The effects of morphine on chained and clocked fixed-interval schedule performance in pigeons.

The present experiment examined the role of stimulus functions and degree of stimulus control on the effects of drugs on behavior maintained by clocked fixed-interval (CFI) schedules. Three pigeons pecked keys under a multiple fixed-interval (FI) 1-min, CFI 1-min schedule of food presentation (the FI CFI condition). During the FI component, the key was lit amber. During the CFI component, the key colors changed in a regular manner across the interval. Three other pigeons pecked keys under a multiple schedule in which a three-link chained FI schedule alternated with a yoked-CFI schedule (the chain yoked-CFI condition). During the chain component, three successive FI 20-s links were associated with different key colors. During the yoked-CFI schedule, the clock stimuli were the same duration as, or 'yoked' to, the corresponding link in the chain component. Therefore, key colors changed at the same times as in the chain component, but independently of key pecking. All pigeons received a range of doses of morphine (1.0-17.0 mg/kg) and saline. Baseline rates of responding during the FI and chain components were generally higher than during the CFI and yoked-CFI components. Morphine decreased overall response rates during all components. During the FI component, morphine increased response rates at the beginning of the intervals. Morphine did not disrupt the patterns of responding maintained during the CFI, yoked-CFI, or chain components, despite the fact that the chained schedule required responding early in the intervals. This finding suggests that external stimulus control plays an important role in determining the drug effects on behavior maintained by CFI or chained schedules.

The effects of morphine on fixed-interval patterning and temporal discrimination.

Changes produced by drugs in response patterns under fixed-interval schedules of reinforcement have been interpreted to result from changes in temporal discrimination. To examine this possibility, this experiment determined the effects of morphine on the response patterning of 4 pigeons during a fixed-interval 1-min schedule of food delivery with interpolated temporal discrimination trials. Twenty of the 50 total intervals were interrupted by choice trials. Pecks to one key color produced food if the interval was interrupted after a short time (after 2 or 4.64 s). Pecks to another key color produced food if the interval was interrupted after a long time (after 24.99 or 58 s). Morphine (1.0 to 10.0 mg/kg) decreased the index of curvature (a measure of response patterning) during fixed intervals and accuracy during temporal discrimination trials. Accuracy was equally disrupted following short and long sample durations. Although morphine disrupted temporal discrimination in the context of a fixed-interval schedule, these effects are inconsistent with interpretations of the disruption of response patterning as a selective overestimation of elapsed time. The effects of morphine may be related to the effects of more conventional external stimuli on response patterning.

Pigeons may not remember the stimuli that reinforced their recent behavior.

In two experiments the conditioned reinforcing and delayed discriminative stimulus functions of stimuli that signal delays to reinforcement were studied. Pigeons' pecks to a center key produced delayed-matching-to-sample trials according to a variable-interval 60-s (or 30-s in 1 pigeon) schedule (Experiment 1) or a multiple variable-interval 20-s variable-interval 120-s schedule (Experiment 2). The trials consisted of a 2-s illumination of one of two sample key colors followed by delays ranging across phases from 0.1 to 27.0 s followed in turn by the presentation of matching and nonmatching comparison stimuli on the side keys. Pecks to the key color that matched the sample were reinforced with 4-s access to grain. Under some conditions of Experiment 1, pecks to nonmatching comparison stimuli produced a 4-s blackout and the start of the next interval. Under other conditions of Experiment 1 and each condition of Experiment 2, pecks to nonmatching stimuli had no effect and trials ended only when pigeons pecked the other, matching stimulus and received food. The functions relating pretrial response rates to delays differed markedly from those relating matching-to-sample accuracy to delays. Specifically, response rates remained relatively high until the longest delays (15.0 to 27.0 s) were arranged, at which point they fell to low levels. Matching accuracy was high at short delays, but fell to chance at delays between 3.0 and 9.0 s. In Experiment 2, both matching accuracy and response rates remained high over a wider range of delays in the variable-interval 120-s component relative to the variable-interval 20-s component. The difference in matching accuracy between the components was not due to an increased tendency in the variable-interval 20-s component toward proactive interference following short intervals. Thus, under these experimental conditions the conditioned reinforcing and the delayed discriminative functions of the sample stimulus depended on the same variables (delay and variable-interval value), but were nevertheless dissociated.

The effects of morphine on clocked fixed-interval performance: stimulus function or strength of stimulus control?

The present experiment was conducted to determine whether the modification of the effects of morphine by food deprivation would occur under conditions of strong stimulus control. Four pigeons pecked response keys under a multiple fixed-interval (FI) 5-min and clocked fixed-interval (CFI) 5-min schedule of food presentation. During the FI component, the key was lit green and the house light was on throughout. During the CFI component, the key light and house light settings changed in a regular manner as the interval elapsed. In all conditions, pigeons received a range of doses of morphine (1.0-10.0 mg/kg) and saline. In the first condition, pigeons were maintained at 80% of their free-feeding weights. When calculated over entire 5-min intervals, morphine produced dose-dependent decreases in the index of curvature (a measure of temporal patterning) during the FI component, but did not affect the index of curvature during the CFI component. A more detailed analysis revealed that the index of curvature during the last stimulus in the CFI sequence was reduced in a dose-dependent manner, similar to the effects obtained for the entire FI component. When the pigeons were maintained at 70% and 90% of their free-feeding weights, measures of the effects of morphine on temporal patterning did not differ as a function of body weight. The effects of morphine on rates of key-pecking, however, were related to body weight. For three of four pigeons, rates of key-pecking were not suppressed until higher doses, and increases in rates of key-pecking were more common at lower doses, when the pigeons were maintained at 70% of their free-feeding weights, than when they were maintained at 90% of their free-feeding weights. It is suggested that the effects of morphine on CFI performance can be understood in terms of the function of the stimuli that comprise the schedule, rather than the strength of the stimulus control engendered.

Food-deprivation level alters the effects of morphine on pigeons' key pecking.

Four pigeons pecked response keys under a multiple fixed-ratio 30 fixed-interval 5-min schedule of food presentation. Components alternated separated by 15-s timeouts; each was presented six times. Pigeons were maintained at 70%, 85%, and greater than 90% of their free-feeding weights across experimental conditions. When response rates were stable, the effects of morphine (0.56 to 10.0 mg/kg) and saline were investigated. Morphine reduced response rates in a dose-dependent manner under the fixed-ratio schedule and at high doses under the fixed-interval schedule. In some cases, low doses of morphine increased rates under the fixed-interval schedule. When pigeons were less food deprived, reductions in pecking rates occurred at lower doses under both schedules for 3 of 4 birds compared to when they were more food deprived. When pigeons were more food deprived, low doses of morphine increased rates of pecking in the initial portions of fixed intervals by a greater magnitude. Thus, food-deprivation levels altered both the rate-decreasing and rate-increasing effects of morphine. These effects may share a common mechanism with increased locomotor activity produced by drugs and with increased drug self-administration under conditions of more severe food deprivation.

Mechanisms underlying the effects of unsignaled delayed reinforcement on key pecking of pigeons under variable-interval schedules.

Three experiments were conducted to test an interpretation of the response-rate-reducing effects of unsignaled nonresetting delays to reinforcement in pigeons. According to this interpretation, rates of key pecking decrease under these conditions because key pecks alternate with hopper-observing behavior. In Experiment 1, 4 pigeons pecked a food key that raised the hopper provided that pecks on a different variable-interval-schedule key met the requirements of a variable-interval 60-s schedule. The stimuli associated with the availability of the hopper (i.e., houselight and keylight off, food key illuminated, feedback following food-key pecks) were gradually removed across phases while the dependent relation between hopper availability and variable-interval-schedule key pecks was maintained. Rates of pecking the variable-interval-schedule key decreased to low levels and rates of food-key pecks increased when variable-interval-schedule key pecks did not produce hopper-correlated stimuli. In Experiment 2, pigeons initially pecked a single key under a variable-interval 60-s schedule. Then the dependent relation between hopper presentation and key pecks was eliminated by arranging a variable-time 60-s schedule. When rates of pecking had decreased to low levels, conditions were changed so that pecks during the final 5 s of each interval changed the keylight color from green to amber. When pecking produced these hopper-correlated stimuli, pecking occurred at high rates, despite the absence of a peck-food dependency. When peck-produced changes in keylight color were uncorrelated with food, rates of pecking fell to low levels. In Experiment 3, details (obtained delays, interresponse-time distributions, eating times) of the transition from high to low response rates produced by the introduction of a 3-s unsignaled delay were tracked from session to session in 3 pigeons that had been initially trained to peck under a conventional variable-interval 60-s schedule. Decreases in response rates soon after the transition to delayed reinforcement were accompanied by decreases in eating times and alterations in interresponse-time distributions. As response rates decreased and became stable, eating times increased and their variability decreased. These findings support an interpretation of the effects of delayed reinforcement that emphasizes the importance of hopper-observing behavior.

Discrimination of methadone and cocaine by pigeons without explicit discrimination training.

Pigeons were trained to peck a key on a variable-interval 2-min schedule of food reinforcement. Prior to each session, either 2.0 mg/kg methadone (n = 3), 3.0 mg/kg cocaine (n = 4), or 5.6 mg/kg cocaine (n = 2) was administered. When each pigeon's rate of pecking was stable, a range of doses of the training drug and saline were administered prior to 20-min extinction sessions separated by at least four training sessions. Rate of pecking during these extinction tests was generally an increasing function of dose, with the lowest rates obtained following saline and low doses and the highest rates obtained following doses near the training doses. Dose functions from pigeons trained with 5.6 mg/kg cocaine were steeper than those from pigeons trained with 3.0 mg/kg cocaine. Pigeons trained with methadone or 3.0 mg/kg cocaine were then given discrimination training, in which food reinforcement followed drug administration and 20-min extinction sessions followed saline administration. Rates of pecking under these conditions quickly diverged until near-zero rates were obtained following saline and high rates were obtained following drug. Discrimination training steepened dose functions for the training drugs, and the effects of several other substituted drugs depended on the pharmacology of the training drug. The pigeons trained with 5.6 mg/kg cocaine were tested with d-amphetamine, methadone, and morphine prior to discrimination training. d-Amphetamine increased rates dose dependently, and methadone and morphine did not. The results suggest that discriminative control by methadone and cocaine was established without explicit discrimination training.

Representing within-session response rates proportionally and entirely.

In this technical article, methods for collecting and representing response rates maintained by schedules of reinforcement are presented. First, the time in a session that each important event (e.g., responses, reinforcers) occurs is collected and stored by a computer. Another computer program is used, then, to convert each response to a percentage of the total responses in a session and to plot these percentages cumulatively as a function of the time in the session that they occurred. In this manner, response rates may be expressed proportionally (i.e., using the same y-axis scale regardless of absolute response rate) without requiring the arbitrary selection of an interval over which responses are aggregated and expressed relative to the entire-session rate. A property of these records is that deviations in the slope of the obtained record from the diagonal, which connects (x, y) = (start of session, 0%) to (x, y) = (end of session, 100%), occurring at any point and for any duration, represent changes in the local response rate from the entire-session rate. This method of representing ongoing responding is illustrated by several records of key pecking of a pigeon on a variable-interval 60-s schedule of food reinforcement. Relative local response rates were also computed from these data at several levels of resolution (i.e., the time over which responses were aggregated), including the level typically employed by those interested in within-session changes in response rates.

Effects of neuropeptide Y, insulin, 2-deoxyglucose, and food deprivation on food-motivated behavior.

The current study demonstrates the ability of neuropeptide Y (NPY) to increase break points under a progressive ratio 1 (PR1) reinforcement schedule. An initial response resulted in delivery of a food reinforcer (45 mg pellet) under the PR1, and an additional response was required for each successive reinforcer. The break point, the number of responses emitted to obtain the last reinforcer, is considered a measure of reinforcing efficacy or motivational strength of the food reinforcer. NPY (0.3-10 micrograms) significantly increased break point to levels comparable to those produced by 36-48 h of food deprivation. Although insulin (3-8 U/kg) and 2-deoxyglucose (150-250 mg/kg) also increased food intake, neither increased break points to levels produced by NPY or food deprivation. These data suggest that NPY may change the value of food in ways that cannot be accounted for by changes in insulin, glucose levels or intracellular glucoprivation. These results emphasize that simply measuring the amount of freely available food eaten is not a fully adequate measure of the strength of the feeding behavior.

Cocaine's effects on food-reinforced pecking in pigeons depend on food-deprivation level.

Four pigeons deprived to 80% of their laboratory free-feeding weights pecked keys under a multiple fixed-ratio 30 fixed-interval 5-min schedule of food presentation. Components alternated strictly with 15-s timeouts separating them; each was presented six times. When rates of pecking were stable, 2 pigeons' weights were reduced to 70%, and the other 2 pigeons' weights were increased to 82.5% to 85% of free-feeding levels. Cocaine (1.0, 3.0, 5.6, and 10.0 mg/kg and saline) was administered 5 min prior to sessions. When each dose had been tested twice, pigeons' weights were adjusted to the level that they had not yet experienced, and cocaine was tested again. Cocaine reduced response rates in a dose-dependent manner under the fixed-ratio schedule and under the fixed-interval schedule at high doses, and increased rates under the fixed-interval schedule at low low doses. Reductions in pecking rates occurred at lower doses under both schedules in 3 of 4 pigeons when they were less food deprived compared to when they were more food deprived. Low doses of cocaine increased low baseline rates of pecking in the initial portions of the fixed-interval schedules by a greater magnitude when pigeons were more food deprived. Thus, food-deprivation levels altered both the rate-decreasing and rate-increasing effects of cocaine. The implications of these results for the mechanisms by which food deprivation increases cocaine self-administration and for the dependence of cocaine's effects on the baseline strength of operant behavior are discussed.

Drug discrimination using a Pavlovian conditional discrimination paradigm in pigeons.

Three pigeons were studied using a discriminated autoshaping procedure in which the presence or absence of methadone served as a conditional stimulus signalling which of two key light CSs would be followed by grain access. Drug sessions alternated randomly with no-drug sessions. Methadone (2.0 mg/kg) was administered prior to drug sessions in which a black vertical line on a white background served as CS+ and a diffuse white keylight served as CS- (reversed for bird 681). Saline or no injection was administered prior to no-drug sessions and the CS+/CS- contingencies were reversed. Discriminated performances emerged in which over 80% of the responding occurred to the appropriate stimulus. Stimulus control by methadone was assessed by presenting a range of methadone doses during 10-trial extinction sessions. A graded dose-effect curve was produced with low doses of methadone controlling saline-appropriate responding and higher doses controlling drug-appropriate responding. A range of doses of morphine, cocaine, and pentobarbital were also tested. Morphine produced methadone-appropriate responding while cocaine and pentobarbital did not.

Discriminative stimulus effects of combinations of drug and visual stimuli in pigeons.

Six pigeons were studied to determine whether the brightness of a houselight interacted with the stimuli produced by methadone, and whether the nature of the interaction depended on the order of training of the two discriminations. Three pigeons were trained to peck the right key after methadone (2.0mg/kg) and the left key after saline, when the houselight was dim. The effects of a range of methadone doses (0.5, 1.0, 2.0mg/kg and saline) were tested. Three other pigeons were trained, in the absence of drug, to peck the right key when the houselight was dim and the left key when the houselight was bright. The effects of a range of houselight intensities were tested. Then, for both groups, right-key pecks were reinforced in the presence of methadone and the dim houselight, and left-key pecks were reinforced in the presence of saline and the bright houselight. Methadone doses were tested in the presence of both houselight brightnesses used in training. All pigeons pecked the methadone-appropriate key after high doses of methadone, regardless of houselight intensity. All pigeons trained to discriminate houselight brightness first, and one of the pigeons trained to discriminate methadone first, pecked according to the houselight condition when saline and lower doses were tested. In the other pigeon trained to discriminate methadone first, pecking was more related to drug dose. These data show that a drug stimulus can compete with external stimuli for behavioral control, that a drug stimulus can assume control over behavior originally controlled by external stimuli, and that discriminations based on external stimuli may be retained when saline or low doses of drug are administered.

Methadone and feeding: sources of differences between home cage and operant chamber assessment procedures.

Methadone administration is reported to increase food intake in studies examining free feeding and to decrease food reinforced operant responding. In light of this apparent paradox, the present study evaluated methadone's effects on food reinforced operant responding under conditions more typical of free feeding studies than operant studies. The effect of methadone (5 mg/kg) on food intake was examined in rats maintained at 100% of their free feeding weights. Methadone did not increase food intake with food available under a fixed ratio 1 (FR 1) reinforcement schedule. Methadone did not alter response rate when each lever press produced a larger reinforcer (225 mg as opposed to 45 mg), but did increase food intake. When response requirements were changed from lever pressing to interruption of an infrared beam, increases in food intake following methadone administration were observed. Thus, the differences between methadone's effects on free feeding vs. operant chamber food intake may be due to procedural factors such as magnitude of reinforcement and response requirements.

Toward a functional analysis of drug treatment for behavior problems of people with developmental disabilities.

A brief review of the use of psychotropic medications for people with developmental disabilities was presented. Although in some cases therapeutic effects were obtained, in many cases no positive effects, or negative ones, were observed. We suggest that prescribing drugs based on topographical features of the problem behavior (e.g., self-hitting), without considering the function the behavior serves for an individual, contributes to the variability in clinical response. Functional analyses of behavior disorders, with appropriate consideration of the neurochemical and developmental variables involved, may provide the basis for a more rational approach to pharmacotherapy for people with developmental disabilities.

Behavioral and neurochemical mechanisms of opioid-antidepressant interactions.

Twelve pigeons key-pecked under a multiple variable interval 15-s, 150-s schedule of food reinforcement. The effects of methadone were studied alone and in combination with chronic daily administration of either imipramine (IMI) or desipramine (DMI). Chronic IMI was also given following reductions in response rates by unsignaled delay-to-reinforcement (UDR). Acute administration of methadone produced dose-dependent reductions in response rates under both schedules of reinforcement. Chronic daily administration of IMI or DMI alone did not result in lasting changes in baseline responding. When administered in combination, chronic daily IMI significantly attenuated the rate-reducing effects of methadone, whereas neither a low nor a high dose of chronic daily DMI was effective. The same dose of chronic daily IMI failed to ameliorate response rate reductions under delayed reinforcement. The behavioral and neurochemical specificity of the antidepressant effect is discussed.

Insulin, 2-deoxy-D-glucose, and food deprivation as discriminative stimuli in rats.

Using a two-lever drug discrimination procedure, two groups of four rats each were trained to discriminate the stimulus effects of 1.0 U/kg insulin or 125 mg/kg 2-deoxy-D-glucose (2-DG) from saline. A third group was trained to discriminate food deprivation produced by feeding 23 h prior to sessions from satiation produced by feeding 2 h prior to sessions. Differential responding was a direct function of dose or deprivation level in each group. Rats trained to discriminate insulin responded as if they had received insulin when they received 2-DG and vice versa. Insulin and 2-DG produced deprivation-appropriate responding in two of four rats trained to discriminate food deprivation. Low insulin and 2-DG doses produced drug-appropriate responding in rats deprived 47 h, but not in rats deprived 23 h. Blood glucose level was altered by the training doses of insulin and 2-DG, but not by 23-h deprivation. These results indicate that operations that induce feeding produce discriminable stimuli, and that these effects overlap or interact. Thus, drug discrimination procedures can be useful in the analysis of ingestive behavior.

Changes in food-maintained progressive-ratio responding of rats following chronic buprenorphine or methadone administration.

Seven rats lever pressed under a progressive ratio 3 (PR 3) schedule of food presentation; the number of responses per reinforcer systematically increased during each session. Break point (i.e., the number of responses in the last completed ratio before session termination) was measured under daily methadone (4.5 mg/kg and 3.0 mg/kg) or buprenorphine (0.3 mg/kg) administered prior to experimental sessions. Both drugs initially eliminated rats' food-maintained progressive-ratio responding. Break points during chronic methadone did not return to baseline levels after 80 drug sessions and a dose reduction. In contrast, break points during chronic buprenorphine administration were considerably above baseline control levels for two rats and returned to baseline levels for the third.

[Leu31,Pro34]neuropeptide Y (NPY), but not NPY 20-36, produces discriminative stimulus effects similar to NPY and induces food intake.

Rats were trained to discriminate between an intracerebroventricular injection of 1.15 nmol of Neuropeptide Y (NPY) and a sham injection. Rats rapidly learned to press the appropriate lever during training. NPY's discriminative stimulus effects were compared to those of saline, and 1.15-3.45 nmol [Leu31,Pro34]NPY, a Y1 receptor agonist and NPY 20-36, Y2 receptor agonist. [Leu31,Pro34]NPY resulted in NPY-appropriate responding, whereas saline and NPY 20-36 did not. [Leu31,Pro34]NPY also increased food intake, but NPY 20-36 did not. This suggests that NPY's discriminative stimulus and orexigenic effects involve the Y1, but not the Y2, receptor.

Effects of methadone on free feeding in satiated rats.

A variety of opioids and opiates are known to increase short-term food intake. In the present study, we evaluated the effects of methadone on free feeding in satiated rats. We assessed the effect of methadone (0, 1.5, 3.0, 5.0, and 10.0 mg/kg) on food intake 1, 2, 4, and 6 h after injection for 3 consecutive days. Two hours after methadone administration, food intake was inversely related to dose, but after 6 h a direct relationship between dose and feeding was obtained. Food intake increased with repeated methadone administration. In Experiment 2, methadone (5.0 mg/kg) was injected and food was made available 0, 1, 2, or 3 h later. Maximal food intake occurred in the third and fourth hours following methadone administration. As in Experiment 1, food intake increased with repeated methadone administration. Increases in food intake following repeated methadone administration may have been due to the development of tolerance to effects of methadone that may interfere with feeding, such as sedation. In Experiment 3, methadone was administered daily or every fifth day, assuming that spacing injections would retard tolerance development. Repeated daily methadone administration was associated with increased food intake earlier in the session, whereas increases in food intake following spaced methadone administration occurred later in the session. These data indicate that methadone increases short-term feeding in satiated rats. This is in contrast to the reported decrease in food-reinforced behavior noted in operant studies. This contrast may be due to sedating or other disabling effects of methadone.