Abstract
The time-dependent increase in cue-triggered opioid seeking, termed “incubation of opioid craving,” is modeled in rodents by examining responding for opioid-associated cues after a period of forced abstinence. With opioid drugs, withdrawal symptoms may heighten cue reactivity by recruiting brain systems involved in both reward seeking and stress responses. Corticotropin releasing factor (CRF) in the bed nucleus of the stria terminalis (BNST) is a critical driver of stress-induced relapse to drug seeking. Here, we sought to determine whether BNST CRF receptor 1 (CRFR1) signaling drives incubation of opioid craving in opioid dependent and non-dependent rats. First, we tested whether BNST CRFR1 signaling drives incubation of opioid craving in rats with short-access fentanyl self-administration experience (2.5 μg/kg/infusion, 3 h/day for 10 days). On Day 1 of forced abstinence, we gave bilateral intra-BNST vehicle injections to all rats and measured lever responding for opioid cues in the absence of fentanyl infusions. On Day 30 of forced abstinence, we gave an identical test after bilateral intra-BNST injections of vehicle or CRFR1 receptor antagonist, R121919 (1 μg/0.3 μL/hemisphere). Vehicle treated rats showed greater responding for opioid associated cues on Day 30 relative to Day 1, and this incubation effect was prevented by intra-BNST R121919 on Day 30. Next, we incorporated an opioid-dependence procedure to investigate whether BNST CRFR1 signaling drives opioid cue-reactivity to a greater extent in opioid-dependent relative to non-dependent rats. We trained rats to self-administer fentanyl for 5 days before initiating the dependence phase and resuming daily fentanyl self-administration sessions for 10 days. We gave intra-BNST R121919 or vehicle injections before testing during acute (Day 5) or protracted (Day 30) withdrawal. During acute withdrawal, antagonizing BNST CRFR1 decreased the number of press bouts without affecting bout size or duration. These patterns of responding with R121919 treatment resulted in less fentanyl-associated conditioned reinforcement during test. Together, these findings suggest a role for BNST CRFR1 signaling in driving cue-reinforced opioid seeking after periods of forced abstinence.
Highlights
Substance use disorder (SUD) consists of cycles of compulsive drug seeking and consumption, followed by periods of abstinence, withdrawal, and relapse (Koob and Volkow, 2016)
Incubation testing: To examine the involvement of bed nucleus of the stria terminalis (BNST) CRF receptor 1 (CRFR1) signaling in incubation of opioid craving, we gave all rats intra-BNST vehicle injections on Day 1, while on Day 30 we gave approximately half the rats intra-BNST vehicle and the other half intra-BNST R121919
Post hoc analysis of cues earned revealed that intra-BNST vehicle treated rats earned more cues on Day 30 compared to Day 1 (t12 = −4.93, p < 0.001) while intra-BNST R121919 treated rats did not (t14 = −0.62, p > 0.05), suggesting incubation is prevented by treatment with the CRFR1 antagonist in the BNST
Summary
Substance use disorder (SUD) consists of cycles of compulsive drug seeking and consumption, followed by periods of abstinence, withdrawal, and relapse (Koob and Volkow, 2016). Drug-associated cues trigger intense craving for drugs of abuse even after periods of abstinence (Sinha, 2011; Li et al, 2015). With opioid drugs of abuse, abstinent opioid-dependent individuals experience aversive withdrawal symptoms that promote relapse (DSM-V). The incubation of drug craving model examines cue-triggered drug seeking in rodents after a period of forced abstinence (Grimm et al, 2001; Pickens et al, 2011; Reiner et al, 2019). During abstinence from opioid drugs of abuse, withdrawal may invigorate cue-driven opioid seeking by recruiting brain systems involved in both stress responses and reward seeking. We postulate that CRF system in the BNST regulates incubation of opioid craving after forced abstinence in opioid dependent and non-dependent rats
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