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PubMed2000

Stimulus effects of phenylpropanolamine optical isomers in (+)amphetamine-trained rats.

There are eight phenylpropanolamine optical isomers related in structure to the central stimulants methamphetamine and amphetamine. Some of these are quite well known, such as (-)ephedrine, whereas others are relatively obscure, such as (-)cathine. Although certain of these phenylpropanolamines, such as (-)ephedrine and (+)cathine, retain central stimulant activity and are about 10- to 25-fold less potent than (+)amphetamine, the eight phenylpropanolamines have been compared only once before in drug discrimination studies. This latter study employed (-)ephedrine as the training drug. Because there are striking similarities between (-)ephedrine and (+)amphetamine as training drugs, it was of interest to determine and compare the effect of all eight phenylpropanolamines in (+)amphetamine trained animals. Using rats trained to discriminate 1 mg/kg of (+)amphetamine from saline vehicle under a variable interval 15-s (VI 15-s) schedule of reinforcement, the (+)amphetamine stimulus generalized only to (-)ephedrine (ED(50) = 4. 5 mg/kg) and (+)cathine (ED(50) = 8.0 mg/kg), and both agents were at least 10 times less potent that (+)amphetamine (ED(50) = 0.37 mg/kg). These results stand in contrast to those obtained with the (-)ephedrine-trained animals where the ephedrine stimulus generalized to all of the phenylpropanolamines except for (-)pseudoephedrine and (-)cathine. It is concluded that although there might be some similarity between the (-)ephedrine and (+)amphetamine stimuli, there are clear differences between them as determined in tests of stimulus generalization under the conditions employed.

Adrenergic alpha-Agonists↗
PubMed1992

Investigation of MDMA-related agents in rats trained to discriminate MDMA from saline.

To determine whether metabolite-related analogs of N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) produce stimulus effects similar to those of the parent compound, and to determine the structural requirements associated with the MDMA stimulus, several MDMA analogs were examined in tests of stimulus generalization using rats trained to discriminate 1.5 mg/kg MDMA from saline. Although several of the analogs produced up to 50-60% MDMA-appropriate responding, none [with the exception of N-methyl-1-(4-methoxyphenyl)-2-aminopropane (PMMA)] resulted in stimulus generalization. The partial generalization, coupled with the possible reduced ability of certain of the agents to penetrate the blood-brain barrier relative to MDMA, suggests that these agents are not behaviorally inactive. PMMA, although not a metabolite of MDMA, is closely related in chemical structure to MDMA and its metabolites; PMMA produces > 80% MDMA-appropriate responding and is approximately three times more potent (ED50 = 0.2 mg/kg) than MDMA itself (ED50 = 0.76 mg/kg). PMMA is a newer scheduled substance with an as yet unknown mechanism of action; however, on the basis of the stimulus generalization observed PMMA may share some behavioral and mechanistic similarity with MDMA. These results also indicate that an intact methylenedioxy ring, such as that found in MDMA but absent in PMMA, is not a prerequisite for MDMA-like activity and further support the notion that ring-opened MDMA metabolites may produce effects that contribute to the actions of MDMA.

3,4-Methylenedioxyamphetamine↗
PubMed1998

Discriminative stimulus properties of the dopamine D3 antagonist PNU-99194A.

It was recently documented that the relatively selective dopamine D3 receptor antagonist, PNU-99194A, is capable of establishing discriminative stimulus control in rats and that the discriminative cue associated with this compound is not similar to that produced by psychostimulants. The present experiment further characterized the discriminative stimulus properties of PNU-99194A by examining several other dopaminergic agents for stimulus generalization in 23 male Sprague-Dawley rats trained to discriminate 10 mg/kg PNU-99194A (SC, 15 min) from vehicle in a two-choice discrimination procedure under an FR10 schedule of food reinforcement. Rats achieved a criterion of ten consecutive sessions with correct lever choice after a median of 35.5 sessions (range 23-78). In substitution tests, the non-selective D2 receptor antagonist, haloperidol (0.01- 0.1 mg/kg), and the mixed D2/D3 antagonists, amisulpiride (3.2-32 mg/kg) and sulpiride (32-200 mg/kg), failed to produce stimulus generalization, while the D3-preferring antagonists, (-)-DS121 (1-10 mg/kg) and (+)-AJ76 (3.2-32 mg/kg), produced complete stimulus generalization. Direct and indirect DA agonists, including apomorphine (0.01-0.32 mg/kg) and d-amphetamine (0.1-1 mg/kg), the D1 agonist SKF38393 (10-100 mg/kg), the D2 selective agonist PNU-95666E (0.32-3.2 mg/kg) and the D3-preferring agonist pramipexole (0.032-1 mg/kg), all produced non-significant amounts of drug-appropriate responding and significantly reduced response rate. It is concluded that PNU-99194A produces a distinctive subjective cue which is probably based on D3 receptor antagonism.

Animals↗
PubMed1997

Assessment of the discriminative stimulus effects of the D3 dopamine antagonist PNU-99194A in rats: comparison with psychomotor stimulants.

The present study examined the discriminative stimulus effects of the D3 dopamine receptor antagonist PNU-99194A [5,6-di-methoxy-2-(dipropylamino)indan-hydrochloride] in male Sprague-Dawley rats. Eight rats were trained to discriminate cocaine (10 mg/kg, i.p.) from saline in a two-choice, water-reinforced drug discrimination procedure. In tests of stimulus generalization, PNU-99194A (1.25-40.0 mg/kg, s.c. and i.p.) did not substitute for cocaine. PNU-99194A (5.0-20 mg/kg) also did not significantly block the discrimination of cocaine (10 mg/kg), nor did it potentiate a low dose (1.25 mg/kg) of cocaine. A separate group of eight rats were trained to discriminate PNU-99194A from saline. These subjects met the discrimination criterion within an average of 68 (S.E.M. = 6.5) training sessions; the ED50 for PNU-99194A was 2.6 mg/kg. In stimulus generalization tests, cocaine (1.25-10 mg/kg) did not substitute for PNU-99194A, when administered by either i.p. or by s.c. injection. In addition, neither amphetamine (0.25-1.0 mg/kg) nor caffeine (8.0-64 mg/kg) produced stimulus generalization in these rats. These results indicate that D3 receptors do not play a critical role in the discriminative stimulus effects of cocaine. Furthermore, although PNU-99194A is capable of establishing and maintaining discriminative stimulus control in rats, the effects of this D3-preferring antagonist are dissimilar from those of psychomotor stimulants. Given the unique behavioral profile of D3 receptor antagonists, the potential utility of these agents as adjunctive treatments for psychostimulant abuse is discussed.

Amphetamine↗
PubMed1994

Assessing and programming generalized behavioral reduction across multiple stimulus parameters.

Generalization across three stimulus parameters was examined for 5 individuals whose self-injurious behavior was maintained by escape from task demands. Prior to treatment, three stimulus parameters (therapist, setting, and demands) were systematically varied across baseline sessions. These variables were held constant during treatment, which consisted of escape extinction. When treatment was completed, three novel stimulus parameters were probed. If the rate of self-injury was high during this probe, treatment was reimplemented with one new stimulus parameter (the other two were the same as in the original treatment condition). Following this second treatment, another probe with three novel stimuli was conducted. If the rate of self-injury was again high, treatment was implemented again while a second stimulus parameter was changed. This sequence continued until generalization was observed across the three parameters. Results showed idiosyncratic differences in generalization. The behavior of 2 subjects showed complete generalization during the first novel probe. A 3rd subject's behavior showed generalization following treatment across two stimulus parameters (setting and therapist). The behavior of the 2 remaining subjects showed a complete lack of generalization across the three parameters; both subjects required training for novelty by randomly varying the stimulus parameters for a substantial number of sessions.

Adult↗
PubMed1987

Effects of pyrazolopyridines and a triazolopyridazine on the pentobarbital discriminative stimulus.

Rats were trained to discriminate injections of racemic pentobarbital (5.0 mg/kg) from saline in a two-lever drug discrimination task. After stable discrimination performance was attained, stimulus generalization studies were conducted with another barbiturate (barbital), benzodiazepine derivatives (diazepam and chlordiazepoxide), pyrazolopyridine derivatives (etazolate, cartazolate, and tracazolate), and a triazolopyridazine (CL 218, 872). The pentobarbital stimulus generalized to all of these compounds, except cartazolate. In addition, the administration of the benzodiazepine receptor antagonist flumazepil prior to benzodiazepine or triazolopyridazine administration produced a dose-related antagonism of each generalization. In contrast, the administration of flumazepil before barbiturate or pyrazolopyridine (i.e., etazolate or tracazolate) injection resulted in no attenuation of these generalizations. The results indicate that while certain barbiturates, benzodiazepines, pyrazolopyridines and triazolopyridazines are capable of producing similar stimulus effects, the behavioral actions of these agents can be differentiated on the basis of their susceptibility to antagonism by flumazepil.

Animals↗
PubMed1980

Evidence that a preferred substrate for type B monoamine oxidase mediates stimulus properties of MAO inhibitors: a possible role for beta-phenylethylamine in the cocaine cue.

In the experiment, rats were trained to discriminate 5 mg/kg cocaine HCl from saline in a two-bar drug discrimination procedure. Stimulus generalization experiments were carried out with six inhibitor drugs of monoamine oxidase. The rank order of absolute potency of these drugs in inducing stimulus generalization with cocaine was: tranylcypromine (ED50 in mg/kg; 1.2)>pheniprazine (3.5)>deprenyl (5)>pargyline (28)>nialamide (approximately 170); at up to 40 mg/kg, clorgyline failed to produce 50% generalization. All six drugs also potentiated tryptamine in producing body tremors and clonic seizures, the rank order of potency being tranylcypromine (0.081)>clorgyline (0.14) greater than or equal to pheniprazine (0.15)>pargyline (1.97)>deprenyl (15.5)>nialamide (18.7). Tryptamine is a common substrate for both type A and type B monoamine oxidase, so that tryptamine potentiation may serve to determine the relative specificity of the doses at which the inhibitor drugs generalized with cocaine. The present data may suggest that endogenous substances which are preferred substrates for type B monoamine oxidase in rat brain can exert control of behavior by virtue of cocaine-like stimulus properties. beta-Phenylethylamine, more so than dopamine, appears to be candidate substance for mediating the discriminative stimulus properties of cocaine and, perhaps, of other central nervous system stimulants.

Animals↗
PubMed1982

Stimulus properties of opioids with mixed agonist and antagonist activity.

The discriminative stimulus properties of opioids with mixed agonist and antagonist activity are heterogeneous in contrast to the relative uniformity of the stimulus properties of classical morphinelike agonists. Patterns of stimulus generalization to mixed agonist-antagonists are critically dependent on factors such as the particular drug used for training, dose of the training drug, and species of the experimental subject. Opioids can be divided into three broad categories on the basis of their patterns of stimulus generalization in rats and squirrel monkeys trained to discriminate saline from morphine, cyclazocine, or phenyclidine (PCP), and these categories predict the ease with which their stimulus effects can be blocked by nalozone or naltrexone. 1) Opioids that are generalized completely to morphine; stimulus effects are easily antagonized. 2) Opioids that are generalized completely to cyclazocine; stimulus effects are antagonized with difficulty. 3) Opioids that are generalized completely to cyclazocine and PCP; stimulus effects not antagonized. The diversity of the stimulus properties of opioids is consistent with evidence that multiple populations of receptors subserve the actions of morphinelike agonists and agonist-antagonists. However, the stimulus effects of opioids in group 3 appear to be mediated by the same neuronal substrates that are acted on by PCP rather than by neuronal sites traditionally associated with the activity of opioids.

Animals↗
PubMed1986

Effects of training dose on discrimination and cross-generalization of chlordiazepoxide, pentobarbital and ethanol in the rat.

Six groups of rats (N = 8), trained to discriminate chlordiazepoxide (5 or 20 mg/kg), pentobarbital (5 or 15 mg/kg) or ethanol (750 or 1500 mg/kg) from saline in a two-lever food-reinforced procedure, were tested for stimulus generalization with the three drugs. Training drug, but not training dose, affected the extent of generalization to a test drug; symmetrical generalization between chlordiazepoxide and pentobarbital and asymmetrical generalization between chlordiazepoxide and ethanol and between pentobarbital and ethanol was observed. Training dose level affected slope and ED50 of the generalization gradients of training drugs and substitution drugs, discriminative performance, response bias and threshold dose for response suppression. Indices of lever selection and percentage drug-appropriate lever responses yielded similar generalization maxima, slopes and ED50S. The potency of chlordiazepoxide relative to the potency of pentobarbital to induce drug stimulus generalization varied across the experimental groups. The results indicate differences between the discriminative effects of chlordiazepoxide, pentobarbital and ethanol. It is suggested that the discriminative effects of chlordiazepoxide, pentobarbital and ethanol are not based on their response rate modulating effects and that training dose is not a determinant for the extent of cross-generalization between these compounds.

Animals↗
PubMed1994

Teaching daily living skills to children with autism in unsupervised settings through pictorial self-management.

We investigated the efficacy of pictorial self-management to teach daily living skills to 3 low-functioning children with autism. Stimulus and response generalization, stimulus control of self-management materials, and maintenance of behavior change were also assessed. Results showed that children with autism could successfully use pictures to manage their behavior in the absence of a treatment provider, generalize their behavior across settings and tasks, and maintain behaviors at follow-up. In addition, when compared to baseline, all children showed a substantial decrease in stereotypic behaviors. When picture order was manipulated in stimulus control probes, the children followed the new picture sequence, suggesting that the pictures were controlling their behavior. Further, a savings effect was demonstrated, in that 2 subjects reached criterion on second and third behaviors within less than 25% of original training time.

Activities of Daily Living↗
PubMed2003

Serotonergic-dopaminergic mediation of MDMA's discriminative stimulus effects in a three-choice discrimination.

(+/-)3,4-Methylenedioxymethamphetamine (MDMA; "Ecstasy") is a common drug of abuse that is often described as both a psychostimulant and a hallucinogen. Two-choice drug discriminations (i.e. drug vs. nondrug) in nonhumans comparing the discriminative stimulus properties of MDMA to psychostimulants or hallucinogens have produced somewhat inconsistent findings. The relative contribution of serotonergic versus dopaminergic actions to MDMA's discriminative stimulus effects may depend on the training stimulus conditions employed. We have previously demonstrated that rats can learn to discriminate the effects of MDMA and D-amphetamine in a three-choice drug discrimination procedure, and that LSD produced nearly complete substitution for MDMA under these conditions, and fenfluramine fully substituted for MDMA. In the present study, 12 rats were trained to discriminate LSD (0.08 mg/kg) and MDMA (1.5 mg/kg) from saline in a three-choice drug discrimination procedure under a fixed-ratio (FR) 10 schedule of food reinforcement. D-Amphetamine produced only partial substitution for MDMA while fenfluramine produced complete stimulus generalization. Low doses of D-amphetamine and fenfluramine produced greater stimulus generalization when administered in combination than when given alone. The serontonin(2) antagonist MDL-100,907 only partially blocked the MDMA cue, but completely antagonized LSD discrimination. The dopamine antagonist haloperidol also failed to block MDMA discrimination. These results indicate that 5-HT release is a salient feature to MDMA's discriminative stimulus effects but that MDMA produces a compound discriminative stimulus.

Animals↗
PubMed1991

Attempts to establish phencyclidine and cocaine discrimination without error.

An attempt was made to train pigeons to discriminate phencyclidine (PCP) from saline using a three-key color-tracking procedure under which birds were trained under a second order schedule [FR10 (FR5)] "without errors." Training without errors was done by not lighting the side key on which responses were not reinforced during the early phases of discrimination training and then gradually increasing the light intensity on that key. Initially, this procedure prevented drug discrimination errors, but as the light intensity increased on the incorrect side key, errors began to appear and then surpassed the error rate of birds trained "with errors." When stimulus control stabilized, there were no differences in stimulus control by the phencyclidine stimulus as a function of the training procedure, as measured by error rates. Birds trained to discriminate PCP from saline with and without errors also showed no differences in the shape of the PCP stimulus generalization curve. A second attempt at training without errors under a second-order schedule was made in a second group of pigeons, using cocaine as the training drug and eliminating the use of the color-tracking procedure. The results were very similar to those with PCP. Few errors occurred in birds trained "without errors" until the incorrect key-light intensity was increased, at which time large numbers of errors began to occur, but ultimately differences in stimulus control as a function of the training procedure disappeared. There was no difference between birds trained with and without errors in the shape of the cocaine stimulus generalization curve. The pigeons trained to discriminate cocaine from saline under a second order FR 10 (FR 5) schedule showed complete generalization to d-amphetamine and partial generalization to phencyclidine and chlorpromazine. Because baseline stimulus control was deteriorating, the schedule was changed to a second order FR 4 (FR 25) and stimulus control by cocaine was reestablished. Under this schedule, partial generalization was observed from cocaine to pentobarbital and chlorpromazine before baseline stimulus control weakened again. Both the broad generalization of the cocaine stimulus and the difficulty in maintaining stimulus control with cocaine have been observed by others; such data suggest that under some conditions the cocaine stimulus may lack specificity.

Journal Article↗
PubMedDate not supplied

The stimulus effect of 5,6,7,8-tetrahydro-1,3-dioxolo[4,5-g]isoquinoline is similar to that of cocaine but different from that of amphetamine.

5,6,7,8-Tetrahydro-1,3-dioxolo[4,5-g]isoquinoline (TDIQ) is a conformationally restricted phenylalkylamine related in structure to amphetamine and N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) that does not act as a locomotor stimulant. To further evaluate this agent, a group of six rats was trained to discriminate 5.0 mg/kg of TDIQ from vehicle and tests of stimulus generalization were conducted to define the stimulus. The TDIQ stimulus (ED(50)=0.9 mg/kg) failed to generalize to the central stimulants (+)amphetamine, methylphenidate or (-)ephedrine but, curiously, generalized to cocaine (ED(50)=1.5 mg/kg). When administered to rats (n=5) trained to discriminate 1.0 mg/kg of (+)amphetamine from vehicle, TDIQ produced a maximum of 7% (+)amphetamine-appropriate responding, whereas when administered to rats (n=7) trained to discriminate 4.0 mg/kg of (-)ephedrine from vehicle, TDIQ produced a maximum of 57% drug-appropriate responding. Administration of MDMA to TDIQ-trained animals resulted in 76% TDIQ-appropriate responding. Tests of stimulus generalization were also conducted with fenfluramine, nisoxetine, clenbuterol, imipramine and buspirone, and tests of antagonism were conducted with haloperidol and R(+)SCH-23390 using the TDIQ-trained animals. Results were inconclusive in that these agents either failed to completely substitute for or failed to completely antagonize the TDIQ stimulus. Nevertheless, the generalization seen with cocaine, the partial generalization seen with (-)ephedrine, MDMA, nisoxetine, clenbuterol and buspirone and the partial antagonism seen with haloperidol suggest that TDIQ might be acting through a mixed mechanism that involves adrenergic, dopaminergic and/or serotonergic systems. Given that TDIQ is an agent that seems to differentiate among the stimuli produced by amphetamine, methylphenidate, ephedrine and cocaine, it is proposed that further tests be undertaken, using animal models of cocaine abuse, to evaluate the potential usefulness of TDIQ as pharmacotherapy in cocaine dependence.

Amphetamine↗
PubMed2006

Predator learning favours mimicry of a less-toxic model in poison frogs.

Batesian mimicry--resemblance of a toxic model by an edible mimic--depends on deceiving predators. Mimetic advantage is considered to be dependent on frequency because an increase in mimic abundance leads to breakdown of the warning signal. Where multiple toxic species are available, batesian polymorphism is predicted--that is, mimics diversify to match sympatric models. Despite the prevalence of batesian mimicry in nature, batesian polymorphism is relatively rare. Here we explore a poison-frog mimicry complex comprising two parapatric models and a geographically dimorphic mimic that shows monomorphism where models co-occur. Contrary to classical predictions, our toxicity assays, field observations and spectral reflectances show that mimics resemble the less-toxic and less-abundant model. We examine "stimulus generalization" as a mechanism for this non-intuitive result with learning experiments using naive avian predators and live poison frogs. We find that predators differ in avoidance generalization depending on toxicity of the model, conferring greater protection to mimics resembling the less-toxic model owing to overlap of generalized avoidance curves. Our work supports a mechanism of toxicity-dependent stimulus generalization, revealing an additional solution for batesian mimicry where multiple models coexist.

Animals↗
PubMed2003

Stimulus preexposure reduces generalization of conditioned taste aversions between alcohol and non-alcohol flavors in infant rats.

Results of 3 experiments showed that infant rats (age 13-17 days) generalize conditioned taste aversions between alcohol and non-alcohol tastes such as a mixture of sucrose and quinine, apple cider vinegar, or coffee. Nonreinforced preexposure to those tastes reduced generalized aversions between them. Generalization between alcohol and sucrose-quinine was reduced not only after preexposure to both tastes, but also when only the nonconditioned taste was preexposed, whereas with alcohol and vinegar, both tastes had to be preexposed to obtain that effect. In no case was generalization reduced when only the to-be-conditioned taste was preexposed. Previous experience with alcohol alone, as well as with similar gustatory stimuli, may enhance subjects' ability to differentiate them during infantile stages in rats.

Animals↗
PubMed1989

Behavioral analysis of zopiclone on the basis of their discriminative stimulus properties in the rat.

Zopiclone is a new cyclopyrrolone derivative which exerts pharmacological activities similar to those of benzodiazepines in behavioral and biochemical studies. In order to clarify the discriminative stimulus properties of zopiclone, 8 rats were trained to discriminate the interoceptive stimulus induced by zopiclone (3.2 mg/kg, i.p.) from those of saline. Following discrimination acquisition, administration of zopiclone resulted in drug-appropriate responding with an ED50 of 1.3 (1.0-1.8) mg/kg. The zopiclone discriminative stimulus generalized to the benzodiazepines diazepam (1.8 mg/kg), nitrazepam (10 mg/kg) and alprazolam (10 mg/kg). A non-benzodiazepine, suriclone, at 3.2 mg/kg, generalized to the zopiclone stimulus in 5 out of 7 rats, but meprobamate, hydroxyzine, tracazolate and muscimol did not. The benzodiazepine antagonist Ro 15-1788 (1 mg/kg) completely blocked zopiclone stimulus. In contrast, however, bicuculline and pentetrazol failed to antagonize it. The serotonin antagonist cinanserin and ritanserin neither generalized to the zopiclone stimulus nor did they exhibit antagonism. These results suggest that the zopiclone discriminative stimulus is mediated by binding to benzodiazepine receptors and appears not to be related to GABAergic or serotonergic system.

Animals↗