Characteristics of pentobarbital discrimination in the gerbil: Transfer and antagonism

Experiment 1. Gerbils were trained in a T-shaped maze to discriminate the effects produced by pentobarbital (P-barb. 15 mg/kg, i.p.) and the effects of saline. The response, a left or right turn in the maze, was thus contingent upon the prevailing training condition (P-barb. or saline). The criterion of performing 8 correct first trial choices in 10 consecutive sessions was reached within 20 training sessions. Tests with descending doses of P-barb. yielded an ED₅₀ of 9 mg/kg. Tests with phenobarbital (40 mg/kg) or diazepam (2 and 4 mg/kg) solely maintained the drug response. P-barb. discrimination was reversed by megimide (ED₅₀: 8.5–9.6 mg/kg) and metrazol (ED₅₀: 24.9–27.9 mg/kg). Thus megimide was approximately 3 times more effective than metrazol. Metrazol (40 and 80 mg/kg) also counteracted the phenobarbital and diazepam response. Picrotoxin (2.5 and 5 mg/kg) was less effective whereas caffeine (100 mg/kg) and piracetam (100–1000 mg/kg) did not upset P-barb. discrimination. Experiment 2. Naive gerbils had to discriminate mixtures of P-barb. (15 mg/kg) plus either 40 or 80 mg/kg of metrazol from saline already at the start of the discriminative training. The drug combinations produced discriminable effects since most gerbils reached the acquisition criterion (8/10), although more slowly than gerbils trained with P-barb. solely. Gerbils trained without a drug stimulus (saline vs. saline) never attained the criterion during 60 consecutive sessions. In conclusion, reversal of established discrimination (Expt. 1) does not necessarily mean that the same drug combination lacks discriminable effects as demonstrated in Experiment 2.     

Discriminative stimulus functions of CNS sedative drugs assessed by drug versus drug discrimination procedures in gerbils

 This study is concerned with dissecting out differences in the discriminative stimulus attributes between drugs from broader pharmacological categories such as sedative/hypnotics where generalization tests often indicate shared stimulus effects. To this end, the discriminative stimulus effects of three to five doses of either chlordiazepoxide (CDP), chlormethiazole (CMZ), ethanol (ETOH), and pentobarbital (P-barb) were studied with gerbils in a two-choice, T-maze task. When the discrimination was based upon the presence versus the absence of drug administration, speed of acquiring the discrimination increased dose-dependently for all four drugs with log of sessions to criterion being a linear function of log dose. The slopes of all four lines were similar. The acquisition of a discrimination based on different doses of the training drug was then examined. A two-to-one ratio of high to low doses was used. Discriminative control developed with CMZ, ETOH, and P-barb, but not with CDP. The side of the T-maze that correlated with the lower training dose was always selected in tests with saline. Gerbils were then trained to discriminate between two drugs using at least two different dose combinations. The CDP versus CMZ, CDP versus ETOH, CMZ versus P-barb, CMZ versus ETOH discriminations were acquired. The CDP versus P-barb discrimination was obtained across doses only after an additional training procedure was instituted such that the P-barb dose was incremented gradually from low to higher doses during discrimination training; the CDP training doses were 20 and 30 mg/kg in two different groups of gerbils, respectively and the dose of P-barb was incremented by 2.5 mg/kg until the final dose of 20 mg/kg was reached with the barbiturate. Thus, although often shown to share similar stimulus effects, members of the broad pharmacological class of CNS sedatives/hypnotics nonetheless were shown to be discriminable from one another. Non-drug tests (vehicle) were used to assess stimulus control between pairs of drugs, equal control being implicated when responding was evenly distributed across the two training conditions. Received: 28 May 1997 / Final version: 11 July 1997     

Discriminative stimulus properties of d-amphetamine-pentobarbital combinations

Pigeons were trained to discriminate IM injections of 1.0 mg/kg d-amphetamine from water, 5.6 mg/kg pentobarbital from water, or 1.0 mg/kg d-amphetamine from 5.6 mg/kg pentobarbital by requiring them to peck different response keys depending on which substance was administered prior to the session. Excellent stimulus control was achieved under all conditions with close to 100% of the responses occurring on the injection-correlated key. In tests with doses different from those used in training, the percentage of responses on the drug key was directly related to drug dose. When d-amphetamine was given to birds trained to discriminate pentobarbital from water or when pentobarbital was given to birds trained to discriminate d-amphetamine from water, responding occurred predominately on the water-correlated key. d-Amphetamine produced a dose-related antagonism of the effects of pentobarbital for birds trained to discriminate pentobarbital from water or from d-amphetamine. Rates of responding on the drug key were generally highes after administration of the drug doses used in discrimination training; but response rates were not systematically related to the percentage of responses occurring on the drug key. All birds were subsequently trained to discriminate a combination of 1.0 mg/kg d-amphetamine and 5.6 mg/kg pentobarbital from either 1.0 mg/kg d-amphetamine or 5.6 mg/kg pentobarbital alone, demonstrating that the discriminative stimulus properties of amphetamine-pentobarbital combinations are different from either drug alone. Several of the drug effects reported were related to the drug discrimination that had been established.Portions of this paper were reported at the 49th annual meeting of the Eastern Psychological Association, Washington, D.C., 1978     

Increased drug sensitivity in the drug discrimination procedure afforded by drug versus drug training

Rats were trained to discriminate norfenfluramine (NF) 1.4 mg/kg from its vehicle or amphetamine (AMPH) 0.8 mg/kg or pentobarbital (PB) 6.0 mg/kg in order to determine the role that drug combination training plays in the rate of learning and sensitivity to lower drug doses. The results suggest that drug versus drug training can increase the rate of drug discrimination learning for some drugs that are learned slowly when trained in a drug versus vehicle training procedure, whereas drug versus drug training does not increase the rate of learning for other drugs that are learned rapidly. Drug versus drug training does, however, appear to increase the level of stimulus control of the training drug for all drugs examined in this study.     

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.     

Antagonism of pentobarbital induced discrimination in the gerbil

Previous work has shown that gerbils that could discriminate the effects of an injection of pentobarbital and the effect of saline, as shown by the animals' differential responding (left or right turn) in a T-shaped maze (state-dependent behavior), choose the saline associated position of the maze when challenged with bemegride in conjunction with the barbiturate.The present study examined whether differential responding in a T-maze would appear when gerbils were required to differentiate a pentobarbital (15 mg/kg)-bemegride (20 mg/kg) mixture from a saline condition (group 2) from the start of the discriminative training. The acquisition rate for this group was compared with that of another group which was required to discriminate the barbiturate, when given alone, from the no drug condition (group 1).Complete discrimination had occurred after 20 training sessions in group 1 whereas none was noted for group 2. Hereafter the bemegride was withdrawn and group 2 continued the regular training with pentobarbital solely vis-à-vis saline. Complete discrimination appeared within the next 10 sessions.After session 20 group 1 were given challenge trials which were interposed in the regular training with bemegride, metrazol, and cocaine. Bemegride (20 mg/kg), metrazol (40 mg/kg), but not cocaine (40 mg/kg), antagonized the pentobarbital (15 mg/kg) produced discrimination.     

Differential generalization to pentobarbital in rats trained to discriminate lorazepam,chlordiazepoxide, diazepam,or triazolam

In drug discrimination studies benzodiazepinetrained animals have typically responded on the drug lever when tested with barbiturates. In a recent study, greater specificity appeared to be shown when lorazepam was used as a training drug. The generality and limits of this finding were explored in the present set of experiments. The asymmetrical cross-generalization found in lorazepam-and pentobarbital-trained baboons was replicated in rats and was shown not to be a function of either lorazepam (0.1., 0.32, or 1.0 mg/kg) or pentobarbital (10 or 25 mg/kg) training dose (i.e., pentobarbital-trained rats responded on the drug lever in tests with lorazepam, but lorazepam-trained rats did not show comparable pentobarbital generalization). In the next experiment, groups of rats were trained to discriminate chlordiazepoxide (10 mg/kg), triazolam (0.1 mg/kg), or diazepam (1.0 mg/kg). Generalization to both lorazepam and pentobarbital was shown by these rats. Finally after daily pentobarbital administration, lorazepam-trained rats made a sufficient number of responses after high pentobarbital doses to permit extension of the range of pentobarbital doses tested. Pentobarbital generalization increased, but still did not occur in all rats and was unreliable in successive tests in the same rats. These results suggest less homogeneity in the discriminative stimulus effects of depressant drugs than generally has been recognized.Portions of these data were presented at the meetings of the Federation of American Societies of Experimental Biology, Anaheim, 1985 (Ator and Griffiths 1985) and Behavioral Pharmacology Society, Rockville MD (1987)     

Effects of chlormethiazole (Heminevrin®) on drug discrimination and open-field behavior in gerbils

Chlormethiazole (CMZ, 80 mg/kg) was used as a discriminative stimulus in gerbils; i.e., the presence or absence of certain effects of the drug controlled the choice behavior (left or right turn) of the animals trained to escape electric shocks in a T-maze. Substitution tests with pentobarbital (5–25 mg/kg) and ethanol (0.5–2.5 g/kg) indicated at least a partial similarity in the stimulus effects of CMZ and the two other drugs. The CMZ stimulus was attenuated by 30 mg/kg of the analeptic bemegride (BMG). In Experiment II, gerbils were trained to discriminate CMZ (80 mg/kg) from either of two doses of ethanol (1.5 or 2.0 g/kg). The acquisition rates for the latter groups appeared some-what slower than that noted for the gerbils in Experiment I, although only one measure significantly differentiated the groups. A qualitative difference is proposed as the basis for the discrimination between CMZ and ethanol. Open-field (O-F) tests 5 min after injections of CMZ (80 mg/kg) depressed both horizontal (ambulation) and vertical (rearing) activity, effects found to be counteracted by BMG (30 mg/kg) during the initial segment of the O-F testing. However, a second O-F test carried out 60 min after injections showed that the behaviors of the gerbils treated with the combination of CMZ and BMG were now markedly depressed. The effects of the drug combination on colonic temperature of the gerbils showed similar changes over time; i.e., the mixture of BMG and CMZ resulted in a normal colonic temperature response 5 min postinjection (p.i.), after which a marked drop of temperature followed at the recordings 60 min p.i.     

Tolerance to the depressant effects of diazepam in the drug discrimination paradigm

Seven groups of rats (n = 35) were run in operant drug experiments. All groups were trained on a Fixed Ratio 10 schedule to discriminate diazepam from saline. Two groups (n = 7, n = 6), after extensive drug discrimination training (doses of 2.0 and 3.0 mg/kg diazepam), were submitted to generalization experiments with various doses of the training drug. Two additional groups, (n = 6, n = 8) in the initial phase of drug discrimination, were trained on intermediate and high doses of diazepam (i.e., 5.0 and 10.0 mg/kg). The development of tolerance to the depressant effects of diazepam for these two groups was compared to the low dose sophisticated rats. Of the above-mentioned groups, two groups were given tests after a waiting period in drug discrimination training. In this test the two groups were compared to an additional group (n = 8) in its initial phases of drug discrimination training. The results show that a large number of low doses (i.e., doses below 3.0 mg/kg) is not able to induce any tolerance to the depressant effects of diazepam in this particular paradigm. Intermediate doses of diazepam (i.e., 3.0 mg/kg), administered in a large number, induced some tolerance to the depressant effects, while another intermediate dose (5.0 mg/kg) and a high dose (10.0 mg/kg) rapidly induced a significant tolerance. Once developed, the tolerance persisted for 51 days.     

The discrimination of drug mixtures using a four-choice procedure in pigeons

Abstract Rationale. The purpose of these experiments was to study drug combinations as discriminative stimuli using a new four-choice procedure. Objectives. To determine whether pigeons could discriminate among a mixture of two drugs, each of the component drugs and saline, and to study other drug combinations in these birds. Methods. Pigeons were trained to discriminate among saline, 5 mg/kg morphine, 5 mg/kg pentobarbital, and a mixture of these two doses using a four-choice procedure. Results. When responding stabilized, the birds responded on the correct key more than 90% of the time. Low doses of all drugs given alone produced responding on the saline key. Higher doses of pentobarbital and chlordiazepoxide produced responding on the pentobarbital key, and higher doses of morphine produced responses on the morphine key. Methamphetamine produced responding on the saline key. None of the drugs given alone produced responding on the mixture key. When pentobarbital was combined with morphine, doses both below and above the combined training doses of these drugs usually produced responding on the mixture key. The combination of chlordiazepoxide with morphine produced similar results. Combinations of methamphetamine with pentobarbital or with morphine produced effects similar to those of pentobarbital or morphine given alone. Conclusions. A wide range of combinations of pentobarbital and morphine, or chlordiazepoxide and morphine produce responding on the mixture key, even though the pigeons were not exposed to these dose combinations during training. The four-choice procedure provides the opportunity to study drug mixtures in a detail not possible with more limited response choices. Electronic Publication     

Ethanol-chlordiazepoxide interactions in the rat

One group of rats (n = 9) was trained to discriminate between the effects induced by 600 mg/kg ethanol and saline, whereas another group (n = 5) had to discriminate between 5.0 mg/kg chlordiazepoxide (CDZ) and saline, administered intraperitoneally (IP) 15 min prior to the training sessions. Once trained, decreasing doses of ethanol in ethanol-trained rats produced decreased discriminative performance; the ED50 was 239.4 mg/kg. Likewise, decreasing doses of CDZ in CDZ-trained rats produced decreased discrimination, with an ED50 = 1.5 mg/kg. Substitution of 1.25-10.0 mg/kg CDZ in ethanol-trained rats produced a transfer of the ethanol-induced interoceptive cue in a dose-responsive manner, whereas ethanol did not substitute for CDZ in CDZ-trained rats. Analysis of dose-response curves suggested that CDZ is acting by a similar mechanism/site in both groups of rats but by a site different than ethanol. Co-administration of the ED50's for ethanol and CDZ in ethanol-trained rats did not produce additive effects. The observed one-way asymmetrical generalization of drug effects, as well as the lack of additive effects of co-administration, are discussed.     

Lorazepam and pentobarbital discrimination: interactions with CGS 8216 and caffeine

Baboons and rats were trained under a two-lever, food-reinforced drug discrimination procedure. The training drug was either lorazepam (1.0 mg/kg) or pentobarbital (5.6 mg/kg in baboons, 10.0 mg/kg in rats). Under test conditions, a range of training drug doses occasioned 100% drug lever responding. CGS 8216 (3.2-10.0 mg/kg) combined with lorazepam produced a complete shift to the no-drug lever in both species; this shift was surmountable with higher doses of lorazepam. CGS 8216 (32.0 mg/kg) combined with pentobarbital produced a statistically significant decrease in drug-lever responding in rats, and in baboons CGS 8216 initially, but not subsequently, produced a complete shift to the no-drug lever. Caffeine (0.32-10.0 mg/kg) combined with lorazepam inconsistently decreased drug-lever responding across multiple determinations in baboons and significantly decreased drug lever responding in rats. Caffeine combined with pentobarbital also yielded an inconsistent decrease in drug lever responding in baboons but there was no effect in rats. Thus the most reliable and complete antagonism across species was obtained with the CGS 8216/lorazepam combinations.     

Dissimilar cannabinoid substitution patterns in mice trained to discriminate Δ(9)-tetrahydrocannabinol or methanandamide from vehicle

Δ(9)-Tetrahydrocannabinol (THC) discrimination in rodents is a behavioral assay that has been used to probe differences among classes of cannabinoids in rats. The purpose of this study was to determine whether traditional and anandamide-like cannabinoids were distinguishable in cannabinoid discrimination procedures in mice. Male mice were trained to discriminate 30 mg/kg THC or 70 mg/kg methanandamide from vehicle in a two-lever milk-reinforced drug discrimination procedure. After acquisition, agonist tests with THC, methanandamide, CP 55940, and anandamide were conducted, as were antagonism tests with rimonabant. Substitution (agonism) and antagonism tests were also carried out in female mice trained to discriminate THC. THC and CP 55940 fully substituted in THC-trained mice of both sexes. Further, THC substitution was rimonabant reversible. In contrast, mice injected with methanandamide or anandamide failed to respond substantially on the THC lever, even up to doses that decreased overall responding. In methanandamide-trained mice, methanandamide fully generalized to the methanandamide training dose. Rimonabant did not reverse this generalization. Although THC, CP 55940, and anandamide also increased responding on the methanandamide lever, the magnitude of substitution was less than for methanandamide. These results suggest incomplete overlap in the underlying mechanisms mediating endocannabinoid pharmacology and marijuana intoxication. Further, they suggest that methanandamide discrimination may involve a non-CB(1) receptor mechanism that is particularly prominent at higher doses.     

Influence of exteroceptive contextual conditions upon internal drug stimulus control

Rats were trained in a spatial T-maze discrimination either in a drugged (D = pentobarbital, 17.5 mg/kg) or in a non-drugged (N = saline) state (drug discrimination learning). Either of two external discriminative stimulus sets (light vs complete darkness) was consistently associated with the D or N state. When tested in the presence of the external stimulus previously associated with training in the D state, the animals made more drug-appropriate choices when tested with low pentobarbital doses as compared to testing in the external stimulus condition previously associated with the N state. This was reflected both in the ED50 values and the slopes of the dose-generalization gradients. The gradients of the controls were intermediate to those of the experimental rats. The present data suggest a new approach for studying interactions between controlling features in environmental events and the internal state.     

Evidence supporting lack of discriminative stimulus properties of a combination of naltrexone and morphine.

The aim of the present experiment was to study the potentially discriminable effects of combinations of morphine and naltrexone during long-term treatment. Three groups of gerbils had to discriminate the effects of morphine (12 mg/kg) and those of either saline (4 ml/kg), naltrexone (2 mg/kg), or a combination of this dose of morphine plus naltrexone injected IP 60 min prior to the start of the discriminative training in a T-shaped maze. Rapid development of drug discriminative control of choice behavior (left or right turn in the maze) was evident in these 3 groups which is in marked contrast to the performance of gerbils trained with morphine-naltrexone combination vs. saline or gerbils trained with naltrexone only vs. saline. Neither of these latter groups reached the criterion of performing 8 correct first-trial choices in 10 consecutive training sessions during the 60 training sessions allowed, while the 3 other groups began their criterion performance after only 7--8 training sessions. Thus the discriminative properties of certain combinations of morphine and naltrexone are weak and therfore are not easily discriminable from the effects induced by saline.     

A taste aversion model of drug discrimination learning: training drug and condition influence rate of learning,sensitivity and drug specificity

A model of drug discrimination based on a lithium chloride (LiCl) flavour aversion was described and examined. Mildly thirsty rats were presented daily with 4 ml of a distinctly flavoured solution which was followed on 50% of the days by an IP injection of LiCl. Prior to the flavour presentation, the rats were injection SC with saline or a training drug (0.04 mg/kg fentanyl or 20 mg/kg pentobarbital) to signal whether LiCl would follow. Almost all rats eventually exhibited stable behaviour that involved drinking most or all of the fluid when it was not to be followed by LiCl and little or no drinking when it was. Such discrimination occurred regardless of whether drug predicted LiCl (learned-discomfort) or predicted no LiCl (learned-safety). However, with fentanyl there were clear differences between rats trained with drug under learned-safety and under learned-discomfort conditions for 1) the rate of acquisition of stable performance as a function of LiCl dose, 2) generalization of the training dose to a test dose that was lower, and 3) elicitation of fentanyl responses by pentobarbital. These findings, together with indications that such effects did not always occur with pentobarbital as the training drug, were discussed from theoretical and practical perspectives.     

Discriminative effects of morphine in the pigeon

Pigeons were trained to discriminate between the effects of morphine (6 mg/kg) and saline injected IM, 45 min prior to training in a box equipped with 2 response keys which were mounted left and right on the front panel. Reinforcement (food) was contingent upon pecking (FR 15) on one key when trained under the influence of morphine (6 mg/kg) and the other key when trained with saline. After the choice of key (left or right) had become conditioned to the presence or absence of the effects of morphine, test sessions under new drug conditions were interspersed between the regular training sessions. The median effective dose of morphine and the time interval since the morphine injection in producing 50% morphine appropriate responding by the pigeons were respectively: 1.6 mg/kg and 6 hr post-injection. A stereoisomeric requirement for the discrimination was evident because treatment with levorphanol (2 mg/kg) resulted in responding on the morphine appropriate key while treatments with the enantiomer dextrorphan (1–10 mg/kg) predominantly while tests with 3 other psychotropic drugs Δ⁹-THC (0.25 and 0.50 mg/kg), d-LSD (0.04 and 0.08 mg/kg) and pentobarbital yielded responding on the saline appropriate key. In addition, methadone (3 and 6 mg/kg) substituted for morphine (4 and 8 mg/kg)) resulted in responding appropriate for the saline-induced training condition. The opioid antagonists naloxone and naltrexone blocked the stimulus effects of morphine (6 mg/kg). Naloxone appeared less potent in this respect than its congener, naltrexone, when the drugs were evaluated 45 min post-injection. Thus the discriminable effects of morphine in the pigeon are qualitatively similar to the results obtained in mammals (gerbils, rats, and squirrel monkeys) required to discriminate morphine from a nondrug condition.     

Limited stimulus generalization between △9-THC and diazepam in pigeons and gerbils

Pigeons trained to discriminate between the presence and absence of ⁹-THC (0.56 mg/kg, IM, intramuscularly) were tested with diazepam (5.6–30 mg/kg), administered IG (intragastrically), and were found to generalize the response associated with the THC training to the diazepam treatment only to a limited extent. Two groups of gerbils trained to discriminate between the presence and absence of IP (intraperitoneally) injected benzodiazepine agonists (5.6 mg/kg of diazepam and Ro 11-3128, respectively) generally did not generalize the drug response to IP administered THC (5.6 and 17.5 mg/kg). In addition, substitution testing with the dopamine autoreceptor blocker (+)-3PPP yielded non-drug responding in the pigeons. Hence neither proposed structural similarity between 3-PPP and THC, nor purported anxiolytic activity by 3-PPP (see Introduction) matched the THC-induced stimulus effects. The data are discussed with reference to the specificity of the THC cue or stimulus.     

Drug discrimination in rats: effects of mixtures of ditran and cholinesterase inhibitors.

Groups of rats were trained in a T-shaped maze to discriminate the effects produced by IP injections of ditran (1.60 mg/kg), either when given singly, or when combined with the acetylcholinesterase inhibitors neostigmine (0.25 mg/kg) or physostigmine (0.50 and 1.00 mg/kg), from the nondrug condition (saline). The results from this state-dependency (StD) model indicated that acquisition of the drug discrimination was similar for the 4 groups of rats. After drug discrimination was established the rats were tested with various drug combinations. Physostigmine (0.50 and 1.00 mg/kg) challenge reversed drug discrimination among rats trained with ditran solely or the ditran plus neostigmine combination. There was no antagonism among the ditran plus physostigmine trained rats. Involvement of the C.N.S. is implicated since tests with neostigmine did not upset ditran discrimination. In addition, survival rate of physostigmine treated mice is increased with ditran. In conclusion, this study indicates the usefulness of employing both training and transfer test procedures when evaluating antagonism in this StD model.     

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.