Ethanol-induced conditioned place aversion in mice

Abstract

Previous studies have shown that ethanol produces conditioned place preference (CPP) in mice when injections are given immediately before exposure to the conditioned stimulus (CS). Paradoxically, however, injection of ethanol immediately after the CS produces conditioned place aversion (CPA). Four experiments were conducted to characterize the parametric boundaries of CPA produced by post-CS ethanol exposure. Experiment 1 showed that CPA is positively related to ethanol dose, with significant CPA at 2 and 4 g / kg, but not at 1 g / kg. Experiment 2 revealed an inverse relationship between CPA and trial duration, i.e. significant CPA occurred when the trial duration was 5, 15 or 30 min, but not when it was 60 or 90 min. Experiment 3 indicated that ethanol pre-exposure (eight daily injections) significantly reduced subsequent development of CPA. Finally, experiment 4 showed that repeated exposure to the CS alone (six 30 min exposures to each CS) after CS-ethanol pairings produced complete extinction of CPA. The same extinction procedure also completely eliminated CPP induced by pre-CS injections of ethanol. Overall, these studies demonstrate that CPA induced by post-CS ethanol injection is influenced by many of the same variables that affect CPP produced by pre-CS ethanol injection in mice. However, these findings do not resolve the issue of whether the 'before-versus-after' effect in ethanol place conditioning is better explained by assuming ethanol produces only rewarding effects or by assuming that ethanol produces both rewarding and aversive effects.

FOS expression induced by an ethanol-paired conditioned stimulus

“…Conversely, After-S mice showed suppressed locomotor activity across conditioning days and on test. Although place preference data were not obtained, these conditioned locomotor effects are consistent with previous studies in DBA/2J mice in which the Before procedure produced CPP and the After procedure produced CPA (Cunningham and Noble, 1992;Cunningham et al, 1997;Cunningham and Henderson, 2000).…”

“…Ethanol-induced taste aversion conditioning has previously been shown by others to increase FOS expression in the nucleus of the solitary tract, the parabrachial nucleus, and the area postrema in subjects subsequently presented with an ethanol-paired tastant (Thiele et al, 1996). In light of data suggesting a genetic correlation between ethanol-induced conditioned taste aversion and ethanol-induced CPA (Cunningham and Ignatoff, 2000), it is possible that brain regions activated by the CS+ in the After-S group may have been missed by not examining FOS changes in the brain stem.…”

“…These two procedures were compared because previous research has shown that they produce opposite effects on behavior in a place-conditioning task. More specifically, pre-CS ethanol produces CPP whereas post-CS ethanol produces conditioned place aversion (CPA) (Cunningham and Henderson, 2000;Cunningham et al, 1997). Because these motivationally opposite behaviors are thought to be independently mediated (Cunningham et al, 2002), Before-S group mice were expected to have different patterns of FOS activation than After-S group mice, and both paired groups were expected to differ from unpaired-drug (Delay-S group) and drug-naive (Naïve-S group) control mice.…”

Ethanol drinking in rodents: is free-choice drinking related to the reinforcing effects of ethanol?

“…While this review integrates findings across both rats and mice, there may be some intrinsic biological differences in response to the reinforcing and aversive effects of ethanol existing between rats and mice. Ethanol-induced CPP is fairly well established among mouse literature (though notably lacking in the C57BL/6J mouse, the prototypical high-drinking strain; see Table 1), but the condition under which rats will exhibit an ethanol CPP remains unclear (Cunningham and Henderson, 2000;Fidler et al, 2004;Tzschentke, 1998). Fidler et al (2004) discusses the role route of administration plays on the development of CPP.…”

“…Furthermore, it has also been proposed Cunningham and Henderson, 2000) that both CPP, conditioned place aversion, and CTA can be produced in the same animal by the same dose of ethanol simply by varying the timing of administration of the ethanol and the nature of the cues paired with ethanol delivery (gustatory or tactile/environmental). One recent study indicated a genetic correlation between CTA and place aversion conditioning wrought by injecting ethanol after exposure to the CS, suggesting that these two phenotypes can be related when measuring the aversive effects of ethanol (Cunningham and Ignatoff, 2000).…”