Variability in prescription opioid intake and reinforcement amongst 129 substrains

Abstract

Opioid abuse in the United States has reached epidemic proportions, with treatment admissions and deaths associated with prescription opioid abuse quadrupling over the past 10 years. Although genetics are theorized to contribute substantially to inter-individual variability in the development, severity and treatment outcomes of opioid abuse/addiction, little direct preclinical study has focused on the behavioral genetics of prescription opioid reinforcement and drug-taking. Herein, we employed different 129 substrains of mice currently available from The Jackson Laboratory (129S1/SvlmJ, 129X1/SvJ, 129S4/SvJaeJ and 129P3/J) as a model system of genetic variation and assayed mice for oral opioid intake and reinforcement, as well as behavioral and somatic signs of dependence. All substrains exhibited a dose-dependent increase in oral oxycodone and heroin preference and intake under limited-access procedures and all, but 129S1/SvlmJ mice, exhibited oxycodone reinforcement. Relative to the other substrains, 129P3/J mice exhibited higher heroin and oxycodone intake. While 129X1/SvJ exhibited the highest anxiety-like behavior during natural opioid withdrawal, somatic and behavior signs of precipitated withdrawal were most robust in 129P3/J mice. These results demonstrate the feasibility and relative sensitivity of our oral opioid self-administration procedures for detecting substrain differences in drug reinforcement/intake among 129 mice, of relevance to the identification of genetic variants contributing to high vs. low oxycodone reinforcement and intake.

The effect of quinine in two bottle choice procedures in C57BL6 mice: Opioid preference, somatic withdrawal, and pharmacokinetic outcomes

“…A subset of these doses has been used in oral operant paradigms with C57BL6 (Wade et al, 2013, 2008) and three bottle choice procedures with 129-derived mice (Jimenez et al, 2017), and served as reinforcers in some cases. Under our experimental conditions, no preference was observed at any concentration tested.…”

“…The use of a saccharin concentration which is only slightly preferred to tap water may help to reveal the reinforcing properties of oral morphine by potentiating consumption such that a higher preference would be observed for morphine-saccharin as opposed to morphine or saccharin alone. Another possibility would be integration of other paradigms which are known to increase liquid intake such as intermittent access (Skupio et al, 2016), drinking in the dark (Jimenez et al, 2017), or post-prandial conditions (Enga et al, 2016) which may increase the likelihood to unveil the reinforcing properties of oral opioids. Adenosine monophosphate, an apparent antagonist of bitter receptors (Ming et al, 1999), may also be used to increase the palatability of morphine or other bitter alkaloids.…”

“…From 1999 to 2015, the number of overdose deaths attributable to prescription opioids has quadrupled (Center for Disease Control, 2017), highlighting prescribed analgesics as a substantial contributing factor to the epidemic. Similar to heroin, prescription opioids possess unwanted effects in addition to their therapeutic properties, notably abuse liability (Jimenez et al, 2017). Unlike heroin, the typical route of administration for prescription opioids is not intravenous, but oral.…”

Female rats consume and prefer oxycodone more than males in a chronic two-bottle oral voluntary choice paradigm

“…Other opioid self-administration paradigms have relied on either oral intermittent access (OIA) or intravenous (IV) self-administration (Carroll and Meisch, 1984;Enga et al, 2016;Gellert and Holtzman, 1978a;Grim et al, 2018;Heyne, 1996;Jimenez et al, 2017;Leung et al, 1986;Meisch, 2001;Nguyen et al, 2018;Nichols and Hsiao, 1967;Shaham et al, 1993;You et al, 2017) . Both OIA and IV self-administration models can lead to dependence and tolerance, and IV models can demonstrate drug-seeking motivation.…”

Fentanyl-induced antinociception, reward, reinforcement, and withdrawal inHnrnph1mutant mice

“…The day following the behavioral test battery, fentanyl-experienced mice were then injected in the morning (~0800 h) with 0.8 mg/kg fentanyl. Eight hours later, mice were injected with 10 mg/kg naltrexone and tested for physiological signs of withdrawal as described previously (Jimenez et al 2017;Szumlinski et al 2019) and detailed in the Supplementary Information. To accommodate all the mice, behavioral testing was conducted in cohorts of 8 mice, with ~24 mice tested per day.…”