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ADDH and methylphenidate responders: effects on behavior controlled by complex reinforcement schedules.

One of the most effective treatments for children with Attention Deficit Disorder with Hyperactivity (ADDH) has been the prescription of methylphenidate (MPH). While laboratory-based evidence indicates that MPH effects may be rate-dependent, little is known about changes evinced in operant behavior controlled by complex reinforcement schedules. The present study examined the effects of several doses of MPH on the operant key-pressing behavior of 20 children with ADDH who were favorable responders to the drug. Following a drug-free training period, each child performed the task across all doses in a randomly assigned sequence under double-blind placebo control conditions. Rate-dependent effects were found for both high- and low-rate reinforcement schedules. The strength of these effects varied across dose. These results have implications for the nature of rate-dependent phenomena in humans and investigations of treatment parameters in the pharmacotherapy of children with ADDH.

Attention Deficit Disorder with Hyperactivity

Tolerance to effects of morphine without cross tolerance to effects of clonidine on schedule-controlled behavior of pigeons.

Schedule-controlled responding was maintained under a multiple fixed-interval, fixed-ratio schedule in pigeons. Dose-related decreases in response rates were produced by clonidine (0.001-0.1 mg/kg) and morphine (0.3-5.6 mg/kg). Chronic administration of morphine produced (1) tolerance to effects of morphine, as evidenced by a decrease in potency of morphine and (2) sensitivity to opioid antagonists, as evidenced by an increase in potency of naloxone. Dose-effect curves for clonidine were not appreciably altered by chronic morphine administration.

Animals

Tolerance to the effects of buprenorphine on schedule-controlled behavior and analgesia in rats.

Responding in rats was maintained under a fixed-ratio 30 schedule of food presentation. When administered acutely buprenorphine (0.018-0.56 mg/kg) produced dose-related decreases in overall rate of responding. In addition to schedule-controlled behavior, the analgesic effects of buprenorphine were evaluated during chronic administration using the tail-flick method. Tolerance developed to the effects of buprenorphine on both measures. In general dose-effect curves for the rate-decreasing effects of buprenorphine were shifted to the right by approximately 2 log units. In one subject, however, tolerance did not develop to the rate-decreasing effects of 10 mg/kg, suggesting that behavioral tolerance to buprenorphine is dose limited. Finally, the data also suggested that tolerance may develop more slowly, yet more completely, to the analgesic than to the rate-decreasing effects of buprenorphine.

Analgesics

Nicotine-induced tolerance and dependence in rats and mice: studies involving schedule-controlled behavior.

Tolerance to nicotine's disruptive effects on operant responding develops rapidly over a 14-36 day repeated dosing period in both rats and mice. This occurred regardless of whether nicotine was administered pre- or post- to each behavioral exposure. Thus, tolerance development appeared to depend on both behavioral as well as pharmacological mechanisms. It is suggested that the pharmacological mechanism(s) involved in the development of tolerance may be related to an up-regulation of brain area nicotinic receptors. As observed with receptor binding studies, mecamylamine did not appear to attenuate the development of pharmacological tolerance to nicotine (does not attenuate nicotinic receptor up-regulation) even though this cholinergic antagonist will antagonize nicotine's acute behavioral disruptive effects completely. However, the fact that mecamylamine may induce some cross-tolerance to nicotine does complicate our interpretation of these data. The development of nicotine tolerance, in part, appears to depend upon an interaction at some acetylcholine-sensitive nicotinic receptor as evidenced by the ability of physostigmine to induce cross-tolerance to nicotine in both the rat and mouse. These data support the view that nicotine may be inducing its effects via at least two separate nicotinic receptors, one of which may be acetylcholine sensitive. Furthermore, binding data suggest that physostigmine's effects were related to a reduction of available central nicotinic receptor sites. In contrast to what humans experience, the rat does not appear as sensitive to nicotine-induced physical dependence, at least when operant behavior is utilized as the dependent variable used to measure withdrawal signs. Other approaches such as drug discrimination and conditioned avoidance paradigms may provide a better alternative to the evaluation of nicotine-induced dependence. Research utilizing schedule-controlled behavior in the mouse, on the other hand, has provided us with an additional model of a nicotine-induced withdrawal syndrome which may be of value in evaluating mechanisms of nicotine dependence. However, as with all of these findings, much work is needed to confirm and further characterize each model in so far as they may provide us with a reliable and specific measure of nicotine dependence.

Animals

The effect of visual feedback and self-scaling on plaque control behavior.

Psychological factors are involved in inducing patients to practice the plaque control necessary for periodontal health. It is suggested that oral hygiene behavior can be modified by increasing visual feedback by means of optical devices, and by giving patients the task of scaling their own teeth. The optical devices used for intraoral inspection must be specifically designed for this task. A pilot study was undertaken to test the modification in plaque control behavior in patients using a specially-designed optical system and performing self-scaling. Twelve patients participated in the study; six were given optical devices and taught self-scaling and plaque control, whereas the other six acted as controls, received a scaling from a hygienist, and were taught plaque control. All subjects received 3 hours of chairside time. Before treatment both groups had mean PHP indiced (plaque) of 3.2. Five months after the completion of treatment, the experimental group had a mean PHP index of 0.7, whereas the control group had a score of 1.9. The patients performing self-scaling demonstrated that they could remove supragingival calculus and extrinsic stains as effectively as a trained hygienist.

Dental Equipment

Environmental influences on the development of tolerance to the effects of physostigmine on schedule-controlled behavior.

The influence of environmental variables on the development of tolerance to physostigmine's effects in rats was examined using multiple fixed-ratio, extinction schedules of food presentation. Initial administration of physostigmine (0.4 mg/kg) produced nearly maximal decreases in the number of food pellets delivered, running response rate, and overall response rate, under multiple FR 10, EXT and multiple FR 50, EXT schedules. With repeated administration, tolerance to physostigmine's effects was observed when 10 responses were required to produce reinforcement but was not observed when 50 responses were required to produce reinforcement. Tolerance under the multiple FR 10, EXT schedule of reinforcement was also observed when physostigmine was administered post-session. When tolerance was acquired, it was retained for up to 25 drug-free days. These results suggest that tolerance to physostigmine's effects on schedule-controlled behavior is strongly influenced by response requirement, independently of physostigmine-induced reinforcement loss. Additionally, tolerance is not dependent on experience with the schedule while under the effects of physostigmine, and is retained for a substantial period of time in the absence of continued physostigmine administration.

Animals

Prazosin attenuates the effects of cocaine on motor activity but not on schedule-controlled behavior in the rat.

The spontaneous motor activity of rats was measured following administration of cocaine alone and in combination with the centrally acting alpha 1-antagonist prazosin. Cocaine alone (18-42 mg/kg) increased motor activity in a dose-related manner. At doses of 1 and 1.8 mg/kg, prazosin attenuated the increases in motor activity produced by cocaine. In rats responding under a fixed-ratio discrimination procedure, cocaine (10-32 mg/kg) produced dose-dependent increases in percent errors and decreases in overall response rate. Across a range of doses (0.32-3.2 mg/kg), prazosin failed to antagonize the effects of cocaine on responding under the discrimination procedure. Rather, the combined effects were frequently greater than those obtained with cocaine alone. The data suggest that in rats activation of alpha 1-adrenergic systems may mediate the effects of cocaine on motor activity but not on schedule-controlled behavior.

Animals

Disruption of schedule-controlled behavior by Ro 15-1788 one day after acute treatment with benzodiazepines.

The behavioral effects of the benzodiazepine antagonist Ro 15-1788 were studied in squirrel monkeys after acute injections of benzodiazepines. Monkeys responded under a multiple schedule of food presentation with alternating fixed-interval (FI) and fixed-ratio (FR) components, Chlordiazepoxide (10 mg/kg) increased FI responding and had little effect on FR responding 1 h after it was administered; FI responding was still elevated during the session on the following day. When Ro 15-1788 (0.1-3 mg/kg) was administered 1 h after chlordiazepoxide, it antagonized the effects of chlordiazepoxide in a dose-related manner. When Ro 15-1788 was administered 1 day after chlordiazepoxide, however, doses of 1 or 3 mg/kg suppressed both FI and FR responding. Suppression of schedule-controlled responding was also observed when Ro 15-1788 (3 mg/kg) was administered 1 day after diazepam (3 or 5.6 mg/kg) or N-desmethyldiazepam (5.6 mg/kg). The results show that Ro 15-1788 can precipitate disruption of schedule-controlled behavior 1 day after acute treatment with benzodiazepines.

Animals

Pyrethroid effects on schedule-controlled behavior: time and dosage relationships.

Pyrethroid insecticides have been divided into Types I and II based on behavioral profiles of toxicity produced by life-threatening dosages. In order to assess potential alterations in acquired (operant) behavior, acute dosage-effect and time-course determinations for permethrin (Type I) and cypermethrin (Type II) were made. Long-Evans rats responded for food according to a multiple schedule consisting of four different variable-interval schedules. Permethrin (100-400 mg/kg) and cypermethrin (7.5-60 mg/kg) were administered PO 1.5 hr pre-session and their effects on response rates and between-component response patterning determined. Permethrin reduced responding in a manner which was independent of the baseline response rate, while the rate reductions following cypermethrin administration showed a dependence on the baseline levels of responding, with low response rates showing differential sensitivity to disruption. When select dosages of each compound were delivered at various pre-session times, onset of and recovery from the rate-decreasing effects were more rapid with cypermethrin, with rates returning to baseline levels by 12 hr post-dosing. Responding was maximally suppressed 24 hr after administration of permethrin and returned to baseline levels 48 hr after administration. The disruption of response patterning following cypermethrin was maximal at 1.5 hr after administration, with complete recovery 12 hr post-dosing. Differential effects on response patterning, in potency, and in the time-course of effects of permethrin and cypermethrin suggest a type-specificity for pyrethroid effects on schedule-controlled behavior at dosages far below those producing lethality in rats.

Animals

Behavioral influences on tolerance to the effects of morphine on schedule-controlled behavior.

Responding of pigeons was maintained under a multiple fixed interval, fixed ratio schedule of food delivery, and 10 mg/kg morphine was administered daily. Responding during both schedule components was initially decreased and measurable tolerance developed to this effect after four daily injections. However, the rate of tolerance development differed depending on whether or not presence of the drug coincided with performance during experimental sessions. Tolerance developed more rapidly when morphine was given before daily experimental sessions than when morphine was given daily but animals did not perform daily in experimental sessions. Tolerance to the rate-decreasing effects of morphine depended on relations between presence of the drug and exposure to experimental sessions.

Animals

Contrasting effects of morphine on schedule-controlled behavior in the chimpanzee and baboon.

Schedule-controlled key pressing was maintained in two chimpanzees and three baboons under a multiple 10-minute fixed-interval (FI 10-min) 30-response fixed-ratio (FR 30) schedule of food delivery. Characteristic rates and patterns of responding were maintained under the FI and FR schedules, and the performance of the two species differed in no systematic way. The acute i.m. administration of morphine (0.1-3.0 mg/kg) prior to selected 2-hour sessions increased mean rates of responding under the FI schedule in the chimpanzee, but decreased responding in the baboon. At a dose of 3.0 mg/kg of morphine, responding under the FI schedule in the chimpanzee increased 4-fold and responding in the baboon decreased to less than 25% of control levels. Mean response rates under the FR schedule were also increased by morphine in the chimpanzee, but responding under the FR schedule was little affected in the baboon except at the higher doses which decreased response rates below control levels. Respiratory rate in the chimpanzee was markedly depressed at 5.6 mg/kg of morphine and one chimpanzee died. A similar depression of respiration was not observed in the increase responding in a nonhuman primate, the chimpanzee, and that the behavioral effects of morphine in the chimpanzee are qualitatively different from the effects in monkeys.

Animals

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.

Animals

Do redundant visual and auditory target variables facilitate control behavior?

The compensatory tracking paradigm has been used extensively in pioneering work on Control Theory, a cybernetic model of behavior. In most studies subjects have been asked to control or maintain at a steady state a single variable or aspect of the stimulus display. The present study utilized three groups of subjects, comparing their performance effectiveness in controlling: (1) a visual stimulus (cursor) versus (2) an auditory stimulus (tone) versus (3) a combined, redundant-cue condition employing both cursor and tone. Freshman volunteers responded to a computer display using a joystick controller; their task was to keep stationary a stimulus that was subject to a smoothed, quasirandom disturbance. Contrary to predictions, subjects in the cursor-alone group performed more effectively than subjects in the combined cursor-tone group. While speculative interpretations are offered, further research is needed to clarify these results.

Adolescent