Lever-press Durations Research Articles

Orbitofrontal cortex populations are differentially recruited to support actions

The ability to use information from one's prior actions is necessary for decision-making. While orbitofrontal cortex (OFC) has been hypothesized as key for inferences made using cue and value-related information, whether OFC populations contribute to the use of information from volitional actions to guide behavior is not clear. Here, we used a self-paced lever-press hold-down task in which mice infer prior lever-press durations to guide subsequent action performance. We show that the activity of genetically identified lateral OFC (lOFC) subpopulations differentially instantiate current and prior action information during ongoing action execution. Transient state-dependent lOFC circuit disruptions of specified subpopulations reduced the encoding of ongoing press durations but did not disrupt the use of prior action information to guide future action performance. In contrast, a chronic functional loss of lOFC circuit activity resulted in increased reliance on recently executed lever-press durations and impaired contingency reversal, suggesting the recruitment of compensatory mechanisms that resulted in repetitive action control. Our results identify a novel role for lOFC in the integration of action information to guide adaptive behavior.

Longer operant lever-press duration requirements induce fewer but longer response bouts in rats.

Operant behavior is organized in bouts that are particularly visible under variable-interval (VI) schedules of reinforcement. Previous research showed that increasing the work required to produce a response decreases the rate at which bouts are emitted and increases the minimum interresponse time (IRT). In the current study, the minimum effective IRT was directly manipulated by changing the minimum duration of effective lever presses reinforced on a VI 40-s schedule. Contrary to assumptions of previous models, response durations were variable. Response durations were typically 0.5 s greater than the minimum duration threshold; durations that exceeded this threshold were approximately log-normally distributed. As the required duration threshold increased, rats emitted fewer but longer bouts. This effect may reflect an effort-induced reduction in motivation and a duration-induced facilitation of a response-outcome association.

Lever-press duration as a measure of frustration in sucrose and drug reinforcement.

Currently there is little research into the role of frustration in substance use disorders despite research showing that frustration tolerance in humans is associated with a lower likelihood of developing substance use problems, better outcomes in recovery, and fewer relapses. In order to address this need, our studies use a rat model to focus on frustration-related behavior in natural reward and addiction-related behavioral procedures. Frustration is defined as when a subject is unable to achieve a reinforcer, receives less of a reinforcer than anticipated, or has to work harder to achieve a reinforcer. In these studies, bar-press durations increase when rats are in a state of frustration during self-administration of sucrose, fentanyl, or cocaine. These data also show that average bar-press durations do not correlate with the number of bar presses, meaning that press duration is an independent measurement that represents a behavioral construct distinct from craving, which is typically measured with number of bar presses. Essentially, these results support that bar press durations can be used as a real-time measure of frustration as a 4th major facet of addiction-related behavior, adding to craving, impulsivity, and habit.

Analysis of Short Lever-Press Durations in Rats Responding Under a Fixed-Duration Schedule

When reinforcement schedules demand that rats depress a lever for a minimum period of time, most lever presses will meet reinforcer requirements, but others will be much shorter. This results in a bimodal distribution of lever-press durations, with one peak near the reinforced duration value, and a smaller peak at less than 1 s. We conducted an experimental and descriptive analysis of short-duration presses in rats responding under a schedule that delivered edible reinforcers for 10 s of lever depression. All rats emitted biting and idiosyncratic behavior that may have both added and subtracted to the downward force necessary to maintain lever depression for extended periods. Movement of the response levers due to vigorous biting and sniffing, as well as premature hopper entries were both responsible for response durations that fell short of reinforcer requirements. Maintenance of long lever-press durations during fixed-time schedules in two out of three rats suggested that timing failure was unlikely a factor underlying bimodal distributions of response durations.

Free-operant discounting: Initial results from an adjusting-duration procedure.

Rats responded under a procedure in which relatively short lever-press durations produced 1 food pellet and longer presses produced 4 food pellets. Because duration is a continuous dimension of behavior, it was possible to arrange conditions in which a smaller reinforcer was available up until the m

Control of response duration by delayed reinforcers: A systematic replication

Three rats responded under schedules of delayed reinforcement in which sweetened condensed milk delivery depended upon lever-press durations exceeding or falling under a programmed value. For all rats, response durations increased compared to those emitted under a fixed-ratio 1 schedule when unsignaled delayed reinforcers were programmed for lever-press durations exceeding 1 s. For two of the rats, response durations also decreased when delayed reinforcer delivery was programmed for durations less than 1 s. Extinction reduced response rate, but did not affect response duration. Data suggest that the rate decreasing effects of unsignaled delayed reinforcers may be separated from the effects those reinforcers have on a targeted continuous dimension.

Response duration is sensitive to both immediate and delayed reinforcement.

We investigated the duration of lever pressing by rats when the delivery of appetitive reinforcers was contingent upon response duration. In the first experiment, response durations increased when duration requirements were imposed, and they decreased when duration requirements were removed. This effect occurred whether reinforcers were immediate or delayed by 8 s. In order to maintain the integrity of the delay intervals, reinforcer delivery was dependent upon both lever depression and release. In a second experiment, lever depression only and a response duration of at least 4 s were required for reinforcer delivery. Compared to immediate reinforcement conditions, delayed reinforcers increased both variability and the length of the maximum response durations. In a third experiment, immediate reinforcers were delivered contingent upon lever depression and release under a variety of duration requirements. Median lever-press durations tracked the contingencies rapidly. Across all three experiments, rats emitted numerous response durations that were too short to satisfy the reinforcer requirements, and bimodal distributions similar to those produced by differential reinforcement of low rate schedules were evident for most rats. In many aspects, response duration responds to reinforcement parameters in a fashion similar to rate of discrete responding, but an examination of this continuous dimension of behavior may provide additional information about environment-behavior relationships.

Modulation of Variation by Response-Reward Spatial Proximity

There has been a recent surge in the experimental investigation of the control of behavioral variability. Currently, it is understood that variability in behavior is predictably modulated by reinforcement parameters (e.g., a probability of reward delivery and reward magnitude). In two experiments, we investigated how spatial proximity between response and reward locations impacts the production of behavioral variability in both response rate and lever press duration. Rats were trained to lever press on two levers in a standard operant chamber that only differed from one another in their proximity to a food niche (i.e., Near vs. Far); a second experimental factor, the probability of reward, was signaled by an auditory cue. In Experiment 1, trials with a high-probability stimulus terminated with reward on 100% of trials, while trials with a low-probability stimulus terminated with reward 25% of the time. We conducted a similar procedure in Experiment 2, but reduced the likelihood of reward on low-probability trials to 10%; additionally, we collected data in a post-acquisition extinction test. Overall, reduced proximity and probability increased variation of response rate, whereas only the probability factor affected lever press duration. Proximity also interacted with probability to influence variation in response rate. These findings extend the factors modulating behavioral variability to include the spatial proximity between a response and reward.

Effects of sarin on the operant behavior of guinea pigs

The present study evaluated the dose–response effects of subacute exposure to sublethal doses of the organophosphorus (OP) chemical warfare nerve agent (CWNA) sarin (GB) on the operant behavior of guinea pigs. Dietary restricted guinea pigs, trained to respond for food under a progressive ratio (PR) schedule of reinforcement, were injected five times per week (Monday–Friday) for 2 weeks with fractions (0.1, 0.2, and 0.4) of the established LD 50 of GB (42 μg/kg). Changes in body weight, whole blood (WB) acetylcholinesterase (AChE) levels, and operant performances were monitored over the 2 weeks of GB exposure and for an additional 2 weeks following the termination of exposures. There were dose-related changes in body weight and WB AChE levels throughout the exposure and post-exposure periods. Several parameters of PR performance were disrupted during exposure to 0.4 LD 50 GB, however, concurrent weight loss indicated the presence of overt toxicity. PR performance recovered following the termination of exposures. Lower doses (0.1 and 0.2 LD 50) of GB failed to produce reliable effects on operant performance during the exposure period. Overall responding decreased during exposure to 0.4 LD 50 GB, resulting in reduced response rates and break points. The decrease in overall response rates was attributed to an increase in pausing since there was no decrease in running rate. Motor effects of 0.4 LD 50 GB were evident as an increase in the proportion of lever press durations ≥ 1.0 s. In the present study, doses of GB lower than 0.4 LD 50 produced no marked alteration of operant performance in guinea pigs, although WB AChE levels were maximally inhibited to 20% of control.

Behavioral pharmacology of AR-A000002, a novel, selective 5-hydroxytryptamine(1B) antagonist.

The present review summarizes the behavioral pharmacology conducted to profile the anxiolytic and antidepressant potential of the selective 5-hydroxytryptamine (HT)(1B) antagonist (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide (AR-A000002). AR-A000002 functions as a 5-HT(1B) antagonist in vivo, which was shown by the antagonism of the discriminative stimulus effects in the guinea pig of the 5-HT(1B) agonist 3-(N-methylpyrrolidin-2R-ylmethyl)-5-(3-nitropyrid-2-ylamino)-lH-indole (CP135,807). Anxiolytic activity of AR-A000002 was demonstrated in the separation-induced vocalization paradigm in guinea pig pups, and in a suppressed responding procedure in pigeons and guinea pigs, but only a weak trend was noted in a suppressed responding procedure in squirrel monkeys. Antidepressant efficacy was shown in a number of paradigms. In pigeons and guinea pigs responding under a differential reinforcement of low rates schedule of reinforcement (DRL), AR-A000002 increased the number of reinforcers earned without altering the number of responses made. In guinea pigs trained under a response duration differentiation paradigm, AR-A000002 increased mean lever-press duration. Finally, AR-A000002 was shown to block escape failures in guinea pigs submitted to a learned helplessness paradigm. Taken together, these data suggest utility for 5-HT(1B) antagonists in the treatment of both anxiety and affective disorders.

Placental to fetal transfer of mercury and fetotoxicity.

Mercury vapor is known penetrate the placental barrier more easily than inorganic mercury. A relative amount of mercury accumulates in the fetus after exposure of pregnant animals to mercury vapor. Mercury concentration in fetal organs is much lower than that in maternal organs except the liver, and fetal liver shows significantly higher mercury concentrations than maternal liver. In fetal liver, a substantial portion of mercury is bound to metallothionein (MT), which plays an important role as a reservoir of mercury during the prenatal period. The mercury retained in fetal liver is redistributed to other organs, such as the brain and kidney, with diminishing MT levels during postnatal development. Consequently, an increase in mercury concentration in the brain and kidney of the neonate is observed. In studies on animal offspring in utero exposed to mercury vapor, behavioral changes, such as radial arm maze, morris maze and lever-press durations, are observed when the levels of mercury vapor exceed the threshold limit value (TLV).

Aging unmasks adverse effects of gestational exposure to methylmercury in rats

The consequences of developmental exposure to methylmercury on behavior in aged animals were investigated. Methylmercury exposure was arranged by placing 0, 0.5 or 6.4 ppm Hg in the drinking water of female rats at least 4 weeks before mating and continuing until post-natal (PN) day 16. Brain Hg concentrations in cohorts of low- and high-dose offspring were 0.5 and 9.1 ppm at birth and 0.04 and 0.52 ppm at weaning (described in another report). Lever pressing of female offspring was maintained under a Multiple Differential Reinforcement of High Rate 9:4 Extinction schedule of food reinforcement (Mult DRH 9:4 EXT). Under the DRH 9:4 schedule, a food reinforcer was delivered when nine responses occurred within 4 s. Under the Extinction schedule, responding had no programmed consequences. No exposure-related differences in reinforcement rate under the DRH schedule or discrimination between the DRH and extinction components were apparent initially. At 950 days of age, the overall response rates of controls had shown a gradual decline over the previous 500 days to about 80% of their beginning levels, but, otherwise, most controls were healthy. A gradual decline in the reinforcement rate began to appear in low- and high-dose rats at about 500 and 800 days of age, respectively. Microanalyses of the nine-response burst maintained by the DRH schedule revealed that the lever-press duration increased, the inter-response time (IRT) was unaffected, and the time between response bursts increased. Overall, the nine-response burst remained intact as a coherent response unit. The increased time between response bursts caused the decline in reinforcement rate. All rats displayed these effects as they aged, but the mercury-exposed rats did so sooner.

Quantifying the molecular structure of behavior

One difficulty in analyzing the molecular structure of behavior lies in reducing the data to a manageable size so that they can be described concisely but without a loss of important information. An approach to quantifying and comparing distributions of interresponse times (IRTs) and lever-press durations is described and then used to examine the acute effects of caffeine (an adenosine antagonist), cocaine, and three adenosine agonists in rats chronically consuming either tap water or water containing 1.0 mg/ml caffeine. The adenosine agonists used were R(-)N6-(2-phenylisopropyl)adenosine [R-PIA (preferential A1 receptor agonist)], 5'-(N-cyclopropyl)-carboxamidoadenosine [CPCA (preferential A2 agonist)], and 5'-N-ethylcarboxamidoadenosine [NECA (about equal agonist activity at A1 and A2 receptors)]. The rats' behavior was maintained under a Multiple Fixed-Interval (FI) 120 s, Duration > 5 s schedule of reinforcement. Under the FI schedule, the first lever-press after 120 s resulted in pellet delivery. Under the Duration > 5 s schedule, all lever-press durations greater than 5 s were reinforced. Molecular analyses of distributions of true IRTs (exclusive of lever-press durations) and lever-press durations were conducted by regressing percentiles of the distribution obtained from drug conditions against percentiles obtained from control conditions, a technique called empirical percentile-percentile analysis (or quantile-quantile analysis). The pattern of effects on response durations differed from that seen in IRTs. After acute administration of adenosine agonists, the distributions of lever-press durations under the FI schedule and subcriterion durations under the Duration > 5 s schedule were shifted rightward by a constant proportion, indicative of a generalized slowing of responding by these drugs. The effects of adenosine agonists on IRTs could be described by a power-function relationship whereby long IRTs were increased more than shorter ones. A rate-increasing dose of caffeine (10 mg/kg) did nothing to the molecular structure of lever-press durations or of IRTs, indicating that rate increases seen after this dose were due to an earlier onset of responding in the fixed-interval and were unaccompanied by disruptions in the physical execution of the response. The molecular structure of interresponse time distributions seen at the rate-decreasing dose of caffeine (60 mg/kg) resembled that of a rate-decreasing dose of cocaine, but not of the adenosine agonists. Both caffeine and cocaine produced a curvilinear relationship between drug and control percentiles such that very short IRTs were unaffected, but long ones were lengthened five- to 10-fold. This same dose of caffeine lengthened lever-press durations in a manner that resembled adenosine agonists but not cocaine. Percentile-percentile analyses reveal details about drug effects on the temporal structure of behavior and its physical execution that are not visible in molar analyses.

Behavioral characterization of caffeine and adenosine agonists during chronic caffeine exposure

Many of the behavioral actions of caffeine are mediated by its blockade of adenosine receptors, a notion that may have implications for tolerance and supersensitivity associated with chronic caffeine exposure. To examine possible interactions between chronic caffeine and adenosine-related actions of several drugs, the acute effects of caffeine and three adenosine agonists on behavior maintained by a Multiple Fixed-Interval (FI), Duration > 5 s schedule of reinforcement were studied using rats chronically consuming either 0 (tap water control), 0.5 mg/ml, or 1.0 mg/ml of caffeine in their drinking water. 5'-(N-cyclopropyl)-carboxamidoadenosine [CPCA (preferential A2 agonist)], 5'-N-ethylcarboxamidoadenosine [NECA (about equal agonist activity at A1 and A2 receptors)], and R(-)N6-(2-phenylisopropyl)adenosine [R-PIA (preferential A1 agonist)], as well as caffeine (nonspecific adenosine antagonist), were administered acutely i.p. after behavior stabilized. Dose-related decreases in overall response rate were produced by all adenosine agonists. Acute administration of all adenosine agonists and higher doses of caffeine increased average lever-press durations under the FI schedule from about 0.3 s to between 1 and 3 s, a three- to 10-fold increase. CPCA and NECA were 10 times more potent than R-PIA on all measures. Caffeine increased overall response rate under the FI schedule at doses of 3-30 mg/kg in nontolerant rats, and decreased rates at higher doses, which also increased lever-press durations. Insurmountable tolerance was seen to the rate-increasing effects of caffeine on behavior under the FI schedule, in rats exposed chronically to caffeine. Modest evidence of surmountable tolerance was seen in the rate-decreasing effects on the Duration > 5 s schedule. No tolerance to increases in lever-press durations or decreases in response rates was detected. Chronic exposure to caffeine did not alter the acute effects of the adenosine agonists: on all measures and with all adenosine agonists, the dose-effect curves for the three caffeine-exposure groups were indistinguishable from one another. The relative potencies suggest that the acute actions of adenosine agonists are related to A2 receptors. This is consistent with the failure to detect supersensitivity, since upregulation associated with chronic caffeine exposure appears primarily in A1 receptors.

Ethanol self-administration and motor deficits in adult C57BL/6J mice exposed prenatally to cocaine

Daily injections of 10 mg/kg cocaine on gestation days 12–18 did not alter maternal weight gain or offspring birth weight, viability, growth, or adult weight compared to saline controls. Adult male and female offspring were food deprived and trained to lever press for ethanol. Responding on an FR2 schedule and ethanol intake (g/kg) were recorded as measures of the reinforcing effects of ethanol. Lever press duration was used to assess motor performance. Results demonstrate that C57 mice will work for and consume large quantities of ethanol and that prenatal cocaine exposure increased the amounts ingested by both male and female mice. Prenatal-cocaine-exposed males also exhibited motor deficits as indicated by longer response duration times compared to controls. The consumption of large amounts of ethanol exacerbated the motor impairment in prenatal-cocaine males and revealed such deficits in cocaine females. The present results demonstrate that maternal cocaine exposure, at doses having no observable effect upon pregnancy, birth, or offspring growth, can increase the consumption of ethanol and enhance its motor impairing effects on fully mature offspring.

Behavioral Consequences ofin UteroExposure to Mercury Vapor: Alterations in Lever-Press Durations and Learning in Squirrel Monkeys

Exposure to mercury vaporin uteroresults in the accumulation of mercury in the cerebellum, hippocampus, and other regions of the nervous system associated with motor function and learning, but little is known about the functional consequences of prenatal exposure. The offspring of pregnant squirrel monkeys exposed to 0.5 or 1.0 mg/m3of mercury vapor during the last 23 or more of gestation were studied. Median maternal blood levels ranged from 0.025 to 0.18 μg/g and exposures were estimated to range from 20 to 62 μg/day, with cumulative doses of 1304 to 4305 μg. Unexposed monkeys born at about the same time served as controls. The monkeys’ lever pressing was maintained under various Concurrent Random-Interval Random-Interval schedules of reinforcement. Time allocation on each lever was examined during behavioral transitions and in steady state. No difference in sensitivity to reinforcer ratios was identified in steady state, but there was much more variability in the steady-state performance of exposed monkeys, as indicated by the standard deviation of the regression, than in controls. Logistic regression was used to examine the transition to new schedule parameters. Exposed monkeys were found to produce smaller or slower transitions than controls. The magnitude and stability of lever-press durations for controls and exposed monkeys were indistinguishable early in the experiment, but at the end the exposed monkeys had longer lever-press durations and the session-to-session variability was much greater. One monkey's exposure began during the third week of gestation (earlier than any of the others) and the behavior of this monkey was so erratic that some of the analyses could not be accomplished. Long-term effects of prenatal mercury vapor exposure included instability in lever-press durations and steady-state performance under concurrent schedules of reinforcement as well as aberrant transitions. The levels used were close to those reported in occupational settings under conditions of poor hygiene, but were at least 10- to 50-fold greater than those more commonly reported.

Differential Reinforcement of Response Duration (DRRD) in weanling rats: A comparison with adult subjects

Weanling (21-day) and adult (3-month-old) albino rats were reinforced for lever press durations of 0.5, 1.0, 1.5, 2.0 and 2.5 seconds. Six sessions were performed at DRRD 0.5 seconds, 12 at the other values, at a pace of 3 (at DRRD 0.5 seconds) or 6 sessions a day. Adult rats emit lower response rates, higher median response durations and earn more reinforcements than weanling subjects. The effect of age on the coefficient of variation of the response duration distribution is not significant, but this measure is, on average, higher for the weanling rats. Age-related differences are discussed in relationship to general activity, food motivation, schedule control and timing mechanisms. Methodological variables and the relationship of these results to the laws of temporal differentiation are also evaluated.

Response Feedback and Response Duration Differentiation in the Albino Rat

Twelve male albino rats were reinforced for lever press durations of 0.5, 1.0, 1.5, 2.0 and 2.5 seconds. Half of the subjects (F) received an auditory feedback after non-reinforced responses. The 6 other (Controls, C) worked without feedback. F rats emitted on the average higher mean response durations and earned more reinforcements than C subjects. The standard deviation and coefficient of variation of their response duration distributions were significantly lower than those of group C. These results tend to show that feedback stimulus following non-reinforced responses improve the accuracy of performance in the response duration differentiation schedule.

Chronic postweaning lead exposure and response duration performance

Twenty-one-day-old male weanling rats were started on a chronic exposure regimen of 0, 100, or 300 ppm lead acetate in distilled water. They were trained to press a lever for food reward at 55 days of age. Subsequently, a schedule of differential reinforcement of minimum response duration was imposed, in which only lever press durations greater than or equal to a required duration were followed by food presentation. Under these conditions, response durations of control animals approximated schedule requirements; lead treatment shortened response durations. Treated rats also paused for longer periods before initiating responses. Differences between the treated groups were not apparent. Individual differences were observed in susceptibility to lead-induced behavioral changes. Some treated animals tended to show greater session-to-session variability than did controls. Even when a tone was added to signal that the required duration had elapsed, certain treated rats failed to show modal response duration values consistent with the schedule requirement. Failure to improve performance of lead-treated rats by external stimulus control has not previously been reported.

Importance of cue location for intact and fimbria-fornix-lesioned rats

Hooded rats were trained in a straight alley to repeatedly press a lever placed at one end of the alley until a discriminative auditory signal (SD) appeared and then to run for a water reward (Rd) available at the other end. During training SD was spatially contiguous with Rd; then SD was placed above the bar (spatially discontiguous with Rd). In normal animals SD-Rd discontiguity caused abrupt and significant increases in lever press duration, latency to leave the lever area, and lever press perseveration (conflict). Conflict was not seen in postoperatively trained fimbria-fornix-damaged rats. However, if lesions were made after training but prior to testing under the SD-Rd discontiguity condition, conflict occurred also in the lesioned subjects. Our results indicate that normal rats learn and maintain responding to informative cues throughout conditioning, and this persisting cue-directed response (sign tracking) is absent in fimbria-fornix-lesioned rats. It is suggested that the impaired performance of fimbria-fornix-lesioned rats lies in their ability to create a new goal independent of the primary reinforcer.