Fixed-ratio Response Requirement Research Articles

Operant social self-administration in male CD1 mice.

We recently introduced a model of operant social reward in which female CD1 mice lever press for access to affiliative social interaction with a cagemate peer mouse of the same sex and strain. Here we determined the generality of the operant social self-administration model to male CD1 mice who, under certain conditions, will lever press to attack a subordinate male mouse. We trained male CD1 mice to lever press for food and social interaction with a same sex and strain cagemate peer under different fixed-ratio (FR) schedule response requirements (FR1 to FR6). We then tested their motivation to seek social interaction after 15days of isolation in the presence of cues previously paired with social self-administration. We also determined the effect of housing conditions on operant social self-administration and seeking. Finally, we determined sex differences in operant social self-administration and seeking, and the effect of housing conditions on unconditioned affiliative and antagonistic (aggressive) social interactions in both sexes. Male CD1 mice lever pressed for access to a cagemate peer under different FR response requirements and seek social interaction after 15 isolation days; these effects were independent of housing conditions. There were no sex differences in operant social self-administration and seeking. Finally, group-housed CD1 male mice did not display unconditioned aggressive behavior toward a peer male CD1 mouse. Adult socially housed male CD1 mice can be used in studies on operant social reward without the potential confound of operant responding to engage in aggressive interactions.

Magnitude and predictors of elasticity of demand for morphine are similar in male and female rats.

Sex differences in vulnerability to opioid use disorder (OUD) have been reported in some clinical and preclinical studies, but findings are mixed and further research is needed in this area. The goal of this study was to compare elasticity of demand (reinforcement efficacy) in an i.v. morphine self-administration (SA) model in male and female rats using a translationally relevant behavioral economics approach. Rate of acquisition and predictors of individual differences in demand (e.g., cumulative morphine infusions during acquisition) were also evaluated in both sexes. Acquisition of morphine SA (0.4 mg/kg/infusion) under a fixed ratio (FR) 1 schedule of reinforcement was slower and infusions earned were lower in females than in males (n = 30-31/sex), but infusions earned did not differ between sexes during the FR 2 and FR 3 phases of acquisition. Increases in the FR response requirement across sessions during demand testing (FR 1-FR 96) resulted in a progressive reduction in morphine infusions in both sexes. Morphine consumption was well-described by an exponential demand function in both sexes and was associated with considerable individual vulnerability. There were no sex differences in elasticity of demand (rate of decline in morphine consumption with increasing price) or intensity of demand (consumption at zero price). A higher number of infusions earned during the FR 2 and FR 3 phases of acquisition and greater maximum response rates during demand testing were associated with lower demand elasticity (i.e., greater reinforcing efficacy) in both males and females, whereas other relationships were sex-specific (e.g., higher intensity of demand was associated with lower elasticity of demand in males but not in females). Our findings indicate similar elasticity of demand and predictors of individual differences in demand for morphine in male and female rats, although sex differences were observed in initial rate of acquisition and in some correlations between morphine SA measures. These data are consistent with findings of similar OUD vulnerability in males and females in some human and animal studies.

Working hard to avoid: Fixed-ratio response effort and maladaptive avoidance in humans.

Maladaptive avoidance of safe stimuli is a defining feature of anxiety and related disorders. Avoidance may involve physical effort or the completion of a fixed series of responses to prevent occurrence of, or cues associated with, the aversive event. Understanding the role of response effort in the acquisition and extinction of avoidance may facilitate the development of new clinical treatments for maladaptive avoidance. Despite this, little is known about the impact of response effort on extinction-resistant avoidance in humans. Here, we describe findings from two laboratory-based treatment studies designed to investigate the impact of high and low response effort on the extinction (Experiment 1) and return (Experiment 2) of avoidance. Response effort was operationalised as completion of fixed-ratio (FR) reinforcement schedules for both danger and safety cues in a multi-cue avoidance paradigm with behavioural, self-report, and physiology measures. Completion of the FR response requirements cancelled upcoming shock presentations following danger cues and had no impact on the consequences that followed safety cues. Both experiments found persistence of high response-effort avoidance across danger and safety cues and sustained (Experiment 1) and reinstated (Experiment 2) levels of fear and threat expectancy. Skin conductance responses evoked by all cues were similar across experiments. The present findings and paradigm have implications for translational research on maladaptive anxious coping and treatment development.

Assessing the performance of brushtail possums (Trichosurus vulpecula) on the Mechner counting procedure.

This study assessed brushtail possums' performance on the Mechner counting procedure. Six brushtail possums were required to produce different Fixed-Ratio (FR) response targets by lever pressing. Their responses provided access to food reinforcement delivered either upon completing the target FR response requirement on a single lever or, in different conditions, on completing the target FR before producing an additional response on a second lever. The mean number of responses on the first lever before switching to the second lever typically occurred just above the target FR response requirement (FR: 4, 8, 16, 32 and 64). The variability in the number of switches between the levers around the target FR decreased from the first 10days to the last 10days, indicating an improvement in counting accuracy over sessions. The time to switch between the first and second lever was consistently variable across response requirements suggesting that it is unlikely the possums were using time to predict when to switch levers. This research further supports the use of the Mechner procedure as a method for measuring counting ability in animals and confirms the possibility of numerical competence in a marsupial species.

Waving Through the Window: A Model of Volitional Social Interaction in Female Mice

BackgroundMouse models of social behavior fail to account for volitional aspects of social interaction, and current neurobiological investigation of social behavior is performed almost exclusively using C57BL/6J mice, the background strain of most transgenic mice. Here, we introduce a mouse model of operant social self-administration and choice, using a custom-made apparatus. MethodsFirst, we trained adolescent and adult female C57BL/6J and CD1 mice to self-administer palatable food pellets and then to lever press under increasing fixed-ratio response requirements for access to an age-matched female social partner. Next, we tested their motivation to seek social interaction using a progressive ratio reinforcement schedule, relapse to social seeking after social isolation, and choice between palatable food versus social interaction. We also tested social conditioned place preference in adult female CD1 and C57BL/6J mice. ResultsAdolescent and adult female mice of both strains showed similar rates of food self-administration. In contrast, CD1 mice demonstrated significantly stronger social self-administration than C57BL/6J mice under both reinforcement schedules. CD1 but not C57BL/6J mice demonstrated robust social seeking after social isolation. In the choice task, CD1 mice preferred social interaction, whereas C57BL/6J mice preferred food. CD1 but not C57BL/6J mice demonstrated robust social conditioned place preference. The strain differences were age independent. ConclusionsOur data show that CD1 mice are a better strain for studying female social reward learning. Our mouse operant social model provides a tool for research on neurobiological substrates of female social reward and disruption of social reward in psychiatric disorders using mouse-specific genetic tools.

Role of estrogen receptor-α on food demand elasticity.

Estrogens have been shown to have an inhibitory effect on food intake under free-feeding conditions, yet the effects of estrogens on food-maintained operant responding have been studied to a much lesser extent and, thus, are not well understood. Therefore, the purpose of the present experiment was to use a behavioral economics paradigm to assess differences in demand elasticity between mice with knockout of the estrogen receptor subtype α, knockout of subtype β, and their wild type controls. The mice responded in a closed economy, and the price of food was increased by increasing the fixed-ratio response requirement every four sessions. Overall, we found that mice with the knockout of receptor subtype α had the most elastic demand functions. Therefore, under these conditions, estrogens increased food seeking via activation of the receptor subtype α. The results were inconsistent with those reported by previous studies that employed free-feeding conditions.

Effects of Environmental Manipulations and Treatment with Bupropion and Risperidone on Choice between Methamphetamine and Food in Rhesus Monkeys.

Preclinical and human laboratory choice procedures have been invaluable in improving our knowledge of the neurobiological mechanisms of drug reinforcement and in the drug development process for candidate medications to treat drug addiction. However, little is known about the neuropharmacological mechanisms of methamphetamine vs food choice. The aims of this study were to develop a methamphetamine vs food choice procedure and determine treatment effects with two clinically relevant compounds: the monoamine uptake inhibitor bupropion and the dopamine antagonist risperidone. Rhesus monkeys (n=6) responded under a concurrent schedule of food delivery (1-g pellets, fixed-ratio (FR) 100 schedule) and intravenous methamphetamine injections (0-0.32 mg/kg/injection, FR10 schedule) during 7-day bupropion (0.32-1.8 mg/kg/h) and risperidone (0.001-0.0056 mg/kg/h) treatment periods. For comparison, effects of removing food pellets or methamphetamine injections and FR response requirement manipulations were also examined. Under saline treatment conditions, food was preferred over no methamphetamine or small unit methamphetamine doses (0.01-0.032 mg/kg/injection). Larger methamphetamine doses resulted in greater methamphetamine preference and 0.32 mg/kg/injection methamphetamine maintained near exclusive preference. Removing food availability increased methamphetamine choice, whereas removing methamphetamine availability decreased methamphetamine choice. Methamphetamine choice was not significantly altered when the FR response requirements for food and drug were the same (FR100:FR100 or FR10:FR10). Risperidone treatment increased methamphetamine choice, whereas bupropion treatment did not alter methamphetamine choice up to doses that decreased rates of operant behavior. Overall, these negative results with bupropion and risperidone are concordant with previous human laboratory and clinical trials and support the potential validity of this preclinical methamphetamine vs food choice model.

Interaction Between Behavioral and Pharmacological Treatment Strategies to Decrease Cocaine Choice in Rhesus Monkeys

Behavioral and pharmacotherapeutic approaches constitute two prominent strategies for treating cocaine dependence. This study investigated interactions between behavioral and pharmacological strategies in a preclinical model of cocaine vs food choice. Six rhesus monkeys, implanted with a chronic indwelling double-lumen venous catheter, initially responded under a concurrent schedule of food delivery (1-g pellets, fixed-ratio (FR) 100 schedule) and cocaine injections (0-0.1 mg/kg/injection, FR 10 schedule) during continuous 7-day treatment periods with saline or the agonist medication phenmetrazine (0.032-0.1 mg/kg/h). Subsequently, the FR response requirement for cocaine or food was varied (food, FR 100; cocaine, FR 1-100; cocaine, FR 10; food, FR 10-300), and effects of phenmetrazine on cocaine vs food choice were redetermined. Decreases in the cocaine FR or increases in the food FR resulted in leftward shifts in the cocaine choice dose-effect curve, whereas increases in the cocaine FR or decreases in the food FR resulted in rightward shifts in the cocaine choice dose-effect curve. The efficacy of phenmetrazine to decrease cocaine choice varied systematically as a function of the prevailing response requirements, such that phenmetrazine efficacy was greatest when cocaine choice was maintained by relatively low unit cocaine doses. These results suggest that efficacy of pharmacotherapies to modulate cocaine use can be influenced by behavioral contingencies of cocaine availability. Agonist medications may be most effective under contingencies that engender choice of relatively low cocaine doses.

TITRATING‐DELAY MATCHING‐TO‐SAMPLE IN THE PIGEON

The titrating-delay matching-to-sample (TDMTS) procedure offers researchers an additional behavioral task thought to capture some important features of remembering. In this procedure, the delay between sample offset and comparison onset adjusts as a function of the subject's performance. Specifically, correct matches increase the delay and incorrect matches decrease the delay, and steady-state titrated delays serve as the primary dependent measure. The present series of experiments investigated the effects of several procedural variables on performance in TDMTS procedures in an effort to elucidate better its features to allow for more precision in future use. Experiment 1 reports results from a parametric analysis of fixed-ratio response requirements on the sample key that indicated improved remembering in the form of higher daily titrated delay values as the requirement was increased. Experiment 2 investigated the extent to which the initial delay value in each session affected session-wide delay values. Results indicated that regardless of value of the initial delay, the subjects' performances adjusted the delay values in the direction of the known baseline delay-value levels. Experiment 3 manipulated the step size by which delay values were adjusted and the results indicated that larger step sizes increased both session-to-session variability and within-session range of titrated delay values, although the average values remained approximately the same. These results suggest that the TDMTS task serves as a promising procedure to study what many refer to as memory.

Fixed-ratio schedules of cocaine self-administration in rhesus monkeys: joint control of responding by past and upcoming doses

By manipulating a signaled upcoming cocaine dose, we investigated how the dose just received and the upcoming dose jointly controlled cocaine self-administration. Three rhesus monkeys self-administered cocaine according to a multiple schedule differing in dose following completion of a fixed-ratio response requirement. The larger dose (0.03 or 0.056 mg/kg) was 10-fold higher than the smaller dose (0.003 or 0.0056 mg/kg). Following each infusion, there was an equal probability that the next dose would be large or small. This resulted in four types of signaled transitions: from a small dose to a small dose, small to large, large to large, and large to small. Across conditions the response requirement was increased. At lower ratios, pauses were brief and run rates were controlled by the upcoming dose. At larger ratios, pauses were pronounced, and run rates suppressed, in transitions from a large to a small dose. The behavioral disruption engendered by this transition occurred with both dose combinations. The results suggest that negative discriminable shifts in drug availability disrupt ongoing responding.

The effects of cocaine on pigeons' choices between fixed-ratio and geometrically escalating schedules: A preliminary study.

Choice patterns over time in situations of diminishing returns have been compared to computations based on the Sums-of-Reciprocals Principle or the Linear Optimality Principle. The present experiment was designed to examine the effect of cocaine on choice in situations of diminishing returns, using the above averaging techniques for reference lines to identify potential invariances. After determining appropriate dosages, pigeons were exposed to a concurrent-chains schedule in which brief initial links led to either of two terminal links. One terminal link consisted of 15 responses (FR15), and the other was a geometrically increasing progressive-ratio schedule (GPR) whose rate of escalation was determined with a multiplier of 1.15. A selection of the FR schedule reset the GPR to its initial response requirement of five. Consistent with earlier research, computations based on the sums-of-reciprocals principal better described choice patterns during baseline (nondrug) conditions. However, patterns shifted towards the reference line generated using the linear optimality averaging principle during the drug conditions. Although neither technique precisely accounted for behavior, it is clear that behavior patterns were systematically altered by cocaine in a way that indicated sensitivity to reinforcement prospects over longer periods of time than the sums-of-reciprocals principle predicts. Marked residual effects on choice were also visible during the return to baseline, as behavior patterns were slow or did not return to those during initial baseline. This study provided a preliminary analysis of the effects of cocaine on choice in situations involving diminishing returns. Key Words: cocaine; resistance to choice patterns; concurrent-chains schedule; persistence; key peck; pigeons. ********** This experiment was an attempt to formulate some elementary principles concerning behavior patterns affected by acute and chronic drug procedures. Both biological and economic traditions include accounts of behavior patterns in homogeneous environments that involve optimization of resources. In the laboratory, investigators of behavior generate reference lines, or potential invariances in net gain, to predict and describe behavior (Nevin, 1984). Two approaches that are often distinguished from one another are short term, or molecular (e.g., Hinson & Staddon, 1983; Navarick, 1979) and long-term, or molar (Baum, 1973). In choice situations, a molecular approach is based on analyzing the moment-to-moment proximity of reinforcers available from each of the available alternatives, and evaluating the sensitivity of behavior to them. A Molar approach involves long term consideration of actions and the consequences of those actions, involving an extended pattern of choice or series of selections, and the degree to which the remote reinforcers influence choice. Experiments that involve choices between fixed-ratio (FR) and progressive ratio (PR) schedules of reinforcement have provided evidence relevant to assessing the degree of molarity characteristic of choice patterns. Initially, the PR response requirement is smaller than the FR response requirement and therefore preferred. In a concurrent-chains procedure, a switch point is the point at which the subject selects the FR alternative after several selections of the PR alternative, resetting the PR to its initial response requirement. Switch points can be compared to reference lines generated by the linear optimality principle (a molar computation) and the sums-of-reciprocals principle (a self-limiting molar computation), allowing the experimenter to identify potential invariances. In their experiments with chimpanzees, Hodos and Trumble (1967) studied schedule selections in a recurring choice situation where the alternatives were a progressive-ratio (PR) and a fixed-ratio (FR) schedule of reinforcement. Both alternatives were concurrently available at every choice point until a response was made, making the non-selected alternative unavailable. …

Glucocorticoid receptor impairment enhances impulsive responding in transgenic mice performing on a simultaneous visual discrimination task.

Transgenic mice with impaired glucocorticoid receptor (GR) function were tested for their ability to learn and perform a series of simultaneous visual discriminations which allowed a dissociation between accuracy of discrimination from those of motivation and behavioural disinhibition. Animals were first trained on an operant five-choice simultaneous discrimination autoshaping procedure, followed by a continuous reinforcement schedule on that task. Subsequently, the number of choices was limited to two and data were analysed according to the mathematical methods of signal detection theory (SDT). The effects of GR-antisense expression on accuracy when different rates of responding were required were studied under different fixed ratio response requirements (FR1-FR10). Autoshaping was retarded in transgenic animals and accuracy was impaired in both the five-choice and the two-choice discrimination tasks, although transgenic mice showed clear evidence for learning. Under conditions of low response requirements, transgenic mice showed increased response and cognitive biases, but reduced perceptual bias, and a behavioural disinhibition, characterized by a reduction in errors of omission, decreased response latencies and increased number of responses during the inter-trial interval. Increasing the response requirement improved performance in transgenic animals as reflected by enhanced accuracy. Moreover, transgenics were less susceptible to the deleterious effects of higher response requirements, as indicated by relatively unaffected bias measures in this group, while bias increased in controls. These results indicate that altered performance in GR-antisense transgenic animals cannot simply be interpreted as a mnemonic deficit, but that altered motivation and enhanced impulsive responding may account for some of these impairments.

Effects of a stimulus associated with fixed-ratio postreinforcement pause in the rat

Rats presented with a stimulus paired with the postreinforcement pause (PRP) of fixed-ratio (FR) responding showed a temporary decrease in PRP and pause duration between the first and second responses. This suppression of pausing increased with increased ratio magnitude, and recovery from suppression was slower at the higher requirement. These results are consistent with an interpretation involving acquired punishing properties by the PRP-paired stimulus, and suggest that the PRP represents an avoidance response wherein the FR response requirement itself serves as an aversive condition with increases in its negative properties as the FR magnitude increases.

AN INVERSE RELATIONSHIP BETWEEN BASELINE FIXED‐INTERVAL RESPONSE RATE AND THE EFFECTS OF A TANDEM RESPONSE REQUIREMENT

Previous experiments examining the effects of adding a tandem fixed-ratio response requirement on fixed-interval schedule performance have reported inconsistent results. One variable that may account for such inconsistencies is the baseline response rate in the fixed-interval condition. This possibility was investigated in the present study. Rats were given histories with either interresponse times greater than 11 s or fixed-ratio 40 schedules of reinforcement, which engendered either relatively low or high rates of responding, respectively, in the subsequent fixed-interval condition. A tandem ratio response requirement (fixed-ratio 9) was then introduced. The effects of adding this tandem response requirement were inversely related to the baseline fixed-interval response rates; low rates of responding in the fixed-interval condition were markedly increased, whereas high rates of responding were relatively unaffected. This inverse relationship appears to be similar to the rate-dependent relations observed in behavioral pharmacology. These results may provide an explanation for the inconsistent findings reported in previous studies on tandem fixed-interval fixed-ratio schedules and suggest that principles of behavioral pharmacology research may be applicable to the study of the effects of nonpharmacological variables on schedule-controlled behavior.

Progressive-ratio performance maintained by drug infusions: Comparison of cocaine, diethylpropion, chlorphentermine, and fenfluramine

Cocaine, diethylpropion, chlorphentermine, and fenfluramine were compared on a drug-maintained progressive-ratio procedure in baboons. Intravenous infusions of drug were contingent on completion of a fixed-ratio response requirement (fixed number of lever-press responses) with a 3-h time-out period following each infusion. Prior to testing each dose of drug, stable self-infusion performance was first established with 0.4 mg/kg cocaine when the fixed-ratio requirement was 160. Subsequently, a test dose of drug was substituted for the standard dose of cocaine. If the dose of drug maintained a criterion level of self-infusion performance (six or more infusions per day for 2 days), the ratio requirement was systematically increased every day until the ‘breaking point’ at which the self-infusion performance fell below a criterion level (one or zero infusionsper day). Fenfluramine did not maintain criterion self-infusion performance at any dose tested (0.02–5.0 mg/kg). The dose ranges of the other drugs that maintained maximum breaking points were 1.0–5.6 mg/kg for chlorphentermine, 1.0–3.0 mg/kg for diethylpropion, and 0.1–0.4 mg/kg for cocaine. Within-animal comparison of the maximum breaking points indicated that cocaine maintained the highest breaking points, followed in order by diethylpropion, chlorphentermine, and fenfluramine. The rank ordering of these drugs with the breaking point measure corresponds well with both the results of other animal experiments on measurement of reinforcing efficacy of these drugs and with the clinical information about the human subjective effects and abuse of these drugs.

SWITCHING FROM COMPETITION TO SHARING OR COOPERATION AT LARGE RESPONSE REQUIREMENTS: COMPETITION REQUIRES MORE RESPONDING1

Two pairs of high-school students matched-to-sample for money. On each trial, a subject could either respond on one lever to take the matching-to-sample problem himself (taking response) or respond on a second lever to give the problem to his coactor (giving response). The first subject to complete the response requirement determined the distribution of the problem. Competition maximizes the amount of responding over trials, i.e., both subjects make taking responses on each trial. Sharing and cooperation minimize responding: only one subject makes a taking response (sharing) or a giving response (cooperation) on each trial, and the subjects alternate responding such that there is an equitable distribution of responses and reinforcers over trials. Large increases in the fixed-ratio response requirement to distribute problems produced: (1) a switch from competition to sharing or cooperation, (2) the expected concomitant change from inequitable to equitable distributions of reinforcers, and (3) a reduction in the amount of responding for three of the four subjects. Previous animal research has shown that large response requirements may have aversive properties. Switching from competition to sharing or cooperation at large response requirements allows a reduction in responding and, at the same time, a moderate number of reinforcers for each subject.

ADJUSTING FIXED-RATIO SCHEDULES IN THE SQUIRREL MONKEY.

On an adjusting schedule of reinforcement, a parameter of the schedule is varied as a function of some characteristic of the animal's performance. In Experiment I, the fixed-ratio response requirement was varied as a function of the time that elapsed before the animal started responding in each fixed-ratio (initial pause). When initial pauses were shorter than a specified duration, the response requirement was increased; when they were longer than the specified duration, the response requirement was decreased. Specified durations of 1, 2, 4, 8, and 15 min were studied. The average response requirement maintained by each monkey was directly related to the length of the specified duration of initial pause. In Experiment II, the fixed-ratio response requirement was constant, but reinforcement occurred only when the initial pause was longer than a specified duration. The average durations of initial pauses were directly related to the length of the specified duration and to the response requirement. Meprobamate consistently decreased the average durations of initial pauses.