Hold-down as an alternative to unit dose in cocaine self-administration experiments: Characterization using a progressive ratio schedule

Abstract

Rationale

Virtually all cocaine self-administration studies have used a “unit dose” as a reinforcing stimulus; the subject is a passive recipient of an experimenter-selected dose.

Objectives

The present experiments examined the consequence of requiring the subject to actively determine the dose and speed of each injection.

Methods

A two-lever procedure was used in which responding on a progressive ratio (PR) schedule provided access to cocaine on a hold down (HD) schedule. With HD, the pump is turned on for the duration that the lever is held down, thus the dose and speed of injection is determined by the behavior of the subject. The procedure allows for the evaluation of both drug taking and drug seeking responses.

Results

The results were qualitatively different from PR self-administration studies using unit dose. The self-administered HD dose varied across the session; the self-administered dose was found to inversely correlate with drug levels at the time of access. Importantly, the 2 L-PR-HD procedure identified a subpopulation of subjects that showed extremes in both drug seeking and drug taking. Subjects at the top end of the distribution displayed unprecedented final ratios (> 900) and rapidly self-administered very large doses (> 1.4 mg; ~ 4.2 mg/kg). Manipulation of drug-taking variables (HD access duration and concentration of drug in the pump) showed that the immediacy of a cocaine bolus, not the duration of access, is the major determinant of drug seeking.

Conclusions

Incorporating a consummatory response into a PR procedure provides a unique perspective on the interactions of drug-seeking and drug-taking.

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Notes

  1. 1.

    The use of a 20-sec timeout can be traced to the original publication of Weeks (1964). It has since been used in virtually all self-administration experiments. It appears that a time out was first imposed to prevent an “accidental” overdose. It is certainly possible that the occasional overdose may be averted during the initial day or two of training; however, there is little evidence that an overdose is an issue once a regular pattern of FR1 responding has been established. The continued use of a 20-sec timeout during an experiment is, in our opinion, unnecessary and may adversely affect the results.

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Acknowledgments

The authors would like to thank Leanne Thomas for administrative support and Holly Vines-Buben, Jordan Crawford, and Amanda Gabriele for assistance with data collection and analysis. We thank the National Institute of Drug Abuse (NIDA) Drug Supply Program for providing cocaine HCl.

Funding

This study is supported by NIDA research grants R01 DA14030 and P50 DA06634.

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Authors

Contributions

DCSR supervised the collection of data. BAZ supervised and performed the behavioral experiments. DCSR and BZ designed the experiments, analyzed the data, and wrote the manuscript.

Corresponding author

Correspondence to David C. S. Roberts.

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The authors declare that they have no conflicts of interest.

All experimental procedures were approved by the Institutional Animal Care and Use Committee at Wake Forest University and conformed to the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

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Roberts, D.C.S., Zimmer, B.A. Hold-down as an alternative to unit dose in cocaine self-administration experiments: Characterization using a progressive ratio schedule. Psychopharmacology (2020). https://doi.org/10.1007/s00213-020-05565-1

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Keywords

  • Cocaine
  • Progressive ratio schedule
  • Hold-down schedule
  • Motivation
  • Vulnerability
  • Addiction
  • Drug taking
  • Drug seeking