5 ].…”