Increased Number and Activity of a Lateral Subpopulation of Hypothalamic Orexin/Hypocretin Neurons Underlies the Expression of an Addicted State in Rats

Abstract

We provide the first evidence that lateral hypothalamic orexin system function extends beyond general reward seeking to play a critical role in expression of a multiphenotype addiction-like state. Thus, the orexin system is a potential novel target for pharmacotherapies designed to treat cocaine addiction. In addition, these data point to the IntA model as a preferred approach to modeling addiction-like behavior in rats.

Demand elasticity predicts addiction endophenotypes and the therapeutic efficacy of an orexin/hypocretin‐1 receptor antagonist in rats

“…Animals were tested under extinction conditions. For both cued and primed reinstatement tests, rats underwent three tests to test the effect of SB at 10 and 30 mg/kg (and vehicle); only data collected under vehicle conditions were analyzed here (effects of SB on reinstatement are reported elsewhere (James et al ., )). Between reinstatement tests, rats received at least two additional extinction sessions, and continued until they met a criteria of <25 active lever presses over 2 days.…”

“…For all behavioral experiments, rats were tested during their dark (active) cycle at the same time each day. Here, we present data from a total of 87 rats collected over several experiments that were conducted between January 2015 and January 2018; other data arising from these experiments are presented elsewhere (James et al ., ). All experiments were approved by the Rutgers University Institutional Animal Care and Use Committee, and were conducted according to specifications of the Guide for the care and use of laboratory animals (National Research Council, ).…”

“…Previous studies demonstrated that baseline demand measures remain stable over weeks (Bentzley et al ., ), a finding confirmed here in ShA animals (see below). Here, we focus our analyses on demand scores from the first session following ShA, LgA or IntA, as this timepoint is associated with the most pronounced changes in the LgA group (James et al ., ); using these data allowed us to best assess the demand paradigm as a predictor of LgA‐induced changes in addiction behavior. Rats underwent testing for compulsive (punished) responding, and then extinction training, followed by tests of cued‐ or primed reinstatement behavior.…”

“…Thus, here we sought to determine whether α, as assessed in rats after only limited drug exposure, can predict those individuals most at risk of transitioning to compulsive drug seekers after more drug exposure. To do this, we analyzed data from a number of studies carried out in our laboratory whereby ‘baseline α’ was measured in rats immediately following the acquisition of cocaine self‐administration behavior but prior to rats being exposed to either long or intermittent self‐administration schedules, both of which model the transition to uncontrolled drug‐seeking (Ahmed & Koob, ; Zimmer et al ., ; Allain et al ., ; Kawa et al ., ; James & Aston‐Jones, ; James et al ., ). We report that baseline α predicts those individuals that exhibit greater economic demand, compulsive seeking and reinstatement liability following long or intermittent access.…”

“…Consistent with this, OxR1 antagonists reduce seeking of various drugs of abuse, particularly when high levels of effort are required to obtain the drug, or when motivation for drug reward is enhanced by external stimuli such as stress or drug‐related cues (Mahler et al ., ; James et al ., ). However, several reports indicate that there is significant individual variability in responsivity to OxR1 antagonists, such that the greatest effects are observed in individuals with high baseline intake or motivation for drug (Lawrence et al ., ; Moorman & Aston‐Jones, ; Jupp et al ., ; Bentzley & Aston‐Jones, ; Lopez et al ., ; Moorman et al ., ; James et al ., ). These observations led us to hypothesize that motivation for drug, as assessed by the behavioral economics paradigm, could also predict those individuals most likely to respond to the anti‐drug‐seeking properties of the commonly used OxR1 antagonist SB‐334867 (SB).…”