Dose-dependent Decreases In Response Rate Research Articles

Differential cross-tolerance to the effects of nicotinic acetylcholine receptor drugs in C57BL/6J mice following chronic varenicline.

Varenicline is a smoking cessation pharmacotherapy with a presumed mechanism of action of partial efficacy at the α4β2 nicotinic acetylcholine receptor (nAChR); however, the extent to which daily varenicline use leads to changes in nAChR sensitivity is unclear. This study examined the consequences of daily varenicline treatment on disruptions in operant responding (i.e. rate-decreasing effects) and hypothermia induced by administration of nicotine, epibatidine, cytisine, and cocaine in C57BL/6J mice. Furthermore, mecamylamine was used to assess the involvement of nAChRs in the effects of varenicline. Mice were trained under a fixed ratio 20 of milk reinforcement, and rectal temperatures were measured after 30 min following drug-administration. Varenicline, nicotine, epibatidine, and cytisine produced dose-dependent decreases in response rate and rectal temperature. Chronic varenicline (30 mg/kg) engendered tolerance to varenicline, but more cross-tolerance to nicotine, for both disruptions in operant responding and hypothermia. Cross-tolerance only developed to the hypothermic effects of epibatidine, and no cross-tolerance developed to any effects of cytisine and cocaine. In varenicline-tolerant mice, mecamylamine did not antagonize the effects of varenicline. The varying magnitudes of tolerance and cross-tolerance among effects and drugs are indicative of a nonuniform nAChR pharmacology in vivo.

Role of gamma-aminobutyric acid type A (GABAA) receptor subtypes in acute benzodiazepine physical dependence-like effects: evidence from squirrel monkeys responding under a schedule of food presentation

Assays of schedule-controlled responding can be used to characterize the pharmacology of benzodiazepines and other GABAA receptor modulators, and are sensitive to changes in drug effects that are related to physical dependence. The present study used this approach to investigate the role of GABAA receptor subtypes in mediating dependence-like effects following benzodiazepine administration. Squirrel monkeys (n = 6) were trained on a fixed-ratio schedule of food reinforcement. Initially, the response rate-decreasing effects of chlordiazepoxide (0.1-10mg/kg; nonselective GABAA receptor agonist), zolpidem (0.032-1.0mg/kg; α1 subunit-containing GABAA subtype-preferring agonist), and HZ-166 (0.1-10mg/kg; functionally selective α2 and α3 subunit-containing GABAA receptor agonist) were assessed. Next, acute dependence-like effects following single injections of chlordiazepoxide, zolpidem, and HZ-166 were assessed with flumazenil (0.1-3.2mg/kg; nonselective GABAA receptor antagonist). Finally, acute dependence-like effects following zolpidem administration were assessed with βCCt and 3-PBC (0.1-3.2mg/kg and 0.32-10mg/kg, respectively; α1 subunit-containing GABAA receptor antagonists). Chlordiazepoxide, zolpidem, and HZ-166 produced dose- and time-dependent decreases in response rates, whereas flumazenil, βCCT, and 3-PBC were ineffective. After the drug effects waned, flumazenil produced dose-dependent decreases in response rates following administration of 10mg/kg chlordiazepoxide and 1.0mg/kg zolpidem, but not following any dose of HZ-166. Further, both βCCT and 3-PBC produced dose-dependent decreases in response rates when administered after 1.0mg/kg zolpidem. These data raise the possibility that α1 subunit-containing GABAA receptors play a major role in physical dependence-related behaviors following a single injection of a benzodiazepine.

Differential effects of chronic alcohol on GABA(A)‐ and NMDA‐receptor mediated disruptions in learning in rhesus monkeys

To examine the chronic effects of alcohol on learning, 2 groups (−ETOH, +ETOH) of young male rhesus monkeys trained to respond under a task with acquisition and performance components received ethanol 4 consecutive days per week for 12 months via an intragastric catheter. Cumulative dose-effect curves for both flunitrazepam (0.056–0.56 mg/kg, i.m.) and ketamine (1.8–10 mg/kg, i.m.) were determined in each group before and after chronic ethanol. During the three days of the week when ethanol was not administered, little or no disruptions were observed in either response rate or the percentage of errors (accuracy) in either component compared to control subjects. During the two days of testing during ethanol administration, modest disruptions in response rate and percent errors occurred in the acquisition components; the disruptions were larger on the initial day than on the second day. When cumulative doses of flunitrazepam and ketamine were administered in the absence of ethanol, dose-dependent decreases in response rate and accuracy occurred in both components. Over time, however, chronic ethanol administration shifted the dose-effect curves for flunitrazepam to the right, whereas the curves for ketamine were unchanged. These results indicate that chronic alcohol administration may produce larger changes in GABA(A) receptor function than NMDA receptor function in monkeys. Supported by USPHS AA09803.

Interactions between the reinforcing effects of cocaine and heroin in a drug-vs-food choice procedure in rhesus monkeys: a dose-addition analysis

Concurrent abuse of cocaine and heroin is a common form of polydrug abuse, but the interactions between the reinforcing effects of cocaine and heroin are poorly understood. Dose-addition analysis is a tool for the quantitative assessment of drug interactions, but this analysis has not been applied to evaluation of the reinforcing effects of cocaine and heroin. To evaluate interactions between the reinforcing effects of cocaine and heroin using dose-addition analysis. Rhesus monkeys were trained under a concurrent-choice schedule of food delivery (1 gm pellets) and drug injections (cocaine or heroin, 0-0.1 mg kg(-1) injection(-1)). Full dose-effect curves were determined for cocaine alone and heroin alone. Subsequently, full dose-effect curves were determined for three fixed-proportion mixtures of cocaine and heroin (fixed proportions of 1:3.2, 1:1 and 3.2:1 cocaine/heroin). Dose-addition analysis was used to assess whether cocaine/heroin interactions were super-additive, additive, or sub-additive. Cocaine, heroin, and all cocaine/heroin mixtures maintained dose-dependent and monotonic increases in drug choice and dose-dependent decreases in response rates. Choice dose-effect curves for cocaine/heroin mixtures were shifted to the left of dose-effect curves for cocaine or heroin alone, and dose-addition analysis indicated that cocaine/heroin interactions on drug choice were sub-additive or additive. Cocaine/heroin interactions on response-rate measures were also sub-additive or additive. These results confirm that mixtures of cocaine and heroin produce reinforcing effects in rhesus monkeys; however, cocaine/heroin interactions were only or sub-additive or additive. Thus, these results do not support the hypothesis that simultaneously delivered cocaine and heroin produces super-additive reinforcing effects.

Changes due to food deprivation in the effects of cocaine on the responding of pigeons

The responding of eight pigeons was maintained under a fixed-ratio 30 schedule of food reinforcement. While the pigeons were maintained at 80% of their free-feeding body weights the effects of presession injection of a range of cocaine doses (1.0 or 3.0mg/kg to 10.0 or 17.0mg/kg) were determined. The weights of one group of pigeons were then increased to between 90 and 100% of their free-feeding weights, while the other group's weights were reduced to 70% of their free-feeding weights. The effects of cocaine were determined again. Following this, pigeons' weights were adjusted to the percentage of free-feeding weight to which they had not yet been exposed, and the effects of cocaine determined a third time. Cocaine produced dose-dependent decreases in response rates. Decreases were observed at smaller cocaine doses when pigeons were relatively food-satiated (i.e. 90-100% of free-feeding weight); larger doses were required to decrease responding when pigeons were maintained at 70% free-feeding weight. If increased resistance to the behaviorally suppressive effects of cocaine when food deprivation levels are increased occurs also when cocaine is self-administered, this could help account for increases in amounts of cocaine-reinforced behavior under conditions of food deprivation.

Differential interaction of cholecystokinin with morphine and phencyclidine: Effects on operant behavior in pigeons

To extend previous operant research in rats with morphine and cholecystokinin (CCK), these two substances were given alone and in combination to pigeons. In one component of a multiple schedule, responding of pigeons (key pecking) was reinforced under a fixed-ratio (FR 50) schedule of food presentation. In the other component, responding had no programmed consequence (timeout). Each session consisted of four 10-min timeout components alternating with four 5-min FR components. In Experiment 1, cumulative dose-effect curves for morphine were obtained by giving an IM injection before each of four FR components; successive injections increased the cumulative dose by 1 4 log-unit steps. In general, as the cumulative dose of morphine increased, the overall response rate in each FR component decreased. Dose-dependent decreases in response rate also occurred when single noncumulative doses of CCK were administered alone 20 min prior to the start of the session. This effect of CCK alone diminished as the session progressed. When CCK was given as a pretreatment before cumulative doses of morphine, the morphine dose-effect curve for response rate shifted to the left. At intermediate doses of CCK, the “potentiation” was so complete that two of three subjects failed to respond during any of the four FR components (i.e., the dose-effect curve for morphine had shifted approximately 1 log-unit to the left). In order to evaluate the pharmacological specificity of this effect, cumulative doses of phencyclidine were administered in combination with CCK (Experiment 2). Unlike the interaction between morphine and CCK, the interaction between phencyclidine and CCK was reciprocal. After pretreatment with each dose of CCK, high doses of phencyclidine tended to produce smaller rate-decreasing effects than those obtained with phencyclidine alone. Moreover, low doses of phencyclidine attenuated the rate-decreasing effects of the higher doses of CCK in the initial FR components. The results of Experiment 1 extend the generality of previous findings in rats with morphine and CCK on schedule-controlled behavior, while the results of Experiment 2 indicate distinct differences in the way in which CCK interacts with morphine and phencyclidine.

Effects of MK-801 stereoisomers on schedule-controlled behavior in rats

Behavioral effects of (+)MK-801 (0.03-0.32 mg/kg) and (-)MK-801 (0.32-3.20 mg/kg) were evaluated in rats using a multiple fixed-ratio, fixed-interval (FR20, FI2) schedule of food presentation. Both enantiomers produced dose-dependent decreases in response rate under the FR20 and in this respect (+)MK-801 was approximately ten times as potent as (-)MK-801. Under the FI2 schedule component, the (+) enantiomer produced substantial increases as well as decreases in response rate whereas the (-) enantiomer produced only decreases. When 0.178 mg/kg (+)MK-801 and 1.78 mg/kg (-)MK-801 were administered for 11 consecutive days, tolerance developed to the decrease in response rate under the FR20 schedule component. Tolerance to the effects of the (+) enantiomer under the FI2 schedule component was indicated by progressively larger increases in response rate than those observed during acute administration. These results support potential therapeutic applications of MK-801.

Effects of mu, kappa and sigma opioids on fixed consecutive number responding in rats

Responding in rats was maintained under a fixed consecutive number 20 schedule. Under this schedule, at least 20 consecutive responses were required on one lever before a response on a second lever produced food. Morphine, buprenorphine, ethylketocyclazocine (ECK), N-allylnormetazocine (NANM) and d-cyclazocine all caused dose-dependent decreases in response rate. With the exception of buprenorphine and EKC, each drug also produced a decrease in the percent of reinforced runs. Differences among the drugs were more apparent, however, on the basis of the conditional probability of switching to the second lever after any given run length on the first lever. Morphine increased the probability of premature switching and decreased the probability of switching after run lengths greater than 20. Buprenorphine decreased the probability of switching at all run lengths and EKC produced occasional increases in premature switching. In sharp contrast to the other opioids tested, NANM and d-cyclazocine generally increased the probability of switching at all run lengths. Thus, it appears that the fixed consecutive number schedule may be a sensitive procedure for distinguishing among the behavioral effects of various opioid agonists.

The discriminative stimulus properties of barbiturate stereoisomers.

Pigeons were trained to discriminate an IM injection of racemic pentobarbital sodium (5.0 mg/kg) from saline under a second-order color-tracking schedule of mixed grain presentation. In a time-course study, maximal pentobarbital-appropriate responding occurred 15 min after administration of 5.0 mg/kg racemic pentobarbital sodium, the pretreatment time used for subsequent experiments. Racemic pentobarbital sodium, the R(+) and S(-) isomers of pentobarbital, racemic secobarbital sodium, and the R(+) and S(-) isomers of secobarbital all produced dose-dependent increases in pentobarbital-appropriate responding. Racemic secobarbital sodium, the secobarbital isomers, and the R(+) isomer of pentobarbital were equipotent to each other and slightly less potent than racemic pentobarbital and the S(-)-pentobarbital isomer in this regard. Except for R(+)-pentobarbital, all barbiturates caused dose-dependent decreases in response rate over the dose range tested.

Potentiation of disruptive effects of dextromethorphan by naloxone on fixed-interval performance in rats

A centrally acting antitussive agent dextromethorphan (DM) was tested to determine its possible interaction with naloxone in rats responding under a fixed-interval schedule of positive reinforcement. A sugar sweetened milk reward was used as a positive reinforcer. Under the same experimental conditions the effects of morphine alone and in combination with naloxone were also determined. Low dose DM (10 mg/kg) produced a slight increase, while higher doses (20-40 mg/kg) produced dose-dependent decreases in response rate. Morphine (0.3, 1.0 and 3.0 mg/kg) produced dose-dependent decreases in response rate. When doses of naloxone (0.1-1.0 mg/kg) were administered after the injection of DM the rate-decreasing effects of DM were potentiated even after the rate-increasing dose of naloxone (0.1 mg/kg) was used. When a dose of naloxone (0.1 mg/kg) was administered after the injection of morphine the rate-decreasing effects of morphine were markedly antagonized, i.e., the morphine dose-response curve was shifted to the right. The observed potentiation of DM disruption by naloxone on fixed-interval performance in rats is consistent with findings showing that naloxone potentiates the disruptive behavioral effects of a number of drugs that are psychotomimetic in man.

Differential effects of formamidine pesticides on fixed-interval behavior in rats

Chlordimeform (CDM), amitraz (AMZ), and formetanate (FMT) are members of the formamidine class of pesticides. To date, effects on operant behavior have been determined only for CDM. This experiment compared the effects of CDM, AMZ, and FMT on schedule-controlled responding. Nine male Long-Evans rats were trained during 1-hr sessions to lever-press under a multiple fixed-interval (FI)-1-min FI-5-min schedule of milk reinforcement. Dose-effect determinations for each compound administered ip, 20 min presession, were carried out in each subject. The dose ranges were: CDM HCl, 0.3–20 mg/kg; FMT HCl, 0.03 – 0.75 mg/kg; and AMZ, 5–75 mg/kg. Under baseline conditions response rates were higher under the FI-1-min than under FI-5-min, and index of curvature (IOC) values (a measure of within-interval response patterning) were generally higher under FI-5-min. All compounds produced dose-dependent decreases in response rate. CDM significantly decreased only FI-1-min response rates; a similar effect of AMZ was seen only at an intermediate dose. FMT decreased responding to the same extent in both components. CDM produced pronounced changes in the pattern of responding in both components, with IOC decreased more under FI-5-min than under FI-1-min. AMZ produced significant decreases in IOC only under FI-5-min. FMT did not appreciably decrease IOC in either component. High doses of AMZ produced general signs of poor health that persisted for several days. In addition, a greater effect on response rates and IOC in both components was obtained when AMZ (75 mg/kg) was given more than 10 days following another dose compared to when it was given 7 days or less after another dose. Formamidine pesticides produce differential effects on FI schedule-controlled behavior that are in turn modulated by the parameter value of the FI schedule.

Effects of tripelennamine and pentazocine alone and in combination on fixed-ratio responding of rats

The effects of tripelennamine (3, 6, 12, 18, and 24 mg/kg) and pentazocine (5, 10, 20, 30, and 40 mg/kg), given alone and in selected combinations, were determined in rats performing under a fixed-ratio 30 schedule of food delivery. Each drug alone produced generally dosedependent decreases in response rates. Combinations typically produced effects identical in direction to, and occasionally greater in magnitude than, those predicted by a simple additive model.

RETRACTED: Effects of methylphenidate on the fixed-ratio performance of mentally retarded children

The effects of methylphenidate on the lever-pressing of 12 mentally retarded children maintained under fixed-ratio 5, 10 and 20 schedules of food delivery were examined. For five children, methylphenidate at oral doses of 0.3, 0.7 and 1.0 mg/kg produced generally dose-dependent decreases in response rates, whereas for the other seven children the two lower doses increased response rates while the highest dose decreased responding. The differential effects of methylphenidate across participants could not be attributed to differences in control response rates or demographic factors. However, each child whose rate of fixed-ratio responding was increased by methylphenidate also demonstrated a therapeutic response to the drug.

Effects of phenytoin on schedule-controlled performance of rats

The present study examined the effects of acute administrations of phenytoin on the lever pressing of rats maintained under fixed-ratio, fixed-interval, and interresponse-time-greater-than-T schedules of food delivery. The drug typically produced dose-dependent decreases in response rates under fixed-ratio and fixed-interval schedules, while response rates under the interresponse-time-greater-than-T schedule were affected little by the drug. These findings indicate that phenytoin effects on schedule-controlled responding differ from those of other anticonvulsants.

Threshold differences for naloxone and naltrexone in the hypothalamus and midbrain using fixed ratio brain self-stimulation in rats.

Rats were implanted with stimulating electrodes aimed either at the medial forebrain bundle-lateral hypothalamus (MFB-LH) or the midbrain-central gray (MID-GG), and were trained to lever-press for brain self-stimulation on a fixed ratio: 15 schedule of reinforcement. The dose-dependent effects of morphine (0.1-3.0 mg/kg), naloxone (0.1-30 mg/kg), and naltrexone (0.1-30 mg/kg) were then determined during 1 h test sessions. Both naloxone and naltrexone decreased the rate of responding in the MFB-LH as well as in the MID-CG. However, decrements in response rates were produced in the MID-CG by both naloxone and naltrexone at one tenth the doses required to produce similar decrements with electrodes in the MFB-LH. Dose-dependent decreases in response rates produced morphine occurred at the same doses in the two electrode sites. At both sites, the decreases in response rates produced by the highest dose of morphine were antagonized completely by a low dose of naloxone (0.1 mg/kg). At an intermediate dose of naloxone (1.0 mg/kg), antagonism occurred in the MFB-LH but not in the MID-CG. At a high dose of naloxone (10 mg/kg), a depression in lever-pressing occurred at both sites in the morphine-treated animal indicating that the depressive action predominated over antagonism. These data explain the lack of consistency of the effects of naloxone on brain self-stimulation previously reported by different laboratories, and demonstrate that the use of partial reinforcement schedules in a rational approach to the evaluation of opioid effects on brain self-stimulation behavior.

Fixed-ratio escape and avoidance-escape from naloxone in morphine-dependent monkeys: effects of naloxone dose and morphine pretreatment.

Lever pressing by rhesus monkeys was maintained by morphine injections during four equally spaced sessions each day. During other periods, lever pressing was maintained by timeout from a continuous naloxone infusion (escape), or by timeout from a stimulus that preceded naloxone injections, or termination of the injections (avoidance-escape). As naloxone dose increased in the escape procedure, response rate increased to a maximum and then decreased. In the avoidance-escape procedure, response rate generally increased as naloxone dose increased, but the changes in rate were small compared to the excape procedure. Substitution of saline for naloxone in the escape procedure led to a very low response rates within three sessions. In the avoidance-escape procedure, rate decrements produced by saline substitution appeared to be related to the behavioral history of the monkey. Previous escape experience led to more rapid decreases in responding when saline was introduced, whereas responding was maintained for 15 sessions in a monkey without prior escape conditioning. Morphine pretreatment produced comparable, dose-dependent decreases in response rates in both procedures. The rate-decreasing effects of morphine were exacerbated when no naloxone was delivered in the escape procedure.