Proximal ethanol pretreatment interferes with acquisition of ethanol-induced conditioned place preference

Abstract

Neurobiological mechanisms underlying rewarding and aversive effects of drugs are often studied by examining effects of various pretreatments on acquisition of conditioned place preference (CPP) or conditioned place aversion (CPA). However, few studies have looked at effects of pretreatment with the same drug used during conditioning. Such studies might offer insight into agonist actions on conditioning while also mimicking real world contingencies experienced by drug users. Previous work from our laboratory, which showed that same drug pre-exposure interfered with acquisition of ethanol CPA but not CPP, was limited by the use of only one pre-treatment time interval (65 min). Thus, the present studies were designed to study other intervals (− 5, − 15, − 30). Pretreatment of DBA/2J mice with ethanol (2 g/kg) reduced the activity response normally evoked by the conditioning dose (2 g/kg) at all pretreatment times, but acquisition of CPP was disrupted only by pretreatment at − 5 min. The overall pattern of findings suggests that ethanol's early pharmacological effects interfered with learning the association between the conditioned stimulus (CS) and ethanol 5 min later. Thus, one would expect ethanol agonists, when administered in close proximity to CS-ethanol pairings, to interfere with control of ethanol seeking by that CS.

Introduction

Neurobiological mechanisms underlying the rewarding and aversive effects of drugs are often studied by examining effects of various pretreatment drugs on the acquisition of drug-seeking or drug-avoidance behavior. This strategy has gained widespread acceptance in the place conditioning procedure, which may be especially well suited for evaluating effects of pretreatment drugs due to the ability to separate effects on acquisition from effects on expression of place conditioning (e.g., Hoffman, 1989, Swerdlow et al., 1989, Tzschentke, 1998). For example, one can examine the effect of a pretreatment drug (e.g., a receptor agonist or antagonist) given shortly before each pairing of the conditioned stimulus (CS) with a rewarding drug (unconditioned stimulus or US). The effect of this treatment is later evaluated by measuring the animal's preference for the CS in the absence of any drug treatment. If place preference is weaker in the drug pretreatment group than in a vehicle control group, it is usually assumed that the pretreatment drug interfered either with the US drug's rewarding effect or with learning of the CS-US association (e.g., Boyce-Rustay and Cunningham, 2004).

One particularly interesting, but little studied, instance of drug pretreatment is the case in which the pretreatment drug is the same as the US drug. The question of interest in such studies is whether the recent and still present effects of the first drug exposure affect conditioning to cues paired with the second drug exposure. Effects of proximal pretreatment with the US drug are of potential interest for several reasons. First, a situation in which environmental cues are paired with multiple exposures to the same drug at short intervals may more closely approximate the natural conditioning history of habitual drug users. For example, alcohol abusers and alcoholics typically ingest their second drink (and third, etc.) while still under the influence of the previous drink. The ability of ethanol to induce conditioning to novel environmental stimuli that are first introduced at the time of later drinks in a sequence is not known. In other words, real world conditioning contingencies are not necessarily well mimicked by the usual laboratory experiment in which the CS is paired with the onset of a single contingent drug exposure and successive pairings occur a day or more apart, after effects of the previous dose have subsided. Given the possibility of acute tolerance or alterations in pharmacokinetics, one might reasonably expect a reduced conditioning effect from a second drug dose that follows closely after a previous dose. Finally, another reason for being interested in effects of same drug pre-exposure is that a drug is its own best agonist. Thus, knowing the effects of same drug pre-exposure might be helpful when interpreting the effects of other pretreatment drugs thought to be agonists at the same site of action as the US drug.

Previous studies in this laboratory were the first to show that same drug pretreatment interferes with acquisition of conditioned place aversion induced by post-CS injection of an ethanol US. However, same drug pre-exposure had absolutely no effect on acquisition of conditioned place preference produced by pre-CS injection of the same ethanol US (Cunningham et al., 2002). In both studies, the pretreatment injection occurred 65 min before the conditioning trial injection. The failure to see a pretreatment effect on acquisition of conditioned preference was surprising since measurement of activity during the conditioning trial indicated a strong residual (activity suppressing) effect of the pretreatment ethanol injection despite the 1 h delay. The fact that the same proximal pretreatment procedure had different effects on conditioned preference and conditioned aversion produced by the same US argued against simple associative interference interpretations based on degradation of the CS-US contingency (e.g., Rescorla, 1968) or information value of the CS (Rescorla, 1972). Rather, this outcome was viewed as supporting the conclusion that ethanol pre-exposure differentially affected the motivational consequences of the unconditioned responses (URs) that are normally responsible for conditioned preference and conditioned aversion. In other words, the aversive UR was simply more sensitive to ethanol pre-exposure than the rewarding UR (Cunningham et al., 2002).

One limitation on the conclusions from this earlier study is that only one pretreatment time interval (i.e., 65 min) was examined. Thus, Experiment 1 was designed to examine the effects of several shorter pretreatment intervals (5, 15 or 30 min) on the acquisition of ethanol-induced conditioned place preference. The effects of pretreatment within this time range are of particular interest in light of the previous finding that conditioned place preference can be induced when the ethanol US injection itself is given 30 min before exposure to the CS+ (Cunningham et al., 1997). If injection of the US drug 30 min before the CS is able to condition a preference for the CS, one might expect that administration of a same drug pretreatment 30 min (or less) before the CS-US pairing would enhance acquisition of conditioned preference due to temporal summation of ethanol's rewarding effects. Unexpectedly, however, Experiment 1 showed that ethanol pre-exposure interfered with acquisition of conditioned place preference, but only at the 5-min pretreatment interval. Experiment 2 was designed to replicate this unexpected finding and to compare the ethanol pre-exposure group with control groups that received either a saline pretreatment or no pretreatment.