Effects of response-contingent clock stimuli on behavior maintained by intravenous codeine in the rhesus monkey.

Response-contingent brief presentations of clock stimuli differentially correlated with food availability altered rates of codeine-maintained lever pressing. Rhesus monkeys performed under a two lever multiple schedule: Multiple fixed interval clock 5 min variable interval 2 min. Different colored lights were presented during successive 75 sec period of the fixed-interval clock component. Lever pressing under the FI Clock schedule was maintained by presentation of 1 g Noyes pellets, and lever pressing under the VI schedule by 0.05 mg/kg infusions of codeine PO4. Characteristic schedule-controlled performance developed in both schedule components. When the clock stimulus from the first or the final period of the FI Clock schedule was presented contingent upon completion of a short fixed ratio of responses during the variable-interval schedule component, the first clock stimulus decreased and the final clock stimulus increased rates of codeine-maintained lever pressing. Neither the first nor the final clock stimulus altered the frequency of codeine injection. The effect of each clock stimulus was accentuated by increasing the duration of stimulus presentation and by decreasing the response requirement for stimulus illumination. These rate-altering effects of the clock stimuli were most pronounced when different reinforcers were presented in the two components of the multiple schedule when either food or intravenous codeine injection was available under both components of the multiple schedule, response-contingent clock stimulus presentation did not alter response rates under the VI schedule.     

Schedule induced behavior: A review of its generality,determinants and pharmacological data

Adjunctive or schedule induced behavior can be defined as an increase in the frequency of occurrence of an unreinforced behavior in the presence of conditions requiring an intermittent reinforced response, compared with the frequency of that behavior when no intermittent response is required. Although recognition has been given to the occurrence of other schedule induced behaviors it has most frequently been studied as schedule induced polydipsia in a rat on a food delivery schedule. In the present paper recent work on other schedule induced behaviors is reviewed including behaviors occurring in conjunction with nonconsumatory schedule parameters. These range from wheel running in the rat to game playing and maze solving in humans. This paper is also concerned with the review of pharmacological variables including the effects of peripheral and central administration. It is concluded that there may be either quantitative or qualitative differences in drug effects when schedule induced drinking is compared with deprivation induced drinking. A general activation theory [61] that adjunctive behavior is the result of an increase in the excitability of motor pathways which lead through the lateral hypothalamus can account for the data presented in this and earlier reviews but is too broad in its conception to make specific predictions about the relationships between schedule induced and schedule controlled behavior.     

Doxorubicin: alteration of dose scheduling as a means of reducing cardiotoxicity

The long-term therapeutic potential of doxorubicin is often limited by the predictable development of a dose-related cardiomyopathy. Empiric limitations of cumulative doses to 450-550 mg/m2 minimize the incidence of this potentially fatal toxicity. This review presents recent studies performed to examine the potential for altered dose schedule to reduce or delay this toxicity and maintain therapeutic efficacy. Altering doxorubicin's dosing schedule from the standard three-weekly regimen to a continuous infusion or weekly schedule has been shown to delay cardiotoxicity. Data presented suggest that doxorubicin administered on a weekly schedule significantly reduces cardiotoxicity as compared with a three-weekly schedule and allows approximately 160 mg/m2 more of the drug to be administered to reach the same level of cardiotoxicity as measured by endomyocardial biopsy. This corresponds clinically to two additional months of therapy. Cumulated response data suggest that continuous infusion or weekly schedules of doxorubicin are equally efficacious as the standard three-weekly schedule.     

Reflections on cancer therapy.

A schedule for treatment of cancer patients with low-dose combined chemotherapy infusions is presented for discussion. This schedule is designed to activate the immune system. Active agents such as mistletoe preparations etc. which are at present still controversial, balneological applications, diet, ethics and nursing home facilities are mentioned. Finally the question is raised as to whether it may be appropriate under certain circumstances in the individual case to institute abortive cytostatic treatment even in suspicion of a cancerous condition, i.e. at a time when the organ diagnosis has not yet been substantiated.     

Behavioral tolerance to stimulating effects of pentobarbital: A within-subject determination

Squirrel monkeys were trained to press a lever under a multiple schedule of food presentation. In one stimulus condition responses that terminated interresponse times greater than 28 sec were followed by food presentation. In the other stimulus condition, an interval schedule of food presentation was presented that provided approximately the same frequency and distribution of food delivery as that observed under the interresponse-time schedule. Except when it was administered for the first time, 5.6 mg/kg sodium pentobarbital produced reliable increases in responding during the interresponse-time schedule. Behavioral tolerance to the rate-increasing effect was assessed in individual subjects by first administering the drug daily following each session, and then giving it daily before each session. Following post-session drugging, the effects of 5.6 mg/kg were not changed, but tolerance developed when the drug was administered pre-session. The way in which tolerance developed was consistent with the reinforcement-loss hypothesis.     

Effects of cocaine alone and in combination with prazosin or ondansetron on multiple fixed-interval fixed-ratio performance in pigeons.

Three pigeons were trained to respond on a two-component multiple schedule in which the components alternated regularly. In one component of the schedule, food was presented when the pigeon successfully completed a fixed-interval 120-s schedule within 150 s. In the other component of the schedule, food presentation occurred when the pigeon managed to complete a fixed-ratio 30 schedule within 30 s. Once responding had stabilized under both components of the schedule, pigeons were challenged with different doses of cocaine alone or cocaine in combination with 1.0 mg/kg prazosin (a selective alpha 1-adrenergic antagonist) or 0.10 or 0.50 mg/kg ondansetron (a selective 5-hydroxytryptamine3 antagonist). All drugs were injected intramuscularly 5 min before the start of selected experimental sessions. For two subjects, low doses of cocaine increased the low response rates maintained by the fixed-interval schedule while decreasing the high rates maintained by the fixed-ratio schedule. At intermediate doses, both high and low rates decreased but higher rates were more susceptible to disruption than low rates. The highest doses of cocaine completely eliminated responding in both schedule components. The high-rate behavior of the third subject was not affected by low or intermediate doses of cocaine, while low rates decreased at doses up to 5.6 mg/kg. The higher doses of cocaine eliminated responding in this subject as well. Prazosin and both doses of ondansetron antagonized the behavioral effects of cocaine at doses that ranged from 1.0-3.0 mg/kg. Redetermination of the dose-effect curve for cocaine at the conclusion of the experiment revealed that the curve had significantly shifted to the right.     

Effects of amphetamine and pimozide on reinforcement and motor parameters in variable-interval performance

The effects of amphetamine and pimozide were studied in rats performing on variable-interval (VI) schedules of reinforcement. In experiment 1, a five-component multiple VI schedule was used; in experiments 2 and 3, two VI schedules were presented on alternate days; a fourth experiment was carried out to validate the two VI methods. The Herrnstein matching law was used to distinguish between changes in reinforcer efficacy and changes in motor capacity. In both procedures, amphetamine, at 0.5 mg/kg, caused changes compatible with an increase in reinforcer efficacy with no change in motor capacity; higher doses (only tested in the multiple schedule) appeared further to increase reinforcer efficacy and also to decrease motor capacity. In the multiple schedule, pimozide caused changes compatible with either a decrease in reinforcer efficacy or a decrease in motor capacity, depending on the order of presentation of the schedule components; in the alternating schedule, pimozide had both effects. These discrepancies appeared to be due to changes in the effect of pimozide over time, which could not be explained either by satiation or by a gradual onset of drug action.     

Cocaine self-administration in monkeys: effects on the acquisition and performance of response sequences

A three-component multiple schedule of intravenous cocaine self-administration (0.01-0.3 mg/kg), repeated acquisition and performance was used to examine the effects of self-administered cocaine on learning in rhesus monkeys. A 0.03 mg/kg infusion of cocaine maintained reliable self-administration without markedly decreasing overall response rate or increasing the percentage of errors in the acquisition and performance components in which food was presented. When saline was substituted for 0.03 mg/kg of cocaine, there was little or no effect on responding in the acquisition or performance components while the number of infusions and response rate in the self-administration component decreased. These effects occurred to a greater extent under a FR 90 schedule (Experiment 2) as compared to a FR 30 schedule (Experiment 1) of cocaine self administration. Substitution of higher infusion doses of cocaine also decreased response rate and the number of infusions in the self-administration components, and substantially decreased responding in the acquisition components; decreases in overall accuracy of responding were evident when responding in this schedule component occurred. Taken together, these data indicate that learning is generally more sensitive than performance to the disruptive effects of self-administered cocaine.     

Chlorpromazine effects on behavior under escape and fixed-time delivery of shock

Chlorpromazine has typically been found to reduce responding maintained by negative reinforcement. In squirrel monkeys, however, it has been shown to increase manipulative responses that occur just prior to shock presented under a fixed-time schedule. The present study compared chlorpromazine effects on behavior of rats under a fixed-time schedule of shock delivery and a schedule involving escape from shock. In all conditions, shock was delivered to the tail of rats held in partial restraint, and the response measured was displacement of a panel positioned directly in front of the rat's nose. The escape and fixed-time schedules generated similar temporal patterns and rates of responding under both schedules, and had no differential effect on the temporal distribution of responses within the shock-shock interval.     

Disruption of learning by excitatory amino acid receptor antagonists

Compounds that act as competitive or uncompetitive N-methyl-D-aspartate (NMDA) antagonists, glycine/NMDA-site antagonists, or alpha-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxalzolepropionic acid (AMPA)-receptor antagonists were evaluated for effects on a repeated acquisition of behavioral chains schedule by rats. Responding by rats was maintained by food presentation under a repeated acquisition or a performance procedure. Under the repeated acquisition procedure, subjects acquired a different three-response chain each daily session. Thus, each day a new learning curve could be generated for each animal thereby providing a repeated measure of learning. Food was presented under a second-order fixed-ratio three (FR3) schedule. Under the performance schedule rats responded under the same second-order FR3 schedule of food presentation: however, instead of a new sequence being presented each day, the same sequence of responding was required for each daily session. Both the competitive (CGS 19755) and uncompetitive (dizocilpine) NMDA antagonists distrupted repeated acquisition at doses that did not disrupt performance. In contrast, the glycine/NMDA antagonist MDL 104,653 or the competitive AMPA receptor antagonist LY 293558 did not disrupt acquisition or performance up to doses that suppressed responding. These results suggest there are different roles for various excitatory amino acid receptors, or sites on the NMDA receptor, in the neural bases of learning and that the disruption of acquisition by glutamate antagonists is dependent upon the particular receptor at which they have activity as well as the particular modulatory site of action.     

Interactions between naloxone and narcotic analgesics under three schedules that induce polydipsia

A pattern of schedule-induced polydipsia was maintained in rats by a fixed-time schedule where food pellets were presented every 90 sec, a fixed-interval schedule where licking the drinking tube produced pellets every 90 sec, or a fixed-interval schedule where lever presses produced pellets every 90 sec. Under all 3 schedules, injections of morphine, methadone, etonitazene and meperidine generally decreased licking rates and amounts of water consumed, as well as rates of lever-pressing under the schedules where lever presses were required. Naloxone (1 mg/kg) almost completely blocked the effects of morphine and etonitazene, but the effects of methadone sometimes were blocked to a lesser degree. Small increases in the rate of licking and amount of water consumed after the lowest dose of meperidine under the schedule requiring lever-presses were blocked by naloxone, but the higher doses of meperidine that decreased licking, lever-pressing and amount of water consumed under the three schedules were not blocked by naloxone. These data suggest that there are important differences in the ability of naloxone to antagonize the behavioral effects of different narcotic analgesics.     

Irt>t schedule controlled behavior in 'learned-helpless' rats: effects from a cannabinoid agonist

Human depression is partly a congenital disorder. Aspects of the behavior accompanying depression can be magnified by genetic manipulation of bred animal species. Learned Helplessness (LH) is a trait-mark behavior that successfully breeds in rodents. Here, 'congenital' LH (cLH) rats were trained to recognize and respond to 12s long interval cues (irt>12s schedule). Rats compliant to an irt>t schedule will space responses evenly and respond rhythmically. Irt>t schedule derived data are plotted in histograms showing irt (interresponse time) frequencies. A pause response peak emerges, for outbred rats, at irt values approximating the minimum interval for reinforcement. cLH rats [n=9] complied poorly to schedule contingencies when diluent (vehicle) was injected before testing. Moderate and high dose injections of a CB 1 receptor selective agonist drug (AM 411), however, increased operant schedule compliance and normalized the cLH rats' irt>t histogram distributions. Performance indicators for cLH rats are presented alongside coordinate measures from a comparison group [n=5] of normally bred Sprague-Dawley (SD) rats. In both cLH and SD rats, treatment session histograms revealed shifts of the pause response peak not accompanied by a change in motor responsiveness. The irt>12s histogram shifts were absent when AM 411 dosages were arranged to follow pre-medication injections of a CB 1 receptor selective antagonist drug (AM 251). In short, AM 411 increased timing acuity in rats prone to behavioral despair but had opposite timing effects in normally bred SD rats.     

Influence of intravenous self-administered psychomotor stimulants on performance of rhesus monkeys in a multiple schedule paradigm

Rhesus monkeys were trained to complete three multiple schedules. The schedules consisted of three components: a fixed interval (component 1), a variable interval (component 2), and a fixed ratio (component 3). During components 1 and 2, pressing lever 1 was always reinforced by food delivery. During component 3, pressing lever 2 resulted in either food delivery or intravenous infusions of saline solution, solutions of cocaine, of d-amphetamine, of phenmetrazine, or fenetylline. In schedule I, animals were presented with all three components independent of key-pressing behavior during components 1 and 2. In schedule II the availability of component 2 was dependent on completion of component 1. Component 3 was made available only on completion of component 2. Noncompletion of components 1 or 2 resulted in timeoutperiods of 15 and 10 min, respectively. Schedule III was identical with schedule II, except that in schedule III the completion of components was indicated only by a change in the lever lights. The influence of self-administered drugs on behavior in all three components was evaluated. Self-administration of psychomotor stimulants impaired the performance of animals and delayed completion of components 1 and 2 of schedules I, II, and III. The effects on behavior were similar with low drug intake in schedule III, moderate intake in schedule II, and high drug intake in schedule I. These effects were strong with self-administration of phenmetrazine, moderate with self-administration of cocaine and d-amphetamine, and weak with self-administration of fenetylline.Dedicated to Professor Dr. Herbert Grünewald on the occasion of his sixtieth anniersary.This study was in part supported by a grant of the Federal State Department of Youth. Family and Health of the Federal Republic of Germany     

Schedule-induced drinking in humans: a potential factor in excessive alcohol use

The timed delivery of monetary reinforcement by a computer-controlled slot machine altered the amount of fluid drunk adjunctively by human subjects. In separate experiments, subjects were allowed access to one of three fluids, water, non-alcoholic beer, or alcoholic beer, while receiving monetary reinforcement from the slot machine on one of two Fixed-Interval schedules (FI30 s or FI90 s). The largest difference in intake between the two schedule conditions occurred when water was the fluid available, but a similar trend in consumption was observed in the other studies. Greater consumption occurred when reinforcement was presented on the FI90-s schedule, which was predicted from previous studies using animals. The possible interaction of schedule-induced drinking with other variables known to influence human alcohol consumption is discussed.     

Comparison of sucrose-sucrose to sucrose-ethanol concurrent responding in the rat: Reinforcement schedule and fluid concentration effects

Rats maintained at 80% of their ad lib body weight were trained on a two bar concurrent fixed ratio 8-fixed ratio 8 schedule with sucrose solutions presented at schedule completion. When the solutions were available on the same schedule of reinforcement, rats consistently responded more on the lever associated with the higher sucrose concentration over either less concentrated sucrose solutions or water. However, when a preferred 20% sucrose solution was placed on a high fixed ratio requirement (FR64) and a less preferred 2% sucrose solution remained on the lower ratio requirement (FR8), the rats were observed to increase their responding on the lever associated with presentation of the 2% sucrose solution. Response rates for the low concentrated sucrose solution increased to levels comparable to those seen when that solution was paired with water. These results were compared to prior studies using ethanol and sucrose as the available fluids.     

Tolerance to cocaine's effects on schedule-controlled behavior: role of delay between pause-ending responses and reinforcement

The schedule of reinforcement under which behavior is maintained is an important contributor to whether tolerance to the behavioral effects of cocaine develops. Schedule parameter value (for example, fixed-ratio size) has been shown to affect the development of tolerance under some schedule types but not others, but the specific procedural variables causing this effect remain to be identified. To date, schedule-parameter-related tolerance has developed when a longer pause after reinforcement does not lead to a shorter delay between the response that ends the pause and reinforcement. The current study investigated the importance of this variable in pigeons using a multiple chained Fixed-Ratio 1, Fixed-Time x schedule, in which the first key peck in a trial produced a stimulus change and initiated a delay at the end of which food was presented regardless of whether or not additional pecks were made during the delay. Dose-response curves were assessed before, during and after chronic (daily) administration of cocaine. Tolerance to the pause-increasing effects of cocaine occurred to a similar degree regardless of the scheduled time between the end of the pause and reinforcement. Therefore, the relationship between pause length and delay to reinforcement does not provide an explanation for schedule-parameter-related tolerance.     

Some effects of adiphenine,benactyzine, and chlorpromazine upon several operant behaviors

Summary Adiphenine, benactyzine, and chlorpromazine were studied in four tests of operant behavior: a fixed interval schedule of reinforcement, a variable interval schedule, avoidance conditioning, and a conditioned emotional response. Adiphenine was essentially inactive under all conditions studied. Benactyzine exhibited both rate-increasing and ratedecreasing activity, depending on the dose, the time after administration, and the behavioral test. Chlorpromazine showed a consistent depressant action in all tests, following the usual dose-response relationship.A slightly modified version of this paper was presented at the 1956 fall meetings of the American Society for Pharmacology and Experimental Therapeutics.     

面向RP的工业CT切片数据格式转换软件开发

针对原始的工业CT切片数据,应用矢量化软件提取工件封闭轮廓点数据,并通过轮廓配准、数据精简、三角网格划分、端面处理对轮廓点数据进行处理,实现了面向RP的工业CT切片数据格式转换.为使构成STL文件的三角网格更加优化,文中提出了平均点距值法数据精简与Delaunay三角化的网格精简相结合的数据精简算法,实例验证了该方法的正确性.     

普鲁卡因青霉素的溶液微粒结晶Ⅲ.结晶工艺优化

通过实验研究各操作参数对普鲁卡因青霉素结晶产品粒度的影响,来考察混合对普鲁卡因青霉素溶液微粒结晶过程的影响,从而得到了最佳结晶工艺,并应用于工业生产中。     

Antipsychotic drug effects on the behavior of squirrel monkeys differentially controlled by noxious stimuli

The effects of several antipsychotic compounds were examined on two types of behavioral performances of squirrel monkeys. Both behaviors occurred simultaneously and were maintained separately by different schedules using noxious stimuli. Steady rates of responding were maintained when a chain pulling response postponed electric shock delivery (avoidance schedule). Concurrently, positively accelerated rates of responding were maintained on a lever where the first response after 3 min produced electric shock (fixed-interval 3-min schedule). The effects of the different drugs depended both upon whether the behavior postponed or presented shock and on the particular drug. Chlorpromazine (0.001–0.03 mg/kg), haloperidol (0.001–0.01 mg/kg), molindone (0.001–0.03 mg/kg) and thiothixene (0.001–0.03 mg/kg) increased slightly or had no effect on responding under the shock-postponement schedule at doses that decreased responding maintained by shock presentation. The effects of clozapine, a clinically effective antipsychotic compound, differed markedly from the other antipsychotic drugs. Clozapine (0.01–1.0 mg/kg) increased responding maintained by the presentation of shock at doses that decreased responding under the shock-postponement schedule. Higher doses of these drugs decreased responding under both schedules and, with the exception of clozapine, resulted in increased frequency of shocks under the postponement schedule.