Intermittent self-administration of fentanyl induces a multifaceted addiction state associated with persistent changes in the orexin system

Abstract

The orexin (hypocretin) system plays a critical role in motivated drug-taking. Cocaine selfadministration with the intermittent access (IntA) procedure produces a robust addiction-like state that is orexin-dependent. Here, we sought to determine the role of the orexin system in opioid addiction using IntA self-administration of fentanyl. Different groups of male rats were either given continuous access in 1h (short access; ShA), or 6h periods (long access, LgA), or IntA (5min of access separated by 25min of no-access) to fentanyl for 14 days. IntA produced a greater escalation of fentanyl intake, motivation for fentanyl on a behavioral economics task, persistent drug seeking during abstinence, and cued-induced reinstatement compared to rats given ShA or LgA. We found that addiction behaviors induced by IntA to fentanyl were reversed by the orexin-1 receptor antagonist SB-334867. IntA to fentanyl was also associated with a persistent increase in the number of orexin-expressing neurons.Together, results indicate that the IntA model is a useful tool in the study of opioid addiction, and that the orexin system is critical for the maintenance of addiction behaviors induced by IntA selfadministration of fentanyl.

The dual orexin/hypocretin receptor antagonist suvorexant reduces addiction-like behaviors for the opioid fentanyl

“…Recently, we demonstrated that the selective OxR1 antagonist SB increased fentanyl demand elasticity (decreased motivation) in rats with limited drug access, an effect that was greatest in highly motivated rats [16]. We also found that highly motivated rats after IntA to fentanyl are more sensitive to the anti-addiction properties of SB compared to rats given ShA [12] a finding that is consistent with evidence that SB preferentially reduces motivation for other drugs of abuse in high-motivation individuals [14,17,[42][43][44]. Here, we show that suvorexant has anti-addiction properties similar to the selective OxR1 antagonist, SB.…”

“…Next, we tested the efficacy of suvorexant on several addiction-relevant indices in rats with a history of intermittent access (IntA) to fentanyl. IntA is a self-administration procedure that models the transition to a multiphenotypic addiction-like state in rats [12]. To confirm the induction of an addictionlike state in IntA rats, we compared their demand values to a short access (ShA) control group that was tested concurrently; we previously demonstrated that ShA does not result in an addiction-like state [12].…”

“…IntA sessions were 6h in duration, during which 5min drug access periods (signaled by illumination of the houselight and extension of the levers) were separated by 25min no drug access time outs (houselight off, levers retracted). During drug access periods, animals could press on a FR1 schedule for a 3.6s infusion of fentanyl (0.5µg) that was paired with a light and tone cue; infusions were not followed by a timeout period [12]. ShA rats (n=8) were given continuous access to fentanyl on an FR1 schedule in 1h sessions.…”

“…Moreover, higher numbers of orexin-expressing neurons are observed in the brains of human heroin users [11], as well as in rats that exhibit a strong addiction-like phenotype for fentanyl. [12] Orexin peptides bind to two G-protein coupled receptors (orexin receptor 1, OxR1; and orexin receptor 2, OxR2) that are widely distributed throughout the brain, including in key reward and arousal centers [13]. Evidence generally supports a functional dichotomy for OxR1 vs OxR2 signaling, whereby OxR1 signaling preferentially mediates reward behaviors and OxR2 signaling modulates arousal and sleep [5].…”

“…We report that suvorexant reduced increased demand elasticity (decreased motivation) for fentanyl without affecting low-effort fentanyl intake; these effects were most pronounced in rats with the strongest motivation for fentanyl. Moreover, following induction of a strong addiction phenotype by intermittent access (IntA) self-administration of fentanyl [12], suvorexant was more effective at increasing demand elasticity, and also attenuated compulsive responding for fentanyl and reduced cued reinstatement of extinguished fentanyl seeking. Taken together, these data indicate that suvorexant is effective at reducing the OUD behavioral phenotype, particularly in individuals with the severe cases of OUD.…”