Effects of drugs on responding under concurrent fixed-interval schedules and concurrent fixed-ratio schedules

Pigeons were trained to respond under concurrent fixed-interval fixed-interval (concurrent FI FI) schedules with Fl values (in seconds) of 30/300, 60/240, 60/60, 240/60 and 300/30. A second group was trained to respond under concurrent fixed-ratio fixed-ratio (concurrent FR FR) with FR values of 10/40, 10/20, 20/20, 20/10 and 40/10. Under the concurrent Fl Fl schedules, pigeons responded much less often on the key with the higher reinforcement density than would be predicted basing on a perfect matching of the ratio of responses made to the ratio of reinforcers delivered, and the pigeons also showed a bias towards responding on the left key. Pentobarbital, methamphetamine, morphine and phencyclidine had little effect on bias, but high doses of methamphetamine, morphine and phencyclidine decreased undermatching. Under the concurrent FR FR schedules, pigeons responded almost entirely on the key with the higher reinforcement density. Only pentobarbital consistently disrupted this pattern of responding.     

Discrimination of pentobarbital doses and drug mixtures under fixed-ratio and fixed-interval reinforcement schedules

Pigeons were trained to discriminate among 5 mg/kg pentobarbital, 10mg/kg pentobarbital, and saline, under either fixed-interval (FI) or fixed-ratio (FR) reinforcement schedules. When baseline responding stabilized, a higher percentage of responses occurred on the key that produced the reinforcer under the FR schedule than under the FI schedule. After low doses of pentobarbital, responding shifted from the saline key to the 5 mg/kg pentobarbital key; at higher doses of pentobarbital responding shifted to the 10mg/kg pentobarbital key under both schedules. After low doses of ethanol and chlordiazepoxide, responding shifted from the saline key to the 5 mg/kg pentobarbital key, but after high doses of these drugs, responding continued to occur on the 5 mg/kg pentobarbital key under both reinforcement schedules. A 5 mg/kg dose of pentobarbital increased responding on the 10 mg/kg pentobarbital key when it was combined with pentobarbital, ethanol or chlordiazepoxide. Phencyclidine and D-amphetamine produced responding largely on the saline key under both reinforcement schedules. Under the FR schedule, pentobarbital dose-response curves were usually quantal, whereas under the FI schedule the pentobarbital dose-response curves usually were graded.     

Effects of training history on drug discrimination under concurrent fixed-interval schedules

Pigeons with previous pentobarbital-discrimination training under concurrent VI 60 VI 240 and concurrent FI 60 FI 240 schedules were trained to respond under a concurrent FI 15 FI 285 schedule of food presentation. A second group of pigeons was trained only under the concurrent FI 15 FI 285 schedule. When responding stabilized during training sessions, both groups made 75-85% of their responses on the key where responses produced the reinforcer under the FI 15 component of the concurrent schedule. When the schedule was changed to concurrent FI 150 FI 150, the presence or absence of pentobarbital continued to control responding for the group with the extensive training history, but responding by the other group was rapidly controlled by the new reinforcement schedule. These data suggest that the behavioral history of the subject can be an important determinant of stimulus control by drugs. Despite these effects of training history on drug-discrimination responding, during the first minute of the session, the dose-response curves for pentobarbital, chlordiazepoxide, ethanol, phencyclidine and methamphetamine were similar in both groups of pigeons.     

Methohexital and cocaine self-administration under fixed-ratio and second-order schedules

Behavior maintained by either cocaine or methohexital was compared under two different schedules of drug delivery. Under a fixed-ratio 10 schedule, each tenth response produced an injection and responding was characterized by pauses alternating with high rates that were sustained until the drug injection. Under a second-order schedule, each tenth response produced a brief visual stimulus, and the first sequence of ten responses emitted after the lapse of a ten-minute interval produced the stimulus and the drug injection. Responding under the second-order schedule was characterized by an overall positive acceleration in responding that consisted of fixed-ratio response patterns terminating in the presentation of a brief stimulus. Under either schedule, each drug maintained maximal rates of responding at intermediate doses. In most respects, rates and patterns of responding depended more on the schedule of drug delivery than on the particular drug maintaining responding.     

The interaction of d-amphetamine and naloxone differs for rats trained on separate fixed-interval or fixed-ratio schedules of reinforcement

The effects of d-amphetamine and naloxone were investigated using two groups of rats trained on either an FR30 or F12 schedule of reinforcement. Amphetamine (0.1-1.0 mg/kg), and naloxone (1.0 and 10 mg/kg) administered separately reduced responding on the FR procedure in a dose-dependent manner. The combined administration of naloxone with amphetamine had an additive suppressive effect on responding. The same doses of amphetamine and naloxone, when given separately, did not significantly depress responding in the FI procedures. However, naloxone/amphetamine combinations produced a marked inhibition of lever-pressing. Naloxone did not alter the characteristic pattern of responding engendered by amphetamine in this schedule, as measured by the quarter-life and Index of Curvature. It appears that the type of procedure used is a critical factor in demonstrating the effects of naloxone on behavior, and the nature of naloxone/amphetamine interactions.     

Pentobarbital,promazine, d-amphetamine,and scopolamine effects on behavior under multiple and primed schedules of reinforcement

Pigeons responded under compound fixedinterval (FI) fixed-ratio (FR) schedules of food presentation. Distinctive discrimininative stimuli were either continuously present during each component schedule (multiple FI FR) or were present only for a brief period at the beginning of each component (primed FI FR). Similar rates and patterns of responding were maintained under the multiple and primed schedules. Pentobarbital, scopolamine, and d-amphetamine decreased FR responding, but promazine had little effect at the doses studied. d-Amphetamine and promazine increased FI responding at certain doses, pentobarbital had little effect, and scopolamine decreased responding. There were no systematic differences in the effects of drugs under the multiple and primed schedules, in spite of the differences in discriminative stimuli under the conditions.     

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.     

Self-administration of orally-delivered phencyclidine and ethanol under concurrent fixed-ratio schedules in rhesus monkeys

In 1946 von Euler identified the major transmitter of sympathetic nerve fibers, norepinephrine (NE), and about a decade later Vogt (1954) provided the first evidence that NE may also serve as a neurotransmitter in the central nervous system (CNS). Since that time, a literal explosion in CNS neurotransmitter research has taken place involving histological, biochemical, physiological, pharmacological and clinical investigations, Yet, it is only now that we are beginning to understand the biological function of NE in brain, in particular because of recent advances regarding the physiology and regulation of NE neurons in locus coeruleus (LC), a bilateral pontine structure with a uniquely wide-spread terminal network reaching throughout the neuroaxis and in primates accounting for about 70% of all brain NE. Recently, the neurobiology of the LC noradrenergic network was extensively reviewed by Foote et al. (1983), and its implication in vigilance as well as global orientation of behavior towards imperative, environmental sensory stimuli was outlined. Yet, more recent information regarding the peripheral, autonomic regulation of LC neurons in brain provides fundamentally new biological aspects on behavior and mental function which seem to allow a more integrated view of the rôle of brain NE in the overall function of the individual than previously understood. The purpose of this review is to summarize these findings and, furthermore, to outline some putative implications for psychiatry and neuropsychopharmacology. In particular, the new data seem to allow a better understanding of how autonomic vulnerability or visceral dysfunction may precipitate or aggravate mental symptoms and disorder.     

Simple alternation of components in a multiple fixed-interval fixed-ratio schedule of food reinforcement in the rat

Three rats pressed a lever on a multiple fixed-interval 60-sec (FI) fixed-ratio 30-response (FR) schedule of food reinforcement. After 1 year of training in which the FI and FR components were programmed to occur with a probability of 0.5 (random alternation), stimulus control was weak: the response rates early in the FI were high and variable. When FI and FR components were programmed to occur one after the other (simple alternation), stimulus control was strong: the response rates early in the FI were low while the rates late in the FI remained high. Results indicate that simple alternation might facilitate the acquisition of a stable baseline for drug testing.     

Effect of intracerebroventricular bradykinin,angiotensin II,and substance P on multiple fixed-interval fixed-ratio responding in rabbits

The dose-effect relationships of intraventricularly injected bradykinin, angiotensin II, and substance P on lever-lifting behavior of rabbits in a multiple fixed-interval 2-min, fixed-ratio 15 responses (mult. FI 2 FR 15) schedule of sweetened water presentation were determined. Bradykinin, in doses of 30 and 56 ng, increased FI response rates, with lower rates being relatively more increased than higher rates while FR responding was not affected. Conversely, 3 ng of angiotensin II increased only FR response rates. Higher doses of both peptides, up to 1.7 and 1.0 g, respectively, caused dose-dependent decreases in both FI and FR response rates, mainly as a consequence of complete response supression at the beginning of the experimental session. Doses of 0.1, 0.3, and 1.0 g of substance P caused dosedependent decreases in FI and FR response rates with no initial pause, FI response rates being more affected than FR rates. But 3.0 g of substance P caused an initial response suppression as well as comparable decreases in both FI and FR rates. Combined treatments of bradykinin with selected doses of amphetamine, haloperidol, atropine, morphine, and naloxone caused effects on multiple FI FR performance that did not consistently differ from the effect of bradykinin alone. These results show that small amounts of bradykinin, angiotensin II, and substance P cause specific and selective effects on operant behavior when injected into the cerebral ventricles, indicating that these endogenous peptides may play functional roles in behavioral regulation.     

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     

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.     

Effects of cocaine alone and in combination with prazosin or ondansetron on multiple fixed-interval fixed-ratio performance in pigeons.

Three pigeons were trained to respond on a two-component multiple schedule in which the components alternated regularly. In one component of the schedule, food was presented when the pigeon successfully completed a fixed-interval 120-s schedule within 150 s. In the other component of the schedule, food presentation occurred when the pigeon managed to complete a fixed-ratio 30 schedule within 30 s. Once responding had stabilized under both components of the schedule, pigeons were challenged with different doses of cocaine alone or cocaine in combination with 1.0 mg/kg prazosin (a selective alpha 1-adrenergic antagonist) or 0.10 or 0.50 mg/kg ondansetron (a selective 5-hydroxytryptamine3 antagonist). All drugs were injected intramuscularly 5 min before the start of selected experimental sessions. For two subjects, low doses of cocaine increased the low response rates maintained by the fixed-interval schedule while decreasing the high rates maintained by the fixed-ratio schedule. At intermediate doses, both high and low rates decreased but higher rates were more susceptible to disruption than low rates. The highest doses of cocaine completely eliminated responding in both schedule components. The high-rate behavior of the third subject was not affected by low or intermediate doses of cocaine, while low rates decreased at doses up to 5.6 mg/kg. The higher doses of cocaine eliminated responding in this subject as well. Prazosin and both doses of ondansetron antagonized the behavioral effects of cocaine at doses that ranged from 1.0-3.0 mg/kg. Redetermination of the dose-effect curve for cocaine at the conclusion of the experiment revealed that the curve had significantly shifted to the right.     

Effects of phencyclidine-like drugs on responding under multiple fixed ratio, fixed interval schedules

The effects of phencyclidine and a series of related drugs were studied on rates and patterns of responding by rats under a multiple fixed-interval 300s, fixed-ratio 30-response schedule of food presentation. Dizocilipine produced large increases in the rate of FI responding and smaller increases in the rate of FR responding. TCP slightly increased the rate of FI responding and PCE slightly increased the rate of FR responding. Higher doses of all drugs decreased rates of responding under both schedule components with the potency order of dizocilpine > PCE > PCP > TCP > ketamine. This relative potency for decreasing rates of FI and FR responding correlated highly with the affinity of these drugs for PCP receptors, suggesting that the rate decreasing effects of these drugs are mediated through these receptors. An analysis of local rates of responding within the FI suggested that dizocilpine was different from the arylcyclohexylamines in that it was the only drug that increased rates of responding late in the FI component. Previous reports have shown that the ability of arylcyclohexylamines to increase punished responding and to act as discriminative stimuli are correlated highly with binding to PCP receptors. The present experiments suggest that decreases in rates of responding under multiple schedule control are also mediated by PCP receptors.     

Application of fixed-interval schedules to intracranial self-stimulation for assessing psychomotor stimulants

Rats were implanted with stimulating electrodes aimed at the medial forebrain bundlelateral hypothalamus (MFB-LH) and were trained to lever-press for brain stimulation on a fixed-interval 15-sec schedule of reinforcement. When behavior had stabilized, the animals were tested with graded doses of d-amphetamine (0.1–1.0 mg/kg), cocaine (3.0–30 mg/kg), and nomifensine (1.0–10 mg/kg). Separate groups of animals were tested in a locomotor activity procedure over the same dose ranges. All three drugs produced graded increases in rates of responding which ranged from 180–295% of saline control levels following the highest dose of each drug. In contrast, there were no significant changes in numbers of reinforcements at any of the doses used. When tested in a locomotor activity device, all three drugs produced similar increases in activity with increasing dosage. Although currently little used, the fixed-interval schedule of brain self-stimulation can be helpful in making comparisons of the stimulant properties of abused drugs, such as amphetamine and cocaine, and less well-known drugs with abuse potential such as nomifensine. © 1992 Wiley-Liss, Inc.     

Effect of baclofen on cocaine self-administration in rats reinforced under fixed-ratio 1 and progressive-ratio schedules

Rationale: Recent reports have indicated that the γ-aminobutyric acid (GABA)_B agonist baclofen attenuates the reinforcing effects of cocaine. Objectives: To further evaluate the effect of baclofen on cocaine self-administration under a fixed ratio (FR) and progressive ratio (PR) schedule of reinforcement. Methods: In the first series of experiments, three dose–response curves were generated that examined the effect of three doses of baclofen (1.8, 3.2, or 5.6 mg/kg, i.p.) against four unit-injection doses of cocaine (0.19, 0.38, 0.75, and 1.5 mg/kg per injection) reinforced under a FR1 schedule. For comparison, an additional group of rats was pretreated with haloperidol (32, 56, or 100 μg/kg, i.p.). A separate experiment examined the effect of baclofen (1.8, 3.2, or 5.6 mg/kg, i.p.) on responding for concurrently available cocaine or food reinforcement. Results: Under the FR1 schedule, baclofen suppressed intake of low but not high unit injection doses of cocaine. In contrast to haloperidol, baclofen had no effect on the distribution of inter-injection intervals and, instead, produced long pauses in cocaine self-administration. Baclofen dose dependently reduced cocaine- reinforced responding on a PR schedule; concurrent access to a food-reinforced lever demonstrated that the animals retained the capacity to respond at high rates. Conclusion: The effect of baclofen pretreatment on cocaine self-administration is dependent on the unit injection dose of cocaine and on the response requirements of the schedule. Received: 22 July 1999 / Final version: 23 September 1999     

Stimulus control by diazepam of behavior maintained under fixed-ratio stimulus-shock termination schedules in rats

The stimulus control of behavior by diazepam (1.0 mg/kg) was investigated where responding was maintained under fixed-ratio (FR) schedules of stimulus-shock termination in rats. The size of the FR requirement was either 1, 5, 10, or 20 responses. At each FR requirement, dose-effect curves were determined for diazepam, flurazepam, pentobarbital and cyproheptadine. Diazepam-like discriminative stimuli were produced by flurazepam and pentobarbital but not by cyproheptadine. The magnitude of the FR requirement had no significant effect on the dose-effect curves for percentage of responses emitted on the diazepam-appropriate choice lever for any of the four drugs. On the other hand, the effects of these drugs on rates of responding depended on the magnitude of the FR requirement. None of the drugs altered response rates under the FR1 schedule. Diazepam tended to increase response rates under the FR5 schedule, but had no effect or decreased rates under the FR10 and FR20 schedules. Flurazepam and pentobarbital predominantly decreased rates at FR requirements of 5, 10 or 20 responses. Cyproheptadine had no significant effect on response rates at any schedule parameter. Together with previous reports, the present results indicate that the discriminative effects of diazepam are similar under schedules employing noxious (this study) or non-noxious (other reports) consequences, even though the effects on response rates of diazepam-like drugs differ depending on the schedule of reinforcement and consequent event maintaining the behavior.     

Intravenous self-administration of fencamfamine and cocaine by beagle dogs under fixed-ratio and progressive-ratio schedules of reinforcement

Catheterized beagle dogs were given access to response-contingent intravenous injections of fencamfamine (FEN) or cocaine (COC) injections under a fixed-ratio (FR) schedule of reinforcement. Both drugs maintained self-administration behavior considerably above saline levels; there was an inverted U-shaped relationship between the number of injections per daily session and the dose per injection. Presession treatment with the dopaminergic antagonist pimozide (PIM) appreciably altered both the FEN and COC dose-effect curves, suggesting a dopaminergic component in the reinforcing properties of these substances. When tested under a progressive-ratio (PR) schedule, both FEN and COC maintained nearly identical FR-values which were considerably above those seen for saline. It appears from these data that FEN may have a cocaine-like abuse potential.     

Naloxone as a stimulus in drug discrimination learning: generalization to other opiate antagonists.

Nonopiate dependent animals were trained to discriminate the opiate antagonist naloxone (1 mg/kg) from distilled water within the conditioned taste aversion baseline of drug discrimination learning. Specifically, rats injected with naloxone prior to a saccharin-LiCl pairing, and with its vehicle prior to saccharin alone, rapidly acquired the drug discrimination, avoiding saccharin following the administration of naloxone and consuming saccharin following its vehicle after only three conditioning trials. Once the discrimination was acquired, generalization tests revealed that the opiate antagonists diprenorphine and naltrexone and the mixed opiate agonist/antagonist nalorphine completely generalized to the naloxone cue at doses of 1.8, 5.6 and 18 mg/kg, respectively. That discriminative control was established with a low dose of naloxone (i.e., 1 mg/kg) and other compounds with opiate antagonist activity generalized to the naloxone cue suggest that the stimulus effects of naloxone were likely mediated through the opiate receptor. Because each of these compounds are reported to bind to the mu receptor (with varying affinities and varying degrees of selectivity), the stimulus properties of naloxone are likely mediated at this specific receptor subtype.