Research report
The amygdala mediates memory consolidation for an amphetamine conditioned place preference

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Abstract

Drug-induced conditioned place preference (CPP) behavior requires memory for an association between environmental cues and the affective state produced by the drug treatment. The present study investigated whether memory consolidation underlying an amphetamine CPP could be modulated by post-training intra-amygdala infusion of the local anesthetic drug bupivacaine. On 4 alternating days adult male Long–Evans rats received peripheral injections of amphetamine (2.0 mg/kg) or saline vehicle prior to confinement for 30 min to one of two compartments of a place preference apparatus, followed by post-training intra-amygdala infusions of bupivacaine (0.75% solution/1.0 μl) or saline. On day 5 the rats were given a drug-free 20-min test session, and the amount of time spent in each of the pairing compartments of the apparatus was recorded. On the test day, rats receiving post-training intra-amygdala saline injections displayed an amphetamine conditioned place preference. Post-training intra-amygdala infusions of bupivacaine blocked amphetamine CPP. Intra-amygdala infusions of bupivacaine that were delayed 1 h post-training did not block amphetamine CPP, indicating a time-dependent effect of the treatment on memory storage processes. Pre-training or pre-retention test intra-amygdala infusions of bupivacaine also blocked acquisition and expression of an amphetamine CPP, respectively. The findings indicate that the mechanism(s) by which amphetamine elicits conditioned approach responses to environmental cues can be manipulated post-training, and suggest a role for the amygdala in acquisition, consolidation, and expression of amphetamine CPP behavior.

Introduction

Research examining the neurobiological bases of drug addiction has traditionally focused on mechanisms mediating the rewarding properties of various drugs of abuse. One behavioral paradigm that has been used extensively to examine the affective properties of drugs is the conditioned place preference (CPP) task (for reviews, see [1], [5]). In the CPP task, typically rats receive drug and vehicle injections on alternate training days, and these treatments are paired with confined exposure to distinct environmental cues in a place preference apparatus. On a subsequent drug-free test day, rats are allowed access to the entire apparatus, and the affective properties of the drug treatment are inferred by comparing the amount of time spent in the environments previously paired with drug or vehicle administration. Naturally occurring stimuli such as food and water, as well as various drugs of abuse (e.g. amphetamine, cocaine, benzodiazepines, and heroin) reliably produce conditioned place preferences in rats [1], [5].

Interpretation of CPP data has primarily been considered in the context of study of the neurobiological bases of drug-induced reward or affect. However, as animals are in a drug-free state on the test day, the expression of a CPP requires memory for the association between environmental cues and the affective state produced by the treatment [44]. Despite widespread use of the CPP paradigm by investigators interested in the neurobiological bases of addiction, the neuroanatomical bases of the mnemonic processes involved in conditioned place preference have received relatively little empirical investigation. Studies using irreversible pre-training or pre-retention lesion techniques implicate the amygdala in acquisition of a food CPP [24], a cocaine CPP [3], and acquisition/expression of a sucrose [13] and amphetamine [19] conditioned place preference. However, following irreversible lesions it is difficult to assess whether amygdala lesions block CPP behavior via impairment of non-mnemonic processes (e.g. motor, sensory, motivational, or attentional), reward-signaling processes, or by impairing memory processes underlying the formation of stimulus–reward associations.

The use of post-training manipulations, in which a reversible lesion or drug treatment is administered shortly after training and subjects are subsequently tested for retention at a later time point (e.g. 24 h), provides a methodology for dissociating mnemonic and non-mnemonic factors [25], [26]. Numerous studies employing post-training hormonal and pharmacological treatments implicate the amygdala in memory storage processes (for review, see [34]). We recently observed that post-training intra-amygdala infusion of the anesthetic drug lidocaine blocks memory consolidation mediating a food CPP [39]; however, the extent to which amygdala function mediates memory consolidation processes underlying amphetamine CPP behavior is unknown. Determining whether the role of the amygdala in memory consolidation in this task generalizes to an addictive psychostimulant drug may have implications for understanding the neurobiological mechanism(s) mediating learned aspects of drug-seeking behavior. Therefore, in the present study rats received injections of amphetamine or saline prior to exposure to a specific pairing compartment of a place preference apparatus, followed by an immediate post-training intra-amygdala infusion of the local anesthetic bupivacaine, an agent that produces a temporary and reversible inactivation of neural tissue [8]. On a drug-free test day, the ability of post-training intra-amygdala bupivacaine to block memory consolidation mediating an amphetamine CPP was assessed. Additional groups of rats received either pre-training or pre-retention intra-amygdala infusions of bupivacaine, in order to assess whether this treatment would also block acquisition and expression of an amphetamine CPP.

Section snippets

Subjects

The subjects were 46 adult male Long–Evans rats (300–350 g). The rats were individually housed in a temperature-controlled environment on a 12-h light/dark cycle with the lights on from 07:00 to 19:00 h, and had ad libitum access to food and water.

Apparatus

The place preference apparatus was the same as that previously described [39], and was constructed of wood with Plexiglas front doors. It consisted of three different compartments, two of which were identical in size (45×45×30 cm high). One

Results

The effect of pre-training intra-amygdala infusions of bupivacaine on acquisition of an amphetamine CPP is illustrated in Fig. 2 (top). A two-way one-repeated measures analysis of variance (ANOVA) with pre-training treatment as an independent variable, and paired (amphetamine) versus unpaired (saline) side as a repeated measure revealed a significant interaction (F1,12=5.35, P<0.05). Post-hoc two-tailed paired t-tests revealed that the subjects receiving pre-training intra-amygdala saline

Amygdala mediates memory consolidation for an amphetamine CPP

The conditioned place preference task has been used extensively in the investigation of the neurobiological bases of the rewarding affective properties of various drugs. The expression of a CPP on the drug-free test day presumably requires memory for the association between environmental cues and the affective state produced by the treatment [44]. However, the neuroanatomical bases of the mnemonic processes underlying CPP behavior are not well understood. In the present study, post-training

Acknowledgements

Research supported by NIH grant R29MH056973 (M. P.). We thank two anonymous reviewers for helpful comments on an earlier version of the manuscript.

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