Reference-dose place conditioning with ethanol in mice: Empirical and theoretical analysis

Rationale: A frequently expressed criticism of the conditioned place preference (CPP) procedure is that it sometimes lacks a graded dose-response curve for many drugs. Objective: We used a combination of standard and reference-dose CPP procedures to examine the dose-response curve for ethanol-induced CPP in DBA/2J mice. Materials and methods: In the standard procedure, ethanol (0.5, 1.5, 2, and 4 g/kg) was paired with a distinctive floor cue, whereas saline was paired with a different floor cue. In the reference-dose procedure, each cue was paired with a different dose of ethanol. All mice received four 5-min trials of each type in both procedures. Results: Standard procedures yielded similar levels of CPP at doses of 1.5, 2, and 4 g/kg, whereas 0.5 g/kg did not produce significant CPP. However, in the reference-dose procedure, exposure to the 0.5-g/kg dose interfered with CPP normally produced by 1.5 or 2 g/kg. Moreover, mice showed significant preference for the 4-g/kg-paired cue over the 1.5-g/kg-paired cue. Conclusions: These studies show that a reference-dose procedure can reveal effects of low doses that are sometimes difficult to detect in a standard procedure. The reference-dose procedure may also uncover differences between higher doses that normally produce similar preference. Efficacy of the reference-dose procedure may be explained by a theoretical analysis that assumes the procedure places behavior between the extremes of the performance range, offering a more sensitive method for detecting effects of manipulations that produce small changes and/or differences in the rewarding effects of ethanol.