Discrimination of an amphetamine-pentobarbitone mixture by rats in an AND-OR paradigm

Rats were trained to discriminate a mixture of amphetamine plus pentobarbitone from either drug separately in a two-bar procedure with food reinforcement. Discrimination was 86% accurate after 48 sessions, and no dose of amphetamine or pentobarbitone alone produced mixture-appropriate responding. Some mixtures increased response rates whereas the same doses of each drug separately had little effect. The same rats were then trained to discriminate a mixture from saline. There was a continuing lack of discriminative response to amphetamine and only a partial response to pentobarbitone, and under these conditions mixtures did not increase overall response rates. Thus, the way rats are trained, and their previous history, can determine the characteristics of the cue obtained.     

Training dose as a decisive factor for discrimination of a drug mixture in rats

The impact of training dose on the characteristics of a discrimination maintained by a mixture of two dissimilar drugs has been investigated in order to refine this approach to the study of drug interactions. Three groups of rats (n = 10) were trained to discriminate mixtures of (+)-amphetamine (0.2-0.8mg/kg) plus pentobarbitone (5-20mg/kg) from saline, in a two-lever operant procedure with food reinforcement, with the ratio of the doses held constant (amphetamine: pentobarbitone, 1:25). Discriminations were acquired to an accuracy of 90-97%. There was full generalisation to amphetamine alone, but only in rats trained with mixtures of the smaller doses of the single drugs. There was partial generalisation when either apomorphine (50%) or nicotine (63%) was administered alone, and the magnitude of these responses was inversely related to the dose of mixture used for training. Doses of pentobarbitone half of those used for training produced little discriminative response when administered alone to rats trained with the two smallest doses of the mixture; the same doses of pentobarbitone increased responses to amphetamine or apomorphine in a more than additive manner. Strikingly, some doses of apomorphine and pentobarbitone that did not generalise when administered separately, produced full generalisation when administered together, but only in rats trained with the smaller doses of the mixture. In contrast, pentobarbitone did not enhance generalisation to nicotine in any group. It was concluded that, on the one hand, patterns of generalisation to single drugs followed an orderly pattern resembling those for discriminations established with single drugs. On the other hand, there was a complex pattern of generalization from one mixture to another; thus, altering the doses of drugs used for training markedly influenced discriminations of an abused drug mixture, but no simple rules to predict the influence of training dose have been ascertained.     

Attentional effects of nicotine and amphetamine in rats at different levels of motivation

Rationale The effects of drugs on performance of tasks used to assess attention might be confounded with changes in motivation. Few studies have investigated the role of motivational factors in such situations.Objectives To determine how changes in motivation for food influence performance of the 5-choice serial reaction time task and whether the effects of nicotine and amphetamine can be explained by motivational changes.Methods Male hooded Lister rats were trained to respond to a 1-s light stimulus presented randomly in one of five apertures in order to obtain food reinforcers. For three groups of rats (n=9–10), access to food was restricted to maintain body weights at 80, 90 or 95% of control weights. Saline and nicotine (0.025–0.2 mg/kg) were tested in each group, with and without pre-feeding (5 g). In a second experiment, saline and amphetamine (0.03–0.9 mg/kg s.c.) were tested without pre-feeding.Results High levels of motivation for food were associated with increases in anticipatory responses, fewer omission errors, shorter response latencies and completion of more trials, without change in accuracy. Nicotine, but not amphetamine, increased accuracy and the number of trials completed; whereas amphetamine, but not nicotine, increased omission errors. Both drugs decreased anticipatory responding at the largest doses tested. There were few interactions of motivational level with drug effects.Conclusions The improvements in performance produced by nicotine did not resemble the effect of increased motivation, but some effects of amphetamine resembled those of reducing the level of motivation for food. Motivational levels did not confound assessments of the attentional effects of the drugs in terms of response accuracy.     

Ethanol-amphetamine interaction effects on spontaneous motor activity and fixed-interval responding

The spontaneous motor activity (SMA) of rats was recorded after injections of saline, d-amphetamine sulfate (0.8 mg/kg), and ethanol (400, 800, 1200, and 1600 mg/kg). Each drug treatment was given separately, and the amphetamine treatment was also combined with each ethanol dose. Ethanol, when injected without amphetamine, produced a dose-related decrement in SMA. Amphetamine, injected without ethanol, produced an increase in SMA. The combination of ethanol at 400 mg/kg with amphetamine potentiated the amphetamine-stimulant effect, but higher doses of ethanol counteracted amphetamine-produced increment in SMA. In a second experiment, similar combinations of ethanol and amphetamine were administered to rats leverpressing for food pellets under a fixed-interval reinforcement schedule. The effect of amphetamine alone depended on baseline rate and varied among individual rats. Ethanol had a depressant effect on response rates, but combinations of the two drug treatments produced rates that, in most rats, were higher than after any single drug or saline treatment.     

The effect of viloxazine on drug-induced inhibition of food intake in the rat

In male Wistar rats trained to eat their normal daily dietary requirement in a restricted 2 h period, dose-dependent decreases in food consumption were produced by fenfluramine, tiflorex, mazindol and amphetamine. The antidepressant drug viloxazine (Vivalan) alone did not alter food intake significantly, nor did the drug prevent the inhibitory effects of either mazindol or amphetamine. However, complete prevention of the inhibitory effect of fenfluramine was achieved with 7.5 mg kg-1 viloxazine, while 40 mg kg-1 viloxazine similarly prevented the anorectic action of tiflorex. An interaction involving 5-hydroxytryptaminergic mechanisms is suggested, and since viloxazine given after fenfluramine or tiflorex produced no reversal of the inhibition of food intake, it is suggested that viloxazine prevents access of the anorectic agents to their site of action. The clinical significance of these interactions is discussed.     

The effect of viloxazine on drug-induced inhibition of food intake in the rat

In male Wistar rats trained to eat their normal daily dietary requirement in a restricted 2 h period, dose-dependent decreases in food consumption were produced by fenfluramine, tiflorex, mazindol and amphetamine. The antidepressant drug viloxazine (Vivalan) alone did not alter food intake significantly, nor did the drug prevent the inhibitory effects of either mazindol or amphetamine. However, complete prevention of the inhibitory effect of fenfluramine was achieved with 7·5 mg kg^?1 viloxazine, while 40 mg kg^?1 viloxazine similarly prevented the anorectic action of tiflorex. An interaction involving 5-hydroxytryptaminergic mechanisms is suggested, and since viloxazine given after fenfluramine or tiflorex produced no reversal of the inhibition of food intake, it is suggested that viloxazine prevents access of the anorectic agents to their site of action. The clinical significance of these interactions is discussed.     

The interaction of d-amphetamine and naloxone differs for rats trained on separate fixed-interval or fixed-ratio schedules of reinforcement

The effects of d-amphetamine and naloxone were investigated using two groups of rats trained on either an FR30 or F12 schedule of reinforcement. Amphetamine (0.1-1.0 mg/kg), and naloxone (1.0 and 10 mg/kg) administered separately reduced responding on the FR procedure in a dose-dependent manner. The combined administration of naloxone with amphetamine had an additive suppressive effect on responding. The same doses of amphetamine and naloxone, when given separately, did not significantly depress responding in the FI procedures. However, naloxone/amphetamine combinations produced a marked inhibition of lever-pressing. Naloxone did not alter the characteristic pattern of responding engendered by amphetamine in this schedule, as measured by the quarter-life and Index of Curvature. It appears that the type of procedure used is a critical factor in demonstrating the effects of naloxone on behavior, and the nature of naloxone/amphetamine interactions.     

Performance influence on the development of tolerance to amphetamine

This experiment was performed to determine whether performance of a behavior in the drug state was necessary for behavioral tolerance to the effects of that drug to occur. Eight rats trained on a DRL 17.5-sec schedule received daily injections of 1.5 mg/kg d-amphetamine sulfate; four received amphetamine 30 min presession, and four received amphetamine 30 min postsession. Amphetamine given presession initially resulted in a disruption of timing behavior, an increase in response rate, an increase in short IRTs and a decrease in the number of reinforcements received. With continued administration of presession amphetamine the rats developed a partial tolerance to these disruptive effects. Postsession amphetamine had no effect on performance. When tolerance developed in rats receiving presession amphetamine, they were switched to postsession amphetamine; rats receiving postsession amphetamine were switched to presession amphetamine. Amphetamine produced the same disruption of performance in the rats switched to presession amphetamine as was observed in the initial pressession amphetamine group, indicating that tolerance did not develop to amphetamine given postsession. In addition changes in the pattern of responding were observed when amphetamine was initially administered presession.     

Pharmacological properties of thalidomide (α-phthalimido glutarimide), a new sedative hypnotic drug

Thalidomide (α-phthalimidoglutarimide, “Distaval,” “Contergan”) is a new sedative hypnotic drug which produces no toxic effects when administered orally to animals in massive doses. This lack of toxicity may be due to limited absorption. The drug has a quietening effect on the central nervous system, reducing the voluntary activity of laboratory animals and promoting sleep. Unlike the barbiturate drugs it does not cause an initial excitation in mice, incoordination or narcosis. It potentiates the actions of other central nervous system depressants, in particular the barbiturates. Its sedative effects are counteracted by central nervous system stimulants. It has no deleterious side effects and does not affect the heart, respiration or autonomic nervous system.     

Acute behavioral and cardiac effects of cocaine and alcohol combinations in humans

Subjects received acute doses of orally administered alcohol (0–1.0 g/kg) and intranasal cocaine (4–96 mg/70 kg) alone and in combination in two experiments. Results generally were consistent across both experiments. Cocaine administered alone improved Digit Symbol Substitution Test (DSST) performance, increased subject ratings of stimulant-like effects, heart rate and blood pressure, and decreased skin temperature. Alcohol administered alone disrupted DSST performance, increased ratings of drunkenness, heart rate and skin temperature, and decreased blood pressure. Combining cocaine and alcohol attenuated the disruptions in DSST performance observed with alcohol alone, and either did not change or attenuated the improvements in performance observed with cocaine alone. Combining the drugs also attenuated effects observed with the drugs alone on skin temperature and, to a lesser extent, blood pressure. By contrast, drug combinations increased heart rate above levels observed when cocaine or alcohol were administered alone. Effects of the drug combinations on subject ratings were variable.     

Effects of GABA agonists and GABA-A receptor modulators on cocaine discrimination in rhesus monkeys

RATIONALE: Dopaminergic systems thought to mediate the abuse-related effects of cocaine are under inhibitory control by GABAergic systems. These findings suggest that GABA agonists may attenuate some abuse-related effects of cocaine. OBJECTIVE: To assess the effects of GABA receptor agonists and GABA-A receptor modulators on cocaine discrimination in rhesus monkeys. METHODS: Rhesus monkeys were trained to discriminate 0.4 mg/kg cocaine from saline in a two-key, food-reinforced drug discrimination task. The effects of the GABA-A agonist muscimol, the GABA-B agonist baclofen, the barbiturate GABA-A receptor modulator pentobarbital, and the benzodiazepine GABA-A modulators triazolam and imidazenil were examined alone and as pretreatments to cocaine. For comparison, the effects of pentobarbital pretreatment on the cocaine-like discriminative stimulus effects of amphetamine were also examined. RESULTS: When administered alone, the GABA agonists and GABA-A receptor modulators produced primarily saline-appropriate responding. When administered as pretreatments to cocaine, pentobarbital attenuated the discriminative stimulus effects of cocaine in all monkeys tested, and the high efficacy benzodiazepine agonist triazolam attenuated cocaine's effects in three of five monkeys. Muscimol, baclofen and the low efficacy benzodiazepine agonist imidazenil did not alter cocaine's discriminative stimulus effects. Although pentobarbital blocked the effects of the monoamine reuptake blocker cocaine, it did not alter the cocaine-like effects of the monoamine releaser amphetamine. CONCLUSIONS: These results are consistent with the hypothesis that GABA-A receptor modulators attenuate the discriminative stimulus effects of cocaine in rhesus monkeys by decreasing the activity of dopaminergic systems. Direct GABA receptor agonists may be less effective in blocking the abuse-related effects of cocaine in rhesus monkeys.     

The effects of clobazam and lorazepam on aspects of psychomotor performance and car handling ability.

1 Laboratory tests of psychomotor performance and 'on road' assessments of car handling ability were made following repeated doses of clobazam 10 mg three times daily, lorazepam 1 mg three times daily and matching placebo 1 capsule three times daily. 2 Both active compounds produced on impairment, compared to placebo, in some mental arithmetic and letter cancellation tasks, but these effects were neither widespread nor consistent. 3 Lorazepam produced a significant impairment of car driving tasks and analogue rating scales of subjective alertness. The pronounced sedative activity of the drug was also shown in the verbal reports of side effects and in indices of early morning sedation derived from the Leeds Sleep Evaluation Questionnaire. 4 Clobazam did not produce either the objective, or the subjective impairment of performance and alertness found with lorazepam. 5 The results taken as a whole show important differences between the 1,4 benzodiazepine, lorazepam, and the 1,5 benzodiazepine, clobazam, in their effects on the integrity of psychomotor performance related to car driving ability.     

Effects of d-amphetamine,morphine, naloxone,and drug combinations on visual discrimination in rats

The effects of d-amphetamine, morphine, and naloxone on visual discrimination were investigated using a two-choice discrete-trial procedure in which rats were trained to discriminate the position of a lightflash. Morphine (0.3–5.6 mg/kg) but not amphetamine (0.1–1.0 mg/kg) caused a significant dose-dependent disruption in discriminative performance. Both amphetamine and morphine increased response latencies. Naloxone (1.0 mg/kg) prevented the disruption of any aspect of performance by up to 100 mg/kg morphine. Performance after naloxone/amphetamine co-administration was not significantly different from that observed after amphetamine alone. Naloxone alone (0.3–10 mg/kg) had no effect on discrimination, spatial bias or response latencies. These results suggest that morphine and amphetamine affect different components of discrimination performance. Offprint requests to: S.G. Holzman     

Die Wirkung von Training und Amphetamin auf Ausdauer und Geschwindigkeit der Schwimmleistung der Ratte

Summary The effects on swimming performance of a 7 day training period and a subsequent application of 1,5 and 4 mg/kg amphetamine were measured in four groups of 10–12 rats each.In group 1 endurance was measured until the rats sank 40 cm below the water surface. In group 2 endurance was measured until the rats were breathing out 40 cm below the water surface. In these two groups training did not improve performance. 1,5 mg/kg amphetamine produced a small and non significant improvement. 4 mg/kg amphetamine produced an improvement which was significant for both groups together.In group 3 the rats had to swim 10 times in a row toward an escape ladder situated at the end of a water alley. In group 4 the task was essentially the same, however, the rats had to lift a load of a set of pullies by pulling at the thread attached to their tail, while swimming toward the escape end of the alley. Training produced in group 3 a small improvement of swimming speed and in group 4 a considerable one. Amphetamine had no effect in group 3 and produced in group 4 an impairment which was highly significant for the swimming condition with pulling the load and just below the level of significance for the condition without pulling the load.These opposite effects of amphetamine on endurance and speed of swimming are discussed in terms of the different requirements of the two behavioral tasks.     

Amphetamine disrupts successive but not simultaneous visual discrimination in the monkey

Three adolescent marmosets were trained on simultaneous and successive versions of a red-white visual discrimination task. The effects of doses of 0.2–1.2 mg/kg d-amphetamine on the performance of these tasks were assessed using a balanced design. It was found that while there was no drug effect on performance of the simultaneous task, amphetamine exerted a dose dependent disruptive effect on the successive version of the task. It is argued that amphetamine disrupts response control rather than discriminative ability and, in this respect, resembles the effect of orbitofrontal and limbic lesions in contrast to other neocortical lesions.     

The effect of amphetamine on Kamin blocking and overshadowing

Schizophrenic patients show deficits on stimulus salience tasks such as latent inhibition and blocking, which measure the ability to disregard irrelevant stimuli. Amphetamine-treated animals show similar deficits in analogous tasks, thereby providing a model of the stimulus-selection deficits observed in schizophrenia. In two experiments, the effect of the indirect dopamine (DA) agonist D-amphetamine sulphate (1.0 mg/kg, i.p.) on Kamin blocking and overshadowing were examined and compared, in the rat, using the conditioned lick suppression procedure. The aim was to provide some insight into the behavioural and pharmacological mechanisms underlying amphetamine effects in both paradigms. In experiment 1, it was shown that amphetamine selectively disrupted Kamin blocking, when given either at stage 2 alone, or at both stages of the task. In experiment 2, amphetamine treatment significantly abolished Kamin blocking and overshadowing, when administered prior to compound conditioning in both tasks. These data suggest that dopamine may play a critical role in mediating performance in tasks measuring stimulus salience processes. The results are discussed in the framework of the role of DA in stimulus-selection performance.     

Influencing the specificity of drug mixture discriminations by varying the training procedure

Studies of the discriminative stimulus effects of drug mixtures provide an approach to polydrug abuse and to studies on single drugs with multiple effects. The experiments described here investigated whether the use of the AND-OR procedure increases the specificity of drug mixture discriminations. Rats were trained to discriminate a mixture of nicotine (0.4 mg/ kg) plus midazolam (0.2 mg/kg) from saline (AND-discrimination, n = 10) or to discriminate the same mixture from its component drugs alone (AND-OR discrimination, n = 10). The studies used two-lever operant procedures with a tandem variable interval 1 min fixed ratio 10 (FR 10) schedule of food reinforcement. Under AND-discrimination conditions, there was partial generalization to amphetamine and pentobarbitone when each drug was administered singly. With the AND-OR-discrimination, there was no generalization to amphetamine and partial generalization to pentobarbitone. In 'single substitution' tests, pentobarbitone or amphetamine was co-administered with the training doses of nicotine and midazolam, respectively; there was full generalization in the AND-discrimination and no generalization under AND-OR conditions. In 'dual substitution' tests, mixtures of amphetamine plus pentobarbitone produced full generalization under AND-discrimination conditions, and partial generalization in the AND-OR procedure. Wherever comparisons were made, generalization was less under AND-OR- than under the AND-discrimination procedure, confirming that the AND-OR procedure can increase the specificity of discriminations based on drug mixtures. The similarity with findings reported previously for training with mixtures of amphetamine plus pentobarbitone suggests that this may reflect a general principle rather than a phenomenon restricted to particular training drugs.     

The interaction between benzodiazepine antagonists and barbiturate-induced cerebrovascular and cerebral metabolic depression

It has been reported that pentobarbital facilities binding to benzodiazepine receptors binding at anesthetic concentrations and that this action may play a role in the anesthetic potency of this barbiturate. The interaction between pentobarbital and benzodiazepine receptors was tested with Ro 15-1788 which is reported to be a pure benzodiazepine antagonist and 3-hydroxymethyl-beta-carboline (3-HMC), an antagonist which has inverse activity alone. Cerebral blood flow (CBF) and cerebral oxygen consumption (CMRO2) were measured in rats after injections of pentobarbital with and without the antagonists. Pentobarbital produced dose-dependent decreases in cerebral blood flow and cerebral oxygen consumption at 15 and 30 mg/kg. The antagonist Ro 15-1788 (10 mg/kg) stimulated cerebral blood flow and cerebral oxygen consumption alone but did not alter the cerebral depression produced by pentobarbital. The cerebral metabolic stimulation produced by Ro 15-1788 was unexpected since the drug is reported to be a pure antagonist without agonistic activity, but the lack of effect on pentobarbital-induced cerebral depression is consistent with other reports. 3-Hydroxymethyl-beta-carboline at 10 mg/kg did not stimulate cerebral blood flow and cerebral oxygen consumption but significantly antagonized the decrease in cerebral oxygen consumption produced by 15 mg/kg pentobarbital. 3-Hydroxymethyl-beta-carboline had no significant effect on decreases in cerebral blood flow and cerebral oxygen consumption produced by phenobarbital, a barbiturate which is reported not to alter binding to benzodiazepine receptors. The ability of 3-HMC to antagonize the effects of pentobarbital would be consistent with an action of both drugs at the benzodiazepine receptor but not by altering binding to an endogenous receptor.     

Effects of a single experience on subsequent reactions to drugs

The activity of rats in an unfamiliar environment was studied in order to determine how far their reactions to an amphetamine-barbiturate mixture depended on whether or not they had been under the influence of this mixture while exposed to the same environment once before. The environment consisted of a Y-shaped runway, and the activity studied was the number of entries into the arms of the Y during a three-minute trial; the two trials took place three days apart. At the first trial the drug mixture practically doubled activity. At the second trial rats which had been under the influence of the drug mixture at the first trial were again made more active by the drug mixture, but the drug mixture did not increase the activity of rats which had received only saline at the first trial. These results showed that a single brief exposure to an unfamiliar environment can markedly affect subsequent reactions to drugs, and interactions of this kind may have to be taken into account when it is desired to use animals repeatedly in tests of the action of drugs on behaviour. The drug mixture also produced ataxia which was assessed quantitatively by measuring the variability of the “splay” of the rats' footprints; ataxia was unaffected by previous experience.     

Convulsant versus typical barbiturates: effects on locomotor activity

The present studies examined the effects of a typical (secobarbital) and a convulsant (cyclohexylideneethyl-5-barbituric acid [CHEB]) barbiturate on spontaneous locomotor activity in rats. Administered alone, secobarbital produced a mild stimulation of activity at a low (2.5 mg/kg) dose, and a dose-dependent depression of locomotor activity at higher (5-20 mg/kg) doses. Surprisingly, the convulsant barbiturate CHEB produced a depression of locomotor activity at all subconvulsant doses tested (2.5-20 mg/kg). IP administration of CHEB was also observed to produce abdominal muscle contractions (writhing). In a second experiment, it was found that the writhe-inducing compound para-phenyl-quinone (PPQ) did not affect locomotor activity, indicating that the depression of activity produced by CHEB was not secondary to its writhe-producing effects. In a third experiment, the "barbiturate antagonist" potential of CHEB was examined. Treatment with 10 mg/kg CHEB did not significantly alter the depression of locomotor activity produced by 10 mg/kg secobarbital. These data suggest that (1) typical and convulsant barbiturates are not strict opposites in terms of all of their behavioral actions and (2) CHEB may not be effective as a "barbiturate antagonist."