Sep 26, 1985 - nisse Physiologie Biologischen Chemieund Experimen- tellen Pharmakologie, 60, 1-56. Kilbey, M. M., & Ellinwood, E. H., Jr. (1977). Reverse.
1987, 47, 363-376
JOURNAL OF THE EXPERIMENTAL ANALYSIS OF BEHAVIOR
NUMBER 3
(MAY)
COCAINE TOLERANCE: ACUTE VERSUS CHRONIC EFFECTS AS DEPENDENT UPON FIXED-RATIO SIZE SANDRA H. HOFFMAN, MARC N. BRANCH, AND GLEN M. SIZEMORE UNIVERSITY OF FLORIDA The effects of cocaine on operant behavior were studied by examining fixed-ratio value as a factor in the development of tolerance. Pigeons pecked a response key under a three-component multiple schedule, with each bird being exposed to fixed-ratio values that were categorized as small, medium, or large. Administered acutely, cocaine (1.0 to 10.0 mg/kg) produced dose-related decreases in overall rate of responding. Responding maintained by the largest ratio was decreased by lower doses than those required to reduce rates of responding maintained by the other two ratio schedules. Following repeated daily administration of 5.6 mg/kg of cocaine, dose-effect functions (obtained from sessions during the chronic regimen by making substitutions for the daily dose) indicated tolerance under the smaller ratios, but no tolerance or less tolerance under the largest ratio. Thus, whether tolerance developed, and the degree to which it developed, depended on the ratio value. The results are partially consistent with the notion that tolerance to drug effects on schedule-controlled behavior will develop if drug administration initially reduces reinforcement frequency, but they indicate that reinforcement loss alone is not a sufficient condition for the generation of tolerance under such conditions. The findings suggest that amount of responding required for reinforcement, or "effort," may contribute to the development of tolerance to effects of cocaine. Key words: fixed ratio, cocaine, tolerance, multiple schedule, behavioral tolerance, key peck, pigeons
either tolerance, whereby higher doses were needed to produce an effect, or no change in effect, depending upon the dependent measure (Castellani, Ellinwood, & Kilbey, 1978; Matsuzaki, Spingler, Misra, & Mule, 1976; Mercier & Dessaigne, 1960; Moore & Thompson, 1978; Thompson, 1977; Wilson & Brenkert, 1978; Woolverton, Kandel, & Schuster, 1978a, 1978b). Factors responsible for these differing outcomes have not been elucidated fully, but Woolverton et al. (1978b) showed that behavvariables can modulate the changes in the ioral K. A. Lattal served as action editor for this manuscript. The research was supported by USPHS Grant No. DA- potency of cocaine during or following chronic 01416 from NIDA and Research Contract No. DAM17- administration. Specifically, they found that 83C-3188 from U.S. Army Medical Research and rats given daily presession administration of Development Command. In conducting this research the cocaine developed tolerance to the disruptive investigators adhered to the "Guide for the Care and Use of Laboratory Animals," prepared by the Committee on effects of cocaine on milk drinking. However, Care and Use of Laboratory Animals of the Institute of an equivalent number of postsession adminisLaboratory Animal Resources, National Research Coun- trations increased the disruptive effects of the cil (DHEW Publication No. (NIH) 78-23, Revised 1978). drug. It was necessary, therefore, for milk The authors would like to express appreciation to Juliet drinking to occur under the influence of the Brown and Carolyn Baum for their assistance in the care and training of the animals. Word-processing equipment drug for tolerance to develop. Identification of for the production of the manuscript was graciously sup- specific behavioral variables that contribute to plied by Rudy Vuchinich and Jalie Tucker. Finally, the tolerance development, however, was not a foexpert secretarial assistance of Geraldine Lennon is greatly cus of their study. The present experiment appreciated. Requests for reprints should be sent to Marc N. Branch, attempted to isolate specific behavioral factors Department of Psychology, University of Florida, Gaines- that modulate effects of repeated cocaine administration. ville, Florida 32611. Examinations of repeated cocaine administration have not yielded a consistent pattern of changes in the behavioral effects of the drug. Several investigators have reported sensitization or "reverse tolerance" following repeated administrations. That is, with repeated exposure, lower doses sufficed to produce a particular effect (Downs & Eddy, 1932a, 1932b; Kilbey & Ellinwood, 1977; Post, Kopanda, & Black, 1976). In contrast, others have found
363
SANDRA H. HOFFMAN et al.
364
We examined the effects of cocaine on behavior maintained by fixed-ratio (FR) schedules when differently valued FR schedules were arranged as components of a multiple schedule (cf. Ferster & Skinner, 1957). Typically, responding controlled by reinforcement schedules reveals tolerance following repeated cocaine administration (e.g., Branch & Dearing, 1982; Woolverton et al., 1978a), but there are exceptions (e.g., Thompson, 1977). Several investigators have studied acute effects of cocaine on schedule-controlled behavior (e.g., Barrett, 1976; Gonzalez & Goldberg, 1977; MacPhail & Seiden, 1975; Spealman, Goldberg, Kelleher, Goldberg, & Charlton, 1977; Woolverton et al., 1978a). A consistent finding has been that effects of the drug have been influenced by the reinforcement schedule. For example, Gonzalez and Goldberg (1977) found that the effects of cocaine on overall response rate depended upon whether responding was maintained by an FR 30 schedule or by a fixed-interval (FI) 1 0-min schedule of food presentation, when these were components of a multiple schedule. With increasing doses, response rates decreased under the FR schedule, but under the FT schedule rates increased at intermediate doses. These findings are consistent with those of many other experiments illustrating the importance of reinforcement schedules in determining drug effects (Kelleher & Morse, 1968; McKearney & Barrett, 1978; McMillan & Leander, 1976). There also is ample evidence that even when type of schedule is held constant, schedule parameters can influence acute drug effects (e.g., McMillan, 1969). The present study was predicated on the possibility that such variables might be important when examining chronic cocaine administration. METHOD
Subjects Three adult male White Carneaux pigeons served as subjects. Two of the pigeons were maintained at 80% of their free-feeding weights. Pigeon 880 was maintained at 65% of its free-feeding weight. Although this may appear an extreme level of deprivation, this bird had an unusually high free-feeding weight, and consistent responding was not maintained when this subject was at 80% of its free-feeding weight. This pigeon exhibited a healthy ap-
pearance throughout the study while kept at 65% of its free-feeding weight. Between experimental sessions the pigeons were housed individually with continuous access to water and health grit in a room with constant temperature and humidity, and a 16:8 hr light/ dark cycle. Two of the subjects (P860 and P880) were experimentally naive at the beginning of the experiment. Pigeon P3891 had a history of responding under interval schedules of reinforcement. Apparatus Sessions were conducted in a Lehigh Valley Electronics Model 1519C pigeon conditioning chamber, with internal dimensions of 35 cm by 33 cm by 35 cm. On one wall, three translucent Plexiglas® response keys were mounted behind 2.5-cm-diameter holes in a horizontal row. Only the center key was operative during this experiment, and a static force greater than 0.15 N was required to operate the key. Each response was followed by a 60-ms tone produced by a Mallory Sonalert (2900 Hz, 28 Vdc, model #628). The key could be transilluminated by red, yellow, or green lights. A rectangular opening (5.2 cm by 5.8 cm) was located 10.2 cm below the center key. Mixed grain could be made available through this opening by operating a grain feeder. When food was made available the opening was illuminated by a 1.2-W lamp and all other lights in the chamber were extinguished. At the top center of the wall a shielded 1.2-W lamp served as a houselight. The chamber was located in a darkened room in which white masking noise was continuously present. A fan mounted on the chamber provided ventilation. Experimental events were arranged and data were recorded by a Digital Equipment Corporation PDP8-E® or -F (depending on which was currently functional) computer operating under the control of SuperSKED® software (Snapper & Inglis, 1978). Behavioral Procedures The naive subjects' key pecking was shaped by reinforcing successive approximations. The final schedule arrangement was a three-component multiple schedule in which each component consisted of five consecutive repetitions of a fixed-ratio schedule of food delivery. The components differed with respect to ratio value. A small ratio value was correlated with a red
COCAINE TOLERANCE
keylight, a medium ratio value with a yellow keylight, and a large ratio value with a green keylight. The session began with illumination of the houselight and one of the three stimulus lights, randomly selected, appearing on the key. The completion of each fixed ratio resulted in 3-s access to food. After the fifth reinforcement in a component, a 60-s timeout (TO) occurred during which all lights in the chamber were extinguished and the key was inoperative. The next component was selected randomly from the two remaining components, and the third component in each block of three was the one that had not yet been selected. Each session contained three blocks, and thus three exposures to each of the three components. If the pigeon did not complete a component within an allotted time, the 60-s TO was presented, followed by the next component. The small-ratio component limit was 2 min, that for the medium-ratio component was 6 min, and the large-ratio component limit was 25 min. These values were chosen such that time limits were twice as long as the longest duration of a component observed once stable responding had been established and before drugs were administered. Initially, an attempt was made to establish performance under an arrangement wherein each block consisted of the three components appearing in a fixed order, from smallest ratio to largest. The ratios studied were FR 5, FR 25, and FR 125. Responding in the large-ratio component was poorly maintained under these conditions. Following the change to randomized selection of component order, however, consistent performances were established in all components for 2 subjects. Large-ratio performance still was not consistently maintained in P880, so the large ratio was reduced to FR 50 for this subject. Sessions were conducted daily, 6 or 7 days per week during determination of acute drug effects, and 7 days per week during chronic drug administration. Assessment of Acute Drug Effects Cocaine hydrochloride was dissolved in 0.9% sodium chloride (saline) solution. Dosages were determined in terms of the salt. Injections were made into the pectoral muscle immediately before selected sessions and were spaced by at least 3 days. Injection volume was 1 mL/kg, and each dose was administered twice. Dosages were administered in two ascending se-
365
ries: saline, 1.0 mg/kg, 3.0 mg/kg, 5.6 mg/ kg, and 10.0 mg/kg. Assessment of Chronic Effects After the assessment of acute drug effects and at least 10 consecutive days of responding without drug administration, the effects of chronic administration of cocaine were assessed by injecting 5.6 mg/kg of the drug immediately prior to each session. This condition was in effect for 71 days for P860, 101 days for P880, and 83 days for P3891. This particular dose was chosen because when administered acutely, it did not completely eliminate responding but did suppress responding in all three components. As a result, it was possible to observe either tolerance or sensitization to the effects of the chronic dose. The site of injection alternated each day between the left and right pectoral muscle to minimize bruising. Doses of cocaine other than 5.6 mg/kg and injections of saline occasionally were substituted for the usual daily dose once session-to-session performance under daily administration of 5.6 mg/kg had stabilized, as determined by visual inspection of the daily plots of response rates. Behavior under the chronic drug regimen was judged stable after 58 injections (P860), 47 injections (P880), or 31 injections (P3891). Substitutions (probes) were spaced by at least 3 days, and each dose was examined at least twice in Subjects P880 and P3891 and once in Subject P860. (Subject P860 died before all doses could be administered twice.) Doses always were administered in ascending series so that any systematic changes in the dose-response curves that might occur over successive assessments of drug effects could easily be observed.
RESULTS 2 show representative cu1 and Figures mulative response records of key pecking by Pigeons P860 and P880, respectively. With acute administration (left panels), the larger doses of cocaine decreased response rate in all three components, with large-ratio responding being most sensitive to the rate-decreasing effects (i.e., it was reduced to a greater degree). For P860, pecking was almost completely eliminated at 5.6 mg/kg with some slight recovery at the end of the session. A dose of 10.0 mg/kg suppressed virtually all key pecking for
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SANDRA H. HOFFMAN et al.
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the duration of the session. For P880, whose ratios recovered to near control levels, whereas largest ratio was FR 50, large doses of cocaine responding under the largest ratio remained either depressed (P880) or eliminated (P860). reduced responding but did not eliminate it. Complete dose-effect curves for rates of reCumulative records produced during chronic administration of 5.6 mg/kg reveal that tol- sponding of each subject under acute and erance developed in the rate-reducing effects chronic conditions are presented in Figure 3. of cocaine. The records shown are from the Acute administration of cocaine produced dose56th day of the chronic regimen for P860 (Fig- related decreases in response rate, with the ure 1, right column, second row), and from effect being dependent on ratio size. No effect the 47th day for P880 (Figure 2, right column, of the drug on performance under the small second row). For P860 tolerance was evident ratio (FR 5) was observed until 5.6 mg/kg in small- and middle-ratio performance, but was administered. In 2 of 3 subjects (P3891 little tolerance occurred under the large-ratio and P880) rate decreases occurred (at least one schedule. Tolerance to the effects of 5.6 mg/ determination fell outside control ranges) unkg also is evident in P880's cumulative re- der FR 25 at 3.0 mg/kg, and P3891's rate sponse records. Response rates were higher in decreased at 1.0 mg/kg under this schedule. all three components and session length was Response rates under the large ratio were most shorter after chronic dosing. There was less sensitive to the effects of cocaine. Response recovery under the largest ratio (FR 50) than rates of Subjects P860 and P880 were deunder the two smaller ratios. The schedule- creased below their control ranges at all doses. related differences in tolerance development Only one of the two administrations of 1.0 mg/ across ratio values were most pronounced when kg decreased rates for Subject P3891, but all 10.0 mg/kg was studied (bottom rows, Figures other doses produced a decrease. Figure 3 also shows that tolerance developed 1 and 2); responding under the smaller two
COCAINE TOLERANCE
367
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during daily ("chronic") administration of 5.6 mg/kg and that the tolerance depended on ratio value. The rate-decreasing effects of 5.6 mg/kg and 10.0 mg/kg seen under acute conditions under FR 5 were attenuated in all 3 subjects. Tolerance was also evident in the responding of 2 of the subjects (P860 and P880) under FR 25. Under the large-ratio schedule, only P880's performance indicated the development of tolerance (i.e., the dose-effect curve was shifted to the right). Dose-related decreases from baseline were still apparent, however, and thus the degree to which tolerance developed was not as great under the large ratio as under the smaller two ratios for this subject. Data were collected separately during each three-component block to allow an estimate of
the time course of drug action across a session as well as a more detailed description of performance. Analyses based on these data are presented for Pigeons P860, P3891, and P880 in Figures 4, 5, and 6, respectively. Figure 4 shows that under acute conditions for P860, graded effects of cocaine on responding under FR 5 were not observed within blocks; responding was either unaffected or completely eliminated. The two smaller doses (1.0 mg/kg and 3.0 mg/kg) did not reduce overall rate under FR 5 in any block. The variability in effects in the first block when 5.6 mg/kg was administered acutely depended on whether FR 5 was the first component presented. Specifically, responding was similar to that observed following saline administration if FR 5 was the first component to appear
SANDRA H. HOFFMAN et al. 32-
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COCAINE (mg/kg) function of cocaine dose. Filled circles are data from acute administrations, and Fig. 3. Mean open circles are data obtained from sessions embedded within a series of sessions preceded by injections of 5.6 mg/kg of cocaine. Vertical bars show ranges. Points above C are means from all sessions that immediately preceded those in which acute injections were made. Points above V are from sessions preceded by injections of the saline vehicle. The open circles above 5.6 mg/kg indicate sessions that occurred immediately before sessions in which probe doses were tested. The number of values upon which each mean is based can be found in Table 1. Each row shows the data for 1 pigeon, and each column shows data for a different component of the multiple schedule. The left column shows data from the FR 5 component, the middle column shows data from the FR 25 component, and the right column shows data from the FR 125 (FR 50 for P880) component. response rates as a
during a session. Otherwise, responding was eliminated during the component. This effect also was evident during the initial sessions of chronic administration of 5.6 mg/kg. Acute administration of 10.0 mg/kg usually either suppressed responding completely or the pigeon emitted one or two responses during the component before the time limit expired (see Figure 1). Following chronic administration, tolerance was evident in the overall rate-decreasing effects of 5.6 mg/kg and 10.0 mg/kg under FR
5 across all three blocks. In contrast to acute effects wherein 5.6 mg/kg completely suppressed responding under FR 25 in the first two blocks and 10.0 mg/kg eliminated responding across all blocks, tolerance to these two doses occurred across all three blocks under the chronic-administration condition. The figure reveals complete recovery of performance at these two doses. Responding under FR 125 was decreased at all acutely administered doses with the exception of 1.0 mg/kg in the third (last) block. Under chronic admin-
COCAINE TOLERANCE
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COCAINE (mg/kg) Fig. 4. Mean response rates for Pigeon 860 across components of the multiple schedule (rows) and blocks of the sessions (columns) as a function of cocaine dose. Data in the top row show effects during the first, second, and third exposure to FR 5 within a session. Data in the second and third rows show data for the other two ratios in a similar fashion. Filled circles are from acute administrations and open circles from administrations interspersed between repeated daily administrations of 5.6 mg/kg of cocaine. Vertical bars indicate ranges. Points above C are from sessions that preceded those in which acute administrations were studied. Points above V show effects of administering the saline vehicle. Open circles above 5.6 mg/kg are averages from sessions that occurred immediately before sessions in which probes were conducted. The number of values in each mean can be found in Table 1.
istration, there was little evidence of tolerance except for a slight increase in mean overall rate in the last block following 3.0 mg/kg or 5.6 mg/kg. Figure 5 shows dose effects across blocks of the session after acute and chronic administration of cocaine for Pigeon P3891. Under the small ratio, acute injection of 5.6 mg/kg depressed responding in the first block, but not in the second and third blocks, while 10.0 mg/ kg suppressed responding across all blocks. Tolerance to these effects was evident during chronic administration and was more pronounced during the last two blocks. Under FR 25, both 3.0 mg/kg and 5.6 mg/kg showed a clear diminution of effect as the session pro-
gressed following acute administration. A dose of 10.0 mg/kg, however, produced large decreases in all blocks. Tolerance was evident at doses of 3.0 mg/kg and 5.6 mg/kg in the first block, and at the 10.0 mg/kg dose in the second and third blocks. Administered acutely, all doses were effective in producing rate decreases in the first block under FR 125. One acute administration of 3.0 mg/kg and all administrations of 5.6 mg/kg and 10.0 mg/kg resulted in rate decreases in the second block, while only 10.0 mg/kg resulted in rate decreases in the third block. No tolerance was evident in any of the blocks under FR 125 following chronic administration of 5.6 mg/ kg.
SANDRA H. HOFFMAN et al.
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COCAINE (mg/kg) Fig. 5. Mean session (columns)
response rates for Pigeon 3891 across components of the multiple schedule as a function of cocaine dose. Details are the same as for Figure 4.
Figure 6 illustrates dose effects across blocks for pigeon P880. Under FR 5, mean overall rate was depressed following acute 5.6 mg/kg in the first but not the second or third blocks, whereas 10.0 mg/kg depressed responding in the first block, one administration in the second block, but never in the third block. During the chronic regimen, tolerance occurred in the first block at 5.6 mg/kg and 10.0 mg/kg, and at 10.0 mg/kg in the second block. Under FR 25, response rate decreased after acute 5.6 mg/ kg and 10.0 mg/kg in the first and second blocks, following one administration of 3.0 mg/ kg in the first and second blocks, and after one administration of 5.6 mg/kg in the third block. Chronic administration resulted in tolerance across all three blocks to the rate-decreasing effect of the drug. Under the large ratio (FR
(rows) and blocks of the
50), acute administrations of 1.0 mg/kg, 3.0 mg/kg, 5.6 mg/kg, and 10.0 mg/kg decreased overall response rate in the first and second blocks, while only 5.6 mg/kg and 10.0 mg/kg decreased responding in the last block. Following repeated injection of 5.6 mg/kg, tolerance was evident at 1.0 mg/kg and 3.0 mg/ kg in the first two blocks. No tolerance was evident in the first block under 5.6 mg/kg and 10.0 mg/kg, but tolerance did develop in the second and third blocks to effects of these two doses. To summarize, drug effects generally tended to diminish as the session progressed (i.e., across blocks). Larger doses were required to produce rate decreases later in the session when the drug was administered acutely, an effect that was especially noticeable in performance un-
COCAINE TOLERANCE
371
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COCAINE (mg/kg) Fig. 6. Mean session (columns)
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response rates as a
der the two smaller ratios. That is, large-ratio performance tended to recover less across the session. Tolerance subsequent to chronic dosing was most likely to be observed in the third block and least likely to be observed in the first block. A more molecular analysis of drug effects across the course of a session can be accomplished by referring to Table 1, which shows the effects of each dose on the preratio pause and on running rate (rate computed exclusive of pause time). Data are presented individually for each block of a session. In the calculation of the mean pause values, only terminated pauses were included except in the case where no responses occurred in a component. In those instances mean pause was set at the time limit for a component. These data, too, illustrate that effects tended to diminish across the session. They also reveal that when the mean response rates shown in Figure 3 were in the
control range during the chronic drug regimen the performance was typical of that observed under nondrug conditions. That is, as suggested by the cumulative records shown in Figures 1 and 2, the normal pause-then-respondrapidly pattern was recovered for the lower ratios during repeated dosing with 5.6 mg/kg. Another trend illustrated in the table is that under conditions of acute administration, running rate under the shorter ratios was less likely to take on values between zero and control levels (i.e., intermediate values) than was responding under the large ratio. That is, running rate for the shorter ratios tended to be at control levels or be severely reduced. DISCUSSION Whether tolerance developed, or the degree to which it developed, following presession administration of cocaine depended on the ra-
SANDRA H. HOFFMAN et al.
372
Table 1 Mean running rates (R/s) and mean preratio pause(s) as a function of dose of cocaine, fixedratio values, block of the session, and acute or chronic administration.
Dosea
Acute Block 2 Rate Pause
N
Chronic Block 1 Rate Pause
2 1 1 5 1
3.76 3.68 3.33 3.72 3.43
0.98 1.02 1.00 0.73 0.92
3.47 3.12 3.45 3.18 3.09
1.25 1.52 1.38 1.43 1.66
2.77 0.63 0.16 0.32 0
45.20 84.92 352.75 888.17 1,500.0
4.38 4.20 3.68 2.51 2.51
1.06 1.10 1.34 16.48 1.89
3.75 2.35 2.51 1.11 0
1.48 9.28 7.40 54.72 360.00
2 2 2 8 2
2.21 1.62 0.24 0.00 0
118.65 116.76 1,417.60
-
1.87 2.07 2.91 2.29 3.89
1.90 2.25 1.43 2.99 1.54
2.91 2.52 2.85 1.66 2.30
2.33 3.55 3.05 53.28 3.34
N
FR
Block 1 Rateb Pausec
10 2 2 2 2 2 10 2 2 2 2 2 10 2 2 2 2 2
5 5 5 5 5 5 25 25 25 25 25 25 125 125 125 125 125 125
3.28 3.48 3.64 3.46 1.62 0.02 3.44 3.46 3.24 3.20 0 0 2.15 1.28 0.85 0.37 0.02 0
0.88 0.85 0.80 0.97 60.47 61.10 1.60 1.61 1.14 1.19 360.00 360.00 69.08 53.33 55.65 167.50 796.50 1,500.00
3.05 3.33 3.82 3.68 0.00 0.03 3.61 3.61 3.63 3.36 0 0 2.55 1.73 0.77 0.03 0 0
0.87 0.91 0.72 0.83 120.00 90.10 1.75 2.03 1.09 1.44 360.00 360.00 68.39 91.51 42.03 848.55 1,500.00 1,500.00
3.15 3.36 3.52 3.71 1.74 0.02 3.76 3.71 3.81 3.44 3.11 0 2.69 1.69 2.25 1.78 0.01 0
0.79 0.96 0.79 0.83 60.49 94.95 1.75 1.84 1.10 1.08 1.55 360.00 50.53 50.27 32.55 824.03 1,363.40 1,500.00
10 2 2 2 2 2 10 2 2 2 2 2 10 2 2 2 2 2
5 5 5 5 5 5 25 25 25 25 25 25 125 125 125 125 125 125
4.71 4.07 5.12 3.90 0 0 4.40 4.87 8.10 0.70 0.01 0 2.64 3.04 0.92 0.15 0 0
0.88 0.88 0.77 0.94 120.00 120.00 1.75 1.64 6.59 14.75 329.25 360.00 44.91 42.32 154.65 824.40
4.19 4.43 4.73 3.81 3.68 0 3.75 3.95 3.97 2.90
4.42 4.50 4.52 3.84 4.34 0 3.55 3.34 3.70 3.07 2.64 0 1.91 2.09 1.89 0.77 1.44 0
0.86 0.64 0.85 1.13 1.00 120.00 2.19 1.72 3.30 3.37 2.54 360.00 93.55 64.17 32.79 85.78 41.05 1,500.00
-
1,500.00 1,500.00
0.77 0.69 0.80 1.08 1.05 120.00 2.18 1.91 3.23 3.36 2.98 360.00 89.47 84.31 44.28 792.97 581.50 1,500.00
12 3 2 3 2 2 12 3 2 3 2 2
5 5 5 5 5 5 25 25 25 25 25 25
3.78 3.92 2.85 3.65 0 0 2.66 2.09 2.39 1.66 0 0
1.12 1.07 1.09 1.17 120.00 120.00 2.44 6.63 2.30 17.94 360.00 360.00
1.09 1.06 1.19 0.86 1.30 60.47 2.45 2.09 2.16 60.33 1.30 194.10
3.53 4.19 3.18 3.00 3.27 3.11 3.14 3.08 2.86 2.77 1.28 2.22
1.07 1.15 1.15 0.80 1.16 1.09 2.27 2.20 4.29 1.76 1.15 2.04
Block 3 Rate Pause
P860 Cd
Ve 1.0 3.0 5.6 10.0 C V 1.0 3.0 5.6 10.0 C V 1.0 3.0 5.6 10.0 P3891
C V 1.0 3.0 5.6 10.0 C V 1.0 3.0 5.6 10.0 C V 1.0 3.0 5.6 10.0 P880 C V 1.0 3.0 5.6 10.0 C V 1.0 3.0 5.6 10.0
2.71 0 2.08 2.84 1.15 0.61 0.78 0 3.41 3.47 3.84
3.58 3.73 1.92 2.90 2.87 2.63 2.23 0.26 0.17
-
2 1 1 5 1 -
2 1 1 5 1 2 2 2 8 2 -
2 2 2 8 2 -
2 2 2 8 2
1,291.70 1,500.00
-
2 2 2 8 2
COCAINE TOLERANCE
Table 1 (Continued)
Chronic Block 2 Pause Rate
Block 3 Pause Rate
3.47 3.29 4.10 4.07 3.43
0.70 0.68 0.68 0.77 0.84
3.24 4.31 4.24 4.00 4.17
0.71 0.72 0.72 0.69 0.78
3.61 3.60 3.51 3.38 3.13
1.42 1.26 1.10 1.14 1.42
3.84 3.86 3.81 3.52 3.28
1.49 1.50 1.30 1.16 1.28
1.67 0.81 0.14 0.08 0.01
54.29 71.10 159.80 627.96 307.10
3.27 0.89 2.29 0.28
42.13 99.80 108.74 548.53 1,500.00
4.72 4.27 4.42 3.74 3.75
0.91 0.99 1.06 1.20 1.21
5.12 4.64 3.68 4.12 3.68
0.91 0.95 1.10 1.15 1.10
3.96 2.89 2.44 1.94 1.30
1.96 3.20 15.90 13.61 12.52
3.30 2.72 2.59 2.34 1.70
1.81 2.35 6.65 5.12 16.96
1.83 0.65 0.01 0.01
74.55 71.05 860.55 944.13 1,500.00
1.99 0.57 1.27 0.32 0.02
44.36 59.34 161.21 392.35 889.05
3.14 4.29 3.24 3.41 3.17
1.23 1.37 1.41 1.33 1.42
3.50 3.29 3.05 2.94 2.14
1.30 1.55 1.35 1.35 1.37
3.00 2.94 3.45 3.30 2.77
1.78 2.08 2.27 2.40 2.26
2.98 2.98 3.20 2.75 2.85
1.86 2.10 2.20 2.15 2.43
0
0
373
tio value. Tolerance developed under the FR 5 schedule for all 3 subjects, but under the largest ratio was observed only for P880. The largest ratio, however, for P880 was FR 50, whereas for the other 2 subjects the largest ratio was FR 125. Even for P880, tolerance developed to a lesser degree under FR 50 than under the two smaller ratios. The consistent pattern, therefore, was that greater tolerance to cocaine developed under small ratios than under large ratios. These conclusions regarding tolerance are based on performances that probably reflect asymptotic effects under the chronic injection regimen used. That is, the data indicate that the effects of chronic administration had reached a steady state; the successive determinations of the dose-effect curve revealed no systematic differences, and effects of 5.6 mg/kg over the sessions during which dose effects were examined were consistent. The most widely supported hypothesis concerning behavioral tolerance to drug effects is that tolerance is more likely if the drug initially decreases reinforcement frequency (CorfieldSumner & Stolerman, 1978; Schuster, Dockens, & Woods, 1966). Although the present study was not designed to test this hypothesis directly, the data from the experiments are at least partially consistent with it. Decreases in response rate under fixed-ratio schedules result in decreased reinforcement frequency; cocaine, administered acutely, decreased response rates. Thus, in all cases in which tolerance was observed in the present study, acute drug injections decreased reinforcement frequency. On the other hand, there were substantial drugproduced decreases in reinforcement frequency during the large ratio, yet tolerance was not observed in 2 of 3 subjects, and the third showed less tolerance in this component. The present data, consequently, suggest that there may be boundary conditions beyond which reinforcement loss contributes less to the development of tolerance. The failure to observe tolerance during the largest fixed ratio, however, may have been due to the use of a multiple schedule that provided a context of smaller ratios. That is, it is possible that tolerance would be observed under FR 125 if it were studied in isolation or in a context of even larger ratios. It would be premature to conclude that a ratio value of 125 represents any sort of fixed limit above which tolerance will not be observed.
SANDRA H. HOFFMAN et al.
374
Table 1 (Continued)
Dosea
N
FR
Rateb
Block 1 Pausec
Acute Block 2 Rate Pause
C 12 50 2.43 13.45 2.48 20.58 V 3 50 2.28 15.94 2.43 23.56 1.0 2 50 0.39 16.37 0.59 19.59 3.0 3 50 0.57 33.72 0.67 26.14 2 5.6 50 0.24 552.87 0.34 16.38 10.0 2 50 0 1,500.00 0.21 297.73 a In mg/kg. bIn R/s exclusive of pause time. c In seconds. d Sessions that preceded those during which injections were made. eSessions that were preceded by injections of the vehicle, saline.
The differential effects of cocaine in the present study may have been due to the amount of "effort" or "behavioral cost" required in each component. (The three FR schedules prescribed different numbers of responses necessary for reinforcement.) The acute and chronic effects of cocaine that were schedule dependent may have been specifically dependent on these "effort" differences. The findings are consistent with the suggestion of Branch and Dearing (1982) that cocaine tolerance may depend on the amount of behavior required for reinforcement. Differences in reinforcement frequency, however, also may have played a role. Rate of reinforcement was about 25 per minute under FR 5, 6 to 7 per minute under FR 25, and considerably lower under the larger ratios. Independent evaluation of the role of reinforcement frequency will require further experimentation. An account of the present results can be based on the concept of response strength. Nevin (1974, 1979) suggested that reinforcement schedules produce variations in resistance to change that are consistent across a number of methods for producing the change. Behavior that is more resistant to change is defined as "stronger." In the present study, the smaller the ratio value the greater the resistance to disruption by the acute administration of the drug. If acute effects of cocaine can be considered a way to index the "strength" of responding, then perhaps "response strength" may predict tolerance. The stronger the baseline responding (the more resistant to change from baseline rates following acute drug administration) the more likely that tolerance
Rate 2.37 2.50 0.93 0.82 0.29 0.33
Block 3 Pause 19.25 26.30 18.42 16.44 39.40 21.72
Chronic Block 1 Rate Pause
N -
2 2 2 8 2
-
2.94 2.16 1.18 0.37 0.12
11.19 20.86 34.79 88.46 371.68
will develop when a drug is administered chronically. Conversely, the development of tolerance might predict the "strength" of responding. It is noteworthy, however, that Cohen (1986) compared drugs as response disruptors with more conventional manipulations (e.g., extinction) and found substantial differences. Consequently, it may not be appropriate to use drugs to index response strength. In contrast to the results of the present study, many researchers have observed sensitization or ''reverse tolerance" following chronic administration of cocaine (Downs & Eddy, 1932a, 1932b; Kilbey & Ellinwood, 1977; Post et al., 1976). Most of these investigators, however, have measured "naturally occurring" behavior such as locomotor activity. Comparison of effective doses in the aforementioned studies with those used in studies involving operant behavior suggests that operant behavior usually appears to be more sensitive to effects of cocaine (i.e., lower doses are needed to produce reliable changes), and tolerance is the typical finding when operant behavior is subjected to chronic cocaine administration (Branch & Dearing, 1982; Moore & Thompson, 1978; Spealman et al., 1977; Thompson, 1977). The finding that acute administration of cocaine produced dose-related decreases in overall response rate under all three fixed-ratio values is consistent with those of other experiments in which effects of cocaine on responding maintained by fixed-ratio schedules have been studied (Bacotti, 1980; Branch & Dearing, 1982; Gonzalez & Goldberg, 1977; Johanson, 1978; MacPhail & Seiden, 1975; Spealman et al., 1977). The present results
COCAINE TOLERANCE Table 1 (Continued) Chronic Block 2 Pause Rate 2.34 2.47 2.54 2.00 1.12
16.14 5.25 3.79 5.67 13.02
Block 3 Pause Rate 3.01 2.69 2.13 2.16 0.71
13.73 8.35 4.33 7.64 17.82
375
The effects of a drug on operant responding frequently are dependent on baseline rate of responding (see Dews & Wenger, 1977, and Sanger & Blackman, 1976, for reviews). Application of this rate-dependency description to the present experiment would predict an orderly monotonic relation between baseline rate and degree of suppression under acute dosing. The present data, however, do not fit this prediction. Consider, for example, the effects of 3.0 mg/kg of cocaine (see Figure 3). The magnitude of the decrease produced by this dosage grew (both absoluely and proportionately) as the ratio value increased. Baseline response rate, however, increased and then decreased as ratio value increased. The relation between baseline rate and magnitude of drug effect was not a simple one. A final interesting finding was that the substitution of saline for the daily maintenance dose of 5.6 mg/kg of cocaine resulted in performance that was indistinguishable from that observed under nondrug conditions. That is, even after more than 50 consecutive days during which each session was preceded by an injection of cocaine, control performance could be restored immediately by omitting drug injection. This result is consistent with that reported by Branch and Dearing (1982) who also found that control performance recovered immediately after lengthy exposure to repeated cocaine administration. It appears, then, that in pigeons repeated daily doses of cocaine do not result in marked drug dependence, for disruption of performance upon withdrawal of a chronically administered drug is one of the main indicators of drug dependence (Schuster & Thompson, 1969).
extend the generality of this effect to a multiple schedule. The acute effects of cocaine on responding maintained under fixed-ratio schedule, therefore, do not appear to be especially sensitive to the context in which performance is maintained (see, however, Thompson & Moerschbaecher, 1980). The rate changes also were consistent with previous findings that operant responding of pigeons tends to be completely suppressed at the beginning of a session but recovers towards the end of a session (Bacotti, 1980). Both cumulative response records (Figures 1 and 2) and summarized time-course data (Figures 4, 5, and 6 and Table 1) for sessions with administration of larger doses showed more marked reduction in responding at the beginning of a session than occurred later in the session. This effect, however, seems to have been modulated by ratio value. Performance under the large ratio was more sensitive to the rate-decreasing effects of cocaine. Time-course data show that the degree of recovery across the three blocks was dependent on ratio value, with relatively less recovery under the large ratio. The relation observed in the present study between fixed-ratio value and response rate REFERENCES under nondrug conditions also is consistent with Bacotti, A. V. (1980). Effects of cocaine and morphine previous findings. Overall response rate inon concurrent schedule-controlled performances. Jourcreases with increases in ratio size over a range nal ofPharmacology and Experimental Therapeutics, 212, 280-286. of small FR values (Boren, 1961) and then decreases as the ratio is increased further (Fel- Barrett, J. E. (1976). Effects of alcohol, chlordiazepoxide, cocaine and pentobarbital on responding mainton & Lyon, 1966; Powell, 1968). In the prestained under fixed-interval schedules of food or shock ent experiment, overall rate under FR 25 was Boren, J. J. (1961). Resistance to extinction as a function higher than overall rate under FR 5, but also of the fixed ratio. Journal of Experimental Psychology, 61, 304-308. higher than overall rate under FR 125 or FR M. N., & Dearing, M. E. (1982). Effects of 50. In addition to corroborating the existing Branch, acute and daily cocaine administration on performance literature, these results also indicate that the under a delayed-matching-to-sample procedure. Pharsubjects used in the present study were in no macology Biochemistry and Behavior, 16, 713-718. Castellani, S. A., Ellinwood, E. H., Jr., & Kilbey, M. M. way atypical.
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