Schedule-induced polydipsia alters cocaine-but not ethanol-induced suppression of saccharin consumption

Drug and Alcohol Dependence 91 (2007) 18–25

Schedule-induced polydipsia alters cocaine-but not ethanol-induced suppression of saccharin consumption Stephen J. Kohut ∗ , Samantha L. Handler, Robin L. Hertzbach, Anthony L. Riley Psychopharmacology Laboratory, Department of Psychology, American University, 4400 Massachusetts Avenue, NW, Washington, DC 20016, United States Received 22 February 2007; received in revised form 25 April 2007; accepted 26 April 2007

Abstract Under traditional water-deprived conditions, both LiCl and morphine produce comparable suppression of saccharin consumption after repeated pairings. However, under conditions of spaced food deliveries (i.e., schedule-induced polydipsia; SIP), morphine produces a significantly weaker suppression than LiCl. The differential responses have been attributed to an increase in the rewarding effects of drugs of abuse (such as morphine) that masked the expression of the aversive effects, a masking not evident with LiCl which has no reported rewarding effects. The present study extended this characterization to two additional drugs of abuse; cocaine and ethanol. Following schedule-induced saccharin consumption, female Sprague–Dawley rats were given injections of LiCl, cocaine, ethanol (at doses comparably effective in conditioning taste aversions under water deprivation) or distilled water vehicle. Although cocaine and ethanol both suppressed SIP, only cocaine produced a significantly delayed suppression relative to LiCl. The differential effects of cocaine (and morphine), but not ethanol, may be a function of the different reward profiles of these drugs. Given the differential ability of drugs of abuse to suppress consumption under conditions of spaced feedings, the SIP procedure may be a useful baseline to assess the rewarding effects of such drugs. Further, given the differential results with cocaine and ethanol, the relative rewarding effects of drugs may be differentially indexed in this preparation, as well. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Schedule-induced polydipsia; Conditioned taste aversion; Cocaine; Ethanol; LiCl; Reward; Drug use and abuse

1. Introduction We have previously reported that the consumption of saccharin under spaced food deliveries (i.e., schedule-induced polydipsia; SIP; see Falk, 1969) is differentially affected by the post-session administration of morphine or LiCl at doses that comparably suppress saccharin consumption under traditional water-deprived conditions (see Myracle et al., 2005). Specifically, LiCl produces a rapid and robust suppression of saccharin consumption, whereas the morphine-induced suppression is weaker and delayed. This effect is not seen under a massed feeding schedule in which the same number of food pellets are presented as a single meal. Under those conditions, both LiCl and morphine produce complete and rapid suppression. It was suggested that these differential effects of morphine

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Corresponding author. Tel.: +1 202 885 1721; fax: +1 202 885 1081. E-mail address: [email protected] (S.J. Kohut). URL: http\\:eagle2.american.edu/∼sk2897a (S.J. Kohut).

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and LiCl may be a function of an increase in the rewarding effects of drugs of abuse under the conditions of spaced food delivery (see Falk, 1983, 1998; Falk and Tang, 1989). Such an increase would be evident for morphine (which has both aversive and rewarding effects) but not LiCl (a classical emetic with no known rewarding effects). An increase in the salience of the rewarding effects could mask or affect the acquisition and/or display of morphine’s aversive effects (e.g., drug novelty; Gamzu, 1977; Hunt and Amit, 1987; Parker, 2003; drug toxicity; Riley and Tuck, 1985), impacting its ability to condition an aversion. If spaced food deliveries impact the salience of morphine’s rewarding effects, other drugs of abuse might also be expected to be weaker than classical emetics in suppressing saccharin consumption within the SIP design. To assess this, the present study examined two additional drugs of abuse, i.e., cocaine (Experiment 1) and ethanol (Experiment 2), for their ability to suppress schedule-induced saccharin consumption (relative to LiCl). Specifically, different groups of rats were given spaced food deliveries (once every 30 s, for a total of 60 food pellet

S.J. Kohut et al. / Drug and Alcohol Dependence 91 (2007) 18–25

deliveries), during which time a novel saccharin solution was made available. Immediately after the session, rats were injected with LiCl, cocaine hydrochloride, ethanol or the distilled water vehicle. The doses of LiCl (25.6 mg/kg), cocaine (32 mg/kg) and ethanol (1.6 g/kg) were chosen for their ability to produce comparable conditioned taste aversions (CTA) under traditional water-deprived conditions (see Busse et al., 2005; Kohut and Riley, unpublished data). That is, animals displayed a similar avoidance of a saccharin solution when trained and tested with these doses in the CTA design under water deprivation (see inserts, Figs. 1 and 3). This ensured that any effects seen under the conditions of SIP would be due to the environmental contingencies of the preparation and not the general strength of the drugs being used. Although both cocaine and ethanol are abused, these drugs differ in their ability to support behaviors that index their strength as reinforcers. In measures of reward such as conditioned place preference (CPP; see van der Kooy, 1987), cocaine has been repeatedly shown to produce reliable place preferences across a range of doses including up to 40 mg/kg (see Durazzo et al., 1994; Le Pen et al., 1996; Busse et al., 2003; for a comprehensive review, see Tzschentke, 1998). On the other hand, it has been difficult to demonstrate ethanol’s positively reinforcing effects in this same measure of reward. In fact, ethanol has been shown to typically produce conditioned place aversions at doses greater than 0.8 g/kg (Cunningham, 1979, 1980; Cunningham et al., 2002). Place preferences in general are typically evident only after extensive pre-exposure and/or many conditioning cycles (Reid et al., 1985; Bozarth, 1990). Given these differences between cocaine and ethanol, it might be expected that they would produce differential suppression of schedule-induced saccharin consumption, although both would be expected to produce suppression weaker than LiCl which has no known rewarding effects. 2. Methods 2.1. Subjects The subjects were 58 experimentally na¨ıve female rats of Sprague–Dawley descent (purchased from Harlan Sprague–Dawley, Indianapolis, IN) approximately 60 days of age at the outset of the study. All subjects were individually housed in polycarbonate bins (22 cm × 23 cm × 20 cm) filled with approximately 3 cm of wood chip bedding. They were maintained on a 12:12 light:dark cycle (lights on 06:00 h) and at an ambient temperature of 23 ◦ C. Subjects were maintained at 85% of their free feeding weight during experimental procedures but had ad libitum access to water in the home cage throughout the study. All experimental procedures took place between 06:30 and 11:00 h. The research was conducted according to recommendations by the Guide for the Care and Use of Laboratory Animals (1996) as adopted and promulgated by the National Institutes of Health (NIH) and the Guidelines for the Care and Use of Mammals in Neuroscience and Behavioral Research (2003) and was approved by the American University Institutional Animal Care and Use Committee.

2.2. Apparatus The experimental chambers have been described in detail elsewhere (see Myracle et al., 2005). Briefly, six identical operant chambers (27.7 cm × 19.8 cm × 20.0 cm) were used throughout the experiment. The chambers consisted of Plexiglas walls with a stainless steel grid floor. A food cup was

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centered on the front wall above the grid floor and 11.5 cm below a continuously illuminated 28-V houselight. A graduated Nalgene drinking tube fitted with a metal lick spout was located to the right of the food cup and was situated such that the metal lick spout was flush with the outer wall of the chamber. The room was dimly illuminated by an overhead lamp, and a white noise generator was used during all experimental sessions. Responding, in the form of licks, was detected by contact drinkometers (Lafayette Model 58008). All experimental events were programmed on a desktop Dell Optiplex GX150 that was connected to the boxes via a Med Associates Interface.

2.3. Drugs and solutions Cocaine hydrochloride (generously supplied by the National Institute on Drug Abuse) was prepared in a distilled water vehicle at a concentration of 10 mg/ml and administered at a dose of 32 mg/kg (subcutaneously; sc). Lithium Chloride (LiCl; Sigma Pharmaceuticals, St. Louis, MO) was prepared as a 0.15 M solution also in a distilled water vehicle and administered sc at a dose of 0.6 mEq/kg (25.6 mg/kg). Ethanol was prepared as a 15% solution with distilled water (v/v) and administered at a dose of 1.6 g/kg intraperitoneally (ip). Vehicle injections were distilled water and given either sc or ip (see Procedure: Phase 2). Saccharin (0.1% sodium saccharin, Sigma Pharmaceuticals, St. Louis, MO) was prepared as a 1 g/l solution in tap water.

2.4. Procedure • Phase 1: Adaptation Following 1 week of handling and ad libitum food access, all animals were food restricted to 85% of their free feeding weight. Once the animals’ weights had stabilized, experimental procedures began. On Day 1, all animals were placed in the experimental chambers for a 30-min session during which a single 45-mg food pellet (Bio-Serve) was delivered on a fixed-time 30 s (FT 30) schedule for a total of 60 pellets. Water was freely available throughout the session. Absolute consumption of water was recorded by subtracting the volume of water remaining after the session from the amount at the beginning. Licks to the tube were recorded in 5-s intervals after the delivery of each food pellet for the analysis of the postpellet temporal distribution of licking. The number of food pellets left in the hopper and/or on the chamber floor was recorded to determine the total number of pellets consumed during the session. Approximately 20 min after the conclusion of the session, each subject was given sufficient food to maintain body weight at 85%. • Phase II: Conditioning Conditioning began when water consumption was stable for three consecutive days as determined by a one-way analysis of variance (Experiment 1: 21 days; Experiment 2: 26 days). On the first day of conditioning, subjects were treated the same as during the adaptation phase except that a novel saccharin solution replaced water as the available fluid in the experimental chamber. Immediately following the first saccharin session, subjects in each experiment were ranked and assigned to one of three groups such that mean saccharin consumption was comparable among the three experimental groups. Subjects in Experiment 1 were given an injection of LiCl (Group L, n = 10), cocaine (Group C, n = 10) or the distilled water vehicle (Group V, n = 10). Subcutaneous cocaine at the concentration used in the present assessment (i.e., 10 mg/ml) is known to produce necrotic lesions at the injection site. In order to minimize discomfort, the injections were rotated throughout acquisition, along the rat’s dorsum so that no injection was given in the same area twice. The subjects in Experiment 2 were given an injection of LiCl (Group L, n = 9), ethanol (Group E, n = 10) or the distilled water vehicle (Group V, n = 9). Subjects in the vehicle groups received distilled water injected equivolume to the specific treatment groups in the respective studies with half of the subjects injected intraperitoneally (as a control for ethanol) and half injected subcutaneously (as a control for either cocaine or LiCl). Following the appropriate injection, each subject was returned to its home cage. Conditioning occurred every fourth day for a total of five saccharin-drug pairings. On the three intervening recovery days, sessions were conducted identically to the adaptation phase in which subjects had access to water in the experimental chamber but received no injections following these sessions. No injections were given on the final conditioning day.

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Fig. 1. Mean (±S.E.M.) saccharin consumption on each of the five conditioning trials for animals injected with LiCl (), cocaine (O) and vehicle () under spaced food deliveries. Insert: mean (±S.E.M.) saccharin consumption for animals injected with LiCl and cocaine under traditional water-deprived conditions (adapted from Busse et al., 2005). # Significantly different from cocaine group. *Significantly different from vehicle group.

2.5. Statistical analysis For each experiment, absolute saccharin consumption was analyzed for the three groups using a 3 × 5 repeated measures analysis of variance (ANOVA) with the between-subjects variable of Drug (Experiment 1: LiCl, cocaine or distilled water; Experiment 2: LiCl, ethanol or distilled water) and the withinsubjects variable of Trial (1–5). The temporal distribution of licks for each conditioning trial was analyzed for each experiment using a 3 × 6 repeated measures ANOVA with the between-subjects variable of Drug (Experiment 1: LiCl, cocaine or distilled water; Experiment 2: LiCl, ethanol or distilled water) and the within-subjects variable of 5-s Postpellet Interval (1–6). The repeated measures ANOVAs were followed by one-way ANOVAs for each interval and pair-wise comparisons using Tukey’s post hoc tests. All determinations of statistical significance were made at p < .05. All statistical analyses were conducted using the Statistical Package for the Social Sciences, Version 13.0.

3. Results 3.1. Experiment 1 3.1.1. Absolute consumption. The repeated measures ANOVA on saccharin consumption over the five conditioning trials revealed a significant effect of Drug [F(2, 27) = 35.189, p ≤ .001] and Trial [F(4, 108) = 7.904, p ≤ .001] and a significant Drug × Trial interaction [F(8, 108) = 16.358, p ≤ .001]. Subsequent one-way ANOVAs revealed no significant differences in consumption among the three groups on the initial saccharin presentation. On this exposure, subjects drank an average of 17.38 ± 1.02 ml of saccharin. On the second trial, subjects in Group L drank significantly less saccharin than the other groups (p < .05). On Trial 3, both Groups L and C drank significantly less saccharin than Group V (both p’s < .05) and Group L also drank significantly less than Group C (p < .05). On Trials 4 and 5, Groups L and C drank significantly less saccharin than Group V (both p’s < .05), although on these trials Groups L and C did not differ. The mean (±S.E.M.) absolute

saccharin consumption for each group across all trials is shown in Fig. 1. 3.1.2. Temporal distribution of licks. To determine the postpellet temporal distribution of licking on each of the five conditioning trials, the number of licks by the animals in each drug condition was averaged for each 5-s period of the 30-s interpellet interval across all 60 pellets for each session. Fig. 2 represents the mean (±S.E.M.) distribution of licks for each conditioning trial. A repeated measures ANOVA yielded a significant effect of Interval on all trials (all F’s(5, 135) ≥ 18.397, p’s < .001). A main effect of Drug was found on Trials 2, 3 and 4 (all F’s(2, 27) ≥ 3.524, p’s < .05), and a Drug × Interval interaction was found on Trial 2 [F(10, 135) = 60.940, p < .05] and Trial 5 [F(10, 135) = 35.276, p < .05]. Subjects in all groups showed an inverted U-shaped pattern of licking such that they licked immediately following the delivery of a pellet, peaked shortly thereafter and diminished before the next pellet delivery (a pattern typical of schedule-induced drinking; see Falk, 1969). This pattern was maintained across all trials. Group V slightly reduced the overall number of licks per interval as the trials progressed, but maintained the same level of absolute consumption, suggesting that they became more efficient in licking over trials. On Trials 2, 3 and 4, Group L made fewer overall licks than both Groups V and C. Given the significant Drug × Interval interaction on Trials 2 and 5, individual ANOVAs were conducted for each interval to determine where the significant differences occurred (see Fig. 2). Groups C and V did not differ on Trial 2 at any interval, but did so at the final three intervals (4–6) on Trial 5. Group L showed a decrease in overall licking beginning on Trial 2 such that it was different from Groups C and V at Interval 4 but different from Group V only at Interval 5. On the final Trial (5), Group L and C did not differ at any interval, but both differed from Group V at Intervals 4–6.

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Fig. 2. Mean (±S.E.M.) number of licks for each 5-s period of the 30-s interpellet interval across all 60 food pellets on each conditioning trial for animals injected with LiCl (open bars), cocaine (hatched bars) and vehicle (closed bars). # Significantly different from cocaine group. *Significantly different from vehicle group.

3.2. Experiment 2 3.2.1. Absolute consumption. The repeated measures ANOVA on saccharin consumption over the five conditioning trials revealed a significant effect of Drug [F(2, 25) = 17.240, p ≤ .001] and Trial [F(4, 100) = 4.518, p ≤ .05] and a significant Drug × Trial interaction [F(8, 100) = 9.719, p ≤ .001]. On the initial saccharin exposure, subjects drank an average of 16.35 ± 1.33 ml of saccharin with no significant differences among any of the groups. On conditioning Trial 2, subjects in Groups L and E drank significantly less saccharin than subjects in Group V (p ≤ .001). These relative differences among the groups were maintained for the remainder of the trials (all p’s ≤ .001) with no difference between Groups L and E on any trial (all p’s ≥ .05). The mean (±S.E.M.) absolute saccharin consumption for each group across all trials is shown in Fig. 3.

3.2.2. Temporal distribution of licks. An analysis of the postpellet distribution of licks for Experiment 2 revealed a significant effect of Interval on all trials [all F’s(5, 125) ≥ 23.458, p’s < .001]. On Trials 2, 4 and 5, there was a main effect of Drug [all F’s(2, 25) ≥ 3.737, p’s < .05] as well as a significant Drug × Interval interaction [all F’s(10, 125) ≥ 2.670, p’s < .05]. Fig. 4 presents the mean (±S.E.M.) distribution of licks for each conditioning trial. Again, all groups displayed the typical inverted U-shaped distribution of licking with peak levels appearing at the second 5-s interval. This overall pattern was maintained for Group V with a slight reduction by Trial 5, again suggesting that this group became more efficient at licking across trials. On Trials 2, 4 and 5, Group V made more overall licks than Groups L and E, while on Trial 5 Group L made more licks than Group E (but less than Group V). Given the Drug × Interval interaction on Trials 2, 4 and 5, individual ANOVAs were

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Fig. 3. Mean (±S.E.M.) saccharin consumption on each of the five conditioning trials for animals injected with LiCl (), ethanol () and vehicle () under spaced food deliveries. Insert: mean (±S.E.M.) saccharin consumption for animals injected with LiCl and ethanol under traditional water-deprived conditions (unpublished data from Kohut and Riley). *Significantly different from vehicle group.

conducted to determine at what interval differences occurred among groups (see Fig. 4). Groups L and E licked significantly less than Group V at Intervals 3–6 on Trial 2. On Trial 4, Group E licked significantly less than Group V at all intervals, while Group L licked less than Group V at Intervals 4–6 only. On Trial 5, Group E differed from Group V at Interval 2 only. Groups L and E did not differ at any interval on Trials 2, 4 or 5. 4. Discussion As described, saccharin consumption within the SIP design is differentially affected by LiCl and morphine. Specifically, LiCl produces a rapid and robust suppression of saccharin consumption, while morphine produces an effect that is weaker and delayed (Myracle et al., 2005). The effects of LiCl and morphine on saccharin consumption are not different under massed feeding conditions in which food is delivered in a single mass meal, i.e., not spaced, suggesting that spaced food deliveries may be important in the differential effects of these two drugs. The authors argued that the spaced feeding procedure may have increased the salience of the rewarding effects of morphine (Falk, 1983, 1998; Falk and Tang, 1989), an increase that masked its aversive effect that suppresses fluid consumption in other aversion designs (see Garcia and Ervin, 1968; Parker, 2003). Such an effect of masking would not be evident with LiCl for which rewarding effects have not been reported. The present experiments attempted to extend the abovementioned characterization of morphine under SIP to two additional drugs of abuse (cocaine and ethanol). As reported in Experiment 1, cocaine and LiCl differentially affected the schedule-induced consumption of the drug-associated saccharin solution. Specifically, cocaine resulted in a weaker and delayed suppression of saccharin consumption relative to that induced

by LiCl. This differential suppression was not a function of the relative strengths of these two compounds as aversion-inducing agents, given that they comparably suppress the consumption of the drug-associated solution under traditional water-deprived conditions (Busse et al., 2005; Kohut and Riley, unpublished observations; see Fig. 1: insert). Similar to the effects reported with morphine (see Myracle et al., 2005), the relatively weaker (and delayed) suppression seen with cocaine appears to be a function of the spaced food deliveries under the SIP procedure. This pattern is also represented in the temporal distribution of licking data where cocaine-treated animals produced more licks than LiCl-treated animals at the same trials where absolute consumption was different. Given that cocaine has rewarding effects (as indexed in other preparations; see below), this effect on SIP is consistent with the position that the spaced food deliveries increased the overall salience of cocaine’s rewarding effects to a degree that its aversive effects (Goudie et al., 1978; Freeman et al., 2004) were masked, resulting in the weaker suppression of consumption. Interestingly, in Experiment 2 ethanol and LiCl both produced an immediate and pronounced suppression of saccharin consumption under the SIP baseline. This effect was also reflected in the temporal distribution of licking data where ethanol produced a decrease in licking that paralleled that produced by LiCl. Thus, although ethanol is a compound with known abuse potential, spaced food deliveries did not alter the suppression produced by ethanol as it did with cocaine (and morphine). Clearly, spaced food deliveries alone are not sufficient to reverse or attenuate the aversive effects of ethanol. The fact that SIP differentially affects (or is affected by) drugs of abuse such as cocaine, but not ethanol, may reflect the relative reinforcing effects of these drugs. Previous reports attempting to assess the rewarding value of cocaine and ethanol suggest that the reinforcing effects of these drugs are quite different.

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Fig. 4. Mean (±S.E.M.) number of licks for each 5-s period of the 30-s interpellet interval across all 60 food pellets on each conditioning trial for animals injected with LiCl (open bars), ethanol (hatched bars) and vehicle (closed bars). *Significantly different from vehicle group.

For example, cocaine conditions place preferences relatively easily under a number of parameters (Durazzo et al., 1994; Tzschentke, 1998; Bardo and Bevins, 2000; Busse et al., 2003), while preferences with ethanol seem to depend on the specific parameters being used (i.e., dose, see above; Cunningham et al., 2002, 2003). In fact, most reports suggest that ethanol conditions place aversions rather than place preferences in drug na¨ıve rats (Cunningham, 1979, 1980). Place preferences are usually attained only after extensive pre-exposure to the drug (e.g., Reid et al., 1985) or with many conditioning trials (Bozarth, 1990; Bienkowski et al., 1996). These results with cocaine and ethanol in the present study also parallel those seen with similar doses in place preference studies in which cocaine (32 mg/kg) and ethanol (1.6 g/kg) are rewarding and aversive, respectively. Thus, while both cocaine and ethanol are drugs of abuse, their respective reward profiles appear to be very different. Given

that both cocaine and ethanol induce comparable aversions under water deprivation (at specific doses, compare inserts of Figs. 1 and 3), it is likely that these differences in reward mediate the differential effects of spaced feeding on their suppression of saccharin consumption in the SIP design. The basis for a change in the rewarding effects of drugs of abuse under the conditions of spaced food deliveries remains unknown. One possible explanation is in the stress-induction of the SIP procedure itself. Specifically, schedule-induced polydipsia has been used as an animal model of stress and anxiety-related disorders such as obsessive compulsive disorder (see Keehn, 1979). The excessive fluid consumption may be a coping response to the stressful procedure of spaced feeding (though see Killeen, 1975 for alternative explanation). Although there is debate over the particular role that activation of the hypothalamic–pituitary–adrenal (HPA) axis may play in this

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behavior (Mittleman et al., 1988; Jones et al., 1989; Levine and Levine, 1989; Mittleman et al., 1992; Cole and Koob, 1993), a recent report by Lopez-Grancha et al. (2005) suggests that corticosterone levels (a direct measure of HPA activity) are increased in polydipsic rats after extended training (i.e., after the subjects have learned the schedule of spaced food deliveries). Although corticosterone was not assayed in the present experiments, based on this earlier work, it is possible that the stress associated with the SIP procedure (i.e., spaced pellet deliveries; see also Shurtleff et al., 1983) was sufficient to increase the rewarding value of cocaine (see Goeders and Guerin, 1996; for reviews see Piazza and Le Moal, 1996; Goeders, 1997), thereby, impacting its suppressive effects on SIP. The role that stress may play in the heightened response to the rewarding effects of drugs of abuse may be rooted in the ability of SIP to increase dopamine efflux in the nucleus accumbens (see Mittleman et al., 1992). Dopaminergic systems have been shown to play a role in nonregulatory behaviors (such as SIP) as they are disrupted by lesions to mesolimbic dopamine projections whereas other regulatory behaviors (such as eating and drinking) are not affected (Koob et al., 1978; Robbins and Koob, 1980; Mittleman et al., 1990). Thus, the increased dopamine efflux due to the spaced feedings in the SIP procedure may produce an additive effect with those drugs of abuse that work to increase dopamine in these same areas. Other manipulations that assess HPA activity may shed more light on the role that stress plays in the differential effects of drugs of abuse and LiCl within this design (see DeCarolis et al., 2003). The present analysis argues that drugs of abuse have both aversive and rewarding effects. Generally, the aversive effects of such compounds are evidenced by their ability to suppress consumption of drug-associated tastes (see Garcia and Ervin, 1968; Riley and Tuck, 1985; Parker, 2003), e.g., under water deprivation or free-access conditions. A variety of drugs have been shown to suppress fluid consumption under spaced feedings, i.e., schedule-induced polydipsia (for review see Riley and Wetherington, 1989). As such, the SIP design, like consumption under fluid deprivation, can clearly index the aversive effects of such drugs (see Grigson, 1997 for an alternative explanation of taste avoidance behavior). The present paper (along with Myracle et al., 2005) suggests that the SIP design may also be useful in assessing a drug’s overall rewarding value. If the differential effects of drugs such as cocaine and morphine on SIP (relative to those of classical emetics) reflect an increase in their reward salience under the SIP procedure, this baseline may be useful in indexing such effects in other drugs of abuse. Assessments with other compounds and under other conditions known to impact the rewarding effects of drugs, e.g., prior exposure, drug dose, cue and stress-induction, pharmacological antagonism, may provide more direct tests of this possibility and its overall utility as such an index. Acknowledgements This work was supported in part by a grant from the Mellon Foundation to Anthony L. Riley. Data from Experiment 1 was presented at the 36th annual meeting of the Society for Neu-

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