The discriminative stimulus effects of morphine in pigeons responding under a progressive ratio schedule of food presentation

The purpose of this study was to determine whether progressive ratio (PR) schedules might provide additional information, as compared with fixed ratio or fixed interval schedules, on pharmacologic features of discriminative stimuli (e.g. stimulus intensity). Five pigeons discriminated between 5.6 mg/kg morphine and saline under an arithmetic PR5 schedule of food presentation. The final ratio before pigeons either stopped responding for 5 min or switched responding from the selected to the non-selected key was designated as the last completed ratio (LCR). Pigeons responded 6.8% on the drug key following saline and 96.4% on the drug key following 5.6 mg/kg morphine. The average LCR value for saline was not significantly different from the average LCR value for morphine. A larger dose of morphine (10.0 mg/kg) increased the LCR value and significantly decreased rates of responding. Smaller doses of morphine (0.32 and 1.0 mg/kg) occasioned primarily saline-appropriate responding and decreased LCR values. Buprenorphine substituted for morphine and significantly increased LCR values, whereas nalbuphine produced only partial (20-80%) morphine-key responding and significantly decreased LCR. Cocaine did not substitute for morphine or modify LCR compared with saline control. Together, these results suggest that the stimulus effects of micro-opioids vary on a dimension (e.g. intensity) that can be quantified using PR schedules.     

Differential cross-tolerance to mu and kappa opioid agonists in morphine-tolerant rats responding under a schedule of food presentation

If different populations of opioid receptors mediate the actions of mu and kappa opioid agonists, then tolerance induced by the chronic administration of a mu agonist should confer cross-tolerance to other mu agonists but not necessarily to those compounds whose effects are mediated by the kappa receptor. This hypothesis was evaluated in the present investigation by examining the effects of the mu agonists morphine,l-methadone and fentanyl, the kappa agonists U50,488 and bremazocine, and the mixed kappa/mu agonist ethylketocyclazocine in rats responding under a fixed-ratio 30 schedule of food presentation before, during and after exposure to a regimen of chronic morphine administration. For comparison, naloxone was evaluated as a representative mu antagonist and the phenothiazine chlorpromazine as a control drug. During all phases of the experiment, each of these compounds produced dose-related decreases in rate of responding. During the daily administration of 40 mg/kg morphine, tolerance developed to the rate-decreasing effects of morphine,l-methadone and fentanyl, and an enhanced sensitivity to the effects of naloxone. In contrast to the effects obtained with these mu opioids, there was no evidence that chronic morphine administration produced tolerance or enhanced sensitivity to the rate-decreasing effects of U50,488, bremazocine, ethylketocyclazocine and chlorpromazine. The present findings demonstrate that the chronic administration of morphine results in the selective development of tolerance to other mu agonists. In addition, the lack of cross-tolerance between morphine and the kappa agonists examined demonstrate that this behavioral preparation is a useful tool for differentiating the effects of compounds acting at different opioid receptor types.     

Differential cross-tolerance to opioid agonists in morphine-tolerant squirrel monkeys responding under a schedule of food presentation

The effects of various mu and kappa opioid agonists were evaluated in three squirrel monkeys responding under a fixed-ratio 30 schedule of food presentation before, during and after a regimen of chronic morphine administration. Initially, dose-effect curves for the mu opioid agonists morphine and l-methadone, the kappa opioid agonists U50,488 and tifluadom, the mixed mu/kappa opioid agonist ethylketocyclazocine, and the non-opioid compound pentobarbital were determined in non-tolerant squirrel monkeys. Subsequently, monkeys were administered up to 3.0 mg/kg of morphine twice daily for 8-9 weeks, which resulted in a 1/2 to 3/4 log unit shift to the right of the morphine dose-effect curve relative to its prechronic position. During the chronic morphine regimen, the l-methadone dose-effect curve shifted to the right approximately 3/4 log unit, while the U50,488 and pentobarbital dose-effect curves did not change. In contrast, the ethylketocyclazocine and tifluadom dose-effect curves shifted to the left approximately 1/4 and 3/4 log unit, respectively. The lack of cross-tolerance between mu and kappa agonists in morphine-tolerant squirrel monkeys observed in the present study provides further support for the differentiation of mu and kappa agonists. The occurrence of leftward shifts in the dose-effect curves of some opioid compounds with kappa agonist activity during the regimen of chronic morphine administration suggests that morphine tolerance modulates their     

Naloxone and diprenorphine reduce responding for brain self-stimulation in a fixed-ratio schedule in rats

Rats were implanted with bipolar stimulating electrodes in the midbrain-central gray area (MID-CG) and trained to lever-press for intracranial self-stimulation (ICSS) on a continuous reinforcement schedule (CRF). When behavior was stable, animals were tested in 30 min ICSS sessions following the administration of either naloxone or diprenorphine, both over the dose-range 0.001-10 mg/kg, or with vehicle. Following testing on the CRF schedule, animals were re-trained on a fixed-ratio:30 (FR:30) schedule. When behavior had again stabilized, testing with naloxone, diprenorphine and vehicle was repeated. In the CRF tests, neither naloxone nor diprenorphine had any effects on response rates over the 10,000-fold dose-range used. In the FR:30 tests, however, both drugs significantly reduced response rates at the 10 mg/kg dose, and the reduction produced by naloxone was significantly greater than that produce by diprenorphine. These results suggested that diprenorphine is qualitatively similar to naloxone in altering the rate of responding maintained by ICSS, but is less potent than the prototypical opioid antagonist in this paradigm.     

Situational specificity of tolerance to effects of phencyclidine on responding of rats under fixed-ratio and spaced-responding schedules

Responding of rats (n=5) was maintained under DRL (lever) and Time-Delay (nose-key) schedules of food presentation in different experimental chambers during two separate daily sessions. Tolerance that developed to rate-decreasing effects of phencyclidine for nose-key pressing under the Time-Delay schedule did not extend to effects of phencyclidine on lever pressing under the DRL schedule. In a second experiment, both lever and nose-key pressing of rats were maintained under individual and multiple fixed-ratio schedules. One group of animals (n=5) experienced both the individual and the multiple schedules in the same experimental chamber and another group (n=5) experienced the individual and the multiple schedules in different experimental chambers. Tolerance that developed to behavioral effects of phencyclidine during the individual schedule did not extend to responding on even the same manipulandum under the multiple schedule in a different experimental chamber. In contrast, tolerance that developed to behavioral effects of phencyclidine during the individual schedule did extend to responding on even the different manipulandum under the multiple schedule in the same experimental chamber. Thus, tolerance that developed in the environment that was coincident with the pharmacologic actions of phencyclidine did not extend to similar operants in adifferent environmental condition, but did extend even to a different operant and schedule context in thesame environmental condition.Animals used in this study were maintained in accordance with guidelines of the Animal Care Committee of the Worcester Foundation for Experimental Biology and of the Guide for Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources, National Research Council, Department of Health, Education and Welfare, Publication Number (NIH)85-23, revised 1985     

Effects of methamphetamine on fixed-ratio responding of food satiated and food deprived rats

After the initial training of the lever pressing response for sweetened condensed milk, rats were put on different fixed-ratio (FR) schedules of reinforcement under conditions of being food satiated and food deprived. Doses of methamphetamine ranging from 0.125 to 1.0 mg/kg were tested in these rats for effects on response rates. Response rates of the satiated rats at the higher FR requirements were slower than those of the deprived rats. At the doses of methamphetamine used, the satiated animals responded at slower than their control response rates and the deprived rats tended to respond faster than control rates.     

Methamphetamine effects on responding under a multiple schedule of shock presentation

Squirrel monkeys responded under a multiple 3-min variable-interval (VI) 10-response fixed-ratio (FR) schedule of response-dependent electric shock presentation. Methamphetamine (0.01-0.17 mg/kg) produced dose-dependent increases in relatively low rates of responding whether these occurred during the FR or the VI component of the schedule. In the one monkey with a relatively high control rate of responding during the VI component, methamphetamine only produced decreases in responding. Responding during the FR component was increased by methamphetamine, even in the monkey whose responding appeared to be suppressed during this component. Previous experiments have shown only further decreases after amphetamines in responding suppressed by response-dependent shock. The present experiments indicate that, in addition to the frequency and intensity of the electric shock and to the schedule maintaining the reference behavior, the nature of the event maintaining the reference behavior can be important in determining the effects of amphetamines. The effects of methamphetamine depend not only on the intensive and temporal characteristics of the ongoing schedule-controlled behavior itself, but also on the past and present context in which the behavior occurs.     

Effects of valproic acid and ethosuximide on the responding of pigeons maintained under a multiple fixed-ratio fixed-interval schedule of food delivery

The effects of valproic acid and ethosuximide were examined in pigeons responding under a multiple Fixed-Ratio 50 Fixed-Interval 90-sec schedule of food delivery. When given acutely 30 min prior to behavioral testing, both valproic acid (40, 60, 80, 100, and 120 mg/kg) and ethosuximide (40, 60, 80, 100, and 120 mg/kg) produced generally dose-dependent decreases in responding under both the Fixed-Ratio and Fixed-Interval components. Detailed analysis of drug effects on the temporal distribution of responding under the Fixed-Interval failed to reveal rate-dependent effects for either drug. Varying the presession injection interval from 15 to 120 min indicated that both valproic acid and ethosuximide reduced responding to the greatest extent when given 30 or 60 min before behavioral testing. These results indicate that the anticonvulsants valproic acid and ethosuximide similarly affect schedule-controlled responding, although previous studies have revealed the drugs to have different effects under other procedures.     

Effects of fixed-ratio length on the development of tolerance to decreased responding by l-nantradol

Key pecking of pigeons was maintained under either a 100-response or a 300-response fixed-ratio schedule of food presentation, and animals received 0.03 mg/kg/day l-natradol prior to experimental sessions. Tolerance developed for initial rate decreases under fixed ratio 100 in 10–12 sessions, but tolerance did not develop under fixed ratio 300 for up to 30 sessions. When the fixed ratio was changed from 300 back to 100, tolerance developed in three to four sessions, and when the fixed ratio was changed from 100 back to 300, tolerance diminished in two to three sessions. The importance of fixed-ratio parameter for the observation of tolerance extends the generality of the influence of reinforcement processes on tolerance.     

Ethanol,pentobarbital, and chlordiazepoxide effects in squirrel monkeys responding under fixed-ratio food presentation and stimulus-shock termination schedules

Rats were lesioned unilaterally in the medial forebrain bundle with either the catecholamine neurotoxin 6-hydroxydopamine or the indoleamine neurotoxin 5,6-dihydroxytryptamine. Their rotational responses in automated rotameters to a challenge with the dopamine-receptor agonist apomorphine were compared using four different techniques in current use, and by assessment of complete rotation curves using both conventional statistical procedures and elementary computer-derived elements of curvature. The rotational responses of the two groups, characterized neurochemically by identical depletions of striatal dopamine but with a greater depletion of striatal 5-hydroxytryptamine in 5,6-dihydroxytryptamine-lesioned animals, were indistinguishable using each of the four current techniques. Assessment of rotation curves by both methods revealed significant differences between the two groups, characterised by faster onset and offset of the rotational response in 5,6-dihydroxytryptamine-lesioned animals. Some current techniques may implicitly exclude the detection of such time-course differences in rotational behaviour. Assessment of complete rotation curves may best allow valid comparisons between experimental groups.     

Effects of cocaine in pigeons responding under a progressive-ratio schedule of food delivery

Although the progressive-ratio schedule has been used frequently to quantify the reinforcing effectiveness of self-administered drugs, it has seldom been used to examine the effects of drugs on food-maintained behavior and has never been used to evaluate the effects of cocaine on such behavior. In the present study, the effects of acute administrations of cocaine were evaluated in pigeons responding under a progressive-ratio 5 schedule of food delivery that continued for 1 h or until responding ceased for 5 consecutive min, whichever occurred first. The largest ratio completed each session (breaking point) was the primary dependent variable. In general, acute administrations of cocaine at 0.56 to 3.2 mg/kg increased breaking points, whereas doses above 5.6 mg/kg decreased breaking points. Although cocaine reduces food intake and subjective hunger for food, the present data indicate that the drug reduces the reinforcing effectiveness of food only at high doses.     

Food,water and ethanol consumption by rats under a fixed-interval schedule of food presentation

Rats could lever press 24 hours a day for 97 mg food pellets under a fixed-interval (FI) 90 second schedule. During the first 4 days, an ethanol solution was the only available fluid, after which both water and ethanol solutions were available. At ethanol concentrations (w/v) of 5%, 7.5% and 10%, total caloric intake and total fluid intake remained constant, while ethanol consumption was inversely proportional to the concentration of the solution. When the FI 90 s schedule was changed to FI 45 s, or to FI 180 s, there were only small changes in total caloric intake, total fluid intake and in percentages of total fluid consumptipn and total caloric intake as ethanol. The data suggest that the intake of ethanol under this fixed-interval schedule depends more on the ethanol concentration than on the calories obtained from ethanol drinking.     

Effects of d-amphetamine and ethanol on responding of squirrel monkeys maintained under fixed-ratio schedules of food presentation and stimulus-shock termination.

Effects of d-amphetamine and ethanol were assessed on comparable behaviors maintained under fixed-ratio schedules of either food presentation or termination of electric shock and an accompanying visual stimulus. Ethanol affected the behaviors similarly in all important aspects; d-amphetamine increased rates of responding maintained by stimulus-shock termination at doses that did not affect rates of food-maintained responding. The increases in responding maintained by stimulus-shock termination were not solely due to decreases in the pause prior to the initiation of responding.     

Effects of fixed-ratio requirement on observed tolerance to decreased responding by clonidine

Responding of rats was maintained under either a 10- or a 40-response fixed-ratio schedule, and "local" rates of responding were 0.29-0.37 responses per sec for both schedules. Clonidine decreased responding for both schedules in a similar and dose-dependent manner, and the largest dose tested (0.3 mg/kg) completely suppressed behavior. When 0.1 mg/kg was administered immediately prior to 30 daily experimental sessions, FR10 responding recovered to control levels within 15 sessions, whereas FR40 responding recovered only to approximately 60% of control level at asymptote. These results continue to identify boundary conditions for the influence of reinforcer loss on tolerance development, and they emphasize the overriding influence of behavioral processes on observed tolerance to the behavioral effects of drugs.     

Effect of xylene inhalation on fixed-ratio responding in rats

The effect of xylene inhalation was studied on operant behavior under a fixed-ratio (FR24) schedule in rats. Experiments were performed while rats were being exposed to xylene vapor in an inhalational (flow-through) behavioral chamber. Rats were exposed successively to three graded concentrations (113, 216 and 430 ppm) of xylene vapor each for 2 hr in range-finding studies during 6 1/4-hr sessions. The reinforcement rate which is correlated with FR responding was shown to be decreased at hr 1, hr 3 and hr 5. However at hr 2, hr 4 and hr 6 the reinforcement rate in rats increased approaching the control levels, thereby indicating development of tolerance. When rats were exposed to one of the three graded concentrations of xylene for 2 hr on separate days, they also showed a decrease in the reinforcement rate at hr 1; development of acute tolerance was also noted in this schedule. Exposure to the lowest (98.5 ppm) level of xylene used during 5-hr sessions caused no significant decrease in the reinforcement rate. This study thus attempts to identify a minimum effective concentration of xylene and indicates the development of acute tolerance to behavioral effect of xylene.     

The effects of acutely administered cocaine on responding maintained by a progressive-ratio schedule of food presentation

Lever pressing in rats (N=5) was reinforced under a progressive-ratio (PR) schedule of food presentation, in which the number of responses required increased exponentially. The session was terminated when 1 h passed without completion of the scheduled ratio. Doses of cocaine (5.6-42.0 mg/kg; one subject received a dose of 56.0 mg/kg) as well as saline were administered i.p. prior to the session. Under non-drug conditions, breakpoints were typically less than 100, and substantial responding usually occurred only during about the first 10 min of the session. The rate of responding usually increased over the first 2-8 reinforcers and then decreased for the last few reinforcers obtained. For four of five rats, breakpoint, overall rate of response, and session duration were first increased above control and vehicle levels by increasing doses of cocaine. Larger doses produced smaller increases, no effect, or decreases. Cocaine, in the range of doses near the apex of the breakpoint dose-effect functions, suppressed rates of responding at the small ratios present at the beginning of the session. It is suggested that cocaine increases low rates of response if: (1). rates are low due to extinction; and (2). the stimuli present are those present when the response is reinforced.     

Specificity of chronic effects of diazepam on responding of rats under fixed-ratio schedules

Behavioral effects of diazepam were studied in rats responding in different daily sessions using different operant chambers and manipulanda. In one experiment, key pressing was maintained in a first session under a 40-response fixed-ratio schedule; lever pressing was maintained in a second session under a 40-response fixed-ratio schedule; and a third session consisted of a multiple schedule comprising both key and lever pressing maintained under a 40-response fixed-ratio schedule. In a second experiment, the first session consisted of a multiple schedule with both key and lever pressing maintained under a 40-response fixed-ratio schedule and the second session consisted of lever pressing maintained under a 40-response fixed-ratio schedule. After studying effects of widely spaced injections of diazepam (0.3-3.0 mg/kg) on responding for each separate schedule, animals received 1.7 mg/kg/day diazepam in order to study chronic effects of the diazepam on behavior among the different schedule-conditions. In both experiments, tolerance to rate-decreasing effects of diazepam in a particular schedule component did not extend to any other schedule component when the manipulandum or chamber was different, but did extend to other schedule components when the manipulandum or chamber was the same. These results suggest that behavioral effects of chronically administered diazepam were influenced not only by pharmacologic processes, but also by learned relationships among its interoceptive effects, reinforcement contingencies, and particular behavioral environments.