Alteration of response patterning by d-amphetamine on repeated acquisition in rats

The acute effects of d-amphetamine on response patterning in a repeated acquisition baseline were investigated with rats. Each session the animals acquired a different four-member response sequence on three levels. Each sequence (trial) completion produced a food pellet. Errors produced a brief timeout that was reset by responses made during the timeout. Acute doses of d-amphetamine (0.5–4.0 mg/kg) and saline were administered 30 min presession. The response patterns analyzed were perseverative responses to a single lever (runs), and a response to each lever in either a left-to-right or right-to-left direction (tranerses). The trial position, frequency, and lever location of error and timeout responses that occurred in the context of runs and traverses were studied. In contrast to control sessions, higher doses of d-amphetamine produced increases in the number of error and timeout responses emitted. The majority of these responses occurred as runs; traverse responding did not exceed control levels. Furthermore, the run error and timeout responding tended to occur early in the session and on a siingle response lever. The results are consistent with the view that d-amphetamine disrupts stimulus control and produces perseverative responding which may account for previous reports of disruption in repeated acquisition tasks following d-amphetamine administration.     

Effects of d-amphetamine,Org 2766, scopolamine,and physostigmine on repeated acquisition of four-response chains in rat

Adult rats were trained to emit a different four-response sequence on three levers for food reinforcement in each daily two-hour session. Four sequences of putatively equal difficulty were used, with each sequence recurring every fourth session. Within-session errors declined as a function of practice. Most subjects showed a significant idiosyncratic sequence bias. d-amphetamine, tested at 0.1–2.0 mg/kg, increased errors as a function of dose. Org 2766 had no effect. Scopolamine and physostigmine, tested at 0.01–1.0 mg/kg, increased errors only at the highest doses, which produced tremor or ataxia. Results were generally consistent with previous results from other species. It was concluded that repeated acquisition in the rat is feasible for behavioral pharmacology and toxicology but that long training times and sequence bias limit its practicality.     

Lack of blockade of central dopaminergic receptors by narcotics: comparison with chlorpromazine

d-Amphetamine and saline were used as discriminative stimuli in rats. After 0.6 mg/kg d-amphetamine administration, food reinforcement was contingent upon pressin 1 lever in 2-lever operant chamber. Responding on the other lever was reinforced only after saline injection of equal volume. The animals learned to discriminate between d-amphetamine and saline to a criterion of 85% correct. Administration of 2.5, 5.0 and 7.5 mg/kg morphine, and 0.02 and 0.04 mg/kg fentanyl produced saline-appropriate responses. Pretreatment with morphine and fentanyl had no significant effect on the d-amphetamine induced discriminative stimulus. In contrast, 1.25 and 2.5 mg/kg chlorpromazine antagonized d-amphetamine discrimination. These results indicate that despite their similar effect on brain dopamine turnover, morphine and fentanyl do not act on the same receptor site(s) as the neuroleptics, that is, they probably do not block brain dopamine receptors.     

Discriminative stimulus properties of d-amphetamine and related compounds in rats

The discriminative stimulus properties of amphetamine were demonstrated in rats trained to discriminate between 0.8 mg/kg of d-amphetamine sulfate and saline. During the discriminative training, animals were shaped on a DRL 15-second schedule to respond to one of two levers for a food reward when they were given d-amphetamine, and to respond to the other lever when they were treated with saline. Tests for the discriminative stimulus properties consisted of 10-min extinction sessions in which the reinforcement delivery was disconnected. Animals receiving low doses (0.2–0.4 mg/kg) of d-amphetamine exhibited mostly saline-like responses, but at a dose of 0.8 mg/kg they produced more than 80% responses on the amphetamine lever. Doses higher than 2.4 mg/kg caused an initial stereotyped behavior and the animals showed a period of latency before responding on the amphetamine lever. In order to elucidate the structural characteristics of d-amphetamine involved in the production of the discriminative stimulus properties, a number of amphetamine derivatives and related compounds were administered to these animals. 1-Amphetamine, ephedrine, norephedrine, 4-methoxyamphetamine and methylphenidate all produced the discriminative stimulus properties similar to d-amphetamine, but doses of 2–10 times greater than d-amphetamine were necessary. Mescaline, STP and DOET did not produce the d-amphetamine-like responses. These results suggest that most psychomotor stimulants, although having different structures, are likely to produce discriminative stimulus properties similar to d-amphetamine.     

Effects of amphetamine on food and fruit drink self-administration

The effects of oral d-amphetamine (0.12-1.0 mg/kg) on the responding of adult baboons were examined during choice sessions. In Experiment 1, responding on 1 lever was reinforced with 1 food pellet, and responding on a 2nd lever was reinforced with 4 food pellets. The response requirement (fixed ratio [FR]) on the latter lever was 4 times the FR value; that is, the unit price (responses/g) was the same. Amphetamine decreased responding on both levers similarly under all conditions. In Experiment 2, responding on 1 lever was reinforced with 1 pellet, and responding on a 2nd lever was reinforced with a sweet fruit drink. Amphetamine decreased responding reinforced by food to the greatest extent when the FR value was large and fruit drink was available. Findings indicate that choice procedures can provide baselines that allow the evaluation of the specificity of a manipulation on intake of a commodity.     

Intravenous diazepam in humans: Effects on acquisition and performance of response chains

A technique based upon an individual-subject design was used to investigate the effects of intravenous diazepam on the acquisition and performance of response chains in humans. In each of two conditions subjects were required to emit a different sequence of ten responses in a predetermined order on three levers. The conditions alternated within each session under a multiple schedule. In the performance condition the sequence of responses was the same each session. The second condition was a repeated-acquisition task. In this condition subjects were required to learn a different sequence of responses each session. Diazepam produced dose-dependent decreases in the overall rate of responding in each subject under both conditions. In two of the three subjects tested, errors were increased in the learning condition at doses lower than those required to disrupt accuracy in the performace condition. In one subject, accuracy in both the learning and performance conditions was equisensitive to the disruptive effects of diazepam. These data are consistent with the effects of the benzodiazepines in analogous animal procedures. Furthermore, the data suggest that the behavioral effects of intravenous diazepam may exhibit marked variations across subjects at clinically relevant doses (5–10 mg).     

Action of caffeine, d-amphetamine, diazepam and imipramine in a dynamic behavioural situation

A study has been made of how the chronic administration of caffeine, d-amphetamine, imipramine and diazepam affect rat behaviour in four successive trials in which the contingency for food delivery was switched from one lever where responses were previously reinforced to the other lever where responses had no programmed consequences (reversal). A complete extinction in the first reversal was obtained with diazepam 0.3 mg/kg/day. Caffeine (6 and 18 mg/kg/day) had no effect in the first reversal and damaged rat performance in the successive reversals. Imipramine (0.6 and 4 mg/kg/day) had the same effect but only in the fourth reversal. Amphetamine (0.16 and 0.7 mg/kg/day) caused a clear damage of rat performance only in the third and fourth reversals.     

Effects of d-amphetamine and cocaine on repeated acquisition with timeout from avoidance

The acute effects of d-amphetamine and cocaine on a repeated acquisition baseline with timeout from avoidance were investigated in two rats. Each session the animals acquired one of two different three-member response sequences. Each sequence member was associated with a different response lever. The first two correct responses of each sequence postponed shock for a fixed period of time. The third correct response initiated a signalled timeout (30 sec) from avoidance. Incorrect responses did not postpone shock. The baseline performance was characterized by a decrease in errors within each session, similar to patterns of repeated acquisition maintained by food. In comparison to control sessions, both d-amphetamine and cocaine increased errors and altered the pattern of within-session acquisition. d-Amphetamine increased the rate of sequence completion and the rate of shock delivery in both animals. Cocaine increased the rate of sequence completion in one animal and increased the rate of shock delivery for the other.     

Evaluation of the reinforcing effects of monoamine reuptake inhibitors under a concurrent schedule of food and i.v. drug delivery in rhesus monkeys.

Most medications prescribed for attention-deficit-hyperactivity disorder are psychomotor stimulants with reinforcing effects in laboratory animals (eg methylphenidate). The present studies were conducted to evaluate the reinforcing effects of the recently approved medication atomoxetine in monkeys trained to 'choose' between automated deliveries of either an i.v. injection or food. Rhesus monkeys were trained to lever-press under concurrent schedules of reinforcement; responses on one lever resulted in an injection of either saline or drug, and responses on the alternative lever resulted in food delivery. Data were collected on four measures: response rates, percentage of total responses occurring on the injection-lever (% ILR), number of injections earned, and number of food pellets earned. Dose-effect functions were determined for cocaine (0.003-0.3 mg/kg/inj), methylphenidate (0.003-0.1 mg/kg/inj), amphetamine (0.003-0.1 mg/kg/inj), atomoxetine (0.01-0.3 mg/kg/inj), and desipramine (0.03-1.0 mg/kg/inj) using a double alternation schedule of saline and drug availability. Results indicate that the distribution of behavior changed according to the drug and dose available for self-injection. Saline availability was typically associated with high rates of food-maintained responding. The % ILR increased from 3+/-1% when saline was available to >90% when >0.03 mg/kg/inj of cocaine, methylphenidate or d-amphetamine was available. However, no dose of atomoxetine or desipramine maintained self-administration behavior on the injection-lever. The number of food pellets earned per session decreased as the dose of each drug increased, indicative of behavioral activity with all five drugs. The reinforcing effects of cocaine, methylphenidate, and d-amphetamine in these studies are consistent with previous findings in nonhuman primates and with their documented abuse liability. The absence of reinforcing effects of atomoxetine support the view that, like desipramine, it has no evident abuse potential.     

The behavior of spontaneously hypertensive and Wistar Kyoto rats under a paced fixed consecutive number schedule of reinforcement.

Spontaneously hypertensive (SHR) and Wistar Kyoto rats (WKY) were trained under paced FCN schedules of reinforcement to complete a minimum number of consecutive responses on one lever, before responding on a second. The levers were retracted from the test chamber for a short period after each response to control the speed at which the rats could complete the sequence (paced FCN). Changes in the average chain length may reflect the influence of impulsivity on the execution of behavioral patterns. Although they quickly learned to press the levers, SHR rats performed poorly compared to the WKY rats when the chain length requirement was increased to FCN 6 and FCN 8. Eventually stable performance was obtained under paced FCN 6, although the SHR rats continued to have a consistently lower average chain length. Both strains of rats were treated with imipramine (10 mg/kg), chlordiazepoxide (3 and 10 mg/kg), d-amphetamine (0.4 and 0.8 mg/kg), haloperidol (0.05 and 0.1 mg/kg), 8-OH-DPAT (0.1 mg/kg), WAY-100635 (0.1 mg/kg), and DOI (0.3 and 1.0 mg/kg). The SHR rats were less sensitive to the effects of d-amphetamine, chlordiazepoxide, and DOI and slightly more sensitive to the effects of haloperidol. All of these drugs reduced the average chain length. There was no difference in the response of the two strains to imipramine and 8-OH-DPAT, both of which increased the average chain length. These results support the suggestion that SHR rats may more impulsive than WKY rats. The data with d-amphetamine and haloperidol support biochemical findings that these rats have a deficit in dopaminergic function, and the strain differences in response to chlordiazepoxide and DOI suggest that that there may be differences in GABAergic and 5-HT2-mediated neurotransmission relevant to regulating impulse control in the rat.     

Discriminative stimulus effects of etorphine in rhesus monkeys

Two rhesus monkeys were trained to discriminate the IM injection of etorphine (0.001 mg/kg) from saline in a task in which 20 consecutive responses on one of two levers resulted in food delivery. In both monkeys, etorphine (0.0001–0.0018), meperidine (0.1–1.0 mg/kg), morphine (0.1–3.2 mg/kg), and codeine (0.3–3.2) produced dose-related increases in the percentage of total session responses that occurred on the etorphine-appropriate lever. In contrast, ethylketazocine, SKF-10047, and pentazocine, at doses up to and including those that suppressed response rates, produced responses primarily on the saline-appropriate lever. Thus, etorphine-like narcotics, including morphine, have discriminative stimulus effects in rhesus monkeys which can be distinguished from those produced by narcotics with nonmorphine-like actions such as ethylketazocine, SKF-10047, and pentazocine.     

Effects of carbon monoxide in combination with behaviorally active drugs on fixed-ratio performance in the mouse

The effects of carbon monoxide (3.75, 7.5, 15 and 30 ml/kg, IP) alone and in combination with ethanol (1.1 g/kg), nicotine (1.1 mg/kg), caffeine (36.1 mg/kg), chlorpromazine (2.2 mg/kg), diazepam (10 mg/kg), pentobarbital (23.1 mg/kg), d-amphetamine (1.4 mg/kg) or morphine (13.3 mg/kg) were evaluated in mice. Animals were trained to lever press under a fixed-ratio 32 schedule of water reinforcement. Response rates following CO-drug combinations were compared with the expected additive effects determined by the sum of the effects of each agent administered alone. CO (15 and 30 ml/kg) in combination with ethanol produced supra-additive effects. CO-chlorpromazine and CO-d-amphetamine combinations often produced greater than additive response-rate suppression, although differences from additivity did not reach statistical significance. The effects on response rates following CO in combination with nicotine, caffeine, diazepam, pentobarbital, or morphine were additive. These results suggest that concurrent use of therapeutic or abused drugs and CO exposure may place an individual at higher risk for behavioral toxicity.     

Onset and offset of the Diazepam stimulus complex

Rats were trained to discriminate 3.0 mg/kg diazepam from saline in a two lever operant procedure. The time from injection to test session was 30 minutes. The diazepam discrimination consisted of initial responses on the lever paired with saline, but after training shifted to the lever paired with diazepam (onset). When tested with saline immediately after injection, animals responded consistently on the saline lever throughout the test. A shift from the drug lever to the saline lever at a later time point was also observed (offset). In addition, it was not possible to establish a peripheral diazepam drug stimulus complex. The result show that diazepam exerts discriminative control from 10 to 210 minutes after intraperitonal injections, confirming a central action of the diazepam drug stimulus complex. The method might be useful in experimentation on drug control of lever selection.     

Biphasic effects of 7-OH-DPAT on the acquisition of responding for conditioned reward in rats.

Previous studies have shown that dopamine (DA) receptor subtype-specific agonists differentially affect responding for conditioned reward D1-like agonists impair, whereas D2-like agonists enhance responding. The present study compared the effects of the D2-like agonists bromocriptine and 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT). Food-deprived rats (N=159) were preexposed to a chamber with two levers, one producing a tone (3 s) and the other turning the house lights off (3 s), for five 40-min sessions. In four subsequent 65-min conditioning sessions with the levers removed, the lights-off stimulus was paired with food (80 presentations per session). During two 40-min test sessions, the lights-off (CR) and tone (NCR) levers were replaced and responses at each lever were recorded. Confirming previous results, bromocriptine (0.50-5.0 mg/kg) dose-dependently enhanced responding on the lever producing conditioned reward. In contrast, 7-OH-DPAT had a biphasic effect on responding for conditioned reward. Low doses (0.10-0.25 mg/kg) reduced CR lever responding, whereas a higher dose of 1.0 mg/kg enhanced such responding. An intermediate dose of 0.50 mg/kg neither impaired nor enhanced CR lever responding. The biphasic profile of 7-OH-DPAT may arise through differential actions at D3 vs. D2 receptors or presynaptic vs. postsynaptic DA receptors at low and high doses, respectively.     

Rapid substitution procedure for intravenous drug self-administration studies in rhesus monkeys.

Rhesus monkeys were trained to press a lever one hundred times (FR 100) to obtain either a food pellet or an intravenous drug injection. Two daily experimental sessions, one in the morning and one in the afternoon, were divided into three 15 minute periods each. In Periods 1 and 3 lever pressing behavior was maintained by the delivery of food. Period 2 lever pressing was maintained by the intravenous injection of a drug solution. The drug available each day followed a four day sequence of cocaine (30 microgram/kg/injection), saline (1.0 ml/injection), cocaine, and test compound. This four day sequence was repeated to test a series of 16 psychoactive compounds at two doses each. These drugs were compared to saline for their ability to maintain Period 2 responding during the afternoon session. Morphine, oxymorphone, codeine, pentazocine, d-amphetamine and methylphenidate all maintained responding at rates significantly greater than for saline. Cyclazocine, naloxone, levallorphan, scopolamine, chlorpromazine, fenfluramine, and (+/-)-9-nor-9-alpha-hydroxy-hexahydrocannabinol (alpha-HHC) did not maintain responding during Period 2. The results with procaine, beta-HHC and nalorphine were considered equivocal. The authors suggest the use of a rapid substitution procedure as a method of initial screening of drugs with potential reinforcement efficacy.     

The effects of amphetamine, apomorphine, SKF 38393, quinpirole and bromocriptine on responding for conditioned reward in rats

The present study investigated the effects of the dopamine (DA) D1 selective agonist, SKF 38393, and the D2 selective agonists, quinpirole and bromocriptine, on responding for conditioned reward. The nonselective DA agonist apomorphine and the indirect agonist amphetamine, were also evaluated. Male rats (n = 302) were tested in a procedure consisting of three distinct phases. During the pre-exposure phase the rats were exposed to an operant chamber containing two levers; one lever produced a lights-off stimulus (3s) and the other a tone stimulus (3s). This was followed by 4 conditioning sessions during which the levers were removed and rats received pairings of the lights-off stimulus (80 per day) and food, presented according to a variable time 45s schedule. Two test sessions followed during which the levers were present and the number of responses made on each lever was calculated as a ratio of the number of responses made during pre-exposure. Drugs were administered prior to each test session. A saline group showed a higher ratio of responding for the lights-off stimulus than the tone stimulus, indicating that the lights-off stimulus had become a conditioned reward. Amphetamine (0.01-2.0mg/kg) and to a lesser extent, quinpirole (0.01-5.0mg/kg) and bromocriptine (0.05-10.0mg/kg) dose-dependently increased responding and specifically enhanced responding on the lever producing the conditioned reward. Apomorphine (0.1-5.0mg/kg) increased responding on both levers at higher doses but the conditioned reward effect was lost. SKF 38393 (0.1-10.0mg/kg) appeared to impair the acquisition of responding for conditioned reward. The results were interpreted as indicating that responding for conditioned reward may be dependent on a D1 receptor-mediated reward signal.     

A brief brain ischemia produces morphological damage of hippocampal CA1 pyramidal cells without affecting the sensitivities of psychoactive drugs in two types of discrete avoidance tasks in Mongolian gerbils

Effects of subcutaneous administration of psychoactive drugs: methamphetamine (0.13-1 mg/kg), chlorpromazine (0.5-2 mg/kg), physostigmine (0.05-0.2 mg/kg), scopolamine (0.031-0.5 mg/kg), pentobarbital (5-20 mg/kg), diazepam (0.5-2 mg/kg) and morphine (1.3-5 mg/kg) on discrete lever-press and shuttle avoidance responses were investigated in Mongolian gerbils that had received a brief (5 min) bilateral brain ischemic operation. Although some of the ischemic animals tended to show a retardation of acquisition of the avoidance responses, the established baselines were almost identical between the sham-operated and ischemic groups. In the lever-press task, morphine increased the response rate, whereas chlorpromazine, physostigmine, pentobarbital and diazepam decreased both the response and avoidance rates in a dose-dependent manner. In the shuttle avoidance task, both the response and avoidance rates were dose-dependently increased by methamphetamine, scopolamine and morphine, but chlorpromazine, physostigmine, pentobarbital and diazepam dose-dependently decreased them. These drug effects were almost the same between the sham-operated and ischemic groups. However, the ischemic-operation produced a significant loss of pyramidal cells in the CA1 sector of the hippocampus, the remaining level being less than 10% that of the sham-operated control animals.     

Specificity of chronic effects of diazepam on responding of rats under fixed-ratio schedules

Behavioral effects of diazepam were studied in rats responding in different daily sessions using different operant chambers and manipulanda. In one experiment, key pressing was maintained in a first session under a 40-response fixed-ratio schedule; lever pressing was maintained in a second session under a 40-response fixed-ratio schedule; and a third session consisted of a multiple schedule comprising both key and lever pressing maintained under a 40-response fixed-ratio schedule. In a second experiment, the first session consisted of a multiple schedule with both key and lever pressing maintained under a 40-response fixed-ratio schedule and the second session consisted of lever pressing maintained under a 40-response fixed-ratio schedule. After studying effects of widely spaced injections of diazepam (0.3-3.0 mg/kg) on responding for each separate schedule, animals received 1.7 mg/kg/day diazepam in order to study chronic effects of the diazepam on behavior among the different schedule-conditions. In both experiments, tolerance to rate-decreasing effects of diazepam in a particular schedule component did not extend to any other schedule component when the manipulandum or chamber was different, but did extend to other schedule components when the manipulandum or chamber was the same. These results suggest that behavioral effects of chronically administered diazepam were influenced not only by pharmacologic processes, but also by learned relationships among its interoceptive effects, reinforcement contingencies, and particular behavioral environments.     

The pharmacology of impulsive behaviour in rats II: the effects of amphetamine, haloperidol, imipramine, chlordiazepoxide and other drugs on fixed consecutive number schedules (FCN 8 and FCN 32)

 The effects of drugs on one aspect of impulsive behaviour were evaluated using a schedule in which rats were trained to complete a fixed consecutive number of responses on one of two levers before pressing the second to obtain a reinforcer (FCN). Terminating the chain before completing the FCN resulted in the omission of the food, and can be considered an impulsive decision. Two groups of food-deprived rats were trained to press either 8 or 32 times on the left lever (FCN lever) of a two lever operant chamber before pressing the right lever (Reinforcement lever) to deliver a food pellet. Responding on the Reinforcement lever before completion of the sequence resulted in a short time-out and the rat had to begin the sequence again. After responding had stabilised, the rats were treated with a range of doses of a number of drugs. Impulsivity was assessed by several measures, including the mean chain length and the proportion of chains terminating in food delivery, and the distribution of chain lengths was analysed. The efficiency of the rats was similar under both FCN 8 and FCN 32, although it was more difficult to maintain a consistent baseline under FCN 32. Under the FCN 8 schedule, significant decreases in chain length were obtained with d-amphetamine (0.8–2.4 mg/kg), haloperidol (0.1 mg/kg), ethanol (1 and 3 g/kg) and chlordiazepoxide (10.0 mg/kg), and there were alterations in other measures consistent with an increase in impulsivity. Imipramine (1–10 mg/kg), citalopram (1–10 mg/kg) and metergoline (0.3–3.0 mg/kg) had no effect on mean chain length, although the first two drugs shifted the chain length distribution to the left. d-Amphetamine (0.4–1.2 mg/kg) and PCPA (100 mg/kg) reduced chain length and had other effects consistent with increased impulsivity under FCN 32 schedule, whereas imipramine had little, and citalopram no, effect. Taken generally, effect of the active drugs was relatively non-specific, including both a reduction in response rate and alterations in choice measures proposed to reflect an increase in impulsivity. Detailed analysis of the effect of amphetamine revealed that three processes were at work: chain shortening, an increased preference for the lever most closely associated with food delivery, and a gradual shift in the control over responding from the response sequence (pattern) to the individual lever press (act). Received: 24 April 1997 / Final version: 14 January 1998     

Interactions of diazepam and pentobarbital with RO 15-4513 on intracranial self-stimulation discrimination behavior in rats

Rats implanted with electrodes in the lateral hypothalamus were trained in a discrete trial procedure to make a differential response (right or left lever press) in the presence or absence of brain stimulation. When a high level of accuracy (95% correct) was attained in the discrimination, testing with vehicle, RO 15-4513, diazepam (1.0-10 mg/kg), diazepam plus RO 15-4513 (1.0 mg/kg), pentobarbital (1.0-17.5 mg/kg) and pentobarbital plus RO 15-4513 began. Diazepam, at 10 mg/kg, disrupted the discrimination behavior, and it also decreased the total number of lever-presses and increased the time to complete the session. These effects were blocked by the coadministration of 1.0 mg/kg RO 15-4513. Pentobarbital produced effects similar to those of diazepam, but these effects were only reversed to a limited extent by RO 15-4513. By itself, however, RO 15-4513 also decreased the total number of lever presses and increased the time to complete the session. Results were consistent with our previous findings with alcohol and RO 15-4513, and supported the notion that diazepam and alcohol have some similar effects at the GABA-benzodiazepine receptor complex.