Post-training amphetamine administration enhances memory consolidation in appetitive Pavlovian conditioning: Implications for drug addiction

Neurobiology of Learning and Memory 86 (2006) 305–310 www.elsevier.com/locate/ynlme

Post-training amphetamine administration enhances memory consolidation in appetitive Pavlovian conditioning: Implications for drug addiction Nicholas W. Simon a, Barry Setlow a,b,¤ a

Department of Psychology, Texas A&M University, College Station, TX 77843-4235, USA b Faculty of Neuroscience, Texas A&M University, College Station, TX 77843-4235, USA Received 9 March 2006; revised 19 April 2006; accepted 20 April 2006 Available online 5 June 2006

Abstract It has been suggested that some of the addictive potential of psychostimulant drugs of abuse such as amphetamine may result from their ability to enhance memory for drug-related experiences through actions on memory consolidation. This experiment examined whether amphetamine can speciWcally enhance consolidation of memory for a Pavlovian association between a neutral conditioned stimulus (CS—a light) and a rewarding unconditioned stimulus (US—food), as Pavlovian conditioning of this sort plays a major role in drug addiction. Male Long-Evans rats were given six training sessions consisting of 8 CS presentations followed by delivery of the food into a recessed food cup. After the 1st, 3rd, and 5th session, rats received subcutaneous injections of amphetamine (1.0 or 2.0 mg/kg) or saline vehicle immediately following training. Conditioned responding was assessed using the percentage of time rats spent in the food cup during the CS relative to a pre-CS baseline period. Both amphetamine-treated groups showed signiWcantly more selective conditioned responding than saline controls. In a control experiment, there were no diVerences among groups given saline, 1.0 or 2.0 mg/kg amphetamine 2 h post-training, suggesting that immediate post-training amphetamine enhanced performance speciWcally through actions on memory consolidation rather than through non-mnemonic processes. This procedure modeled Pavlovian learning involved in drug addiction, in which the emotional valence of a drug reward is transferred to neutral drug-predictive stimuli such as drug paraphernalia. These data suggest that amphetamine may contribute to its addictive potential through actions speciWcally on memory consolidation. © 2006 Elsevier Inc. All rights reserved. Keywords: Pavlovian conditioning; Amphetamine; Drug addiction; Memory consolidation; Learning; Post-training; Classical conditioning

1. Introduction Pavlovian conditioning plays a signiWcant role in drug addiction. Cues that are consistently predictive of drug intake (such as drug paraphernalia or drug-taking contexts) can become associated with rewarding properties of the drug itself. This associative learning results in retrieval of drug-related experiences and aVect upon encounters with these cues, which may lead to craving and relapse. The strong inXuence of Pavlovian conditioning provides an

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explanation for the diYculty drug users have with maintaining drug abstinence long after physical dependence is no longer evident (Childress et al., 1999; Ciccocioppo, Martin-Fardon, & Weiss, 2004; Everitt, Dickinson, & Robbins, 2001; Shaham, Shalev, Lu, de Wit, & Stewart, 2003). It has been proposed that psychostimulant drugs (such as amphetamine and cocaine) may actually strengthen the inXuence of Pavlovian conditioning over drug addiction through their actions on memory consolidation processes (White, 1996). Psychostimulants can enhance memory for previously learned information (for review, see McGaugh, 1966; McGaugh, 2000), and this drug-induced memory enhancement process would be expected to strengthen associations between the drug and the cues preceding it. Enhanced

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memory for associations between drug-predictive cues and drug outcomes would lead to a higher likelihood of drug craving, seeking, and ultimately, relapse in the presence of these cues (Berke & Hyman, 2000; Everitt et al., 2001; White, 1996). A common method used to provide evidence that a drug is acting on memory consolidation (rather than enhancing performance due to non-mnemonic mechanisms such as locomotion, motivation, or attention) is to administer the drug immediately after learning (i.e., during the memory consolidation period). This allows testing of the eVects of a drug on memory (e.g., 24 h later) in the absence of direct drug eVects on acquisition or retrieval performance. Using this technique, it has been demonstrated that systemic posttraining administration of the indirect dopamine agonist Damphetamine enhances retention across a wide variety of tasks in both rodents and humans (Krivanek & McGaugh, 1969; Martinez et al., 1980; Oscos, Martinez, & McGaugh, 1988; Packard & McGaugh, 1994; Packard & White, 1989; Soetens, D’Hooge, & Hueting, 1993). Despite the wealth of data showing that amphetamine can enhance memory through actions on consolidation processes, few experiments have speciWcally modeled Pavlovian learning and memory processes thought to be critically involved in drug addiction. As a Wrst step toward understanding the inXuence of psychostimulant actions on memory consolidation on their addictive properties, the current study examined the inXuence of immediate posttraining systemic amphetamine administration on an appetitive conditioned stimulus (CS—light)—unconditioned stimulus (US—food) association. This procedure speciWcally isolates Pavlovian associative processes (i.e., associations between cues predictive of drug reward and the drug itself) thought to be important in drug addiction (Childress et al., 1999; Robbins & Everitt, 2005). It was predicted that post-training amphetamine would result in enhanced foodseeking behavior in the presence of the CS, analogous to the enhanced drug-seeking observed in the presence of drug-predictive cues (Shaham et al., 2003). Because subjects were given amphetamine three times over the course of the experiment, an additional control experiment was necessary. Previous non-contingent amphetamine administration can enhance both conditioned responding to Pavlovian cues and instrumental responding for access to such cues (Harmer & Phillips, 1998; Taylor & Jentsch, 2001; Wyvell & Berridge, 2001), and even a single exposure to a high dose of amphetamine (5.0 mg/kg) is suYcient to induce long-lasting locomotor and neurochemical sensitization (Vanderschuren et al., 1999). Hence, enhanced performance in amphetamine-treated subjects may be a result of amphetamine sensitization rather than actions on memory consolidation. To control for this possibility, a second experiment examined the eVects of amphetamine administered 2 h after training. This 2-h time point has been shown previously to be beyond the window in which amphetamine inXuences memory consolidation (Oscos et al., 1988; Packard & McGaugh, 1994). If amphetamine administration 2 h posttraining did not enhance performance similarly to immediate

post-training amphetamine, then it could be concluded that amphetamine can inXuence Pavlovian conditioning speciWcally through actions on memory consolidation processes. 2. Materials and methods 2.1. Subjects The subjects were 67 male Long-Evans rats (Charles River Laboratories, Raleigh, NC) weighing 300–325 g upon arrival. Rats were individually housed in a climate-controlled vivarium in the Department of Psychology at Texas A&M University, and kept on a 12 h light/dark cycle (lights on at 8am) with free access to water at all times. Five days prior to the start of behavioral testing, rats were food-restricted to 85% of their free-feeding weight, and were maintained as such through the duration of the experiment. All procedures were conducted in accordance with the Texas A&M University Laboratory Animal Care Committee and NIH guidelines.

2.2. Behavioral apparatus Behavioral testing was conducted in four identical standard rat test chambers (30.5 £ 25.4 £ 30.5 cm) with metal front and back walls, transparent Plexiglas side walls, and a Xoor composed of steel rods (0.4 cm in diameter) spaced 1.1 cm apart. A recessed pellet delivery trough (food cup, 4.1 £ 3.2 cm) equipped with a photobeam to detect head entries was located 2.2 cm above the Xoor in the center of the front wall. A pellet feeder delivered the 45 mg grain-based food pellets (Research Diets, New Brunswick, NJ) into the food cup. A 1.12 W lamp that served as the conditioned stimulus (CS) was located 14 cm above the Xoor over the pellet trough, and a ceiling-mounted infrared activity monitor recorded movement throughout the chamber. Each chamber was located in a soundattenuating cubicle. A 1.12 W bulb mounted on the inside back wall of the cubicle at the level of the ceiling of the test chamber provided constant background illumination throughout the test sessions. The test chambers were connected to a computer running Graphic State 3.1 software, which controlled stimulus delivery and collected response data. All components of this system were obtained from Coulbourn Instruments (Allentown, PA).

2.3. Drug D-Amphetamine sulfate was kindly provided by the Drug Supply Program at the National Institute on Drug Abuse. It was dissolved in 0.9% saline (which was used for control injections) and administered subcutaneously at a volume of 1 ml/kg at doses of 1.0 or 2.0 mg/kg. These doses were chosen based on their eVectiveness at enhancing memory in other tasks (Oscos et al., 1988; Williams, Packard, & McGaugh, 1994).

2.4. Procedures On the day prior to the start of the experiment, each rat was given Wve of the 45 mg food pellets in its home cage to reduce neophobia to the food. The experiment began with a 64 min magazine training session consisting of 16 deliveries of the US (two 45 mg food pellets) at inter-trial intervals of 4 § 2 min. Next, the rats received six daily 32 min sessions of Pavlovian conditioning, each consisting of eight 10 s presentations of the light CS immediately followed by the US, at inter-trial intervals of 4 § 2 min. Entries into the food cup and general activity were recorded during these sessions in 5 s blocks during the 1st and 2nd halves of the 10 s CS and during a 5 s pre-CS baseline period immediately prior to CS presentations. Extensive previous work with this behavioral procedure (e.g., Holland, 1979; Setlow, Gallagher, & Holland, 2002) has shown that conditioned food cup entry is weighted toward the second half of a 10 s visual CS, and thus we focused our analysis on this time period. The primary measure of interest in this experiment was the percentage of time within a 5 s block that rats spent in the food cup. Learning in the task was assessed using a

N.W. Simon, B. Setlow / Neurobiology of Learning and Memory 86 (2006) 305–310 measure of selectivity of conditioned responses to the visual CS (Harmer & Phillips, 1998; Phillips, Setzu, & Hitchcott, 2003), which was the % time in food cup during the second half of the CS divided by the sum of % time in food cup during the second half of the CS plus % time in food cup during the pre-CS baseline. By this measure, a value of 0.5 represents equal responding during the CS and pre-CS periods (i.e., no evidence of conditioned responding to the CS). Prior to the start of each experiment, subjects were randomly assigned to one of three groups. In Experiment 1, the three groups of subjects were given subcutaneous injections of either saline (n D 14), 1.0 (n D 12), or 2.0 (n D 13) mg/kg D-amphetamine, immediately after completion of sessions 1, 3, and 5 of Pavlovian training. In Experiment 2, the three groups were given subcutaneous injections of saline (n D 10), 1.0 (n D 8), or 2.0 (n D 10) mg/kg D-amphetamine 2 h after the completion of sessions 1, 3, and 5. No injections were given after sessions 2, 4, and 6.

2.5. Data analysis Raw data Wles were exported from Graphic State software and compiled using a custom macro written for Microsoft Excel (Dr. Jonathan Lifshitz, Dept. of Anatomy and Neurobiology, Virginia Commonwealth University). Statistical analyses were conducted in SPSS 12.0. Data were analyzed using two-factor repeated measures ANOVAs (drug condition £ session) with LSD post hoc tests where appropriate. In all cases, p values less than .05 were considered signiWcant.

3. Results In Experiment 1, all three groups given immediate posttraining injections acquired selective conditioned responses to the CS over the course of the six sessions (Fig. 1), as evidenced by an increase in selective conditioned responding from baseline (0.5). This impression was conWrmed by twofactor ANOVA, which revealed a main eVect of session (F5,180 D 17.49, p < .05). In addition, immediate post-training amphetamine administration produced an increase in selective conditioned responding relative to saline controls. There was a signiWcant main eVect of drug condition among these groups (F2,36 D 3.84, p < .05), and LSD comparisons revealed that both the 1.0 and 2.0 mg/kg amphetamine groups showed signiWcantly greater selective conditioned responding than the saline group (ps < .05). In Experiment 2, all three groups given injections 2 h post-

Fig. 1. Selectivity of conditioned responding in groups given saline or amphetamine immediately after training. Subjects given both doses of amphetamine displayed enhanced response selectivity over the course of the 6 days of training compared to saline controls. Data points represent means § SEM.

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training acquired selective conditioned responses to the CS over the course of the six sessions (Fig. 2), as evidenced by an increase in selective conditioned responding from baseline (F5,125 D 20.33, p < .05). In contrast to the results of Experiment 1, however, amphetamine administration 2 h post-training did not aVect selective conditioned responding. There was neither a main eVect of drug condition (F2,25 D .79, p D .47) nor an interaction between the factors of drug condition and session (F10,25 D .92, p D .41). Because increases in locomotor activity due to repeated amphetamine exposure (locomotor sensitization) could potentially account for the eVects of amphetamine on selective conditioned responding found in Experiment 1, we examined locomotor activity as assessed by the ceilingmounted activity monitor. There were no diVerences in locomotor activity among drug groups during either the second half of the CS (F2,36 D .88, p D .42) or during the preCS baseline period (F2,36 D .26, p D .77). There was also no diVerence in the ratio of locomotor activity between the CS and pre-CS period (Fig. 3), calculated as: locomotor activity during the second half of the CS/(locomotor activity during the second half of the CS + locomotor activity during the pre-CS baseline) (F2,36 D 1.11, p D .37).

Fig. 2. Selectivity of conditioned responding in groups given saline or amphetamine 2 h after training. There were no signiWcant diVerences between groups. Data points represent means § SEM.

Fig. 3. Selectivity of locomotor activity in groups given saline or amphetamine immediately after training. There were no signiWcant diVerences between groups. Data points represent means § SEM.

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4. Discussion Rats given amphetamine injections immediately after experiencing a series of Pavlovian light-food pairings demonstrated an enhanced learned association between these stimuli in comparison to rats given saline control injections. These data demonstrate that simple, isolated Pavlovian conditioning can be enhanced by post-training amphetamine exposure, and that stimulant-induced enhancement of memory consolidation may contribute to Pavlovian inXuences over drug addiction. In this experiment, food was used as the rewarding outcome rather than the drug itself (as would be the case in drug addiction). This procedure is advantageous in that it allows isolation of amphetamine’s eVects on memory consolidation from amphetamine’s rewarding, goal-related eVects. Although a self-administration procedure would more eVectively model human drug addiction, it would not allow separation of these two eVects (White, 1996). There were no diVerences among groups given saline or amphetamine injections 2 h post-training, suggesting that the enhanced performance observed in the immediate posttraining amphetamine groups was not related to sensitization, motivational changes, or other non-mnemonic processes; had this been the case, the amphetamine-treated 2-h post-training groups would have displayed enhanced performance similar to that observed in the immediate post-training groups. Furthermore, there were no diVerences in locomotion between the amphetamine and saline groups, providing evidence that changes in motor activity associated with amphetamine exposure do not account for the observed enhancement in Pavlovian conditioning. Finally, the observed results are not likely attributable to amphetamineinduced changes in the value of the food US. Immediate post-training amphetamine would have been expected to decrease the value of the food through conditioned tasteaversion mechanisms (Lin, Atrens, Christie, & Jackson, 1994), resulting in a decrease in conditioned responding. The data presented here suggest that immediate posttraining amphetamine administration enhanced memory for associative learning in appetitive classical conditioning. However, it is not entirely clear whether this enhancement resulted from an increased rate of acquisition or an increased asymptotic level of performance. Bearing on this issue, it is notable that performance in both the immediate post-training saline group and in all 2 h post-training groups appeared to reach asymptote on days 3–4, whereas performance in the immediate post-training 2.0 mg/kg group was still improving on day 6 (see Fig. 1). This observation suggests that immediate post-training amphetamine (particularly at the higher dose) produced “supra-normal” learning/memory for the Pavlovian associations in the task, rather than (or in addition to) “normal” learning at a faster rate. In support of this contention, pilot data from an experiment in which rats were trained in this task for 12 days (not shown) revealed no additional increase in performance beyond day 6, implying that performance under

these conditions reaches asymptote on or before day 6 of training. Previous post-training stimulant administration experiments have demonstrated enhanced retention in various tasks in which Pavlovian conditioning plays a role in learning, but have not eVectively isolated this form of learning. For example, several of these tasks required performance of an instrumental response in order to acquire a rewarding outcome (or to avoid an aversive outcome) (e.g., Krivanek & McGaugh, 1969; Martinez et al., 1980; Packard & McGaugh, 1994; Packard & White, 1989). In the current experiment, reward delivery (as well as the duration of the CS) was not response-contingent. Oscos et al. (1988) found that amphetamine enhanced a form of learning that did not involve any response contingencies, but the aspect of performance measured in that experiment was an autoshaped response that involved orienting to the CS rather than to the reward itself. Post-training amphetamine has also been found to enhance conditioned taste aversion learning (Fenu & Di Chiara, 2003); however, this form of Pavlovian conditioning involves transfer of a negative emotional value to the CS, which would not relate to human drug addiction in the same manner as the current study (i.e., the transfer of positive emotional valence of the US to the CS). It should be noted that several studies have found no eVects (Dalley et al., 2005) or even impairing eVects (Scavio, Clift, & Wills, 1992) of post-training amphetamine administration in Pavlovian conditioning tasks. Although the reasons for these diVerences is unclear, it should be noted that the eVects on memory of post-training drug administration depend strongly on both drug dose and the level of arousal present at the time of training. Thus, a drug may either enhance or impair memory depending upon the dose (thus producing the classic inverted-U-shaped dose–response curve), and even the same dose of a drug may have diVerent eVects depending upon the level of arousal during training (e.g. Cahill & Alkire, 2003; Gold & McGaugh, 1975; McGaugh, 1989). Based on the results of this study, it appears that systemic amphetamine administered post-training serves to facilitate isolated Pavlovian conditioning. The fact that an amphetamine-induced increase in the selectivity of conditioned responding was observed supports this contention. Memory for non-associative aspects of the training experience (e.g., better memory for the training context) would not be expected to produce this enhanced selectivity. These results provide a framework in which to further analyze mechanisms of stimulant drug facilitation of memory consolidation. It is well-established that Pavlovian conditioning is not a unitary phenomenon, but rather a composite of diVerent forms of learning occurring in parallel (Rescorla, 1988). For example, in the procedure used in these experiments, the CS can become associated with a representation of the food outcome, with aVective reactions produced by the food, and/or with the motor response necessary to obtain the food (Holland, 1990; Holland, 2004; Holland & Rescorla, 1975). Some or all of these associative processes

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may contribute to stimulant drug addiction (Everitt et al., 2001; White, 1996). It will be of interest in future experiments to determine speciWcally which of these associative processes are enhanced by amphetamine administration (e.g., Zorawski & Killcross, 2003). Given that amphetamine was administered systemically in these experiments, the speciWc brain systems in which it acted to enhance retention cannot be easily determined. Other studies have found that immediate post-training amphetamine injected directly into the shell of the nucleus accumbens or a D3 dopamine receptor agonist injected into the central nucleus of the amygdala can enhance retention in a Pavlovian conditioning task similar to that used here (Hitchcott, Bonardi, & Phillips, 1997; Phillips, Setzu, Vugler, & Hitchcott, 2003), and both basolateral amygdala and orbitofrontal cortex have also been implicated in associative processes involved in appetitive Pavlovian conditioning (Pickens et al., 2003). Immediate post-training amphetamine injections into other brain regions (dorsal striatum and hippocampus) can also enhance retention in other behavioral tasks (Packard, Cahill, & McGaugh, 1994). Determination of the neural loci of action of the eVects observed here will aid in determining the speciWc Pavlovian associative processes aVected by amphetamine administration (HatWeld, Han, Conley, Gallagher, & Holland, 1996; Setlow, Holland, & Gallagher, 2002). This procedure used in these experiments modeled the Pavlovian conditioning involved in drug addictive behavior, in which the emotional valence of a rewarding outcome (the drug) is transferred to neutral stimuli predictive of that outcome. The Wndings support the theory that druginduced enhancements in memory consolidation may facilitate the addictive potential of stimulant drugs of abuse, as stronger learned associations between drugs and drug-predictive cues should lead to stronger drug-related memories and aVect upon re-exposure to these cues. A thorough understanding of the inXuence of psychostimulant-induced enhancement of memory consolidation in addiction could prove valuable for developing treatments to decrease the control of drug-related cues over behavior. The potential to prevent or reverse these memory enhancing eVects (thereby decreasing the strength of associations between drug-predictive cues and drugs themselves) will require additional information regarding the speciWc associative processes enhanced by psychostimulants and the particular neural systems involved. Acknowledgments We thank the Drug Supply Program at the National Institute on Drug Abuse for kindly providing the Damphetamine sulfate, Ian Mendez, Hillary Owen, Chris Schaefer, Melanie Holsaeter and Valerie Newman for assistance with the experiments, and Drs. Mark Packard and Jennifer Bizon for their comments on the manuscript. Supported by a Proposal Planning Grant from Texas A&M University, and NIH DA018764.

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