Rate-dependent effects of d- and l-amphetamine on schedule-controlled responding in pigeons and squirrel monkeys

The effects of d- and l-amphetamine were studied on key-pressing responses of squirrel monkeys maintained under fixed-interval schedules of electric shock presentation, and on key-pecking responses of pigeons maintained under multiple fixed-ratio, fixed-interval schedules of food presentation. Under the fixed-interval schedules, responding followed a pause and occurred at increasing rates as the interval elapsed. Both isomers produced comparable increases in rates of responding under relatively long fixed-interval schedules with small to intermediate doses; maximal effects of the d-isomer were obtained at doses one-half log unit smaller than the doses of the l-isomer. Responding of pigeons maintained under relatively short fixed-interval schedules was only decreased by either amphetamine isomer. Responding of pigeons maintained under fixed-ratio schedules occurred at the highest rates and was also only decreased by either amphetamine isomer. Decreases in response rate produced by the d-isomer were generally obtained at doses one-half log unit smaller than doses of the l-isomer that produced comparable effects. Both isomers increased responding that occurred at low rates early in the fixed-interval to a proportionally greater extent than higher rates from later in the interval. The highest rates in the fixed-interval were generally decreased. Differences in potency between the two isomers in producing rate-dependent effects were small, most noticable with larger doses, and less than the potency differences between the two isomers in producing changes in response rate.     

Comparison of fixed-ratio and progressive-ratio schedules of maintenance of stimulant drug-reinforced responding

The effectiveness of doses of i.v. cocaine and nomifensine in maintaining lever-press responding in rhesus monkeys was evaluated under two schedules, fixed- and progressive-ratio (FR, PR). The doses that maintained maximum rates of responding under the fixed-ratio schedule were 0.32 mg/kg per injection cocaine and 0.10 mg/kg per injection nomifensine. The fixed-ratio rates maintained by this dose of nomifensine were slightly lower than those maintained by cocaine. Under the progressive-ratio schedule, the maximum response rates developed with 0.32 mg/kg per injection cocaine and 0.32 mg/kg per injection nomifensine. Maximum performances under the progressive ratio were slightly higher with cocaine than with nomifensine. Taken in conjunction with existing data for other drugs and conditions, these data indicate that progressive-ratio schedules may yield information on the relative reinforcing effects of drugs that differs only slightly from that obtained with fixed-ratio schedules.     

Opioid-induced response-rate decrements in pigeons responding under variable-interval schedules: reinforcement mechanisms

Opioid drugs may produce some of their behavioral effects by altering the effectiveness of reinforcing events. The present investigation examined effects of two opioids (methadone and buprenorphine) on pigeons' key-pecking. Different reinforcement rates were arranged using five variable-interval (VI) food-presentation schedules, permitting an application of Heyman's Matching Law analysis and Nevin's Resistance to Change Hypothesis to behavioral actions of opioid drugs. Key-pecking by four pigeons was reinforced by 3-s access to mixed grain under a five component multiple VI schedule. VI values used were 5, 10, 30, 75 and 150s. Each component was in effect for 5min followed by 1min of darkness. Peck rates were high under the VI5-s and VI10-s schedules. As the mean interval value increased, peck rates decreased. Methadone (0.5, 1.5, 2.5, 3.75, and 5.0mg/kg) and buprenorphine (0.25, 0.5, 1.0, 3.0, and 5.0mg/kg), administered 30min prior to experimental sessions, dose dependently decreased peck rates in all subjects. Peck rates under longer VI schedules (75 and 150s) tended to be more greatly disrupted than those maintained under shorter VI schedules (e.g. 10s). Dose-by-dose analysis of key-pecking rate changes under each schedule, and analysis of drug-induced changes in Matching Law parameters suggest that peck rate decreases resulted, in part, from decrements in the reinforcer's ability to maintain behavior.     

Effects of cocaine and morphine under mixed-ratio schedules of food delivery: support for a behavioral momentum analysis

Previous studies have shown that ratio size influenced the development of tolerance under simple and multiple schedules, but not under progressive-ratio (PR) schedules. PR schedules share certain features with mixed-ratio (MR) schedules, and pilot data suggested that ratio size fails to modulate tolerance to cocaine or morphine under MR schedules. The present study examined more comprehensively the pre- and postchronic effects of cocaine and (in separate birds) morphine under MR schedules with fixed-ratio (FR) 5 and FR 95, FR 25 and FR 75, and FR 50 and FR 50 components. Acute doses of cocaine and morphine initially were given in an ascending series (beginning with 0.56 mg/kg) until responding was reduced to near-zero levels. Chronic (daily) dosing with a dose that reduced, but did not eliminate, responding then occurred until response rates stabilized. Finally, postchronic dose-response determinations were conducted. Both cocaine and morphine reduced response rates at all FR values. Tolerance was consistently observed to the effects of morphine, but not to those of cocaine. With both drugs the degree of tolerance observed did not vary as a function of FR value. These findings, like those obtained under PR schedules, indicate that ratio size does not always modulate drug tolerance. A behavioral momentum analysis of drug action appears to account for whether or not ratio size modulates tolerance, and such an analysis is provided.     

COMPARISON OF THE EFFECTS OF d-AMPHETAMINE ON FI AND DRL SCHEDULE PERFORMANCE OF SELF-STIMULATING RATS

1. Six rats bar-pressed for intracranial self-stimulation in a Skinner box on fixed interval and differential reinforcement of low rate schedules with an interval parameter of 1.3 s. 2. After amphetamine timing efficiency was reduced immediately on both the schedules; it recovered after 60 min on the DRL schedule but not within 120 min on the FI schedule. Response rates increased on both the schedules. 3. The increased response rates correlated with the low efficiency on the DRL but not on the FI schedule. 4. The selective sparing of DRL performance is in line with the similarity between the effects of amphetamine and frontal cortical lesions.     

Psychopharmacological action of nicotinamide adenine dinucleotide

Summary The effect of nicotinamide adenine dinucleotide (NAD) upon the response rates in variable interval and Sidman Avoidance schedules was studied in rats. Bar pressing on the variable interval reinforcement schedule was significantly reduced during the 15 min following the administration of 10 mg/kg i.p. and during the 60 min following the administration of 30 mg/kg NAD. Response rates on the Sidman Avoidance schedule were significantly reduced during the 60 min following the administration of 100 mg/kg NAD.     

Rate-dependency hypothesis and the rate-decreasing effects of d-amphetamine on schedule-induced drinking

The high levels of drinking induced by intermittent food-reinforcement schedules are dose-dependently reduced by acute doses of d-amphetamine. The present study evaluated whether the effects of d-amphetamine on this schedule-induced drinking reflect the reduction of high rates of responding. Twenty-four rats were divided into six groups (n = 4) according to the interval and time durations of a multiple fixed-time (FT) fixed-interval (FI) schedule (15s, 30s, 60s, 120s, 240s and 480s). FT components were signalled by a tone and by lever withdrawal. Doses of 0.25 to 4.0mg/kg of d-amphetamine were administered i.p. 10min before test sessions. d-amphetamine produced similar dose-dependent reductions in rate of licking induced by FT and FI schedules. Rate-decreasing effects on operant lever pressing were also found after administrations of d-amphetamine. The dose-dependent decrements produced by d-amphetamine were a function of the inter-food interval length in both schedule-induced and operant behaviours. These rate-decreasing effects were rate-dependent, but d-amphetamine interacted differentially with control rates of adjunctive and operant behaviours, causing a greater suppression of the lower rates of adjunctive licking and the higher rates of operant lever pressing.     

Effects of clozapine,haloperidol and thiothixene on schedule-controlled responding and schedule-induced eating and drinking of rabbits

Lever-lift responding by Dutch Belted rabbits was maintained either by the presentation of 0.25% saccharin solution or food pellets under a multiple fixed-interval 3-minute (FI), 30-response fixed-ratio (FR) schedule. Rabbits responding under the schedule of saccharin presentation were water deprived and had food available continuously. During experimental sessions these rabbits ate during the initial portion of many intervals. With rabbits responding under the food-presentation schedule, water was available continuously; these rabbits drank during the initial portion of the interval. Clozapine (0.1–1.0 mg/kg), haloperidol (0.003–0.03 mg/kg) and thiothixine (0.003–0.03 mg/kg) all increased responding under the FI schedules to a maximum of approximately 200 percent of control and generally did not affect or decreased responding under the FR schedules. These effects occurred under schedules where either food or saccharin maintained responding. Higher doses (1–3 mg/kg clozapine and 0.1 mg/kg haloperidol or thiothixine) decreased responding under all schedules. Doses of these drugs that increased responding also increased the amount of eating and drinking that occurred during the experimental session. Although clozapine, a novel antipsychotic compound, typically affects operant performances differently than other antipsychotic drugs, its effects on conditioned rabbit behavior appear similar to those of other antipsychotics. Further, although antipsychotic drugs generally decrease performances in several mammalian species, effects of these agents in the rabbit are similar to those found with humans and chimpanzees. The similarity of antipsychotic drug effects in the rabbit to those found in the human and chimpanzee, together with the comparable effects obtained even with “atypical” compounds, plus the development of schedule-induced eating and drinking suggest that the rabbit may be a very useful addition to research in behavioral pharmacology.     

Rate-dependent effects of amphetamine on responding under random-interval schedules of reinforcement in the rat

The parameters of 12 random-interval schedules (cycle length and interreinforcement interval) were varied systematically in order to examine the ability of these schedules to separate the usual relationship between response rate and reinforcement frequency using rats. Response rates varied over a two-fold range for the same frequency of reinforcement under random-interval 30-sec schedules. However, cycle length did not alter response rates significantly at other interreinforcement intervals. Subsequently, the effects of amphetamine on random-interval responding were examined in order to evaluate the roles of control rates of responding and reinforcement in amphetamine's actions. Amphetamine's effects were significantly correlated with both control response rate and control rate of reinforcement. However, by comparison, control response rate was the better predictor of amphetamine behavioral effects. The results support the rate dependency hypothesis that control rate of responding is closely associated with amphetamine's effects on operant behavior.     

Relative reinforcing effects of different benzodiazepine doses for rhesus monkeys

The relative reinforcing effects of different doses of benzodiazepines were determined by giving rhesus monkeys concurrent access to different diazepam and midazolam concentrations. For each monkey a dose response function was obtained using three drug concentrations: low (L), intermediate (I), and high (H). The benzodiazepine and the water vehicle were concurrently available under independent fixed-ratio (FR) schedules. After establishing that each concentration was a reinforcer in comparison to vehicle, relative preference for the different concentrations was examined by making pairs of concentrations concurrently available under independent FR schedules. Three pairs were studied (H vs. L, H vs. I, and I vs. L). With both drugs, higher concentrations maintained greater response rates than lower concentrations. Thus, relative reinforcing effects increased with dose. These findings are similar to those obtained with other reinforcing drugs and provide further evidence that benzodiazepines share significant characteristics with other drug reinforcers. Importantly, absolute response rates (responses per session) obtained when only one drug dose was present were not reliably predictive of subsequent preferences for the dose. Both benzodiazepines served as effective reinforcers in that consistent levels of responding were maintained across doses and above vehicle levels under concurrent FR 32 schedules. As with other reinforcing drugs, the reinforcing effects of benzodiazepines increase with increases in dose over a broad range of values.     

Effect of amphetamine on nondiscriminated key-pecking avoidance in pigeons

Dose-effect curves for amphetamine on keypecking behavior of pigeons maintained by two-component multiple schedules of shock postponement were determined. During the first experimental phase, the response-shock interval (RS) was held constant and the shock-shock interval (SS) varied. Under these conditions, shock rate was greater during the component with the shorter SS. However, response rates were comparable in both components. Also, the magnitude of the response rate increments caused by appropriate doses of amphetamine during both schedule components were similar. During the second experimental phase, the SS was held constant and the RS varied. As a consequence, baseline response rate was considerably lower in the component with the longer RS than in the short RS component. Shock presentations were also less frequent during the former than during the latter component, but the differences in shock rate between the components were comparable or smaller than those observed during the first experimental phase. Under these conditions, the effects of amphetamine in the two schedule components were markedly different, lower response rates being considerably more increased than higher rates.     

Oral self-administration of pentobarbital by rhesus monkeys: relative reinforcing effects under concurrent signalled differential-reinforcement-of-low-rates schedules

During daily 3-h sessions two separate pentobarbital solutions were concurrently available to rhesus monkeys under signalled differential-reinforcement-of-low-rates (signalled DRL) schedules of mouth contacts with spouts. The schedules were synchronized so that each time the 30-s DRL interval expired, lights above both spouts were illuminated and a liquid delivery could be obtained either from the left or right spout, but not both. First water and then each of four ‘comparison-concentration’ pentobarbital solutions (0.0625, 0.25, 1 and 4 mg/ml) were successively available under one schedule for a block of sessions. Concurrently, deliveries of a ‘standard concentration’ solution were available from the second spout under an identical DRL schedule; the concentration of this standard solution remained constant throughout the testing of the series of comparison solutions. Three pentobarbital concentrations (4, 1 and 0.25 mg/ml) in turn served as the standard concentration. Relative reinforcing effects were directly related to pentobarbital concentration: in general, within pairs of concurrently available pentobarbital solutions more behavior was maintained by the higher of the two drug concentrations. These findings are discussed in the context of previous studies using ratio and interval schedules which have found relative reinforcing effects to be directly related to reinforcer magnitude.     

Effects of the cannabinoid CB(1) receptor antagonist, SR141716A, after Delta(9)-tetrahydrocannabinol withdrawal

Rats were trained to lever press according to variable interval 10 s schedules during daily experimental sessions composed of six 3 min food reinforcement periods and were treated twice daily for 6 days with either vehicle or escalating regimens of Delta(9)-tetrahydrocannabinol. On days 7 and 8, the rats were challenged with vehicle and cumulative doses of SR141716A (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4, -dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxyamide hydrochloride), a cannabinoid CB(1) receptor antagonist, up to 3 and 9 mg/kg, respectively. Response rates increased during Delta(9)-tetrahydrocannabinol withdrawal and towards those of the vehicle treatment group suggesting a waning of the direct effects of Delta(9)-tetrahydrocannabinol. SR141716A reduced response rates but only in rats pre-treated with Delta(9)-tetrahydrocannabinol. These data suggest that dependence upon Delta(9)-tetrahydrocannabinol was induced and SR141716A precipitated withdrawal.     

Oral self-administration of N-allylnormetazocine (SKF-10,047) stereoisomers in rhesus monkeys: substitution during phencyclidine self-administration and withdrawal

Orally-delivered N-allylnormetazocine (NANM) and its isomers were tested for their ability to function as reinforcers by substituting them for phencyclidine (PCP). Two monkeys were trained to self-administer PCP (0.25 mg/ml) and water under concurrent fixed-ratio (FR) 16 schedules during 3-hr sessions. Liquid deliveries were contingent upon lip-contact responses on solenoid-operated drinking devices. When the dextro (+)-isomer of NANM (0.062-1 mg/ml) was substituted for PCP, response rates increased and then decreased in an inverted U-shaped concentration-response function with peak response rates comparable to those maintained by PCP. Drug intake ranged from 2.8 to 25.7 mg/kg across the two monkeys and five concentrations. Water-maintained responding was considerably lower than drug-maintained behavior indicating that NANM was functioning as a reinforcer. As previously reported for PCP, almost all of the (+)-NANM was self-administered during the first half of the session. Substitution of the levo (-)-isomer of NANM resulted in an immediate decline to low response rates that were not distinguishable from those maintained by water. The racemic form (+/-) of NANM was also not self-administered in excess of concurrent water. In the second experiment concurrent PCP- and water-maintained responding were reestablished under FR 8 schedules during three 6.5-hr sessions daily. Food (6 g/pellet) was available under FR 64 and FR 80 schedules during three 1-hr sessions immediately preceding the liquid components. Water was then substituted for PCP for four days and PCP, (+)-, (-)- or (+/-)-NANM were reinstated in subsequent replications of the experiment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Discriminative stimulus effects of nicotine in rats trained under different schedules of reinforcement

There have been few comparisons between different schedules of reinforcement for establishing drugs as discriminative stimuli. Fixed-ratio (FR) 10 and tandem variable-interval 1-min FR-10 schedules have been compared directly in a conventional, nicotine-saline discrimination paradigm with food reinforcement in rats. The discrimination was acquired rapidly under both schedules, with stimulus control by nicotine (0.1 mg/kg SC) being very slightly superior under the FR schedule. In 5-min extinction tests with nicotine, rats maintained under the FR schedule yielded a clear dose-response curve with a bar-selection (quantal) index; in these rats, discrimination of nicotine appeared generally poor, and dose-response curves were shallow, when the percentage of drug-appropriate responding (quantitative index) was calculated. In contrast, rats under the tandem schedule yielded clear dose-response data with both indices. In tests with (+)-amphetamine full generalization was obtained with both schedules, and with both quantitative and quantal indices. Tests of generalization to morphine were negative regardless of the training schedule or index employed. In rats under the FR-10 schedule, overall response rates declined both within and across extinction tests; the relatively high rates of responding maintained by the tandem schedule were more sensitive to the response rate-decreasing effects of morphine and amphetamine. The results confirm that orderly data may be obtained with either a FR or a tandem schedule provided that an appropriate index of discriminative response is employed. The results generally support the validity of current practices, and there will probably be no marked differences between conclusions depending on which schedule is used.     

Nucleus accumbens dopamine depletions and time-constrained progressive ratio performance: effects of different ratio requirements.

Two experiments were conducted to determine the effects of accumbens dopamine (DA) depletions on progressive ratio responding for food reinforcement. In one version of this schedule, ratio requirement increased by one response after each reinforcer was obtained (PROG1). In the other version, ratio requirement increased by five responses after each reinforcer was obtained (PROG5). For both versions, 60-min sessions were conducted. Accumbens DA depletions produced by local injections of 6-OHDA substantially decreased the number of responses on both schedules. The deficits in the response number induced by DA depletions persisted through the two weeks of postsurgical testing for both the PROG1 and PROG5 schedules. However, there were differences between the effects of DA depletions on the two schedules in terms of the time to complete the last ratio. Although time to complete the last ratio was significantly reduced by DA depletions only in the first week of testing on the PROG1 schedule, rats recovered on this measure by the second week after surgery. In contrast, DA-depleted rats on the PROG5 schedule showed a more persistent suppression of the time to complete the last ratio, which lasted through both weeks of postsurgical testing. Performance on schedules that generate low baseline rates of responding (e.g., continuous, fixed, and variable interval) is relatively unaffected by accumbens DA depletions; nevertheless, accumbens DA depletions substantially impair progressive ratio response output. The high work output necessary for responding on the PROG5 schedule may make these animals more sensitive to the effects of accumbens DA depletions.     

Reinforcement schedule effects in rats trained to discriminate 3,4-methylenedioxymethamphetamine (MDMA) or cocaine

Rationale Relatively few studies have compared the discriminative stimulus effects of 3,4-methylenedioxymethamphetamine (MDMA) and cocaine, and findings from different laboratories are somewhat inconsistent. One possible reason for discrepant results may be the use of different reinforcement schedules during discrimination training.Objective The present study compared fixed ratio (FR) 20 and variable interval (VI) 15-s reinforcement schedules to determine their influence on discrimination acquisition, response rates, frequency of reinforcements, and stimulus generalization in rats trained to discriminate cocaine or MDMA.Materials and methods Thirty-two male Sprague–Dawley rats were trained to discriminate cocaine (10 mg/kg; n=16) or MDMA (1.5 mg/kg; n=16) from saline under either a FR 20 or a VI 15-s schedule of food reinforcement. Stimulus generalization tests were conducted with a range of doses of cocaine, MDMA, d-amphetamine, and lysergic acid diethylamide in all four training groups.Results The FR 20 schedule facilitated more rapid discrimination acquisition compared to the VI 15-s schedule and established differential response rates and frequency of reinforcement under drug and vehicle conditions. However, reinforcement schedule had little influence on stimulus generalization between MDMA and cocaine. Cocaine produced partial substitution for MDMA in both training groups (FR 20, 51%; VI 15-s, 58%). Likewise, MDMA produced only partial substitution for cocaine in both training groups (FR 20, 40%; VI 15-s, 72%).Conclusions The present findings suggest that the number of sessions required to establish discriminative stimulus control varies with different reinforcement schedules. Nevertheless, training schedules alone do not appear to have significant effects on stimulus generalization between MDMA and cocaine.     

Effects of minimum-interreinforcer interval on ethanol-maintained performance of rats

Dipper cups filled with an 8% (w/v) ethanol solution were presented to Long-Evans hooded rats according to either a multiple Extinction chi sec Fixed-Ratio 1 or a chain Differential-Reinforcement-of-Other-Behavior chi sec Fixed-Ratio 1 schedule or reinforcement. The scheduled value of the extinction and differential-reinforcement-of-other-behavior components was varied to manipulate minimum-interreinforcer interval. Minimum-interreinforcer intervals from 0 sec (baseline condition of continuous reinforcement) to 480 sec were tested in an ascending series followed by a descending, retest series. Increasing the minimum-interreinforcer interval reduced the number of ethanol presentations obtained under both reinforcement schedules. These reductions were not due to ceiling effects imposed by the maximum number of possible deliveries obtainable within a session. The number of ethanol presentations obtained was always less than the maximum number of possible deliveries obtainable within a session. The number of ethanol presentations obtained was always less than the maximum number permitted by the value of the minimum-interreinforcer interval. Thus, imposing minimum-interreinforcer intervals between drinking opportunities reduces the level of ethanol self-administration relative to continuous-access baseline conditions.     

Increasing the work requirements lowers the threshold of naloxone for reducing self-stimulation in the midbrain of rats

Rats were trained to lever-press for intracranial self-stimulation (ICSS) with electrodes in the midbrain central gray area. The effects of naloxone (0.1-30.0 mg/kg, SC) on a continuous reinforcement (CRF) schedule were determined. Rats were then re-trained on higher fixed-ratio (FR) schedules, and naloxone was re-tested at FR: 5, 10, 15 and 20. Only moderate reductions in lever-pressing rates were obtained at the highest dose of naloxone under CRF and FR: 5 schedules. In contrast, pronounced, dose-dependent reductions in ICSS rates occurred at FR: 10, 15 and 20. The time-course for this reduction at FR: 20 was consistent with an opiate-antagonistic action of naloxone. The modest decrease in locomotor activity produced by naloxone in a matched group of control rats was not sufficient to account for the effects on ICSS. The threshold of naloxone for reducing the rate of ICSS lever-pressing was lowered by increasing the effort and/or time requirement for each reinforcement.     

Effects of drugs on behavior before and during chronic diazepam administration.

The effects of diazepam, pentobarbital, and phencyclidine (PCP) were studied on punished and unpunished responding maintained by fixed-interval schedules before and during chronic administration of diazepam. Before chronic diazepam administration, increasing doses of diazepam and PCP increased and then decreased rates of both punished and unpunished responding. Increases in punished responding were larger than increases in unpunished responding. Pentobarbital only increased punished responding, while higher doses decreased both rates of punished and unpunished responding. During chronic diazepam administration, rates of punished and unpunished responding showed further increases with all three drugs and the dose-effect curves also shifted to the right. Analysis of local rates of responding within fixed-interval components suggested that increases in low rates early in the interval were responsible for the rate increases produced by these drugs before chronic diazepam administration. During chronic diazepam administration low rates early in the interval showed greater increases after all three drugs and their ability to produce rate-increasing effects extended further into the interval. The similar effects of these drugs before and during chronic diazepam administration suggests a similar mechanism despite the widely recognized differences in their interaction with receptors. This common mechanism may relate to rate-increasing effects more than to specific effects on punished responding.