Abstract
Rationale and objectives
Drug-seeking behavior occurs more readily in some individuals than others. This phenomenon is considered in studies of drug self-administration in which high drug-seeking/taking individuals can be identified. In contrast, studies of conditioned place preference (CPP) often involve a random sample of drug-naïve rodents that includes phenotypes not considered relevant to addiction. The main objective of the current studies was to determine if a priori identification of different conditioning phenotypes could improve the validity and sensitivity of CPP expression as a preclinical test for vulnerability to addiction.
Methods and results
Analysis of cocaine place conditioning data from 443 Swiss-Webster mice revealed a trimodal distribution with peaks corresponding to means of k = 3 clusters. The cluster means occurred at high, low, or negative preference scores, the latter suggesting a phenotype acquiring conditioned place aversion (CPA). The same clusters were identified in mice conditioned with methamphetamine, MDPV, or amphetamine, and these clusters remained stable and reliable during three additional expression tests spaced at 24 h. A meta-analysis of effect sizes obtained from CPP literature revealed a positively skewed distribution affected by sample size, consistent with the existence of a CPA phenotype within the populations tested. A dopamine receptor antagonist, flupentixol, blocked cocaine CPP expression in a group containing all phenotypes, but sensitivity improved markedly when CPA phenotypes were excluded from the dataset.
Conclusions
These studies suggest that taking phenotype into consideration when designing place conditioning studies will improve their application as a preclinical tool in addiction biology and drug discovery.
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Funding
Support for this research was provided by contracts N01DA-7–8872 and N01DA-13–8908 from the National Institute on Drug Abuse. All locomotor activity data were generated under NIDA contracts. The CPP data were part of the development of protocols for cocaine-conditioned place preference for NIDA. NIDA had no further role in the design, analysis, or publication of this report.
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• Ritu A. Shetty — writing, conception and design, data acquisition, data analyses, literature search, plotting graphs.
• Margaret A. Rutledge — writing, design, data analyses (all data), and literature search
• Alison LeBouf — data collection and analyses (phenotype and reliability studies)
• James T. Mock — data interpretation and presentation (Fig. 1 and Fig. 2)
• Gita Pathak — data interpretation and presentation (Fig. 6)
• Michael J. Forster — writing, editing, conception, interpretation, data analyses
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Shetty, R.A., Rutledge, M., LeBouf, A. et al. Expression of stable and reliable preference and aversion phenotypes following place conditioning with psychostimulants. Psychopharmacology 239, 2593–2603 (2022). https://doi.org/10.1007/s00213-022-06130-8
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DOI: https://doi.org/10.1007/s00213-022-06130-8