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The modulation of cocaine-induced conditioned place preferences by alcohol: effects of cocaine dose
Progress in Neuro-Psychopharmacology & Biological Psychiatry 28 (2004) 149 – 155 www.elsevier.com/locate/pnpbp
The modulation of cocaine-induced conditioned place preferences by alcohol: effects of cocaine dose Gregory D. Busse*, Elizabeth T. Lawrence, Anthony L. Riley Psychopharmacology Laboratory, Department of Psychology, American University, 4400 Massachusetts Avenue, NW, Washington, DC 20016, USA Accepted 17 September 2003
Abstract Busse and Riley [Biol. Psychiatry 26 (2002) 1373] have recently reported that alcohol dose dependently attenuated cocaine-induced place preferences. Although the mechanism for this effect is not known, it is possible that it is due to alcohol potentiating the aversive properties of cocaine, a potentiation that masks or abates cocaine’s rewarding effects in this preparation. Given that the affective properties of cocaine (both aversive and rewarding) have been reported to be dose dependent, it might be expected that alcohol’s ability to affect cocaine-induced place preferences would be influenced by changes in cocaine dose. To address this possibility, the following experiments assessed the effects of alcohol (0.5 g/kg) on place preferences induced by high (20, 30 and 40 mg/kg: Experiment 1) and low (2.5 and 5 mg/kg; Experiment 2) doses of cocaine. Specifically, every other day for four cycles male Sprague – Dawley rats were injected with cocaine, alcohol or one of several cocaine/alcohol combinations immediately before being placed on one side of a two-compartment place preference chamber. On alternate days, they were placed on the other side of the chamber after being injected with the drug vehicle(s). In Experiment 1, all doses of cocaine (20, 30 and 40 mg/kg) produced a significant preference for the drug-paired compartment, whereas alcohol alone produced no effect. When given in combination, alcohol attenuated the cocaine-induced place preference (at 30 and 40 mg/kg cocaine). In Experiment 2, neither cocaine (2.5 or 5 mg/kg) nor alcohol produced a significant effect when given alone. However, animals receiving the combination of alcohol and cocaine (5 mg/kg) displayed a significant place preference. These findings indicate that alcohol can both weaken and strengthen cocaineinduced place preferences, possibly via its effects on the rewarding and aversive properties of cocaine. The effect of alcohol is dependent on the dose of cocaine. D 2003 Elsevier Inc. All rights reserved. Keywords: Alcohol; Aversion; Cocaine; Conditioned place preference; Polydrug; Rats; Reward
1. Introduction Busse and Riley (2002) have recently reported the modulatory effects of alcohol on cocaine-induced conditioned place preferences (CPP) (Bardo et al., 1995; Schechter and Calcagnetti, 1993, 1998; Tzschentke, 1998). Specifically, alcohol (administered at a dose of 0.5 g/kg) significantly attenuated place preferences conditioned by 20 mg/kg cocaine. With an increase in the dose of alcohol (1.5 g/kg), the cocaine-induced place preference was totally abated. Although alcohol appears to reduce the reinforcing effects of cocaine, as assayed in the conditioned place Abbreviations: A, alcohol; C, cocaine; CPP, conditioned place preference; DP, drug-paired compartment; VP, vehicle-paired compartment; ICSS, intracranial self-stimulation; N, neutral compartment. * Corresponding author. Tel.: +1-202-885-1731; fax: +1-202-8851081. E-mail address: [email protected] (G.D. Busse). 0278-5846/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2003.09.031
preference design, it should be noted that this attenuation is opposite to that reported in several other preparations. For example, alcohol has been reported to potentiate cocaine’s threshold lowering effect on intracranial self-stimulation (ICSS) (Lewis and June, 1994) as well as increase the self-reported euphorigenic effects of cocaine in humans (Farre` et al., 1993; McCance-Katz et al., 1998), both of which suggest that alcohol increases the reinforcing effects of cocaine. Although the basis of alcohol’s ability to reduce cocaineinduced place preferences is not known, several possibilities exist. For example, given that the place preference design is sensitive to both the rewarding and aversive properties of drugs (Parker and McDonald, 2000; Tzschentke, 1998), any aversive effects that resulted from the administration of alcohol may have offset the rewarding properties of cocaine. This, in turn, may have resulted in an attenuated cocaineinduced place preference. In fact, others have reported
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similar attenuated place preferences by combining compounds with rewarding and aversive properties (MartinIverson et al., 1997; Meririnne et al., 1999; Neisewander et al., 1990; Zarrindast et al., 2002). However, given that in the Busse and Riley (2002) report alcohol did not condition a significant place aversion at either 0.5 or 1.5 g/kg, it is unlikely that an increase in the aversive properties of alcohol was responsible for the attenuated cocaine-induced place preferences. That a stronger attenuation in place preferences occurred when cocaine was coadministered with the higher dose of alcohol (without any notable change in alcohol’s effects in the place preference design) further questions a summation explanation. A second possibility for the reduced place preferences in animals given concurrent injections of alcohol and cocaine is that alcohol potentiated the aversive properties of cocaine. That is, it is possible that coadministration of alcohol increased the aversive properties of cocaine, an effect that masked (or interacted with) cocaine’s rewarding properties and resulted in a reduction in the overall rewarding effects of cocaine and, consequently, a reduced place preference. Evidence in support of this position comes from tasteaversion studies that demonstrate potentiated cocaine-induced taste aversions (at doses similar to that used by Busse and Riley, 2002) when alcohol was coadministered (Etkind et al., 1998; Grakalic and Riley, 2002). For example, both Etkind et al. (1998) and Grakalic and Riley (2002) reported a potentiation in the aversive properties of 25 mg/kg cocaine when this drug was combined with 0.56 g/kg alcohol. As noted earlier, Busse and Riley (2002) reported that the attenuating effects of alcohol on cocaine-induced place preferences were dose dependent with greater attenuation as the dose of alcohol was increased. If alcohol’s ability to attenuate cocaine-induced place preferences is a function of alcohol potentiating the aversive properties of cocaine, it might be expected that this attenuation would also be affected by changes in the cocaine dose, given that the affective (i.e., aversive and reinforcing) properties of cocaine have been reported to be dose dependent in both the taste aversion (Ferrari et al., 1991) and place preference (Spyraki et al., 1982) designs. This was addressed in the following studies in which the effects of alcohol were examined on place preferences induced by high (Experiment 1) and low (Experiment 2) doses of cocaine.
2. Methods 2.1. Animals One hundred and fifty-four drug naı¨ve, male Sprague – Dawley rats, weighing approximately 250 to 400 g at the start of the experiment, were housed in separate hanging wire-mesh cages in a room maintained on a 12:12 L/D cycle (lights on at 0800 h) and at an ambient temperature of 23 jC. Food and water were available ad libitum throughout
the experiment. Animals were handled daily beginning 2 weeks before the start of the experiment to limit any effects of handling stress during conditioning and testing. 2.2. Drugs Cocaine hydrochloride (generously supplied by the National Institute on Drug Abuse) was dissolved in distilled water and was injected intraperitoneally in a concentration of 10 mg/ml. Alcohol was prepared in a 15% (vol/vol) solution with distilled water and was also injected intraperitoneally. Animals receiving the combination were administered separate injections of cocaine and alcohol within 1 s of each other in a nonsystematic order. 2.3. Apparatus and conditioning procedure The place conditioning apparatus consisted of four identical shuttle-box chambers (94.5 41 37.5 cm). Each chamber had three compartments separated by two removable Plexiglas barriers. One compartment (40 41 37.5 cm) was black and had a smooth Plexiglas floor. Another compartment (40 41 37.5 cm) was white and had a natural wood grain floor with black sandpaper strips (2.54 41 cm) placed horizontally 2.54 cm apart. A third (central) compartment (11 41 37.5 cm) was gray and had a wire-mesh (23 gauge) floor. Each chamber was dimly lit with a 60-W halogen bulb placed approximately 1.54 m overhead. Using the unbiased design (Bardo et al., 1995), place conditioning occurred immediately following an injection of the drug or its vehicle over the course of four consecutive, two 30-min/day conditioning cycles (8 days). This design entailed counterbalancing the animals so that on one conditioning cycle, half of the subjects were injected with the drug(s) before placement in the black compartment, while the remaining subjects were injected with the drug(s) before placement in the white compartment. On the alternate day of the conditioning cycle, those animals that were injected with the drug(s) before placement in the black compartment were injected with the vehicle and placed in the white compartment, while those conditioned to the white compartment were injected with the vehicle and placed in the black compartment. Animals were counterbalanced so that half of the subjects were injected with the drug(s) on Day 1 of the conditioning cycle, while the remaining half was injected with the drug(s) on Day 2 of the conditioning cycle. Using such a procedure eliminates the need for habituation to the chambers and measurement of a preconditioning preference (Bardo et al., 1995). In addition, such a procedure has been found to result in more robust findings (Bardo et al., 1995). Following conditioning (Day 9), animals were tested for their chamber preference by placing subjects in the center, gray (neutral, N) compartment, removing the Plexiglas barriers and allowing them to have free access to the entire
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chamber for 15 min. Activity was recorded by four 8-mm Canon ES-50 camcorders located approximately 1.93 m directly above the place preference chambers. The animal’s location, as noted in previous reports (Gong et al., 1997), was determined by the position of its forepaws. Conditioning and testing were carried out between 0900 and 1600 h. 2.4. Statistical analysis Time spent ( F S.E.M.) in each compartment was recorded and scored. The time animals spent in the two conditioning compartments was transformed to a percentage and compared with a Student’s related sample t test to determine if animals in each group spent more time in the drug-paired (DP) or vehicle-paired (VP) compartment. Animals were considered to be displaying a CPP if the percentage of time spent on the DP side was statistically greater (a=.05) than the percentage of time spent on the VP side (Shippenberg and Heidbreder, 1995). A one-way ANOVA was also used to compare the mean difference in percentage of time spent in either the DP or VP compartment, thus, allowing for a direct comparison of compartment preference among groups (a=.05; Bonferroni correction). This was calculated by subtracting the percentage of time spent in the VP compartment from the DP compartment. Therefore, a positive score would indicate that, on average, animals spent more time in the DP compartment, while a negative score would reflect that animals, on average, spent more time in the VP compartment.
3. Results 3.1. Experiment 1: effect of alcohol on place preferences conditioned with high doses of cocaine 3.1.1. Animals and procedure Animals were assigned to receive either 20, 30 or 40 mg/ kg cocaine (Groups C20, n = 16; C30, n = 16, C40, n = 16, respectively), alcohol (0.5 g/kg; Group A, n = 16), or a cocaine/alcohol combination (20, 30 or 40 mg/kg cocaine plus 0.5 g/kg alcohol; Groups C20A, n = 16; C30A, n = 17; C40A, n = 18, respectively) immediately before placement in the chamber. Place conditioning was conducted following the procedure described above. Table 1 summarizes the average time ( F S.E.M.) animals spent in each compartment for each group. Comparisons of the relative percentage of time spent in the DP and VP compartments using a paired Student’s related sample t test (Fig. 1a –g) revealed that animals in Groups C20, C30 and C40 spent a greater percentage of time in the DP than VP compartment [t(15) = 5.718, P < .0001; t(15) = 9.667, P < .0001; t(14) = 2.536, P=.0237, respectively], indicating significant place preferences induced by cocaine. No statistical difference was found for Group A in the percentage of
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Table 1 Time in seconds ( F S.E.M.) spent in the DP, VP and N compartments of the place preference chamber on test day for Groups A, C20, C30, C40, C20A, C30A and C40A Group
Compartment DP
A C20 C30 C40 C20A C30A C40A
266 445 474 377 393 379 387
VP (15) (22) (18) (24) (19) (28) (73)
321 216 201 270 245 275 347
N (20) (20) (15) (23) (16) (23) (76)
312 240 225 254 262 247 166
(14) (10) (15) (23) (15) (14) (35)
time spent in the DP and VP compartments [t(15) = 1.725, P=.0532], although this effect approached significance. The percentage of time that animals in Group C20A spent in the DP compartment was significantly greater than the percentage of time spent in the VP compartment [t(15) = 4.642, P=.0003], while no statistical difference was noted between the percentage of time spent in the DP and VP compartments in Group C30A [t(14) = 2.111, P=.0532] and Group C40A [t(10) = 0.354, P=.7309], suggestive of an attenuated cocaine-induced place preference. Comparisons among groups indicated that animals in Group C20 spent approximately 35% ( F 6%) more time in the DP than the VP compartment, while animals in Group C30 spent approximately 40% ( F 4%) more time in the DP than the VP compartment. Interestingly, animals in Group C40 spent only 17% ( F 7%) more time in the DP than the VP compartment. In contrast, animals in Group A spent about 9% ( F 5%) more time in the VP than the DP compartment. Finally, animals in Group C20A spent approximately 23% ( F 5%) more time in the DP compartment than the VP compartment. Animals in Group C30A spent approximately 15% ( F 7%) more time in the DP compartment than the VP compartment, while animals in Group C40A spent approximately 6% ( F 17%) more time in the DP compartment than the VP compartment. A one-way ANOVA on these differences indicated a significant main effect for groups [ F(5,88) = 9.447, P < .0001; animals in Group C40A were excluded from this analysis due to an increase in toxicity with this drug combination (see below)]. Post hoc analysis (Bonferroni corrected P < .005) confirmed a significant difference between the percentage of time spent in the preferred compartment for Groups C20 and A ( P < .0001), Groups C30 and A ( P < .0001) and Groups C40 and A ( P=.0023). Although no difference in the percentage of time spent in the preferred compartment was noted between Groups C20 and C30, animals in Group C40 spent significantly less percentage of time in the preferred compartment than animals in Group C30 ( P=.0042). Post hoc analysis also noted a significant difference between Groups C20A and A ( P < .0001) and Groups C30A and A ( P=.0041). There was no statistical difference in the percentage of time spent
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Fig. 1. Percent of time ( F S.E.M.) spent by animals in Groups C20 (a), C30 (b), C40 (c), A (d), C20A (e), C30A (f) and C40A (g) in the DP and VP compartments on test day. * Significant difference between percentage of time in the DP and VP compartment ( P < .01).
in each compartment between Groups C20 and C20A ( P=.1512). A significant difference in compartment preference was evident between Group C30 and C30A ( P=.0024), demonstrating an attenuating effect of alcohol on the place preference conditioned at this higher dose of cocaine. 3.2. Experiment 2: effect of alcohol on place preferences conditioned with low doses of cocaine As described, alcohol attenuated the ability of cocaine (at 30 and 40 mg/kg) to induce a place preference, a result similar to that reported by Busse and Riley (2002). Although the basis for this attenuation is not known, the results are consistent with the position that alcohol potentiated the aversive properties of cocaine and, in so doing, affected its ability to condition a place preference. As noted, such potentiation has been reported in other assessments of the affective properties of cocaine, specifically the taste aver-
sion design, in which alcohol increased the ability of ineffective doses of cocaine to induce a taste aversion (Etkind et al., 1998; Grakalic and Riley, 2002). Although the current assessment demonstrates that alcohol attenuates cocaine-induced place preferences, it should be noted that the doses of cocaine used in the present assessment are relatively high and similar to ones previously reported to induce aversions in other preparations (see above). Given that these doses alone have aversive effects, the potential exists for their potentiation by alcohol. As noted, the aversive and rewarding effects of cocaine are both dose dependent (Ferrari et al., 1991; Spyraki et al., 1982) and there are doses of cocaine at which no aversive effects are reported. Accordingly, if alcohol can potentiate the rewarding effects of cocaine such an effect may be more likely seen at these lower (and less aversive) doses. This was examined in Experiment 2, which assessed the ability of alcohol (0.5 g/kg) to increase place preferences conditioned by relatively low doses of cocaine (2.5 and 5 mg/kg).
G.D. Busse et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 28 (2004) 149–155 Table 2 Time in seconds ( F S.E.M.) spent in the DP, VP and N compartments of the place preference chamber on test day for Groups A, C2.5, C5, C2.5A and C5A Group
Compartment DP
A C2.5 C5 C2.5A C5A
256 334 350 350 330
VP (43) (32) (33) (38) (24)
372 279 284 275 265
N (35) (24) (43) (35) (13)
272 287 266 275 305
(29) (22) (18) (21) (26)
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C5A spent a significantly greater percentage of time in the DP than the VP compartment [t(7) = 2.499, P=.0410], indicating that conditioning animals with the combination of alcohol and cocaine (5 mg/kg) resulted in a conditioned place preference. A one-way ANOVA indicated no significant difference in the percent difference in time spent in compartments among groups [ F(4,34) = 2.000, P=.1167].
4. Discussion 3.2.1. Animals and procedure Subjects were assigned to receive either 2.5 or 5 mg/kg cocaine (Groups C2.5 and C5, respectively, n = 8 and 7 per group, respectively), 0.5 g/kg alcohol (Group A; n = 8) or the combination (Groups C2.5A and C5A, respectively; n = 8 per group) immediately before placement in the chamber. Place conditioning was conducted following the procedure described above. Table 2 summarizes the average time ( F S.E.M.) animals spent in each compartment for each group. Comparisons of the relative percentage of time spent in the DP and VP compartments using a Student’s related sample t test (see Fig. 2a– e) revealed that neither animals in Group C2.5 nor Group C5 differed in the percentage of time spent in the DP and the VP compartments [t(7) = 0.983, P=.3582; t(6) = 0.977, P=.3663, respectively], indicating that neither of the doses of cocaine conditioned a significant place preference. No statistical difference was found for Group A in the percentage of time spent in the DP and the VP compartments [t(7) = 1.795, P=.1158]. Although the percentage of time that animals in Group C2.5A spent in the DP compartment was not significantly greater than the percentage of time spent in the VP compartment [t(7) = 1.024, P=.3399], animals in Group
4.1. Effects of alcohol on cocaine-induced place preferences In Experiment 1, conditioning with 20, 30 and 40 mg/kg cocaine (Groups C20, C30 and C40, respectively) produced a significant preference for the DP compartment, findings consistent with other reports of cocaine-induced CPP (Le Pen et al., 1996; Mayer and Parker, 1993; O’Dell et al., 1996). Conversely, administration of 0.5 g/kg alcohol resulted in a nonsignificant aversion to the DP compartment, a finding consistent with other reports of the effects of alcohol in the CPP design (Busse and Riley, 2002; Stewart and Grupp, 1981; van der Kooy et al., 1983). Although the combination of 20 mg/kg cocaine and 0.5 g/kg alcohol conditioned a significant place preference, the combination of 30 and 40 mg/kg cocaine with 0.5 g/kg alcohol resulted in an attenuated CPP. This attenuation was also evident in the between-group comparisons. That is, the percentage of time animals in Group C30A spent in the DP compartment was significantly less than animals in Group C30. No statistical evaluation was made in the percentage of time spent in the DP compartment paired with the drug between animals in Groups C40 and C40A, primarily because the drug combination resulted in an increase in lethality (39%; Busse and Riley, 2003).
Fig. 2. Percent of time ( F S.E.M.) spent by animals in Groups C2.5 (a), C5 (b), A (c), C2.5A (d) and C5A (e) in the DP and VP compartments on test day. * Significant difference between percentage of time in the DP and VP compartment ( P < .05).
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In Experiment 2, neither 2.5 nor 5 mg/kg cocaine conditioned a significant preference for the DP compartment, an effect similar to that reported by Cervo et al. (2002). Administration of 0.5 g/kg alcohol (Group A) resulted in a nonsignificant aversion to the DP compartment. Although the combination of 2.5 mg/kg cocaine and 0.5 g/ kg alcohol (Group C2.5A) resulted in no conditioned effect, the combination of 5 mg/kg cocaine and 0.5 g/kg alcohol (Group C5A) resulted in a significant preference for the DP compartment. Together, Experiments 1 and 2 demonstrate that alcohol can modulate the ability of cocaine to condition a place preference, and that the direction of this effect is dependent on the dose of cocaine used to condition place preferences. 4.2. Basis for the cocaine and alcohol interaction The basis for these differential effects of alcohol on cocaine-induced place preferences is not known, although it is possible that the direction of the effect may be dependent on the relative balance of the rewarding and aversive properties of any particular dose of cocaine and how alcohol affects these relative properties. That is, a reduction in place preferences may be more likely when combining alcohol with a dose of cocaine with significant aversive properties, whereas an increase in place preferences may be more likely when alcohol is combined with a dose of cocaine that has minimal to no aversive properties. In Experiment 1, animals injected with cocaine alone (at all doses) showed significant place preferences. Furthermore, the preference conditioned at 30 mg/kg was significantly greater than that conditioned at 40 mg/kg. The fact that there were no differences between 20 and 30 mg/kg could reflect the maximal reinforcing effects of cocaine in the place preference design wherein an increase in the dose of cocaine to 30 mg/kg would have no greater reinforcing effects than 20 mg/kg (Belzung et al., 2000; Spyraki et al., 1982). Furthermore, that the place preference conditioned at 40 mg/kg was significantly less than that at 30 mg/kg could be a reflection of the aversive properties of cocaine at this dose, which may have impacted the degree of place preference conditioned at this dose. In fact, others have also noted similar dose effects in the ICSS design wherein high doses of self-administered cocaine (approximately 40 mg/kg) shift the motivation from consumption to avoidance (Kenny et al., 2003). Thus, the occurrence (and interaction) of the reinforcing and aversive effects may have shaped the dose – response function of cocaine within the place preference design. When alcohol was administered concurrently with cocaine, several actions may have occurred. Alcohol may have potentiated any aversive effects of cocaine, a potentiation that reduced the overall perceived rewarding effects at these doses to a level that resulted in weaker place preferences. Previous work in taste aversion learning has shown that these doses of cocaine (i.e., 20– 40 mg/kg) do, in fact, condition aversions and that the aversive effects of such
doses can be potentiated by the concurrent administration of alcohol (Etkind et al., 1998; Grakalic and Riley, 2002). Alcohol may also have potentiated the reinforcing effects of cocaine at these doses, although the concurrent potentiation of its aversive effects may have masked their display. In Experiment 2, no place preference was noted at either dose of cocaine (2.5 or 5 mg/kg), suggesting that these doses had minimal (or subthreshold) reinforcing effects (Cervo et al., 2002; Gong et al., 1995). These same doses are generally reported to be ineffective in conditioning taste aversions, suggesting that they have minimal (or subthreshold) aversive effects (Ferrari et al., 1991). In fact, doses as high as 18 mg/kg have no ability to condition aversions, so these doses are well below those that generally produce aversions. When alcohol was given concurrent with these lower doses of cocaine, there may be a potentiation of the rewarding effects of cocaine, a potentiation reflected in a greater CPP. Interestingly, Cervo et al. (2002) have recently reported that while neither 2.5 nor 5 mg/kg cocaine conditioned a place preference (as reported in the present paper), when the 5-HT1A agonist CP-94,354 was administered concurrent with cocaine, place preferences were seen. Thus, such doses of cocaine appear to be at the threshold for producing place preferences and when combined with selective compounds they become effective in the place preference design. Although there may have been some potentiation of cocaine’s aversive effects as well, the overall aversiveness may still be below the threshold to condition an aversion or affect the display of the place preference. This argument suggests that although the doses of cocaine used to condition preferences in Experiments 1 and 2 have rewarding properties, only the relatively high doses of cocaine used in Experiment 1 have significant aversive properties. As such, if alcohol can potentiate the rewarding and aversive properties of cocaine, an increase in preferences may only be seen when combining alcohol with a dose of cocaine that has minimal to no aversive effects. This finding is consistent with others reporting an alcoholinduced increase in the rewarding properties of cocaine in animals (Lewis and June, 1994). Specifically, Lewis and June (1994) demonstrated that doses of alcohol and cocaine that were alone ineffective in the ICSS design resulted in a reduction in the threshold for brain stimulation when combined, suggestive of an increase in reward.
5. Conclusion The rewarding and aversive effects of cocaine have been found to be dose dependent in both the taste aversion (Ferrari et al., 1991) and place preference (Spyraki et al., 1982) designs. The interaction of these aversive and reinforcing effects may be important in the expression of conditioned place preferences. When alcohol was given concurrent with cocaine, the specific effects of alcohol were found to be dependent on the dose of cocaine, presumably
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due to alcohol’s potentiation of the reinforcing and aversive effects of cocaine at specific doses. That is, alcohol potentiated both the rewarding and aversive properties of cocaine, with the relative balance of the properties determining whether alcohol increased or weakened cocaine-induced place preferences. The dose of cocaine taken concurrently with alcohol may determine whether an individual is more or less likely to find the combination rewarding.
Acknowledgements This work was supported in part by a grant from the Mellon Foundation to ALR.
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The modulation of cocaine-induced conditioned place preferences by alcohol: effects of cocaine dose Gregory D. Busse*, Elizabeth T. Lawrence, Anthony L. Riley Psychopharmacology Laboratory, Department of Psychology, American University, 4400 Massachusetts Avenue, NW, Washington, DC 20016, USA Accepted 17 September 2003
Abstract Busse and Riley [Biol. Psychiatry 26 (2002) 1373] have recently reported that alcohol dose dependently attenuated cocaine-induced place preferences. Although the mechanism for this effect is not known, it is possible that it is due to alcohol potentiating the aversive properties of cocaine, a potentiation that masks or abates cocaine’s rewarding effects in this preparation. Given that the affective properties of cocaine (both aversive and rewarding) have been reported to be dose dependent, it might be expected that alcohol’s ability to affect cocaine-induced place preferences would be influenced by changes in cocaine dose. To address this possibility, the following experiments assessed the effects of alcohol (0.5 g/kg) on place preferences induced by high (20, 30 and 40 mg/kg: Experiment 1) and low (2.5 and 5 mg/kg; Experiment 2) doses of cocaine. Specifically, every other day for four cycles male Sprague – Dawley rats were injected with cocaine, alcohol or one of several cocaine/alcohol combinations immediately before being placed on one side of a two-compartment place preference chamber. On alternate days, they were placed on the other side of the chamber after being injected with the drug vehicle(s). In Experiment 1, all doses of cocaine (20, 30 and 40 mg/kg) produced a significant preference for the drug-paired compartment, whereas alcohol alone produced no effect. When given in combination, alcohol attenuated the cocaine-induced place preference (at 30 and 40 mg/kg cocaine). In Experiment 2, neither cocaine (2.5 or 5 mg/kg) nor alcohol produced a significant effect when given alone. However, animals receiving the combination of alcohol and cocaine (5 mg/kg) displayed a significant place preference. These findings indicate that alcohol can both weaken and strengthen cocaineinduced place preferences, possibly via its effects on the rewarding and aversive properties of cocaine. The effect of alcohol is dependent on the dose of cocaine. D 2003 Elsevier Inc. All rights reserved. Keywords: Alcohol; Aversion; Cocaine; Conditioned place preference; Polydrug; Rats; Reward
1. Introduction Busse and Riley (2002) have recently reported the modulatory effects of alcohol on cocaine-induced conditioned place preferences (CPP) (Bardo et al., 1995; Schechter and Calcagnetti, 1993, 1998; Tzschentke, 1998). Specifically, alcohol (administered at a dose of 0.5 g/kg) significantly attenuated place preferences conditioned by 20 mg/kg cocaine. With an increase in the dose of alcohol (1.5 g/kg), the cocaine-induced place preference was totally abated. Although alcohol appears to reduce the reinforcing effects of cocaine, as assayed in the conditioned place Abbreviations: A, alcohol; C, cocaine; CPP, conditioned place preference; DP, drug-paired compartment; VP, vehicle-paired compartment; ICSS, intracranial self-stimulation; N, neutral compartment. * Corresponding author. Tel.: +1-202-885-1731; fax: +1-202-8851081. E-mail address: [email protected] (G.D. Busse). 0278-5846/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2003.09.031
preference design, it should be noted that this attenuation is opposite to that reported in several other preparations. For example, alcohol has been reported to potentiate cocaine’s threshold lowering effect on intracranial self-stimulation (ICSS) (Lewis and June, 1994) as well as increase the self-reported euphorigenic effects of cocaine in humans (Farre` et al., 1993; McCance-Katz et al., 1998), both of which suggest that alcohol increases the reinforcing effects of cocaine. Although the basis of alcohol’s ability to reduce cocaineinduced place preferences is not known, several possibilities exist. For example, given that the place preference design is sensitive to both the rewarding and aversive properties of drugs (Parker and McDonald, 2000; Tzschentke, 1998), any aversive effects that resulted from the administration of alcohol may have offset the rewarding properties of cocaine. This, in turn, may have resulted in an attenuated cocaineinduced place preference. In fact, others have reported
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similar attenuated place preferences by combining compounds with rewarding and aversive properties (MartinIverson et al., 1997; Meririnne et al., 1999; Neisewander et al., 1990; Zarrindast et al., 2002). However, given that in the Busse and Riley (2002) report alcohol did not condition a significant place aversion at either 0.5 or 1.5 g/kg, it is unlikely that an increase in the aversive properties of alcohol was responsible for the attenuated cocaine-induced place preferences. That a stronger attenuation in place preferences occurred when cocaine was coadministered with the higher dose of alcohol (without any notable change in alcohol’s effects in the place preference design) further questions a summation explanation. A second possibility for the reduced place preferences in animals given concurrent injections of alcohol and cocaine is that alcohol potentiated the aversive properties of cocaine. That is, it is possible that coadministration of alcohol increased the aversive properties of cocaine, an effect that masked (or interacted with) cocaine’s rewarding properties and resulted in a reduction in the overall rewarding effects of cocaine and, consequently, a reduced place preference. Evidence in support of this position comes from tasteaversion studies that demonstrate potentiated cocaine-induced taste aversions (at doses similar to that used by Busse and Riley, 2002) when alcohol was coadministered (Etkind et al., 1998; Grakalic and Riley, 2002). For example, both Etkind et al. (1998) and Grakalic and Riley (2002) reported a potentiation in the aversive properties of 25 mg/kg cocaine when this drug was combined with 0.56 g/kg alcohol. As noted earlier, Busse and Riley (2002) reported that the attenuating effects of alcohol on cocaine-induced place preferences were dose dependent with greater attenuation as the dose of alcohol was increased. If alcohol’s ability to attenuate cocaine-induced place preferences is a function of alcohol potentiating the aversive properties of cocaine, it might be expected that this attenuation would also be affected by changes in the cocaine dose, given that the affective (i.e., aversive and reinforcing) properties of cocaine have been reported to be dose dependent in both the taste aversion (Ferrari et al., 1991) and place preference (Spyraki et al., 1982) designs. This was addressed in the following studies in which the effects of alcohol were examined on place preferences induced by high (Experiment 1) and low (Experiment 2) doses of cocaine.
2. Methods 2.1. Animals One hundred and fifty-four drug naı¨ve, male Sprague – Dawley rats, weighing approximately 250 to 400 g at the start of the experiment, were housed in separate hanging wire-mesh cages in a room maintained on a 12:12 L/D cycle (lights on at 0800 h) and at an ambient temperature of 23 jC. Food and water were available ad libitum throughout
the experiment. Animals were handled daily beginning 2 weeks before the start of the experiment to limit any effects of handling stress during conditioning and testing. 2.2. Drugs Cocaine hydrochloride (generously supplied by the National Institute on Drug Abuse) was dissolved in distilled water and was injected intraperitoneally in a concentration of 10 mg/ml. Alcohol was prepared in a 15% (vol/vol) solution with distilled water and was also injected intraperitoneally. Animals receiving the combination were administered separate injections of cocaine and alcohol within 1 s of each other in a nonsystematic order. 2.3. Apparatus and conditioning procedure The place conditioning apparatus consisted of four identical shuttle-box chambers (94.5 41 37.5 cm). Each chamber had three compartments separated by two removable Plexiglas barriers. One compartment (40 41 37.5 cm) was black and had a smooth Plexiglas floor. Another compartment (40 41 37.5 cm) was white and had a natural wood grain floor with black sandpaper strips (2.54 41 cm) placed horizontally 2.54 cm apart. A third (central) compartment (11 41 37.5 cm) was gray and had a wire-mesh (23 gauge) floor. Each chamber was dimly lit with a 60-W halogen bulb placed approximately 1.54 m overhead. Using the unbiased design (Bardo et al., 1995), place conditioning occurred immediately following an injection of the drug or its vehicle over the course of four consecutive, two 30-min/day conditioning cycles (8 days). This design entailed counterbalancing the animals so that on one conditioning cycle, half of the subjects were injected with the drug(s) before placement in the black compartment, while the remaining subjects were injected with the drug(s) before placement in the white compartment. On the alternate day of the conditioning cycle, those animals that were injected with the drug(s) before placement in the black compartment were injected with the vehicle and placed in the white compartment, while those conditioned to the white compartment were injected with the vehicle and placed in the black compartment. Animals were counterbalanced so that half of the subjects were injected with the drug(s) on Day 1 of the conditioning cycle, while the remaining half was injected with the drug(s) on Day 2 of the conditioning cycle. Using such a procedure eliminates the need for habituation to the chambers and measurement of a preconditioning preference (Bardo et al., 1995). In addition, such a procedure has been found to result in more robust findings (Bardo et al., 1995). Following conditioning (Day 9), animals were tested for their chamber preference by placing subjects in the center, gray (neutral, N) compartment, removing the Plexiglas barriers and allowing them to have free access to the entire
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chamber for 15 min. Activity was recorded by four 8-mm Canon ES-50 camcorders located approximately 1.93 m directly above the place preference chambers. The animal’s location, as noted in previous reports (Gong et al., 1997), was determined by the position of its forepaws. Conditioning and testing were carried out between 0900 and 1600 h. 2.4. Statistical analysis Time spent ( F S.E.M.) in each compartment was recorded and scored. The time animals spent in the two conditioning compartments was transformed to a percentage and compared with a Student’s related sample t test to determine if animals in each group spent more time in the drug-paired (DP) or vehicle-paired (VP) compartment. Animals were considered to be displaying a CPP if the percentage of time spent on the DP side was statistically greater (a=.05) than the percentage of time spent on the VP side (Shippenberg and Heidbreder, 1995). A one-way ANOVA was also used to compare the mean difference in percentage of time spent in either the DP or VP compartment, thus, allowing for a direct comparison of compartment preference among groups (a=.05; Bonferroni correction). This was calculated by subtracting the percentage of time spent in the VP compartment from the DP compartment. Therefore, a positive score would indicate that, on average, animals spent more time in the DP compartment, while a negative score would reflect that animals, on average, spent more time in the VP compartment.
3. Results 3.1. Experiment 1: effect of alcohol on place preferences conditioned with high doses of cocaine 3.1.1. Animals and procedure Animals were assigned to receive either 20, 30 or 40 mg/ kg cocaine (Groups C20, n = 16; C30, n = 16, C40, n = 16, respectively), alcohol (0.5 g/kg; Group A, n = 16), or a cocaine/alcohol combination (20, 30 or 40 mg/kg cocaine plus 0.5 g/kg alcohol; Groups C20A, n = 16; C30A, n = 17; C40A, n = 18, respectively) immediately before placement in the chamber. Place conditioning was conducted following the procedure described above. Table 1 summarizes the average time ( F S.E.M.) animals spent in each compartment for each group. Comparisons of the relative percentage of time spent in the DP and VP compartments using a paired Student’s related sample t test (Fig. 1a –g) revealed that animals in Groups C20, C30 and C40 spent a greater percentage of time in the DP than VP compartment [t(15) = 5.718, P < .0001; t(15) = 9.667, P < .0001; t(14) = 2.536, P=.0237, respectively], indicating significant place preferences induced by cocaine. No statistical difference was found for Group A in the percentage of
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Table 1 Time in seconds ( F S.E.M.) spent in the DP, VP and N compartments of the place preference chamber on test day for Groups A, C20, C30, C40, C20A, C30A and C40A Group
Compartment DP
A C20 C30 C40 C20A C30A C40A
266 445 474 377 393 379 387
VP (15) (22) (18) (24) (19) (28) (73)
321 216 201 270 245 275 347
N (20) (20) (15) (23) (16) (23) (76)
312 240 225 254 262 247 166
(14) (10) (15) (23) (15) (14) (35)
time spent in the DP and VP compartments [t(15) = 1.725, P=.0532], although this effect approached significance. The percentage of time that animals in Group C20A spent in the DP compartment was significantly greater than the percentage of time spent in the VP compartment [t(15) = 4.642, P=.0003], while no statistical difference was noted between the percentage of time spent in the DP and VP compartments in Group C30A [t(14) = 2.111, P=.0532] and Group C40A [t(10) = 0.354, P=.7309], suggestive of an attenuated cocaine-induced place preference. Comparisons among groups indicated that animals in Group C20 spent approximately 35% ( F 6%) more time in the DP than the VP compartment, while animals in Group C30 spent approximately 40% ( F 4%) more time in the DP than the VP compartment. Interestingly, animals in Group C40 spent only 17% ( F 7%) more time in the DP than the VP compartment. In contrast, animals in Group A spent about 9% ( F 5%) more time in the VP than the DP compartment. Finally, animals in Group C20A spent approximately 23% ( F 5%) more time in the DP compartment than the VP compartment. Animals in Group C30A spent approximately 15% ( F 7%) more time in the DP compartment than the VP compartment, while animals in Group C40A spent approximately 6% ( F 17%) more time in the DP compartment than the VP compartment. A one-way ANOVA on these differences indicated a significant main effect for groups [ F(5,88) = 9.447, P < .0001; animals in Group C40A were excluded from this analysis due to an increase in toxicity with this drug combination (see below)]. Post hoc analysis (Bonferroni corrected P < .005) confirmed a significant difference between the percentage of time spent in the preferred compartment for Groups C20 and A ( P < .0001), Groups C30 and A ( P < .0001) and Groups C40 and A ( P=.0023). Although no difference in the percentage of time spent in the preferred compartment was noted between Groups C20 and C30, animals in Group C40 spent significantly less percentage of time in the preferred compartment than animals in Group C30 ( P=.0042). Post hoc analysis also noted a significant difference between Groups C20A and A ( P < .0001) and Groups C30A and A ( P=.0041). There was no statistical difference in the percentage of time spent
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Fig. 1. Percent of time ( F S.E.M.) spent by animals in Groups C20 (a), C30 (b), C40 (c), A (d), C20A (e), C30A (f) and C40A (g) in the DP and VP compartments on test day. * Significant difference between percentage of time in the DP and VP compartment ( P < .01).
in each compartment between Groups C20 and C20A ( P=.1512). A significant difference in compartment preference was evident between Group C30 and C30A ( P=.0024), demonstrating an attenuating effect of alcohol on the place preference conditioned at this higher dose of cocaine. 3.2. Experiment 2: effect of alcohol on place preferences conditioned with low doses of cocaine As described, alcohol attenuated the ability of cocaine (at 30 and 40 mg/kg) to induce a place preference, a result similar to that reported by Busse and Riley (2002). Although the basis for this attenuation is not known, the results are consistent with the position that alcohol potentiated the aversive properties of cocaine and, in so doing, affected its ability to condition a place preference. As noted, such potentiation has been reported in other assessments of the affective properties of cocaine, specifically the taste aver-
sion design, in which alcohol increased the ability of ineffective doses of cocaine to induce a taste aversion (Etkind et al., 1998; Grakalic and Riley, 2002). Although the current assessment demonstrates that alcohol attenuates cocaine-induced place preferences, it should be noted that the doses of cocaine used in the present assessment are relatively high and similar to ones previously reported to induce aversions in other preparations (see above). Given that these doses alone have aversive effects, the potential exists for their potentiation by alcohol. As noted, the aversive and rewarding effects of cocaine are both dose dependent (Ferrari et al., 1991; Spyraki et al., 1982) and there are doses of cocaine at which no aversive effects are reported. Accordingly, if alcohol can potentiate the rewarding effects of cocaine such an effect may be more likely seen at these lower (and less aversive) doses. This was examined in Experiment 2, which assessed the ability of alcohol (0.5 g/kg) to increase place preferences conditioned by relatively low doses of cocaine (2.5 and 5 mg/kg).
G.D. Busse et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 28 (2004) 149–155 Table 2 Time in seconds ( F S.E.M.) spent in the DP, VP and N compartments of the place preference chamber on test day for Groups A, C2.5, C5, C2.5A and C5A Group
Compartment DP
A C2.5 C5 C2.5A C5A
256 334 350 350 330
VP (43) (32) (33) (38) (24)
372 279 284 275 265
N (35) (24) (43) (35) (13)
272 287 266 275 305
(29) (22) (18) (21) (26)
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C5A spent a significantly greater percentage of time in the DP than the VP compartment [t(7) = 2.499, P=.0410], indicating that conditioning animals with the combination of alcohol and cocaine (5 mg/kg) resulted in a conditioned place preference. A one-way ANOVA indicated no significant difference in the percent difference in time spent in compartments among groups [ F(4,34) = 2.000, P=.1167].
4. Discussion 3.2.1. Animals and procedure Subjects were assigned to receive either 2.5 or 5 mg/kg cocaine (Groups C2.5 and C5, respectively, n = 8 and 7 per group, respectively), 0.5 g/kg alcohol (Group A; n = 8) or the combination (Groups C2.5A and C5A, respectively; n = 8 per group) immediately before placement in the chamber. Place conditioning was conducted following the procedure described above. Table 2 summarizes the average time ( F S.E.M.) animals spent in each compartment for each group. Comparisons of the relative percentage of time spent in the DP and VP compartments using a Student’s related sample t test (see Fig. 2a– e) revealed that neither animals in Group C2.5 nor Group C5 differed in the percentage of time spent in the DP and the VP compartments [t(7) = 0.983, P=.3582; t(6) = 0.977, P=.3663, respectively], indicating that neither of the doses of cocaine conditioned a significant place preference. No statistical difference was found for Group A in the percentage of time spent in the DP and the VP compartments [t(7) = 1.795, P=.1158]. Although the percentage of time that animals in Group C2.5A spent in the DP compartment was not significantly greater than the percentage of time spent in the VP compartment [t(7) = 1.024, P=.3399], animals in Group
4.1. Effects of alcohol on cocaine-induced place preferences In Experiment 1, conditioning with 20, 30 and 40 mg/kg cocaine (Groups C20, C30 and C40, respectively) produced a significant preference for the DP compartment, findings consistent with other reports of cocaine-induced CPP (Le Pen et al., 1996; Mayer and Parker, 1993; O’Dell et al., 1996). Conversely, administration of 0.5 g/kg alcohol resulted in a nonsignificant aversion to the DP compartment, a finding consistent with other reports of the effects of alcohol in the CPP design (Busse and Riley, 2002; Stewart and Grupp, 1981; van der Kooy et al., 1983). Although the combination of 20 mg/kg cocaine and 0.5 g/kg alcohol conditioned a significant place preference, the combination of 30 and 40 mg/kg cocaine with 0.5 g/kg alcohol resulted in an attenuated CPP. This attenuation was also evident in the between-group comparisons. That is, the percentage of time animals in Group C30A spent in the DP compartment was significantly less than animals in Group C30. No statistical evaluation was made in the percentage of time spent in the DP compartment paired with the drug between animals in Groups C40 and C40A, primarily because the drug combination resulted in an increase in lethality (39%; Busse and Riley, 2003).
Fig. 2. Percent of time ( F S.E.M.) spent by animals in Groups C2.5 (a), C5 (b), A (c), C2.5A (d) and C5A (e) in the DP and VP compartments on test day. * Significant difference between percentage of time in the DP and VP compartment ( P < .05).
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In Experiment 2, neither 2.5 nor 5 mg/kg cocaine conditioned a significant preference for the DP compartment, an effect similar to that reported by Cervo et al. (2002). Administration of 0.5 g/kg alcohol (Group A) resulted in a nonsignificant aversion to the DP compartment. Although the combination of 2.5 mg/kg cocaine and 0.5 g/ kg alcohol (Group C2.5A) resulted in no conditioned effect, the combination of 5 mg/kg cocaine and 0.5 g/kg alcohol (Group C5A) resulted in a significant preference for the DP compartment. Together, Experiments 1 and 2 demonstrate that alcohol can modulate the ability of cocaine to condition a place preference, and that the direction of this effect is dependent on the dose of cocaine used to condition place preferences. 4.2. Basis for the cocaine and alcohol interaction The basis for these differential effects of alcohol on cocaine-induced place preferences is not known, although it is possible that the direction of the effect may be dependent on the relative balance of the rewarding and aversive properties of any particular dose of cocaine and how alcohol affects these relative properties. That is, a reduction in place preferences may be more likely when combining alcohol with a dose of cocaine with significant aversive properties, whereas an increase in place preferences may be more likely when alcohol is combined with a dose of cocaine that has minimal to no aversive properties. In Experiment 1, animals injected with cocaine alone (at all doses) showed significant place preferences. Furthermore, the preference conditioned at 30 mg/kg was significantly greater than that conditioned at 40 mg/kg. The fact that there were no differences between 20 and 30 mg/kg could reflect the maximal reinforcing effects of cocaine in the place preference design wherein an increase in the dose of cocaine to 30 mg/kg would have no greater reinforcing effects than 20 mg/kg (Belzung et al., 2000; Spyraki et al., 1982). Furthermore, that the place preference conditioned at 40 mg/kg was significantly less than that at 30 mg/kg could be a reflection of the aversive properties of cocaine at this dose, which may have impacted the degree of place preference conditioned at this dose. In fact, others have also noted similar dose effects in the ICSS design wherein high doses of self-administered cocaine (approximately 40 mg/kg) shift the motivation from consumption to avoidance (Kenny et al., 2003). Thus, the occurrence (and interaction) of the reinforcing and aversive effects may have shaped the dose – response function of cocaine within the place preference design. When alcohol was administered concurrently with cocaine, several actions may have occurred. Alcohol may have potentiated any aversive effects of cocaine, a potentiation that reduced the overall perceived rewarding effects at these doses to a level that resulted in weaker place preferences. Previous work in taste aversion learning has shown that these doses of cocaine (i.e., 20– 40 mg/kg) do, in fact, condition aversions and that the aversive effects of such
doses can be potentiated by the concurrent administration of alcohol (Etkind et al., 1998; Grakalic and Riley, 2002). Alcohol may also have potentiated the reinforcing effects of cocaine at these doses, although the concurrent potentiation of its aversive effects may have masked their display. In Experiment 2, no place preference was noted at either dose of cocaine (2.5 or 5 mg/kg), suggesting that these doses had minimal (or subthreshold) reinforcing effects (Cervo et al., 2002; Gong et al., 1995). These same doses are generally reported to be ineffective in conditioning taste aversions, suggesting that they have minimal (or subthreshold) aversive effects (Ferrari et al., 1991). In fact, doses as high as 18 mg/kg have no ability to condition aversions, so these doses are well below those that generally produce aversions. When alcohol was given concurrent with these lower doses of cocaine, there may be a potentiation of the rewarding effects of cocaine, a potentiation reflected in a greater CPP. Interestingly, Cervo et al. (2002) have recently reported that while neither 2.5 nor 5 mg/kg cocaine conditioned a place preference (as reported in the present paper), when the 5-HT1A agonist CP-94,354 was administered concurrent with cocaine, place preferences were seen. Thus, such doses of cocaine appear to be at the threshold for producing place preferences and when combined with selective compounds they become effective in the place preference design. Although there may have been some potentiation of cocaine’s aversive effects as well, the overall aversiveness may still be below the threshold to condition an aversion or affect the display of the place preference. This argument suggests that although the doses of cocaine used to condition preferences in Experiments 1 and 2 have rewarding properties, only the relatively high doses of cocaine used in Experiment 1 have significant aversive properties. As such, if alcohol can potentiate the rewarding and aversive properties of cocaine, an increase in preferences may only be seen when combining alcohol with a dose of cocaine that has minimal to no aversive effects. This finding is consistent with others reporting an alcoholinduced increase in the rewarding properties of cocaine in animals (Lewis and June, 1994). Specifically, Lewis and June (1994) demonstrated that doses of alcohol and cocaine that were alone ineffective in the ICSS design resulted in a reduction in the threshold for brain stimulation when combined, suggestive of an increase in reward.
5. Conclusion The rewarding and aversive effects of cocaine have been found to be dose dependent in both the taste aversion (Ferrari et al., 1991) and place preference (Spyraki et al., 1982) designs. The interaction of these aversive and reinforcing effects may be important in the expression of conditioned place preferences. When alcohol was given concurrent with cocaine, the specific effects of alcohol were found to be dependent on the dose of cocaine, presumably
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due to alcohol’s potentiation of the reinforcing and aversive effects of cocaine at specific doses. That is, alcohol potentiated both the rewarding and aversive properties of cocaine, with the relative balance of the properties determining whether alcohol increased or weakened cocaine-induced place preferences. The dose of cocaine taken concurrently with alcohol may determine whether an individual is more or less likely to find the combination rewarding.
Acknowledgements This work was supported in part by a grant from the Mellon Foundation to ALR.
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