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.

BOLD Imaging in Awake Wild-Type and Mu-Opioid Receptor Knock-Out Mice Reveals On-Target Activation Maps in Response to Oxycodone

“…In addition, OXY has reinforcing effects as measured by self-administration and condition place preference studies in rodents (Beardsley et al, 2004; Zhang Y. et al, 2009; Rutten et al, 2011; Bryant et al, 2014; Zhang et al, 2015). The mesocorticolimbic dopaminergic system is a key pathway involved in drug reinforcement (Koob, 1992) and as such, we anticipated OXY would affect activity in this neural circuit.…”

Effects of Acute and Repeated Administration of Oxycodone and Naloxone-Precipitated Withdrawal on Intracranial Self-Stimulation in Rats

“…In terms of its reinforcing-related effects, oxycodone has been reported to be self-administered by laboratory animals, including rats (Beardsley et al, 2004) and mice (Zhang et al, 2009(Zhang et al, , 2015. Oxycodone also produces conditioned place preference in rats (Rutten et al, 2011) and mice Kirkpatrick and Bryant, 2014). Oxycodone dependence reports are also relatively rare.…”

Behavioral flexibility and response selection are impaired after limited exposure to oxycodone

“…Oxycodone hydrochloride (Oxy, Sigma-Aldrich) was prepared daily (3 mg/kg in 0.9% sterile saline) and injected subcutaneously into the dorsal flank of rats twice daily (1000 and 1500 h) for 5 d. This dose and administration route is comparable to those used to induce place preference (Olmstead and Burns 2005;Rutten et al 2011;Campbell et al 2012). A comparable volume of saline (Sal, 0.2 mL) was administered to control rats.…”