Validation of volume measurements in esophageal pseudotumors using 3D endoluminal ultrasound.

The purpose of this study was to validate the accuracy and reliability of volume measurements using three-dimensional (3D) endoluminal ultrasound (ELUS) in canine pseudotumor esophageal specimens in vitro. Pseudotumors were created by injecting various volumes of US gel (0.1-1.0 ml) into canine esophageal specimens. A stepping-motor was used to pull either a 9, 12.5 or 20 MHz transducer through the lumen of the specimen at 1.5 mm/s. Images were downloaded to a LIFE computer system for 3D reconstruction. Volume measurements were made by two investigators and compared to spiral CT images. Averaging across all measurements, the average magnitude of error was 8.7% in individual US determinations and 11. 9% in CT measures. Volumes estimated from images spaced 0.5 and 1.0 mm apart, from images in the original and reconstructed planes, and from different scan frequencies, produced percentage errors that were not statistically significantly different from each other on ELUS. 3D ELUS can be used accurately and reproducibly to measure tumor volumes with a low mean percent in vitro.

Creation and first 20 years of the society for the stimulus properties of drugs (SSPD).

Clinical observations and novels in the 19th century recognized that memory of some events can be retrieved only under the influence of the same drug condition that was present during the event. This dissociative effect of drugs probably reflects the same drug effects that were later called the discriminative stimulus effects of drugs. The Society for Stimulus Properties of Drugs (SSPD) was founded in 1978 as a forum for communications and periodic meetings on this drug effect. During its early years many of its members were psychologists, but subsequent to that time the most frequent research application has been for the pharmacological purpose of identifying new drugs that have the same discriminative stimulus attributes as a prototype training drug. The majority of members have been in the United States, but several major international meetings have been in Europe. The methods used by the society's members involve both neuropharmacological and psychological processes, allowing them to make unique contributions to the study of both mind and brain.

The relative salience of morphine and contextual cues as conditioned stimuli.

Two experiments were conducted to delineate further the properties of conditioning when morphine is used as a conditioned stimulus (CS) in the conditioned suppression of drinking paradigm. Experiment 1 used a test for overshadowing designed to compare the relative salience of contextual cues (metal box) and morphine induced cues (6 mg/kg, IP) as CSs when each was paired with a foot shock unconditioned stimulus (US) in water deprived rats. Six groups (six rats each) were exposed to conditioning procedures during which the conditioning context was present 19 h (groups 1 and 2), 90 min (groups 3 and 4), or 5 min (groups 5 and 6) before shock onset, and morphine (in groups 1, 3, and 5) or saline (in groups 2, 4, and 6) was injected 10 min before shock. Subsequently, the magnitude of suppression of drinking in response to morphine, to the metal box, and to morphine plus the metal box was measured. Only group 1 (19 h group) suppressed drinking in response to morphine, while groups 3-6 suppressed drinking whenever tested in the metal box. The results indicate that morphine cues acted as a CS that elicited suppression of drinking in group 1, and that contextual cues present up to 90 min before morphine cues overshadowed morphine. Experiment 2 showed that expression of the conditioned response to morphine was blocked by naloxone.

Centrally acting drugs act as conditioned stimuli in a conditioned suppression of drinking task.

An experiment was conducted to test whether centrally acting drugs could act as conditioned stimuli (CS) in a classical conditioning paradigm in which electric shock acted as the unconditioned stimulus (US) and suppression of drinking was used as an indicator of a conditioned response (CR). Thirsty rats were allowed to drink water during daily classical conditioning sessions which took place in their home cages. The CS was either a drug injected before the session or a "cocktail" of sensory stimuli (light + tone + vibration) turned on at the beginning of the session. Part way through some sessions the animals received electric foot shock as the US. Two different drugs and the sensory cocktail were used as CSs in a discriminated classical conditioning paradigm in which one drug or stimulus (the CS+) predicted the subsequent occurrence of shock, and the other two conditions acted as CS- stimuli and predicted absence of shock. After an average of 5.7 pairings of the CS+ with shock, conditioned suppression of drinking was observed; the CR occurred only during tests preceded by the CS+ drug or stimulus. At one time or another during the experiment, pentobarbital, phencyclidine, morphine, and pentylenetetrazol were employed as the CS+. Each acquired the ability to elicit a CR, although pentobarbital was noticeably less effective than the other three drugs. All conditioning trials took place in hanging metal cages, but the CR generalized into plastic cages with sawdust floors. Each rat received three successive phases of conditioning with a different CS+ condition employed in each phase; each phase of conditioning was followed by extinction of the CR.(ABSTRACT TRUNCATED AT 250 WORDS)

Morphine as a conditioned stimulus in a conditioned emotional response paradigm.

A Pavlovian conditioning experiment was conducted to determine whether morphine (6 mg/kg, IP) could act as a conditioned stimulus (CS) when paired with an electric shock unconditioned stimulus (US), and later produce a conditioned suppression of drinking (CR) in water deprived rats. Seven groups were tested for conditioning after exposure to one of the following conditioning procedures: (1) morphine paired with shock; (2) morphine alone with no shock; (3) shock but no morphine; (4) no shock and no morphine; (5) morphine paired with vocalizations of shocked rats; (6) saline paired with shock; (7) saline alone with no shock. Groups 1 and 2 tested whether morphine could act as a CS. Groups 3 and 4 tested for sensitization. Group 5 tested whether exposure to the vocalizations of other rats could act as a US when paired with a morphine CS. Groups 6 and 7 tested whether cues associated with the injection procedure could act as a CS. Only subjects in group 1 showed conditioned suppression of drinking, when compared to control groups. Overall, the results indicate that morphine could act as a conditioned stimulus and that several of the more obvious possible sources of artifact did not significantly contribute to the CR that is produced.

Historical context of state dependent learning and discriminative drug effects.

Drug-induced state dependent learning (SDL), as well as similar effects on memory retrieval exercised by physiological states, have been known since 1830. Before 1950, understanding of this area derived primarily from clinical descriptions of somnambulism, dream recall, fugue states, and cases of multiple personality. After 1950, experimental demonstrations of the properties of SDL and drug discriminations (DDs), along with a series of changes in the DD procedure, have led to the DD paradigm that is currently employed, and which has properties that make it an extremely useful tool for preclinical investigation of a variety of pharmacological and psychological questions. These conceptual and technical developments have resulted in widespread acceptance of the DD paradigm as a preclinical research method. This paper reviews the nineteeth and twentieth century history of clinical observations, concepts, and experiments, that have led to our current status of knowledge about drug discriminations and SDL.

Discriminable effects of phencyclidine analogs evaluated by multiple drug (PCP versus OTHER) discrimination training.

This study tested structural analogs of phencyclidine (PCP) using drug discrimination procedures to determine which analogs produced discriminable effects similar to those of PCP. It also tested the utility of multiple-drug discrimination training (PCP versus other drugs or saline) as a method for increasing the specificity produced by training. All discrimination training took place in two-lever operant compartments using FR-10 reinforcement of presses on the correct lever. During training, rats were required to concurrently discriminate PCP from one or more other drug conditions. Rats in group 1 discriminated PCP (lever 1) versus saline (lever 2). Rats in group 2 discriminated PCP (lever 1) versus saline, fentanyl, phenobarbital, amphetamine, or mescaline (lever 2). In both groups 1 and 2, the required discriminations were rapidly learned. The percentage of PCP choices and the ED50 doses obtained during tests for generalization did not differ significantly in groups 1 and 2. Drugs to which responding on the PCP lever generalized included 1-[1-(2-thienyl)cyclohexyl]piperidine, N-ethyl-1-phenylcyclohexylamine, 1-phenylcyclohexylamine, ketamine, 1-(1-phenylcyclohexyl)morpholine, 1-[1-(2-thienyl)cyclohexyl]morpholine, N,N-diethyl-1-phenylcyclohexylamine, N-(iso-propyl)-1-phenylcyclohexylamine, N-methyl-1-phenylcyclohexylamine, N-(n-propyl)-1-phenylcyclohexylamine, Dextrorphan, (dl)-N-allyl-N-normetazocine, N-N-dimethyl-1-phenylcyclohexylamine, N-(n-butyl)-1-phenylcyclohexylamine, 1-[1-(2-thienyl)cyclohexyl]pyrrolidine, and N-(s-butyl)-1-phenylcyclohexylamine, in agreement with previous reports. Rats in group 3 discriminated PCP (lever 1) versus saline, cyclazocine, dextrorphan, phenobarbital, or mescaline (lever 2).(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of four-drug discriminations in training compartments with four identical levers versus four different responses manipulanda.

Rats were trained to discriminate between four dissimilar drugs (phenobarbital, nicotine, fentanyl, and methylphenidate) in compartments which contained either four identical levers or four dissimilar response manipulanda. During successive training sessions, the drug condition was cycled through the four training conditions. The objective was to compare speed of acquisition and asymptotic accuracy of discriminative control in the following types of compartments: (1) Undecorated compartments with four identical levers; (2) Compartments with four dissimilar response manipulanda (lever, wheel, nosepoke, panel); (3) Four-lever compartments with a unique sensory environment surrounding each lever; (4) Compartments with four dissimilar manipulanda, each surrounded by a unique sensory environment. The required four-drug discrimination were learned in all training compartments. Independent variables that produced statistically significant effects on speed of acquisition and/or asymptotic accuracy included drug, dosage, use/nonuse of four dissimilar response manipulanda, and presence/absence of environmental decorations around each manipulandum. Although the use of four different response manipulanda and/or the use of distinctive decorations surrounding each of the four manipulanda did increase speed of acquisition, these manipulations also resulted in biases towards/against particular individual environments or manipulanda during the acquisition phase of the experiment. Such biases can complicate the interpretation of results of conventional drug discrimination studies, especially if they persist into the asymptotic accuracy phase, which was not observed in the present study.

Similarities and differences between behavioral control by drug-produced stimuli and by sensory stimuli.

Drug-induced state-dependent learning and drug discriminations may be based on sensory stimuli induced by drug actions, or at least on events in the brain that have properties analogous to those of sensory stimuli. A variety of comparisons between behavioral control by drug-induced stimuli and by classically defined interoceptive and exteroceptive stimuli are possible. These allow inferences to be made about the nature of drug stimuli, the properties of behavioral paradigms that we use to investigate them, and the mechanisms by which drugs achieve behavioral control in drug discrimination and state-dependent learning paradigms. Each of these topics is selectively reviewed in this paper.

Methods for measuring the strength of discriminable drug effects.

Drug discriminations can be used to investigate a variety of preclinical psychopharmacological issues. These discriminations are based on the so-called "discriminable" or "discriminative stimulus" effects of drugs. In order to conduct some types of drug discrimination studies, it is helpful or necessary to know the amount or degree of discriminability of the various drugs employed. This paper describes several methods for determining the degree of discriminability of drugs, and evaluates these methods primarily using data obtained by training rats to discriminate drug vs. no drug in a shock-escape T-maze task. The results suggest that useful indices of degree of discriminability can be computed from the rapidity with which drug discriminations are learned. Indices based on average accuracy during acquisition were found to be somewhat superior to indices based on sessions to criterion.

Optimal training parameters in the two-bar fixed-ratio drug discrimination task.

In a two-lever compartment, thirsty rats were trained to press one bar when drugged with phenobarbital and the other bar when undrugged using water as a reinforcer. Several different training procedures were employed in order to compare their effects on speed of acquisition and/or asymptotic accuracy of discrimination. Results were as follows: (1) Some shaping procedures allowed more rapid acquisition of discriminative control than others. The "traditional" shaping procedure was significantly less efficient than any others tested. (2) Several indices of degree of discriminability based on the speed of acquisition of discriminations were compared and evaluated. Some varied linearly with 1n dosage. (3) Variations in session duration from 5 to 60 minutes did not alter asymptotic accuracy. (4) Fixed ratio sizes ranging from FR-3 to FR-30 resulted in similar asymptotic accuracies. Overall, the results define alterations in the fixed-ratio training procedure that will make it somewhat easier to use. However, no procedures were found that fundamentally improved the properties of the paradigm.

Test for a neurochemically specific mechanism mediating drug discriminations and for stimulus masking.

Five groups of rats were trained to discriminate methysergide, morphine, nicotine, pentobarbital, or scopolamine, respectively, from no injection in a T-maze shock-escape drug discrimination task. After these discriminations were learned, rats received substitution tests, before which they were injected with the training drug and with an additional drug. The additional drugs were mainly transmitter depletors, antagonists, or agonists. The experiment was designed to test whether drug discriminations might be mediated by brain mechanisms operated by one of the manipulated neurotransmitters, and to test whether one discriminable drug could mask or occlude the effects of a second discriminable drug. Neither hypothesis was supported by the results.

Multiple drug training as a method for increasing the specificity of the drug discrimination procedure.

In a two-lever appetitively reinforced bar-pressing task, one group of rats learned a phenobarbital vs. saline discrimination. Groups 2 to 4 were reinforced for pressing one lever when given phenobarbital and for pressing the other level when given saline or any one of three drugs. In Group 2, the other drugs were the stimulants amphetamine, cocaine and bemegride. In Group 3, the other drugs lacked either strong stimulant or depressant effects (fentanyl, nicotine and cyclazocine). In Group 4, the other drugs were the depressants ethanol, chlordiazepoxide and ketamine. All rats learned the required multiple drug (phenobarbital vs. other) discrimination after one to four training sessions per drug. After discrimination training was completed, tests for substitution with various depressant drugs showed that the degree to which these drugs substituted for phenobarbital differed greatly across groups. Substitution was most complete in rats trained with phenobarbital vs. saline and least complete when the other training drugs were depressants. The results indicate that the degree of specificity produced by phenobarbital vs. other drug discrimination training can be systematically altered by varying the drugs included in the other category.

Comparison of the degree of discriminability of various drugs using the T-maze drug discrimination paradigm.

This paper reports preclinical data that may predict the amount of state-dependent learning likely to be produced in humans by various psychoactive drugs. In a T-maze, rats were required to turn right when drugged and left when not drugged to escape from electric shock. The number of training sessions required to learn this drug versus no drug discrimination was used as an indicator of the degree of discriminability of the training drug. Using this procedure, the discriminability of more than 100 common psychoactive drugs was determined at one or more doses. Sessions to criterion usually decreased as dosage was increased. Maximum discriminability occurred at the highest usable dose in most cases, and differed considerably for drugs of various types. The results suggest that the majority of psychoactive drugs can be investigated by use of the drug discrimination technique, and that state-dependent learning effects will not accompany clinical use of most psychoactive drugs unless intoxicating doses are used.

Investigation of narcotics and antitussives using drug discrimination techniques.

Rats learned drug discriminations in a shock-escape T-maze task. They were trained to turn right in the maze following injection of a drug (D) and left when no injection (N) was given. Number of training sessions before criterion performance (STC) was used to indicate degree of discriminability of the training drug. STC decreased monotonically as dosage increased, and reached a minimum of 3 to 26 with various agonists. Most agonists were not highly discriminable. Daily maintenance injections of morphine, 200 to 600 mg/kg, increased the STC of morphine, 15 mg/kg, significantly, but complete tolerance to discriminable drug actions was not observed. After rats discriminated D vs. N, they were tested with novel drugs to determine which would elicit D choices. Most morphine-like agonists substituted for one another during substitution tests; the tested agonists included alphaprodine, codeine, fentanyl, heroin, meperidine, methadone, morphine, piminodine and propoxyphene. In a few instances, one of these agonists failed to substitute for another. Naloxone and naltrexone antagonized the discriminable effects of morphine. Cyclazocine, levallorphan, naltrexone, dextromethorphan, ethoheptazine and the narcotic agonists did not substitute for one another, suggesting that six dissimilar discriminable effects were produced by these drugs.

Drug discrimination training with progressively lowered doses.

Rats were trained to discriminate drug from no-drug conditions in a two-lever operant task. Moderately high dosages were used initially. Whenever the discrimination was learned, training was continued with progressively reduced dosages. Eventually the rats discriminated extremely low doses of phenobarbital, chlordiazepoxide, cyclazocine, and fentanyl.