Differential modification of pentobarbital stimulus control by d-amphetamine and ethanol

The ability of d-amphetamine and ethanol to alter discriminative stimulus control by pentobarbital was examined in pigeons. Saline and pentobarbital (5.6 mg/kg) were established as discriminative stimuli for food-maintained responding in six birds. Dose-response functions for stimulus control and response rate were determined for pentobarbital alone and in combination with selected doses of d-amphetamine or ethanol. In tests of stimulus generalization, d-amphetamine alone did not exert pentobarbital-like stimulus control, while ethanol alone evoked variable degrees of pentobarbital-like stimulus control. d-Amphetamine attenuated pentobarbital stimulus control. Doses of 1.0 or 3.2 mg/kg d-amphetamine increased the dose of pentobarbital required for stimulus control in five of six birds. Combinations of high d-amphetamine and pentobarbital doses yielded less than additive rate suppression. Ethanol produced variable effects on pentobarbital stimulus control, with moderate doses generally decreasing, and high doses increasing, the dose of pentobarbital required for stimulus control. A high ethanol dose decreased the pentobarbital dose required for rate suppression. Taken together, these data demonstrate that pentobarbital stimulus control can be altered by drugs within or without the sedative hypnotic class.     

Behavioral analogues of anxiety animal models

In the absence of fully characterized biological indexes, anxiety is at present measured as unpleasant effects reported verbally by patients. Because of the subjective nature of the syndrome, animal analogues have been difficult to design, but quests for new anxiolytics and a deeper understanding of the neurobiology of anxiety have fostered the development of several animal models. Usually, animals are exposed to exteroceptive or interoceptive stimuli which can be interpreted as capable of causing anxiety in humans. Then, the animals are observed for responses or behavioral deficits resulting from those stimuli in order to provide an index of anxiety. Behavioral responses that are reliably produced by those stimuli and that are also antagonized by anxiolytic drugs are accepted as analogues of anxiety. Exteroceptive stimuli, useful in this respect, consist of a variety of noxious treatments such as exposure to conflictsituations or unavoidable electric shock, whereas interoceptive stimuli consist of treatment with anxiogenic drugs or electrical stimulation of selected brain areas. Elicitation of unconditioned behavior or changes in the rate of conditioned (learned) responding have been employed as measures of anxiety responses following application of either exteroceptive or interoceptive stimuli. These measures, although useful in detecting anxiolytic drugs, possess several weaknesses. They suffer from difficulties in obtaining quantitative and objective data, they do not differentiate between anxiety and stress or fear, they are unable to measure further deterioration of behavior expected to occur when more potent anxiogenic stimuli are tested and they often present difficulty in differentiating direct motor effects of a number of stimuli not related to anxiety. More recently, interest in the development of other analogues of anxiety has led to the use of drug-discrimination paradigms. In this approach, interoceptive discriminative stimuli, produced by anxiogenic drugs, are used as analogues of anxiety in animals. As an example of this approach, data are reviewed showing that pentylenetetrazol, an anxiogenic drug in humans, produces interoceptive stimuli which can be readily discriminated by rats. Further, these stimuli can be easily quantified through dose-response analysis. All known anxiogenic drugs generalize to pentylenetetrazol-induced interoceptive discriminative stimuli. Similarly, other anxiety-provoking situations in humans, such as withdrawal from dependence on benzodiazepines, also generalize to the pentylenetetrazol-induced stimuli. Alternatively, all known anxiolytic drugs antagonize these stimuli with a relative potency similar to those reported clinically. The data obtained from the drug discrimination procedure are collected through automatic devices, are objective and are in a format easily amenable to quantitative statistical treatment. Moreover, the measurements are independent of response rates and are, therefore, not confounded by the motor effects of either drug or other anxiogenic treatments. The novel development in animal analogues of anxiety as indicated by the drug discrimination technique shows potential for facilitating research on the neurobiology of anxiety as well as on mechanisms underlying anxiety disorders. It also provides a novel approach for the discovery of new drugs to treat anxiety.     

Drug-induced reinstatement of extinguished self-administration behavior in monkeys

Responding was established in squirrel monkeys under a modified progressive ratio schedule of IV d-amphetamine or cocaine self-administration. Substitution of saline for the drug solutions resulted in extinction of the self-administration behavior. IV injections of certain doses of d-amphetamine or cocaine, immediately prior to test sessions in which response-contingent saline infusions were delivered, reinstated the rate and pattern of responding observed during sessions in which drug was self-administered. Presession IV injections of several doses of pentobarbital or chlorpromazine failed to consistently reinstate responding. These results were interpreted in terms of the discriminative control of drug self-administration behavior by the current drug state of the subject.     

Effect of multiple discrimination reversals on acquisition of a drug discrimination task in rats

There are many similarities between exteroceptive stimuli and interoceptive stimuli. Nevertheless, it has been suggested that behavior maintained by drug stimuli might be more difficult to reverse than behavior controlled by exteroceptive stimuli. Once a discrimination is established with an exteroceptive stimulus, it can be reversed by switching the reinforcement contingencies, and repeated reversals result in progressively faster relearning of the discrimination. To determine whether faster relearning of successive discrimination reversals also occurs when the discrimination is controlled by an internal drug stimulus, we trained rats to discriminate 3.2mg/kg phencyclidine-(PCP) from saline, in a two-lever food-reinforced operant task. After this discrimination was acquired, the reinforcement contingencies were reversed. A number of such discrimination reversals were performed to determine whether fewer trials would be needed to reach criterion performance with each reversal. Each time the reinforcement contingencies were switched, fewer training sessions were required for the subjects to reach criterion. These results are similar to those observed when a discrimination has been established with exteroceptive stimuli. The present study provides further evidence of the similarity between interoceptive drug stimuli and exteroceptive sensory stimuli.     

Discriminative stimulus effects of pentobarbital in pigeons

Pigeons were trained to discriminate the IM injection of pentobarbital (5 or 10 mg/kg) from saline in a task in which 20 consecutive pecks on one of two response keys produced access to mixed grain. Pentobarbital (1.0–17.8 mg/kg) produced a dose-related increase in the percentage of the total session responses that occurred on the pentobarbital-appropriate key. The concomitant administration of bemegride (5.6–17.8 mg/kg) antagonized the discriminative control of behavior exerted by the training dose of pentobarbital. Benzodiazepines, diazepam (1.0 mg/kg) and clobazam (3.2 mg/kg), and barbiturates, methohexital (10 mg/kg), phenobarbital (56 mg/kg), and barbital (56 mg/kg), produced responding on the pentobarbital-appropriate key similar to that produced by pentobarbital. In contrast, narcotics such as morphine, ethylketazocine, cyclazocine, and SKF-10,047, at doses up to and including those that markedly suppressed response rates, produced responding predominantly on the saline-appropriate key. Similarly, the anticonvulsants, valproate, phenytoin, and ethosuximide occasioned only saline-appropriate behavior, indicating that not all anticonvulsants share discriminative stimulus effects with pentobarbital. Muscimol, a direct GABA agonist, and baclofen, a structural analogue of GABA, also failed to produce pentobarbital-appropriate responding. Ketamine, dextrorphan, and ethanol (0.3–3.2 g/kg, orally) produced intermediate levels of pentobarbital-appropriate responding, suggesting that the discriminative effects of these drugs may be somewhat like those of pentobarbital.     

Drug discrimination and generalization in pigeons

In a three-key operant conditioning situation six pigeons were trained to select the response key which was associated with each of three drug treatment conditions: d-amphetamine (2 mg/kg), pentobarbital (5 mg/kg), and saline. Thus, the drug state served as a discriminative stimulus for food reinforcement. After 20 sessions of discrimination training in each of the three conditions, more than 90% of the responses were correctly emitted in the presence of the appropriate drug or saline stimulus. Acquisition of the discrimination progressed at approximately equal rates for the three treatments. Subsequent to discrimination training, generalization gradients were obtained for several doses of the training drugs and for dose ranges of cocaine, morphine, and methocarbamol. The pigeons responded to morphine by choosing the key paired with pentobarbital during training; further, cocaine administration resulted in choice of the amphetamine key. However, metocarbamol, over the doses used, produced responding more characteristic of saline than of the other training drugs. The data suggest that a three-key operant discrimination procedure using pigeons provides a sensitive method for investigating the stimulus properties of relatively low doses of behaviorally relevant drugs.     

Phenytoin: Similarity to tricyclic antidepressants

Rats were trained to discriminate between the stimulus properties of intraperitoneal injections of 10 mg/kg phenytoin and its pH-adjusted vehicle in a two-lever, food-motivated operant task. Once trained, rats showed a dose-related decrease in discriminative performance with lower phenytoin doses. Administration of pentobarbital and chlordiazepoxide produced vehicle-appropriate responding, whereas injection of imipramine and amitriptyline produced intermediate results. Desipramine, at an intraperitoneal dose of 10 mg/kg, produced a pattern of responding similar to that observed after the training dose of phenytoin. These results demonstrate, for the first time, the ability of a non-disruptive dose of phenytoin to act as a behavioral discriminative stimulus in the rat and suggest the possibility of a common interoceptive cue property with tricyclic antidepressants.     

Drug effects on the repeated generalization of a visual discrimination acquired under one trial per day conditions

Six pigeons were trained to respond under concurrent fixed-ratio extinction schedules of food reinforcement (FR 50) on the side keys of a three key chamber. Presence or absence of continuously-flashing, colored lights on the center key signalled which key pecking response (left or right) would be reinforced over the course of an entire experimental session; thus, the lights were analogous to a drug cue in drug-discrimination situations. In test (generalization) sessions of one FR in duration, the percentage of light on the center key was varied from 0 to 100%. During these sessions, saline, lysergic acid diethylamide (LSD; 0.04–0.20 mg/kg) and morphine (3.75 mg/kg) produced orderly, log-linear light generalization gradients, but only LSD shifted the gradient to the right (by approximately 50%). These results demonstrate the potential value of the method for assessing the effects of drugs on both exteroceptive (light) and interoceptive (drug) stimulus control. The method has the additional advantage that the effects of drugs on such control (i.e., on stimulus generalization) are relatively unaffected by corresponding effects on response control (e.g., rate of responding).     

The effect of training dose on discrimination of compound drug-exteroceptive stimuli

Rats were trained to discriminate between two compound stimulus arrays that included exteroceptive (ES) and interoceptive (IS) stimulus components. The ES components were illumination and tactile cues, and the IS components were produced by d-amphetamine (A) or Na pentobarbital (P) treatment (drug versus drug discrimination). The relative ES-IS strength was then determined by testing with mismatched stimulus arrays consisting of combinations of ES and IS components that had not been presented simultaneously during training. Additional tests were done with ES only (no drug treatments). At training doses of 0.8 mg/kg A versus 10 mg/kg P, the ES were less salient than, but did share stimulus control with, the stronger IS components. In a second group, trained with lower doses (0.5 mg/kg A versus 4 mg/kg P), the ES were much more salient than the IS, although again, both types of stimuli did acquire some control. This dose-related sharing of stimulus control between ES and IS components is similar to relationships among components of compound arrays consisting entirely of ES, and thus further illustrates similarity between drug-produced and exteroceptive stimuli.     

Selective blockade of the discriminative stimulus effects of pentobarbital in pigeons

The ability of CNS stimulants to block the discriminative effects of pentobarbital was studied in pigeons trained to discriminate IM pentobarbital (5 mg/kg) from saline. Pentobarbital, when administered alone, consistently produced greater than 90% pentobarbital-appropriate responding. The concomitant administration of pentobarbital and increasing doses of bemegride or pentylenetetrazol resulted in a dose-related decrease in pentobarbital-appropriate responses. In contrast, picrotoxin, another CNS stimulant, had little or no effect on pentobarbital-appropriate responding produced by pentobarbital.     

Reinforcing and discriminative stimulus effects of Ca-acetyl homotaurine in animals

Ca-acetyl homotaurine (Ca-AOTA) has been proposed as an adjunct for ethanol detoxification. The purpose of the present experiment was to determine whether Ca-AOTA would be predicted to have abuse potential. Rhesus monkeys that were experienced in the intravenous self-administration of cocaine (n = 2) or pentobarbital (n = 2) were given the opportunity to self-administer various doses of Ca-AOTA or its vehicle (0.9% saline). Ca-AOTA (1.0-10.0 mg/kg/injection, intravenously) was not self-administered above saline levels. The discriminative stimulus effects of Ca-AOTA were evaluated in a drug discrimination procedure in which animals were trained to make one response after a training drug and a different response after saline. Rhesus monkeys trained to discriminate d-amphetamine (n = 3) or pentobarbital (n = 3) from saline were tested with doses of Ca-AOTA ranging from 10 to 100 mg/kg (PO by nasogastric tube) and at 3 different pretreatment times (1, 2, or 4 hr). Ca-AOTA failed to engender drug-appropriate responding at any dose or pretreatment condition in either group of monkeys. In addition, Ca-AOTA was tested in 4 pigeons trained to discriminate pentobarbital from saline. Ca-AOTA administration did not result in pentobarbital-appropriate responding in doses ranging from 30-300 mg/kg (IM) and pretreatment times ranging from 30 to 240 min. The lack of both reinforcing properties and discriminative stimulus properties similar to d-amphetamine or pentobarbital suggests that Ca-AOTA has little or no abuse potential.     

The effect of d-amphetamine on performance on two operant timing schedules

RATIONALE: Previous experiments have shown that d-amphetamine disrupts timing behaviour in rats. It has been proposed that d-amphetamine's effects reflect a reduction in the period of the pacemaker of the hypothetical internal clock. However, some studies have obtained conflicting results. OBJECTIVE: To examine the effects of d-amphetamine (0.2, 0.4, 0.8 mg kg(-1) i.p.) on performance on two quantitative timing schedules: a free-operant schedule, in which rats were trained to distribute their responses differentially between two levers during the course of a 50-s trial (free-operant psychophysical procedure), and a discrete-trials schedule, in which rats were trained to discriminate the duration of light stimuli (interval bisection task). METHODS: In experiment 1, rats were trained under the free-operant psychophysical procedure to respond on two levers (A and B) in 50-s trials in which reinforcement was provided intermittently for responding on A during the first half and on B during the second half of the trial. For one group, repetitive switching between levers was permitted; for another group, it was prevented. In experiment 2, rats were exposed to press lever A after a 2-s stimulus and lever B after an 8-s stimulus, and were then tested with stimuli of intermediate duration. For one group, a 'poke response' (depression of a central tray flap) was required after stimulus presentation to effect lever presentation; for the other group, this requirement did not operate. In both experiments, quantitative indices of timing were derived from the psychophysical functions (%B responding vs time). RESULTS: In experiment 1, d-amphetamine increased the Weber fraction and displaced the psychophysical curve to the left in both versions of the schedule, as well as producing rate-dependent suppression of responding. In experiment 2, d-amphetamine increased the Weber fraction in both versions of the task without displacing the curve. CONCLUSIONS: These results confirm the disruptive effect of d-amphetamine on timing. The results of experiment 1 are consistent with the proposal that the drug reduces the period of the hypothetical pacemaker. However, the results of experiment 2 do not support this suggestion. Taken together, the results support the notion that different neural mechanisms may be involved in timing tasks involving temporal distribution of responding and discrimination of the duration of exteroceptive stimuli.     

A role for receptors of N-methyl-D-aspartic acid in the discriminative stimulus properties of phencyclidine

Ketamine and (+)-N-allylnormetazocine ((+)-NANM) were found to generalize in a rat operant drug discrimination paradigm to the interoceptive stimulus induced by phencyclidine (PCP). Intraperitoneal administration of the non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, MK-801, and intracerebroventricular injection of the competitive antagonist, 2-DL-amino-7-phosphonoheptanoic acid (2-APH), also resulted in a dose-dependent generalisation to the PCP discriminative stimulus. The results suggest that NMDA receptor antagonism may play an important role in the mediation of the discriminative stimulus properties of PCP. The low potency of MK-801 and 2-APH to displace [3H](+)-NANM binding in vitro argues against an involvement of the haloperidol-sensitive sigma recognition site in the behaviour.     

Effects of altering motivation for food in rats trained with food reinforcement to discriminate between d-amphetamine and saline injections

Previous studies have shown that altering motivation typically affects stimulus generalization in animals trained to discriminate exteroceptive stimuli, but few studies have evaluated the effects of manipulating motivation on drug stimuli. In the few published studies, motivation levels were manipulated by arranging different feeding conditions prior to stimulus generalization tests with rats trained to discriminate morphine from vehicle and in pigeons trained to discriminate phencyclidine or pentobarbital from vehicle. In the present study, rats maintained at 80% of free-feeding weights were trained to discriminate between injections of 1.0 mg/kg d-amphetamine and saline in a two-lever food-reinforced operant procedure. Generalization tests were then conducted with a range of d-amphetamine doses (0, 0.03, 0.1, and 0.3, 1.0 mg/kg) when the rats were not fed before experimental sessions (high motivation) and when they were pre-fed 1 g of food (moderate motivation) or their daily ration of food (low motivation) 1 h before test sessions. Changing the motivation level significantly affected response rate and latency to the first response in generalizations tests, but did not significantly affect mean percentage of drug-appropriate responding (a continuous measure) or percentage of animals that selected the drug-appropriate lever (a quantal measure). The present findings indicate that manipulating motivation for food minimally impacts d-amphetamine discrimination, however, the range of conditions used to examine the effects of motivating operations on stimulus control by d-amphetamine drugs and other drugs is limited and the topic may warrant further investigation.     

Discriminative stimulus effects of NMDA in pigeons and monkeys

White Carneaux pigeons (Columbo livia) and rhesus monkeys (Macaca mulatta) were trained to discriminate NMDA from saline in a two-response operant procedure. Both species dose dependently generalized NMDA to the training stimulus, although training was difficult and stimulus control was difficult to maintain. The competitive antagonist CGS 19755 (0.32 and 1.0mg/kg) blocked the discriminative stimulus produced by the training dose of NMDA in pigeons and monkeys. The same doses of CGS 19755 produced rightward, but not dose-dependent, shifts in the NMDA dose-response function in pigeons The non-competitive NMDA antagonist PCP was unable to block the discriminative stimulus produced by the training dose of NMDA in pigeons. Kainate and AMPA, as well as morphine, pentobarbital and d-amphetamine, engendered >/= 90% NMDA-appropriate responding in at least 50% of pigeons tested. The finding that compounds form several different classes generalize to the training dose of NMDA suggests that the present discrimination lacks pharmacological selectivity. This discrimination may not serve efficiently as a procedure in which to examine NMDA agonist and/or antagonist activity.     

Discriminative stimulus effects of pentobarbital in rhesus monkeys: Tests of stimulus generalization and duration of action

Rhesus monkeys were trained to emit 20 or 30 consecutive responses on one lever following an IM injection of pentobarbital (10 or 18 mg/kg) and the same number of consecutive responses on another lever following an injection of saline. The required number of correct consecutive responses in both cases resulted in food delivery. When responding was reliably under the control of the presession injection, the ability of a variety of other compounds to produce pentobarbital-appropriate responding was examined. Diazepam, clobazam, methohexital, pentobarbital, and phenobarbital, given 10 or 20 min before the session, produced dose-related pentobarbital-appropriate responding in each monkey. Ethylketazocine and dextromethorphan produced responding primarily on the saline-appropriate lever, whereas codeine, cyclazocine, dextrorphan and ketamine resulted in responding that was, on the average, intermediate between that appropriate for pentobarbital and that appropriate for saline. When tested at various times after their injection, methohexital (3.2 mg/kg) and pentobarbital (10 mg/kg) produced pentobarbital-appropriate responding within 10 min. Barbital (56 mg/kg) resulted in pentobarbital-appropriate responding only if at least 1 h intervened between the injection and the experimental session. The discriminative effects of methohexital, pentobarbital, and barbital lasted approximately 20–60, 120–240, and 480–720 min, respectively. The time-course of the discriminative stimulus effects of barbiturates in the rhesus monkey appears to parallel closely other pharmacological actions of these compounds.     

Pharmacological characterization of the discriminative stimulus properties of the dopamine D1 agonist, SKF 81297

A range of selective dopamine D1 and D2 receptor agonists and antagonists was used to characterize to the discriminative stimuli produced by d-amphetamine (0.5mg/kg) and the D1 agonists SKF 81297 (0.1mg/kg). In rats trained to discriminate d-amphetamine (0.5mg/kg) from saline, d-amphetamine produced a dose-related increase in per cent drug lever responding, and SKF 81297 did not show any d-amphetamine-like discriminative stimulus effects; neither did SKF 81297 potentiate nor antagonize the d-amphetamine discriminative stimulus. In rats trained to discriminate SKF 81297 (0.1mg/kg) from saline, SKF 81297 produced a dose-related increase in per cent drug lever responding, and SKF 38393 and SKF 83565 elicited full SKF 81297-like effects despite the fact that these compounds have widely differing efficacies for stimulating adenylate cyclase. SKF 81297 had a 25-fold greater potency than SKF 38393 in this assay. The D2 agonists, PHNO and ropinirole, did not display any SKF 81297-like discriminative stimulus effects. The SKF 81297 discriminative stimulus was completely blocked by the D1 antagonist SCH 23390 but was not blocked by the D2 antagonist BRL 34778.     

Discriminative stimulus effects of alcohol in humans

The discriminative stimulus effects of alcohol were examined in 11 healthy moderate alcohol users. Study days occurred 5 days per week for 12–25 total days. Each day, participants completed visual-analog reports of drug effect and drug-discrimination tasks at 30-min intervals for 2.5 h following oral alcohol administration. Participants completed three phases. During the training phase, which occurred on the first 4 study days, participants were trained to discriminate color-coded placebo and alcohol doses (0 vs. 0.45 g per liter of body water (g/lbw)). Participants then completed a control phase, during which accurate drug-discrimination performance was verified. Finally, participants completed a testing phase, during which both training and intermediate doses (0.15 and 0.30 g/lbw) were administered. During the testing phase, 25 and 100% of responses occurred on the alcohol key at the 0- and 0.45-g/lbw doses, respectively, indicating that discrimination responding remained intact. At the low dose (0.15 g/lbw), 25% of the subjects responded on the alcohol key, whereas 75% of the subjects responded on the alcohol key at the moderate dose (0.30 g/lbw), indicating dose-related generalization to the training doses. These results confirm cross-species generality in the discriminative stimulus effects of alcohol, and further establishes the utility of human laboratory drug-discrimination procedures for analysis of the functional effects of alcohol.     

Interaction of d-amphetamine with pentobarbital and chlordiazepoxide: Effects on punished and unpunished behavior of pigeons

Key pecking of two pigeons was maintained under a multiple schedule of food presentation. In the presence of one keylight stimulus responding produced food according to a fixed-interval 5-min schedule. Additionally, during this component, each 50th response produced electric shock. When a different keylight stimulus was present, key pecking resulted in food delivery under a variable-interval 3-min schedule. Responding was suppressed by schock presentation (punishment) but was still positively accelerated throughout each fixed-interval cycle; steady response rates occurred during the alternate component when only the variable-interval schedule was in effect. Overall rates of punished responding were largely unchanged with d-amphetamine (0.1–3.0 mg/kg); unpunished responding was generally either increased slightly or was decreased. Pentobarbital and chlordiazepoxide (1.0–17.0 mg/kg) administered alone increased both punished and unpunished responding at most doses. Combinations of d-amphetamine with either pentobarbital or chlordiazepoxide produced increases in punished responding that exceed those obtained with either of these drugs alone. The combined effects of d-amphetamine and either pentobarbital or chlordiazepoxide on unpunished responding depended on the individual dose combinations. Combinations of d-amphetamine with pentobarbital or chlordiazepoxide produced effects on both punished and unpunished responding that differed substantially from those obtained when any of these drugs were administered separately.     

Discriminative stimulus properties of muscarinic agonists

In a two-lever, food-reinforced drug-discrimination paradigm separate groups of rats were trained to discriminate either arecoline, pilocarpine or oxotremorine from saline. The discriminative cues of all three agonists were potently blocked by scopolamine, but only by 30–60 fold higher doses of methylscopolamine. The three agonists all suppressed overall response rate. These rate-suppressant effects were not blocked by scopolamine in doses which blocked the discriminative cues. In generalization tests, arecoline elicited selection of the drug-appropriate lever in all groups of trained animals. Pilocarpine was discriminated as drug by all pilocarpine-trained animals and by a majority of oxotremorine-trained animals, but was not significantly discriminated by the arecoline-trained group. Oxotremorine was discriminated by all oxotremorine-trained animals but only by some pilocarpine-trained animals, and was not significantly discriminated by the arecoline-trained group. Morphine, haloperidol, chlordiazepoxide, pentobarbital and nicotine were not generalized to any of the training drugs. The discriminative stimuli produced by the training drugs are therefore specific and exhibit properties indicative of an origin at central muscarinic receptors but may not be identical.