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A rat model of operant negative reinforcement in opioid-dependent males and females

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Abstract

Rationale and objective

Avoidance of opioid withdrawal plays a key role in human opioid addiction. Here, we present a procedure for studying operant negative reinforcement in rats that was inspired by primate procedures where opioid-dependent subjects lever-press to prevent naloxone infusions.

Methods

In Experiment 1, we trained rats (n = 30, 15 females) to lever-press to escape and then avoid mild footshocks (0.13–0.27 mA) for 35 days (30 trials/d). Next, we catheterized them and implanted minipumps containing methadone (10 mg/kg/day) or saline. We then paired (4 times, single session) a light cue (20-s) with a naloxone infusion (20 µg/kg, i.v) that precipitated opioid withdrawal. Next, we trained the rats to escape naloxone injections for 10 days (30 trials/d). Each trial started with the onset of the opioid-withdrawal cue. After 20-s, the lever extended, and an infusion of naloxone (1 to 2.2 µg/kg/infusion) began; a lever-press during an 11-s window terminated the withdrawal-paired cue and the infusion. In Experiment 2, we trained rats (n = 34, 17 females) on the same procedure but decreased the footshock escape/avoidance training to 20 days.

Results

All rats learned to lever-press to escape or avoid mild footshocks. In both experiments, a subset, 56% (10/18) and 33% (8/24) of methadone-dependent rats learned to lever-press to escape naloxone infusions.

Conclusions

We introduce an operant negative reinforcement procedure where a subset of opioid-dependent rats learned to lever-press to escape withdrawal-inducing naloxone infusions. The procedure can be used to study mechanisms of individual differences in opioid negative reinforcement-related behaviors in opioid-dependent rats.

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Data availability

Raw data and the results of their primary analyses are available on request from Jonathan J. Chow (jonathan.chow@nih.gov) or Yavin Shaham (yavin.shaham@nih.gov).

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Acknowledgements

The study was supported by the Intramural Research Program of the NIH, NIDA.

Funding

This research was supported by the Intramural Research Program of NIDA (ZIA-DA000434-17, YS) and support from the NIH CCB fellowship (JJC) and NIH NIGMS PRAT fellowship (FI2GM142476, JJC).

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Authors and Affiliations

  1. Intramural Research Program, NIDA, NIH, Baltimore, USA

    Jonathan J. Chow, Kayla M. Pitts, Jules M. Chabot & Yavin Shaham

  2. Department of Psychology, University of Toronto Scarborough, Toronto, ON, Canada

    Rutsuko Ito

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  1. Jonathan J. Chow
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  2. Kayla M. Pitts
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  3. Jules M. Chabot
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  4. Rutsuko Ito
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Contributions

JJC, RI, and YS conceptualized the research. JJC, KMP, and JMC performed the research and collected the data. JJC and KMP analyzed the data. JJC, KMP, and YS wrote the manuscript. All authors provided editorial comments and approved of the final version.

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Correspondence to Jonathan J. Chow or Yavin Shaham.

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Chow, J.J., Pitts, K.M., Chabot, J.M. et al. A rat model of operant negative reinforcement in opioid-dependent males and females. Psychopharmacology (2024). https://doi.org/10.1007/s00213-024-06594-w

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