title: Critical evaluation of the use of extinction paradigms for the assessment of opioid-induced conditioned place preference in rats.
abstract: The rewarding effects of drugs of abuse are often studied by means of the conditioned place preference (CPP) paradigm. CPP is one of the most widely used models in behavioral pharmacology, yet its theoretical underpinnings are not well understood, and there are very few studies on the methodological and theoretical aspects of this model. An important drawback of the classical CPP paradigm is that it often does not show dose-dependent results. The persistence of the conditioned response, i.e. the time required until the CPP effect is extinct, may be related to the strength of conditioning, which in turn may be related to the rewarding efficacy of a drug. Resistance to extinction may therefore be a useful additional measure to quantify the rewarding effect of drugs. In the present study we examined the persistence of drug-environment associations after conditioning with morphine (1, 3 and 10 mg/kg i.p.), oxycodone (0.3, 1 and 3 mg/kg i.p.) and heroin (0.05, 0.25 and 0.5 mg/kg i.p.) by repeated retesting in the CPP apparatus (15-min sessions, 5 days/week) until the rats reached extinction (i.e. less than 55% preference over 3 consecutive sessions). Following an unbiased CPP protocol, morphine, oxycodone and heroin induced CPP with minimal effective doses of 3, 1 and 0.25 mg/kg, respectively, and with similar effect sizes for each CPP-inducing dose. The number of sessions required for extinction was positively correlated with the dose of the drug (experiment 1: 18 and 45 sessions for 3 and 10 mg/kg morphine, and 19 and 27 sessions for 1 and 3 mg/kg oxycodone; experiment 2: 12 and 24 sessions for 3 and 10 mg/kg morphine, and 10 and 14 sessions for 0.25 and 0.5 mg/kg heroin). These findings suggest that the use of an extinction paradigm can extend the quantitative assessment of the rewarding effect of drugs - however, within certain limits only. The present paradigm appears to be less suited for comparing the rewarding efficacy of different drugs due to great test-retest variability. Finally, the additional potential gain of information using this paradigm has to be weighed against the considerably large amount of additional time and effort.
authors.affiliation: Department of Pharmacology, Global Preclinical Research and Development, Grünenthal GmbH, Aachen, Germany. kris.rutten@grunenthal.com
authors.forename: Kris
authors.initials: K
authors.lastname: Rutten
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: van der Kam
authors.forename: Jean
authors.initials: J
authors.lastname: De Vry
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Tzschentke
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D003213:Conditioning, Psychological / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005108:Extinction, Psychological / Q000187:drug effects*; D003932:Heroin / Q000494:pharmacology; D008297:Male; D009020:Morphine / Q000494:pharmacology; D010098:Oxycodone / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019966:Substance-Related Disorders
chemical_list: D000701:Analgesics, Opioid; D003932:Heroin; D009020:Morphine; D010098:Oxycodone