- Email: [email protected]
Like drugs for chocolate
Physiology & Behavior 76 (2002) 389 – 395
Discussion
Like drugs for chocolate: Separate rewards modulated by common mechanisms? Patricia Sue Grigson* Department of Behavioral Science, Penn State College of Medicine, Hershey, PA 17033, USA Accepted 28 March 2002
It is difficult to imagine, at first glance, how single cells in the nucleus accumbens might come to selectively fire during cocaine-reinforced lever pressing. Are we to believe that there is, in fact, an innate circuit for cocaine that is separate from that mediating the response to natural rewards? This conclusion is particularly difficult to reconcile with the mass of published data providing evidence for common substrates [1– 4]. Indeed, the data in the first three manuscripts of this series provided strong evidence for overlap between the substrates mediating the rewarding properties of drugs of abuse and those of natural rewards, such as water, food, and sucrose. The following is a summary of these human and animal data showing that: (a) Opiates increase responsiveness to food. (b) Food intake increases the release of endogenous opiates. (c) Preference for sweets is highly correlated with preference for drugs. (d) Food restriction increases craving and drug self-administration behavior. (e) A sensitization-like response is induced by repeated exposure to drugs, foods, and food restriction. (f) Conditioned cues elicit craving for food and for drugs. We will then view these findings in light of the separate circuits revealed by Carelli’s more fine-grained electrophysiological analysis and consider a potentially unifying construct.
1. Opiates increase responsiveness to food As described by Pelchat and Kelley et al., opiates increase the perceived palatability of food in both humans and animals. Pelchat discussed data showing that treatment with opiate blockers decreased hedonic ratings of sugars and hedonic ratings of odors of palatable foods in humans [5,6]. Kelley et al. also cited human data showing that treatment with an opiate antagonist reduced the preference for sweet high-fat foods in bulimics, obese bulimics, and normal weight controls [7]. Parallel findings have been reported
* Tel.: +1-717-531-5772; fax: +1-717-531-6916. E-mail address: [email protected] (P.S. Grigson). 0031-9384/02/$ – see front matter D 2002 Published by Elsevier Science Inc. PII: S 0 0 3 1 - 9 3 8 4 ( 0 2 ) 0 0 7 5 8 - 8
for rats. According to Kelley et al., it has been known for decades that the peripheral administration of opiates increases food intake in rats [8]. In addition to peripheral administration, Kelley et al. demonstrated that opiates administered directly into the nucleus accumbens also increase intake of palatable substances such as sucrose, saccharin, fat, or salt. This effect, as with the human data, was blocked by pretreatment with a mu opiate antagonist. Finally, according to Kelley et al., this opiate-induced increase in intake in rats also is accompanied by an increase in appetitive behaviors in the taste reactivity test, indicating an increase in palatability [9], and by an increase in break point, indicating an increase in the willingness to work for food. Opiates, then, increase the apparent palatability of a natural reward, the willingness to work for that natural reward, and once given access, ingestion of the natural reward as well.
2. Food intake increases the release of endogenous opiates Not only do opiates increase responding for food, but both Pelchat and Kelley et al. described data showing that ingestion of food (particularly sweets) can induce the release of endogenous opiates as well. Consumption of sugar water reduced crying when human infants received a heal stick, and this effect was blocked by treatment with an opiate antagonist [10]. In rats, chronic sucrose intake enhances morphine-induced analgesia [11,12]. Kelley et al. showed that repeated exposure to chocolate Ensure (3 h/day for 2 weeks) lead to a decrease in the expression of preproenkephalin (PPE) in the nucleus accumbens core and shell, the lateral striatum and the dorsal striatum. PPE is a precursor peptide for enkephalin synthesis in enkephalin-containing neurons. Kelley et al. suggested that the decrease in PPE reflects a compensatory mechanism in response to repeated Ensure-induced release of opioid peptide. Support for this suggestion is provided by the finding that chronic exposure to morphine, like chocolate Ensure, also has been reported
390
P.S. Grigson / Physiology & Behavior 76 (2002) 389–395
to lead to a decrease in the expression of PPE, in this case, in the locus coeruleus [13].
3. Preference for sweets is highly correlated with preference for drugs As discussed by Pelchat, Kelley et al. and Carr, the liking for sweets is highly correlated with the liking for, and the response to, drugs of abuse and alcohol. According to Pelchat, liking for sweets is related to liking for alcohol in humans and humans with a family history of alcoholism exhibit peak preference for a higher concentration of sucrose than do individuals who are family history negative [14]. In addition, there also is a high degree of comorbidity between eating disorders and drug and alcohol abuse in humans [15,16]. Bulik [17] reported that 34.3% of the bulimic subjects tested were drug dependent and 48.6% abused alcohol compared with 2.9% and 8.6% of the control population, respectively. Similar patterns between the preference for sweets and responsiveness to drugs of abuse have been reported in rats. As discussed by Carr, the propensity to ingest sweets predicts the locomotor activating effects of psychostimulants and the rapidity with which rats acquire drug self-administration [18 –20]. These data provide further evidence that responding for drugs of abuse is enmeshed with the natural reward substrate.
4. Food restriction increases craving and drug self-administration behavior The data described by both Pelchat and Carr show that food restriction clearly augments craving in humans and responsiveness for drugs of abuse in rats. Pelchat showed that food restriction (i.e., access to a bland diet) increased craving in humans. Similarly, Pelchat cited data showing that craving for chocolate or a vanilla-flavored beverage was augmented in humans with a history of eating the chocolate or the vanilla beverage when hungry [21,22]. Consuming the food when in a state of hunger, then, may increase the probability that a human will exhibit craving for the food at a later date. Consistent with the human data, food restriction increases responsiveness for drugs of abuse in animals. As discussed by Carr, food restriction augments the development of a conditioned place preference for drugs of abuse, drug self-administration, locomotor activating effects, the threshold lowering effects in LHSS and the accompanying cellular activating effects [23 –28]. Carr showed that these facilitatory effects of food restriction on the actions of drugs of abuse in the LHSS paradigm are pervasive, occurring with amphetamine, MK-801, cocaine and DPDPE. Finally, in addition to increasing responsiveness for drugs of abuse, recent data show that food restriction also can induce reinstatement of cocaine-seeking behavior following a period of abstinence [29].
5. A sensitization-like response is induced by repeated exposure to drugs, foods and food restriction Sensitization refers to an increase in the response to a stimulus as a function of repeated exposure to that stimulus. Given that dependence upon a drug of abuse generally increases with repeated exposure to the drug, the behavioral expression of sensitization, and the underlying mechanisms, have been important areas of study in addiction research. Repeated exposure to a drug of abuse leads to an increase in the locomotor activating effects of drugs [30], an increase in the appetite stimulating effect of opiates (Kelley et al., this issue) and an increase in the rewarding properties of the drug as measured by conditioned place preference [31] or drug self-administration behavior [32]. As with repeated exposure to drugs of abuse, repeated exposure to natural rewards also can lead to ‘addiction-like’ responses. As discussed above, Kelley et al. showed that repeated exposure to chocolate Ensure (3 h/day for 2 weeks) lead to a decrease in the expression of PPE in reward-related structures. As discussed, this may reflect a compensatory response to repeated Ensure-induced release of endogenous opiates. Dimitriou et al. [33] showed that repeated access to fat (2 h/day on Monday, Wednesday and Friday) lead to binge-like ingestive behavior. Similarly, Hoebel et al. [34] provided evidence for naloxone-precipitated withdrawal in rats with a history of repeated access to a palatable glucose solution. Finally, like repeated exposure to drugs or food, Carr reported that chronic food restriction also lead to ‘sensitization’ of the rewarding efficacy of drugs of abuse. As discussed, this ‘sensitization’ was reversed following a week of refeeding. Thus, repeated exposure to drugs of abuse, natural rewards (e.g., fat or glucose) or even chronic food restriction can lead to sensitization, a potential behavioral and physiological manifestation of addiction.
6. Conditioned cues elicit craving for food and drugs As discussed, addiction is a disease of chronic relapse, and craving, induced by exposure to drug-related cues, is one of the primary precipitating factors in relapse. According to Pelchat, craving in humans is conditionable such that cravings for food increase in the presence of food-related cues including the sight, the smell, or even the imagery of the craved food [35,36]. Pelchat and Schaefer [22] showed that these cravings can occur in the absence of need. In addition to food, addicted humans also exhibit cravings for drugs of abuse following exposure to drug-related cues [37]. Similar findings have been widely reported in rats where exposure to drug-related cues leads to an increase in drugseeking behavior [38 – 40]. Carelli reported consistent findings. Presentation of the auditory/light cue that had been paired with the infusion of cocaine led to an increase in firing of single cells in the nucleus accumbens and the pattern of activity mirrored that which was exhibited when
P.S. Grigson / Physiology & Behavior 76 (2002) 389–395
the rat was responding for cocaine. Park and Carr [41] reported that ingestion of a small palatable meal and exposure to the meal-paired environment induced a similar pattern of c-Fos expression in the ventral tegmental area. Both of these responses were blocked by naloxone, suggesting an opioid –dopamine linkage in the response to food reward and food-related cues. Finally, Kelley et al. provided evidence for conditioning, and for common substrates as well, by showing that exposure to a nicotine- or a chocolatepaired context increased the expression of Fos in similar regions in the brain. Thus, exposure to food- or drug-related cues can lead to food and drug craving in humans, drugseeking in rats, activation of accumbens neurons, and the expression of Fos activity in reward-related structures.
7. Separate cells/separate circuits On the basis of the four manuscripts alone, a mediating role in reward processing has been implicated for the orbital frontal cortex, central nucleus of the amygdala, hypothalamus, ventral tegmental area, nucleus accumbens and nucleus of the solitary tract. These data suggest that the ‘reward circuit’ is complex and that multiple interconnected regions may be involved in the response to natural rewards and to drugs of abuse. In spite of this evidence, however, Carelli’s electrophysiological data in the nucleus accumbens clearly showed that nearly all neurons that responded to sucrose also responded to food and to water, but only 8% of the cells that responded to cocaine also responded to these natural rewards. Thus, the neurons in the nucleus accumbens that respond to natural rewards are largely separate from those that respond to cocaine. Although these data seem at odds with those contributing to the above discussion, the dissociation of mechanisms mediating natural rewards and drugs of abuse is not unprecedented. Caine and Koob [42] showed that a 6-OHDA lesion of the nucleus accumbens selectively reduced operant responding for cocaine while leaving operant responding for food intact. Wojnicki et al. [43] reported that treatment with phentermine decreased cocaine-maintained, but not food-maintained, responding in rhesus monkeys. As discussed, stress induced by foot shock will reinstate drug-seeking behavior [29]. It will not, however, reinstate responding maintained by food [44,45] or responding maintained by sucrose [46]. Finally, Chiamulera et al. [47] recently showed that mGluR5 receptor knockout mice failed to exhibit either cocaine-induced hyperactivity or cocaine self-administration behavior, but responding for food was intact. Even so, it is difficult to accept that a subset of neurons in the nucleus accumbens is prepared to code selectively for drugs of abuse, in this case, cocaine. Why, or how, might this be so? Surely, the brain is not designed to detect and respond to drugs of abuse. Or is it? Three hypotheses might be proposed for the interpretation of the Carelli data. First, the activity of the ‘cocaine cells’ may, in fact, relate to the
391
nature of the stimulus and, while these cells are not sensitive to food, water, or sucrose, they may be sensitive to another natural reward such as sex, for example. Carelli has considered, but has not yet tested, this hypothesis. A second hypothesis is that the activity of the ‘cocaine cells’ relates to the intensity, rather than to the nature, of the stimulus. In this light, it is not unreasonable to suppose that the intravenous infusion of cocaine was more intense than was brief access to food, water, or even a palatable sucrose solution. Of course, the intravenous administration of heroin should presumably rival the intravenous administration of cocaine in intensity, but Chang et al. [48] reported that heroin and cocaine also are encoded by different cells in the nucleus accumbens and in the medial prefrontal cortex. This finding indicates that there is not a simple natural reward versus drug of abuse dichotomy in the nucleus accumbens and that coding for intensity is not likely the explanation. This leads to a third, and very interesting, hypothesis. Perhaps single cells in the nucleus accumbens (and possibly in other structures as well) are like stem cells, so to speak, a clean slate waiting to ‘imprint’ upon (code for) any stimulus in the environment that might be deemed rewarding. This idea is intriguing, given the range of stimuli that human beings and animals find rewarding, and the need for plasticity—i.e., the need for adjustment with changing requirements, availability of resources, and experience. Although to the author’s knowledge, this type of plasticity has not been considered previously for reward-sensitive cells in the nucleus accumbens (or elsewhere), the dynamic effect of experience on the activity of hippocampal place cells, for example, is well documented [49,50]. Perhaps it is just this type of plasticity that is required to seek the range of rewards necessary for life, such as salt, calcium, potassium, amino acids, iron, sweets, food, water, warmth and a mate. Further studies will be required to test this hypothesis and to determine whether the code for a given rewarding stimulus is static or, alternatively, whether it can be modified ‘online’ by changing need states (e.g., by the rapid onset of insulin-induced hypoglycemia or by sodium depletion induced by the intracerebroventricular administration of angiotensin II).
8. A model If we accept that any rewarding stimulus, regardless of its nature, will be encoded by particular cells in the nucleus accumbens (in rats, the same cell in the nucleus accumbens may encode for food, water, and sucrose because rats are prandial eaters, i.e., they drink when they eat), we still must consider how it is that drugs of abuse so readily and persistently gain control of the behavior of the organism. Humans and animals alike have the opportunity to engage in a range of behaviors at any given time. They do, however, typically engage in only one motivated behavior at any one time. They eat, or they drink, they copulate, or they tend to their young. While each of these motivated behaviors is
392
P.S. Grigson / Physiology & Behavior 76 (2002) 389–395
mediated by very different substrates [51 –57], ultimately, the behaviors must be compared by some common substrate so that the most appropriate (i.e., the most rewarding) behavior can come to the fore. According to Cabanac [58], ‘‘access to behavior is assigned to the motivation that is strongest at a given point in time’’. So what is the nature of this common substrate and why are drugs of abuse so compelling for some animals and for some humans? The following is a model for consideration. The model will need to be tested, where possible, and the mechanisms delineated. Some of the premises have been posed before and others have not. The general premises of the model are as follows: (1) Naturally motivated behaviors (e.g., food intake, water intake, sodium appetite, and sexual behavior) have independent mechanisms for response initiation and termination (see Fig. 1). (2) These self-regulated systems, however, are not completely independent of one another. By sharing a common reward circuit (see Fig. 2), activation of one of these motivational systems can simultaneously inhibit the others (e.g., engaging in eating behavior will inhibit sexual activity). (3) Although each motivated behavior has its own internal mechanism for satiety, along with some inhibition from other activated behaviors, the common reward substrate, itself, by nature, has no means for ‘satiety’ because this substrate needs to be able to be continuously activated by ever changing motivational systems as the animal seamlessly switches from one motivated behavior to another. Smith [59] recently has provided careful microstructural data documenting the behavior of rats as they switch from feeding to drinking and vice versa. (4) This essential feature (i.e., that the reward substrate is, by nature, prepared for continuous activation) is the Achilles’ heel for the addicted subject because drugs of abuse act directly upon this reward substrate. Thus, although there is evidence for within session regulation of drug selfadministration behavior in rats (for a brief review, see Ref. [3]), there appears to be little or no internal means of ‘satiety’ because drug self-administration behavior escalates greatly when the daily access period is lengthened [60] and unlimited access can result in death [61]. Indeed, while
Fig. 1. Naturally motivated behaviors (e.g., food intake, water intake, salt intake, or sexual behavior) have mechanisms to initiate (+) responding and to inhibit ( ) responding (i.e., satiety) as well.
Fig. 2. These motivated behaviors, however, are not fully independent of one another. By sharing a common reward circuit, activation of one of these motivational systems simultaneously inhibits engagement in others. By comparison, the common reward circuit has no real means for ‘satiety’, because it must be able to be continuously activated as the organism switches from one motivated behavior to another.
human cocaine addicts tend to ‘binge’ and ‘crash’, Gawin et al. [62] reported that a cocaine binge in humans generally ends ‘‘only when all accessible supplies are exhausted’’. (5) When drugs of abuse are on board or, in particular, when an animal or human is engaged in drug-seeking behavior, important competing motivational systems are inhibited (see Fig. 3). In accordance, drug-addicted humans are more often absent from work and more often have their children removed from the home due to neglect [63,64]. Drug-addicted humans also weigh less [65]. Thirsty rats avoid intake of a palatable saccharin cue when it predicts the opportunity to self-administer cocaine [66] and, when tested on Postpartum Day 16, lactating female rats prefer a cocaine-paired environment to an environment that has been paired with their own pups [67]. (6) Finally, while there is no direct means of ‘satiety’ for drug-related behavior, there remains a critical indirect means of inhibition whereby powerful natural rewards can, in some circumstances, come to override responding for a drug of abuse (see Fig. 4). For example, Carroll et al. [68] and Carroll and Lac [69] showed that simultaneous access to a highly palatable gustatory stimulus, such as a glucose+saccharin mixture, delays acquisition and maintenance of
Fig. 3. When drugs of abuse are on board, or when an animal or a human is engaged in drug-seeking behavior, competing motivational systems are inhibited.
P.S. Grigson / Physiology & Behavior 76 (2002) 389–395
Fig. 4. Although there is no direct means for ‘satiety’ of drug-related behavior, there is an essential indirect means of inhibition whereby powerful natural rewards (e.g., a highly palatable glucose+saccharin mixture) can, in some circumstances, come to override responding for a drug of abuse.
cocaine self-administration. Nader and Woolverton [70] showed that the availability of an alternative food reinforcer decreased total drug intake in rhesus monkeys. Similarly, Higgins et al. [71] showed that the availability of vouchers for ski lift passes or higher education, for example, decreased cocaine use (i.e., increased abstinence) in humans.
9. Summary and conclusions There is a great deal of evidence for interaction across motivated systems and the interaction can lead to either a facilitation or an inhibition of responding. The change in responding for one reward as a consequence of having experience with another reward is, itself, evidence for a common substrate. The circuitry of two motivated behaviors may be linked for several reasons. First, they may work in concert as a regulatory system. Thus, it is not surprising that food intake has a direct effect on the ingestion of fluid [72,59]. Water intake can affect salt intake and salt intake generally is accompanied by water intake [73,74]. Second, two motivational systems may interact because of a single common underlying mechanism of action. As discussed, opiate action on the mu receptor is important in food intake and Kelley et al. clearly demonstrated that the central administration of a selective mu agonist increased intake of a range of palatable food sources. Similarly, although the mechanism is more complicated, the data of Pelchat and Carr show that food restriction has a direct effect on craving for food in humans and responsiveness to the rewarding properties of a range of drugs of abuse as well. Of interest, is whether food deprivation also would facilitate the expression of other motivated behaviors (i.e., whether food deprivation activates a general motivational system). Finally, two motivational systems may interact because, although mediated by distinct mechanisms of action, they ultimately must engage the same final common pathway to
393
gain access to behavior. A reward comparison effect (i.e., the adjustment in responding for one stimulus as a consequence of having experienced another) serves as a clear example of this type of interaction between rewards and, consequently, as a window on the underlying common substrate. Reward comparison is commonplace. It can occur between different levels of the same type of reward (for a review, see Ref. [75]), leading to exaggerated increases or decreases in behavior, and across different motivated behaviors as well [76,77]. With respect to addiction, this reward comparison process is both our heartbreak and our hope. As described, drugs of abuse can override responding for natural rewards. Addicted humans often weighs less, and their children are more often removed from the home due to neglect. The addicted rat will forego intake of an otherwise palatable saccharin solution when waiting for the opportunity to self-administer cocaine [66]. On the other hand, the simultaneous availability of a highly palatable glucose+saccharin mixture, food or even vouchers greatly reduces cocaine self-administration behavior in rats, monkeys and man, respectively [68,70,71]. Finally, it must be noted that comparison of rewards, whether to advantage or detriment, requires accurate identification of the nature and the intensity of the stimuli. It is in this capacity, then, that the nucleus accumbens may contribute to reward comparison and, ultimately, response output. As such, Carelli’s data show that the activity of single cells tracks different reward types, Geary and Smith [78] showed that responsiveness for a 10% sucrose solution is disrupted (essentially halved) following the administration of a dopamine antagonist, and Mogensen [79] has suggested that the accumbens ‘‘translates the motivational determinants of behavior, mediated by the limbic system, into actions’’.
Acknowledgments The author wishes to thank the National Institute on Drug Abuse for sponsoring the symposium held at the meeting of the Society for the Study of Ingestive Behavior in June 2001 and for their support (DA 09815 and DA 12473). Appreciation also is given to Anne Baldwin, Robert C. Twining, Robert A. Wheeler, Gina Carelli, Ann Kelley, and Ken Carr for reading a draft of the manuscript.
References [1] DiChiara G, Acquas E, Tanda G, Cadoni C. Drugs of abuse: biochemical surrogates of specific aspects of natural rewards? Biochem Soc Symp 1993;59:65 – 81. [2] Schroeder BE, Binzak JM, Kelley AE. A common profile of prefrontal cortical activation following exposure to nicotine- or chocolateassociated contextual cues. Neuroscience 2001;105:535 – 45. [3] Wise RA. Drug self-administration viewed as ingestive behaviour. Appetite 1997;28:1 – 5. [4] Wise RA. Drug-activation of brain reward pathways. Drug Alcohol Depend 1998;51:13 – 22.
394
P.S. Grigson / Physiology & Behavior 76 (2002) 389–395
[5] Fantino M, Hosotte J, Apfelbaum M. An opioid antagonist, naltrexone, reduces preference for sucrose in humans. Am J Physiol 1986; 251:R91 – 6. [6] Yeomans MR, Gray RW. Effects of naltrexone on food intake and changes in subjective appetite after eating: evidence for opioid involvement in the appetizer effect. Physiol Behav 1997;62:15 – 21. [7] Drewnowski AD, Krahn DD, Demitrack MA, Nairn K, Gosnell BA. Taste responses and preferences for sweet high-fat foods: evidence for opioid involvement. Physiol Behav 1992;51:371 – 9. [8] Martin WR, Wikler A, Eades CG, Pescor FT. Tolerance to the physical dependence on morphine in rats. Psychopharmacology 1963;4: 247 – 60. [9] Doyle TG, Berridge KC, Gosnell BA. Morphine enhances hedonic taste palatability in rats. Pharmacol Biochem Behav 1993;46:745 – 9. [10] Blass EM, Hoffmeyer LB. Sucrose as an analgesic for newborn infants. Pediatrics 1991;87:215 – 8. [11] D’Anci KE, Kanarek RB, Marks-Kaufman R. Duration of sucrose availability differentially alters morphine-induced analgesia in rats. Pharmacol Biochem Behav 1996;54:693 – 7. [12] Kanarek RB, Mandillo S, Wiatr C. Chronic sucrose intake augments antinoception induced by injections of mu but not kappa opioid receptor agonists into the periaqueductal gray matter in male and female rats. Brain Res 2001;920:97 – 105. [13] Van Bockstaele EJ, Peoples J, Menko AS, McHugh K, Drolet G. Decreases in endogenous opioid peptides in the rat medullo-coerulear pathway after chronic morphine treatment. J Neurosci 2000;20: 8659 – 66. [14] Kampov-Polevoy AB, Garbutt JC, Janowsky DS. Association between preference for sweets and excessive alcohol intake: a review of animal and human studies. Alcohol Alcohol 1999;34:386 – 95. [15] Loxton NJ, Dawe S. Alcohol abuse and dysfunctional eating in adolescent girls: the influence of individual differences in sensitivity to reward and punishment. Int J Eat Disord 2001;29:455 – 62. [16] Wolf WL, Maisto SA. The relationship between eating disorders and substance use: moving beyond co-prevalence research. Clin Psychol Rev 2000;20:617 – 31. [17] Bulik CM. Drug and alcohol abuse by bulimic women and their families. Am J Psychiatry 1987;144:1604 – 6. [18] Gosnell BA. Sucrose intake predicts rate of acquisition of cocaine self-administration. Psychopharmacology 2000;149:286 – 92. [19] Gosnell BA, Lane KE, Bell SM, Krahn DD. Intravenous morphine self-administration by rats with low versus high saccharin preferences. Psychopharmacology 1995;117:248 – 52. [20] Sills TL, Vaccarino FJ. Individual differences in sugar intake predict the locomotor response to acute and repeated amphetamine administration. Psychopharmacology 1994;116:1 – 8. [21] Gibson EL, Desmond E. Chocolate craving and hunger state. Appetite 1999;32:219 – 40. [22] Pelchat ML, Schaefer S. Dietary monotony and food cravings in young and elderly adults. Physiol Behav 2000;68:353 – 9. [23] Bell SM, Stewart RB, Thompson SC, Meisch RA. Food-deprivation increases cocaine-induced conditioned place preference and locomotor activity in rats. Psychopharmacology 1997;131:1 – 8. [24] Carroll ME, Meisch RA. Determinants of increased drug self-administration due to food deprivation. Psychopharmacology 1984;74: 197 – 200. [25] Carr KD, Kim G-Y, Cabeza de Vaca S. Chronic food restriction in rats augments the central rewarding effects of cocaine and the delta1 opioid agonist, DPDPE, but not the delta2 agonist, deltorphin-II. Psychopharmacology 2000;152:200 – 7. [26] Carr KD, Kutchukhidze N. Chronic food restriction increases Fos-like immunoreactivity (FLI) induced in rat forebrain by intraventricular amphetamine. Brain Res 2000;861:88 – 96. [27] Carr KD, Kutchukhidze N. Effect of chronic food restriction on Foslike immunoreactivity (FLI) induced in rat brain regions by intraventricular MK-801. Brain Res 2000;8763:283 – 6. [28] Deroche V, Piazza PV, Casolini P, Le Moal M, Simon H. Sensitization
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
[40]
[41]
[42]
[43]
[44]
[45]
[46]
[47]
to the psychomotor effects of amphetamine and morphine induced by food restriction depends upon corticosterone secretion. Brain Res 1993;611:352 – 6. Shalev U, Highfield D, Yap J, Shaham Y. Stress and relapse to drug seeking in rats: studies on the generality of the effect. Psychopharmacology 2000;150:337 – 46. Vanderschuren LJMJ, Tjon GHK, Nestby P, Mulder AH, Schoffelmeer ANM, De Vries TJ. Morphine-induced long-term sensitization to the locomotor effects of morphine and amphetamine depends on the temporal pattern of the pretreatment regimen. Psychopharmacology 1997;131:115 – 22. Lett BT. Repeated exposures intensify rather than diminish the rewarding effects of amphetamine, morphine, and cocaine. Psychopharmacology 1989;98:357 – 62. Horger BA, Shelton K, Schenk S. Preexposure sensitizes rats to the rewarding effects of cocaine. Pharmacol Biochem Behav 1990;37: 707 – 11. Dimitriou SG, Rice HB, Corwin RL. Effects of limited access to a fat option on food intake and body composition in female rats. Int J Eat Disord 2000;28:436 – 45. Hoebel BG, Patten CS, Colantouni C, Rada PV. Sugar withdrawal causes symptoms of anxiety and acetylcholine release in the nucleus accumbens. Soc For Neurosci Abstr 2000;26:1340. Fedoroff IC, Polivy J, Herman CP. The effect of pre-exposure to food cues on the eating behavior of restrained and unrestrained eaters. Appetite 1997;28:33 – 47. Tuomisto T, Hetherinton MM, Morris MF, Tuomisto MT, Turjanmaa R, Lappalainen R. Psychological and physiological characteristics of sweet food ‘‘addiction’’. Int J Eat Disord 1999;25:169 – 75. Ehrman RN, Robbins SJ, Childress AR, O’Brian CP. Conditioned responses to cocaine-related stimuli in cocaine abuse patients. Psychopharmacology 1992;107:523 – 9. Gracy KN, Dankiewicz LA, Weiss F, Koob GF. Heroin-specific stimuli reinstate operant heroin-seeking behavior in rats after prolonged extinction. Pharmacol Biochem Behav 2000;65:489 – 94. Meil WM, See RE. Lesions of the basolateral amygdala abolish the ability of drug associated cues to reinstate responding during withdrawal from self-administered cocaine. Behav Brain Res 1997;87: 139 – 48. Neisewander JL, Baker DA, Fuchs RA, Tran-Nguyen LTL, Palmer A, Marshall JF. Fos protein expression and cocaine-seeking behavior in rats after exposure to a cocaine self-administration environment. J Neurosci 2000;20:798 – 805. Park TH, Carr KD. Neuroanatomical patterns of fos-like immunoreactivity induced by a palatable meal and meal-paired environment in saline- and naltrexone-treated rats. Brain Res 1998;14:169 – 80. Caine SB, Koob GF. Effects of mesolimbic dopamine depletions on responding maintained by cocaine and food. J Exp Anal Behav 1994;61:213 – 21. Wojnicki FHE, Rothman RB, Rice KC, Glowa JR. Effect of phentermine on responding maintained under multiple fixed-ratio schedules of food and cocaine presentation in the rhesus monkey. J Pharmacol Exp Ther 1999;288:550 – 60. Ahmed SH, Koob GF. Cocaine- but not food-seeking behavior is reinstated by stress after extinction. Psychopharmacology 1997;132: 289 – 95. Mantsch JR, Goeders NE. Ketoconazole blocks the stress-induced reinstatement of cocaine-seeking behavior in rats: relationship to the discriminative stimulus effects of cocaine. Psychopharmacology 1999; 142:399 – 407. Buczek Y, Le AD, Wang A, Stewart J, Shaham Y. Stress reinstates nicotine seeking but not sucrose solution seeking in rats. Psychopharmacology 1999;144:183 – 8. Chiamulera C, Epping-Jordan MP, Zocchi A, Marcon C, Cottiny C, Tacconi S, Corsi M, Orzi F, Conquet F. Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice. Nat Neurosci 2001;4:873 – 4.
P.S. Grigson / Physiology & Behavior 76 (2002) 389–395 [48] Chang JY, Janak PH, Woodward DJ. Comparison of mesocorticolimbic neuronal responses during cocaine and heroin self-administration in freely moving rats. J Neurosci 1998;18:3098 – 115. [49] O’Keefe J, Dostrovsky J. The hippocampus as a spatial map: preliminary evidence from unit activity in the freely-moving rat. Brain Res 1971;34:171 – 5. [50] Ekstrom AD, Meltzer J, McNaughton BL, Barnes CA. NMDA receptor antagonism blocks experience-dependent expansion of hippocampal ‘‘place fields’’. Neuron 2001;31:631 – 8. [51] Eisen S, Davis JD, Rauhofer E, Smith GP. Gastric negative feedback produced by volume and nutrient during a meal in rats. Am J Physiol 2001;281:R1201 – 14. [52] Murphy AZ, Hoffman GE. Distribution of gonadal steroid receptorcontaining neurons in the preoptic-periaqueductal gray – brainstem pathway: a potential circuit for the initiation of male sexual behavior. J Comp Neurol 2001;438:191 – 212. [53] Nicolaidis S, Rowland N. Intravenous self-feeding: long-term regulation of energy balance in rats. Science 1977;195:589 – 91. [54] Norgren R. Gustatory system. In: Paxinos G, editor. The rat nervous system. 2nd ed. San Diego (CA): Academic Press, 1995. p. 751 – 71. [55] Stricker EM, Sved AF. Thirst. Nutrition 2000;16:821 – 6. [56] Johnson AK, de Olmos J, Pastuskovas CV, Zardetto-Smith AM, Vivas L. The extended amygdala and salt appetite. Ann NY Acad Sci 1999;877:258 – 80. [57] Woods SC, Seeley RJ. Adiposity signals and the control of energy homeostasis. Nutrition 2000;16:894 – 902. [58] Cabanac M. Emotion and phylogeny. Jpn J Physiol 1999;49:1 – 10. [59] Smith JC. Microstructure of the rat’s intake of food, sucrose and saccharin in 24-hour tests. Neurosci Biobehav Rev 2000;24:199 – 212. [60] Ahmed SH, Koob GF. Long-lasting increase in the set point for cocaine self-administration after escalation in rats. Psychopharmacology 1999;146:303 – 12. [61] Johanson C-E, Fischman MW. The pharmacology of cocaine related to its abuse. Pharm Rev 1989;41:3 – 52. [62] Gawin FH, Herbert MD, Kleber MD. Abstinence symptomology and psychiatric diagnosis in cocaine abusers. Arch Gen Psychiatry 1986; 43:107 – 13. [63] Jones S, Casswell S, Zhang J-F. The economic costs of alcohol-related absenteeism and reduced productivity among the working population of New Zealand. Addiction 1995;90:1455 – 61. [64] Nair P, Black MM, Schuler M, Keane V, Snow L, Rigney BA. Risk factors for disruption in primary care giving among infants of substance abusing woman. Child Abuse Neglect 1997;21:1039 – 51.
395
[65] Santolaria-Fernandez FJ, Gomez-Sirvent JL, Gonzalez-Reimers CE, Batista-Lopez JN, Jorge-Hernandez JA, Rodriguez-Moreno F, Martinez-Riera A, Hernandez-Garcia MT. Nutritional assessment of drug addicts. Drug Alcohol Depend 1995;38:11 – 8. [66] Grigson PS, Twining RC. Cocaine-induced suppression of saccharin intake: a model of drug-induced devaluation of natural rewards. Behav Neurosci 2002;116:321 – 33. [67] Mattson BJ, Williams S, Rosenblatt JS, Morrell JI. Comparison of two positive reinforcing stimuli: pups and cocaine throughout the postpartum period. Behav Neurosci 2001;115:683 – 94. [68] Carroll ME, Lac ST, Nygaard SL. A concurrently available nondrug reinforcer prevents the acquisition or decreases the maintenance of cocaine-reinforced behavior. Psychopharmacology 1989;97:23 – 9. [69] Carroll ME, Lac ST. Autoshaping i.v. cocaine self-administration in rats: effects of nondrug alternative reinforcers on acquisition. Psychopharmacology 1993;110:5 – 12. [70] Nader MA, Woolverton WL. Effects of increasing the magnitude of an alternative reinforcer on drug choice in a discrete-trials choice procedure. Psychopharmacology 1991;105:169 – 74. [71] Higgins ST, Budney AJ, Bickel WK, Hughes JR, Foerg F, Badger G. Achieving cocaine abstinence with a behavioral approach. Am J Psychiatry 1991;150:763 – 9. [72] Kissileff HR. Food-associated drinking in the rat. J Comp Physiol Psychol 1969;67:284 – 300. [73] Stricker EM, Verbalis JG. Hormones and behavior: the biological bases of thirst and sodium appetite. Am Sci 1988;76:261. [74] Johnson AK, de Olmos J, Pastuskovas CV, Zardetto-Smith AM, Vivas L. The extended amygdala and salt appetite. Ann NY Acad Sci 1999;877:258 – 80. [75] Flaherty CF. Incentive relativity. New York (NY): Cambridge University Press, 1996. [76] Grigson PS. Conditioned taste aversions and drugs of abuse: a reinterpretation. Behav Neurosci 1997;111:129 – 36. [77] Grigson PS. Drugs of abuse and reward comparison: a brief review. Appetite 2000;35:89 – 91. [78] Geary N, Smith GP. Pimozide decreases the positive reinforcing effect of sham fed sucrose in the rat. Pharmacol Biochem Behav 1985; 22:787 – 90. [79] Mogenson GJ. Limbic – motor integration. Prog Psychobiol Physiol Psychiatry 1987;12:117 – 70.
Discussion
Like drugs for chocolate: Separate rewards modulated by common mechanisms? Patricia Sue Grigson* Department of Behavioral Science, Penn State College of Medicine, Hershey, PA 17033, USA Accepted 28 March 2002
It is difficult to imagine, at first glance, how single cells in the nucleus accumbens might come to selectively fire during cocaine-reinforced lever pressing. Are we to believe that there is, in fact, an innate circuit for cocaine that is separate from that mediating the response to natural rewards? This conclusion is particularly difficult to reconcile with the mass of published data providing evidence for common substrates [1– 4]. Indeed, the data in the first three manuscripts of this series provided strong evidence for overlap between the substrates mediating the rewarding properties of drugs of abuse and those of natural rewards, such as water, food, and sucrose. The following is a summary of these human and animal data showing that: (a) Opiates increase responsiveness to food. (b) Food intake increases the release of endogenous opiates. (c) Preference for sweets is highly correlated with preference for drugs. (d) Food restriction increases craving and drug self-administration behavior. (e) A sensitization-like response is induced by repeated exposure to drugs, foods, and food restriction. (f) Conditioned cues elicit craving for food and for drugs. We will then view these findings in light of the separate circuits revealed by Carelli’s more fine-grained electrophysiological analysis and consider a potentially unifying construct.
1. Opiates increase responsiveness to food As described by Pelchat and Kelley et al., opiates increase the perceived palatability of food in both humans and animals. Pelchat discussed data showing that treatment with opiate blockers decreased hedonic ratings of sugars and hedonic ratings of odors of palatable foods in humans [5,6]. Kelley et al. also cited human data showing that treatment with an opiate antagonist reduced the preference for sweet high-fat foods in bulimics, obese bulimics, and normal weight controls [7]. Parallel findings have been reported
* Tel.: +1-717-531-5772; fax: +1-717-531-6916. E-mail address: [email protected] (P.S. Grigson). 0031-9384/02/$ – see front matter D 2002 Published by Elsevier Science Inc. PII: S 0 0 3 1 - 9 3 8 4 ( 0 2 ) 0 0 7 5 8 - 8
for rats. According to Kelley et al., it has been known for decades that the peripheral administration of opiates increases food intake in rats [8]. In addition to peripheral administration, Kelley et al. demonstrated that opiates administered directly into the nucleus accumbens also increase intake of palatable substances such as sucrose, saccharin, fat, or salt. This effect, as with the human data, was blocked by pretreatment with a mu opiate antagonist. Finally, according to Kelley et al., this opiate-induced increase in intake in rats also is accompanied by an increase in appetitive behaviors in the taste reactivity test, indicating an increase in palatability [9], and by an increase in break point, indicating an increase in the willingness to work for food. Opiates, then, increase the apparent palatability of a natural reward, the willingness to work for that natural reward, and once given access, ingestion of the natural reward as well.
2. Food intake increases the release of endogenous opiates Not only do opiates increase responding for food, but both Pelchat and Kelley et al. described data showing that ingestion of food (particularly sweets) can induce the release of endogenous opiates as well. Consumption of sugar water reduced crying when human infants received a heal stick, and this effect was blocked by treatment with an opiate antagonist [10]. In rats, chronic sucrose intake enhances morphine-induced analgesia [11,12]. Kelley et al. showed that repeated exposure to chocolate Ensure (3 h/day for 2 weeks) lead to a decrease in the expression of preproenkephalin (PPE) in the nucleus accumbens core and shell, the lateral striatum and the dorsal striatum. PPE is a precursor peptide for enkephalin synthesis in enkephalin-containing neurons. Kelley et al. suggested that the decrease in PPE reflects a compensatory mechanism in response to repeated Ensure-induced release of opioid peptide. Support for this suggestion is provided by the finding that chronic exposure to morphine, like chocolate Ensure, also has been reported
390
P.S. Grigson / Physiology & Behavior 76 (2002) 389–395
to lead to a decrease in the expression of PPE, in this case, in the locus coeruleus [13].
3. Preference for sweets is highly correlated with preference for drugs As discussed by Pelchat, Kelley et al. and Carr, the liking for sweets is highly correlated with the liking for, and the response to, drugs of abuse and alcohol. According to Pelchat, liking for sweets is related to liking for alcohol in humans and humans with a family history of alcoholism exhibit peak preference for a higher concentration of sucrose than do individuals who are family history negative [14]. In addition, there also is a high degree of comorbidity between eating disorders and drug and alcohol abuse in humans [15,16]. Bulik [17] reported that 34.3% of the bulimic subjects tested were drug dependent and 48.6% abused alcohol compared with 2.9% and 8.6% of the control population, respectively. Similar patterns between the preference for sweets and responsiveness to drugs of abuse have been reported in rats. As discussed by Carr, the propensity to ingest sweets predicts the locomotor activating effects of psychostimulants and the rapidity with which rats acquire drug self-administration [18 –20]. These data provide further evidence that responding for drugs of abuse is enmeshed with the natural reward substrate.
4. Food restriction increases craving and drug self-administration behavior The data described by both Pelchat and Carr show that food restriction clearly augments craving in humans and responsiveness for drugs of abuse in rats. Pelchat showed that food restriction (i.e., access to a bland diet) increased craving in humans. Similarly, Pelchat cited data showing that craving for chocolate or a vanilla-flavored beverage was augmented in humans with a history of eating the chocolate or the vanilla beverage when hungry [21,22]. Consuming the food when in a state of hunger, then, may increase the probability that a human will exhibit craving for the food at a later date. Consistent with the human data, food restriction increases responsiveness for drugs of abuse in animals. As discussed by Carr, food restriction augments the development of a conditioned place preference for drugs of abuse, drug self-administration, locomotor activating effects, the threshold lowering effects in LHSS and the accompanying cellular activating effects [23 –28]. Carr showed that these facilitatory effects of food restriction on the actions of drugs of abuse in the LHSS paradigm are pervasive, occurring with amphetamine, MK-801, cocaine and DPDPE. Finally, in addition to increasing responsiveness for drugs of abuse, recent data show that food restriction also can induce reinstatement of cocaine-seeking behavior following a period of abstinence [29].
5. A sensitization-like response is induced by repeated exposure to drugs, foods and food restriction Sensitization refers to an increase in the response to a stimulus as a function of repeated exposure to that stimulus. Given that dependence upon a drug of abuse generally increases with repeated exposure to the drug, the behavioral expression of sensitization, and the underlying mechanisms, have been important areas of study in addiction research. Repeated exposure to a drug of abuse leads to an increase in the locomotor activating effects of drugs [30], an increase in the appetite stimulating effect of opiates (Kelley et al., this issue) and an increase in the rewarding properties of the drug as measured by conditioned place preference [31] or drug self-administration behavior [32]. As with repeated exposure to drugs of abuse, repeated exposure to natural rewards also can lead to ‘addiction-like’ responses. As discussed above, Kelley et al. showed that repeated exposure to chocolate Ensure (3 h/day for 2 weeks) lead to a decrease in the expression of PPE in reward-related structures. As discussed, this may reflect a compensatory response to repeated Ensure-induced release of endogenous opiates. Dimitriou et al. [33] showed that repeated access to fat (2 h/day on Monday, Wednesday and Friday) lead to binge-like ingestive behavior. Similarly, Hoebel et al. [34] provided evidence for naloxone-precipitated withdrawal in rats with a history of repeated access to a palatable glucose solution. Finally, like repeated exposure to drugs or food, Carr reported that chronic food restriction also lead to ‘sensitization’ of the rewarding efficacy of drugs of abuse. As discussed, this ‘sensitization’ was reversed following a week of refeeding. Thus, repeated exposure to drugs of abuse, natural rewards (e.g., fat or glucose) or even chronic food restriction can lead to sensitization, a potential behavioral and physiological manifestation of addiction.
6. Conditioned cues elicit craving for food and drugs As discussed, addiction is a disease of chronic relapse, and craving, induced by exposure to drug-related cues, is one of the primary precipitating factors in relapse. According to Pelchat, craving in humans is conditionable such that cravings for food increase in the presence of food-related cues including the sight, the smell, or even the imagery of the craved food [35,36]. Pelchat and Schaefer [22] showed that these cravings can occur in the absence of need. In addition to food, addicted humans also exhibit cravings for drugs of abuse following exposure to drug-related cues [37]. Similar findings have been widely reported in rats where exposure to drug-related cues leads to an increase in drugseeking behavior [38 – 40]. Carelli reported consistent findings. Presentation of the auditory/light cue that had been paired with the infusion of cocaine led to an increase in firing of single cells in the nucleus accumbens and the pattern of activity mirrored that which was exhibited when
P.S. Grigson / Physiology & Behavior 76 (2002) 389–395
the rat was responding for cocaine. Park and Carr [41] reported that ingestion of a small palatable meal and exposure to the meal-paired environment induced a similar pattern of c-Fos expression in the ventral tegmental area. Both of these responses were blocked by naloxone, suggesting an opioid –dopamine linkage in the response to food reward and food-related cues. Finally, Kelley et al. provided evidence for conditioning, and for common substrates as well, by showing that exposure to a nicotine- or a chocolatepaired context increased the expression of Fos in similar regions in the brain. Thus, exposure to food- or drug-related cues can lead to food and drug craving in humans, drugseeking in rats, activation of accumbens neurons, and the expression of Fos activity in reward-related structures.
7. Separate cells/separate circuits On the basis of the four manuscripts alone, a mediating role in reward processing has been implicated for the orbital frontal cortex, central nucleus of the amygdala, hypothalamus, ventral tegmental area, nucleus accumbens and nucleus of the solitary tract. These data suggest that the ‘reward circuit’ is complex and that multiple interconnected regions may be involved in the response to natural rewards and to drugs of abuse. In spite of this evidence, however, Carelli’s electrophysiological data in the nucleus accumbens clearly showed that nearly all neurons that responded to sucrose also responded to food and to water, but only 8% of the cells that responded to cocaine also responded to these natural rewards. Thus, the neurons in the nucleus accumbens that respond to natural rewards are largely separate from those that respond to cocaine. Although these data seem at odds with those contributing to the above discussion, the dissociation of mechanisms mediating natural rewards and drugs of abuse is not unprecedented. Caine and Koob [42] showed that a 6-OHDA lesion of the nucleus accumbens selectively reduced operant responding for cocaine while leaving operant responding for food intact. Wojnicki et al. [43] reported that treatment with phentermine decreased cocaine-maintained, but not food-maintained, responding in rhesus monkeys. As discussed, stress induced by foot shock will reinstate drug-seeking behavior [29]. It will not, however, reinstate responding maintained by food [44,45] or responding maintained by sucrose [46]. Finally, Chiamulera et al. [47] recently showed that mGluR5 receptor knockout mice failed to exhibit either cocaine-induced hyperactivity or cocaine self-administration behavior, but responding for food was intact. Even so, it is difficult to accept that a subset of neurons in the nucleus accumbens is prepared to code selectively for drugs of abuse, in this case, cocaine. Why, or how, might this be so? Surely, the brain is not designed to detect and respond to drugs of abuse. Or is it? Three hypotheses might be proposed for the interpretation of the Carelli data. First, the activity of the ‘cocaine cells’ may, in fact, relate to the
391
nature of the stimulus and, while these cells are not sensitive to food, water, or sucrose, they may be sensitive to another natural reward such as sex, for example. Carelli has considered, but has not yet tested, this hypothesis. A second hypothesis is that the activity of the ‘cocaine cells’ relates to the intensity, rather than to the nature, of the stimulus. In this light, it is not unreasonable to suppose that the intravenous infusion of cocaine was more intense than was brief access to food, water, or even a palatable sucrose solution. Of course, the intravenous administration of heroin should presumably rival the intravenous administration of cocaine in intensity, but Chang et al. [48] reported that heroin and cocaine also are encoded by different cells in the nucleus accumbens and in the medial prefrontal cortex. This finding indicates that there is not a simple natural reward versus drug of abuse dichotomy in the nucleus accumbens and that coding for intensity is not likely the explanation. This leads to a third, and very interesting, hypothesis. Perhaps single cells in the nucleus accumbens (and possibly in other structures as well) are like stem cells, so to speak, a clean slate waiting to ‘imprint’ upon (code for) any stimulus in the environment that might be deemed rewarding. This idea is intriguing, given the range of stimuli that human beings and animals find rewarding, and the need for plasticity—i.e., the need for adjustment with changing requirements, availability of resources, and experience. Although to the author’s knowledge, this type of plasticity has not been considered previously for reward-sensitive cells in the nucleus accumbens (or elsewhere), the dynamic effect of experience on the activity of hippocampal place cells, for example, is well documented [49,50]. Perhaps it is just this type of plasticity that is required to seek the range of rewards necessary for life, such as salt, calcium, potassium, amino acids, iron, sweets, food, water, warmth and a mate. Further studies will be required to test this hypothesis and to determine whether the code for a given rewarding stimulus is static or, alternatively, whether it can be modified ‘online’ by changing need states (e.g., by the rapid onset of insulin-induced hypoglycemia or by sodium depletion induced by the intracerebroventricular administration of angiotensin II).
8. A model If we accept that any rewarding stimulus, regardless of its nature, will be encoded by particular cells in the nucleus accumbens (in rats, the same cell in the nucleus accumbens may encode for food, water, and sucrose because rats are prandial eaters, i.e., they drink when they eat), we still must consider how it is that drugs of abuse so readily and persistently gain control of the behavior of the organism. Humans and animals alike have the opportunity to engage in a range of behaviors at any given time. They do, however, typically engage in only one motivated behavior at any one time. They eat, or they drink, they copulate, or they tend to their young. While each of these motivated behaviors is
392
P.S. Grigson / Physiology & Behavior 76 (2002) 389–395
mediated by very different substrates [51 –57], ultimately, the behaviors must be compared by some common substrate so that the most appropriate (i.e., the most rewarding) behavior can come to the fore. According to Cabanac [58], ‘‘access to behavior is assigned to the motivation that is strongest at a given point in time’’. So what is the nature of this common substrate and why are drugs of abuse so compelling for some animals and for some humans? The following is a model for consideration. The model will need to be tested, where possible, and the mechanisms delineated. Some of the premises have been posed before and others have not. The general premises of the model are as follows: (1) Naturally motivated behaviors (e.g., food intake, water intake, sodium appetite, and sexual behavior) have independent mechanisms for response initiation and termination (see Fig. 1). (2) These self-regulated systems, however, are not completely independent of one another. By sharing a common reward circuit (see Fig. 2), activation of one of these motivational systems can simultaneously inhibit the others (e.g., engaging in eating behavior will inhibit sexual activity). (3) Although each motivated behavior has its own internal mechanism for satiety, along with some inhibition from other activated behaviors, the common reward substrate, itself, by nature, has no means for ‘satiety’ because this substrate needs to be able to be continuously activated by ever changing motivational systems as the animal seamlessly switches from one motivated behavior to another. Smith [59] recently has provided careful microstructural data documenting the behavior of rats as they switch from feeding to drinking and vice versa. (4) This essential feature (i.e., that the reward substrate is, by nature, prepared for continuous activation) is the Achilles’ heel for the addicted subject because drugs of abuse act directly upon this reward substrate. Thus, although there is evidence for within session regulation of drug selfadministration behavior in rats (for a brief review, see Ref. [3]), there appears to be little or no internal means of ‘satiety’ because drug self-administration behavior escalates greatly when the daily access period is lengthened [60] and unlimited access can result in death [61]. Indeed, while
Fig. 1. Naturally motivated behaviors (e.g., food intake, water intake, salt intake, or sexual behavior) have mechanisms to initiate (+) responding and to inhibit ( ) responding (i.e., satiety) as well.
Fig. 2. These motivated behaviors, however, are not fully independent of one another. By sharing a common reward circuit, activation of one of these motivational systems simultaneously inhibits engagement in others. By comparison, the common reward circuit has no real means for ‘satiety’, because it must be able to be continuously activated as the organism switches from one motivated behavior to another.
human cocaine addicts tend to ‘binge’ and ‘crash’, Gawin et al. [62] reported that a cocaine binge in humans generally ends ‘‘only when all accessible supplies are exhausted’’. (5) When drugs of abuse are on board or, in particular, when an animal or human is engaged in drug-seeking behavior, important competing motivational systems are inhibited (see Fig. 3). In accordance, drug-addicted humans are more often absent from work and more often have their children removed from the home due to neglect [63,64]. Drug-addicted humans also weigh less [65]. Thirsty rats avoid intake of a palatable saccharin cue when it predicts the opportunity to self-administer cocaine [66] and, when tested on Postpartum Day 16, lactating female rats prefer a cocaine-paired environment to an environment that has been paired with their own pups [67]. (6) Finally, while there is no direct means of ‘satiety’ for drug-related behavior, there remains a critical indirect means of inhibition whereby powerful natural rewards can, in some circumstances, come to override responding for a drug of abuse (see Fig. 4). For example, Carroll et al. [68] and Carroll and Lac [69] showed that simultaneous access to a highly palatable gustatory stimulus, such as a glucose+saccharin mixture, delays acquisition and maintenance of
Fig. 3. When drugs of abuse are on board, or when an animal or a human is engaged in drug-seeking behavior, competing motivational systems are inhibited.
P.S. Grigson / Physiology & Behavior 76 (2002) 389–395
Fig. 4. Although there is no direct means for ‘satiety’ of drug-related behavior, there is an essential indirect means of inhibition whereby powerful natural rewards (e.g., a highly palatable glucose+saccharin mixture) can, in some circumstances, come to override responding for a drug of abuse.
cocaine self-administration. Nader and Woolverton [70] showed that the availability of an alternative food reinforcer decreased total drug intake in rhesus monkeys. Similarly, Higgins et al. [71] showed that the availability of vouchers for ski lift passes or higher education, for example, decreased cocaine use (i.e., increased abstinence) in humans.
9. Summary and conclusions There is a great deal of evidence for interaction across motivated systems and the interaction can lead to either a facilitation or an inhibition of responding. The change in responding for one reward as a consequence of having experience with another reward is, itself, evidence for a common substrate. The circuitry of two motivated behaviors may be linked for several reasons. First, they may work in concert as a regulatory system. Thus, it is not surprising that food intake has a direct effect on the ingestion of fluid [72,59]. Water intake can affect salt intake and salt intake generally is accompanied by water intake [73,74]. Second, two motivational systems may interact because of a single common underlying mechanism of action. As discussed, opiate action on the mu receptor is important in food intake and Kelley et al. clearly demonstrated that the central administration of a selective mu agonist increased intake of a range of palatable food sources. Similarly, although the mechanism is more complicated, the data of Pelchat and Carr show that food restriction has a direct effect on craving for food in humans and responsiveness to the rewarding properties of a range of drugs of abuse as well. Of interest, is whether food deprivation also would facilitate the expression of other motivated behaviors (i.e., whether food deprivation activates a general motivational system). Finally, two motivational systems may interact because, although mediated by distinct mechanisms of action, they ultimately must engage the same final common pathway to
393
gain access to behavior. A reward comparison effect (i.e., the adjustment in responding for one stimulus as a consequence of having experienced another) serves as a clear example of this type of interaction between rewards and, consequently, as a window on the underlying common substrate. Reward comparison is commonplace. It can occur between different levels of the same type of reward (for a review, see Ref. [75]), leading to exaggerated increases or decreases in behavior, and across different motivated behaviors as well [76,77]. With respect to addiction, this reward comparison process is both our heartbreak and our hope. As described, drugs of abuse can override responding for natural rewards. Addicted humans often weighs less, and their children are more often removed from the home due to neglect. The addicted rat will forego intake of an otherwise palatable saccharin solution when waiting for the opportunity to self-administer cocaine [66]. On the other hand, the simultaneous availability of a highly palatable glucose+saccharin mixture, food or even vouchers greatly reduces cocaine self-administration behavior in rats, monkeys and man, respectively [68,70,71]. Finally, it must be noted that comparison of rewards, whether to advantage or detriment, requires accurate identification of the nature and the intensity of the stimuli. It is in this capacity, then, that the nucleus accumbens may contribute to reward comparison and, ultimately, response output. As such, Carelli’s data show that the activity of single cells tracks different reward types, Geary and Smith [78] showed that responsiveness for a 10% sucrose solution is disrupted (essentially halved) following the administration of a dopamine antagonist, and Mogensen [79] has suggested that the accumbens ‘‘translates the motivational determinants of behavior, mediated by the limbic system, into actions’’.
Acknowledgments The author wishes to thank the National Institute on Drug Abuse for sponsoring the symposium held at the meeting of the Society for the Study of Ingestive Behavior in June 2001 and for their support (DA 09815 and DA 12473). Appreciation also is given to Anne Baldwin, Robert C. Twining, Robert A. Wheeler, Gina Carelli, Ann Kelley, and Ken Carr for reading a draft of the manuscript.
References [1] DiChiara G, Acquas E, Tanda G, Cadoni C. Drugs of abuse: biochemical surrogates of specific aspects of natural rewards? Biochem Soc Symp 1993;59:65 – 81. [2] Schroeder BE, Binzak JM, Kelley AE. A common profile of prefrontal cortical activation following exposure to nicotine- or chocolateassociated contextual cues. Neuroscience 2001;105:535 – 45. [3] Wise RA. Drug self-administration viewed as ingestive behaviour. Appetite 1997;28:1 – 5. [4] Wise RA. Drug-activation of brain reward pathways. Drug Alcohol Depend 1998;51:13 – 22.
394
P.S. Grigson / Physiology & Behavior 76 (2002) 389–395
[5] Fantino M, Hosotte J, Apfelbaum M. An opioid antagonist, naltrexone, reduces preference for sucrose in humans. Am J Physiol 1986; 251:R91 – 6. [6] Yeomans MR, Gray RW. Effects of naltrexone on food intake and changes in subjective appetite after eating: evidence for opioid involvement in the appetizer effect. Physiol Behav 1997;62:15 – 21. [7] Drewnowski AD, Krahn DD, Demitrack MA, Nairn K, Gosnell BA. Taste responses and preferences for sweet high-fat foods: evidence for opioid involvement. Physiol Behav 1992;51:371 – 9. [8] Martin WR, Wikler A, Eades CG, Pescor FT. Tolerance to the physical dependence on morphine in rats. Psychopharmacology 1963;4: 247 – 60. [9] Doyle TG, Berridge KC, Gosnell BA. Morphine enhances hedonic taste palatability in rats. Pharmacol Biochem Behav 1993;46:745 – 9. [10] Blass EM, Hoffmeyer LB. Sucrose as an analgesic for newborn infants. Pediatrics 1991;87:215 – 8. [11] D’Anci KE, Kanarek RB, Marks-Kaufman R. Duration of sucrose availability differentially alters morphine-induced analgesia in rats. Pharmacol Biochem Behav 1996;54:693 – 7. [12] Kanarek RB, Mandillo S, Wiatr C. Chronic sucrose intake augments antinoception induced by injections of mu but not kappa opioid receptor agonists into the periaqueductal gray matter in male and female rats. Brain Res 2001;920:97 – 105. [13] Van Bockstaele EJ, Peoples J, Menko AS, McHugh K, Drolet G. Decreases in endogenous opioid peptides in the rat medullo-coerulear pathway after chronic morphine treatment. J Neurosci 2000;20: 8659 – 66. [14] Kampov-Polevoy AB, Garbutt JC, Janowsky DS. Association between preference for sweets and excessive alcohol intake: a review of animal and human studies. Alcohol Alcohol 1999;34:386 – 95. [15] Loxton NJ, Dawe S. Alcohol abuse and dysfunctional eating in adolescent girls: the influence of individual differences in sensitivity to reward and punishment. Int J Eat Disord 2001;29:455 – 62. [16] Wolf WL, Maisto SA. The relationship between eating disorders and substance use: moving beyond co-prevalence research. Clin Psychol Rev 2000;20:617 – 31. [17] Bulik CM. Drug and alcohol abuse by bulimic women and their families. Am J Psychiatry 1987;144:1604 – 6. [18] Gosnell BA. Sucrose intake predicts rate of acquisition of cocaine self-administration. Psychopharmacology 2000;149:286 – 92. [19] Gosnell BA, Lane KE, Bell SM, Krahn DD. Intravenous morphine self-administration by rats with low versus high saccharin preferences. Psychopharmacology 1995;117:248 – 52. [20] Sills TL, Vaccarino FJ. Individual differences in sugar intake predict the locomotor response to acute and repeated amphetamine administration. Psychopharmacology 1994;116:1 – 8. [21] Gibson EL, Desmond E. Chocolate craving and hunger state. Appetite 1999;32:219 – 40. [22] Pelchat ML, Schaefer S. Dietary monotony and food cravings in young and elderly adults. Physiol Behav 2000;68:353 – 9. [23] Bell SM, Stewart RB, Thompson SC, Meisch RA. Food-deprivation increases cocaine-induced conditioned place preference and locomotor activity in rats. Psychopharmacology 1997;131:1 – 8. [24] Carroll ME, Meisch RA. Determinants of increased drug self-administration due to food deprivation. Psychopharmacology 1984;74: 197 – 200. [25] Carr KD, Kim G-Y, Cabeza de Vaca S. Chronic food restriction in rats augments the central rewarding effects of cocaine and the delta1 opioid agonist, DPDPE, but not the delta2 agonist, deltorphin-II. Psychopharmacology 2000;152:200 – 7. [26] Carr KD, Kutchukhidze N. Chronic food restriction increases Fos-like immunoreactivity (FLI) induced in rat forebrain by intraventricular amphetamine. Brain Res 2000;861:88 – 96. [27] Carr KD, Kutchukhidze N. Effect of chronic food restriction on Foslike immunoreactivity (FLI) induced in rat brain regions by intraventricular MK-801. Brain Res 2000;8763:283 – 6. [28] Deroche V, Piazza PV, Casolini P, Le Moal M, Simon H. Sensitization
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
[40]
[41]
[42]
[43]
[44]
[45]
[46]
[47]
to the psychomotor effects of amphetamine and morphine induced by food restriction depends upon corticosterone secretion. Brain Res 1993;611:352 – 6. Shalev U, Highfield D, Yap J, Shaham Y. Stress and relapse to drug seeking in rats: studies on the generality of the effect. Psychopharmacology 2000;150:337 – 46. Vanderschuren LJMJ, Tjon GHK, Nestby P, Mulder AH, Schoffelmeer ANM, De Vries TJ. Morphine-induced long-term sensitization to the locomotor effects of morphine and amphetamine depends on the temporal pattern of the pretreatment regimen. Psychopharmacology 1997;131:115 – 22. Lett BT. Repeated exposures intensify rather than diminish the rewarding effects of amphetamine, morphine, and cocaine. Psychopharmacology 1989;98:357 – 62. Horger BA, Shelton K, Schenk S. Preexposure sensitizes rats to the rewarding effects of cocaine. Pharmacol Biochem Behav 1990;37: 707 – 11. Dimitriou SG, Rice HB, Corwin RL. Effects of limited access to a fat option on food intake and body composition in female rats. Int J Eat Disord 2000;28:436 – 45. Hoebel BG, Patten CS, Colantouni C, Rada PV. Sugar withdrawal causes symptoms of anxiety and acetylcholine release in the nucleus accumbens. Soc For Neurosci Abstr 2000;26:1340. Fedoroff IC, Polivy J, Herman CP. The effect of pre-exposure to food cues on the eating behavior of restrained and unrestrained eaters. Appetite 1997;28:33 – 47. Tuomisto T, Hetherinton MM, Morris MF, Tuomisto MT, Turjanmaa R, Lappalainen R. Psychological and physiological characteristics of sweet food ‘‘addiction’’. Int J Eat Disord 1999;25:169 – 75. Ehrman RN, Robbins SJ, Childress AR, O’Brian CP. Conditioned responses to cocaine-related stimuli in cocaine abuse patients. Psychopharmacology 1992;107:523 – 9. Gracy KN, Dankiewicz LA, Weiss F, Koob GF. Heroin-specific stimuli reinstate operant heroin-seeking behavior in rats after prolonged extinction. Pharmacol Biochem Behav 2000;65:489 – 94. Meil WM, See RE. Lesions of the basolateral amygdala abolish the ability of drug associated cues to reinstate responding during withdrawal from self-administered cocaine. Behav Brain Res 1997;87: 139 – 48. Neisewander JL, Baker DA, Fuchs RA, Tran-Nguyen LTL, Palmer A, Marshall JF. Fos protein expression and cocaine-seeking behavior in rats after exposure to a cocaine self-administration environment. J Neurosci 2000;20:798 – 805. Park TH, Carr KD. Neuroanatomical patterns of fos-like immunoreactivity induced by a palatable meal and meal-paired environment in saline- and naltrexone-treated rats. Brain Res 1998;14:169 – 80. Caine SB, Koob GF. Effects of mesolimbic dopamine depletions on responding maintained by cocaine and food. J Exp Anal Behav 1994;61:213 – 21. Wojnicki FHE, Rothman RB, Rice KC, Glowa JR. Effect of phentermine on responding maintained under multiple fixed-ratio schedules of food and cocaine presentation in the rhesus monkey. J Pharmacol Exp Ther 1999;288:550 – 60. Ahmed SH, Koob GF. Cocaine- but not food-seeking behavior is reinstated by stress after extinction. Psychopharmacology 1997;132: 289 – 95. Mantsch JR, Goeders NE. Ketoconazole blocks the stress-induced reinstatement of cocaine-seeking behavior in rats: relationship to the discriminative stimulus effects of cocaine. Psychopharmacology 1999; 142:399 – 407. Buczek Y, Le AD, Wang A, Stewart J, Shaham Y. Stress reinstates nicotine seeking but not sucrose solution seeking in rats. Psychopharmacology 1999;144:183 – 8. Chiamulera C, Epping-Jordan MP, Zocchi A, Marcon C, Cottiny C, Tacconi S, Corsi M, Orzi F, Conquet F. Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice. Nat Neurosci 2001;4:873 – 4.
P.S. Grigson / Physiology & Behavior 76 (2002) 389–395 [48] Chang JY, Janak PH, Woodward DJ. Comparison of mesocorticolimbic neuronal responses during cocaine and heroin self-administration in freely moving rats. J Neurosci 1998;18:3098 – 115. [49] O’Keefe J, Dostrovsky J. The hippocampus as a spatial map: preliminary evidence from unit activity in the freely-moving rat. Brain Res 1971;34:171 – 5. [50] Ekstrom AD, Meltzer J, McNaughton BL, Barnes CA. NMDA receptor antagonism blocks experience-dependent expansion of hippocampal ‘‘place fields’’. Neuron 2001;31:631 – 8. [51] Eisen S, Davis JD, Rauhofer E, Smith GP. Gastric negative feedback produced by volume and nutrient during a meal in rats. Am J Physiol 2001;281:R1201 – 14. [52] Murphy AZ, Hoffman GE. Distribution of gonadal steroid receptorcontaining neurons in the preoptic-periaqueductal gray – brainstem pathway: a potential circuit for the initiation of male sexual behavior. J Comp Neurol 2001;438:191 – 212. [53] Nicolaidis S, Rowland N. Intravenous self-feeding: long-term regulation of energy balance in rats. Science 1977;195:589 – 91. [54] Norgren R. Gustatory system. In: Paxinos G, editor. The rat nervous system. 2nd ed. San Diego (CA): Academic Press, 1995. p. 751 – 71. [55] Stricker EM, Sved AF. Thirst. Nutrition 2000;16:821 – 6. [56] Johnson AK, de Olmos J, Pastuskovas CV, Zardetto-Smith AM, Vivas L. The extended amygdala and salt appetite. Ann NY Acad Sci 1999;877:258 – 80. [57] Woods SC, Seeley RJ. Adiposity signals and the control of energy homeostasis. Nutrition 2000;16:894 – 902. [58] Cabanac M. Emotion and phylogeny. Jpn J Physiol 1999;49:1 – 10. [59] Smith JC. Microstructure of the rat’s intake of food, sucrose and saccharin in 24-hour tests. Neurosci Biobehav Rev 2000;24:199 – 212. [60] Ahmed SH, Koob GF. Long-lasting increase in the set point for cocaine self-administration after escalation in rats. Psychopharmacology 1999;146:303 – 12. [61] Johanson C-E, Fischman MW. The pharmacology of cocaine related to its abuse. Pharm Rev 1989;41:3 – 52. [62] Gawin FH, Herbert MD, Kleber MD. Abstinence symptomology and psychiatric diagnosis in cocaine abusers. Arch Gen Psychiatry 1986; 43:107 – 13. [63] Jones S, Casswell S, Zhang J-F. The economic costs of alcohol-related absenteeism and reduced productivity among the working population of New Zealand. Addiction 1995;90:1455 – 61. [64] Nair P, Black MM, Schuler M, Keane V, Snow L, Rigney BA. Risk factors for disruption in primary care giving among infants of substance abusing woman. Child Abuse Neglect 1997;21:1039 – 51.
395
[65] Santolaria-Fernandez FJ, Gomez-Sirvent JL, Gonzalez-Reimers CE, Batista-Lopez JN, Jorge-Hernandez JA, Rodriguez-Moreno F, Martinez-Riera A, Hernandez-Garcia MT. Nutritional assessment of drug addicts. Drug Alcohol Depend 1995;38:11 – 8. [66] Grigson PS, Twining RC. Cocaine-induced suppression of saccharin intake: a model of drug-induced devaluation of natural rewards. Behav Neurosci 2002;116:321 – 33. [67] Mattson BJ, Williams S, Rosenblatt JS, Morrell JI. Comparison of two positive reinforcing stimuli: pups and cocaine throughout the postpartum period. Behav Neurosci 2001;115:683 – 94. [68] Carroll ME, Lac ST, Nygaard SL. A concurrently available nondrug reinforcer prevents the acquisition or decreases the maintenance of cocaine-reinforced behavior. Psychopharmacology 1989;97:23 – 9. [69] Carroll ME, Lac ST. Autoshaping i.v. cocaine self-administration in rats: effects of nondrug alternative reinforcers on acquisition. Psychopharmacology 1993;110:5 – 12. [70] Nader MA, Woolverton WL. Effects of increasing the magnitude of an alternative reinforcer on drug choice in a discrete-trials choice procedure. Psychopharmacology 1991;105:169 – 74. [71] Higgins ST, Budney AJ, Bickel WK, Hughes JR, Foerg F, Badger G. Achieving cocaine abstinence with a behavioral approach. Am J Psychiatry 1991;150:763 – 9. [72] Kissileff HR. Food-associated drinking in the rat. J Comp Physiol Psychol 1969;67:284 – 300. [73] Stricker EM, Verbalis JG. Hormones and behavior: the biological bases of thirst and sodium appetite. Am Sci 1988;76:261. [74] Johnson AK, de Olmos J, Pastuskovas CV, Zardetto-Smith AM, Vivas L. The extended amygdala and salt appetite. Ann NY Acad Sci 1999;877:258 – 80. [75] Flaherty CF. Incentive relativity. New York (NY): Cambridge University Press, 1996. [76] Grigson PS. Conditioned taste aversions and drugs of abuse: a reinterpretation. Behav Neurosci 1997;111:129 – 36. [77] Grigson PS. Drugs of abuse and reward comparison: a brief review. Appetite 2000;35:89 – 91. [78] Geary N, Smith GP. Pimozide decreases the positive reinforcing effect of sham fed sucrose in the rat. Pharmacol Biochem Behav 1985; 22:787 – 90. [79] Mogenson GJ. Limbic – motor integration. Prog Psychobiol Physiol Psychiatry 1987;12:117 – 70.