Effects of Methylphenidate and Morphine on Delay-Discount Functions Obtained Within Sessions

JOURNAL OF THE EXPERIMENTAL ANALYSIS OF BEHAVIOR 2005, 83, 297–314 NUMBER 3(MAY)

EFFECTS OF METHYLPHENIDATE AND MORPHINE ON DELAY-DISCOUNT FUNCTIONS OBTAINED WITHIN SESSIONS

RAYMOND C. PITTS AND A. PATRICK MCKINNEY

UNIVERSITY OF NORTH CAROLINA WILMINGTON

Four rats responded under a ‘‘self-control’’ procedure designed to obtain delay-discount functions within sessions. Each session consisted of seven blocks, with seven trials within each block. Each block consisted of two initial forced-choice trials followed by five free-choice trials. On choice trials, the rats could press either of two retractable levers. A press on one lever was followed by presentation of a smaller reinforcer (a single dipper presentation of a sucrose solution); a press on the other lever was followed by presentation of a larger reinforcer (four consecutive dipper presentations). The delay associated with the smaller reinforcer always was 0 s, whereas the signaled delay associated with the larger reinforcer increased across blocks (from 0 to 50 s). Under these conditions, the percentage of choices of the larger reinforcer decreased across blocks, and relatively reliable delay-discount functions were obtained within sessions. Doses of methylphenidate (1.0 to 17.0 mg/kg) and morphine (0.3 to 17.0 mg/kg) were then administered prior to selected sessions. Typically, intermediate doses of methylphenidate shifted the discount functions to the right (increased choices of the larger reinforcer). For 2 of the rats, this effect was pronounced; for the other 2 rats, this effect occurred after the range of delays for the larger reinforcer was decreased (0 to 20 s). On the other hand, in most cases morphine produced a slight leftward shift in the discount function (decreased choices of the larger reinforcer). The present procedure appears to be a useful and efficient method to characterize drug effects on an entire delay- discount function. As with many procedures used to study self-control choices, however, sources of control other than reinforcement delay and amount may have been operating in the present study, and these sources must be considered when interpreting drug effects. Key words: delay discounting, self-control, choice, methylphenidate, morphine, lever press, rats ______

When experimental subjects are confronted former and show ‘‘self-control’’ when it with a choice between a smaller, more chooses the latter (see Logue, 1988). Under immediate reinforcer and a larger, more these types of conditions (hereafter referred to delayed reinforcer, an individual is said to as ‘‘self-control procedures’’), selecting the behave ‘‘impulsively’’ when it chooses the smaller, more immediate reinforcer apparently results from the diminished effectiveness of This research was supported by a Charles L. Cahill the larger reinforcer by the longer delay. Data Award and a Summer Research Initiative awarded to from a number of studies suggest that the the first author from the University of North Carolina effectiveness of a reinforcer is a decreasing, Wilmington (UNCW). Preparation of this paper was supported by a UNCW research reassignment award to hyperbolic function of its delay (e.g., Green, the first author. The animals used in this study were cared Myerson, Holt, Slevin, & Estle, 2004; Mazur, for in accordance with the guidelines established by the 1987, 1988; Richards, Mitchell, de Wit, & UNCW Institutional Animal Care and Use Committee and Seiden, 1997). Such ‘‘delay discounting’’ by the Office of Laboratory Animal Welfare of the National Institutes of Health. Some of these data were presented appears to represent an important behavioral previously at the 2001 meeting of the Association for process. Indeed, several maladaptive behavior Behavior Analysis in New Orleans, LA. The authors wish to patterns have been conceptualized within this thank Drs. Christine Hughes and Mark Galizio for their framework, including drug abuse, needle helpful comments on an earlier version of this paper, Dr. David Eckerman for the generous gift of the operant- sharing by drug users, overeating, procrastina- conditioning chambers, members of the Psychology tion, and attention deficit hyperactivity dis- Department at the University of Canterbury in New order (ADHD), to name just a few (e.g., Zealand (particularly Drs. Randolph Grace and Anthony Logue, 1995, 2000; Mazur, 1996; Odum, McLean) for their generosity during the first author’s research reassignment, and Dustin Stairs for his help with Madden, Badger, & Bickel, 2000; Rachlin, animal care. 1974; Simpson & Vuchinich, 2000). Address correspondence to Raymond C. Pitts, Drugs classified as psychomotor stimulants Department of Psychology, University of North Carolina (e.g., amphetamines and amphetamine- Wilmington, 601 S. College Road, Wilmington, North Carolina 28403-5612 (e-mail: [email protected]). like drugs) are often used therapeutically doi: 10.1901/jeab.2005.47-04 for impulsive/attentional disorders (e.g.,

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Campbell, Cueva, & Adams, 1999). A number Slatta, and Arntzen (1988) arranged condi- of recent studies have examined the effects of tions in which rats’ nose pokes to a target hole these drugs under self-control procedures in within a 4 6 5 array of holes were reinforced the laboratory. Under conditions most fre- according to a fixed-interval (FI) schedule. quently used to study self-control choices (i.e., Under nondrug conditions, nose poking when the delay to the larger reinforcer is showed a typical scalloped pattern. Further- explicitly signaled), stimulants typically in- more, the proportion of pokes to the target crease choices of the larger delayed reinforcer; and adjacent locations was an increasing this has been reported with both nonhumans function of time in the FI. Administration of (e.g., Cardinal, Robbins, & Everitt, 2000; Pitts lower doses of methylphenidate produced an & Febbo, 2004; Richards, Sabol, & de Wit, increase in the proportion of pokes to the 1999; Wade, de Wit, & Richards, 2000) and target and adjacent locations during the early humans (de Wit, Enggasser, & Richards, 2002; portion of the FI. Although there are several Pietras, Cherek, Lane, Tcheremissine, & potential interpretations, Sagvolden et al. Steinberg, 2003). It should be noted that in suggested that the methylphenidate-induced a few studies, decreases rather than increases change in the spatio-temporal distribution of in self-control choices following stimulant nose pokes might reflect an altered delay-of- administration have been obtained (e.g., reinforcement gradient. That is, they sug- Charrier & Theibot, 1996; Evenden & Ryan, gested that methylphenidate attenuated the 1996; Logue, Tobin, Chelonis, Wang, Geary, & effects of reinforcement delay on responses Schachter, 1992). The specific variables re- early in the FI. Indeed, although there are sponsible for these differences across studies a variety of interpretations (e.g., Dews & have not been elucidated conclusively, but Wenger, 1977; Meck, 1983), the characteristic some data indicate that the nature of the increase in response rates early in the inter- stimulus conditions associated with the delay reinforcement interval under traditional FI may be important (see Cardinal et al., 2000; schedules of reinforcement following admin- also see Pitts & Febbo, 2004 and Richards istration of psychomotor stimulants can be et al., 1999 for additional discussions of these viewed as an attenuation of the effects of differences). reinforcement delay. Methylphenidate is classified as a mild The purpose of the present study was to stimulant with effects generally similar to examine effects of methylphenidate on choice those of the amphetamines under a variety of under a self-control procedure with rats. In an conditions (see Hoffman & Lefkowitz, 1996). attempt to characterize methylphenidate’s Despite its frequent use as a treatment for effects on the function relating choice to attentional disorders, its effects under labora- delay, a procedure similar to that used by tory self-control procedures have not been Evenden and Ryan (e.g., 1996, 1999) was studied nearly as extensively as those of the employed. These investigators used a within- amphetamines. To our knowledge, there are session procedure in which the delay to a larger no published reports of the effects of methyl- reinforcer escalates across blocks of choice phenidate on self-control choices in nonhu- trials. This procedure provides an efficient man animals. Pietras et al. (2003) examined method for examining drug effects on the effects of methylphenidate on delay-discount- entire delay-discount function. In the present ing in adult humans with a history of criminal study, rats were given repeated choices be- behavior. They reported that methylphenidate tween a larger reinforcer and a smaller, increased choices of a larger, more delayed immediate reinforcer. Each session began with reinforcer (points that were exchanged for the delay to the larger reinforcer set equal to money at the end of each session) in 7 of 11 that of the smaller reinforcer (0 s). The subjects. signaled delay to the larger reinforcer was In addition to the data with methylpheni- manipulated across blocks of trials such date reported by Pietras et al. (2003), and the that a delay-discount function was obtained data with other psychomotor stimulants within each session. After stable daily dis- reviewed above, there are other reasons to count functions were established, effects of suspect that methylphenidate might increase various doses of methylphenidate were self-control choices in nonhumans. Sagvolden, examined. DRUGS AND DELAY-DISCOUNT FUNCTIONS 299

For comparison, effects of the m-opiate When the dipper was raised, the cup con- agonist morphine also were assessed. It was tained a 0.02 cc drop of a 15% (w/v) solution reported recently that this drug decreased of sucrose in water, a 28 V DC lamp illu- self-control choices in rats responding under minated the opening, all other lights in the an adjusting-amount procedure (Kieres, chamber were extinguished, and the levers Hausknecht, Farrar, Acheson, de Wit, & were retracted. Each dipper presentation pro- Richards, 2004). Thus the present study provided 3-s access to the sucrose solution. When vided an assessment of the reliability and extended, each lever required a downward generality of those findings, along with in- force of approximately 0.25 N to operate; lever formation about the effects of morphine on extension/retraction required approximately the shape of the entire discount function. 1.0 s. Continuous white noise was present in the surrounding room and within each enclosure METHOD to mask extraneous sounds, and each enclo- Subjects sure was equipped with a ventilation fan that Four male Holtzman Sprague-Dawley rats provided air circulation within the experimen- (P1, P2, P3, and P4), between 90 and 120 days tal space. Experimental events were programmed and data were recorded from an old at the start of the study, served as subjects. adjoining room by an MS-DOS-controlled The rats were housed individually in a colony 80486 microcomputer using Med AssociatesH room and were maintained under a regimen (Georgia, VT) software and interface equip- of food and water restriction. This regimen ment operating at 0.01-s resolution. involved providing access to food and water for 1 hr, beginning approximately 30 min after Procedure each session (or at the corresponding time on days in which sessions were not conducted). Preliminary training. Following adaptation This resulted in approximately 21 hr of food to the chamber (two 30-min sessions) and and water deprivation prior to each experi- magazine training, lever pressing was shaped mental session. Under this regimen, the rats’ by differentially reinforcing successive approx- weights ranged from approximately 350 to imations. Initially, 2 rats (P1 and P2) were 450 g. trained to press the right lever and 2 rats (P3 and P4) were trained to press the left lever. Apparatus During these sessions, the houselight was illuminated, the active lever was extended, Two identical Lehigh Valley Electronics and the lamp above it was illuminated. After modular operant-conditioning chambers shaping, each response was reinforced (fixed- (model #E10-10SF, 29.0 cm long, 25.0 cm ratio [FR] 1) for two sessions; responses on the wide, and 29.0 cm high) were contained initially active lever were reinforced during the within sound-attenuating enclosures. The first session and responses on the other lever front and back walls and the ceiling of each were reinforced during the second session. In chamber were made of stainless steel, and each of these sessions, the inactive lever was the side walls were made of Plexiglas. The retracted and the lamp above it was off. These front wall of each chamber contained a 28-V sessions terminated following the 30th dipper DC houselight (#1820 bulb), two retractable presentation. Next, lever pressing was rein- levers (Med AssociatesH model #ENV112BM), forced under a multiple FR 1 FR 1 schedule. In two 28-V DC stimulus lamps (#1820 bulbs, one component, the left lever was extended each covered by a white lens cap), and a 3.0 by and in the other component, the right lever 4.0 cm opening into which a dipper cup could was extended. For Rats P1 and P4, while the be raised. The houselight was centered 3.0 cm right lever was extended, the lamp above it below the ceiling. Each lever was located blinked (0.3 s on, 0.3 s off) and while the left 7.0 cm from the grid floor, with the edge lever was extended, the lamp above it was con- 1.0 cm from its respective side wall. Each tinuously illuminated; for Rats P2 and P3, this stimulus lamp was located 7.0 cm directly relation was reversed. Each press on the lever above its corresponding lever, and the dipper below the blinking lamp retracted the lever opening was centered 4.0 cm from the floor. and produced four consecutive presentations 300 RAYMOND C. PITTS and A. PATRICK MCKINNEY of the dipper, each separated by 0.5 s (the remaining blocks while the contingencies larger reinforcer). Each press of the lever associated with the smaller reinforcer re- below the continuously illuminated lamp mained the same. Under these conditions, retracted the lever and produced one pre- each choice of the larger reinforcer initiated sentation of the dipper (the smaller reinforc- a signaled delay. During the delay, the house- er). Each exposure to a component lasted for light and the lamp above the other lever were one reinforcer, and each reinforcer delivery extinguished, both levers were retracted, and was followed by a 5-s blackout, during which the lamp above the lever associated with the both levers were retracted. Sessions ended larger reinforcer continued to blink. At the after 42 reinforcer deliveries (21 of each type). termination of the delay, the blinking lamp The order of exposure to the components was extinguished and the larger reinforcer was within each session was semirandom with the delivered. restriction that no component could be pre- For each block, the first two trials were sented for more than three consecutive reinforced trials, one of each choice type, in which forcers. only one of the levers was extended and the After 10 sessions, a discrete-trials choice contingencies associated with pressing that procedure was implemented. Each session lever for that block were in effect. That is, for consisted of 42 trials and each trial began with each block, the forced trial involving the larger the illumination of the houselight. After 2 s, reinforcer arranged the delay value in effect both levers extended, and the lights above for the remaining choice trials of that block. them were illuminated (one blinking and one The order of the forced trials across blocks was continuously). The contingencies associated semirandomly determined with the restriction with each lever were the same as those that no trial type could appear first for more described above; pressing one lever (below than three consecutive blocks. The remaining the blinking lamp) produced the larger re- five trials of each block were choice trials. inforcer and pressing the other lever (below Trials were separated by ITIs. Within blocks, the continuously illuminated lamp) produced each trial was presented 90 s following the the smaller reinforcer. Each lever press choice response of the previous trial. Thus the retracted both levers and resulted in an duration of each ITI was 90 s minus delay and immediate presentation of the corresponding reinforcement time. The ITIs between blocks reinforcer. Trials were separated by 60-s in- were longer than those between trials within tertrial intervals (ITIs), during which all lights a block; the first trial of each block was were extinguished and the levers retracted. presented 120 s following the choice response For each of the rats, this procedure remained on the last trial of the previous block. With this in effect until an exclusive preference for the arrangement, the rate at which trials occurred larger reinforcer occurred for at least five was unaffected by choice (i.e., choosing the consecutive sessions; this required between 21 smaller reinforcer did not increase the rate at and 27 sessions. which the rats could choose). Thus ITIs Experimental procedure. During the remain- following choices of the larger reinforcer were der of the study, the delay to the larger shorter than those following choices of the reinforcer was manipulated within each ses- smaller reinforcer. sion. Each session lasted 49 trials or 90 min, Initially, different sequences of larger re- whichever occurred first. The events compris- inforcer delays were implemented, each for ing the trials were similar to those described several sessions, in hopes of achieving a sensi- above: the houselight illuminated for 2 s, tive baseline against which to assess effects of followed by lever extension and illumination drugs. The sequence of delay values used of the corresponding lever lamp(s). The 49- during drug testing was 0, 5, 10, 20, 30, 40, trial sessions were divided into seven blocks of and 50 s. These values were arrived at by seven trials each. During the first block of each examining daily functions for each rat (see session, the contingencies were exactly as Data Analysis) and selecting those that pro- those described above; the rats chose between duced a pattern of choice most closely re- the immediate larger reinforcer and the sembling an exclusive preference for the immediate smaller reinforcer. The delay to larger reinforcer for the first block or two, the larger reinforcer was increased across the followed by a transition to an exclusive DRUGS AND DELAY-DISCOUNT FUNCTIONS 301 preference for the smaller reinforcer over the functions). Methylphenidate was tested first last two or three blocks. Following determina- (all 4 rats), followed by morphine (Rats P1, tion of dose-effect functions at these values, P2, and P3). The delay values for Rats P2 and the sequence of delays for Rats P2 and P4 was P4 then were altered and, after stable per- changed to 0, 2, 4, 8, 12, 16, and 20 s and the formance was reestablished, effects of several dose-effect functions for methylphenidate doses of methylphenidate were redetermined. were redetermined (see Pharmacological pro- A 2-week period without injection intervened cedure). between termination of testing with one drug Once or twice per week (on Monday, and initiation of testing with another; sched- Tuesday, and/or Wednesday), a no-delay uled experimental sessions continued during control procedure was conducted in which this period. Effects of each dose and saline the larger reinforcer was presented immedi- were determined at least twice, and in some ately (0-s delay) in all blocks. These sessions cases three or four times (when effects of the provided an indication of the degree to which first two determinations were discrepant). the choice pattern in a given session was Doses were tested in an irregular order with controlled by the currently programmed the restriction that no dose was tested a delays rather than (or in addition to) other second time before all doses had been tested variables (e.g., a particular choice history). On once. Because of their advanced ages, re- rare occasions, a subject (usually Rat P4) determination of the methylphenidate dose- chose the smaller reinforcer on several trials effect function at the altered delay values during a no-delay control session. When this for Rats P2 and P4 involved a single deter- occurred, the next scheduled injection was mination of selected doses. cancelled and additional no-delay control sessions were conducted until a substantial Data Analysis preference for the larger reinforcer during The primary dependent measure was the these conditions was recovered. number of larger reinforcer choices per block Sessions were conducted 5 days per week (maximum value 5 5). For each session, (Monday through Friday). Once choice pat- a discount function for each rat was obtained terns under the experimental procedure by plotting the number of larger reinforcer appeared consistent for 10 consecutive ses- choices as a function of its delay; for the no- sions, as determined by inspection of daily delay control sessions, the number of large discount functions, drug testing was imple- reinforcer choices was plotted as a function of mented. The number of baseline sessions block. Drug effects were characterized by conducted at the 0- to 50-s delay sequence averaging the discount functions across ses- prior to the initiation of drug testing was 88 sions for no-injection control conditions, for (13 of which were no-delay control sessions), sessions following saline injections (‘‘saline 99 (22), 87 (13), and 98 (23) for Rats P1, P2, sessions’’), and for sessions following injection P3, and P4, respectively. of each drug dose. Whenever a session ended Pharmacological procedure. Methylphenidate via the time limit, the analysis included all hydrochloride (Sigma) and morphine sulfate trials up through the last completed block (from the National Institute on Drug Abuse; (i.e., trials from incomplete blocks were generously donated by Dr. Mark Galizio) were excluded). dissolved in 0.9% sodium chloride (saline) To characterize dose-effect functions, a sin- and injected i.p. in a volume of 1.0 ml/kg. gle measure for each session was obtained. Saline, methylphenidate (1.0 to 17.0 mg/kg), This measure, referred to as the delay of or morphine (0.3 to 17.0 mg/kg) was injected indifference, served as an estimate of the delay 15 min prior to selected sessions. Doses are value at which both options would be chosen expressed in terms of the salt forms listed equally. The delay of indifference was above. Injections always occurred on Fridays, obtained by finding the two delay values with the data from the preceding Thursday adjacent to the point at which the function serving as a no-injection control. A scheduled crossed 2.5 (the midpoint on the y axis), and injection was cancelled if the data from its no- then estimating that point by interpolation. injection control appeared atypical (as de- Finally, overall response latency was collected termined by inspection of the discount on both forced and choice trials (defined as 302 RAYMOND C. PITTS and A. PATRICK MCKINNEY the time between extension of the lever(s) and drug were expressed as a percentage of data the subsequent press). These data were con- obtained during the corresponding saline verted to overall response speed (1/latency). If sessions (‘‘percent saline’’), in which the a session ended via the time limit and the average effect of each dose was divided by latency timer was running (i.e., if the session the average effect of saline and the result ended while the levers were extended), the multiplied by 100. time was included in the denominator of the speed calculation. Session averages for RESULTS delay of indifference and response speed were obtained under no-injection control condi- Control Performance tions and following administration of each Figure 1 shows discount functions for each dose and saline. Dose-effect functions for each rat under no-injection control conditions

Fig. 1. Number of larger reinforcer choices by individual rats as a function of delay, or block. Filled symbols show means from all no-injection control sessions (‘‘Drug Control’’) during determination of the effects of methylphenidate (n 5 12 for Rats P1, P2, and P3; n 5 11 for Rat P4); unfilled symbols show means from all no-delay control sessions (‘‘No Delays’’) during determination of the effects of methylphenidate (n 5 13 for Rat P1; n 5 12 for Rats P2 and P3; n 5 11 for Rat P4). Error bars show 95% confidence intervals. Absence of an error bar indicates that the confidence intervals fell within the area covered by the symbol. For Rat P2, the means at the 30-, 40-, and 50-s delays were obtained from fewer values than other means in the function as this rat occasionally failed to complete all blocks of the session (i.e., the session ended via the time limit). Only data from completed blocks were included in the analysis. DRUGS AND DELAY-DISCOUNT FUNCTIONS 303

(filled circles). During the first block, when Figure 4). Typically, administration of saline the delay for both reinforcers was 0 s, each rat had no effect on choice (see Figures 2 and 3). chose the larger reinforcer nearly exclusively. Figure 1 also shows performance under no- As its delay increased, the likelihood of delay control conditions (unfilled circles), in choosing the larger reinforcer decreased for which the delays for both the larger and all rats. Once the delay reached 30 s, all rats smaller reinforcer were 0 s across all blocks. chose the smaller reinforcer nearly exclusively. For all rats under these conditions, choices of The discount functions for Rats P2 and P4 the larger reinforcer substantially exceeded were steeper than those for P1 and P3. For those of the smaller reinforcer for all of Rats P1 and P3, a delay of 20 s was required to the blocks. For 3 of the 4 rats (P1 was the shift preference from the larger to the smaller exception), the likelihood of choosing the reinforcer, whereas for P2 and P4, nearly larger reinforcer was slightly lower in the later exclusive preference for the smaller reinforcer blocks than in the earlier blocks; this was most occurred at the 10-s delay. Note that Rat P2 prevalent with Rat P4. Note that Rat P2 often was slow to respond and, thus, sessions completed all of the sessions under the no- occasionally ended via the time limit (see delay control condition.

Fig. 2. Effects of selected doses of methylphenidate (MPD) on the discount functions for individual rats. Data in the center column for Rats P2 and P4 are from sessions with the original delay sequence, and data in the right column for these rats are from sessions with the altered delay sequence. Filled symbols show means from two to four determinations of the effects of saline; unfilled symbols in the left and center columns show means from two to three determinations of the indicated dose; unfilled symbols in the right column show effects of a single determination (note that a range for saline is shown in Rat P4(2)—this rat received saline twice under these conditions). Partial functions (e.g., Rat P4(2) at 17.0 mg/kg), noted by arrows, indicate that the rat did not complete the session(s) under this condition (i.e., sessions ended via the time limit); only data from completed blocks were included in the analysis. Error bars show ranges. 304 RAYMOND C. PITTS and A. PATRICK MCKINNEY

Table 1 Mean number of choices of the larger reinforcer for each rat at each delay for control sessions, saline sessions, and at each dose of methylphenidate under the original delay sequence (MPD1) and under the altered delay sequence (MPD2). Numbers in parentheses next to each condition label indicate the number of observations, and numbers in parentheses beside each mean value indicate ranges.

Delay to large reinforcer (s) Rat P1 0 5 10 20 30 40 50 Control (12) 5.00 (5–5) 4.92 (4–5) 3.31 (2–5) 0.83 (0–2) 0.47 (0–2) 0.08 (0–1) 0.00 (0–0) Sal (3) 5.00 (5–5) 5.00 (5–5) 4.33 (3–5) 0.00 (0–0) 0.00 (0–0) 0.33 (0–1) 0.67 (0–1) 1.0 mg/kg (2) 5.00 (5–5) 5.00 (5–5) 3.00 (2–4) 1.50 (1–2) 0.50 (0–1) 0.00 (0–0) 0.00 (0–0) 3.0 mg/kg (2) 5.00 (5–5) 5.00 (5–5) 5.00 (5–5) 2.50 (1–4) 0.00 (0–0) 0.00 (0–0) 0.00 (0–0) 5.6 mg/kg (2) 5.00 (5–5) 4.50 (4–5) 4.50 (4–5) 3.00 (2–4) 1.00 (0–2) 0.00 (0–0) 0.00 (0–0) 10.0 mg/kg (3) 5.00 (5–5) 5.00 (5–5) 3.67 (2–5) 2.33 (2–3) 0.67 (0–2) 0.67 (0–1) 0.50 (0–1)a Rat P2 MPD 1 0 5 10 20 30 40 50 Control (12) 4.54 (3–5) 1.08 (0–3) 0.62 (0–1) 0.23 (0–1) 0.00 (0–0)a 0.00 (0–0)a 0.00 (0–0)a Sal (4) 4.75 (4–5) 0.50 (0–1) 0.00 (0–0) 0.00 (0–0) 0.00 (0–0)a 0.00 (0–0)a 0.00 (0–0)a 1.0 mg/kg (2) 4.50 (4–5) 0.00 (0–0) 0.00 (0–0) 0.00 (0–0) 0.00 (0–0) 0.00a 0.00a 3.0 mg/kg (2) 5.00 (5–5) 2.00 (2–2) 0.50 (0–1) –b –b –b –b 5.6 mg/kg (2) 4.50 (4–5) 1.50 (0–3) 0.00 (0–0) 0.00a 0.00a –b –b 10.0 mg/kg (1) 5.00 2.00 –b –b –b –b –b MPD 2 0 2 4 8 12 16 20 Control (5) 5.00 (5–5) 2.20 (1–5) 1.00 (0–3) 0.40 (0–1) 0.00 (0–0) 0.00 (0–0) 0.00 (0–0) Sal (1) 5.00 3.00 1.00 0.00 0.00 0.00 0.00 1.0 mg/kg (1) 5.00 5.00 1.00 1.00 0.00 0.00 0.00 3.0 mg/kg (1) 5.00 2.00 1.00 0.00 0.00 0.00 1.00 5.6 mg/kg (1) 5.00 4.00 5.00 2.00 0.00 0.00 0.00 10.0 mg/kg (1) 5.00 1.00 3.00 2.00 –b –b –b Rat P3 0 5 10 20 30 40 50 Control (12) 5.00 (5–5) 4.83 (4–5) 3.17 (1–5) 0.75 (0–2) 0.17 (0–1) 0.17 (0–1) 0.00 (0–0) Sal (4) 5.00 (5–5) 4.50 (4–5) 2.25 (1–4) 0.25 (0–1) 0.00 (0–0) 0.00 (0–0) 0.00 (0–0) 1.0 mg/kg (2) 5.00 (5–5) 5.00 (5–5) 5.00 (5–5) 0.00 (0–0) 0.00 (0–0) 0.50 (0–1) 0.50 (0–1) 3.0 mg/kg (2) 5.00 (5–5) 5.00 (5–5) 5.00 (5–5) 4.0 (4–4) 2.00 (1–3) 0.50 (0–1) 0.50 (0–1) 5.6 mg/kg (2) 5.00 (5–5) 5.00 (5–5) 3.50 (2–5) 2.50 (1–4) 2.50 (1–4) 1.50 (1–2) 1.50 (1–2) 10.0 mg/kg (2) 4.50 (4–5) 4.50 (4–5) 1.00 (1–1) 0.00a –b –b –b Rat P4 MPD 1 0 5 10 20 30 40 50 Control (11) 4.82 (4–5) 1.73 (0–4) 0.55 (0–2) 0.00 (0–0) 0.00 (0–0) 0.00 (0–0) 0.00 (0–0) Sal (2) 4.50 (4–5) 1.67 (1–4) 0.00 (0–0) 0.00 (0–0) 0.00 (0–0) 0.00 (0–0) 0.00 (0–0) 1.0 mg/kg (2) 4.00 (3–5) 1.00 (0–2) 0.00 (0–0) 0.00 (0–0) 0.50 (0–1) 0.00 (0–0) 0.00 (0–0) 3.0 mg/kg (2) 4.00 (3–5) 3.00 (1–5) 0.00 (0–0) 0.50 (0–1) 0.00 (0–0) 0.00 (0–0) 0.50 (0–1) 5.6 mg/kg (2) 4.50 (4–5) 2.50 (2–3) 0.50 (0–1) 0.00 (0–0) 0.00 (0–0) 0.50 (0–1) 0.00 (0–0) 10.0 mg/kg (2) 4.50 (4–5) 2.00 (1–3) 0.50 (0–1) 0.00 (0–0) 0.00 (0–0) 0.00 (0–0) 0.00 (0–0) MPD 2 0 2 4 8 12 16 20 Control (7) 4.43 (3–5) 2.00 (0–4) 0.00 (0–0) 0.00 (0–0) 0.00 (0–0) 0.14 (0–1) 0.00 (0–0) Sal (2) 3.50 (3–4) 0.50 (0–1) 0.00 (0–0) 0.00 (0–0) 0.00 (0–0) 0.00 (0–0) 0.00 (0–0) 1.0 mg/kg (1) 5.00 1.00 0.00 0.00 0.00 0.00 0.00 3.0 mg/kg (1) 5.00 1.00 0.00 0.00 0.00 0.00 0.00 5.6 mg/kg (1) 3.00 1.00 0.00 0.00 0.00 0.00 0.00 10.0 mg/kg (1) 5.00 3.00 2.00 0.00 0.00 2.00 0.00 17.0 mg/kg (1) 4.00 5.00 3.00 2.00 –b –b –b a did not finish this block in a subset of sessions; data presented only for sessions in which block was completed. b did not finish this block in any of the sessions.

Effects of Methylphenidate largest effects on choice; lower doses produced Figure 2 shows effects of selected methyl- little or no effect on choice and higher doses phenidate doses on the discount functions of tended to suppress responding substantially each rat, compared with performance follow- (see Figures 3 and 4). Table 1 shows data for ing saline administration (filled circles). The no-injection and saline control conditions and doses selected were those that produced the for all of the methylphenidate doses. For Rats DRUGS AND DELAY-DISCOUNT FUNCTIONS 305

Fig. 3. Dose-effect functions for methylphenidate on the delay of indifference (see text for a description of this measure), plotted as a percentage of data obtained from saline sessions. Dashed lines indicate the range of effects of saline; upper and lower lines show the results of taking the highest and lowest values, respectively, dividing those by the mean value and multiplying the result by 100. Note that the y axes differ across rats. A white dot within a symbol indicates that some of the data were obtained from sessions that ended via the time limit (only data from completed blocks were included). Vertical lines show ranges. The absence of a vertical line indicates that the range fell within that covered by the data point. Note that data in the right panels for Rats P2 and P4, and for 10.0 mg/kg in the center panel for Rat P2, were from a single determination (except that saline was given twice to Rat P4 at the altered delay sequence).

P1 and P3 (left panels), both 3.0 and 5.6 mg/ larger reinforcer at the 5-s delay and, for Rat kg clearly shifted the discount function to the P4, at some of the longer delays. None of the right. That is, at these doses, Rats P1 and P3 doses, however, shifted the discount function selected the larger reinforcer at longer delays appreciably in these rats. Note that Rat P2 did than under saline. For example, following not finish the sessions at either dose (see saline administration, a delay of 20 s produced response speed data in Figure 4). exclusive or nearly exclusive selection of the Altering the delays modified the effects of smaller reinforcer. At both 3.0 and 5.6 mg/kg, methylphenidate on the delay-discount func- however, both of these rats chose the larger tions for Rats P2 and P4 (right panels of reinforcer on 50% or more of the trials. Note Figure 2; also see Table 1). Under the altered that for both of these rats, 5.6 mg/kg pro- delay sequence, the effects of methylphenidate duced a larger effect than 3.0 mg/kg at the for Rats P2 and P4 were comparable to those longer delays, whereas at the shorter delays, obtained with P1 and P3 under the original the reverse was the case. delay sequence; for Rats P2 and P4, however, For Rats P2 and P4 at the original delay slightly higher doses were required to achieve values (middle panels of Figure 2), 3.0 and this effect. For Rat P2, 5.6 mg/kg produced 5.6 mg/kg slightly increased choice of the a substantial rightward shift in the function, 306 RAYMOND C. PITTS and A. PATRICK MCKINNEY

Fig. 4. Dose-effect functions for methylphenidate on response speed (see text for a description of this measure), plotted as a percentage of data obtained from saline sessions. Note that the y axes differ across rats. All other characteristics of this figure are as described in the caption of Figure 3. whereas this dose had only a slight effect at the saline, the average delay of indifference was original delays (other than to reduce response higher for Rats P1 and P3 (13.89 and 9.79 s, speed; see Figure 4). At this dose, Rat P2 respectively) than for Rats P2 and P4 (2.66 and finished the session under the altered delays, 4.69 s, respectively). For Rats P1 and P3, both but not under the original delays. At 10.0 mg/ 3.0 and 5.6 mg/kg increased this measure, kg, the number of larger reinforcer choices although for Rat P3 the effect of 5.6 mg/kg was increased for Rat P2 at delays of 4 and 8 s, was somewhat inconsistent. For Rat P1, the although this rat did not finish the session. For largest increase occurred at 5.6 mg/kg (from Rat P4, 10.0 mg/kg shifted the entire function 13.89 to 22.50 s, or more than 150% of saline), to the right and 17.0 mg/kg increased choices whereas for Rat P3, the largest increase of the larger reinforcer at the 2-, 4-, 8-, and 12-s occurred at 3.0 mg/kg (from 9.79 s to delays, although the session ended via the time 28.34 s, or more than 250% of saline). For limit at the higher dose. It should be noted Rat P2 at the original delays, 3.0, 5.6, and that, under nondrug conditions, the effects of 10.0 mg/kg all increased delay of indifference delay on choice were more pronounced at the to approximately 150% of saline. Note, how- altered delay sequence, particularly for Rat P4. ever, that, because the delay of indifference at That is, the actual delay at which choice shifted saline for this rat was relatively short (2.66 s), to the smaller reinforcer was shorter under the this effect represents a small absolute change altered delay sequence. (to between 3.85 and 4.16 s). None of the Figure 3 shows dose-effect functions for doses affected the delay of indifference for Rat methylphenidate on the delay of indifference P4 at the original delays. In contrast, the right (percent saline). These data corroborate those panels of Figure 3 show that for both Rats P2 shown in Figure 2. Following administration of and P4 under the altered delay sequence, the DRUGS AND DELAY-DISCOUNT FUNCTIONS 307

Fig. 5. Effects of selected doses of morphine (MOR) on the discount functions for Rats P1, P2, and P3. All other characteristics of this figure are as described in the caption of Figure 2. delay of indifference was substantially in- did not finish the session, even under nondrug creased by at least one dose (5.6 mg/kg for conditions, and responding was nearly com- Rat P2, and 10.0 and 17.0 mg/kg for Rat P4). pletely suppressed at doses above 1.0 mg/kg. For both rats, particularly P4, the delay of In contrast, none of the doses affected re- indifference measure under saline was slightly sponse speed for Rat P4 at the original delays. lower at the altered delay sequence than at the When the delay sequence was altered (right original sequence. panels), response speed for Rat P2 increased Figure 4 shows methylphenidate dose-effect under nondrug conditions (this rat reliably functions for response speed (percentage finished each session) and was less sensitive saline). For the most part, this drug produced to the effects of methylphenidate. For Rat dose-related decreases in this measure. For P4, this measure was less variable under Rats P1 and P3 (left panels), response speed the altered delay sequence than under the was decreased at the highest dose (10.0 mg/ original sequence. Note that under the kg), but was unaffected by doses that increased altered delays, the methylphenidate-induced the delay of indifference (3.0 and 5.6 mg/kg). shifts in the discount functions for both Rats For Rats P2 and P4, response speed during P2 (at 5.6 mg/kg) and P4 (at 10.0 mg/kg) saline sessions was highly variable at the origi- were accompanied by decreases in response nal delays (middle panels). Rat P2 sometimes speed. 308 RAYMOND C. PITTS and A. PATRICK MCKINNEY

Table 2 Mean number of choices of the larger reinforcer during determination of the morphine dose- effect curve. All characteristics of this table are identical to those described for Table 1.

Delay to large reinforcer (s) Rat P1 0 5 10 20 30 40 50 Control (13) 4.85 (4–5) 4.69 (3–5) 2.92 (0–5) 1.23 (1–3) 0.08 (0–1) 0.00 (0–0) 0.08 (0–1) Sal (3) 5.00 (5–5) 4.67 (4–5) 1.67 (1–2) 0.67 (0–1) 0.00 (0–0) 0.00 (0–0) 0.00 (0–0) 1.0 mg/kg (2) 5.00 (5–5) 5.00 (5–5) 2.50 (2–3) 0.00 (0–0) 0.00 (0–0) 0.00 (0–0) 0.00 (0–0) 3.0 mg/kg (2) 5.00 (5–5) 3.50 (2–5) 0.50 (0–1) 0.50 (0–1) 0.50 (0–1) 0.00 (0–0) 0.00 (0–0) 5.6 mg/kg (2) 5.00 (5–5) 4.50 (4–5) 1.00 (1–1) 0.00 (0–0) 0.00 (0–0) 0.00 (0–0) 0.00 (0–0) 10.0 mg/kg (2)5.00 (5–5) 3.50 (3–4) 0.50 (0–1) 0.00 (0–0) 0.50 (0–1) 0.00 (0–0) 0.50 (0–1) 17.0 mg/kg (2)5.00 (5–5) 1.50 (1–2) 1.00a 0.00a 0.00a –b –b Rat P2 Control (9) 4.40 (3–5) 0.80 (0–2) 0.00 (0–0) 0.00 (0–0) 0.00 (0–0) 0.00 (0–0)a 0.00 (0–0)a Sal (2) 5.00 (5–5) 0.50 (0–1) 0.00 (0–0) 0.00 (0–0) 0.00 (0–0) 0.00 (0–0) 0.00 (0–0) 0.3 mg/kg (2) 4.00 (3–5) 0.00 (0–0) 0.00 (0–0) 0.00 (0–0) 0.00 (0–0) 0.00 (0–0) 0.00 (0–0)a 1.0 mg/kg (2) 2.50 (2–3) 1.00 (1–1) 0.00 (0–0) 0.00 (0–0) 0.00 (0–0) 0.50 (0–1) 0.00 (0–0) 3.0 mg/kg (2) 0.00 (0–0) 0.00 (0–0) 0.00 (0–0) 0.00a 0.00a 0.00a 0.00a 5.6 mg/kg (1) –b –b –b –b –b –b –b Rat P3 Control (12) 5.00 (5–5) 4.50 (4–5) 1.42 (0–3) 0.17 (0–1) 0.08 (0–1) 0.08 (0–1) 0.17 (0–1) Sal (3) 5.00 (5–5) 4.00 (3–5) 0.67 (0–2) 0.00 (0–0) 0.00 (0–0) 0.33 (0–1) 0.00 (0–0) 1.0 mg/kg (2) 5.00 (5–5) 5.00 (5–5) 3.00 (3–3) 0.50 (0–1) 1.00 (1–1) 0.00 (0–0) 0.00 (0–0) 3.0 mg/kg (2) 5.00 (5–5) 3.00 (1–5) 2.00 (0–4) 2.00 (0–4) 1.00 (0–2) 0.50 (0–1) 0.00 (0–0) 5.6 mg/kg (2) 5.00 (5–5) 2.50 (2–3) 0.00 (0–0) 0.00 (0–0) 0.00 (0–0) 0.00 (0–0) 0.00 (0–0) 10.0 mg/kg (2)5.00 (5–5) 2.50 (2–3) 1.00 (0–2) 0.00 (0–0) 0.00a 0.00a 0.00a 17.0 mg/kg (1)4.00 –b –b –b –b –b –b a did not finish this block in a subset of sessions; data presented only for sessions in which block was completed. b did not finish this block in any of the sessions.

Effects of Morphine measure (note the aforementioned variation Figure 5 shows effects of selected morphine in the effects of 3.0 mg/kg). For all rats, at doses on the discount functions for Rats P1, least one (usually lower) morphine dose P2, and P3 (Table 2 contains data for all increased average response speed, although doses). With the exception of Rat P3 at this effect sometimes was quite variable (e.g., 3.0 mg/kg, these doses of morphine either Rat P2 at 1.0 mg/kg); higher doses decreased did not change, or produced a small leftward speed in all rats. shift in the discount function. A leftward shift occurred at 3.0 and 5.6 mg/kg for Rat P1, at DISCUSSION 1.0 and 3.0 mg/kg for Rat P2, and at 5.6 mg/ kg for Rat P3. At 3.0 mg/kg, Rat P2 chose the In the present study, reasonably consistent smaller reinforcer exclusively at all delay within-session, delay-discount functions were values. It should be noted that the discount generated in individual rats. The general function for Rat P3 at 3.0 mg/kg is the average characteristics of these functions resembled of two determinations, one in which the curve those obtained from previous studies using was shifted dramatically to the right and one in a similar within-session procedure (e.g., which the curve was shifted slightly to the left. Evenden & Ryan, 1996; 1999), as well as those Unfortunately, this dose was not administered obtained when delay parameters were manip- a third time. ulated across sessions (e.g., Green et al. 2004; Figure 6 shows dose-effect functions for Mazur, 1987, 1988; Richards et al., 1997). For 2 morphine on the delay of indifference (top of the rats (P1 and P3), at least two doses of panels) and response speed (bottom panels), methylphenidate clearly increased choices of expressed as a percentage of saline data. For a larger, more delayed reinforcer, resulting in Rats P1 and P2, morphine produced dose- a shift of the delay-discount functions to the related decreases in delay of indifference. For right. For the other 2 rats (P2 and P4), this Rat P3, 1.0 and 3.0 mg/kg increased, and effect was achieved following at least one dose 5.6 and 10.0 mg/kg slightly decreased, this under the altered delay sequence. In contrast, DRUGS AND DELAY-DISCOUNT FUNCTIONS 309

Fig. 6. Dose-effect functions for morphine on delay of indifference (top row) and response speed for Rat P1 (left column), Rat P2 (center column), and Rat P3 (right column), plotted as a percentage of data from saline sessions. Note that the y axes differ across rats. The absence of a data point in the top panels indicate that the dose was given but responding was suppressed to the extent that the delay of indifference could not be calculated (i.e., no blocks were completed). All other characteristics of this figure are as described in the captions of Figures 3 and 4. morphine tended to shift the discount func- self-control choice produced by morphine tion to the left. The different effects of methyl- here generally were comparable to the effects phenidate and morphine on choice are obtained by Kieres et al. (2004) under an potentially important. Not only do they sug- adjusting-amount procedure. These similari- gest a different profile of effects on self-control ties across studies likely are important. For choices for these two drugs, they also indicate example, the data from these studies illustrate that the present procedure is sensitive to some of the conditions under which psy- a range of drug effects. A shift to the right of chomotor stimulants may provide thera- the discount function, for example, is not an peutic benefit and illustrate some of the inevitable effect of pharmacological manipu- conditions under which opiates may produce lation. adverse effects on decision making. When The methylphenidate-induced increases in combined with knowledge of the physiological self-control choice obtained in the present and pharmacological actions of these drugs, study with rats were similar to those obtained these results suggest potential targets for by Pietras et al. (2003) with humans, and investigation of the neurobiological mechan- similar to the effects of amphetamines isms associated with behavioral processes in- obtained by several investigators (e.g., de Wit volved in self-control choices. et al., 2002; Pitts & Febbo, 2004; Richards et al., There are important limitations, however, in 1999; Wade et al., 2000). Furthermore, drawing general conclusions about the drug although not overwhelming, the decreases in effects on self-control choices. For example, 310 RAYMOND C. PITTS and A. PATRICK MCKINNEY individual differences in the effects of stimu- stimuli present during the delay to the larger lants are common in previous studies that reinforcer were unique (i.e., whether or not report individual-subject data (e.g., Pietras et they also were present during the ITI). al., 2003; Pitts & Febbo, 2004). Indeed, there Variability in the effects of stimulants on were clear differences in the effects of meth- self-control choices, both within and across ylphenidate across rats in the present study. studies, has important implications. Although Similarly, Pietras et al. reported that methyl- stimulants have been shown to attenuate phenidate failed to increase self-control patterns of behavior typically considered ‘‘im- choices in 4 of the 11 human subjects studied. pulsive’’ under a variety of procedures (e.g., de Whether or not such variation across indivi- Wit et al., 2002), it could be argued that duals is more characteristic with methylpheni- preference for a smaller, more immediate, date than with other stimulants is uncertain; reinforcer has become the gold standard test reports of individual-subject data have been of ‘‘impulsivity’’ (see Logue, 1995). Given the rare in previous studies with amphetamines variability in effects of stimulants under these (but see Pitts & Febbo, 2004). procedures, broad conclusions that stimulant The occasional reports of stimulant-induced drugs have a uniform and fundamental effect decreases in self-control choices also must be on some construct termed ‘‘impulsivity’’ may considered (e.g., Charrier & Thiebot, 1996; be unwarranted. Evenden & Ryan, 1996; Logue et al., 1992). It Additional sources of control should be is not clear why these investigators found considered when interpreting drug effects decreases, rather than increases, in self-control under self-control procedures. Several of the choices following stimulant administration. studies, including the present one, have in- Richards et al. (1999) suggested that these volved changing conditions within sessions results may relate to certain procedural charac- (e.g., Evenden & Ryan, 1996, 1999; Pietras et teristics. One possibility is that the differences al., 2003; Pitts & Febbo, 2004; Richards et al., in drug effects across studies depend on the 1999; Wade et al., 2000). Such procedures nature of the stimulus conditions associated might recruit sources of control over choice with the delays. In many of the studies that other than reinforcement amount and delay. show stimulant-induced increases in self-con- For example, in the present study it was trol choices (e.g., Pietras et al., 2003; Pitts & necessary to conduct no-delay control sessions Febbo, 2004; Richards et al., 1999; Wade et al., regularly (once or twice weekly) to maintain 2000; the present study), distinct stimulus relatively consistent delay-discount functions. conditions prevailed during the delays. After Despite regular exposure to the no-delay reinforcement, delay-correlated stimuli were control, the tendency to choose the larger turned off and the chamber was darkened reinforcer decreased slightly across blocks dur- until the start of the next trial. In the studies ing these sessions, particularly for Rats P2 and by Charrier and Thiebot and Evenden and P4 (Figure 1). Evenden and Ryan (1996, 1999) Ryan, choice trials were initiated by extension and Cardinal et al. (2000) reported a similar of retractable levers (as in the present study). effect. Furthermore, changing the sequence of Following a choice of the larger, delayed delays for Rats P2 and P4 did not affect the reinforcer, the levers retracted (which also discount functions as much as might have been occurred after a choice of the immediate predicted. Thus, under conditions in which reinforcer), but apparently no other stimulus reinforcement contingencies change within change occurred. Upon termination of the sessions, choice on a given trial can be delay, food was presented, but again, no controlled, at least in part, by variables other apparent stimulus change was programmed. than (or perhaps only indirectly related to) the That is, in those studies, the stimuli present amount and delay values in effect on that trial. during the delay and immediately after food For example, an extensive history of exposure to presentation were the same. These differences escalating delays might establish a persistent in delay-correlated stimuli across studies may pattern of behavior that is relatively resistant to be important in determining drug effects. short-term variation in conditions. Cardinal et al. (2000) reported that effects of It also is possible that drug-induced ‘‘per- d-amphetamine on self-control choices dif- severation’’ may have played a role in the shifts fered depending upon whether or not the of the discount functions obtained in the DRUGS AND DELAY-DISCOUNT FUNCTIONS 311 present study. Under control conditions, all an indirect role in determining the effects of rats began each session by responding exclu- methylphenidate on choice, particularly with sively on the large-reinforcer option. As the Rat P2. For this rat, methylphenidate did not delay increased, responding shifted to the appreciably alter the discount function at the small-reinforcer option. Methylphenidate may original delays. However, Rat P2 was particu- have increased, and morphine may have larly slow to respond under nondrug condi- decreased, the tendency to continue engaging tions at the original delays, and response speed in the response that was prevalent at the was quite sensitive to the effects of methylphe- beginning of the session (selecting the larger nidate. This may have prevented any effect of reinforcer). This interpretation of the present methylphenidate on choice from being results is weakened somewhat, however, by expressed at the moderate doses. Under the reports that both stimulants and opiates tend altered delays, Rat P2’s response speed in- to increase behavioral stereotypy, or persever- creased under nondrug conditions such that ation (e.g., Hoelter, Tzschentke, & Schmidt, all the trials typically were completed within 1996; Loh, Smith, & Roberts, 1993). the time limit. At these delays, 5.6 mg/kg Nevertheless, the contribution of persevera- methylphenidate shifted the discount function tion could be addressed by arranging a de- to the right. creasing sequence of delays within the session Despite the inconsistencies in drug effects, (see Cardinal et al., 2000), or by presenting particularly those of stimulants, under self- the delays in a random order with each in the control procedures both within and across presence of a distinctive stimulus. studies, and the associated methodological Although methylphenidate and morphine and theoretical issues, it is worth considering affected choice differently in the present some of the potential behavioral mechanisms study, both drugs tended to decrease response that might be involved in the effects of speed at the higher doses; at lower doses, methylphenidate and morphine on choice in morphine occasionally increased response the present study. The most obvious interpre- speed. With methylphenidate, the rightward tation involves a drug-induced change in the shifts in the discount curves occasionally were sensitivity to the discounting effects of re- accompanied by decreases in response speed, inforcement delay. That is, it is possible that but this was not always the case. Average methylphenidate decreases and morphine response speed was unchanged in several increases sensitivity to the discounting effects instances in which the average delay of in- of reinforcement delay. Such an interpretation difference was increased (see Figures 3 and 4). for methylphenidate is consistent with data With morphine, the relations between changes reported by Pitts and Febbo (2004). They used in response speed and changes in delay of an equation based upon the generalized indifference were inconsistent (see Figure 6). matching law (e.g., Baum, 1974) and hyper- Thus it seems unlikely that the effects of these bolic discounting (Mazur, 1987) to obtain drugs on choice depended upon their effects parameter estimates for sensitivity to reinforce- on response speed. Interestingly, although ment delay in pigeons responding under a self- individual-subject data were not presented, control procedure. They found that metham- Kieres et al. (2004) reported morphine-in- phetamine-induced increases in choices for duced decreases in self-control choices only at a larger delayed reinforcer were consistently doses that produced statistically significant accompanied by decreases in the estimates for decreases in speed with which the rats initiated sensitivity to reinforcement delay. At present, the trials and increases in the speed with which it is unclear whether or not the effects of choices were made. They interpreted the morphine in the present study indicate an former as a decrease in motivation and the increased sensitivity to reinforcement delay. latter as an increase in impulsivity. At this A drug-induced change in self-control point, however, the specific relation, if any, choice also could reflect a change in the between drug-induced changes in self-control sensitivity to the effects of reinforcement choices and response speed has not been amount. Thus it is possible that methylpheni- clarified sufficiently. date increased self-control choices in the Response speed under baseline conditions present study by increasing sensitivity to rein the present study, however, may have played inforcement amount. Conversely, morphine 312 RAYMOND C. PITTS and A. PATRICK MCKINNEY may have decreased self-control choices by Finally, the possibility that the present decreasing sensitivity to reinforcement results relate to drug-induced changes in amount; the decreased choice of the larger ‘‘timing’’ should be considered. Following reinforcer at the 0-s delay for Rat P2 is certain doses of psychomotor stimulants, sub- consistent with this interpretation. An account jects respond earlier than usual under proce- of the present data in terms of sensitivity to dures often used to assess temporal discri- reinforcement amount is consistent with pre- mination (e.g., Eckerman, Segbefia, Manning, vious data showing that methylphenidate can & Breese, 1987; Maricq, Roberts, & Church, increase (Heyman, 1992) and that opiates can 1981; Meck, 1983). That is, in these proce- decrease (Egli, Schaal, Thompson, & Cleary, dures, stimulants appear to produce an over- 1992; Lancaster & Dallery, 1999) sensitivity to estimation of the passage of time; subjects reinforcement rate. Although this interpreta- respond as if more time has elapsed than is tion is possible, its application to the effects of actually the case. Interestingly, a straightfor- methylphenidate in the present study is ward application of this interpretation predicts weakened by data reported by Pitts and effects of methylphenidate opposite of those Febbo (2004). They found that, although obtained here. That is, if a dose changed the effects on estimates of sensitivity to reinforce- effect of a 10-s delay to that of a longer (e.g., ment amount were somewhat inconsistent 20-s) delay, then we would expect the delay- across pigeons, methamphetamine tended to discount function to shift to the left. Thus the decrease, rather than increase, this mea- present data with methylphenidate are diffi- sure. Note, however, that only two reinforce- cult to interpret as an overestimation of delay. ment amounts were used in both the Pitts and Some of the data with morphine (a leftward Febbo study and the present study. A more shift of the discount function), however, are definitive assessment of the effects of drugs on consistent with this interpretation. It should be sensitivity to reinforcement amount requires noted, however, that results from a variety of study of a wider range of amounts. studies with both stimulants and opiates under Several investigators have suggested that procedures involving temporal discrimination stimulant-induced increases in self-control are readily interpreted as rate-dependent choices may reflect effects on conditioned effects (e.g., Knealing & Schaal, 2002; Odum, reinforcement (e.g., Pietras et al, 2003; Lieving, & Schaal, 2002), in which drug Richards et al., 1999). Results from several administration increases low-probability behav- experiments indicate that stimulants, includ- ior and/or decreases high-probability behavior ing methylphenidate, can increase the effec- (see Dews, 1958; Dews & Wenger, 1977). tiveness of conditioned reinforcers (e.g., Files, Neither the results for methylphenidate nor Branch, & Clody, 1989; Hill, 1970; Robbins, morphine on choice in the present study, 1978). Thus, in the present study, methylphe- however, appear to reflect ‘‘purely’’ rate-de- nidate may have increased self-control choices pendent drug effects. Such effects likely would by increasing the conditioned-reinforcing ef- have occurred as a flattening of the discount fectiveness of the stimuli associated with the function, in which the high probability choices delay to the larger reinforcer. Pitts and Febbo of the larger reinforcer at the short delays were (2004), however, found that methamphet- decreased and the low probability choices of amine increased self-control choices under the larger reinforcer at the longer delays were conditions in which both the larger and increased. smaller reinforcers were presented after sig- In summary, at intermediate doses, methyl- naled delays (the delay to the larger reinforcer phenidate tended to increase and morphine usually was longer). Because a choice of either tended to decrease choices of a signaled the larger or the smaller reinforcer resulted in larger, delayed reinforcer in rats. The specific presentation of a conditioned reinforcer, their behavioral mechanism(s) involved in these results are difficult to interpret on the basis of effects is (are) not yet clear, but a drug- a drug-induced enhancement of conditioned induced change in the sensitivity to reinforce- reinforcement. Thus clarification of the role of ment delay is a viable possibility. Variability in drug-induced changes in conditioned rein- the effects of drugs on self-control choices, forcement as a basis for stimulant effects on both within and across studies, however, self-control choice awaits additional research. suggests that caution may be in order. The DRUGS AND DELAY-DISCOUNT FUNCTIONS 313 various procedures used to study self-control Green, L., Myerson, J., Holt, D. D., Slevin, J. R., & Estle, S. choices likely contain unique, and potentially J. (2004). Discounting of delayed food rewards in pigeons and rats: Is there a magnitude effect? Journal important, sources of control over drug effects of the Experimental Analysis of Behavior, 81, 39–50. that may not be characterized easily within the Heyman, G. M. (1992). Effects of methylphenidate on framework of the commonly used construct of response rate and measures of motor performance ‘‘impulsivity.’’ and reinforcement efficacy. Psychopharmacology, 109, 145–152. Hill, R. T. (1970). Facilitation of conditioned reinforcement as a mechanism of psychomotor stimulation. In REFERENCES E. Costa & S. Garattini (Eds.), International symposium Baum, W. M. (1974). On two types of deviation from on amphetamines and related compounds (pp. 781–795). the matching law: Bias and undermatching. Journal New York: Raven Press. of the Experimental Analysis of Behavior, 22,231– Hoelter, S. M., Tzschentke, T. M., & Schmidt, W. J. (1996). 242. Effects of amphetamine, morphine, and dizo- Campbell, M., Cueva, J. E., & Adams, P. B. (1999). cilpine (MK-801) on spontaneous alternation in the Pharmacotherapy of impulsive-aggressive behavior. 8-arm radial maze. Behavioural Brain Research, 81, In C. R. Cloninger (Ed.), Personality and psychopathology 53–60. (pp. 431–455). Washington, DC: American Psychiatric Hoffman, B. B., & Lefkowitz, R. J. (1996). Catecholamines, Press. sympathomimetic drugs, and adrenergic receptor Cardinal, R. N., Robbins, T. W., & Everitt, B. J. (2000). antagonists. In J. G. Hardman & L. E. Limbird The effects of d-amphetamine, chlordiazepoxide, (Eds.), Goodman and Gilman’s the pharmacological basis a-flupenthixol and behavioural manipulations on of therapeutics (9th ed., pp. 199–248). New York: choice of signalled and unsignalled delayed rein- McGraw Hill. forcement in rats. Psychopharmacology, 152, 362– Kieres, A. W., Hausknecht, K. A., Farrar, A. M., Acheson, 375. A., de Wit, H., & Richards, J. B. (2004). Effects of morphine and naltrexone on impulsive decision Charrier,D.,&Thiebot,M.H.(1996).Effectsof making in rats. Psychopharmacology, 173, 167–174. psychotropic drugs on rat responding in an operant Knealing, T. W., & Schaal, D. W. (2002). Disruption paradigm involving choice between delayed rein- of temporally organized behavior by morphine. forcers. Pharmacology Biochemistry and Behavior, 54, Journal of the Experimental Analysis of Behavior, 77, 149–157. 157–169. de Wit, H., Enggasser, J. L., & Richards, J. B. (2002). Acute Lancaster, J. S., & Dallery, J. (1999). The effects of administration of d-amphetamine decreases impulsiv- morphine on responding under variable-interval ity in healthy volunteers. Neuropsychopharmacology, 27, schedules: Rate-related effects, behavioral mechan- 813–825. isms and Herrnstein’s hyperbola. Behavioural Dews, P. B. (1958). Studies on behavior. IV: Stimulant Pharmacology, 10, 337–347. actions of methamphetamine. Journal of Pharmacology Logue, A. W. (1988). Research on self-control: An and Experimental Therapeutics, 122, 137–147. integrating framework. Behavioral and Brain Sciences, Dews, P. B., & Wenger, G. R. (1977). Rate-dependency of 11, 665–679. the behavioral effects of amphetamine. In T. Logue, A. W. (1995). Self-control: Waiting until tomorrow for Thompson & P. B. Dews (Eds.), Advances in behavioral what you want today. Englewood Cliffs, NJ: Prentice pharmacology (Vol. 1, pp. 167–227). New York: Hall. Academic Press. Logue, A. W. (2000). Self-control and health behavior. In Eckerman, D. A., Segbefia, D., Manning, S., & Breese, G. S. W. K. Bickel & R. E. Vuchinich. (Eds.), Reframing (1987). Effects of methylphenidate and d-amphet- health behavior change with behavioral economics (pp. 167– amine on timing in the rat. Pharmacology Biochemistry 192). Mahwah, NJ: Erlbaum. and Behavior, 27, 513–515. Logue, A. W., Tobin, H., Chelonis, J. J., Wang, R. Y., Geary, Egli, M., Schaal, D. W., Thompson, T., & Cleary, J. (1992). N., & Schachter, S. (1992). Cocaine decreases self- Opioid-induced response-rate decrements in pigeons control in rats: A preliminary report. Psychophar- responding under variable-interval schedules: Rein- macology, 109, 245–247. forcement mechanisms. Behavioural Pharmacology, 3, Loh, E. A., Smith, A. M., & Roberts, D. C. S. (1993). 581–591. Evaluation of response perseveration of rats in the Evenden, J. L., & Ryan, C. N. (1996). The pharmacology of radial arm maze following reinforcing and nonrein- impulsive behavior in rats: The effects of drugs on forcing drugs. Pharmacology, Biochemistry & Behavior, response choice with varying delays of reinforcement. 44, 735–740. Psychopharmacology, 128, 161–170. Maricq, A. V., Roberts, S., & Church, R. M. (1981). Evenden, J. L., & Ryan, C. N. (1999). The pharmacology of Methamphetamine and time estimation. Journal of impulsive behavior in rats VI: The effects of ethanol Experimental Psychology: Animal Behavior Processes, 7, and selective serotonergic drugs on response choice 18–30. with varying delays of reinforcement. Psychophar- Mazur, J. E. (1987). An adjusting procedure for studying macology, 146, 413–421. delayed reinforcement. In M. L. Commons, J. E. Files, F. J., Branch, M. N., & Clody, D. (1989). Effects of Mazur, J. A. Nevin & H. Rachlin (Eds.), Quantitative methylphenidate on responding under extinction in analysis of behavior: Vol. 5. The effect of delay and of the presence and absence of conditioned reinforce- intervening events on reinforcement value (pp. 55–73). ment. Behavioural Pharmacology, 1, 113–121. Hillsdale, NJ: Erlbaum. 314 RAYMOND C. PITTS and A. PATRICK MCKINNEY

Mazur, J. E. (1988). Estimation of indifference points with Richards, J. B., Mitchell, S. H., de Wit, H., & Seiden, L. S. an adjusting-delay procedure. Journal of the (1997). Determination of discount functions in rats Experimental Analysis of Behavior, 49, 37–47. with an adjusting-amount procedure. Journal of the Mazur, J. E. (1996). Procrastination by pigeons: Pre- Experimental Analysis of Behavior, 67, 353–366. ference for larger, more delayed work requirements. Richards, J. B., Sabol, K. E., & de Wit, H. (1999). Effects of Journal of the Experimental Analysis of Behavior, 65, methamphetamine on the adjusting amount pro- 159–171. cedure, a model of impulsive behavior in rats. Meck, W. H. (1983). Selective adjustment of the speed of Psychopharmacology, 146, 432–439. internal clock and memory processes. Journal of Robbins, T. W. (1978). The acquisition of responding with Experimental Psychology: Animal Behavior Processes, 9, conditioned reinforcement: Effects of pipradrol, 171–201. methylphenidate, d-amphetamine, and nomifensine. Odum, A. L., Lieving, L. M., & Schaal, D. W. (2002). Psychopharmacology, 58, 79–87. Effects of d-amphetamine in a temporal discrimina- Sagvolden, T., Slatta, K., & Arntzen, E. (1988). Low doses tion procedure: Selective changes in timing or rate of methylphenidate (Ritalin) may alter the delay-of- dependency? Journal of the Experimental Analysis of reinforcement gradient. Psychopharmacology, 95, Behavior, 78, 195–214. 303–312. Odum, A. L., Madden, G. J., Badger, G. J., & Bickel, W. K. Simpson, C. A., & Vuchinich, R. E. (2000). Temporal (2000). Needle sharing in opioid-dependent out- changes in the value of objects of choice: Discounting, patients: Psychological processes underlying risk. behavior patterns, and health behavior. In W. K. Drug and Alcohol Dependence, 60, 259–266. Bickel & R. E. Vuchinich. (Eds.), Reframing health Pietras, C. J., Cherek, D. R., Lane, S. D., Tcheremissine, O. behavior change with behavioral economics (pp. 193–215). V., & Steinberg, J. L. (2003). Effects of methylpheni- Mahwah, NJ: Erlbaum. date on impulsive choice in adult humans. Psychophar- Wade, T. R., de Wit, H., & Richards, J. B. (2000). Effects of macology, 170, 390–398. dopaminergic drugs on delayed reward as a measure Pitts, R. C., & Febbo, S. M. (2004). Quantitative analyses of of impulsive behavior in rats. Psychopharmacology, 150, methamphetamine’s effects on self-control choices: 90–101. Implications for elucidating behavioral mechanisms of drug action. Behavioural Processes, 66, 213–233. Received June 17, 2004 Rachlin, H. (1974). Self-control. Behaviorism, 2, 94–107. Final acceptance February 17, 2005