Schedule-controlled Responding Research Articles

Effects of d-amphetamine, WIN 35,428, pentobarbital and morphine on schedule-controlled responding in two inbred rat strains that differ in locomotor stimulatory effects of cocaine

Behavioral effects of d-amphetamine, the cocaine analog, WIN 35,428, morphine, and pentobarbital were compared in NBR/NIH and F344CR1BR rats. Either nose-poke or lever-press responding was maintained under 3-min fixed-interval schedules of food presentation. The effects of morphine, WIN 35,428 and pentobarbital depended upon the rat strain studied: morphine increased nose-poke responding in NBR but not F344 rats; significant strain x dose interactions were observed with WIN 35,428; and pentobarbital was more potent in decreasing nose-poke responding in NBR than in F344 rats. No strain differences were observed in the behavioral effects of d-amphetamine. There were also prominent differences in the effects of drugs that were related to the nature of the response requirement. In both rat strains, nose-poke responding was affected differently than lever-press responding by morphine, d-amphetamine, and WIN 35,428. Pentobarbital produced effects that were independent of the specified response topography. A global underlying difference in these rat strains cannot be identified at present to account for the diversity of findings. The behavioral effects of these drugs appear to be influenced by a host of interactive factors including the drug, strain of animal, the baseline response rate and physical dimensions of the response.

Opioid sensitivity as measured by operant schedule-controlled responding: Gregory I. Elmer, ∗ J. O Pieper, ∗ Steven R. Goldberg ∗ and Frank R. George. † ∗National Institute on Drug Abuse Addiction Research Center, Baltimore, MD and †University of New Mexico Albuquerque, NM

Opioid sensitivity as measured by operant schedule-controlled responding: Gregory I. Elmer, ∗ J. O Pieper, ∗ Steven R. Goldberg ∗ and Frank R. George. † ∗National Institute on Drug Abuse Addiction Research Center, Baltimore, MD and †University of New Mexico Albuquerque, NM

Effects of triadimefon on a multiple schedule of fixed-interval performance: Comparison with methylphenidate, d-amphetamine and chlorpromazine

Triadimefon is a fungicide that has recently been shown to increase motor activity and rates of schedule-controlled responding. These findings indicate that triadimefon resembles psychomotor stimulants and in this respect is a unique pesticide. The present experiment was designed to evaluate triadimefon's effects on performance maintained by a multiple schedule of reinforcement and to compare triadimefon to known psychomotor stimulants. Four rats were trained to perform under a mult FI 1-min FI 5-min schedule of milk reinforcement. They then received a series of dosages of triadimefon (10-170 mg/kg, IP) and of methylphenidate (1-17.3 mg/kg, IP) in a counterbalanced order. Triadimefon increased response rates in both the FI 1-min and FI 5-min components. Methylphenidate did not consistently alter response rates in either component. Temporal patterns of responding were disrupted much more in the FI 5-min component than in the FI 1-min component by both triadimefon and methylphenidate. Performances were then evaluated following a series of dosages of d-amphetamine (0.3-3.0 mg/kg, IP) and chlorpromazine (0.5-2.0 mg/kg, IP). Response rates were increased by d-amphetamine in the FI 1-min component but not in the FI 5-min component. Like triadimefon and methylphenidate, d-amphetamine produced a greater disruption of response patterning in FI 5-min than in FI 1-min. Only chlorpromazine decreased response rates in both components. Chlorpromazine also disrupted FI 5-min response patterning, but left FI 1-min patterning intact.(ABSTRACT TRUNCATED AT 250 WORDS)

The pigeon as a model for comparative behavioral pharmacology and toxicology

The effects of several drugs and neurotoxins on schedule-controlled responding are reviewed in a number of species. In general, the behavioral effects of these chemicals in different species differ quantitatively more frequently than qualitatively. The sensitivity of schedule-controlled behavior to chemical effects across species does not show any obvious relationship to position on the phylogenetic tree. Pigeons are more sensitive, less sensitive, or equally sensitive to chemicals than other species, depending on the chemical. Because pigeons are inexpensive, have a long life span and are easy to train and handle, they should receive serious consideration as a species of choice for behavioral testing of potential neurobehavioral toxins.

Operant behavior as a technique for toxicity testing

Behavioral toxicology is a discipline which has evolved out of the need for data on the effects of toxic agents on the function of the central nervous system. To date the field is divided over the question of which behavioral models to use to detect behavioral toxicities. Operant conditioning and schedule-controlled responding have been used as baselines for testing pharmacological agents for nearly 40 years, and there is no reason that the developing field of behavioral toxicology cannot take advantage of the lessons learned during this 40-year period. Behaviors maintained by operant conditioning procedures have proven to be sensitive to a wide range of chemicals. Using these procedures, behavior has been shown to; be sensitive to toxic agents, provide data relevant to the question of behavioral specificity, provide a stable baseline for extended periods of time, and allow for the assessment of specific functions such as temporal discrimination, learning and memory, and sensory system function.

Interactions of corticotropin-releasing factor with antidepressant and anxiolytic drugs: Behavioral studies with pigeons

A number of studies have shown significant interactions between neuronal systems involved with corticotropin-releasing factor (CRF) and either the clinical manifestation of depression and anxiety of the effects of antidepressant or anxiolytic drugs. In the present study, effects of CRF were studied alone and in combination with imipramine and with the sedative-hypnotic/anxiolytic drugs pentobarbital and chlordiazepoxide. Interactions of CRF with the novel, atypical anxiolytic buspirone were also examined. Interactions were evaluated through the use of schedule-controlled responding, responding suppressed by punishment, and drug discrimination procedures using the conditioned key-pecking response of pigeons. Effects of CRF were significantly enhanced when given in combination with imipramine with low noneffective imipramine doses potentiating the rate-reducing effects of CRF. Similarly, in pigeons trained to discriminate imipramine from saline, noneffective doses of CRF shifted the imipramine dose-response curve more than twofold to the left. Low doses of imipramine that produced saline key responding, produced imipramine-key responding when coadministered with CRF. The CRF antagonist α-helical CRF 9–41 did not alter the rate-decreasing effects of imipramine. Effects of CRF on schedule-controlled responding were, however, antagonized by the administration of chlordiazepoxide and pentobarbital but not by buspirone, suggesting that CRF interacts with the GABA/benzodiazepine receptor mechanism complex but not with those systems involved in mediating the effects of buspirone. These results suggest that CRF interacts in significant ways with specific neurotransmitter systems subserving depression and anxiety.

Interactions of clonidine and naloxone on schedule-controlled behavior in opioid-naive mice

Schedule-controlled responding was maintained under a fixed-ratio schedule in mice. Administered alone, clonidine, morphine and naloxone produced dose-related decreases in rates of responding, with clonidine about 100 times more potent than morphine which was about ten times more potent than naloxone. Decreases in response rates produced by high doses of naloxone were antagonized by clonidine (0.003-0.1 mg/kg) in a dose-dependent manner; however, decreases in response rates produced by clonidine (0.3 mg/kg) were not antagonized by naloxone (1.0-100 mg/kg). Effects of high doses of naloxone (100 mg/kg) were not antagonized by morphine (1.0-100 mg/kg) whereas effects of morphine (17.0 mg/kg) were antagonized by naloxone (0.01-1.0 mg/kg). Thus, clonidine can reverse behavior-disrupting effects of naloxone in non-dependent subjects, indicating that at least some of the interactions of these two drugs are not specific to the opioid-dependent state.

Effects of Ro 15-4513 on schedule-controlled responding of pigeons

The partial inverse benzodiazepine agonist Ro 15-4513 has been found to antagonize some of the behavioral and physiological effects of ethanol, but relatively little is known about the behavioral effects of the drug alone. In the present study, pigeons responding under a multiple fixed-ratio 25 interresponse-time-greater-than-6-sec schedule of food delivery were exposed acutely and chronically to Ro 15-4513. Acute administrations of the drug (1.0, 1.8, 3.2, and 5.4 mg/kg) reduced response rates under the fixed-ratio component at some doses, although two birds were more sensitive to the drug than the third subject. Response rates under the interresponse-time-greater-than-6-sec component were not affected by acute administrations of Ro 15-4513. When 5.4 mg/kg Ro 15-4513 was administered prior to 15 consecutive sessions, tolerance developed to the rate-reducing effects of the drug under the fixed-ratio component. These findings, in contrast to those of early investigations in which gross measures of behavior were employed, suggest that Ro 15-4513 is behaviorally active at relatively low doses.

Behavioral and neurochemical effects of the serotonin (5-HT)1A receptor ligand spiroxatrine

The effects of spiroxatrine, a putative antagonist with selectivity for the serotonin (5-HT)1A receptor, were compared with compounds believed to function as agonists at the 5-HT1A receptor. Schedule-controlled responding of pigeons was maintained under a multiple 30-response fixed-ratio (FR), 3-min fixed-interval (FI) schedule or under a schedule in which responding was suppressed by electric shock ("conflict" procedure). Under the multiple schedule, spiroxatrine (0.3-1.0 mg/kg) decreased FR responding but did not affect FI responding; responding was decreased in both schedule components at 3.0 mg/kg. When administered alone, buspirone, a compound believed to produce its anxiolytic effects through 5-HT1A agonist actions, produced effects similar to those of spiroxatrine; in combination, the two drugs produced greater effects than when either was administered alone. As with 5-HT1A agonists such as buspirone and 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) in the pigeon, spiroxatrine (0.01-1.0 mg/kg) increased punished responding. Spiroxatrine and buspirone were potent inhibitors of [3H]8-OH-DPAT binding to pigeon cerebral membranes with IC50 values in the nM range. Neurochemical analyses of metabolite changes produced by spiroxatrine in pigeon cerebrospinal fluid showed buspirone-like effects, with increases in MHPG, DOPAC and HVA at doses that decreased 5-HIAA levels. Spiroxatrine dose-dependently blocked the behavioral effects of the dopamine agonist piribedil indicating that, like buspirone, it also is a potent dopamine antagonist. Spiroxatrine most likely functions as an agonist at the 5-HT1A receptor. As with buspirone, however, spiroxatrine has a prominent dopamine antagonist component.

Effects of combined lead and cadmium exposure: Changes in schedule-controlled responding and in dopamine, serotonin, and their metabolites.

Adult male rats were maintained on 1 of 4 ad-lib diets: Group Control-Diet received a normal laboratory diet that contained no added chemicals: Group Lead-Diet received a diet containing 500 ppm (parts per million) lead: Group Cadmium-Diet received a diet containing 100 ppm cadmium: and Group Lead-Cadmium-Diet received a diet containing both 500 ppm lead and 100 ppm cadmium. After 60 days of exposure to their respective diets, animals were placed on restricted diets (15 g/day) of the identical food received during the exposure period. Each animal was trained to lever press on a fixed-interval 1-min schedule for 21 sessions (1 session day). The results of schedule training showed that lead alone or cadmium alone was associated with increased lever pressing relative to control diet. However, when lead and cadmium were exposed jointly, performance was not significantly different from control performance. Similar attenuation of effects were observed for central neurotransmitter functions. Specifically disturbances in dopamine and serotonin turnover that were produced by lead alone were attenuated by the cotreatment of cadmium and lead. Possible accounts of the apparent antagonism between cadmium and lead are discussed.

Effects of combined lead and cadmium exposure: Changes in schedule-controlled responding and in dopamine, serotonin, and their metabolites.

Effects of combined lead and cadmium exposure: Changes in schedule-controlled responding and in dopamine, serotonin, and their metabolites.

Evidence for antiserotonergic properties of yohimbine

Yohimbine (YOH) is a widely used pharmacological tool employed to produce a selective blockade of alpha 2-adrenergic receptors. In the present study operant behavior was used as a biobehavioral assay to determine the activity of YOH at serotonergic receptors, as indicated by its ability to antagonize the behavioral effects of a serotonergic agonist, lysergic acid diethylamide (LSD). Rats were trained to respond on a Fixed Ratio 15 schedule for food reinforcement. YOH (0.5–5.0 mg/kg) or vehicle and LSD (50 μg/kg) were administered (IP) 30 min and immediately prior, respectively, to the 30-min operant session. In a separate study, the ability of YOH (0.5–2.5 mg/kg) to antagonize a higher dose of LSD (100 μg/kg) was examined. Relatively low doses of YOH (0.5–1.0 mg/kg) were able to partially, but significantly antagonize the LSD-induced suppression and typical hallucinogen-induced disruption of schedule-controlled responding. These results suggest that YOH, even at moderate doses, may act nonselectively as an antagonist at 5-HT receptors, in addition to its antagonist action at alpha 2-adrenergic receptors. This study demonstrates the utility of operant behavior as a biobehavioral assay to study the receptor mediated action of drugs.

Ethanol suppression of schedule-controlled responding: Interactions with Ro 15-4513, Ro 15-1788 and CGS 8216

Rats (N = 14) were trained to respond under a five seconds differential reinforcement of low rate (DRL 5″) schedule and under a fixed ratio 10 (FR10) schedule of reinforcement. Ro 15-1788 did not influence the number of responses in the DRL 5″ schedule, but increased responding in the FR10 schedule. Ethanol (ETOH, 1250 mg/kg) and CGS 8216 (5 mg/kg) suppressed responding in both schedules and these effects were not antagonized by Ro 15-1788. The response suppressing effects of ETOH in both schedules were not influenced by CGS 8216. These results indicate that the response suppressing effects of ETOH and CGS 8216 are not mediated by the BDZ receptor. Ro 15-4513 suppressed responding strongly in the FR10 schedule. The response suppressing effects of Ro 15-4513 were additive with the response suppressing effects of ETOH. In rats (N=11) trained to respond under a variable interval 40 seconds-fixed ratio 10 (VI 40″-FR10) schedule Ro 15-4513 dose-dependently suppressed responding. These results indicate that Ro 15-4513 has sedative effects and is not able to antagonize all the behavioral actions of ETOH.

Effects of mephenytoin on schedule-controlled responding in the Pigeon

Acute and chronic effects of mephenytoin (30–360 mg/kg) were examined in pigeons responding under a multiple fixed-ratio 50 fixed-interval 90-sec schedule of food delivery. The highest dose administered acutely (240 mg/kg) produced substantial reductions in rate of responding under both components of the multiple schedule; the effects of other doses were small and inconsistent. With chronic exposure tolerance appeared to develop to the rate-decreasing effects of the drug.

Effects of methsuximide on schedule-controlled responding in the pigeon

Acute and chronic effects of methsuximide (25, 50, 75, 100 mg/kg), a succinimide with anticonvulsant properties, were examined in pigeons responding under a multiple fixed-ratio 50 fixed-interval 90-sec schedule of food delivery. The clearest acute effect of methsuximide was a substantial reduction in response rates under both components of the multiple schedule when the drug was administered at 100 mg/kg. Detailed analysis of the temporal distribution of responding under the fixed-interval failed to reveal rate-dependent drug effects. Tolerance appeared to develop to the effects of methsuximide when the drug was administered chronically.

Behavioral Toxicology of Volatile Organic Solvents. IV. Comparisons of the Rate-Decreasing Effects of Acetone, Ethyl Acetate, Methyl Ethyl Ketone, Toluene, and Carbon Disulfide on Schedule-Controlled Behavior of Mice

The effects of acetone (ACE), ethyl acetate (EAC), methyl ethyl ketone (MEK), toluene (TOL), and carbon disulfide (CS2) were compared on schedule-controlled responding of mice. Responding (the interruption of a photocell beam located behind a nose-poke hole) was maintained under a fixed interval (FI) 60-second schedule of milk presentation in a sealed inhalation chamber. Cumulative concentration-effect functions were obtained by increasing the concentration of each solvent within the chamber, at 30-minute intervals until responding was abolished. Responding was assessed again 30 minutes after the termination of exposures to levels that abolished responding, to assess the extent of recovery. TOL, CS2, and ACE slightly increased rates of responding at lower concentrations. Each solvent decreased responding in a concentration-related manner at higher concentrations, with responding being decreased 50% by 10,694 ppm ACE, 594 ppm EAC, 2891 ppm MEK, 1784 ppm TOL, and 2242 ppm CS2. Responding recovered 30 minutes after exposures completely for ACE, EAC, and MEK, approximately 75% for TOL, but not at all for CS2. These data suggest that the acute behavioral toxicity of EAC, relative to that found for the other solvents, may be greater than that reflected in current threshold limit values (TLV).

The effect of MDMA (“Ecstasy”) and its optical isomers on schedule-controlled responding in mice

Eleven mice were trained to respond under an FR 20 schedule of reinforcement and, after learning the schedule, were administered doses of saline and the following phenylisopropylamines: (±)-MDMA, S(+)-MDMA, R(−)-MDMA and (+)-amphetamine. Each of the phenylisopropylamines decreased rates of operant responding in a dose-dependent manner. S(+)-MDMA (ED50=3.1 mg/kg) was nearly equipotent with racemic MDMA and four times more potent than R(−)-MDMA (ED50=4.1 and 11.6 mg/kg, respectively), but less potent than (+)-amphetamine (ED50=0.74 mg/kg). The present study constitutes the first enantiometric behavioral-potency comparison for the optical isomers of MDMA.

Cholinergic involvement in the action of formetanate on operant behavior in rats

Formetanate (FMT) is a formamidine acaricide/insecticide with a carbamate moiety in its molecular structure. FMT-induced lethality is reportedly due to inhibition of acetylcholinesterase. Here we report evidence of the neurochemical basis for the sublethal, behavioral effects of FMT in rats. In this experiment, 0.5 mg/kg of FMT (5 min before the 55-min test session) produced a pronounced suppression of response rates in rats trained to lever-press under a multiple fixed-interval 1-min fixed-interval 5 min schedule of milk reinforcement. Injections of scopolamine (0.1 mg/kg) and methylscopolamine (0.1 mg/kg) 15 min before FMT blocked the response rate suppression, whereas pretreatment with either mecamylamine (2 mg/kg) or hexamethonium (2 mg/kg) did not. These data suggest that FMT acts as an indirect agonist on central and peripheral muscarinic receptors, by inhibiting acetylcholinesterase, to produce changes in schedule-controlled responding.

Some effects of d-amphetamine, caffeine, nicotine and cocaine on schedule-controlled responding of the mouse

The effects of d-amphetamine (0.03–10.0 mg kg ), caffeine (0.3–100.0 mg kg ), nicotine (0.003–10.0 mg kg ) and cocaine (0.03–56.0 mg kg ) were compared on responding maintained under three different schedules of food presentation in mice. Cumulative doses of d-amphetamine, nicotine and cocaine only decreased responding maintained under fixed-ratio 30 response, fixed-interval 60-sec and fixed-interval 60-sec schedules with a punishment contingency (suppressed responding). In most cases there was an inverse relationship between the ED 50 (dose which decreased responding by 50%) for the drug and the rate of responding maintained under each schedule. The exceptions were, (i) with both d-amphetamine and cocaine the ED 50 for suppressed responding was smaller than that for non-suppressed fixed-interval responding, and (ii) with nicotine the ED 50 for fixed-ratio responding was smaller than that for fixed-interval responding. In contrast, intermediate doses of caffeine increased suppressed responding, had little effect on fixed-interval responding and decreased fixed-ratio responding. This difference in profile of effect over the range of conditions studied, suggests that the behavioral effects of psychomotor stimulants can be used to examine potential differences in the mechanisms of action of each drug. Such findings may aid in the understanding of the relationships between the neuropharmacological and behavioral effects of psychomotor stimulant drugs.

Pharmacological characterization of supersensitivity to naltrexone in squirrel monkeys: Charles P. France and William H. Morse. Harvard Medical School

Effects of naltrexone and of other drugs in decreasing rates of schedule-controlled responding were studied in squirrel monkeys treated weekly with naltrexone while responding under fixed-ratio schedules of either food presentation (FP) or stimulus-shock termination (SST). By the 5th week of treatment, sensitivity to the rate-decreasing effects of naltrexone had increased 32-fold in FP monkeys (supersensitivity) but had not changed in SST monkeys; continued weekly injections of naltrexone did not change the effects of naltrexone further in either group. FP monkeys were more sensitive than SST monkeys to the rate-decreasing effects of other opioid antagonists and mixed agonist-antagonists; however, for some compounds (e.g., MR 2266) differences between groups did not exceed differences reported in nonsensitized monkeys responding under similar schedule conditions. Differences in sensitivity between FP and SST monkeys appeared to be stereospecific; FP monkeys were 28 times more sensitive than SST monkeys to (-)-cyclazocine, but equally sensitive to (+)-cyclazocine. Sensitivity to opioid agonists and to some nonopioids varied by less than 3-fold between groups and doses of lithium that decreased responding in FP monkeys had no effect in SST monkeys. Neither acute nor repeated injections of morphine altered the sensitivity of FP or SST monkeys to naltrexone; however, morphine attenuated the rate-decreasing effects of naltrexone in FP monkeys, and naltrexone reversed the rate-decreasing effects of morphine in all monkeys. Super-sensitivity to opioid antagonists in squirrel monkeys is behaviorally and pharmacologically selective as well as stereospecific. Although other effects of antagonists might contribute to supersensitivity, opioid antagonistic action appears to be one important component of supersensitivity and cross-supersensitivity among opioid antagonists.