Molecular mechanisms resulting in pathogenic anti-mouse erythrocyte antibodies in New Zealand black mice

A procedure was developed with pigeons to extend the experimental analysis of punished behavior and the effects of anxiolytic drugs. Under this procedure the completion of a fixed-ratio requirement on a changeover key switched between two variable-interval schedules of reinforcement that were programmed on a second response key. Under one schedule, correlated with a green keylight, key pecks produced only food; under the second schedule, correlated with a red keylight, key pecks produced both food and electric shock. Pigeons were switched into the component with shock if they did not enter that component within 5 min. Parameter values of the variable-interval schedules were manipulated systematically and the effects of two clinically active anxiolytic drugs, buspirone and chlordiazepoxide, were examined. Responding was suppressed during the component with shock (punishment) and, under non-drug conditions, pigeons infrequently switched into the punishment component; changeover responses occurred rapidly when switched into the punishment component. Both buspirone (0.1-3.0 mg/kg) and chlordiazepoxide (3.0-30 mg/kg) increased punished responding at doses that had little effect on unpunished responding; d-amphetamine (0.3-5.6 mg/kg), which was studied only under one parameter of the variable-interval schedule, produced greater decreases in rates of punished responding than in unpunished responding.(ABSTRACT TRUNCATED AT 250 WORDS)     

Punished behavior: increases in responding after d-amphetamine

Responding maintained in squirrel monkeys under a 10-min fixed-interval schedule of food presentation was suppressed by presenting a shock after every 30th response (punishment). During alternate 10-min periods of the same experimental session, but in the presence of a different discriminative stimulus, responding either had no effect (extinction) or postponed delivery of an electric shock (avoidance). During sessions when the avoidance schedule was not in effect, d-amphetamine sulfate decreased punished responding. When the avoidance schedule was present during alternate 10-min periods, however, d-amphetamine (0.01 minus 0.56 mg/kg, i.m.) markedly increased responding during punishment components. Increases in responding during avoidance components were also evident. The effects of d-amphetamine on punished responding depend on the context in which that responding occurs.     

Effects of d-amphetamine on responding of squirrel monkeys maintained under second-order schedules of food presentation, electric shock presentation or stimulus-shock termination

The effects of d-amphetamine (0.01-5.6 mg/kg i.m.) were studied on lever pressing of squirrel monkeys maintained under various second-order schedules by a visual stimulus (S) that, with separate monkeys, was occasionally paired with the presentation of either food, electric shock or with the termination of a stimulus in the presence of which shocks occurred. Under one condition, the first response after 5 min produced a 3-sec stimulus change and the fourth stimulus change was followed immediately by food delivery, electric shock presentation or by the termination of a stimulus in the presence of which shocks occurred [fixed-ratio (FR); fixed-interval (FI) [FR 4 (FI 5-min:S)]. The effects of d-amphetamine were also studied under the food- and shock-presentation schedules when food or shock occurred only once, at the end of each session, after completion of 53n 3-min fixed-intervals all of which ended with a brief stimulus change [FR 10 (FI 3-min : S)]. Under a third condition, each thirtieth response produced the 3-sec brief stimulus (FR 30 : S) and the first FR 30 completed after 5 min elapsed produced the stimulus followed by food or, with separate monkeys, electric shock [FI 5-min (FR 30:S)]. Low to intermediate doses of d-amphetamine (0.03-0.3 mg/kg) generally increased and higher doses (0.56-5.6 mg/kg) decreased responding under all conditions. The effects of d-amphetamine on responding maintained by brief stimuli under different types of second-order schedules are generally similar, regardless of the type of reinforcing event or particular second-order schedule.     

Effects of chlordiazepoxide, buspirone and cocaine on behavior suppressed by timeout presentation

Male Wistar rats were exposed to a two-component multiple schedule: a random-interval 30 s schedule of pellet presentation and a conjoint random-interval 30 s schedule of pellet presentation, random-interval 2 s schedule of timeout 10 s presentation. Once responding had stabilized subjects were injected intraperitoneally with vehicle, chlordiazepoxide (1-30 mg/kg), buspirone (0.1-4.2 mg/kg) or cocaine (1-30 mg/kg), 15 min before the start of the experimental session. Before drug administration, punished response rates were less than 30% of unpunished response rates for four of the six subjects, and 60% and 75% for the other two. Low doses of chlordiazepoxide (1 and 3 mg/kg) increased punished responding (range 25-300%), and slightly increased unpunished response rates (by 25% in all but one subject, whose rates increased by 75%). The higher doses of chlordiazepoxide (10-30 mg/kg) dose-dependently decreased response rates in both components. The lower doses of buspirone (0.1 and 0.3 mg/kg) either did not affect, or decreased response rates in both components of the schedule; the higher doses produced dose-dependent decreases. Low doses of cocaine (1, 3 and 5.6 mg/kg) did not affect response rates in either component of the multiple schedule, whereas higher doses produced a dose-dependent decrease in response rates, except for one subject whose punished response rates increased substantially. The behavioral effects of chlordiazepoxide and buspirone observed in the present experiment were similar to those observed in experiments in which response rates were suppressed by shock presentation.     

Punishment alters the discriminative stimulus effects of midazolam.

Experiment 1 examined the effects of punishment on the discriminative stimulus (DS) effects of midazolam (M) and pentobarbital (P) in 3 pigeons. Sessions began with a fixed-interval (Fl) 3-min schedule of food reinforcement. After 40 min, either saline (S) or 0.56 mg/kg of M was injected. A drug-discrimination (DD) component began 10 min later. Pecking the left key produced grain after S injections, whereas pecking the right key produced grain after M. Dose-response curves for M and P were obtained under these conditions and also when every 30th peck during the Fl was punished by shock. The introduction of punishment increased sensitivity to the DS effects of M and P. Experiment 2 examined whether a punishment history increases sensitivity to the DS effects of M. After DD training and testing, pecking was punished for 10 sessions. This history shifted the M dose-response curve to the left for 3 of 4 pigeons. These results emphasize the contribution of behavioral variables to the DS effects of drugs. Environmental variables appear to play a prominent role in guiding sensitivity to the subjective effects of drugs. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Reinforcement magnitude modulation of rate dependent effects in pigeons and rats.

Response rate can influence the behavioral effects of many drugs. Reinforcement magnitude may also influence drug effects. Further, reinforcement magnitude can influence rate-dependent effects. For example, in an earlier report, we showed that rate-dependent effects of two antidepressants depended on reinforcement magnitude. The ability of reinforcement magnitude to interact with rate-dependency has not been well characterized. It is not known whether our previous results are specific to antidepressants or generalize to other drug classes. Here, we further examine rate-magnitude interactions by studying effects of two stimulants (d-amphetamine [0.32–5.6 mg/kg] and cocaine [0.32–10 mg/kg]) and two sedatives (chlordiazepoxide [1.78–32 mg/kg] and pentobarbital [1.0–17.8 mg/kg]) in pigeons responding under a 3-component multiple fixed-interval (FI) 300-s schedule maintained by 2-, 4-, or 8-s of food access. We also examine the effects of d-amphetamine [0.32–3.2 mg/kg] and pentobarbital [1.8–10 mg/kg] in rats responding under a similar multiple FI300-s schedule maintained by 2- or 10- food pellet (45 mg) delivery. In pigeons, cocaine and, to a lesser extent, chlordiazepoxide exerted rate-dependent effects that were diminished by increasing durations of food access. The relationship was less apparent for pentobarbital, and not present for d-amphetamine. In rats, rate-dependent effects of pentobarbital and d-amphetamine were not modulated by reinforcement magnitude. In conclusion, some drugs appear to exert rate-dependent effect which are diminished when reinforcement magnitude is relatively high. Subsequent analysis of the rate-dependency data suggest the effects of reinforcement magnitude may be due to a diminution of drug-induced increases in low-rate behavior that occurs early in the fixed-interval. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

The effect of cocaine and D-amphetamine on punished responding

Various dosages of d-amphetamine (0.1, 0.5, 2.5 mg/kg) and of cocaine (5.0, 20, 40 mg/kg) were administered i.p. to each of 7 rats trained in an experimentally induced conflict procedure. Sessions were 1 hr in duration and consisted of five 12 min periods; responding was reinforced with food on a F124 sec schedule of reinforcement during each period; however, in periods 2 and 4 each response was followed by the application of footshock. Significant increase in responding did not occur in any period following any of the pretreatments. Cocaine (5.0, 20 mg/kg) and d-amphetamine (0.5, 2.5 mg/kg) significantly decreased responding in both punished and unpunished periods. Following these treatments the rate of responding in punished and unpunished components was not significantly different. This suggest that psychomotor stimulants may not selectively increase anxiety, at least at dosages which are not at the same time anorexic.     

Mechanisms underlying the effects of unsignaled delayed reinforcement on key pecking of pigeons under variable-interval schedules

Three experiments were conducted to test an interpretation of the response-rate-reducing effects of unsignaled nonresetting delays to reinforcement in pigeons. According to this interpretation, rates of key pecking decrease under these conditions because key pecks alternate with hopper-observing behavior. In Experiment 1, 4 pigeons pecked a food key that raised the hopper provided that pecks on a different variable-interval-schedule key met the requirements of a variable-interval 60-s schedule. The stimuli associated with the availability of the hopper (i.e., houselight and keylight off, food key illuminated, feedback following food-key pecks) were gradually removed across phases while the dependent relation between hopper availability and variable-interval-schedule key pecks was maintained. Rates of pecking the variable-interval-schedule key decreased to low levels and rates of food-key pecks increased when variable-interval-schedule key pecks did not produce hopper-correlated stimuli. In Experiment 2, pigeons initially pecked a single key under a variable-interval 60-s schedule. Then the dependent relation between hopper presentation and key pecks was eliminated by arranging a variable-time 60-s schedule. When rates of pecking had decreased to low levels, conditions were changed so that pecks during the final 5 s of each interval changed the keylight color from green to amber. When pecking produced these hopper-correlated stimuli, pecking occurred at high rates, despite the absence of a peck-food dependency. When peck-produced changes in keylight color were uncorrelated with food, rates of pecking fell to low levels. In Experiment 3, details (obtained delays, interresponse-time distributions, eating times) of the transition from high to low response rates produced by the introduction of a 3-s unsignaled delay were tracked from session to session in 3 pigeons that had been initially trained to peck under a conventional variable-interval 60-s schedule. Decreases in response rates soon after the transition to delayed reinforcement were accompanied by decreases in eating times and alterations in interresponse-time distributions. As response rates decreased and became stable, eating times increased and their variability decreased. These findings support an interpretation of the effects of delayed reinforcement that emphasizes the importance of hopper-observing behavior.     

CP-135,807, a selective 5-HT1D agonist: effects in drug discrimination and punishment procedures in the pigeon

CP-135,807 [3-(N-methylpyrrolidin-2R-ylmethyl)-5-(3-nitropyrid-2- yl)amino-1H-indole] binds with high affinity to central 5-HT1D receptors, and in functional studies produces dose-dependent decreases in extracellular serotonin. These and other findings have suggested that CP-135,807 may act as a terminal 5-HT autoreceptor agonist. In an attempt to characterize the behavioral activity of selective 5-HT1D ligands, adult male Carneau pigeons were trained to discriminate IM injections of 0.1 mg/kg CP-135,807 from saline under a two-key, fixed ratio schedule of food-reinforced key pecking. CP-135,807 and the structurally unrelated 5-HT1D agonist CP-286,601 fully and dose-dependently substituted for the training dose. In contrast, little substitution was observed following administration of 8-OH-DPAT, a potent 5-HT1A agonist, the 5-HT1B agonist CP-94,253, or the serotonin reuptake inhibitor sertraline. In addition, the discriminative stimulus produced by CP-135,807 was not blocked by WAY 100,635, a selective 5-HT1A antagonist, but was completely and dose-dependently antagonized by the selective 5-HT1D antagonist, GR 127935. In subjects trained under a multiple schedule of punished and unpunished responding, 8-OH-DPAT produced large increases in punished responding while having little effect on unpunished responding. In contrast, CP-135,807 and CP-94,253 produced no antipunishment effects, while GR 127935 produced modest increases in punished responding. Collectively, these results suggest that CP-135,807 produces centrally mediated psychoactive effects that differ distinctly from those of 5-HT1A agonists.     

A history of postponing shock does not appear to alter the discriminative stimulus effects of cocaine

Previous research has shown that the rate of punished lever pressing of monkeys is typically decreased by cocaine administration. However, cocaine increases punished responding in monkeys with a history of responding maintained by the postponement of shock presentation. This raises the question of whether other behavioral effects of cocaine differ following a history of postponing shock. The present experiment examined whether a history of postponing shock alters the discriminative stimulus effects of cocaine. Three squirrel monkeys were trained to discriminate cocaine (0.56 mg/kg, intramuscular) from saline. Presses on the left lever produced food following saline injections whereas presses on the right lever were reinforced following administration of cocaine. Occasional test sessions were conducted in which cocaine (0.1-0.56 mg/kg), midazolam (0.03-0.56 mg/kg) or pentobarbital (0.3-5.6 mg/kg) was injected prior to the session and responding on either lever was reinforced. Discrimination training was discontinued during a second experimental phase in which responding was maintained by shock postponement. Pulling a chain postponed mild shocks for 25 s, whereas shocks occurred every 5 s in the absence of responding. Next, the drug discrimination dose-response curves were redetermined. The dose-response curves for all drugs before and after the shock postponement history were similar. This outcome suggests that the influence of a history of shock postponement is specific to punished responding.     

Food-deprivation level alters the effects of morphine on pigeons' key pecking

Four pigeons pecked response keys under a multiple fixed-ratio 30 fixed-interval 5-min schedule of food presentation. Components alternated separated by 15-s timeouts; each was presented six times. Pigeons were maintained at 70%, 85%, and greater than 90% of their free-feeding weights across experimental conditions. When response rates were stable, the effects of morphine (0.56 to 10.0 mg/kg) and saline were investigated. Morphine reduced response rates in a dose-dependent manner under the fixed-ratio schedule and at high doses under the fixed-interval schedule. In some cases, low doses of morphine increased rates under the fixed-interval schedule. When pigeons were less food deprived, reductions in pecking rates occurred at lower doses under both schedules for 3 of 4 birds compared to when they were more food deprived. When pigeons were more food deprived, low doses of morphine increased rates of pecking in the initial portions of fixed intervals by a greater magnitude. Thus, food-deprivation levels altered both the rate-decreasing and rate-increasing effects of morphine. These effects may share a common mechanism with increased locomotor activity produced by drugs and with increased drug self-administration under conditions of more severe food deprivation.     

Response-independent events in the behavior stream

The metaphor of the behavior stream provides a framework for studying the effects of response-independent food presentations intruded into an environment in which operant responding of pigeons was maintained by variable-interval schedules. In the first two experiments, response rates were reduced when response-independent food was intruded during the variable-interval schedule according to a concomitantly present fixed-time schedule. These reductions were not always an orderly function of the percentage of response-dependent food. Negatively accelerated patterns of key pecking across the fixed-time period occurred in Experiment 1 under the concomitant fixed-time variable-interval schedules. In Experiment 2, positively and negatively accelerated and linear response patterns occurred even though the schedules were similar to those used in Experiment 1. The variable findings in the first two experiments led to three subsequent experiments that were designed to further illuminate the controlling variables of the effects of intruded response-independent events. When the fixed and variable schedules were correlated with distinct operanda by employing a concurrent fixed-interval variable-interval schedule (Experiment 3) or with distinct discriminative stimuli (Experiments 4 and 5), negatively accelerated response patterns were obtained. Even in these latter cases, however, the response patterns were a joint function of the physical separation of the two schedules and the ratio of fixed-time or fixed-interval to variable-interval schedule food presentations. The results of the five experiments are discussed in terms of the contributions of both reinforcement variables and discriminative stimuli in determining the effects of intruding response-independent food into a stream of operant behavior.     

The effects of levo-alpha-acetylmethadol and its metabolites on schedule-controlled behavior in the pigeon

The effects of orally administered levo-alpha-acetylmethadol (LAAM) on the schedule-controlled behavior of the pigeon were compared with those of methadone. Both LAAM and methadone decreased rates of responding under a multiple fixed-interval 5-min, fixed-ratio 30-response schedule of food presentation. Although LAAM had a longer duration of action than methadone, both drugs were similar in the onset and potency of their behavioral effects. The chronic administration of either LAAM or methadone produced tolerance to the respective behavioral effects of each drug. In one set of experiments, the behavioral effects of intramuscularly administered LAAM were compared with those of its active metabolites, levo-alpha-noracetylmethadol and levo-alpha-dinoracetylmethadol. All three drugs decreased rates of responding under both components of the multiple schedule. The onset of these rate-decreasing effects was rapid and the order of potency for the production of these rate-decreases was levo-alpha-noracetylmethadol greater than levo-alpha-dinoracetylmethadol greater than or equal to LAAM. The rate-decreasing effects of LAAM and its metabolites were typical narcotic effects as defined by their reversal by naloxone.     

Pavlovian and instrumental determinants of response suppression in the pigeon.

Exp I demonstrated the formation of a discriminated punishment effect in the absence of a conditioned emotional response. Electric shocks were delivered at random intervals to 3 naive male White Carneaux pigeons pecking for food on a variable-interval schedule. During a 1-min visual conditioned stimulus (CS), scheduled shocks were delayed until a response occurred (punishment). Differential suppression to the CS was observed in addition to overall suppression. Suppression was related to shock intensity. In Exp II with the same Ss, CS suppression was related to the CS and was not an artifact of response pattern or discrimination of shock patterns. The punishment contingency without the CS did not suppress behavior, and the CS without the punishment contingency did not relieve suppression. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of phencyclidine, pentobarbital, and d-amphetamine on the acquisition and performance of conditional discriminations in monkeys

In each of two components of a multiple schedule, monkeys were required to respond on a right or left lever depending upon the stimulus combination (a color and a geometric form) presented. Reinforcement of a response in the presence of one stimulus (the form) was therefore conditioned upon the other stimulus (the color). The completion of a two-member chain of discriminations produced a food pellet. Errors produced a brief timeout. One composition of the multiple schedule was a repeated-acquisition task where the discriminative stimuli for left- or right-lever responses changed each session (learning). In the other component, the discriminative stimuli for left- or right-lever responses were the same each session (performance). Phencyclidine, pentobarbital, and d-amphetamine each produced dose-related decreases in the overall rate of responding in both components of the multiple schedule. At high doses each drug increased the percent errors in each component. At lower doses, however, the three drugs produced selective effects on accuracy. Errors were increased in the learning component at lower doses than those required to disrupt the discrimination in the performance component. A signal detection analysis of the data revealed that none of the drugs tested increased errors by selectively affecting either discriminability or bias.     

Antipunishment activity of diazepam in rats trained to discriminate diazepam from vehicle.

The anxiolytic and discriminative stimulus effects of drugs in the same rats during a single session were examined in this study. Rats were trained to discriminate diazepam (5 mg/kg) from vehicle in a 2-lever drug discrimination procedure and were then trained to press a 3rd lever under a multiple fixed-interval (60 sec), fixed-ratio 5 + shock schedule of food reward. Diazepam produced substitution for itself in all rats; however, it produced antipunishment effects in some of the rats, suggesting that its discriminative stimulus and antipunishment effects are separable. In contrast, the N-methyl-{d}-aspartate antagonists, NPC 17742 and phencyclidine, failed to substitute fully for diazepam and did not increase punished responding in any of the rats. These results are consistent with those of studies showing that drugs from this class produce weaker antipunishment effects than diazepam does. The potential utility of this new method is that it allows direct comparisons of the antipunishment and discriminative stimulus effects of putative anxiolytic drugs during a single session with the same animals. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Multiple interruptions of responding maintained by a fixed-interval schedule of electric-shock presentation in squirrel monkeys.

Recent experiments have demonstrated that the characteristic pattern of responding engendered by a fixed-interval (FI) schedule of food reinforcement can also be established and maintained by response-contingent electric shocks. Under an FI schedule of food presentation, the characteristic pattern of responding survives repeated interruption by stimulus conditons absent at the time of reinforcement. The present experiment, with 3 male squirrel monkeys, demonstrates a similar phenomenon under circumstances in which the sole consequence of FI responding was the delivery of response-contingent shocks. Several possible interpretations of FI performance maintained by electric-shock presentation are discussed. (15 ref.) (French summary) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Comparison of chlordiazepoxide and food deprivation on punished and unpunished responding maintained by food.

Twelve adult rats pressed a lever in daily 1-hr sessions on a modified Geller-Seifter conflict schedule to earn a 45-mg food pellet every 2 min on the average in one component and a pellet accompanied by an incremental footshock for every response in the other component (multiple variable-interval 2-min [food] fixed ratio (FR) 1 [food plus shock]). Body weight (M?=?322 g) and baseline responding were maintained by restricting postsession food to 1 hr. Chlordiazepoxide 25 mg/kg po raised shock-suppressed responding by 79% over baseline. Omitting postsession food for 5 days reduced mean body weight by 10% and raised variable interval (VI) responding by 137% but raised shock-suppressed responding by only 25%. Results suggest that the ability of conventional anxiolytics to raise shock-suppressed responding is therapeutic-class-specific and is not based on appetite enhancement. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Fluvoxamine effects on concurrent ethanol- and food-maintained behaviors.

In previous studies, the selective serotonin reuptake inhibitor fluvoxamine preferentially reduced responding for ethanol compared with responding for food under conditions in which each was available alone in separate groups or in the same subjects under a multiple schedule in which baseline response rates were matched. The impact of providing concurrent access to food on pharmacological effects on ethanol self-administration remains largely unexplored. In this study, acute doses of fluvoxamine (3.0-17.8 mg/kg) were administered 30 min before the experimental session to Lewis rats responding under a concurrent fixed-ratio, fixed-ratio schedule of ethanol and food presentation. Ratios for food were adjusted for each subject to provide matched rates of food and ethanol reinforcement across the 30-min session. Although the number of ethanol and food deliveries did not significantly differ under baseline conditions, response rates did differ. Following fluvoxamine administration, responding for food was decreased more than responding for ethanol. This differential effect did not appear to be related to response rate or fixed-ratio size. Thus, the selectivity of fluvoxamine on ethanol- versus food-maintained responding depends on the context in which the behavior occurs. Such results may help explain inconsistencies between preclinical results and those in humans, and could provide insight into the behavioral determinants of pharmacological effects on ethanol self-administration. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of d-amphetamine, pentobarbital, chlorpromazine and promazine on electric shock postponement responding by the pigeon

The effects of d-amphetamine, pentobarbital, chlorpromazine and promazine on responding under schedules of electric shock postponement were studied in pigeons. Responding was maintained by three different response-shock intervals (10, 20 and 60 seconds). Low doses (0.3-3 mg/kg) of d-amphetamine increased response rates without decreasing shock rates under all three response-shock intervals. The highest dose (10 mg/kg) of d-amphetamine increased the shock rates under all response-shock intervals and decreased the high response rate under the 10-second response-shock interval but did not decrease the lower rates of responding under the 20- and 60-second response-shock intervals. Pentobarbital decreased the high rate of responding maintained under the 10-second response-shock interval at lower dose (10 mg/kg) than the lower rates of under the 20- and 60-second response-shock intervals. The high dose (17.5 mg/kg) of pentobarbital decreased responding and the low doses (1-3 mg/kg) had no effect under all three response-shock intervals. Chlorpromazine (3-100 mg/kg) did not affect the average rate of responding under all response-shock intervals and only slightly increased shock rates under the 20- and 60-second response-shock intervals. Promazine (3-30 mg/kg) increased the rates of responding and decreased shock rates under all three response-shock intervals. Analysis of the temporal patterns of responding within the response-shock interval showed that d-amphetamine tended to induce the animals to respond earlier than they normally would in the response-shock interval while otherwise maintaining the temporal pattern of responding, pentobarbital decreased the probability of responses late in the response-shock interval, and chlorpromazine and promazine increased the probability of responses in the middle of the response-shock interval, producing a lessening of the temporal patterning of responding within the response-shock interval.