Abstract
In the words of the late Charles Flaherty, reward comparison is commonplace. Rats and man, it appears, compare all rewards and this capacity likely contributes to our ability to select the most appropriate reward/behavior (food, water, salt, sex), at the most ideal level (e.g., a certain sweetness), at any given time. A second advantage of our predisposition for reward comparison is that the availability of rich alternative rewards can protect against our becoming addicted to any single reward/behavior. Thus, the potential protective effects of natural rewards/enrichment are addressed. Despite this, behavior can become inflexible when, through the development of addiction, stress, drug, or cues elicit craving, withdrawal, and ultimately, drug-seeking. Drug-seeking corresponds with a ‘window of inopportunity’, when even potent natural rewards have little or no impact on behavior. During this time, there is a unitary solution to the need state, and that solution is drug. The present animal model explores this ‘window of inopportunity’ when natural rewards are devalued and drug-seeking is engaged and considers a mode of possible intervention.
Addiction: The magnitude and nature of the problem
According to figures provided by the National Institute on Drug Abuse http://www.nida.nih.gov/Infofacts/index.html, in 2004, 34.2 million Americans used cocaine at least once, 7.8 million Americans used crack at least once, 2.4 million Americans used heroin (87% under the age of 26), and there were 450,000 current users of ecstasy. There were 14.6 million users of marijuana in 2004 and 70.3 million Americans smoking cigarettes. These large numbers are even more problematic because many individuals become addicted and addiction, more often than not, is not resolved following even extended periods of abstinence. In fact, addiction is a disease of chronic relapse [1], which costs society an estimated $484 billion dollars/year as the addict repeatedly cycles from addiction to abstinence, withdrawal, drug-seeking, and relapse. Clearly, recovery of even part of these dollars through the successful treatment of the disease would constitute quite an economic stimulus package.
Along with society, the addict and his or her family also are adversely affected because addiction is associated with an apparent devaluation of, and inattention to, natural rewards. According to DSM-IV, substance abuse and dependence involve a failure to fulfill major obligations at work, school, or home, the giving up of important social, occupational, or recreational activities, and continued drug use despite recurrent physical, legal, social, or psychological problems. This categorization is substantiated by published data showing that the human addict weighs less, is more often absent from work, fails to respond appropriately to monetary rewards, and more often has his or her children removed from the home due to neglect [2-5].
Natural rewards: Potential for hope
Although it is the case that drug-induced devaluation of natural rewards is an Achilles’ heel for the addict and devastating for his or her family, it also is true that natural rewards may be the addict’s best natural defense against substance abuse, addiction, and relapse. For example, Higgins et al. [6] have shown that abstinence is greatly improved when human drug addicts are given the opportunity to ‘work’ for (i.e., to stay abstinent for) tokens to purchase canoes, bicycles, or college credits, for example. The key, then, is to understand the conditions under which drugs devalue natural rewards and, alternatively, the conditions under which natural rewards might serve to protect against substance abuse and addiction. To this end, we continue to hone the first animal model for the systematic study of drug-induced devaluation of natural rewards[7, 8]. We will describe this model and discuss what has been learned about devaluation, drug-taking, and the potential protective effects of natural rewards on substance abuse, addiction, and relapse.
The Model: Experimenter delivered drug
Since the mid 1950s it has been known that rats avoid intake of a gustatory conditioned stimulus (CS), such as saccharin, after it has been paired with an aversive, illness-inducing agent such as lithium chloride (LiCl) or x-radiation [9-11]. This phenomenon, referred to as a conditioned taste aversion (CTA), was found to occur following a single taste-illness pairing and even when using relatively long intervals between access to the CS and exposure to the aversive unconditioned stimulus (US). As such, the phenomenon generated a great deal of controversy because it challenged then basic principles of animal learning theory.
It was amid this controversy scientists discovered that not only putatively aversive agents, but also drugs of abuse, suppress intake of a gustatory CS following repeated taste-drug pairings [12]. Effective drugs include morphine [13-15], cocaine [16], amphetamine [17], ethanol, flurazepam, chlordiazepoxide [14, 18, 19], nicotine [20], amobarbital and phenobarbital [19] and heroin [21]. Rats, then, avoid intake of a taste cue following pairings with not only LiCl, but also with all drugs of abuse tested, across a range of doses [22], when administered intraperitoneally (ip), subcutaneously (sc), intravenously (iv), and even, in some cases, when administered directly into the nucleus accumbens [17, 23-26].
Given the climate, this phenomenon also was interpreted, almost immediately, as a CTA [18]. Even so, it was viewed as highly paradoxical that such drugs, drugs that were readily self-administered by rats and man [27], also evidenced aversive properties in the CTA paradigm. Indeed, in three key experiments, avoidance of the taste cue was found to be accompanied, in the exact same study, by faster running for the drug [28], more time spent in the drug-paired compartment in a conditioned place preference task [29], and avid self-administration of the drug [24]. Since this time, additional evidence has been generated to show that addictive agents have aversive properties [25, 30, 31] and the aversive response to the taste cue following taste-drug pairings has been attributed to a range of factors including stimulus novelty, drug shyness (i.e., fear of novel drug or drug-induced state), fear [32], and positive conditioned suppression (i.e., where responding is suppressed by stimuli that precede the response-independent presentation of shock or food, for example) [33-36].
While it is the case that rats clearly avoid intake of a taste cue when paired with a putatively aversive US, such as LiCl, for example, in 1982 Flaherty and Checke [37] reported that rats also avoid intake of a saccharin CS when paired, in once daily sessions, with a highly preferred 32% sucrose solution. This phenomenon was referred to as an anticipatory contrast effect because reduced intake of the saccharin cue was thought to be due to anticipation of the availability of the preferred sucrose reward in the very near future. Indeed, in a subsequent within subjects study, it was shown that the reduction in intake of the taste cue depended upon the value of the 32% sucrose reward anticipated in the near future, not upon the memory of the 32% sucrose solution received 24 h earlier [38]. Anticipatory contrast effects, then, depend upon the development of a Pavlovian associative relationship between the saccharin CS and the sucrose US [39] and the lesser reward CS is avoided in anticipation of the imminent availability of the preferred reward US [39, 40].
Given this information, we hypothesized that rats avoid intake of a drug-associated taste cue because the value of the taste cue pales in comparison to the powerful drug reward anticipated in the very near future [7]. By way of indirect support, a great deal of data suggest that drugs of abuse are rewarding and that drug-induced suppression of CS intake is not like that induced by LiCl. Specifically, drugs of abuse are readily self-administered [for review, see 27] and they support the development of conditioned place preferences [41-44]. Unlike drugs of abuse that support a reduction in CS intake, but an increase in instrumental responding (as described above), LiCl suppresses both consummatory and instrumental responding [24, 28, 29]. Rats do not work for LiCl. Finally, as discussed previously [45], Parker [22, 46-49] used the Taste Reactivity test [50] and showed that intraoral delivery of a LiCl-paired CS led to both a decrease in ingestive responses (e.g., tongue protrusions, paw licking, and mouth movements) and an increase in active rejection responses (e.g., gapes, chin rubs, and paw treading). The intraoral delivery of a drug-associated CS, on the other hand, led to a decrease in ingestive responses, with no clear increase in active rejection responses [46-48, 51].
Dissociations of this nature argued against a CTA account, but did little to address the potential merits of the reward comparison hypothesis. To this end, we reasoned that if the reward comparison hypothesis was correct, then drug-induced suppression of CS intake should be sensitive to factors that affect anticipatory contrast effects. LiCl-induced CTAs, on the other hand, should be relatively impervious to these factors/manipulations. In accordance with this prediction, the suppressive effects of drugs of abuse and sucrose, but not those of LiCl, are greatly attenuated by food and water deprivation [52-55]. The suppressive effects of cocaine and sucrose, but not LiCl, are greater in drug sensitive Lewis, than less sensitive Fischer, rats [16, 56]. The suppressive effects of cocaine and sucrose, but not LiCl, are augmented in rats with a history of chronic morphine treatment [57]. Finally, bilateral lesions of the gustatory thalamus or gustatory cortex disrupt the suppressive effects of morphine, cocaine, and sucrose, but have no impact on the development of a LiCl-induced CTA [58-65]. Taken together, the data confirm that drug-induced suppression of CS intake is not mediated by a conditioned taste aversion like that induced by the aversive agent. To the contrary, avoidance of the gustatory CS appears to be due, at least in part, to drug-induced devaluation of the natural reward cue, much like that which occurs when a similar taste cue predicts the impending availability of a palatable sweet (see [45] for a full discussion of these data).
Of course, despite a number of parallels, drugs of abuse are not sweets. Moreover, while there is a great deal of evidence for overlap in the underlying neural substrates [66, 67], there also is evidence for separate circuits [68]. Drug-induced devaluation of CS intake (i.e., an anticipatory contrast-like mechanism), then, may contribute to avoidance of the drug-associated taste cue, but avoidance of the drug-associated taste cue also may be mediated by something else. Specifically, evidence suggests that onset of cue-induced craving and/or withdrawal may contribute to avoidance of the drug-associated taste cue. With experimenter-delivered drug, we have found that avoidance of a saccharin cue following a single saccharin-morphine pairing is accompanied by a full blunting of the accumbens dopamine response to the saccharin reward cue [69]. While negative contrast (reward devaluation) may contribute to this finding with dopamine [70], this blunting also could be explained by the onset of cue-induced craving and/or withdrawal because accumbens dopamine levels also are blunted following the onset of naltrexone-induced withdrawal [71]. Second, using experimenter-delivered drug, we have found large individual differences whereby some rats are more likely to avoid intake of the drug-associated taste cue than are others and greater avoidance of the taste cue is associated with greater cue-induced elevation of circulating corticosterone [72]. As with the dopamine data, the conditioned elevation in circulating corticosterone also could be interpreted as evidence of cue-induced craving and/or withdrawal because circulating corticosterone levels are known to be elevated during naloxone-precipitated withdrawal [73].
The Model: Drug self-administration
Although we have learned a great deal about drug-induced suppression of CS intake using the passive model of drug delivery, use of the drug self-administration paradigm has obvious advantages. At base, we predicted that greater avoidance of CS intake would be associated with greater drug self-administration if, as proposed by the reward comparison hypothesis, avoidance of the taste cue was due to anticipation of the rewarding properties of the drug. To test this hypothesis, rats were catheterized so they could ‘consume’ not only the saccharin cue, but also the cocaine US. Specifically, after 5 min access to 0.15% saccharin, the saccharin spout was withdrawn and an empty spout was advanced. The rats then could respond on a fixed ratio schedule of reinforcement where completion of 10 licks on the empty spout led to an iv infusion of cocaine (0.33 mg/infusion/1 h). As shown previously with slightly different procedures [24], rats suppressed intake of the saccharin CS following repeated daily pairings with self-administered cocaine. Moreover, as with the passive administration of drug [72], individual differences were evident whereby some rats (referred to as large suppressers) were more likely than others (referred to as the small suppressers) to avoid intake of the saccharin cue following daily saccharin-cocaine pairings. These individual differences in intake of the CS also were accompanied by individual differences in ‘intake’ of the drug. Specifically, greater avoidance of the taste cue, was correlated with greater cocaine self-administration and greater cocaine-seeking following a period of one to six months of abstinence [data not shown, see 8].
These drug self-administration data show that avoidance of the taste cue and the propensity to self-administer drug go hand-in-hand. This finding is in keeping with the hypothesis that the reduction in intake of the gustatory CS is due to the rewarding properties of the drug. Of course, it also is in keeping with the idea that, through classical conditioning, the taste cue comes to elicit cue-induced craving and/or withdrawal. The onset of cue-induced withdrawal following taste-naloxone pairings, however, is not only accompanied by avoidance of the taste cue, but also by frank aversive taste reactivity behavior following its intraoral delivery [74]. As stated, rats do not emit clear aversive orofacial responses following brief intraoral delivery of a taste cue paired with experimenter-delivered drug [22, 49, 75]. Whether self-administered drugs, on the other hand, would support the development of such conditioned aversive taste reactivity behavior, however, was not known. In an effort to address this question, we used a within subjects design where the intraoral delivery (200 ul every min over a 30 min period) of one flavored saccharin solution (the CS+) predicted the opportunity to self-administer cocaine for 2 h, while the intraoral delivery of another flavored saccharin solution (the CS-), on a different day, predicted the opportunity to self-administer saline for 2 h [76]. Following conditioning, taste reactivity behavior was measured after the intraoral infusion of the CS- and then the CS+ using an EMG electrode placed into the anterior digastric muscle (a requisite jaw opener) and videotape. Single unit activity also was recorded in real time using a fine microwire array in the nucleus accumbens. The results revealed aversive taste reactivity behavior (i.e., gapes) when the CS+ was infused intraorally at test and greater aversive taste reactivity behavior was associated with greater avoidance of the cocaine-associated taste cue when examined in a separate 2-bottle intake test. Moreover, greater aversive taste reactivity also predicted a shorter latency to take drug, greater within session load up behavior, and faster acquisition of steady state responding for cocaine. Finally, this shift in the affective response to the saccharin cue from reward to aversion was tracked by a similar shift in the coded response of single cells in the NAc from primarily inhibition (as seen with the intraoral delivery of putatively rewarding gustatory stimuli) to primarily excitation (as seen with the intraoral delivery of putatively aversive gustatory stimuli) [77].
Together, the data show that rats associate a taste cue with the availability of a drug of abuse following taste-drug pairings. Avoidance of the taste cue appears, at least in part, to be due to anticipation of the potent rewarding properties of the drug. Thus, the suppressive effects of sweets and drugs, but not LiCl, are similarly affected by the deprivation state of the rat, selectively bred strains (but see [45] for a discussion), a history of chronic morphine treatment, and lesions of the gustatory thalamocoritical pathway. Avoidance of a taste cue that predicts the availability of a highly preferred sucrose solution, however, is likely not one-in-the-same with avoidance of a taste cue that predicts the availability of a drug of abuse. Drugs of abuse have potent CNS properties and preparation for such a perturbation undoubtedly elicits the onset of a conditioned compensatory response [78]. In the absence of drug, the conditioned compensatory response can be experienced as withdrawal in rats and humans and can, in fact, be lethal [79-81]. Thus, we hypothesize that cue-induced craving and/or withdrawal contribute to avoidance of the taste cue following taste-drug pairings. As discussed, such an interpretation can account for avoidance of the taste cue (withdrawal is associated with anhedonia [82]), blunting of the accumbens dopamine response to the taste cue, elevated circulating corticosterone, and the onset of aversive taste reactivity following the intraoral delivery of the drug-associated cue. Were the animal in a state of cue-induced craving and/or withdrawal, the best correction for the onset of this aversive state would be drug. In accordance, and as discussed, greater avoidance of the taste cue and greater aversive taste reactivity was associated with a shorter latency to take drug, greater load-up, greater drug-taking, more rapid acquisition of drug self-administration and greater drug-seeking [8, 76]. Future studies will need to track the development of this conditioned compensatory response to determine how various factors might affect the individual propensity for drug-induced devaluation, cue-induced craving/withdrawal, drug-taking and drug-seeking over time.
Natural Rewards: The best natural defense against substance abuse, addiction, and relapse
As mentioned, while it is the case that drug addicted individuals pay too little attention to natural rewards including food, employment, money, and even caring for one’s offspring, it also is the case that natural rewards can provide great protection against drug taking, drug-seeking, and relapse. The goal here is to determine which natural rewards can be protective, when in development (e.g., adolescence and/or adulthood) they need to be presented to be protective, and whether they are effective in preventing disease in acquisition or in treating disease during maintenance and/or relapse. In general, it appears that all natural rewards can be protective. Drug self-administration is reduced by the availability of a sweet such as saccharin or a glucose + saccharin mixture [83-85]. Drug self-administration is reduced by the availability of a running wheel, particularly in females [86]. Finally, drug self-administration is reduced when rats simply are housed in an enriched environment offering conspecifics and novel objects [87-89].
Exposure to these natural rewards is protective when provided during adolescence and adulthood or when provided during adulthood alone. For example, environmental enrichment provided during adolescence and into adulthood reduces acquisition of drug self-administration behavior in rats [87-89]. Environmental enrichment also is protective in rats when provided during adulthood alone [90]. Sweets and even chow are protective when presented in adulthood concurrent with the opportunity to self-administer drug [83-85]. Finally, the sweets need not be concurrently available to be protective in adult rats. A history of brief daily access (5 min) to a highly palatable 1.0 M sucrose solution (but not 0.1 M sucrose) was sufficient to greatly reduce subsequent acquisition of drug-taking behavior in adult rats [91].
The availability of an alternative natural reward can reduce acquisition, maintenance, and reinstatement of drug-taking behavior. The concurrent availability of a highly palatable glucose + saccharin solution reduced both acquisition and maintenance of cocaine self-administration behavior [85]. Just prior availability of the glucose + saccharin solution reduced drug-induced reinstatement of cocaine-seeking behavior in adult rats [92]. Housing in an enriched environment has been shown to slow acquisition, facilitate extinction, and reduce subsequent drug-induced reinstatement of amphetamine self-administration in rats [87-90]. Finally, as mentioned, the opportunity to earn tokens for non-drug rewards greatly reduced relapse in a cocaine-addicted adult population of humans [6].
The ‘window of inopportunity’: When natural rewards are without effect
So, why if natural rewards are so remarkably protective do we have such a problem with substance abuse and addiction in American society? This circumstance has to do with the paucity of natural rewards/enrichment in some segments of our society, the failure to systematically use alternative natural rewards in the treatment of the disease, and perhaps most importantly, identification of a ‘window of inopportunity’ where alternative natural rewards, regardless of their inherent value, have little or no access to behavior. I will discuss this window, but before doing so must clearly state that, when presented outside of this relatively narrow window, natural rewards are very effective in protecting against acquisition, maintenance, and reinstatement (i.e., relapse) of drug-taking behavior.
So, what is this ‘window of inopportunity’? Basically, when stress, drug, or cues elicit seeking, all bets are off. This is the window of inopportunity. This is the time when natural rewards, no matter how powerful, fail to deter drug-seeking behavior. In our model, we know that 20 min access to a saccharin cue is sufficient to fully blunt the dopamine response to a first injection of morphine [69]. The sweet solution, then, can initially confer some protection against the potent rewarding properties of the drug. Over repeated trials, however, we also know that rats come to avoid the natural reward cue. This occurs because the natural reward, in this case, is a perfect predictor of drug availability. As such, the cue is avoided (it actually becomes aversive under certain conditions [76, 93]) and drug-seeking is initiated. As described, this shift in the affective response to the natural reward cue in the rat is accompanied by a shift in the neural code in single cells in the nucleus accumbens [76]. Likewise, nicotine-addicted humans also exhibit an aversive affective response when cues predict the future opportunity to smoke [94] and, at that time (i.e., when waiting to smoke), the caudate nucleus registers a smaller response to monetary gains and losses [95]. Natural rewards, then, have little impact when one is in anticipation of, or in pursuit of, drug. Indeed, when the drug-addicted animal or human is in a cue-induced state of craving and withdrawal the drug is the best, if not the only, means of correction.
Competing motivations: Closing the ‘window of inopportunity’
Drug-seeking animals and humans, then, behave as though they need the drug. They seek to satisfy this need state much as they seek food when hungry, water when thirsty, and salt when sodium deficient[65]. When these biological drive states are activated, there is a single goal and there can be no substitute. This is the state of the addict when actively engaged in drug-seeking. One means by which to derail this unitary goal-seeking behavior may be to elicit a competing biological need state. Along with satiety (e.g., a reduction in hunger by food intake), onset of a competing motivation (e.g., thirst or salt hunger) serves as an independent means by which to interrupt one ongoing motivated behavior to allow for another [96]. Relevant to this consideration, we have found that acute sleep deprivation completely prevents drug-induced reinstatement during extinction in low drug-taking rats [97]. The need for sleep may not be the drive of choice, but the data suggest that onset of a competing biological need state, such as thirst or salt need, for example, where attention to the new drive is paramount, may disengage drug-seeking behavior and, thereby, close this window of inopportunity. Further study is necessary to test the merits of this hypothesis.
Acknowledgments
The author would like to thank Matthew D. Puhl and Robert C. Twining for their comments on a draft of this manuscript. This work was supported by NIH grants DA09815 and DA12473.
Footnotes
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