Progressive Ratio Breakpoint Research Articles

Comparison of Intravenous Buprenorphine and Methadone Self-Administration by Recently Detoxified Heroin-Dependent Individuals

Although buprenorphine is used worldwide as a safe and effective maintenance medication for opioid dependence, some countries have reported a growing incidence of abuse of this medication. Buprenorphine is considered to have lower abuse potential because of its partial agonist profile, but no studies have directly compared the reinforcing effects of buprenorphine with those of full mu opioid agonists in humans. The present double-blind, placebo-controlled inpatient study compared the reinforcing and subjective effects of intravenously administered buprenorphine (0.5, 2, and 8 mg) and methadone (5, 10, and 20 mg). Participants (n = 6) were detoxified from heroin during the first 1 to 2 weeks after admission. During subsequent weeks, participants received a sample drug dose and $20 on Monday, and they could self-administer either the sampled dose or $20 during one choice session per day on Thursday and Friday. Participants responded under a modified progressive ratio schedule during each choice session. All active doses maintained higher progressive ratio break points (largest completed ratio) than placebo. There were no significant differences in break point values between buprenorphine and methadone or among the different doses of drug. However, several subjective ratings, including "good drug effect", "high", and "liking" dose-dependently increased after administration of buprenorphine and methadone. The peak ratings for these effects did not significantly differ for the two drugs. These results demonstrate that under these experimental conditions, buprenorphine and methadone were equally effective in producing reinforcing and subjective effects.

Nicotine increases alcohol self-administration in non-dependent male smokers

Background Alcohol and tobacco are commonly co-administered, yet little is known about the effects of acute nicotine administration on alcohol consumption in humans. This study sought to determine how nicotine delivered by tobacco smoke influences alcohol intake in humans using a double-blind placebo controlled repeated measures design. Methods During two randomized 120 min sessions 15 male occasional smokers smoked four nicotine-containing or four denicotinized cigarettes at 30 min intervals. Throughout the session, subjects could earn units of their preferred alcoholic beverage and glasses of water using a progressive-ratio (PR) task. Results Wilcoxon signed-rank tests indicated that nicotine increased alcohol self-administration in a significant proportion of participants ( P ≤ 0.03) without affecting water consumption ( P ≥ 0.16). A two-way ANOVA supported this observation further, and, compared to denicotinized cigarettes, the nicotine-containing cigarettes increased PR breakpoints for alcohol but not water, as reflected by a Cigarette × Beverage interaction ( P ≤ 0.055). Conclusions The present data suggest that acute nicotine administration increases alcohol consumption in at least a subset of smokers.

The effects of d-amphetamine on responding for candy and fruit drink using a fixed ratio and a progressive ratio schedule of reinforcer delivery

The first purpose of this study was to compare the effects of d-amphetamine (AMPH) on operant responding reinforced under fixed ratio (FR) or progressive ratio (PR) schedules of reinforcement, testing the hypothesis that responding reinforced under a PR operant schedule would be disrupted by lower doses of AMPH than responding reinforced under a FR operant schedule. The second purpose of this study was to test the generalizability of the first hypothesis by comparing the effects of AMPH on responding reinforced by two different reinforcers under both FR and PR operant schedules. Rhesus monkeys had five to six candy and five to six fruit drink sessions per day, and could receive two reinforcers per session. Responding was initially reinforced under a PR procedure, such that the ratio size increased with each subsequent session. The parameters of the PR schedule were individually selected so that monkeys consumed a similar number of candy and fruit-drink reinforcers each day. The effects of oral AMPH (0.5, 0.75, 1.0 mg/kg) on responding were assessed. Responding was then stabilized using a FR schedule with parameters individually selected so that monkeys consumed a similar number of candy and fruit-drink reinforcers each day, and the effects of oral AMPH were again assessed. The PR breakpoint was significantly greater for candy than fruit-drink. AMPH produced dose-related decreases in both candy and fruit-drink intake, but each AMPH dose decreased the number of fruit-drink deliveries to a greater extent than the number of candy deliveries. The results failed to support the hypothesis that responding under PR schedules of reinforcement would be disrupted by lower doses of AMPH.

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.

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.

Magnesium-maintained self-administration responding in cocaine-trained rats

Magnesium chloride (MgCl2) produces behavioral effects similar to those of psychomotor stimulants in a variety of behavioral situations. Because MgCl2 appears to have stimulant properties, the ability of MgCl2 to maintain responding in a rat self-administration paradigm was examined in seven experiments under different access and schedule conditions in cocaine-trained rats. These varied from the availability of MgCl2 for a single day's test session subsequent to 1 h availability of cocaine, to the availability of MgCl2 for 10 or 20 days after cocaine availability was totally discontinued. Fixed ratio 1, fixed ratio 5, and progressive ratio 1, 2 and 3 schedules of drug delivery were used. The results demonstrate that MgCl2 may substitute for self-administered cocaine because it maintained responding; it did so dose dependently to maintain a constant level of MgCl2 intake; and it did so over a 10-day period of time both with and without access to cocaine on test days. Responding maintained by MgCl2 when cocaine was no longer available was similar under fixed ratio 1 and 5 schedule conditions. The progressive ratio breakpoints for MgCl2 were significantly higher than those for saline, but significantly lower than those for cocaine. These data indicate that MgCl2 has some reinforcing efficacy in cocaine-trained rats, particularly under fixed ratio 1 and 5 schedules, but has a low abuse potential compared to cocaine.

Progressive ratio performance maintained by buprenorphine, heroin and methadone in Macaque monkeys

The relative reinforcing efficacy of buprenorphine (0.01–0.10 mg/kg/inj.), heroin (0.01–0.10 mg/kg/inj.), methadone (0.03–0.25 mg/kg/inj.) and saline were compared in Macaque male monkeys using progressive ratio procedures. Responding for drugs and food (1 g banana pellet) was maintained on a second order FR 4 (VR 16:S) schedule of reinforcement that required an average of 64 responses for each injection or food pellet. After 40 sessions (10 days) of stable performance, the number of responses for each drug injection was systematically increased until monkeys reached a breakpoint defined by 2 consecutive days of no drug injections. Progressive ratio breakpoints for heroin at intermediate and high doses (0.05 and 0.10 mg/kg/inj.) were two to three times higher than for any other drug ( P < 0.05). Breakpoints for buprenophine (0.01–0.10 mg/kg/inj.) were higher than for a low dose of methadone (0.03 mg/kg/inj.) but were equivalent to an intermediate methadone dose (0.10 mg/kg/ inj.). Breakpoints for both low (0.01 mg/kg/inj.) and high (0.10 mg/kg/inj.) buprenorphine doses were greater than for intermediate doses (0.03 and 0.05 mg/kg/inj.) but these differences were not statistically significant. Linear regression and area under the curve analyses were used to quantify the rate at which drug maintained responding decreased by 30% of control levels as response requirements were increased. Extrapolated breakpoints derived from linear regression analyses were significantly correlated ( P < 0.05-0.01) with actual breakpoints for buprenorphine, heroin and methadone. The concordance between ‘extrapolated’ and traditional breakpoint ranking of these drugs suggests that regression analysis techniques can be used to predict traditional breakpoints.