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Augmentation, not blocking, in an A+/AX+ flavor-conditioning procedure.

An A+/AX+ Pavlovian conditioning design typically produces weakened or blocked conditioning to stimulus X. Two experiments were conducted in which rats first received an odor (A+) paired with an emetic US, and then received odor and taste (AX+) paired with the US. In both experiments, the preconditioned odor facilitated conditioning to the taste. In Experiment 1, a group that received two odor-illness pairings in A+ conditioning had a stronger taste aversion than a group that only had a single odor-illness pairing. Experiment 2 demonstrated that the strengthened taste aversion in the A+/AX+ condition was not due to stimulus generalization. The results represent a unique outcome in the flavor-aversion literature that is similar to potentiation. We propose that this facilitated conditioning to X in the A+/AX+ design be termed augmentation.

Animals↗

Stimulus control of instrumental reflexes in dogs: a comparison of alimentary and avoidance behaviors after prefrontal damage.

Two experiments involving parallel procedures to investigate stimulus generalization in prefrontal dogs under alimentary and defensive reinforcement were compared. Twelve dogs in the alimentary study were trained on a 50 percent partial reinforcement schedule, and 24 dogs were trained to avoid shock with either continuous shock availability and response contingent CS termination or with only 50 percent partial shock availability and response independent CS termination. One third of the subjects received bilateral medial prefrontal lesions, 12 dogs were given bilateral lesions of the lateral prefrontal cortex and the remaining subjects served as nonoperated controls. Generalization along the frequency dimension of the tonal CS was assessed during a sampling procedure within normal acquisition training, during complete extinction and following differentiation training. The results indicate specific effects from both the quality and the contingency of reinforcement. Within the limits of each reinforcement treatment, a dissociation occurred such that medial subjects tended to show heightened sensitivity to reinforcement density, while lateral subjects showed characteristic elevated reactivity during all generalization tests.

Animals↗

The discriminative stimulus properties of morphine in female rats chronically depleted of dopamine.

Female rats, 14 days of age, were chronically depleted of brain dopamine (DA) by the intracisternal administration of 6-OHDA 30 minutes following (i.p.) administration of desmethylimipramine (DMI). Dopamine depleted (DA) rats and their respective controls were trained to discriminate morphine from saline in a double bar discrimination task. While dopamine depletion did not hinder learning of the task, it markedly reduced morphine's suppressive effects as measured by response rates. Indications of stimulus generalization to methadone and haloperidol were observed in both groups via dose response tests. In addition, chronic morphine injections appeared to cause a repletion of DA in the DA group. Acute morphine-doses or chronic saline treated DA rats exhibited a 64-85% depletion of DA, while DA rats administered morphine chronically displayed a lesser depletion (42-46%).

Animals↗

Discriminative stimulus effects of S(-)-methcathinone (CAT): a potent stimulant drug of abuse.

Methcathinone ("CAT") is a CNS stimulant that is a very significant drug of abuse in the former Soviet Union. It has also appeared on the clandestine market in the United States and has been recently classified as a Schedule I substance. In the present study, S(-)-methcathinone [S(-)-CAT, 0.50 mg/kg, IP] was employed as the training drug in a two-lever drug discrimination task in rats. Once established, the S(-)-CAT stimulus was shown to have a rapid onset to action (within 5 min) and a duration of effect of approximately 60-90 min. In tests of stimulus generalization (substitution), the S(-)-CAT (ED50 = 0.11 mg/kg) stimulus generalized to S(+)-methamphetamine (ED5 = 0.17 mg/kg), S(-)-cathinone (ED50 = 0.19 mg/kg), S(+)-amphetamine (ED50 = 0.23 mg/kg), aminorex (ED50 = 0.27 mg/kg), (+/-)-CAT (ED50 = 0.25 mg/kg), (+/-)-cathinone (ED50 = 0.41 mg/kg), R(+)-CAT (ED50 = 0.43 mg/kg), cis-4-methylaminorex (ED50 = 0.49 mg/kg), methylphenidate (ED50 = 0.83 mg/kg), and cocaine (ED50= 1.47 mg/kg). S(-)-CAT-stimulus generalization did not occur to fenfluramine, a structurally related nonstimulant anorectic. Lastly, haloperidol (AD50 = 0.18 mg/kg), a dopamine receptor antagonist, potently antagonized the S(-)-CAT stimulus. It is concluded that S(-)-methcathinone is a very potent CNS stimulant, which appears to produce its stimulus effect, at least in part, via a dopaminergic mechanism.

Amphetamine↗

Reinforcement schedule effects in rats trained to discriminate 3,4-methylenedioxymethamphetamine (MDMA) or cocaine.

RATIONALE: Relatively few studies have compared the discriminative stimulus effects of 3,4-methylenedioxymethamphetamine (MDMA) and cocaine, and findings from different laboratories are somewhat inconsistent. One possible reason for discrepant results may be the use of different reinforcement schedules during discrimination training. OBJECTIVE: The present study compared fixed ratio (FR) 20 and variable interval (VI) 15-s reinforcement schedules to determine their influence on discrimination acquisition, response rates, frequency of reinforcements, and stimulus generalization in rats trained to discriminate cocaine or MDMA. MATERIALS AND METHODS: Thirty-two male Sprague-Dawley rats were trained to discriminate cocaine (10 mg/kg; n=16) or MDMA (1.5 mg/kg; n=16) from saline under either a FR 20 or a VI 15-s schedule of food reinforcement. Stimulus generalization tests were conducted with a range of doses of cocaine, MDMA, d-amphetamine, and lysergic acid diethylamide in all four training groups. RESULTS: The FR 20 schedule facilitated more rapid discrimination acquisition compared to the VI 15-s schedule and established differential response rates and frequency of reinforcement under drug and vehicle conditions. However, reinforcement schedule had little influence on stimulus generalization between MDMA and cocaine. Cocaine produced partial substitution for MDMA in both training groups (FR 20, 51%; VI 15-s, 58%). Likewise, MDMA produced only partial substitution for cocaine in both training groups (FR 20, 40%; VI 15-s, 72%). CONCLUSIONS: The present findings suggest that the number of sessions required to establish discriminative stimulus control varies with different reinforcement schedules. Nevertheless, training schedules alone do not appear to have significant effects on stimulus generalization between MDMA and cocaine.

Animals↗

Setting generality and stimulus control in autistic children.

This study was designed to assess the transfer of treatment gains of autistic children across settings. In the first phase, each of 10 autistic children learned a new behavior in a treatment room and transfer to a novel extra-therapy setting was assessed. Four of the 10 children showed no transfer to the novel setting. Therefore, in the second phase, each child who failed to transfer participated in an analysis of stimulus control in order to determine the variables influencing the deficit in transfer. Eachof the four children who did not transfer were selectively responding to an incidental stimulus during the original training in the treatment room. Utilizing a reversal design, each of the four children responded correctly in the extra-therapy setting when the stimulus that was functional during training was identified and introduced into the extra-therapy setting. The extreme selective responding and the resulting bizarre stimulus control found are discussed in relation to the issue of setting generality of treatment gains.

Adolescent↗

Spontaneous coronary artery spasm in variant angina is caused by a local hyperreactivity to a generalized constrictor stimulus.

To assess whether spontaneous coronary artery spasm in patients with variant angina results from local coronary hyperreactivity to a generalized constrictor stimulus or from a stimulus generated only at the site of the hyperreactive segment, the behavior of spastic and nonspastic coronary segments was studied in six patients with variant angina in whom focal coronary spasm developed spontaneously during cardiac catheterization. None of the patients had critical (greater than 50% luminal diameter reduction) organic coronary stenoses. Coronary diameters were measured by computerized quantitative arteriography during control, spontaneous spasm and ergonovine-induced spasm and after intracoronary nitrates were given. During spontaneous spasm, the luminal diameter of spastic and both proximal and distal nonspastic coronary segments was significantly reduced from control values, 64.2%, 13.2% and 14.8%, respectively. Average diameter reduction of unrelated arteries was 12.3%. Ergonovine, which was also administered to four patients, provoked focal spasm at the same site as spontaneous spasm. During intravenous ergonovine, luminal diameter of spastic segments was reduced by 91.5%, that of nonspastic proximal segments by 17.8% and that of nonspastic distal segments by 11.5%. Luminal diameter of unrelated arteries during ergonovine-induced spasm was reduced by 17.7%. Constriction of spastic segments was greater during ergonovine-induced spasm (p less than 0.05), whereas the extent of diameter reduction of nonspastic segments was not significantly different during spontaneous spasm and ergonovine-induced spasm. Intracoronary isosorbide dinitrate dilated spastic and nonspastic coronary segments to a similar extent from control (20.7%, 18% and 16.5%, respectively; p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Cross-generalization between an ethologically [correction of ecologically] relevant stimulus and a pentylenetetrazole-discriminative cue.

Twelve male Sprague-Dawley rats were trained in a two-choice pentylenetetrazole vs. saline drug discrimination (DD) task under an FR10 schedule of food reinforcement. Two-minute reinforced test sessions with the two training stimuli engendered exclusive injection-appropriate responding. Rats were injected with saline and then exposed for 20 min to the presence of a domestic cat pretreated with catnip. Immediately following the predator exposure, rats were tested for stimulus generalization in the DD task. The predator/prey interaction engendered 92% PTZ-appropriate responding. These data suggest that the interoceptive state associated with species-specific defense reactions in rats is similar to the cues produced by a pharmacological agent within a behavioral assay which has been suggested as an animal model of human anxiety.

Animals↗

[Learned equivalence in schizophrenia: novel method for the measurement of memory functions of the hippocampus and basal ganglia].

The purpose of the present study was to investigate basal ganglia (BG) and medial temporal lobe (MTL) dependent learning in patients with schizophrenia. Acquired equivalence is a phenomenon in which prior training to treat two stimuli as equivalent (if two stimuli are associated with the same response) increases generalization between them. The learning of stimulus-response pairs is related to the BG, whereas the MTL system participates in stimulus generalization. Forty-three patients with DSM-IV schizophrenia and 28 matched healthy controls participated in the study. Volunteers received the acquired equivalence associative learning task (FISHES) during which associations between faces and pet fishes are learned. Results revealed that patients with schizophrenia showed a selective deficit on stimulus generalization, whereas stimulus-response learning was unaffected. The number of errors during stimulus-response learning correlated with the daily chlorpromazine-equivalent dose of antipsychotics. In conclusion, patients with schizophrenia showed deficits during MTL-dependent learning, but not during BG-dependent learning. High-dose first generation antipsychotics may disrupt BG-dependent learning by blocking dopaminergic neurotransmission in the nigro-striatal system.

Adult↗

Antagonism of the discriminative stimulus effects of (+)-7-OH-DPAT by remoxipride but not PNU-99194A.

The dopamine (DA) agonist 7-hydroxy-N,N-di-n-propyl-2-amino-tetralin (7-OH-DPAT) has been used extensively as a tool to investigate the role of DA D(3) receptors in the reinforcing and discriminative stimulus properties of psychostimulant drugs. The present study examined the relative importance of D(3) vs. D(2) receptor actions in the discriminative stimulus effects of (+)-7-OH-DPAT (0.03 mg/kg, sc) in 16 male Sprague-Dawley rats trained to discriminate this compound from saline in a two-lever, water-reinforced operant procedure under a FR 20 schedule. Stimulus generalization and antagonism tests were conducted with cocaine and with various selective D(2) and D(3) receptor ligands. In contrast to previous findings that (+)-7-OH-DPAT substitutes for cocaine, the present results demonstrated that cocaine does not produce stimulus generalization in animals trained to discriminate (+)-7-OH-DPAT. Although two D(3)-preferring agonists, PD-128907 and pramipexole, produced complete stimulus generalization to the training drug, two highly selective D(3) antagonists (PNU-99194A, PD 152255) failed to block the discriminative stimulus effects of (+)-7-OH-DPAT. However, the D(2) antagonist remoxipride (3.0 mg/kg) produced a rightward shift in the (+)-7-OH-DPAT dose-response curve. These findings suggest that D(2) receptors are critically involved in mediating the cue properties of (+)-7-OH-DPAT. However, alternative interpretations that PNU-99194A is not entirely D(3) receptor selective should also be considered.

Animals↗

Central stimulants as discriminative stimuli. Asymmetric generalization between (-)ephedrine and S(+)methamphetamine.

Central stimulants readily serve as training stimuli in drug discrimination studies and typically substitute for one another in tests of stimulus generalization regardless of which is used as training drug. We have previously found that, although substitution occurs between (+)amphetamine and (-)ephedrine, substitution did not occur upon administration of S(+)methamphetamine to (-)ephedrine-trained animals. In the present investigation, rats were trained to discriminate S(+)methamphetamine (1 mg/kg) from saline vehicle and tests of stimulus generalization were performed with several stimulants, including (-)ephedrine. The S(+)methamphetamine stimulus (ED(50)=0.06 mg/kg) generalized to R(-)methamphetamine (ED(50)=1.61 mg/kg), S(+)amphetamine (ED(50)=0.28 mg/kg), S(-)methcathinone (ED(50)=0.21 mg/kg), methylphenidate (ED(50)=0.28 mg/kg), cocaine (ED(50)=3.68 mg/kg) and (-)ephedrine (ED(50)=13.1 mg/kg). Hence, stimulus generalization between S(+)methamphetamine and (-)ephedrine is apparently asymmetrical. In a companion study, R(-)methamphetamine was administered to rats trained to discriminate (-)ephedrine (4 mg/kg); substitution occurred and R(-)methamphetamine (ED(50)=0.92 mg/kg) was found to be nearly equipotent with (-)ephedrine (ED(50)=0.8 mg/kg). Although the exact basis for the observed results are unclear, they are discussed in terms of the different effects of (-)ephedrine and the methamphetamine optical isomers on neurotransmitter release and reuptake.

Animals↗

5-HT1 and 5-HT2 binding characteristics of 1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane analogues.

1-(2,5-Dimethoxy-4-bromophenyl)-2-aminopropane (DOB; 1a) is a purported serotonin (5-HT) agonist that binds selectively to central 5-HT2 binding sites. Systematic removal of any or all of the aromatic substituents had relatively little effect on 5-HT1 binding but reduced 5-HT2 binding by approximately 2 or more orders of magnitude. Demethylation of the 2-methoxy group of 1a, or introduction of an N-n-propyl group, doubled 5-HT1-site affinity but decreased 5-HT2-site affinity by 3- and 30-fold, respectively. In tests of stimulus generalization, using rats trained to discriminate DOM from saline, the 2-demethyl and N-propyl derivatives were found to produce stimulus effects similar to those of DOB. In addition, the S-(+) isomer of the iodo analogue of 1a was found to possess one-third the affinity of its R-(-) enantiomer at 5-HT2 sites and also resulted in DOM-stimulus generalization. Of the DOB analogues examined, DOB (1a) possesses optimal selectivity for 5-HT2 binding.

Animals↗

Nicotine and bupropion share a similar discriminative stimulus effect.

Bupropion is a weakly potent central nervous system (CNS) stimulant that is marketed both as an antidepressant and as an anti-smoking aid. The mechanism(s) by which it produces its effects is not well understood. In the present study, the effect of bupropion was examined in rats trained to discriminate the stimulus effect of 0.60 mg/kg of (-)-nicotine from saline in a two-lever drug discrimination task. In tests of stimulus generalization (substitution), the nicotine (ED(50)=0.17 mg/kg) stimulus completely generalized to bupropion (ED(50)=5.50 mg/kg). In addition, interaction studies were conducted that evaluated the effect of 3.0 mg/kg of bupropion, a dose that when given alone produced saline-appropriate responding, in combination with various doses of nicotine. This application resulted in an enhancement of the potency of nicotine (ED(50)=0.05 mg/kg), as indicated by a leftward shift of the nicotine dose-effect function. In tests of stimulus antagonism, various doses of bupropion were administered prior to the training dose of nicotine and were found to be ineffective as antagonists of the nicotine stimulus. In contrast, the nicotinic acetylcholine receptor (nicotine receptor) antagonist mecamylamine (AD(50)=0.40 mg/kg) completely blocked the stimulus effect of nicotine. Mecamylamine did not attenuate the stimulus generalization of bupropion. The results demonstrated that bupropion can produce a nicotine-like response in nicotine-trained animals, but it does so via a mechanism of action that is unlike that of nicotine. It is speculated that bupropion may be somewhat effective as an anti-smoking treatment in people who are motivated to quit smoking because low doses of bupropion produce a nicotine-like effect(s) that serve as a suitable substitute for nicotine.

Animals↗

Wh interrogative production in agrammatic aphasia: an experimental analysis of auditory-visual stimulation and direct-production treatment.

The effects of auditory-visual stimulation treatment derived from principles associated with a stimulation approach for aphasia treatment and direct-production treatment derived from a behavioral or learning approach were examined in 4 neurologically stable agrammatic aphasic subjects. Subjects were trained to produce selected exemplars of wh interrogative morphemes in complete sentence contexts, while the acquisition, response generalization (both within and across interrogative forms), stimulus generalization (to language samples), and maintenance effects of the two treatments were assessed. An alternating treatments design (ATD) in combination with a multiple-baseline design across behaviors and a multiple-baseline design across subjects was employed. Interrogative constructions were counterbalanced across subjects and treatments, and probes were administered daily to assess treatment effects. Results indicated that direct-production treatment was consistently more effective than auditory-visual stimulation treatment in facilitating acquisition of target responses for all subjects. Response generalization within interrogative forms paralleled acquisition regardless of treatment approach. Stimulus generalization to the elicited language-sample condition was not evident, however, trained responses were maintained subsequent to treatment. These data provided support for using direct-production treatment for interrogative intervention with agrammatic aphasic patients and indicated that training a selected number of exemplars of target interrogatives results in generalization of that question form to novel language responses. However, the lack of generalization across interrogatives indicated that wh interrogatives do not constitute a response class and, thus, pointed out a need for programming generalization to untrained members of that linguistic class and to spontaneous language.

Acoustic Stimulation↗

Recovery of conditioned fear by a single postextinction shock: effect of similarity of shock contexts and of time following extinction.

Subjects in six experimental groups (n = 16 each) received one-trial passive avoidance (PA) training in which shock was delivered upon movement from a white wooden floor compartment to a black grid compartment. Then fear was extinguished (30 min) in the black compartment. After either 24 or 168 h, all the groups were treated in a room distinctively different from the training room. At each interval, one group received a shock in an apparatus similar to the conditioning box, another received a shock in a dissimilar apparatus, and another was placed in a neutral box. A PA test trial in the training apparatus indicated reinstatement of extinguished fear in all the groups given a postextinction shock except the 24-h dissimilar group. Control groups revealed that the extinction treatment was effective and that spontaneous recovery was not evident. The results were explained in terms of classical conditioning, stimulus generalization, and the broadening (flattening) of stimulus generalization gradients with time.

Animals↗

Cathinone: an investigation of several N-alkyl and methylenedioxy-substituted analogs.

Structurally, methcathinone is to cathinone what methamphetamine is to amphetamine. Due to increased interest in the abuse of such agents we wished to determine if certain derivatives of cathinone would behave in a manner consistent with what is known about their amphetamine counterparts; that is, can amphetamine structure-activity relationships be extrapolated to cathinone analogs? As expected on the basis of known structure-activity relationships for amphetaminergic agents, both N-monoethylcathinone and N-mono-n-propylcathinone (N-Et CAT and N-Pr CAT; ED50 = 0.77 and 2.03 mg/kg, respectively) produced amphetamine-like stimulus effects in rats trained to discriminate 1 mg/kg of (+)amphetamine from vehicle and were somewhat less potent than racemic methcathinone. In contrast, (-)N,N-dimethylcathinone or (-)Di Me CAT (ED50 = 0.44 mg/kg) was more potent than expected; although (+)N,N-dimethylamphetamine is sevenfold less potent than (+)methamphetamine, (-)Di Me CAT is only about 1.6-fold less potent than (-)methcathinone, and is essentially equipotent with (-)cathinone. In addition, although it has been previously demonstrated that 1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDA) results in stimulus generalization in rats trained to discriminate (+)amphetamine or DOM from vehicle, the cathinone counterpart of MDA (i.e., MDC) resulted in partial (maximum: 58%) generalization in (+)amphetamine-trained animals, and failed to produce >7% DOM-appropriate responding in rats trained to discriminate DOM from vehicle. On the other hand, the N-methyl analog of MDC (i.e., MDMC) behaved in a manner similar to that of the N-methyl analog of MDA (i.e., MDMA); that is, a (+)amphetamine stimulus (MDMC: ED50 = 2.36 mg/kg) but not a DOM stimulus generalized to MDMC. In MDMA-trained rats, stimulus generalization occured both to MDC and MDMC (ED50 = 1.64 and 1.60 mg/kg, respectively). Although this and previous studies have demonstrated that significant parallelisms exist between the structure-activity relationships of amphetamine analogs and cathinone analogs, we now report several unexpected qualitative and/or quantitative differences. It is suggested that caution be used in attempting to draw conclusions or make predictions about the activity and potency of novel cathinone analogs by analogy to the structure-activity relationships derived from amphetamine-related agents; it would appear that each new cathinone analog will require individual investigation.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗

Antagonism of the effects of the hallucinogen DOM and the purported 5-HT agonist quipazine by 5-HT2 antagonists.

Rats trained to discriminate 1.0 mg/kg of 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) from saline in a two-lever operant choice task were administered doses of mescaline, LSD, 5-methoxy-N,N-dimethyltryptamine (5-OMe DMT), quipazine, TFMPP and RU-24969. The DOM-stimulus generalized to the three hallucinogenic agents and to quipazine, but not to the purported serotonin agonists TFMPP or RU-24969. Pretreatment of the animals with the 5-HT2 antagonists ketanserin and pirenperone antagonized the effect produced by DOM. Pirenperone also blocked DOM-stimulus generalization to mescaline, LSD, 5-OMe DMT and quipazine. The results of this study suggest that the discriminative stimulus effects of DOM, the three hallucinogenic agents to which DOM-stimulus generalization occurred, and quipazine, may involve those sub-populations of serotonin receptors that are labeled by tritiated ketanserin (i.e. 5-HT2 sites).

DOM 2,5-Dimethoxy-4-Methylamphetamine↗

Nonvocal language acquisition in adolescents with severe physical disabilities: Bliss symbol versus iconic stimulus formats.

This study compared training in two language systems for three severely handicapped, nonvocal adolescents: the Bliss symbol system and an iconic picture system. Following baseline, training and review trials were implemented using an alternating treatments design. Daily probes were conducted to assess maintenance, stimulus generalization, and response generalization, and data were collected on spontaneous usage of either language system throughout the school day. Results showed that students required approximately four times as many trials to acquire Bliss symbols as iconic pictures, and that students maintained a higher percentage of iconic pictures. Stimulus generalization occurred in both language systems, while the number of correct responses during responses generalization probes was much greater for the iconic system. Finally, students almost always showed more iconic responses than Bliss responses in daily spontaneous usage. These results suggest that an iconic system might be more readily spontaneous usage. These results suggest than an iconic system might be more readily acquired, maintained, and generalized to daily situations. Implications of these findings for the newly verbal person were discussed.

Adolescent↗