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Pyrazoloquinoline benzodiazepine receptor ligands: effects on schedule-controlled behavior in dogs.

The effects of diazepam and the pyrazoloquinoline benzodiazepine receptor ligands CGS8216, CGS9896, and CGS9895 on schedule-controlled responding were studied in dogs. Responding was maintained under a multiple fixed-interval (FI) 5-min fixed-ratio (FR) 30 response schedule of food presentation. Diazepam (PO) produced dose-related decreases in response rates under FR component. Under the FI, rates first increased and then decreased with increasing doses of diazepam. Diazepam also produced a dose-related disruption of the temporal pattern of responding under the FI as measured by decreases in quarter-life values. CGS8216 IV produced dose-related decreases in response rates under both components. The highest oral dose of CGS8216 also decreased rates in both components. CGS8216 was approximately 100 times more potent by the IV route as compared to the oral route. CGS9896 IV had no significant effect on responding under either component of the multiple schedule. However, with increasing doses of CGS9896 PO, response rates under both components first decreased and then returned to control values. CGS9895 PO was without significant effect on responding. When CGS8216 was administered concomitantly with graded doses of diazepam, the former drug blocked the rate-decreasing effects of diazepam under the FR component, but not the rate-increasing effects of diazepam under the FI. The present results demonstrate that although these three pyrazoloquinolines are benzodiazepine receptor ligands, they do not exhibit diazepam-like effects on schedule-controlled behavior.

Animals

Functional reorganization of primary somatosensory cortex in adult owl monkeys after behaviorally controlled tactile stimulation.

1. Multiple microelectrode maps of the hand representation within and across the borders of cortical area 3b were obtained before, immediately after, or several weeks after a period of behaviorally controlled hand use. Owl monkeys were conditioned in a task that produced cutaneous stimulation of a limited sector of skin on the distal phalanges of one or more fingers. 2. Analysis of microelectrode mapping experiment data revealed that 1) stimulated skin surfaces were represented over expanded cortical areas. 2) Most of the cutaneous receptive fields recorded within these expanded cortical representational zones were unusually small. 3) The internal topography of representation of the stimulated and immediately surrounding skin surfaces differed greatly from that recorded in control experiments. Representational discontinuities emerged in this map region, and "hypercolumn" distances in this map sector were grossly abnormal. 4) Borders between the representations of individual digits and digit segments commonly shifted. 5) The functionally defined rostral border of area 3b shifted farther rostralward, manifesting either an expansion of the cutaneous area 3b fingertip representation into cortical field 3a or an emergence of a cutaneous input zone in the caudal aspect of this normally predominantly deep-receptor representational field. 6) Significant lateralward translocations of the borders between the representations of the hand and face were recorded in all cases. 7) The absolute locations--and in some cases the areas or magnifications--of representations of many skin surfaces not directly involved in the trained behavior also changed significantly. However, the most striking areal, positional, and topographic changes were related to the representations of the behaviorally stimulated skin in every studied monkey. 3. These experiments demonstrate that functional cortical remodeling of the S1 koniocortical field, area 3b, results from behavioral manipulations in normal adult owl monkeys. We hypothesize that these studies manifest operation of the basic adaptive cortical process(es) underlying cortical contributions to perception and learning.

Animals

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

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

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

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

Long-term central 5-HT depletions resulting from repeated administration of MDMA enhances the effects of single administration of MDMA on schedule-controlled behavior of rats.

The behavioral effect of single administration of +/- 3,4-methylene-dioxymethamphetamine (MDMA) on rats performing on the differential-reinforcement-of-low-rate 72-second schedule (DRL 72-sec) was compared before and after a period of repeated administration of MDMA known to deplete 5-hydroxytryptamine (5-HT) levels in the brain. Single administration of MDMA decreased reinforcement rate (1, 2, 4, 6 mg/kg) and increased response rate (4,6 mg/kg) of rats performing on the DRL 72-sec schedule. This effect is typical of amphetamines and other psychomotor stimulants. Four weeks after repeated administration of MDMA (6 mg/kg twice daily for 4 days) there was an increase in sensitivity to the effect of single administration of MDMA. Doses of 2, 4 and 6 mg/kg of MDMA resulted in increases in response rate that were significantly greater after repeated MDMA administration than before. Doses of 0.5, 2, and 6 mg/kg of MDMA resulted in decreases of reinforcement rate that were significantly greater after repeated MDMA administration than before. Repeated administration of MDMA resulted in long-term depletion of serotonin levels by 30-50% in the amygdala, neostriatum, hippocampus and the frontal cortex. Norepinephrine and dopamine (DA) levels were not significantly different from control in any of the brain regions analyzed. The behavioral and neurochemical results suggest that serotonergic neurons normally exert an inhibitory action upon the psychomotor stimulant effects of MDMA. Since the psychomotor stimulant effects of amphetamines appear to be mediated primarily by the dopamine system, these results provide evidence that 5-HT and DA may represent opposing systems in the DRL schedule-controlled behavior.

3,4-Methylenedioxyamphetamine

Orogastric, hydrational, and behavioral controls of drinking following water deprivation in rats.

Drinking and its associated behaviors were studied in rats deprived of fluid for 8,24, or 48 hr. The behavior of rats drinking water could be divided into three successive stages: (a) an initial intense burst of drinking that could not be easily disrupted; (b) intermittent drinking, often distinguished by the brief appearance of conflict behavior directed at the drinking spout; and (c) termination of drinking. Drinking stopped well before the fluid loss, reflected in a sizable extracellular deficit, was restored. Intake of water was terminated when serum hyponatremia and hypoosmolality (and presumably cellular overhydration) developed in temporal continguity with drinking. These and other considerations suggest that the cellular fluid phase exerts significant inhibitory as well as excitatory control over drinking.

Animals

Behavioral control of medicine compliance.

This study examined the effectiveness of several behavioral techniques on compliance of college students taking vitamin C on q.i.d. regimen. Compliance was assessed by a new technique using a variation of the urine tracer procedure designed specifically for this study. Subjects were provided vitamin C tablets, with three tablets per week containing phenazopyridine, a drug that produces a bright red-orange urine discoloration. Subjects were requested to indicate when urine discolorations occurred, and compliance was assessed by comparing the time of their report to the time predicted on the basis of the scheduled sequence of vitamin C and phenazopyridine tablets. Baseline compliance was assessed for 72 subjects over a three-week period, with the 40 most noncompliant subjects randomly assigned to four groups for Treatment I. The groups were: self-monitoring, taste, taste and self-monitoring, and a no-treatment control group. The self-monitoring procedure involved recording the time medicine was taken; the taste procedure involved providing the subjects with flavored tablets to increase the saliency of tablet taking; and the self-monitoring and taste procedure involved providing subjects with flavored tablets and asking them to record the flavor of each tablet they ingested. At the end of six weeks, half the subjects in each of these groups participated in response-cost procedures while the remaining subjects continued with their previous procedures. Response-cost procedures were implemented by returning a portion of the subjects' deposit only if a preset compliance criterion was met. Treatment II procedures were implemented for an additional three weeks. Results indicated the self-monitoring and taste plus self-monitoring procedures were superior during Treatment I. The implementation of response cost during Treatment II was associated with a marked improvement in compliance, independent of the history of noncompliance. The effects of the taste plus self-monitoring procedure were maintained during Treatment II and results obtained by this procedure were not significantly different from effects of response cost.

Ascorbic Acid