1. Introduction

Societal problems associated with addiction include costs of physical and psychological treatment, loss of productivity and social cohesion, crime, and accidents [1-3]. In addition, there is growing recognition that drug addiction can result in a range of cognitive and behavioral alterations that can far outlast the period of drug use and may contribute to relapse [4-9]. Animal models of addiction have shown that chronic administration of psychostimulant drugs in particular can cause a variety of long-lasting alterations in drug-related behaviors. For example, it is very well documented that repeated psychostimulant administration can lead to long lasting enhancements (sensitization) of the locomotor stimulant response to these drugs [10-14]. Repeated psychostimulant administration can also enhance, or sensitize, behaviors motivated by drug rewards (incentives). This “incentive sensitization” may contribute to addiction via exaggerated drug “wanting” and motivation to pursue and use drug rewards [15-17].

Chronic exposure to psychostimulants is also associated with long-lasting increases in behavior directed by and toward non-drug rewards, including sex [18-20], gambling [21, 22], and food [23-28]. However, with few exceptions [18] these effects of psychostimulant exposure have been on appetitive (reward “seeking”) rather than consummatory (reward “taking”) components of reward-directed behavior. Moreover, there are several reports that chronic psychostimulant exposure can result in decreases in reward-directed behavior or anhedonia [29-33]. The purpose of the experiments reported here was two-fold: first, to determine how amphetamine exposure would affect both appetitive and consummatory components of behavior, and second, to determine whether a regimen of exposure to the psychostimulant drug amphetamine would cause lasting increases or decreases in reward-directed behavior.

2. Materials and Methods

3. Results

4. Discussion

The results of these experiments demonstrate that exposure to the psychostimulant drug of abuse amphetamine causes long lasting enhancements in both appetitive (“seeking”) and consummatory (“taking”) components of behavior directed toward a natural reward (food). Following one month of withdrawal, amphetamine exposed rats displayed higher levels of instrumental responding for food reward than saline exposed controls (specifically under high response ratio requirements), suggesting enhanced reward-directed motivation similar to that directed toward drug-related rewards following drug use [19, 26-28, 40-42]. Furthermore, under conditions of food satiation, amphetamine-exposed rats ate significantly more food than saline controls in an environment previously associated with food. These findings suggest that incentive sensitization resulting from repeated exposure to amphetamine similarly increases both appetitive (reward seeking) and consummatory (reward taking) behavior. It should be noted that the enhanced food consumption observed in the potentiated eating task was not likely due to enhanced “liking” of the food reward, as repeated drug exposure does not appear to enhance rewards' hedonic properties [25, 43]. Because enhanced consumption was only observed in the amphetamine exposed animals when tested in the food-paired context of the potentiated eating task under satiation conditions (and not during presentation of the food during the training sessions under conditions of food-restriction), it is perhaps more likely that this enhancement was due to enhanced control of motivation and behavior by the reward-associated context [23, 44]. Consistent with this idea, prior amphetamine exposure has been previously shown to have no effect on ad lib food consumption in a novel environment [27].

In a different group of rats, sensitization to the locomotor stimulant effects of acute amphetamine was observed 1 month following exposure to amphetamine using a regimen identical to that used for the instrumental and potentiated eating tasks. Although there was considerable variance associated with the small group sizes used for this experiment, we have shown previously in an experiment using larger group sizes that this amphetamine regimen induces locomotor sensitization [45]. Furthermore, although the experimental design did not afford the opportunity to directly address the relationship between incentive and locomotor sensitization in the current study, the fact that the amphetamine exposure regimen used was sufficient to induce both locomotor sensitization and enhanced instrumental responding for reward, at the same withdrawal timepoint [27, 45, 46], is consistent with the idea that both types of behavioral alterations were mediated by the same set of neural adaptations, likely within the mesoaccumbens dopamine pathway [46-49]. Because rats were tested in the potentiated eating task two months after amphetamine exposure, it is possible that amphetamine's effects on this task resulted from a separate set of neural alterations, as such alterations resulting from drug exposure are known to be time-dependent [13, 50, 51]. However, the fact that locomotor sensitization present at one month is reported to be stable for many months after [13], and the fact that performance across the instrumental and potentiated eating tasks was correlated, argues that amphetamine's effects on these two tasks were mediated through a common neural mechanism.

Some research has found that psychostimulant (including amphetamine) withdrawal is associated with decreased motivation for non-drug rewards, or anhedonia [29, 30, 32, 33, 36, 52]. However, we found no evidence for such decreased motivation resulting from amphetamine exposure. A resolution to this potential conflict may be found in the fact that anhedonia following drug administration is most commonly reported to occur within the first few days of withdrawal, whereas incentive sensitization effects are more frequently reported several weeks after drug exposure [10, 11, 13, 29, 31]. Notably, the decrease in motivation for non-drug rewards that can result from chronic amphetamine exposure appears to dissipate after a week of withdrawal [36, 52], whereas sensitization resulting from amphetamine exposure typically appears only after several weeks of withdrawal and may remain stable for weeks or even years thereafter [13, 51], suggesting that changes in reward motivation resulting from drug exposure follow a biphasic time course.

Amphetamine administration can produce reductions in food intake and subsequent weight loss, which might result in increased food intake during withdrawal [53]. However, it is unlikely that direct amphetamine-induced changes in food intake account for the present results as there were no differences in body weight between amphetamine exposed and control rats at the end of the one month amphetamine withdrawal period, and the two groups ate similar amounts of food during training sessions (when exposed to the paired context) in the potentiated eating task. It is also conceivable that the increase in reward-directed behavior in amphetamine exposed rats was a result of faster learning. Chronic amphetamine exposure can result in lasting increases in evoked dopamine release [18, 51], and increased activity at dopamine receptors can enhance memory through actions on consolidation processes [54, 55]. However, we found no evidence for faster acquisition of lever-pressing in amphetamine exposed rats, as they shaped at a rate similar to controls, and there were no differences in lever pressing under conditions of low response ratios. There was no comparable measure of acquisition in the potentiated eating task, and thus it is possible that amphetamine exposed rats ate more during the test sessions because they had more strongly acquired the association between the paired context and food availability. However, the fact that the context-potentiated eating effect was not significantly greater in the amphetamine exposed group argues against enhanced learning playing a significant role in amphetamine's effects in this task. It should be noted that in the potentiated eating task we did not observe a potentiating effect of the paired context on food consumption in either amphetamine exposed or saline control rats, suggesting that despite our efforts, the two contexts were insufficiently discriminable to obtain a reliable potentiated eating effect [35]. However, the fact that amphetamine exposure reliably enhanced food consumption only in the paired context suggests a possible interaction between the effects of food-paired contextual cues and amphetamine exposure.

The results of these experiments provide support for the concept of incentive sensitization, defined as an augmented assignment of motivational value to rewards and reward-related cues [14-16, 40]. Incentive sensitization has gained support as a mechanism that could explain the progression from casual to compulsive drug use. In concordance with this idea, sensitizing regimens of psychostimulant exposure result in subsequent increases in responding for drug rewards in animal models [40, 41, 56-58], and a similar relationship between prior stimulant exposure and subsequent drug use may exist in humans [59]. These experiments demonstrate that prior amphetamine exposure causes long-lasting enhancements in behavior directed by food reward. Amphetamine-induced neuroadaptations in brain systems underlying incentive motivation may cause rewards to gain enhanced incentive value (i.e. - exaggerated reward “wanting”, or incentive sensitization, perhaps equivalent to drug craving), leading to excessive reward pursuit and consumption. Such lasting incentive sensitization could account in part for the propensity for relapse in drug addiction, particularly in the presence of cues predictive of drug reward. Given the strong overlap between the neural circuitry mediating drug and non-drug rewards, it is not surprising that psychostimulant exposure results in similar increases in responding for non-drug rewards [18, 19, 23, 60]. Indeed, such effects may underlie some components of pathological non-drug reward-related behaviors frequently observed in addiction, such as excessive gambling [21, 22]. A better understanding of the development and expression of incentive sensitization could have considerable implications for the treatment of drug addiction and co-morbid behaviors.