Intra-amygdala anxiogenic drug infusion prior to retrieval biases rats towards the use of habit memory

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Abstract

In a dual-solution plus-maze task that can be acquired using either hippocampus-dependent “cognitive/place” learning or dorsal striatal-dependent “habit/response” learning, pre-acquisition peripheral or intra-basolateral amygdala (BLA) injections of anxiogenic drugs result in the predominant use of response learning. The present experiments examined the effect of anxiogenic drug treatment on the relative use of multiple memory systems when administered prior to memory retrieval. Adult male Long-Evans rats were trained for two days (6 trials/day, 30 s ITI) in a dual-solution plus-maze task to swim from the same start point (south) to an escape platform that was located in a consistent goal arm (west). On day three, prior to a memory retrieval probe trial from a novel start point (north), rats received a peripheral (0.03, 0.1 or 0.3 mg/kg), or intra-BLA (0.1 μg/0.5 μl) injection of the anxiogenic α2-adrenoreceptor antagonist RS 79948-197, or saline. Relative to saline controls, rats receiving either peripheral or intra-BLA infusions of RS 79948-197 predominantly displayed response learning on the probe trial. In an additional experiment peripheral (0.1 mg/kg) or intra-BLA (0.1 μg) drug injections administered prior to both acquisition and retrieval also resulted in the predominant use of response learning. The findings indicate that (1) similar to acquisition, peripheral injection of an anxiogenic drug prior to memory retrieval biases rats towards the use of habit/response memory, (2) intra-BLA infusions of an anxiogenic drug is sufficient to produce this modulatory effect of emotional state on memory retrieval, and (3) state-dependency does not appear to play a role in the effects of anxiogenic drug treatment on multiple memory system use. The findings may have implications for understanding the interaction between brain function, emotion, and the relative use of multiple memory systems in human psychopathology.

Introduction

Converging evidence from studies employing brain lesions (e.g., Packard et al., 1989, Packard and McGaugh, 1992, Packard and McGaugh, 1992, Packard and McGaugh, 1996, Kesner et al., 1993) and post-training intracerebral drug administration in rats (e.g., Packard, 1999, Packard and Teather, 1997, Packard and White, 1991) support the hypothesis that the hippocampus and dorsal striatum selectively mediate cognitive (Tolman, 1932) and stimulus-response habit (Hull, 1943) learning, respectively. A third brain structure, the basolateral amygdala (BLA), has been implicated in stimulus-affect learning (for review see White & McDonald, 2002), and can modulate both hippocampus-dependent and dorsal striatal-dependent memory processes (Packard et al., 1994, Packard and Teather, 1998). Numerous studies have also implicated the BLA in the effects of emotional arousal on memory (for review see McGaugh, 2004). Therefore, within the context of multiple memory systems theory we previously (Packard & Wingard, 2004) investigated the relationship between BLA function, emotional state, and the relative use of cognitive and habit memory in a dual-solution plus-maze task. In this task, rats are trained in a water plus-maze to swim from the same start arm (south) to an escape platform located in a consistent goal arm (west). Rats can acquire this task using hippocampus-dependent “cognitive/place” learning (i.e., approach the goal arm based on knowledge of the spatial location of the platform), or dorsal striatal-dependent “habit/response” learning (i.e., turn left at the choice point and approach the platform; Chang and Gold, 2003, Packard, 1999, Packard and McGaugh, 1996, Schroeder et al., 2002). In our previous study we observed that pre-acquisition peripheral or intra-BLA injections of anxiogenic drugs result in the predominant use of response learning (Packard & Wingard, 2004). These findings suggest that an anxiogenic emotional state induced prior to training favors the relative use of habit memory. Identification of the neural mechanisms by which emotional arousal can produce a bias towards the use of habit memory is important in view of evidence that anxiety and/or stress can be contributing factors to relapse into previously acquired habitual and maladaptive behaviors in human psychopathology (e.g., Herman and Polivy, 1975, Weiss et al., 2001). Therefore, the primary goal of the present experiments was to extend our previous findings by examining the relative use of multiple memory systems when an anxiogenic drug is administered prior to memory retrieval. Accordingly, in experiment one rats trained in a dual-solution water plus-maze task were injected either peripherally or directly into the BLA with the anxiogenic α2-adrenoreceptor antagonist RS 79948-197 or vehicle prior to memory retrieval.

A secondary goal of the present experiments was to examine whether drug-induced state dependency may play in the role in the effects of anxiogenic drug treatment on the relative use of multiple memory systems. According to the state dependency hypothesis, information is best retrieved if the organism is in the same physiological state during initial task acquisition and memory retrieval (Overton, 1964). In the context of the dual-solution plus-maze task, the state dependency hypothesis raises the possibility that in our previous study (Packard & Wingard, 2004), rats receiving injections of an anxiogenic drug prior to acquisition predominantly displayed response learning on the subsequent drug-free memory retrieval probe trial because they were not in the same physiological state at these two behavioral time-points. In order to examine this hypothesis, we conducted an additional experiment in which rats received peripheral or intra-BLA injections of RS 79948-197 prior to both acquisition and memory retrieval. If the predominant use of response learning produced by RS 79948-197 is due to state-dependency, then drug injections at both time-points should “restore” behavior to the same pattern as that observed in control rats. In contrast, if the effects of RS 79948-197 are not due to state-dependency, then injections at both time-points should continue to result in the predominant use of response learning.

Section snippets

Subjects

Subjects were 138 male Long-Evans rats (weighing 275–350 g). They were individually housed in a climate-controlled vivarium with ad libitum access to food and water. The animals were on a 12:12-h light: dark cycle (lights on at 8 a.m.). All experiments were conducted during the light phase of the cycle.

Apparatus

Animals were trained in a black circular water maze (1.83 m diameter, 0.58 m in height; 25 degrees Celsius water-temperature) into which a clear Plexiglas plus-maze (43 cm height, arm-width of 25 cm,

Effect of peripheral injection RS 79948-197 prior to memory retrieval

Acquisition of the plus-maze task is illustrated in Fig. 2 (top). A two-way one-repeated ANOVA comparing saline and RS 79948-197 groups prior to subsequent injection on percent correct during initial task acquisition revealed a non-significant Group effect [F(1, 50) = 0.65, n.s.] and Group × Trial interaction [F(2, 50) = 1.12, n.s.]. A significant Trial effect indicated that all groups improved over training [F(11, 50) = 3.96, p < 0.01]. The findings indicate that all groups acquired at the task at the same

Discussion

We have previously observed that peripheral or intra-BLA administration of the highly selective α2-adrenoceptor antagonist RS 79948-197 prior to acquisition of a dual-solution plus maze task bias rats towards the use of habit/response learning (Packard & Wingard, 2004). The results of experiment one extends these findings and indicates that peripheral or intra-BLA injections of RS 79948-197 also bias rats towards the use of response prior to memory retrieval. The results of experiment two

Acknowledgment

Research supported by NSF Grant IBN-03122212 (M.P).

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