Experimental and Clinical Psychopharmacology 2001, Vol 9, No 2, 144-147 Copyright 2001 by the American Psychological Association, Inc 1064-1297/01/$5.00 DOI: 10.1037//1064-1297.9.2.144 No Thanks, I'm Good Any More and I'll Be Sick: Comment on Lynch and Carroll (2001) Peter R Killeen and Mark P Reilly Arizona State University W J Lynch and M E Carroll's (2001) excellent analyses of drug intake from a regulation perspective are formalized in terms of control systems Satiation corresponds to the set point, deviations below which are called hunger or craving, deviations above which are called surfeit Although simple, the model provides a unifying framework for many of the phenomena Lynch and Carroll describe You never know what is enough unless you know what is more than enough —William Blake, The Marriage of Heaven and Hell Regulation entails both up-regulation and down-regulation For food, the psychological state corresponding to up-regulation is called hunger, and the psychological state corresponding to down-regulation is called surfeit There is a threshold for initiating (or terminating) intake, centered around the set point This quiescent intermediate state is called satiation (see Figure 1, Panel A) Deviations in both directions are aversive: Animals avoid hunger by responding for food and approaching locations where it is present; they avoid surfeit by ceasing to respond for food and leaving locations where it is present Animals must learn when food ceases to be reinforcing because of satiation (Dickinson & Balleine, 1995; Dickinson, Balleine, Watt, Gonzalez, & Boakes, 1995) and when it will be punishing because of surfeit Without the opportunity to learn that large intakes cause surfeit, animals may never learn to down-regulate Many children's eyes are bigger than their stomachs—until their eyes have learned the size of their stomachs Many "bad trips" result from the lag between consumption of drugs and the aversive properties of surfeit This is a special problem for drugs whose immediate effects overshadow their aversive effects Brief sessions should provide greater opportunity to learn than long sessions, because the aversive consequences of overindulgence are not overshadowed by the positive effects of continued consumption This is not the case for extended sessions, which, as Lynch and Carroll note, often lead to toxic overconsumption Lynch and Carroll (2001) provide an excellent overview of an understudied topic, drug intake from a regulation perspective They provide a pertinent summary of the literature, a concise review of procedures used to assess drug intake, and an informed discussion of response-rate-decreasing mechanisms The inverted U dose-response function of drug self-administration is familiar to every reader of this journal The ascending limb reflects the increasing reinforcing effectiveness of the drug as dose increases No controversy there It is the descending limb that often causes consternation, and it is on that that Lynch and Carroll focus their analysis Why should response rates decrease with further increases in dose? Lynch and Carroll entertain three plausible explanations—aversive effects, direct effects, and satiation Satiation as a Set Point Regulation of intake was defined as "responding so as to achieve a relatively constant level of intake over a specified time period" (Lynch & Carroll, 2001, p 6) The specification of the time period is crucial: Regulation over a long interval may not be manifest as regulation over shorter intervals Global equilibria may be based on local oscillations around a dynamic equilibrium An explicit model of regulation reconciles these molar and molecular effects We offer such a model First we list the model's general assumptions and then demonstrate the implications with a simple instantiation The model is appropriate for both food and drug intake, with the modification that in the latter case the set point may shift because of the development of tolerance or sensitization Avoiding Hunger and Surfeit Our model was developed to portray the patterns of intake described by Lynch and Carroll (2001) To be concise we use drugs as the paragon, but the same model governs food self-administration Consider the following control system: Drugs move the state of the organism r units from craving through satiation toward surfeit Drugs are metabolized at the rate of m per unit of time (determined by the drug's pharmacokinetics), moving the organism from surfeit through satiation toward craving Behavior is engaged toward or away from a drag depending on whether the state is one of craving or surfeit (see Figure 1, Panel B) This model assumes that the conditional discriminations of approach to drugs in the presence of craving and avoidance Peter R Killeen and Mark P Reilly, Department of Psychology, Arizona State University Correspondence concerning this article should be addressed to either Peter R Killeen or Mark P Reilly, Department of Psychology, Arizona State University, PO Box 871104, Tempe, Arizona 85287-1104 Electronic mail may be sent to either killeen@asu.edu or mpreilly@asu.edu 144 REGULATING INTAKE, UP AND DOWN: COMMENT a Q 10 Intake Intake i•£3 " 10 11 12 13 Intake Time Figure Panel A: the relation between drive toward food and intake Negative drives correspond to aversions Panel B: the overshoot that results from a satiation threshold Panel C: the resulting cycle of behavior around the set point; in this case, behavior never settles at that point but is in dynamic equilibrium around it Panel D: responding as a function of time Once the animal satiates, it is quiet until metabolism carries it above the action threshold, when it responds until repleted once again of drugs in the presence of surfeit have been learned The motivation of the organism is a joint function of the incentive value of the drug and the deviation of the state from the set point (satiation) 145 Large doses or powerful drugs provide strong incentive motivation and thus move a deprived organism more forcibly toward the set point However, they also satiate the animal more quickly and are often more aversive when the animal is surfeited In such cases, the restoring forces are strong Intake will settle around the point where these forces balance Strong restoring forces often cause oscillation around the equilibrium (Figure 1, Panel C) Weaker drugs and smaller amounts entail weaker restoring forces and a more gradual (overdamped) approach to equilibrium Normally, we eat more slowly toward the end of a meal and stop when satiated This control can be thwarted if a food with high incentive value—a dessert—is quickly presented, leading to overconsumption into the range of surfeit The deviation from set point is called drive Often, there is a lag in the force of surfeit because incentive motivation operates before the drive is adjusted by metabolism of the incentive—food tastes good in the mouth before it distends the stomach Desserts offered too late after the main course are more likely to be rejected as metabolism of the main course has finally carried the organism to the threshold of surfeit Satiation is a neutral state If it requires a minimal amount of drive to move the animal to approach or avoid, then intake will be periodic (Figure 1, Panel D) The Appendix displays the code for the simulations The amount of drug and interinjection interval were varied, with the results presented in Figure The ordinate represents the behavior of the animal; above zero is appetitive-responding and below zero is avoidance-responding The decrease in responding observed in the left portion of the graphs is a satiation curve Patterns generated are similar to those described by Lynch and Carroll (2001) When amount is small and the interdose intervals are long, the animal never reaches a state of surfeit (i.e., it continually self-administers the drug; top curve, top panel) With larger amounts and shorter interdose intervals, however, the animal becomes satiated and ceases to respond for the drug for longer periods of time The period and amplitude of the cycles would increase with increasing values of the threshold parameter If the amount of drug is varied randomly across trials, those trials following a larger than average dose will have a longer than average latency before appetitive-responding resumes Figure shows the results of these simulations, plotted as latency to the next dosage as a function of the amount of the preceding dose The positive correlation of these variables is similar to those reported by Lynch and Carroll (2001) with cocaine and heroin (Lynch, LaBounty, & Carroll, 1998, Figure 3) The characterization follows that this system is critically damped (smooth) for intakes of incentives within the range of the ecological niche of the organism It is overdamped (relatively unresponsive) when incentives are small or infrequent; it is underdamped (overly responsive) when incentives are potent or frequent Regulation comprises a nested set of macro and micro adjustments of the organism Animals that have evolved in an unstable environment reduce intake variance by hoarding food in nests and caches, 146 KILLEEN AND REILLY crops, cheeks, and adipose tissue In one ant species, individuals called "repletes" with highly distensible stomachs are used as storage vessels These behavioral and structural adaptations are the logical extension of internal adjustments concurrently effected on the neural and metabolic levels In conclusion, Lynch and Carroll (2001) convincingly argue that satiation can be one mechanism that regulates intake In general we agree, but in particular we suggest that satiation is not so much a mechanism as a set point in a Amount = Amount = 3; IDI = 28 Preceding amount 24 Figure Results of a second simulation with amount randomly determined at each trial Latency to initiate the next dose is measured in arbitrary units and plotted against the preceding amount IDI = interdose intervals 20 16 "S 12 m 25 50 75 100 125 150 175 200 Time Amount = 80 60 40 D 20 CO regulatory system, one that organisms approach rather than avoid Deviation on either side motivates behavior—either to approach the drug when individuals are up-regulating or to avoid it when they are down-regulating The state underlying up-regulation is hunger in the case of food, craving in the case of drugs The state underlying down-regulation is surfeit Behavioral approach and avoidance is just the coarsest and most visible regulatory mechanism, with capillary, transport, and synaptic mechanisms providing a secondary and more refined defense of the stability of the milieu interior This amplification of Lynch and Carroll's insights may encourage a more unified approach to the behavioral aspects of regulation, as it operates on both sides of the set point of satiety—whether in helpful cooperation or in dysfunctional contest with internal mechanisms References -20 25 50 75 100 125 150 175 200 Time Figure Results of simulation showing responding as a function of time and intake measured in arbitrary units Behavior was simulated at interdose intervals (IDIs) of 1, 5, and 10 The original state was one of depletion, so the trajectories represent the onset of fast responding upon introduction to the chamber, followed by a decreasing satiation trajectory Top panel: With each dose constituting a small amount, depending on the IDI animals may continue to respond at maximal levels, a situation akin to many operant experiments If satiation occurs, regulation around the set point is finely tuned Bottom panel: With larger doses, animals satiate at all IDIs Regulation around the set point is cruder Dickinson, A., & Balleine, B (1995) Motivational control of instrumental action Current Directions in Psychological Science, 4, 162-167 Dickinson, A., Balleine, B., Watt, A., Gonzalez, F., & Boakes, R A (1995) Motivational control after extended training Animal Learning and Behavior, 23, 197-206 Lynch, W J., & Carroll, M E (2001) Regulation of drug intake Experimental and Clinical Psychopharmacology, 9, 131-143 Lynch, W J., LaBounty, L P., & Carroll, M E (1998) A novel paradigm to investigate regulation of drug intake in rats selfadministering cocaine or heroin intravenously Experimental and Clinical Psychopharmacology, 6, 22-31 Microsoft QuickBASIC 4.5 [Computer language] (1985) Redmond, WA: Microsoft Corporation REGULATING INTAKE, UP AND DOWN: COMMENT 147 Appendix Code for Simulations Code for Figure For i = to 200 State = State — metabolism IF (i MOD IDI) = then Reaction = amount A prw * (optimal — State) IF Reaction > (Setpt + threshold) then State = State + amount END IF Behav(num) = Reaction num = num + NEXTi Calculate drive state; for proportional depletion substitute State = State*(metabolism) food or drug is made available every IDI ticks define reaction potential as a power-function of deviation intake occurs only if animal is up-regulating (e.g., hungry enough) record resulting behavior as a function of epoch Code for Figure For i = to 500 Amount = RND * 10 State = State - metabolism IF (i MOD IDI) = then Reaction = A pwr * (optimal — State) IF Reaction > (Setpt + threshold) then State = State + amount k = k + amount (k) = amount time (k) = i latency (k - 1) = i - time (k - 1) END IF END IF Behav(num) = Reaction num = num + NEXTi randomly change amount each trial within range of 0-10 Calculate drive state; for proportional depletion substitute State = State*(metabolism) food or drug is made available every IDI ticks define reaction potential as a power-function of deviation (average incentive motivation is 5) intake occurs only if the animal is up-regulating (e.g., hungry enough) the amount that is received for the last response the epoch at which it is received how long it takes for another approach response to occur after an intake of this magnitude record resulting behavior as a function of epoch Note The above code was written in Quickbasic Variables were set as amount = 3, optimal = 25, pwr = 1, set-point = 0, metabolism = 1, and threshold = Received September 5, 2000 Revision received September 10, 2000 Accepted September 15, 2000 ... These behavioral and structural adaptations are the logical extension of internal adjustments concurrently effected on the neural and metabolic levels In conclusion, Lynch and Carroll (2001) convincingly... appetitive-responding and below zero is avoidance-responding The decrease in responding observed in the left portion of the graphs is a satiation curve Patterns generated are similar to those described by Lynch and. .. 175 200 Time Figure Results of simulation showing responding as a function of time and intake measured in arbitrary units Behavior was simulated at interdose intervals (IDIs) of 1, 5, and 10 The