The effects of clonidine on the partial reinforcement extinction effect (PREE)

Clonidine has been reported to exert anti-anxiety effects in animals and man similar to those of benzodiazepines. The present experiment examined the effects of clonidine administration on the partial reinforcement extinction effect (PREE) which is known to be sensitive to benzodiazepine action. Two groups of rats were trained to run in a straight alley. The continuously reinforced (CRF) group received food reward on every trial. The partially reinforced (PRF) group was rewarded on a quasi-random 50% schedule. All animals were then tested in extinction. Clonidine 50 g/kg was administered in a 2×2 design, i.e., drug-no drug in acquisition and drug-no drug in extinction. The PREE, i.e., increased resistance to extinction exhibited by PRF animals as compared to CRF animals, was obtained in animals that received saline in acquisition, independently of drug treatment in extinction, as well as in animals that received clonidine in both acquisition and extinction, but not in animals that received clonidine in acquisition alone. The administration of clonidine in extinction alone increased resistance to extinction in both the CRF and PRF animals. The increase in resistance to extinction, typically obtained with benzodiazepine treatment, indicates that clonidine exerts anxiolytic effects, supporting the involvement of the noradrenergic system in anxiety. However, clonidine did not fully reproduce the effects of benzodiazepines on the PREE, suggesting that the two classes of drugs may act via different noradrenergic mechanisms.     

Amphetamine does not affect the partial punishment effect (PPE)

The effects of amphetamine on the partial punishment effect (PPE) at one trial per day, were examined. Two groups of animals were trained to run in a straight alley. The continuously reinforced (CRF) group received food reward on every trial. The partially punished (PP) group received food reward on every trial but in addition, received footshocks of a gradually increasing intensity in the goal box on a random 50% of the trials. In the test stage, all animals received both food and footshock on each trial. dl-Amphetamine 1.5 mg/kg was administered in a 2 × 2 design, i.e. drug-no drug in training and drug-no drug in test. The partially punished animals exhibited increased persitence in running to the goal box during test, and this partial punishment effect was unaffected by amphetamine.     

Effects of haloperidol on the multitrial partial reinforcement extinction effect (PREE): evidence for neuroleptic drug action on nonreinforcement but not on reinforcement

Two experiments investigated the effects of haloperidol (0.1 mg/kg) on the partial reinforcement extinction effect (PREE). In experiment 1 two groups of rats were trained to run in a straight alley using six trials/day with an intertrial interval (ITI) of 5–8 min. The continuously reinforced (CRF) group received food reward on every trial. The partially reinforced (PRF) group was rewarded on a quasi-random 50% schedule. All animals were then tested in extinction. Haloperidol was administered in a 2 × 2 design, i.e., drug-no drug in acquisition and drug-no drug in extinction. In experiment 2 two groups of rats were trained to press a lever in an operant chamber using a discrete trial procedure of ten trials/day with an ITI of 60 s. The CRF group was rewarded on each trial and the PRF group was rewarded on a quasi-random 50% schedule. Haloperidol was administered for 22 days prior to the start of the PREE procedure as well as throughout acquisition and extinction. The PREE, i.e., increased resistance to extinction of PRF as compared to CRF animals, was obtained in both experiments in all drug conditions. In both experiments haloperidol increased the rate of extinction. Experiment 1 revealed that this effect was entirely dur to the administration of the drug in extinction, independently of the drug condition in acquisition. In contrast to previous results in a one trial/day procedure, the administration of haloperidol to CRF animals did not increase resistance to extinction, failing to support the notion that neuroleptics attenuate the rewarding properties of reinforcement.     

The partial reinforcement extinction effect after treatment with chlordiazepoxide

Two experiments are reported, in which rats were run in a straight alley for food reward with or without injections of the anti-anxiety drug, chlordiazepoxide (CDP). The experiments were directed to two questions. (1) Can one predict the effects of CDP from knowledge of the effects of a second anti-anxiety drug, sodium amylobarbitone (SA)? (2) Can the effects of CDP be predicted from the hypothesis that anti-anxiety drugs attenuate responses to conditioned frustrative stimuli? The experiments examined the effects of CDP on the partial reinforcement extinction effect (PREE) at one trial a day. CDP injected throughout acquisition and extinction reduced the PREE. This effect was probably due to the presence of the drug during acquisition. Injected during extinction only, CDP increased resistance to extinction in both continuous and partial reinforcement groups. These effects of CDP were closely similar to those previously reported for SA, thus answering question (1) in the affirmative. The effects of CDP on the PREE were also consistent with the conditioned-frustration hypothesis (question 2).     

The abolition of the partial reinforcement extinction effect (PREE) by amphetamine: disruption of control by nonreinforcement

Two groups of rats were trained to run in a straight alley. The continuously reinforced (CRF) group received a food reward on every trial. The partially reinforced (PRF) group was rewarded on a quasi-random 50% schedule. d-Amphetamine 1 mg/kg was administered to PRF animals in acquisition in a 2 X 2 design, i.e., drug-no drug on reinforced trials and drug-no drug on nonreinforced trials. In four CRF groups, the drug was administered in the same sequence as in the PRF groups. Following acquisition, all animals were given 4 days of CRF retraining and tested in extinction. No drug was given in retraining and extinction. The PREE, i.e., increased resistance exhibited by PRF animals as compared to CRF animals, was obtained in groups which received placebo on all acquisition trials or amphetamine on rewarded trials and placebo on nonrewarded trials. The PREE was abolished when amphetamine was administered throughout the acquisition trials or on nonrewarded trials, irrespective of drug treatment on rewarded trials.     

The partial reinforcement extinction effect: Influence of chlordiazepoxide in septal lesioned rats

Rats sustained electrolytic lesions either in the medial septal (MS) or lateral septal (LS) area or they were sham-operated. They were tested in the straight alley with food reward on either continuous (CRF) or partial (PRF) reinforcement at one trial a day and were injected with either 5 mg/kg chlordiazepoxide HCl (CDP) or with saline before the daily trial throughout acquisition and extinction. The effects of the drug on resistance to extinction interacted with those of the LS lesion in ways which were consistent with the hypothesis that CDP acts via the lateral septal area if it is injected during acquisition on a PRF schedule. MS lesions produced only small changes in the effects of CDP. In general, CDP acted to reverse the effects produced by each lesion: Under those conditions in which MS lesions produced faster running speeds, CDP caused the lesioned animals to run slower; and under those conditions in which LS lesions produced slower running speeds, CDP caused the lesioned animals to run faster.     

The effects of amphetamine on a multitrial partial reinforcement extinction effect (PREE) in a runway

Three experiments examined the effects of d-amphetamine (1 mg/kg) administration on the partial reinforcement extinction effect (PREE) using a multitrial procedure. Two groups of rats were trained to run in a straight alley. The continuously reinforced (CRF) group received food reward on every trial. The partially reinforced (PRF) group was rewarded on a quasi-random 50% schedule. All animals were then tested in extinction. Experiments 1 and 2 used 6 trials/day with an intertrial interval (ITI) of 5 min. In Experiment 1 the drug was administered only during acquisition, whereas in Experiment 2 it was administered throughout acquisition and extinction. Experiment 3 used 3 trials/day with a 20 min ITI. The drug was administered throughout acquisition and extinction. In all three experiments, amphetamine-treated animals showed a normal PREE, i.e., increased resistance to extinction in PRF as compared to CRF animals. These results stand in marked contrast to the amphetamine-induced abolition of the PREE with 1 trial/day procedure.     

The effects of amphetamine on a multitrial partial reinforcement extinction effect (PREE) in an operant chamber

Two experiments investigated the effects of d-amphetamine (1 mg/kg) on the partial reinforcement extinction effect (PREE) in an operant chamber using a discrete multitrial procedure. Experiment 1 used a random 50% partial reinforcement (PRF) schedule. Experiment 2 used two 40% PRF schedules: one schedule maximized the number of nonreinforced trials preceding any given reinforced trial (maximum N-length of four) and the second maximized the number of N-R transitions (N-length of one). In both experiments, the continuously reinforced (CRF) animals received a reward on every trial. The PREE, i.e., increased resistance to extinction of PRF as compared to CRF animals, was obtained in the random 50% PRF and the schedule maximizing N-length in both the placebo and amphetamine-treated animals. Both drug and no-drug animals failed to exhibit PREE on the schedule maximizing N-R transitions. These results show that on a PRF schedule with short intertrial intervals, amphetamine-treated animals are not impaired in their capacity to learn sequences of events and to associate the outcomes of preceding trials with subsequent consequences.     

Effect of chlordiazepoxide on the partial reinforcement extinction effect

Rats were trained to run in a straight alley under conditions of partial or continuous reinforcement. Extinction was slower after partial reinforcement. Chlordiazepoxide, administered during acquisition only, had no effect on acquisition but abolished the partial reinforcement extinction effect. The results support the hypothesis that chlordiazepoxide acts by attenuating the effects of averisive stimuli.     

The effect of d-amphetamine on operant behaviour maintained under variable-interval schedules of reinforcement

Dose-response curves were obtained for the effects of d-amphetamine sulphate (0.1–3.2 mg/kg) on the operant performance of rats in variable-interval 4-min and variableinterval 20-min schedules of reinforcement. Response rates maintained under variable-interval 4-min were suppressed in a dose-dependent manner. Response rates maintained under variable-interval 20-min schedules tended to be elevated by low doses and suppressed by higher doses. The degree of response rate suppression was greater in the case of the variable-interval 4-min schedule. The results are consistent with the previously reported effect of d-amphetamine on the values of the two constants of Herrnstein's (1970) equation: the drug reduces the reinforcement frequency needed to maintain the half-maximum response rates (K _h) and lowers the maximum response rate (R _max) (Bradshaw et al. 1981 b). It is suggested that the effects of d-amphetamine on operant performance may involve two processes: an enhancement of motivation and a reduction of the capacity to respond.     

Timing and space usage are disrupted by amphetamine in rats maintained on DRL 24-s and DRL 72-s schedules of reinforcement

Rationale  A differential-reinforcement-of-low-rate schedule (DRL) delivers reinforcement only when the interresponse time (IRT) exceeds a fixed time interval, thereby shaping rats to discriminate the timing of their responses. However, little is known about the motor behavior and location of the rats in the chamber during the IRTs that lead to reinforcement. Although amphetamine is known to disrupt DRL timing behavior, the effects of this drug on non-operant motor behavior during DRL performance has not yet been quantified. Objective  The purpose of this research was to measure the motor behavior (movement trajectories in the horizontal plane and spatial location in the plane) during longer IRTs after either vehicle or amphetamine treatment. Materials and methods  Experimental chambers were constructed with a force-plate actometer as the floor, and while performing the operant task, the rats’ motor behaviors were measured continuously with high temporal and spatial resolution. Separate groups of eight male Sprague–Dawley rats were maintained on either DRL 24-s or DRL 72-s schedules of water reinforcement in 4-h recording sessions. Results  Analyses of IRT distributions showed that the rats’ timing behavior conformed to their respective DRL requirements. In the absence of drug, analysis of motor behavior in pre-reinforcement intervals showed that rats located themselves away from the operandum and exhibited very low levels of movement. Rats exhibited a significant temporal diminution of horizontal movement that reached a minimum 4–8 s before the rats moved to the operandum to execute operant responses. Amphetamine treatment increased locomotion, abolished the temporal movement gradient, and brought the rats closer to the operandum compared to vehicle treatment. Movement changes induced by amphetamine were accompanied by degraded timing behavior. Conclusions  Taken together, the data show that DRL training induced rats to locate themselves away from the operandum and to remain nearly motionless during longer IRTs and that amphetamine treatment interfered with this complex of behavioral features     

Amphetamine and the multitrial partial reinforcement extinction effect (PREE) in an operant chamber: procedural modifications that lead to an attenuation of the PREE.

The partial reinforcement extinction effect (PREE) consists of the fact that animals receiving partial reinforcement (PRF) exhibit higher resistance to extinction than animals receiving continuous reinforcement (CRF). In previous studies, we found that amphetamine (AMPH) did not affect resistance to extinction of PRF animals trained with a multitrial procedure, but abolished resistance to extinction of PRF animals trained with a 1 trial/day procedure. Based on theoretical distinctions regarding the processes underlying the development of increased resistance to extinction at short and long intertrial intervals, we suggested that AMPH disrupts the formation of a context-mediated association between stimuli associated with nonreinforcement and subsequent reinforcement. To examine further this possibility, we designed conditions in a multitrial PRF procedure that do not allow a direct association between stimuli associated with nonreinforcement and reinforcement, and thus promote a context-mediated association between them. Two experiments were conducted in an operant chamber. In experiment 1, instead of the conventional 50% schedule of reinforcement throughout PRF training, days of 33% schedule of reinforcement were interspersed with days of continuous reinforcement; in experiment 2, a block (5 days) of 50% PRF schedule was alternated with a block (5 days) of CRF training, given either prior to or following PRF. In experiment 1, interspersing days of CRF training with days of 33% reinforcement schedule led to an attenuation of the PREE in AMPH-treated animals. In experiment 2, control animals that received CRF training either prior to or following PRF training exhibited a PREE similar to animals trained on PRF alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reversal and nonreversal shifts under amphetamine

Rats were trained in a Y maze on a two-choice simultaneous brightness discrimination with light as S⁺ and dark as S^– (position irrelevant). Half of the animals were then switched to reversal, where the reinforcement contingencies of the original training were reversed, and the other half were switched to nonreversal, in which they learned a simultaneous right-left discrimination. Nonreversal was acquired faster than reversal in saline injected animals. The administration of 1 mg/kg d-amphetamine did not affect the acquisition of the initial brightness discrimination and of nonreversal. In contrast, the drug facilitated dramatically reversal learning.The results indicate that amphetamine enhances the attention to, or the associability of, the discriminative stimuli, leading to rapid learning to these stimuli under changed contingencies of reinforcement. Offprint request to: I. Weiner     

The effect of microinjections of amphetamine into the neostriatum and the nucleus accumbens on self-stimulation behaviour

The effect of micro-injections of dexamphetamine chloride into the neostriatum, the nucleus accumbens, the anterior hypothalamus, and the ventricular system on selfstimulation with electrodes in the ventral tegmentum was studied. Unilateral injections of 10 g into the anterior hypothalamus produced no effect. Injections into the neostriatum tended to depress the self-stimulation rate, whereas injections into the nucleus accumbens increased the rate markedly.Bilateral injections (2×2.5 g and 2×5 g amph.) into the nucleus accumbens were more effective than unilateral injections and were as effective as systemic injections of 1 mg/kg amphetamine (i.p.). Bilateral injections into the neostriatum also increased the self-stimulation rate. Injections of 10 g into the ventricular system resulted in a smaller increase which was not statistically significant. These results are discussed in relation to the involvement of the dopaminergic system in the maintenance of self-stimulation behaviour.     

Measuring impulsivity in mice using a novel operant delayed reinforcement task: effects of behavioural manipulations and<Emphasis Type="Italic"> d-</Emphasis>amphetamine

Rationale The increasing use of genetically modified mice to probe genetic contributions to normal and abnormal behaviours requires the development of sensitive and selective behavioural tasks.Objectives To develop a discrete trial assay of impulsivity (delayed reinforcement) that is tractable in mice utilising a mouse operant nine-hole box apparatus and to specify the task with respect to behavioural and pharmacological manipulations.Methods Mice were trained to respond with a nose-poke to one of two visual stimuli; one response resulted in a small quantity of reinforcer, the other in a larger quantity of reinforcer. As the session proceeded increasing delay was introduced onto the response leading to the large reward. Hence, the nature of the choice was a small quantity of reinforcer immediately versus a larger but progressively delayed amount of reinforcer. At stable baseline performance the mice were challenged with a variety of task manipulations and systemic d-amphetamine in order to discern aspects of the underlying psychological and neurochemical substrates of the choice behaviour.Results The mice showed a systematic shift in responding away from the large reinforcer with increasing delay (0, 2, 4, 8, 12 s), such that at the longest delay >80% of nose-pokes were for the smaller, immediate reinforcer. Task manipulations indicated that behaviour was controlled in a trial discrete manner by the contingency between delay and reward and was not due to non-specific factors such as satiation. d-Amphetamine had complex, dose dependent effects on choice behaviour which revealed dissociations between impulsive choice and hyperactivity. Conclusions We have successfully developed an assay of impulsivity in mice that will be of utility to examine impulsive behaviours and their genetic substrates. In addition, our data provided evidence of distinct dopaminergic mechanisms mediating aspects of impulsivity and hyperactivity.     

An automated method for studying exploratory and stereotyped behaviour in rats

A technique is described for studying exploratory as well as stereotyped behaviour in rats using an automated hole-board. Both visual and automated recordings can be employed using the technique. Hole dipping is monitored automatically using an infra-red detector system. Repetitive patterns of hole-dipping are used as parameters of stereotyped behaviour while the more random patterns of hole-dipping are used as parameters of exploration.There was a high significant correlation between the records of hole-dipping behaviour as recorded visually and automatically. There was also a high significant correlation between the measures of repetitiveness/randomness of hole-dipping behaviour from automatic and visual recordings. The pattern and levels of hole-dipping conformed with expectations both as regards changes with time and with increasing doses of dl-amphetamine.     

Effects of RO 15-1788 on a running response rewarded on continuous or partial reinforcement schedules

Two experiments were run in which rats were rewarded with food for running in a straight alley at one trial a day, followed by extinction of the running response. During acquisition of the response, reward was delivered either on a continuous reinforcement (CRF) or on a quasirandom 50% partial reinforcement (PRF) schedule. The groups given PRF were more resistant to extinction than those given CRF, the well-known partial reinforcement extinction effect. In Experiment 1 different groups of rats were injected during acquisition only with 1, 5 or 10 mg/kg of the benzodiazepine antagonist, RO 15-1788, or with placebo. In Experiment 2, 5 mg/kg RO 15-1788 or placebo were administered in a full cross-over design during acquisition, extinction or both. At the end of Experiment 2 only [³H]-flunitrazepam binding was measured in either the presence or absence of added -aminobutyrate (GABA) in homogenates of hippocampi dissected from the animals that had received behavioural training. The drug affected running speeds during both acquisition and extinction in different ways depending upon the schedule of reinforcement (CRF or PRF) and also gave rise to enhanced GABA stimulation of [³H]-flunitrazepam binding. The results are discussed in relation to the hypothesis that the neurochemical pathways by which reinforcement schedules modify behaviour include a step influenced by benzodiazepine receptors.     

Low-level continuous amphetamine administration selectively increases alcohol consumption

Rats dramatically increased alcohol preference following the subcutaneous implantation of slow-release d-amphetamine pellets, so long as access to ethanol was withheld during the initial 6 days after pellet implantation. This increased ethanol preference was not due to a conditioned flavor aversion, nor to increased caloric intake, nor to alcohol deprivation. d-Amphetamine must be administered in a continuous fashion in order to obtain this effect, for daily injections of the same amount of the drug did not increase ethanol intake. This increased ethanol preference is interpreted as self-medication. This effect may provide a new animal model for the tension-reduction theory of ethanol intake.     

The effects of psychotropic drugs on exploratory and stereotyped behaviour of rats studied on a hole-board

Exploratory and stereotyped behaviour of Male Wistar rats was studied on a hole-board. The two forms of behaviour were differentiated according to the pattern of hole-dipping activity. Increasing doses of dl-amphetamine stimulated both forms of behaviour with stereotyped behaviour becoming predominant particularly at the higher dose levels. At the highest dose of amphetamine used (16 mg/kg) a gradual transition from exploratory to stereotyped behaviour was observed with time. As the drug wore off this transition was reversed. Haloperidol at a dosage of 0.1 and 0.05 mg/kg blocked the response to a high dose of amphetamine whereas a lower dose (0.02 mg/kg) blocked the stereotyped response to amphetamine while some exploratory behaviour still took place. Apomorphine inhibited hole-dipping but at lower doses another form of exploratory behaviour was induced, this behaviour becoming stereotyped as the dose was increased.It is concluded that there is a close relationship between exploratory and stereotyped behaviours. Monoamine systems appear to play a significant role in the regulation of both forms of behaviour.     

Long term effects of chronic chlordiazepoxide (CDP) administration

Three experiments were carried out to test the long-term behavioral effects of 12 days administration of CDP (5 mg/kg/day) in rats. In the first two experiments, 4 weeks after the end of drug administration (CDP or placebo), and after 2 weeks of training to run a straight alley for food reward, animals were tested in extinction, i.e., following omission of reward (Expt. 1) or with punishment, i.e., 0.3 mA electric shock in addition to the food reward (Expt. 2). Drug-treated animals showed significantly increased resistance to extinction and to punishment compared with controls. In the third experiment, 10 weeks after drug administration, animals were exposed to 60 s of intense noise to induce audiogenic seizures. The convulsant metrazol was injected 5 min prior to successive sessions (10 min apart) with doses starting at 10 mg/kg and increased by 10 mg/kg each session up to 40 mg/kg. Drug-treated animals were significantly less susceptible to seizures than their placebo controls. These results suggest that chronic benzodiazepine treatment causes long-term neurochemical changes which are responsible for the observed behavioral effects.