Intravenous fentanyl self-administration in male and female C57BL/6J and DBA/2J mice

Abstract

The genetic mechanisms underlying fentanyl addiction, a highly heritable disease, are unknown. Identifying these mechanisms will lead to better risk assessment, early diagnosis, and improved intervention. To this end, we used intravenous fentanyl self-administration to quantify classical self-administration phenotypes and addiction-like fentanyl seeking in male and female mice from the two founder strains of the BXD recombinant inbred mouse panel (C57BL/6J and DBA/2J). We reached three primary conclusions from these experiments. First, mice from all groups rapidly acquired intravenous fentanyl self-administration and exhibited a dose–response curve, extinction burst, and extinction of the learned self-administration response. Second, fentanyl intake (during acquisition and dose response) and fentanyl seeking (during extinction) were equivalent among groups. Third, strain effects, sex effects, or both were identified for several addiction-like behaviors (cue-induced reinstatement, stress-induced reinstatement, escalation of intravenous fentanyl self-administration). Collectively, these data indicate that C57BL/6J and DBA/2J mice of both sexes were able to acquire, regulate, and extinguish intravenous fentanyl self-administration. Moreover, these data reveal novel strain and sex effects on addiction-like behaviors in the context of intravenous fentanyl self-administration in mice and indicate that the full BXD panel can be used to identify and dissect the genetic mechanisms underlying these effects.

Escalation of intravenous fentanyl self-administration and assessment of withdrawal behavior in male and female mice

“…The current study builds upon previous findings and demonstrates that 2 hours of access to 2.5 µg/kg/infusion of fentanyl over 14 days is sufficient to establish escalation of fentanyl intake and result in withdrawal symptoms in mice. Previous literature has investigated rodent models of opioid dependence, including morphine (47)(48)(49), oxycodone (10,12,50,51), heroin (6,(52)(53)(54), remifentanil (34,(55)(56)(57)(58), and fentanyl (24,33,36,38,(59)(60)(61)(62)(63)(64)(65)(66), using various routes of administration, with the majority of studies done in rats. IVSA of fentanyl has been widely studied in rats (24,25,(59)(60)(61)(62)(67)(68)(69)(70)(71), with findings demonstrating mixed results on the development of dependence and withdrawal signs.…”

“…A separate study showed that when compared to a short access self-administration period, 12-hour self-administration of fentanyl resulted in escalation of fentanyl intake (25). In addition to rats, mouse models of fentanyl self-administration have been developed (33, 63, 66, 72, 73), although fentanyl IVSA in mice remains relatively understudied. One prior study demonstrated that mice maintained stable levels of oral fentanyl consumption and showed a significant preference for the active lever associated with fentanyl in an operant chamber (63).…”

“…Another study utilized a drinking in the dark paradigm to model oral fentanyl self-administration in mice, finding that mice consumed increasing amounts of fentanyl as the dose increased (37). Leonardo et al (33) successfully established fentanyl IVSA in mice, showing rapid acquisition and a dose-responsive curve.…”

“…Thus, it is critical to establish models of FUD in mice, including IVSA models. A previous study showed that mice are capable of initiating IVSA of fentanyl (33), and other mouse models have demonstrated withdrawal symptoms following oral or vapor self-administration (36)(37)(38).…”

Opiate responses are controlled by interactions ofOprm1andFgf12loci in rodents: Correspondence to human GWAS findings

“…The RI strains are made by crossing two inbred strains, followed by intercrossing F1 generations, and more than 20 generations of sibling matings (Silver, 1995). BXDs are the largest genetic reference population, and are made from C57BL/6J crossed with DBA/2J (referred to as B and D parental strains) (Andreux et al, 2012) and has been used to study the effect of several drugs of abuse (Dickson et al, 2016; Leonardo et al, 2023; Parks et al, 2021)…”