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PubMed1984

An experimental paradigm for studying the discriminative stimulus properties of drugs in humans.

An experimental paradigm for studying the discriminative stimulus effects of drugs in human subjects is presented. The paradigm was tested by training subjects to discriminate 10 mg d-amphetamine from placebo. Subjects who successfully learned the discrimination were then tested with two lower doses of d-amphetamine and with 10 mg diazepam. The discriminative stimulus properties of d-amphetamine were dose-dependent, and in two of five subjects the d-amphetamine stimulus generalized to diazepam. The simplicity and versatility of the paradigm give it the potential for use in a wide variety of experimental and clinical situations.

Adult↗
PubMed1975

Effects of prior experience on differential learning under amphetamine.

Differential learning of operant behavior under non-drug and amphetamine states was explained with a "drug-behavior-reinforcement interaction" process. When a drug affects the relationship between ongoing behavior and existing reinforcement contingencies, the sets of behavioral patterns subjected to the process of reinforcement or non-reinforcement under a drug may differ from the patterns under non-drug conditions. If, following sufficient training, the drug conditions are then changed, persistence of these behavioral patterns may result in a difference from those patterns produced if acquisition occurs solely under non-drug conditions. To investigate this process, groups of rats were given varying amounts of non-drug acquisition training on a response-duration differentiation task before being given extended training under 0.75 mg/kg d-amphetamine. All groups were then tested under non-drug conditions. Amphetamine significantly enhanced performance, and this enhancement transferred to subsequent non-drug conditions. However, if non-drug training occurred before drug training, this enhancement was greatly attenuated. Furthermore, only those behavioral components under which amphetamine led to an increase in reinforcement rate showed enhancement in the non-drug state. The results, which supported the present position, were discussed in relation to a "stimulus generalization decrement" explanation of differential learning under amphetamine.

Animals↗
PubMed1980

Hallucinogenic agents as discriminative stimuli: a correlation with serotonin receptor affinities.

A choice between two levers in an operant chamber was used to train 24 rats, under a variable-interval 15 s schedule of sweetened milk reinforcement, to discriminate a hallucinogenic (psychotomimetic) agent, 5-methoxy-N,N-dimethyltryptamine (5-OMe DMT), from saline administration. The 5-OMe DMT stimulus generalized in a dose-related manner to each of 14 tryptamine related analogs. With the exception of one compound, the effective dose for the 5-OMe DMT response correlated highly (r = -0.86) with 5-HT receptor affinity (as determined using an isolated rat fundus preparation).

Animals↗
PubMed1987

Discriminative stimulus effects of a low dose of apomorphine in the rat.

The discriminative stimulus (DS) effect of apomorphine was investigated in rats trained in a two-lever, food-reinforcement procedure. Rats were given subcutaneous injections of saline or 0.1 mg/kg apomorphine HCl, 15 min before training sessions. The training dose of apomorphine was chosen to activate dopamine autoreceptors selectively. Stimulus generalization studies demonstrated that the DS effects generalized completely to other direct-acting dopaminergic agonists such as N-n-propylnorapomorphine (NPNA), pergolide, lergotrile, and bromocriptine. The indirect-acting dopamine agonists, (+)amphetamine, cocaine, and methylphenidate produced predominantly saline-appropriate lever responses. The DS effect of apomorphine at the training dose was incompletely antagonized by haloperidol or metoclopramide. The dopaminergic antagonists tested, however, also partially generalized to apomorphine. Both enantiomers of 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) produced apomorphine-appropriate lever choice with the (-) enantiomer being slightly more potent. The discriminative property of this (0.1 mg/kg) dose of apomorphine has characteristics consistent with selective dopamine autoreceptor activation.

Animals↗
PubMed1989

The role of stress on the language-independence and code-switching phenomena.

This investigation studies the extent to which stress affects the assumed functional separation of coordinate bilingual's linguistic organization. Spanish/English bilinguals were subjects in a GSR linguistic conditioning experiment using two intensities of buzzer sounds (stressful conditions) and two lists of words. One word for each list functioned as the conditioned stimulus. Generalization to semantically, phonemically, and unrelated words occurred in both languages and buzzer conditions. We found a differential impact of the buzzer on the functional separation of the languages, although not in the direction predicted. We concluded that stress produced code-switching, and hence, a primitivization of the subject's cognitive and linguistic functioning is assumed to have occurred. These findings are important in understanding the way stress affects the bilingual's languages at the linguistic and cognitive levels. They are also important in understanding the role of stress in language development and in the transfer of linguistic information.

Adolescent↗
PubMed1988

Habituation in the crab Chasmagnathus granulatus: effect of morphine and naloxone.

The escape response decrement shown by the crab Chasmagnathus granulatus as a consequence of repeated shadow presentation, meets five of the seven tested parametric criteria of habituation. Results concerning stimulus generalization and dishabituation strongly suggest that neither motor fatigue nor sensory adaptation can account for the response waning. The effects of morphine and naloxone on performance were also studied. Neither 50 nor 5 micrograms morphine/g exerted any modulatory effect on memory retention. A dose of 50 micrograms morphine/g produced an anterograde detrimental effect on responsiveness but no long-term training effects could be detected after the drug's period of action. A dose of naloxone of 1.6 micrograms/g did not antagonize the effect of morphine. The potential value of the response habituation as a model for studying both habituation dynamics and the mechanisms that subserve it, and also for elucidating the effects of opiates on this memory process, is discussed.

Animals↗
PubMed1997

In vivo carbon monoxide exposure and hypoxic hypoxia stimulate immediate early gene expression.

This study aimed to examine the influence of acute tissue hypoxygenation on the expression of immediate early genes in different rat tissues. To this end male Sprague-Dawley rats were exposed to 0.1% carbon monoxide for 0.5, 1 and 6 h or to 9% oxygen for 6 h and mRNA levels for c-jun, c-fos, c-myc and EGR-1 were assayed by RNase protection in hearts, kidneys, livers and lungs. We found that hypoxia increased c-jun mRNA levels between twofold (lung) and eightfold (liver) in all organs examined; c-fos mRNA increased between three-fold (lung) and 20-fold (heart); c-myc mRNA increased between twofold (lung) and sixfold (heart); and EGR-1 mRNA increased between twofold (lung) and sixfold (heart). Our findings suggest that acute tissue hypoxygenation is a general stimulus of the expression of immediate early genes in vivo. With regard to the sensitivity to hypoxia, organ differences appear to exist in that the lung is rather insensitive, whilst the heart is rather sensitive.

Animals↗
PubMed1989

Appetitive learning in snails shows characteristics of conditioning in vertebrates.

The snail Lymnaea stagnalis can be rapidly conditioned to produce feeding response to a previously neutral tactile stimulus, repeatedly and specifically paired with positive reinforcement (food). The conditioned response has many of the same characteristics seen in appetitive learning in vertebrates. The relative simplicity of the molluscan CNS and the detailed knowledge of the neural circuitry underlying feeding in Lymnaea will facilitate the neurophysiological analysis of appetitive learning as well as stimulus generalization, discriminative learning and generalization of extinction all described in the present paper.

Animals↗
PubMed1982

Discriminative stimulus effects of monohydroxylated phencyclidine metabolites in Rhesus monkeys.

Rhesus monkeys were trained to discriminate saline from an injection of ketamine. In tests of stimulus generalization, phencyclidine (PCP) produced dose-related ketamine-appropriate responding in each monkey. Two monohydroxylated PCP metabolites also produced ketamine-like discriminative effects, although only at considerably higher doses than did PCP. A third monohydroxylated PCP metabolite produced only sham-appropriate responding. The results suggest that these PCP metabolites contribute little to the behavioral actions of PCP in the monkey.

Animals↗
PubMed1993

Comparison of the behavioral effects of ibogaine from three sources: mediation of discriminative activity.

Ibogaine is an alkaloid employed for its hallucinatory properties in West Central Africa which has been the subject of alleged efficacy as an aid in the interruption and treatment of chemical dependency. The major sources of the Schedule I agent are: Sigma Chemical Co., the National Institute on Drug Abuse and as NDA International Inc.'s Endabuse. The intent of the present study was to, for the first time, train rats to discriminate the interoceptive stimuli produced by (10 mg/kg, intraperitoneally administered) ibogaine. Once trained, these rats were used to investigate the dose-response effects to ibogaine from each of the three suppliers. In addition, stimulus generalization to the dopamine antagonist CGS 10476B, as well as to the serotonergically active compounds fenfluramine, TFMPP (1-(m-trifluoromethylphenyl)piperazine, DOI (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane), MDMA (3,4-methylenedioxymethamphetamine), quipazine and LSD, was tested. The results indicate that ibogaine is readily discriminable from its vehicle and that ibogaine from each of the three supplies produced statistically similar discrimination with ED50 values ranging from 2.5 to 3.4 mg/kg. In addition, various doses of the novel drugs tested produced, at best, intermediate ibogaine-appropriate responding and, thus, no drug tested can be considered to generalize to ibogaine-like stimuli. Discussion concerns the multiple actions of ibogaine that have been cited in the scientific literature. The similarity in potency of ibogaine from three potential suppliers should allow for pre-clinical work using any of these research samples to be comparable.

Animals↗
PubMed1985

Acoustic facilitation of the Hoffmann reflex.

The facilitative effect of a pure tone on the amplitude of the Hoffmann reflex was tested in 11 subjects under four conditions: (i) trying not to respond to the tone, (ii) voluntary abduction of the right index finger in response to the tone, (iii) voluntary plantarflexion of the left leg, and (iv) right plantarflexion in response to the tone. The acoustic stimulus was a 1000-Hz pure tone (80 dB, re 0.0002 dyne/cm2), presented on a random set of trials. Tone onset occurred 100 ms prior to the electrical stimulus that evoked the Hoffmann reflex. The Hoffmann reflex was larger for "tone" trials than for "silent" trials. The facilitative effect was equal in four cases: (i) making no response (NR), (ii) finger abduction (FA), (iii) noninvolved muscle (NIM), and (iv) involved muscle during treadle pressing (IM). The effect of the first tone presented was larger than that of subsequent tones, indicating some habituation of the acoustic effect on the H-reflex. Tests for spontaneous recovery and stimulus generalization were not significant. The results supported the existence of a purely auditory facilitation of spinal excitability.

Acoustic Stimulation↗
PubMed1984

Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents.

The affinities (Ki values) of twenty two psycho-active agents, including LSD, 5-OMe DMT and a series of phenalkylamine derivatives, for cortical 5-HT1 and 5-HT2 binding sites were compared with two measures of behavioral activity. It was found that a significant correlation (r = 0.938) exists between the 5-HT2 binding affinities of these agents and their ED50 values as determined in tests of stimulus generalization using 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) as the training drug. Furthermore, for fifteen of these agents where human data were available, a significant correlation (r = 0.924) also exists between 5-HT2 binding affinities and their human hallucinogenic potencies. The results of this study suggest that the mechanism of action of these agents involves 5-HT2-related events.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1989

Caffeine-phenylethylamine combinations mimic the cocaine discriminative cue.

Twelve male Sprague-Dawley rats were trained in a two-choice, food reinforced, drug discrimination task utilizing 10 mg/kg cocaine and saline as discriminative stimuli. Subjects were tested for stimulus generalization with a wide range of cocaine doses and several dose combinations of caffeine, ephedrine, and phenylpropanolamine (CEP). Caffeine produced only partial generalization. The triple CEP combinations resulted in complete generalization at high doses. All drugs produced response rate decrements at high doses. These data clearly indicate that certain look-alike stimulant products mimic the cocaine cue. The present data parallel human self-report data regarding the similarity in subjective profiles between illicit cocaine and the legal look-alike stimulants.

Animals↗
PubMed1990

Experiments in artificial psychology: conditioning of asynchronous neural network models.

An asynchronous model for the dynamics of neural networks admits learning behaviors characteristic of classical and operant conditioning provided that appropriate plasticity algorithms are chosen. Stimulus generalization and discrimination can also be observed. Studies of such psychological phenomena are carried out by computer simulation of networks with designated sensory, association, and motor neurons, and the results are compared to those for live subjects. Various prescriptions for plasticity are investigated, including those corresponding to reward, punishment, and unlearning routines. These are characterized by their effect on network stability as quantified by a newly proposed stability measure.

Animals↗
PubMed1982

Perceptual cues of reinforcing brain stimulations in the postero-lateral area of the hypothalamus.

In order to study the perception of intracranial reward in the rat, a rewarding hypothalamic brain stimulation served as conditioned stimulus (CS) in an avoidance paradigm. The rate of self-stimulations behavior was used to estimate the strength of intracranial reward and reinforcement. Tests of stimulus generalization were performed by modifying the electrical parameters of the CS so as to form a set of substitute stimuli (SS). Results show that the discrimination gradient depends mainly on the rewarding value of the intracranial stimulation. A Stevensian power function relates the percentage of avoidance responses to the intensity of the self-stimulation behavior, which in turn was estimated by such methods as continuous reinforcement frequency, fixed ratio schedules, weight, choice, self-regulation and cost methods. Moreover, the latency of the avoidance responses is related directly to the magnitude of the self-stimulation elicited by the same brain stimulations. On grounds of this data, we assume that the internal decisional process could discriminate well between the different brain stimuli on the basis of the rewarding value produced. Differences observed between methods evaluating the magnitude of reinforcement induced by the rewarding electrical brain stimuli are thus mainly due to differences in motor performances required by each method to obtain the electrical reward.

Animals↗
PubMedDate not supplied

Discriminative stimulus properties of mescaline: mescaline or metabolite?

The purpose of this study was to investigate possible similarities in the interoceptive stimuli produced by mescaline and its metabolites. Rats were trained in a 2 lever operant chamber to discriminate between the drugged state (mescaline 25 mg/kg) and the nondrugged state (saline). Following acquisition of discriminative response control the rats were pretreated with either saline, aldehyde dehydrogenase inhibitors or amine oxidase inhibitors and tested stimulus generalization produced by i.p. injections of 3, 4, 5-trimethoxyphenylethanol (TMPE), 3, 4, 5-trimethoxyphenylacetaldehyde (TMPA), N-acetylmescaline, mescaline or saline. The results indicated that both aldehyde dehydrogenase and amine oxidase inhibitors enhanced the effects of mescaline, while TMPE, TMPA and N-acetylmescaline failed to exhibit generalization to the mescaline state, regardless of pretreatment. These findings do not indicate the role of a metabolite in the interoceptive cue produced by mescaline.

Aldehyde Oxidoreductases↗
PubMed1982

Comparison of behavioral properties of di- and tri-methoxyphenylisopropylamines.

Prominent among the class of hallucinogenic phenylisopropylamines is the 2,5-dimethoxy substitution pattern; this pattern has long been recognized as being an important feature of the more potent agents within this class. The purpose of this present study was to explore the behavioral properties of a series of methoxylated phenylisopropylamines in order to determine the effect of other substitution patterns and the relative importance of individual methoxy groups. Rats, trained to discriminate the hallucinogenic agent 2,5-dimethoxy-4-methyl-phenylisopropylamine (DOM) from saline in a two-lever drug discrimination task, were challenged with a series of di- and trimethoxyphenylisopropylamines (i.e., DMA and TMA derivatives). DOM-stimulus generalization was found to occur with 2,4-DMA but not with 2,3-DMA, 2.6-DMA, or 3,5-DMA; generalization also occurred with 2,3,4-TMA, 2,3,5-TMA, 2,4,6-TMA and 3,4,5-TMA. The 2,4-dimethoxy pattern also emerges as an important feature among the more active agents.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1987

MDMA as a discriminative stimulus: isomeric comparisons.

Using a two-lever, food-motivated discrimination procedure, eight male rats were trained to discriminate 1.5 mg/kg of racemic 3,4-methylenedioxymethamphetamine (MDMA) from its vehicle, distilled water. Once trained, the rats demonstrated a dose-related decrease in discriminative performance after administration of lower doses of MDMA (ED50 = 0.27 mg/kg). Racemic MDMA-stimulus generalization occurred with both isomers of MDMA with the ED50 of the (+) isomer calculated as 0.50 mg/kg and for the (-) isomer being 1.07. Time-course data indicate that racemic MDMA has a peak effect from 20-60 min post-injection with a declining effect from 120-240 min. This time-course closely resembles that observed by subjective reports in human abusers and, together with previous data, would indicate that the discriminative paradigm would be useful in investigations as to the neurochemical effects of MDMA.

3,4-Methylenedioxyamphetamine↗