Individual differences in orexin‐I receptor modulation of motivation for the opioid remifentanil

Abstract

Orexin-1 receptors (Ox1Rs) have been implicated in the motivation for drugs of abuse. Here, we utilized a within-session behavioral-economic threshold procedure to screen for individual differences in economic demand for the ultra-short acting opioid remifentanil and to test whether antagonism of Ox1Rs reduces remifentanil demand. The behavioral-economic procedure revealed robust individual differences in free consumption of remifentanil (Q 0 parameter; hedonic set point). Rats with low baseline Q 0 (low takers) displayed high demand elasticity (α parameter; reduced responding as drug price increased indicating low motivation for drug), whereas subjects with a higher Q 0 (high takers) exhibit low demand elasticity (low α) by continuing to selfadminister remifentanil despite increased cost (reflecting higher motivation for drug). In a punished responding paradigm utilizing footshock, subjects that were classified as high takers at baseline withstood twice as much shock as low takers to continue self-administering remifentanil. Interestingly, Ox1R antagonism with SB-334867 reduced Q 0 and increased α in low takers but not in high takers. Similarly, the Ox1R antagonist attenuated cue-, but not drug-, induced reinstatement of remifentanil seeking in low takers, but had no significant effect on reinstatement of drug seeking in high takers. Together, these data reveal a novel role of orexins in demand for remifentanil: Ox1Rs modulate demand in low takers but not in individuals that exhibit addictivelike behaviors (high takers). Finally, the behavioral assays in this study can serve as a novel laboratory model for studying individual differences in opioid use disorders.

Oxytocin Acts in Nucleus Accumbens to Attenuate Methamphetamine Seeking and Demand

“…FR1 schedule)(44) and high effort paradigms (e.g., PR schedule)(43, 48). Similar to what has been observed in both experimental animals (16, 31, 32, 47) and humans (28, 49), we found that demand elasticity (α) assessed with our within-session BE model accurately predicted meth seeking behaviors in both sexes. Specifically, α (but not Q 0 ) predicted meth seeking on the first day of extinction and during cue-induced reinstatement, which is analogous to what has been shown with cocaine (16).…”

“…This newly adapted paradigm for meth allows for assessment of important economic variables within one session, which have previously only been assessed for drugs with a short half-life (i.e., cocaine (25, 34, 35) or remifentanil (47)). In both the multi-day and within-session BE paradigms, we confirmed previous findings that females take more meth than males during both low effort (e.g.…”

A Decade of Orexin/Hypocretin and Addiction: Where Are We Now?

“…These effects are driven by signaling at Ox1R, as pretreatment with the Ox2R antagonist 4PT had no effect on cue-induced cocaine seeking [27]. SB-334867 is also effective at blocking reinstatement of alcohol [34, 35, 46, 47], nicotine [48], and remifentanil [49] seeking, and there is evidence that Ox2R antagonists block reinstatement of nicotine seeking [50], but not cue-induced alcohol seeking [51]. …”

Orexin/hypocretin-1 receptor antagonism reduces ethanol self-administration and reinstatement selectively in highly-motivated rats

“…The OX1R-selective antagonist SB-334867 (SB) decreases seeking of multiple drugs of abuse (Bentzley and Aston-Jones, 2015; James et al, 2012; Mahler et al, 2012; Plaza-Zabala et al, 2012; Porter-Stransky et al, 2015). There is a particularly (though not exclusively) (Anderson et al, 2014; Barson et al, 2015; Brown et al, 2013b; Shoblock et al, 2011) strong relationship between the OX1R vs OX2R and alcohol seeking.…”