The Pleasures and Pains of Brain Regulatory Systems for Eating · Diano, 2004 ; Broeberger, 2005 ; Konturek et al., 2005 ; Gao and Horvath, 2007 ; Coll et al., 2008 ). In brief, there

5Obesity Prevention: The Role of Brain and Society on Individual Behavior © 2010, Elsevier Inc.2010

The Pleasures and Pains of Brain Regulatory Systems for Eating

Jaak Panksepp Department of VCAPP, College of Veterinary Medicine, Washington State University,

Pullman, WA, USA

C H A P T E R

1.1 INTRODUCTION

All basic survival needs of the body are repre-sented in genetically ingrained circuits concen-trated in subcortical visceral regions of the brain. Energy balance is regulated by a strict equation ( Figure 1.1 ) that has recently been illuminated in great detail. For many decades, abundant evi-dence has indicated that medial hypothalamic regions, concentrated especially in the arcuate nucleus, contain major detectors for long-term homeostatic energy balance ( Panksepp, 1974 ).

1 1

Diverse neuropeptidergic details of this cir-cuitry have now been clarified ( Horvath and Diano, 2004 ; Broeberger, 2005 ; Konturek et al. , 2005 ; Gao and Horvath, 2007 ; Coll et al. , 2008 ). In brief, there are complex neuropeptide-based neu-ral networks that are able to gauge the energy status of the organism, and to adjust foraging and eating behavior accordingly. This network is constructed of hypothalamic neuropeptides, such as hypocretin/orexin, neuropeptide Y and agouti-related peptide, α -melanocyte-stimulating hormone, and melanin-concentrating hormone;

1.1 Introduction 5

1.2 Satiety Agents versus Aversion-Inducing Agents 6

1.3 Various Methodologies to Evaluate Affective Change in Pre-Clinical Appetite Research 7

1.4 Conditioned Taste Aversions – From Animal Models to Human Brain Analysis? 12

1.5 Conclusion 13

O U T L I N E

CH001.indd 5CH001.indd 5 4/19/2010 7:11:21 PM4/19/2010 7:11:21 PM

1. BRAIN REGULATORY SYSTEMS

1. FROM BRAIN TO BEHAVIOR

6

regulatory circuits that are controlled by periph-eral signals of lipid status, such as leptin; gastro-intestinal hunger hormones, such as ghrelin; as well as more direct metabolic effects on the hypothalamus that are not as well understood. As noted above, this knowledge has been sum-marized superbly many times.

Often missing from the discussion of energy balance dynamics are the evolved psychologi-cal processes that mediate achieved/achieving homeostasis – the nature of the feelings of hun-ger in the brain, and the large variety of ways the pleasures and displeasures of taste can promote or hinder appetite. This is in addition to the many ways feeding behavior can be dis-rupted which have no relevance for the normal mechanisms of energy balance regulation. For instance, hunger makes sweetness taste more pleasant, and satiety makes the same sensation feel less pleasant ( Cabanac, 1992 ).

This chapter will briefly focus on the latter factors, since they need to be considered more closely as investigators search for medicinal agents that may help humans better regulate their weight. It should be noted that consider-able progress is being made in understand-ing how the brain codes taste qualities in both animals ( Berridge, 2003 ; Peci ñ a et al. , 2006 ) and humans ( Rolls, 2008 ; Rolls and Grabenhorst, 2009), but little of that work has yet been related to our understanding of appetite control agents.

1.2 SATIETY AGENTS VERSUS AVERSION-INDUCING AGENTS

Presumably , the feeling that accompanies excessive depletion of energy leads to distress-ing feelings of hunger, while satisfaction of

750 kcal +RAT

20,000 kcalCHOW

10,000 kcal +RAT

19,750 kcalHEAT

Daily intake error<0.7 kcal

+ +=5.5 kg.

FIGURE 1.1 A female rat’s approximate yearly energy balance equation. A great deal is eaten without much change in body weight. With the small increase in body weight, the daily intake error was less than a kilocalorie. The remaining energy was dissipated as heat. Source : Figure 9.4 of Panksepp (1998: 172) , reprinted with permission of Oxford University Press.



71.3 VARIOUS METHODOLOGIES TO EVALUATE AFFECTIVE CHANGE IN PRE-CLINICAL APPETITE RESEARCH

energy needs promotes a mood of contentment. Of course, few investigators of animal models of energy regulation are willing to use such psy-chological concepts; most restrict their discus-sions to measurable entities – changes in food intake, body weight, and various body energy distribution parameters. This is understandable, since we have no direct way of monitoring the psychological states of other animals. Yet this is also shortsighted if such states do exist and if they are of first-rate importance for how ani-mals distribute their food-seeking and consum-matory behaviors.

We would be wise to reconsider our reluc-tance to envision the affective controls of animal behavior, using all the indirect methodological approaches at our disposal. Philosophically, to not consider such issues is tantamount to failing to deal with the real complexities of the brain. Practically, the failure to consider such issues may impair our capacity to sift real satiety-producing neural pathways and neurochemi-cal agents from the many other ways that food intake could be disrupted. Since most pre-clinical investigators in the field have been trained in rigorous behavioristic approaches, where any discussion of mental changes in animals is con-sidered to be inappropriate, a full and open dis-cussion of such issues is rare in the literature. However, considering what we now know about brain evolution and the subcortical sources of affective processes in all mammals ( Panksepp, 1998, 2005, 2008 ), wisdom dictates that we begin to evaluate such issues with more intensive methodologies. If adequate empirical approaches for monitoring affective changes did not exist, it would make no sense to suggest that such issues should be considered. Yet adequate com-prehensive methodologies are available, albeit rarely used. Among the best measures are posi-tive and negative affective states as can be meas-ured with conditioned place preference (CPP) and conditioned place aversion (CPA) measures ( Tzechentke, 2007 ). As will be noted later, there are also other, more direct behavioral measures,

such as the willingness of animals to play. Such affective measures, when used in pre-clinical animal models, would allow us to better ferret out those brain neurochemical pathways that need our most focused attention for the develop-ment of optimal appetite-reducing agents.

Why do we need to consider such issues? Any of a large variety of negative affects can reduce feeding in animals, from anger to being “ zonked-out ” by drugs, with disgust, fearful-ness, separation anxiety, and stomach cramps in between. It is important also not to forget the negative feelings arising from a variety of stressors, including fatigue and sickness pro-moting neurochemical changes in the brain and various painful bodily feelings. If we do not sift such appetite-reducing affects from the normal pathways of satiety at the outset of intensive research programs seeking new satiety-promoting agents, we will be mismanaging our budgets and the efforts of our researchers. Since practically all agents off our pharmaceutical shelves, in high enough doses, can reduce food intake in animals, such affective issues need to be considered at the front end of research pro-grams. Unfortunately, few investigators focus on them as fully as they deserve; usually a con-ditioned taste-aversion (CTA) paradigm is as far as most are prone to go. This is a good start, but, as will be summarized here, there are many more subtle ways to address such issues.

1.3 VARIOUS METHODOLOGIES TO EVALUATE AFFECTIVE CHANGE

IN PRE-CLINICAL APPETITE RESEARCH

There are many easy ways to reduce feed-ing pharmacologically, but only a few of these tell us much about the normal mechanisms of energy regulation. As noted, fearful animals eat less than normal. So do angry and sick ones. There are many affective changes beside satiety




8

that can reduce feeding, and investigators inter-ested in seeking satiety agents have not spent enough time sifting those agents that produce the normal, good feeling of satiety after a sat-isfying meal from all the many other affec-tive changes that can reduce feeding. With the increasing number of neuropeptidergic “ satiety agents ” that have been discovered in the brain ( Table 1.1 ), we must be increasingly wary that many of them are reducing feeding by changing non-homeostatic affective feelings of animals rather than a feeling of satisfaction that emerges from no longer being hungry.

In short, establishing affective criteria whereby one has discovered a “ real ” satiety agent is criti-cal for future progress in developing medicines that will help people to regulate body weight optimally. When the body is out of homeostatic

balance in terms of available energy, one feels hunger pangs and generalized distress that can be easily erased by a restoration of energy home-ostasis. When one has eaten a satisfying meal, the stomach is distended, blood sugar levels rise, and one commonly feels rather sleepy. These physiological manifestations of satiety are accom-panied by a shift from negative to positive affec-tive states that are commonly called satisfaction or contentment. As noted, since it is admittedly hard to peer into the minds of our experimen-tal animals, we need to find a variety of indirect measures that can help us gauge whether agents that reduce objectively monitored body weight and feeding behavior are also accompanied by feelings of satisfaction. If agents produce less desirable affective states, it would be good to know about them early in any research program. The most useful appetite control agents will need to facilitate appropriate affective changes, namely feelings of appetite satisfaction.

Ever since the discovery that the neuropep-tides cholecystokinin and bombesin could reduce appetite, followed soon after by the body-fat regulator leptin, the search for neuro-peptide modulators of food intake has been a booming growth industry. The outstanding neurobehavioral science that has been fostered has had one enormous missing link – a meaningful discussion of how the various agents modify affec-tive change. Without this critical linchpin, which will ultimately be a key to patient satisfaction and hence long-term compliance and efficacy, acceptable appetite control agents are unlikely to be discovered. Hence, affective issues should be evaluated soon after a substance is thought to be a natural satiety-producing agent. Affective change must be the gold standard that allows us to sift true value from empty promissory notes if we are to regulate appetite through a grow-ing knowledge of feeding control and long-term energy balance regulatory networks in the brain ( Panksepp, 1974, 1975 ; Panksepp et al. , 1979 ).

To re-emphasize, it is important to note that injecting animals with practically anything off

TABLE 1.1 Partial list of neuropeptides and other neuromodulators that have been found

to reduce feeding and body weight

Various amino acids Glucagon-like peptide

AgRP Interleukin-1

Amylin Interleukin-6

α -MSH Insulin (central)

Beta-endorphin Leptin

BDNF Norepinephrine

Bombesin Neurotensin

CART NPY

CCK Oxytocin

Corticosterone PrRP

CRH Peptide YY

Dynorphin Serotonin

Galanin Tumor necrosis factor α

Galanin-like peptide Urocortin

Abbreviations: α -MSH, α -Melanocyte Stimulating Hormone; BDNF, Brain Derived Neutrophic Factor; CART, Cocaine- and Amphetamine-Regulated Transcript Corticotropin-Releasing Hormone; PrRP, Proline-Releasing Peptide. Sources : Horvath and Diano, 2004 ; Broeberger, 2005 ; Konturek et al ., 2005 ; Gao and Horvath, 2007 ; Coll et al ., 2008 .




the pharmaceutical shelf, at random, yields many agents that can reduce intake. Most do not reduce appetite normally; appetite is reduced because the animals are feeling anything from mildly unwell, fatigued, or simply very ill to emotionally distraught. Few investigators carry the discussion of their results toward such affec-tive issues, except for the well-accepted fact that aversion can be monitored by CTA (Conditioned Taste Aversions); for the massive literature on CTAs (see http://www.CTALearning.com for an archival resource of the available literature). For instance, Panksepp et al. , (1977 ) provided this service to Hoffman-LaRoche in the 1970s for one of their prime appetite control agents, which dissuaded them from proceeding further.

The problem with just using the CTA meas-ure is that agents which also produce excessive normal satiety can lead to a metabolically medi-ated conditioned reduction in meal size. Hence, other measures are essential. The one proposed early on, namely to follow the post-prandial “ satiety sequence ” of post-meal grooming, exploration, “ house-keeping ” activities and nap ( Antin et al. , 1995 ), is fine as a starter, yet it is missing a few critical keys to solving the affec-tive issue – namely, did the “ satiety agent ” in fact produce a good feeling of satiety?

Now that we have a host of peptides that reduce feeding ( Table 1.1 provides a partial list), the above issue should be foremost in investiga-tors’ minds. However, it is not. For instance, a stress peptide such as corticotrophin releasing factor (CRF), which reduces appetite, is not a sensible candidate for clinical use in a feeding-regulation clinic. It simply makes animals emo-tionally aroused in various negative affective ways, including increasing signs of separa-tion distress. It was also believed that the CRF2 receptor, reacting to urocortin, might be effec-tive, but it has been shown only to produce emo-tional distress ( Panksepp and Bekkedal, 1997 ).

So what should investigators do? Take affect seriously. There are abundant good ways to monitor whether investigators could realistically

consider their favorite peptide to be a realistic satiety agent as opposed to an emotionally dis-ruptive agent. The best measures would reflect increases in behavior rather than reductions (as with the above described “ satiety sequence ” , which is largely a reduction of behavior that also occurs when animals are simply tired). The following half-dozen gold-standard criteria would allow us to sift the most promising (i.e., real appetite control agents) from the less real-istic candidates (after routine CTA studies have been completed).

1. Hunger dramatically reduces the motivation of young animals to indulge in rough-and-tumble play. This amotivational state is immediately reversed by a single meal ( Siviy and Panksepp, 1985 ). In this study, we evaluated the capacity of CCK and bombesin to simulate that effect. CCK had no such capacity, while bombesin did marginally yield some reversal. The effect, however, was not even close to the complete reversal of play suppression that was produced by a single meal. We proceeded to evaluate several other “ promising ” neuropeptides, but none proved to be promising. By fulfilling this criterion substantially, a researcher will have identified a truly promising neuropeptide for further study.

2. As discovered in the late 1960s, rats will not show a hunger-induced elevation of feeding with a rarely provided high-incentive treat. Such an effect is routinely seen when monitoring feeding with normal maintenance chow ( Figure 1.2 ). Thus, it could be argued that for normal satiety, an agent should reduce hunger-induced intake of maintenance food much more than intake of a rarely provided treat. Sickness would be expected to produce more comparable effects on each.

3. If a neuropeptide agent truly simulates a good feeling of satiety following hunger, it should produce a clear conditioned place




10

preference (CPP) in hungry animals, but not in fully satiated animals. Indeed, in fully satiated animals, as could be insured by gavage of part of the next meal a short while before testing, the agent should either produce no CPP or perhaps even a mild conditioned place avoidance (CPA). In this regard, it should be noted that early on CCK produced no CPP response in hungry animals; indeed, it generated a clear aversion ( Swerdlow et al. , 1983 ).

4. Along the same lines, if a neuropeptide really produces feelings of satiety, hungry animals should work for intraventricular administration of the peptide much more under a state of hunger than in a state of satiety.

5. If an animal’s set-point for regulation has been truly shifted downward (i.e., to a leaner body mass), then the long-term hedonic equation should not have been shifted.

One way to monitor this is to give common laboratory animals, such as rats, continuous daily access to two concentrations of sugar. Animals normally systematically shift their intake from the more concentrated to the less concentrated sugar solution ( Figure 1.3 ). Lean animals in a chronic state of hunger, such as those with experimental type 1 diabetes, sustain their preference for the more concentrated solution. If this were to happen with a putative long-term appetite control agent, then the inference should be that the body-weight set-point has not been shifted by the manipulation. If rats shift away from the sweeter solution more rapidly, the inference is that they are, in fact, internally experiencing excess energy repletion.

6. Finally, in line with our main thesis that the very best way to monitor affective change in animals is via their emotional vocalizations, we would suggest that if one paired a conditioned stimulus (CS) with infusion of satiety peptides in hungry animals, then gradually the CS would come to evoke appetitive 50-kHZ ultrasonic vocalizations (USVs) in anticipation of obtaining relief from the hunger. We have already observed this with a single 2-hour feeding period each day ( Burgdorf and Panksepp, 2000 ), as well as a conditioned appetitive response to drugs of reward ( Knutson et al. , 1999 ; Burgdorf et al. , 2001 ). In this case, this maneuver does not work for repeated short CS pairing with small bits of food typically used in operant conditioning. This suggests that the response has to be within the context of ecological validity (animals typically anticipate and take meals). If the CS were to evoke 22-kHz aversion-indicative USVs – a response seen with aversive drugs ( Burgdorf et al. , 2001 ) – then it would be highly unlikely that the peptide was reducing food intake by evoking feelings of satiety.

Hamburger treat

Maintenance chow

Intake as a function of level ofdeprivation with two incentives

18

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14

12

10

8

6

4

2

0

Food

inta

ke (

g)

Ad Lib.

Level of food deprivation

24 h.Deprivation

FIGURE 1.2 A summary of the effects of high-incentive (raw hamburger) and much lower-incentive food (the rat’s normal maintenance chow) on intake as a function of degree of prior food deprivation. Source : Figure 9.3 of Panksepp (1998: 173) , reprinted with permission of Oxford University Press.




The remarkable aspect of current feeding research, with such a cornucopia of appetite control agents, is that essentially none of these criteria have been studied. If it were demon-strated that a presumptive “ satiety peptide ” fulfilled all of these criteria, then this could be the recipe for reducing feeding with the desired positive affective consequences. Without at least fulfilling some of these criteria, claims simply from reductions of amount of food consumed are premature, and reflect hubris rather than sound affective neuroscientific thinking.

Such tests are not often conducted because they are more difficult than the mere meas-urement of food intake. A more troublesome reason for neglect is that the above analysis

also requires investigators to openly consider a variety of affects as real functional proper-ties of mammalian brains ( Panksepp, 1998, 2005 ). Affects are real brain functions that allow animals to anticipate life-sustaining and life-detracting events. There has been one affective measure, conditioned taste aversion (CTA), that has been superbly developed, and it would be worthwhile providing an overview of this work as a trail-marker for what needs to be done with some of the other measures described above. The CTA procedure is now developed to a point where it could be used as one of the most rigorous ways to study appetite-related adverse affective changes in the human brain.

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Raw dataDilute 10%

solution

Concentrated 35%solution

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ml)

80

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glu

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Percent preference

DaysDays

Genetically obese

Normals gettinginsulin

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Normaluntreated

Normals recoveringfrom obesity

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Relative intakes of dilutesolution under variousmetabolic conditions

Glucose crossover

Top: Raw dataBottom: Relative data

1 4 7

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cent

glu

cose

inta

keas

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FIGURE 1.3 Summary of the patterns of sugar water consumption in animals given continuous daily access to two solutions of different concentrations. Animals initially take most of their sugar from the concentrated solution, but gradually shift over to the less sweet dilute source. The right-hand graph summarizes the changes in glucose intake crossover patterns of various groups of rats with distinct energy regulatory problems. Source : Figure 9.10 of Panksepp (1998: 183) , reprinted with permission of Oxford University Press.




12

1.4 CONDITIONED TASTE AVERSIONS – FROM ANIMAL MODELS TO HUMAN BRAIN

ANALYSIS?

In general, it is difficult to bring human emo-tional feelings under tight experimental con-trol in research settings. This is not the case for other powerful affects, such as homeostatic feel-ings (e.g., hunger and thirst, which can easily be evoked hormonally). Likewise, certain sensory affects, such as nausea, can be modeled in ani-mals using the straightforward CTA procedure, for which there is now a massive database ( Riley and Freeman, 2004) – a rich pre-clinical animal literature (for recent reviews, see Sandner, 2004 ; Sewards, 2004 ; Mediavilla et al. , 2005 ), including a fairly precise understanding of the underlying neuroanatomies in other mammals ( Yamamoto et al. , 1994 ; Reilly, 1999 ; Jim é nez and Tapia, 2004 ; Reilly and Bornovalova, 2005 ; de la Torre-Vacas and Ag ü ero-Zapata, 2006 ; Ram í rez-Lugo et al. , 2007 ). The CTA measure and the associated neg-ative affects have widespread implications for human nutritional habits ( Gietzen and Magrum, 2001 ; Scalera, 2002 ).

This model has immediate implications for medical treatments and development of new and more precise therapeutics. CTA is a highly replicable and simple learning paradigm where novel tastes that are not intrinsically nauseating can be imbued with that aversive affect through simple classical conditioning principles (i.e., the pairing of a new taste with a nausea-producing manipulation). Lithium chloride is most com-monly used, even though there are now many more precise brain manipulations, such as stimulation of 5HT3 and Substance P receptors (see below).

Indeed , the human brain consequences of such conditioning could be evaluated with human brain-imaging. The conditioning could be done off-line (i.e., outside the scanner), which prevents people from being confronted with

unconditional nausea-promoting stimuli in the scanner. Such procedures may be also useful for delineating the circuitry for the associated fixed action patterns, such as gaping in rats ( Limebeer et al. , 2006 ).

Beside the ability to control this powerful affect experimentally with a large number of distinct manipulations, the CTA paradigm pro-vides a variety of controls that would be desir-able to pursue both raw affective as well as learned-cognitive interactions (see, for exam-ple, Welzl et al. , 2001 ; Hall and Symonds, 2006 ) that reflect true life experiences but can also be submitted to tight experimental control. Indeed, there are two distinct types of taste conditioning that transpire ( Parker, 2003 ), one related to nau-sea (aversion) and one related to fear (avoid-ance), which can allow investigators to study two very distinct affects under almost identical conditions.

A great strength of this model is the abun-dance of neurochemical manipulations currently available to directly modify specific neurochem-ical aspects of the underlying affect-generating circuitry. This has arisen largely because of the medical importance of controlling nausea and malaise following radiation and chemothera-pies for cancers. Among the most commonly used anti-nausea agents are prochlorperazine, ondansetron and aprepitant. Their mechanisms of action are distinct and well-characterized, pharmacologically, neurochemically and func-tionally – especially for the latter two agents. Ondansetron is a specific serotonin 5-HT3 receptor antagonist, and aprepitant selectively blocks the NK1 tachykinin (i.e., Substance P) receptor. The former generally has a more restricted therapeutic profile ( McAllister and Pratt, 1998 ). Although ondansetron can reverse classic lithium chloride-induced CTAs ( Balleine et al. , 1995 ) as well as aversions induced by imbalanced amino acid diets ( Terry-Nathan et al. , 1995 ), many other nausea-provoking emet-ics are not effectively reversed by ondansetron ( Rudd et al. , 1998 ).



13REFERENCES

The large number of neurochemical manipu-lations for generating nausea, from apomorphine to 5-HT3 and Substance P receptor agonists ( Landauer et al. , 1995 ; Ciccocioppo et al. , 1998 ) provides an armamentarium of convergent manipulations for actually taking the analysis of this affect to a fine circuit level in both animals and humans. At present, there is to our know-ledge not a single brain-imaging study that has sought to study this as a model system – one that has all the desired advantages for a thorough scientific analysis, and perhaps none of the dis-advantages of weak and ephemeral affects that are commonly used in human brain imaging of affective processes. The disadvantage is that these are experiments that one would not want to impose on non-medically sophisticated vol-unteer subjects. This may also be a blessing for obtaining the highest quality data from pro-fessionally qualified individuals.

1.5 CONCLUSION

Affective changes in energy regulatory stud-ies have been neglected because it is widely assumed that qualities of animal minds cannot be systematically studied. That is wrong. Affects are ancient solutions for living, and primary-process variants appear to be a shared heritage in all mammals. Thus, we are finally in a posi-tion empirically to evaluate such issues in ani-mals. Once we begin to do this with the wide array of objective measures that are available, we may be able to identify useful appetite regu-lating agents more readily than if we just con-tinue traditional behavior-only analyses.

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The Pleasures and Pains of Brain Regulatory Systems for Eating · Diano, 2004 ; Broeberger, 2005 ; Konturek et al., 2005 ; Gao and Horvath, 2007 ; Coll et al., 2008 ). In brief, there