Investigating discriminative stimulus modulation of opioid seeking after conflict-induced abstinence in sign- and goal-tracking rats

Abstract

Rationale: Discriminative stimuli (DS) are cues that predict reward availability. DS are resistant to extinction and motivate drug seeking even after long periods of abstinence. Previous studies have demonstrated that sign-tracking (ST) and goal-tracking (GT) differences in Pavlovian approach predict distinct cue-modulated vulnerabilities to cocaine reinstatement. GT rats show heightened reinstatement to contextual and DS, while ST rats show heightened reinstatement to discrete stimuli. Here we examine whether DS modulate reinstatement after electric barrier-induced abstinence and whether tracking-related relapse vulnerabilities generalize to opioid relapse.

Objectives: We examine whether DS-modulated reinstatement to fentanyl seeking persists in the presence of reduced adverse consequences after electric barrier-induced abstinence. We also examine whether tracking differences predict the magnitude of DS-modulated reinstatement of fentanyl seeking after electric barrier-induced abstinence.

Methods: We used Pavlovian lever autoshaping (PLA) training to determine sign-, goal-, and intermediate tracking groups in male and female Sprague Dawley rats. We then trained rats in a DS model of intermittent fentanyl self-administration, and extinguished drug seeking by imposing an electric barrier of increasing intensity. We then measured the level of DS-modulated reinstatement in the presence of a reduced electric barrier intensity.

Results: We report that DS strongly modulate fentanyl seeking after electric barrier-induced abstinence. DS-modulation of fentanyl acquisition, electric barrier-induced abstinence, and reinstatement was similar for sign- and goal-tracking groups.

Conclusions: Discriminative stimuli powerfully motivate opioid seeking, despite continued aversive consequences. Pavlovian approach differences do not predict the level of DS-modulated reinstatement to fentanyl seeking after conflict-induced abstinence.

Keywords: CS; Conflict; DS; Discriminative stimuli; Fentanyl; Goal tracking; Opioid; Reinstatement; Sign tracking.

Fig. 1:

A) Experimental timeline B-D) Pavlovian conditioned approach training: B) Overall PCA tracking score C) Lever contacts D) Food cup contacts

Fig. 2:

Fentanyl motivated behavior for all rats combined. A) Fentanyl self-administration through acquisition (five sessions) and DS training phases (ten sessions). B) Rates of responding in the DS+ and DS− components of DS training sessions, binned by the first five and last five sessions of DS discrimination phase. C) Day 15 of DS training. Data are binned into 1 min segments across the 25 min DS− component and 5 min DS+ component, and the resulting data are averaged across all DS−/DS+ cycles across the session. Inset shows the individual data for the transition between the last bin of the DS− component and the first bin of the DS+ component (**: p<0.01, paired t-test). D) Conflict extinction behavior in the presence of electrified floor barrier in front of nosepokes. E) Poking rates (inactive/active) for the last conflict extinction test (left two columns) and reinstatement test (right two columns). F) Poking rates (DS−/DS+) for the last conflict extinction test (left two columns) and reinstatement test (right two columns). G) Reinstatement test poking rate data binned into 30 s segments across the 2.5 min DS− component and 30 s DS+ component. Data are averaged across all DS−/DS+ cycles in session. Inset shows the individual data for the transition between the last bin of the DS− component and the first (only) bin of the DS+ component (***: p<0.001, paired t-test).

Fig. 3:

Fentanyl Acquisition and DS Training by Tracking Group and Sex. A) Fentanyl self-administration through acquisition (five sessions) and DS training phases (ten sessions) by tracking group. B) Fentanyl self-administration through acquistion and DS training by sex C) Rates of responding in the DS+ and DS− components of DS training sessions, binned by the first five and last five sessions of DS discrimination phase by tracking. D) Rates of responding in the DS+ and DS− components of DS training sessions binned by the first five and last five sessions of DS discrimination phase by sex.

Fig. 4:

Conflict extinction behavior by Tracking Group and Sex. A) Conflict extinction infusions by tracking. B) Conflict extinction active pokes by tracking C) Average shock intensity used across sessions by tracking. D) Conflict extinction infusions by sex. E) Conflict extinction active pokes by sex F) Average shock intensity used across sessions by sex

Fig. 5:

Reinstatement behavior by Tracking Group and Sex. A) Active side poking rates during final conflict session (left) and reinstatement test (right) by tracking B) DS+ poking rates during final conflict session (left) and reinstatement test (right) by tracking C) Linear correlation between PCA score and active poking rate. (R²=.1023, p=0.0971). D) Active side poking rates during final conflict session (left) and reinstatement test (right) by sex. E) DS+ poking rates during final conflict session (left) and reinstatement test (right) by sex. F) Reinstatement DS Scores by tracking (left, black bars) and by sex (right, gray bars) (‘*’ indicates p=0.037, t-test).