Concurrent Progressive-ratio Schedules Research Articles

The Relative Reinforcing Value of Cookies Is Higher Among Head Start Preschoolers With Obesity.

The relative reinforcing value (RRV) of food measures how hard someone will work for a high-energy-dense (HED) food when an alternative reward is concurrently available. Higher RRV for HED food has been linked to obesity, yet this association has not been examined in low-income preschool-age children. Further, the development of individual differences in the RRV of food in early childhood is poorly understood. This cross-sectional study tested the hypothesis that the RRV of HED (cookies) to low-energy-dense (LED; fruit) food would be greater in children with obesity compared to children without obesity in a sample of 130 low-income 3- to 5-year-olds enrolled in Head Start classrooms in Central Pennsylvania. In addition, we examined individual differences in the RRV of food by child characteristics (i.e., age, sex, and reward sensitivity) and food security status. The RRV of food was measured on concurrent progressive-ratio schedules of reinforcement. RRV outcomes included the last schedule reached (breakpoint) for cookies (cookie Pmax) and fruit (fruit Pmax), the breakpoint for cookies in proportion to the total breakpoint for cookies and fruit combined (RRV cookie), and response rates (responses per minute). Parents completed the 18-item food security module to assess household food security status and the Behavioral Activation System scale to assess reward sensitivity. Pearson’s correlations and mixed models assessed associations between continuous and discrete child characteristics with RRV outcomes, respectively. Two-way mixed effects interaction models examined age and sex as moderators of the association between RRV and Body Mass Index z-scores (BMIZ). Statistical significance was defined as p < 0.05. Children with obesity (17%) had a greater cookie Pmax [F (1, 121) = 4.95, p = 0.03], higher RRV cookie [F (1, 121) = 4.28, p = 0.04], and responded at a faster rate for cookies [F (1, 121) = 17.27, p < 0.001] compared to children without obesity. Children with higher cookie response rates had higher BMIZ (r = 0.26, p < 0.01); and RRV cookie was positively associated with BMIZ for older children (5-year-olds: t = 2.40, p = 0.02) and boys (t = 2.55, p = 0.01), but not younger children or girls. The RRV of food did not differ by household food security status. Low-income children with obesity showed greater motivation to work for cookies than fruit compared to their peers without obesity. The RRV of HED food may be an important contributor to increased weight status in boys and future research is needed to better understand developmental trajectories of the RRV of food across childhood.

Pharmacological validation of a translational model of cocaine use disorder: Effects of d-amphetamine maintenance on choice between intravenous cocaine and a nondrug alternative in humans and rhesus monkeys.

Drug self-administration procedures are the gold standard for laboratory research to study mechanisms of drug use disorders and evaluate candidate medications. However, preclinical-to-clinical translation has been hampered by a lack of coordination. To address this limitation, we previously developed homologous intravenous (IV) cocaine choice self-administration procedures in rhesus monkeys and humans, and then demonstrated their functional equivalence. The present studies sought to determine the sensitivity of these procedures to d-amphetamine maintenance. Three (N = 3) rhesus monkeys with histories of cocaine self-administration and 16 (N = 16) humans with cocaine use disorder completed the studies. Monkeys were maintained on IV d-amphetamine (0, 0.019, 0.037 and 0.074 mg/kg/h), and then completed 7 sessions during each condition in which they completed 9 choice trials to receive 0.14 mg/kg/injection IV cocaine (corresponding to 10 mg/70 kg in humans) or 10 food pellets under independent, concurrent progressive-ratio schedules. Humans were maintained on oral extended release d-amphetamine (0, 30 and 60 mg/day, corresponding to the lowest 3 doses in monkeys) and participated in 12 sessions in which they chose money ($6.00) or IV cocaine (0, 3, 10 and 30 mg/70 kg). Blood samples were taken to compare d-amphetamine plasma levels across species. In monkeys and humans, d-amphetamine reduced the number of cocaine choices and produced comparable blood levels at equivalent daily doses. d-Amphetamine had similar efficacy, though lower potency, at reducing choice for an equivalent cocaine dose in monkeys relative to humans. These coordinated studies support the utility of these procedures as a translational model for cocaine use disorder. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Development of a translational model to screen medications for cocaine use disorder II: Choice between intravenous cocaine and money in humans

BackgroundA medication for treating cocaine use disorder has yet to be approved. Laboratory-based evaluation of candidate medications in animals and humans is a valuable means to demonstrate safety, tolerability and initial efficacy of potential medications. However, animal-to-human translation has been hampered by a lack of coordination. Therefore, we designed homologous cocaine self-administration studies in rhesus monkeys (see companion article) and human subjects in an attempt to develop linked, functionally equivalent procedures for research on candidate medications for cocaine use disorder. MethodsEight (N=8) subjects with cocaine use disorder completed 12 experimental sessions in which they responded to receive money ($0.01, $1.00 and $3.00) or intravenous cocaine (0, 3, 10 and 30mg/70kg) under independent, concurrent progressive-ratio schedules. Prior to the completion of 9 choice trials, subjects sampled the cocaine dose available during that session and were informed of the monetary alternative value. ResultsThe allocation of behavior varied systematically as a function of cocaine dose and money value. Moreover, a similar pattern of cocaine choice was demonstrated in rhesus monkeys and humans across different cocaine doses and magnitudes of the species-specific alternative reinforcers. The subjective and cardiovascular responses to IV cocaine were an orderly function of dose, although heart rate and blood pressure remained within safe limits. ConclusionsThese coordinated studies successfully established drug versus non-drug choice procedures in humans and rhesus monkeys that yielded similar cocaine choice behavior across species. This translational research platform will be used in future research to enhance the efficiency of developing interventions to reduce cocaine use.

Concurrent progressive ratio schedules: Effects of reinforcer probability on breakpoint and response allocation

Although progressive ratio (PR) schedules have been used to explore effects of a range of reinforcer parameters (e.g., magnitude, delay), effects of reinforcer probability remain underexplored. The present project used independently progressing concurrent PR PR schedules to examine effects of reinforcer probability on PR breakpoint (highest completed ratio prior to a session terminating 300s pause) and response allocation. The probability of reinforcement on one lever remained at 100% across all conditions while the probability of reinforcement on the other lever was systematically manipulated (i.e., 100%, 50%, 25%, 12.5%, and a replication of 25%). Breakpoints systematically decreased with decreasing reinforcer probabilities while breakpoints on the control lever remained unchanged. Patterns of switching between the two levers were well described by a choice-by-choice unit price model that accounted for the hyperbolic discounting of the value of probabilistic reinforcers.

Concurrent progressive-ratio schedules: built-in controls in the study of delayed reward efficacy.

Delayed rewards maintain lower rates of operant responding than immediate rewards, and when given a choice between immediate and delayed rewards, individuals typically choose the immediate reward, even when it is smaller (a phenomenon called delay discounting). The behavioral and neural mechanisms underlying these behavioral patterns, however, are not conclusively understood. The present study developed a method to examine the efficacy of delayed rewards in a way that is suitable for pharmacological manipulation of delayed reward efficacy (while controlling for general changes in reward efficacy). The progressive ratio (PR) paradigm often used to examine reward efficacy was modified such that two PR schedules for lever pressing concurrently yet independently were presented. Across a series of conditions, a range of delays (3-81s) were arranged on one of the levers while the reward on the other lever remained immediate. PR breakpoints (the highest ratio completed on each lever, our measure of reward efficacy) systematically decreased on the delayed, but not on the immediate reward lever, suggesting that delays decreased reward efficacy. This decrease in breakpoint resulted in bias in within-session responding that was accounted for by models that adjusted reward value by the delay to that reward. Unlike the standard PR paradigm, the present arrangement provided the controls needed to differentiate delay specific from general changes in reward efficacy. The present method should be helpful in the study of the behavioral and neural mechanisms of delayed reward efficacy. Modifications of the present paradigm should be useful for pharmacological studies.

Relationship between intranasal cocaine self-administration and subject-rated effects: predictors of cocaine taking on progressive-ratio schedules.

Subject-rated measures and drug self-administration represent two of the most commonly used methods of assessing abuse potential of drugs, as well as screening intervention efficacy in the human laboratory. Although the results from these methods are often consistent, dissociations between subject-rated and self-administration data have been observed. The purpose of the present retrospective analysis was to examine the relationship between subject-rated effects and intranasal cocaine self-administration to help guide future research design and intervention assessment. Data were combined from two previous studies in which drug and an alternative reinforcer (i.e., money) were available on concurrent progressive-ratio schedules of reinforcement. Pearson correlation coefficients and regression model selection utilizing corrected Akaike information criterion were used to determine which subject-rated measures were associated with and best predicted cocaine self-administration. Eleven subject-rated effects were positively associated with cocaine-maintained breakpoints. A combination of three of these subject ratings (i.e., Like Drug, Performance Improved, and Rush) best predicted cocaine taking. The present findings suggest that, at least under certain conditions with intranasal cocaine, some, but not all, positive subject-rated effects may predict drug self-administration. These findings will be useful in guiding future examinations of putative interventions for cocaine-use disorders.

Influence of acute bupropion pre‐treatment on the effects of intranasal cocaine

The aim of this experiment was to determine the influence of acute bupropion pre-treatment on subject-rated effects and choice of intranasal cocaine versus money. A randomized, within-subject, placebo-controlled, double-blind experiment. An out-patient research unit. Eight cocaine-using adults. Subjects completed nine experimental sessions in which they were pre-treated with 0, 100 or 200 mg oral immediate release bupropion. Ninety minutes later they sampled an intranasal cocaine dose [4 (placebo), 15 or 45 mg] and made six choices between that dose and an alternative reinforcer (US$0.25), available on independent, concurrent progressive ratio schedules. Subjects also completed a battery of subject-rated, performance and physiological measures following the sample doses of cocaine. After 0 mg bupropion, the high dose of cocaine (45 mg) was chosen five of six times on average compared to 2.25 of six choices for placebo cocaine (4 mg) (P < 0.05). Active bupropion reduced choice of 45 mg cocaine to 3.13 (100 mg) or 4.00 (200 mg) out of six drug choices on average. Bupropion also consistently enhanced positive subject-rated effects of cocaine (e.g. good effects; willing to take again) while having no effects of its own. The atypical antidepressant, bupropion, acutely appears to reduce preference for intranasal cocaine versus a small amount of money but to increase reported positive experiences of the drug.

Concurrent progressive-ratio schedules to compare reinforcing effectiveness of different phencyclidine (PCP) concentrations in rhesus monkeys.

Progressive ratio (PR) schedules have become well accepted for testing the reinforcing effectiveness of drugs. This study extends the methods to concurrent PR schedules with different concentrations of orally delivered phencyclidine (PCP). The sensitivity of the procedure is tested by presenting different PCP concentrations with independently-operating PR schedules. PCP self-administration was investigated in seven rhesus monkeys. Six different PCP concentrations (0.03-1.0 mg/ml) and water were randomly paired (21 pairings). Liquid delivery (24 ml) was contingent upon lip-contact responses on solenoid-operated drinking spouts; whereby, the response requirement or fixed-ratio (FR) increased (from 8 to 16, 32, 64, 128... to 4096) after each successful completion of a previous FR and subsequent liquid delivery. Monkeys self administered PCP during daily 3-h sessions, and each pair of concentrations was held constant until behavior had stabilized for at least 4 days. The higher of the two PCP concentrations always maintained greater responding, PR break point (BP), or the last ratio completed, and liquid deliveries than did the lower concentration. However, the monkeys did not exclusively respond on the drinking spout that yielded the higher drug concentration. When examined across all drug pairings, the percentage of total available deliveries of the higher concentration was significantly greater than those of the lower concentration. The monkeys maximized the amount (mg) consumed for the response output. Responding, BPs and liquid deliveries maintained by 0.12 and 0.25 mg/ml PCP were significantly greater than other PCP concentrations; however, drug intake (mg) increased directly with PCP concentration. These results indicate that concurrent PR schedules using oral drug self-administration and a concurrent choice paradigm reliably provide an estimation of relative reinforcing strength, and behavior maintained by these schedules is sensitive to small changes in PCP concentration.

Naltrexone pretreatment decreases the reinforcing effectiveness of ethanol and saccharin but not PCP or food under concurrent progressive-ratio schedules in rhesus monkeys.

The purpose of this experiment was to determine whether attenuation of ethanol consumption by naltrexone is the result of selective changes in the reinforcing effectiveness of drug and non-drug reinforcers. A range of naltrexone doses (0.1-1.0 mg/kg) was administered for 5 days, and the effects on the reinforcing effects of orally delivered 8% (w/v) ethanol, 0.25 mg/ml phencyclidine (PCP), 0.03% (w/v) saccharin and food were studied in eight rhesus monkeys. Food and liquids were available under independent and concurrent progressive-ratio (PR) schedules (ratio range 8-4096) during daily 3-h sessions. Ethanol-maintained responding was attenuated by 0.3 and 1.0 mg/kg doses of naltrexone, while saccharin-maintained responding was decreased at the 1.0 mg/kg dose. Furthermore, there was a significant linear trend that consumption of available ethanol and saccharin was attenuated dose-dependently by naltrexone. Following 5 days of naltrexone pretreatment, ethanol- and saccharin-maintained responding immediately returned to or exceeded baseline levels. Food- and PCP-maintained responding and intake were not significantly affected by any of the naltrexone doses examined. The decreased break point (BP) values for ethanol and saccharin suggest that their reinforcing effects are mediated through opioid reinforcement mechanisms. The lack of naltrexone attenuation of PCP- and food-maintained responding suggests that these reinforcers: 1) are not sensitive to naltrexone antagonism at the doses examined, 2) are mediated by non-opioid reinforcement mechanisms, and/or 3) have less intrinsic palatability.

Progressive ratio and behavioral economic evaluation of the reinforcing efficacy of orally delivered phencyclidine and ethanol in monkeys: effects of feeding conditions.

The effect of feeding conditions on the reinforcing efficacy of orally-delivered drugs was evaluated using a progressive-ratio (PR) paradigm and a behavioral economic analysis of demand. Seven monkeys self-administered phencyclidine (PCP) (0.06, 0.12, 0.25, 0.5, and 1.0 mg/ml) or ethanol (2, 4, 8, 16, and 32% wt/vol) and concurrent water from two drinking spouts under concurrent PR schedules. The ratios increased from 8 to 4096, and 40 liquid deliveries were available after completion of each ratio schedule. The entire range of drug concentrations was presented in nonsystematic order under two feeding conditions, food restriction and food satiation. Drug maintained responses, deliveries and break points were significantly greater than those maintained by water. Food restriction significantly increased the rate of PCP-maintained responses, deliveries and PR break points over the food satiation baseline. There was also a significant interaction between feeding condition and drug concentration. Although ethanol-maintained responses, liquid deliveries and break points consistently increased in five of seven monkeys during food restriction, only drug concentration produced significant differences in these measures. Using break point as a measure of reinforcing efficacy, food restriction increased the reinforcing efficacy of PCP and had a more pronounced effect at higher drug unit prices.