Differential-reinforcement-of-low-rate-schedule performance and nicotine administration: a systematic investigation of dose, dose-regimen, and schedule requirement

Abstract

Differential-reinforcement-of-low-rate (DRL) schedules have been used to evaluate the effects of a wide variety of drugs, including amphetamines, cannabinoids, and antidepressant medication. To earn a reinforcer, organisms operating under a DRL schedule are required to withhold a response for a predetermined amount of time before responding, and therefore this schedule maintains a low rate of responding and can be viewed as a response-inhibition task. In experiment 1, three different DRL schedules (4.5, 9.5, and 29.5 s) were used to evaluate systematically a range of nicotine doses (0.0, 0.1, 0.3, and 0.5 mg/kg). The dose-response effect of nicotine then was compared with the effects of increased reinforcer magnitude on responding. Both the administration of nicotine and increased reinforcer magnitude engendered less accurate DRL-schedule performance compared with baseline conditions, and the dose and magnitude-dependent shifts were most evident on the DRL 29.5-s schedule. Experiment 2 compared the differences between acute and chronic dosing regimens (0.3 mg/kg nicotine) on DRL 29.5-s schedule responding. After 20 consecutive sessions of nicotine dosing, accuracy deteriorated significantly, demonstrating that chronic nicotine dosing leads to a behavioral sensitization apparent on the DRL 29.5-s schedule. The results from both experiments suggest that responding on the DRL 29.5-s schedule is sensitive to both dose-response and regimen-dependent effects of nicotine.

Fig. 1

Results from experiment 1 are depicted as cumulative interresponse time greater than (IRT) frequency distributions with time bins on the horizontal axis and percent cumulative frequency on the vertical axis. (a, c, and e) (on the left) Saline, 0.1, 0.3, and 0.5 mg/kg nicotine doses for each of the 4.5-s, 9.5-s and 29.5-s differential-reinforcement-of-low-rate (DRL)-schedule requirements, and subjects were responding for 0.06 ml of sugar water solution. Each line represents the results from the nonlinear regression model and the data points represent an average from three animals per condition, and two administrations per dose. Open boxes for all figures illustrate the same data for animals responding under saline conditions to obtain 0.06 ml of sugar water solution. Dose-dependent alterations in IRT patterning are evident for subjects operating the 9.5-s and 29.5-s DRL schedule. (b, d, and f) Averages obtained from the reward-manipulation sessions during which subjects experienced four sessions of increased magnitudes of reward per reinforcing event (0.10 ml rather than 0.06 ml of sugar water); half of these sessions were preceded by saline and the other two sessions were preceded by 0.3 mg/kg nicotine injection.

Fig. 2

Mean rate of responses per minute, per group for experiment 1 is depicted in (a). A dose–effect relationship on response rate was evident in the differential-reinforcement-of-low-rate (DRL) 4.5-s group only; *Significant within-group differences due to dose. (b) The cumulative interresponse time greater than (IRT) distributions, per schedule requirement, for the two saline-administration sessions/day that separated each nicotine-dosing day in experiment 1. The figure illustrates the similarity between the cumulative IRT frequency distributions across all saline conditions. ‘Baseline’ performance illustrates the IRT distribution for the five saline administrations before the first dose of nicotine. ‘24-h after’ represents the average data obtained from the first saline-administration session/day after a nicotine administration day, and the next successive day of saline administration is labeled ‘48-h after’. The results depicted in (b) demonstrate that nicotine failed to alter the IRT distributions 24-h after administration.

Fig. 3

Data from experiment 2 are represented as cumulative interresponse time greater than (IRT) frequency distributions (a–d) and the line plots are the results from the nonlinear regression analysis. The ‘predose’ comparison (a) is the average of the final 5 days of differential-reinforcement-of-low-rate (DRL) 29.5-s training for all three groups. The saline group’s performance was unaltered by further exposure to the DRL schedule (b). (d) The dramatic shift in the chronic group’s performance with repeated administrations of nicotine; after consecutive nicotine-dosing sessions, the vast majority of IRTs are not reinforced. (c) The reliability of nicotine-dependent leftward shifts in the IRT distribution for the acute group, and this figure contains an average line plot from all five nicotine-dosing sessions for this group. Nicotine-dosing sessions for the acute group were separated by 5 days/session of saline dosing to allow for drug elimination.

Fig. 4

Time-course analysis of the cumulative IRT frequency distribution for the chronic group. The leftward shift occurs between days 6 and 8 of consecutive daily 0.3 mg/kg nicotine dosing; little difference is apparent between days 10 and 20 of consecutive daily dosing.