Role of dose order in the development of tolerance to effects of cocaine on schedule-controlled behavior in pigeons

Abstract Rationale. Tolerance to behavioral effects of cocaine can be produced by exposure to varying doses. The degree to which tolerance develops may depend on dose order. Objective. To investigate the relationships between three sequences of doses of cocaine in a daily, variable-dosing regimen and the development of tolerance to effects on schedule-controlled behavior. Methods. Twelve pigeons responded daily under a fixed-ratio 20 schedule of reinforcement, and performance was investigated under a range of doses of cocaine (0.3–10.0 mg/kg, i.m.) by administering the drug once every 7 days (acute effects). After determination of acute effects of cocaine, the drug was administered daily with dose varying from day to day. Dose order varied systematically across three groups of four pigeons; doses were delivered in ascending, descending, or "sawtooth" (ascending then descending) sequences. This variable-dosing regimen continued until drug effects were stable (at least 13 cycles through all doses). Results. During the acute-dosing regimen, response rates following small cocaine doses were similar to those under control conditions; following moderate-to-high doses, responding was diminished relative to control rates. During the variable-dosing regimen, tolerance to the rate-decreasing effects of cocaine was observed in all groups, regardless of the order in which the drug was delivered, and the magnitude of tolerance was similar across groups. Systematic differences in the rate of recovery from initial response decrements were observed across groups, with rate of recovery fastest under the ascending sequence. Conclusions. These results suggest that dose order under a variable-dosing regimen does not significantly affect the final attainment of tolerance, although it may contribute to the speed with which tolerance develops. Electronic Publication     

Tolerance to effects of morphine without cross tolerance to effects of clonidine on schedule-controlled behavior of pigeons

Schedule-controlled responding was maintained under a multiple fixed-interval, fixed-ratio schedule in pigeons. Dose-related decreases in response rates were produced by clonidine (0.001–0.1 mg/kg) and morphine (0.3–5.6 mg/kg). Chronic administration of morphine produced (1) tolerance to effects of morphine, as evidenced by a decrease in potency of morphine and (2) sensitivity to opioid antagonists, as evidenced by an increase in potency of naloxone. Dose-effect curves for clonidine were not appreciably altered by chronic morphine administration. Offprint requests to: J.L. Katz     

Effects of pentobarbital on punished behavior: Persistent increases with chronic administration

Food maintained responding by pigeons was suppressed by response-dependent electric shock presentation (punishment). Administration of 5.6 mg/kg pentobarbital IM for 25 days and, later, 10.0 mg/kg pentobarbital for 30 days resulted in profound, sustained, dose-related increases in punished responding and shock presentation.     

Tolerance to the disruptive effects of arecoline on schedule-controlled behavior

The roles of dispositional, physiological, and behavioral factors in the development of tolerance to the effects of arecoline on operant behavior were assessed. In Experiment I, rats were trained to press a lever on a variable-interval 15-s schedule for milk reinforcement. Dose-effect relationships were assessed prior to and during chronic arecoline (1.74 mg/kg/day) treatment. After 21 days of arecoline administration prior to each session, the dose-effect relationship for total number of responses did not shift. However, the dose-effect relationship for total number of reinforcers shifted to the right. In Experiment II, rats were trained to respond on a fixed-ratio 20 schedule for milk reinforcement. Dose-effect relationships were assessed prior to and during chronic arecoline (0.87 mg/kg/day) administration. One group of rats received daily injections of arecoline prior to the session and a second group received arecoline injections 30 min after the session. Daily administration of arecoline resulted in a greater shift to the right of the dose-effect relationship for the presession group than it did for the postsession group. These data demonstrate the importance of behavioral factors in the development of tolerance to arecoline.     

Tolerance to suppressive effects of chlordiazepoxide on operant behavior: Lack of cross tolerance to pentobarbital

Pigeons responded under schedules in which either the 60th response (fixed-ratio schedule) or the first response after 3 minutes (fixed-interval schedule) resulted in food delivery. The effects of chlordiazepoxide HCl (1–30 mg/kg) and pentobarbital sodium (1–17 mg/kg) were determined before and during chronic daily exposure to either 10 or 17 mg/kg chlordiazepoxide—doses that markedly suppressed responding when given acutely. After about three weeks of daily injections of chlordiazepoxide, there was at least a three-fold shift to the right of the dose-effect curve for chlordiazepoxide, but not consistent change in the effects of pentobarbital.     

Effects of repeated administration of cocaine on schedule-controlled behavior of rats

The effects of cocaine (4.0–32 mg/kg) on schedule-controlled behavior of rats were determined before and during a period of repeated administration of cocaine. In rats trained to lever press on a fixed ratio 40 schedule for food delivery, cocaine (8.0–32 mg/kg) initially decreased response rate in a dose-related manner. During the period of repeated administration, the effects of cocaine on response rate and running rate were attenuated in 2 rats and did not change in 2 others. When dose-effect functions of cocaine were determined, a shift to the right was observed in several measures indicating the development of tolerance to these effects of cocaine on performance. In rats trained to lever press on a DRL 20″ schedule for food delivery, cocaine (4.0–32 mg/kg) increased response rates, decreased number of reinforcements per session and shifted interresponce time distributions to the left (shorter IRT's in all rats). During the period of repeated administration, the effects of the daily dose of cocaine (16 mg/kg) on all these measures were attenuated. Tolerance to cocaine was further indicated by a shift in the dose effect function of cocaine to the right during the redetermination.     

Tolerance to antinociceptive effects of morphine without tolerance to its effects on schedule-controlled behavior

The development of tolerance to behavioral effects of morphine was investigated in rats that responded on a two-lever, multiple-trial, multiple differential-reinforcement-of-low-rate fixed-ratio (mult DRL FR) schedule of food presentation. Stable performances were maintained when sessions were conducted just twice per week. The effects of cumulative doses of morphine (1.0–8.0 mg/kg) or chlordiazepoxide (CDP; 4.0–32.0 mg/kg) were evaluated once per week; saline injections were given in the intervening sessions. The effects of saline and morphine on nociception were also evaluated in hot-plate tests conducted on the same subjects 15 min after selected operant sessions. Initially, morphine produced dose-related decreases in response rates and reinforcement rates in the DRL and FR components as well as significant increases in hot-plate response latencies. Following weekly administration of morphine (1.0–8.0 mg/kg) for 10 weeks, there was little or no tolerance to its effects on operant behavior. In contrast, complete tolerance developed to the antinociceptive effects of morphine. These results suggest that tolerance to various behavioral effects of morphine may be dissociated, and that the loss of reinforcement may be insufficient by itself to produce tolerance to effects of morphine on operant behavior. Additionally, whereas CDP initially produced only dose-related decreases in DRL and FR response rates, following weekly morphine the smaller doses of CDP (4.0–16.0 mg/kg) produced increases in response rates. Finally, the effects of cumulative doses of morphine did not differ significantly from the effects of noncumulative doses of the drug.     

Development of behavioral tolerance to morphine and methadone using the schedule-controlled behavior of the pigeon

A multiple fixed-ratio, fixed-interval schedule of food presentation was used to study the development of behavioral tolerance to daily injections of equipotent doses of morphine and methadone in the pigeon. There was evidence that tolerance was developing to the rate-decreasing effects of both drugs after a single injection. Tolerance to morphine developed more rapidly during the first week of injections than did tolerance to methadone. Tolerance to the depressant effects of morphine and methadone was less complete under the fixed-ratio component of the schedule than under the fixed-interval component. After repeated injections, increases in the rate of responding were observed in some birds. These increases depended on the bird, rather than on the narcotic. Thus, the development of tolerance was a function of the drug, of the individual bird, and of the schedule maintaining the behavior.     

The effects of methadone on operant behavior maintained with and without conditioned reinforcement in the pigeon

Effects of methadone on key pecking supplemented with brief stimuli either correlated with or independent of unconditioned reinforcement was investigated. On average, key pecks by pigeons produced brief stimuli (BS) once per minute and food once per 4 min during both components of a multiple schedule (i.e., VI1:BS, VI4:Food). Brief stimuli were paired with food presentation during one component and not related to food during the second component. Acute methadone administration (0.56, 1.0, 1.7, and 3.0 mg/kg) decreased response rates during both components; however, the decrease was smaller by a constant amount during the paired brief stimulus component, regardless of drug dose. These results suggest conditioned reinforcement is not a primary mechanism through which methadone exerts behavioral effects and that reinforcer-correlated stimuli have potential for diminishing the reduced behavioral output observed following methadone administration.     

Tolerance to behavioral effects of physostigmine under interval schedules of positive or negative reinforcement

The present experiments examined whether the rate and type of events maintaining responding help determine physostigmine's behavioral effects. The first two experiments examined the acute and chronic effects of physostigmine, respectively, on lever pressing of rats under variable-interval schedules of food presentation. The third examined the chronic effects of physostigmine on lever pressing under random-interval schedules of shock avoidance. Three different variable intervals (18, 56, and 180 s) and two different random intervals (20 and 60 s) were studied, each associated with a distinctive stimulus. Baseline rates of responding were directly related to the scheduled rate of food delivery or shock avoidance. Acute administration of 0.154–1.233 mol/kg (0.1–0.8 mg/kg) physostigmine sulfate produced monotonic decreases in overall response rate under all schedules of food presentation. Acute effects (per cent of control response rate) did not differ systematically under the various interval values. Large doses (i.e., 0.4 or 0.8 mg/kg) suppressed the rate of food delivery as well. When initially administered, 0.967 mol/kg (0.4 mg/kg) physostigmine salicylate also suppressed avoidance response rates and per cent shocks avoided. Tolerance developed to the effects of this dose of physostigmine salicylate on pellet or shock-avoidance frequency more rapidly than to effects on overall response rate. Tolerance to the latter developed only very gradually and could in the case of shock-avoidance response rates be considered partial at best. Tolerance was not affected by the scheduled rate of food or shock presentation. Blood acetylcholinesterase levels showed no recovery during chronic physostigmine. Tolerance is discussed in terms of the reinforcement-loss hypothesis.The views of the author(s) do not purport to reflect the position of the Department of the Army or the Department of Defense, (para 4-3, AR 360-5)     

Behavioral influences on tolerance to the effects of morphine on schedule-controlled behavior

Responding of pigeons was maintained under a multiple fixed interval, fixed ratio schedule of food delivery, and 10 mg/kg morphine was administered daily. Responding during both schedule components was initially decreased and measureable tolerance developed to this effect after four daily injections. However, the rate of tolerance development differed depending on whether or not presence of the drug conicided with performance during experimental sessions. Tolerance developed more rapidly when morphine was given before daily experimental sessions than when morphine was given daily but animals did not perform daily in experimental sessions. Tolerance to the rate-decreasing effects of morphine depended on relations between presence of the drug and exposure to experimental sessions.     

Effects of delay to reinforcement on the choice between cocaine and food in rhesus monkeys

Rationale Although a delay between behavior and reinforcer has been shown to weaken behavior, little is known about the effects of delay on drug choice.Objectives The present study examined effects of delay between lever press and reinforcer presentation on the choice between a drug and non-drug reinforcer and between different drug doses.Materials and methods Monkeys (n=4) were allowed to choose 32 times/day between cocaine and four food pellets. The delay between lever press and a preferred dose of cocaine (0.05 mg/kg/injection) was increased systematically from 0 to 240 s, while the delay to food remained at 0 s. A second group of monkeys (n=4) was allowed to choose between 0.05 mg/kg/injection and a lower dose of cocaine (0.025 mg/kg/injection). Next, a delay that resulted in less than 20% choice of 0.05 mg/kg/injection cocaine was selected and delay to the alternative was varied.Results Results were similar across groups. The choice of 0.05 mg/kg/injection approximated 100% at 0 delay and decreased to near 0 as delay increased. As the delay to alternative was subsequently increased from 0 to 240 s, choice of 0.05 mg/kg/injection increased, though full cocaine choice was not generally restored. The delay estimated to maintain 50% choice (indifference point) was lower for the cocaine-food choice (mean=64 s) than for the cocaine–cocaine choice (mean=207 s).Conclusions This experiment demonstrates that the choice between cocaine and a non-drug or drug alternative can be modified by increasing the interval between behavior and drug injection. Overall, the results are consistent with a temporal discounting model of drug choice.     

Cocaine and automaintained responding in pigeons: Rate-reducing effects and tolerance thereto with different durations of food delivery

Pigeons were exposed to an automaintenance procedure in which 6-s key illuminations in one color (red or white) were immediately followed by 3-s food deliveries and key illuminations in the other color were followed by 9-s food deliveries. Both conditions engendered consistent responding. With both durations of food delivery, acute and chronic cocaine administrations (1.0–17.8 mg/kg) produced dose-dependent decreases in mean percent trials (key illuminations) with a response and mean total response per session. Tolerance developed to the disruptive effects of cocaine on both response measures. Food duration did not significantly affect either response measure or significantly interact with cocaine dose or drug regimen. The orderliness of the present findings, like those of a related study examining whether probability of food delivery modulated the effects of cocaine on automaintained responding [Porritt, M., Arnold, M., Poling, A., Cocaine and automaintained responding in pigeons: rate-reducing effects and tolerance thereto with different CS–US pairing probabilities. Pharmacol Biochem Behav 2007; 87:405–411.], suggests that the automaintenance procedure is a useful assay for examining tolerance to drug effects on classically-conditioned responding. Unlike the results of that study, however, the present findings are inconsistent with a behavioral momentum analysis of drug effects on such responding.     

Phencyclidine in combination with pentobarbital: Supra-additive effects on complex operant behavior in pigeons

Pigeons acquired a different four-response chain each session by responding sequentially on three keys in the presence of four colors. The response chain was maintained by food presentation under afixed ration schedule. Errors produced a brief timeout but did not reset the chain. When phencyclidine was administered alone, the overall response rate decreased and the percent errors increased with increasing doses. Similar effects were found with a high dose of pentobarbital alone. When phencyclidine was administered in combination with pentobarbital dose-effect curves for rate and accuracy shifted to the left as the dose of pentrobarbital was increased. Cobinations of phencyclidine with a high dose of pentobarbital produced supra-additive effects;i.e., the effects on rate and accuracy were greater than expected from simple addition of the effects of each drug given alone. These results extend the generality of previous findings in patas monkeys in a similar repeated-acquisition task.     

Tolerance to effects of cocaine on schedule-controlled behavior: effects of fixed-interval schedule parameter

Tolerance to the effects of cocaine on key pecking by pigeons, maintained by differently valued fixed-interval schedules of food presentation, was studied. Key pecking was established on a multiple fixed-interval 5-sec fixed-interval 30-sec fixed-interval 120-sec schedule. Cocaine (1.0-10.0 mg/kg) was administered acutely and then chronically (i.e., before each session) in 5.6 mg/kg doses. Acute cocaine administration produced dose-related decreases in response rates under all three schedules. When cocaine was administered chronically, response rates either recovered fully, or increased to the extent that no reinforcers were missed during the sessions. The development of tolerance was not systematically related to the schedule value. Considered in relation to previous research, these results indicate that different control rates of reinforcement, within the schedules and parameters studied, do not contribute to tolerance to cocaine's behavioral effects.     

Some effects of chlorimipramine and imipramine on the schedule-controlled behavior of the pigeon

The effects of imipramine and chlorimipramine on schedule-controlled behavior were compared by examining the effects of both drugs on the performance of pigeons under a multiple fixed-interval 600-s fixed-ratio 30-response (mult FI 600 FR 30) schedule of grain presentation and under a mult FI 200 FI 200 schedule in which responding in one component was punished. Imipramine decreased the rate of FR 30 responding at slightly lower doses than or the same doses as those needed to decrease the rate of FI 600 responding. In contrast, chlorimipramine decreased the rate of FI 600 responding at lower doses than those needed to decrease the rate of FR responding. These effects of chlorimipramine were similar to those of chlorpormazine subsequently determined in the same pigeons. Imipramine and chlorimipramine increased proportionally more or decreased proportionally less the lower rates of responding during the first half of the FI 600 than the higher rates of responding during the second half. When the effects of imipramine or chlorimipramine on performance under the mult FI 200 FI 200 schedule were determined, both imipramine and chlorimipramine affected the rates of punished responding and unpunished responding similarly. Thus, while some effects of chlorimipramine on the schedule-controlled behavior of the pigeon are similar to the effects of imipramine, other effects of chlorimipramine more strongly resemble those of chlorpromazine in the pigeon.     

Environmental influences on the development of tolerance to the effects of physostigmine on schedule-controlled behavior

The influence of environmental variables on the development of tolerance to physostigmine's effects in rats was examined using multiple fixed-ratio, extinction schedules of food presentation. Initial administration of physostigmine (0.4 mg/kg) produced nearly maximal decreases in the number of food pellets delivered, running response rate, and overall response rate, under multiple FR 10, EXT and multiple FR 50, EXT schedules. With repeated administration, tolerance to physostigmine's effects was observed when 10 responses were required to produce reinforcement but was not observed when 50 responses were required to produce reinforcement. Tolerance under the multiple FR 10, EXT schedule of reinforcement was also observed when physostigmine was administered post-session. When tolerance was acquired, it was retained for up to 25 drug-free days. These results suggest that tolerance to physostigmine's effects on schedule-controlled behavior is strongly influenced by response requirement, independent of physostigmine-induced reinforcement loss. Additionally, tolerance is not dependent on experience with the schedule while under the effects of physostigmine, and is retained for a substantial period of time in the absence of continued physostigmine administration.In conducting the research described in this report, the investigators adhere to the Guide for the Care and Use of Laboratory Animals, as promulgated by the Committee on Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources, National Research Council. The views of the authors do not purport to reflect the position of the Department of the Army or the Department of Defense, (para 4-3, AR 360-5)     

Tolerance to the reinforcing effects of cocaine in a progressive ratio paradigm

This experiment used rats to test whether a regimen of chronic cocaine would produce tolerance to cocaine i.v. self-administration under a progressive ratio (PR) schedule of reinforcement. Under this PR schedule, an increasing number of responses was required to complete the ratio for each subsequent cocaine injection, and failure to complete the required ratio for the next injection within 1 h of the previous cocaine injection terminated the session. The number of injections taken in the session was termed the breaking point and used as the dependent variable. Rats were trained under this schedule until breaking point values were stable, after which cocaine dose-effect data were obtained: the breaking point increased as the dose of cocaine increased. Subsequently, rats were assigned to one of two groups for 7 days of chronic treatment: one group was infused with cocaine (18 mg/kg, given over 20 min once every 8 h) and the other group received 0.9% saline. Following termination of chronic treatment, cocaine dose-effect data were redetermined in both groups. Chronic cocaine treatment significantly decreased breaking point values across the entire dose-effect curve, although the effect was observed in only four of seven subjects. In contrast, chronic saline treatment produced no significant effect on the breaking point measures. Following a further 5 days of recovery from chronic treatment, cocaine dose-effect data were redetermined in both groups; these curves were essentially identical to those obtained before chronic treatments. These data support the hypothesis that tolerance occurs to the reinforcing effects of cocaine, as measured by a decrease in the breaking point, at least for a subset of animals.     

Tolerance to the effects of buprenorphine on schedule-controlled behavior and analgesia in rats

Responding in rats was maintained under a fixed-ratio 30 schedule of food presentation. When administered acutely buprenorphine (0.018-0.56 mg/kg) produced dose-related decreases in overall rate of responding. In addition to schedule-controlled behavior, the analgesic effects of buprenorphine were evaluated during chronic administration using the tail-flick method. Tolerance developed to the effects of buprenorphine on both measures. In general dose-effect curves for the rate-decreasing effects of buprenorphine were shifted to the right by approximately 2 log units. In one subject, however, tolerance did not develop to the rate-decreasing effects of 10 mg/kg, suggesting that behavioral tolerance to buprenorphine is dose limited. Finally, the data also suggested that tolerance may develop more slowly, yet more completely, to the analgesic than to the rate-decreasing effects of buprenorphine.     

Development and expression of sensitization to cocaine's reinforcing properties: role of NMDA receptors

Acquisition of cocaine self-administration (0.125, 0.25 or 0.5 mg/kg/infusion) was assessed in rats that had received prior exposure to either saline or amphetamine (2.0 mg/kg). Acquisition of self-administration was dose-dependent, with the highest dose leading to the shortest latency to reliably discriminate between depression of a lever that resulted in drug delivery and an inactive lever. Latency to acquisition of the lever discrimination for rats that had received prior exposure to amphetamine was shorter than for the saline-pretreated counterparts in each cocaine dosage group. This suggests that repeated exposure to this drug prior to self-administration testing sensitized the rats to the reinforcing effects of cocaine. Co-administration of MK-801 (0.25 mg/kg, IP), a non-competitive NMDA antagonist, blocked the ability of chronic exposure to amphetamine to sensitize rats to cocaine. In experienced self-administering rats, acute pretreatment with MK-801 resulted in a loss of discriminative responding. The number of inactive lever responses was consistently higher than the number of active lever responses across all cocaine dosage groups. These data suggest that the NMDA receptor, possibly through interactions with dopamine systems, is critical for both the development and expression of sensitization to cocaine's reinforcing effects produced by intermittent preexposures to amphetamine.