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PubMed1988

Attenuation of the discriminative stimulus properties of ethanol and oxazepam, but not of pentobarbital, by Ro 15-4513 in mice.

The imidazobenzodiazepine Ro 15-4513 has a high affinity for central benzodiazepine binding sites and has been shown to antagonize certain effects of ethanol. The purpose of the present study was to determine if Ro 15-4513 would attenuate the discriminative stimulus properties of ethanol and the other central nervous system depressants pentobarbital and oxazepam. Different groups of mice were trained to discriminate 1.0 or 1.5 g/kg of ethanol, 20 mg/kg of pentobarbital or 10 mg/kg of oxazepam from saline injections in a two-lever operant task. Stimulus generalization tests were conducted with Ro 15-4513 alone (0.01-20 mg/kg) and in combination with the training drugs. The discriminative stimulus effects of ethanol and oxazepam, but not of pentobarbital, were blocked by Ro 15-4513. When given alone in each of the different drug-training groups, Ro 15-4513 did not produce drug-lever responding but decreased overall response rates in a dose-related fashion. Although the alcohols, barbiturates and benzodiazepines share discriminative stimulus properties under many conditions, the selective blockade of their stimulus effects provides further evidence that their actions may be mediated by different cellular mechanisms. These data also show that Ro 15-4513 may attenuate behavioral effects of ethanol relevant to its abuse.

Animals↗

PubMed1980

Phencyclidine-like discriminative effects of opioids in the rat.

Possible commonalities in the discriminative stimulus properties of phencyclidine (PCP) and opioids were investigated in rats trained to discriminate between i.p. injections of saline and 2.0 mg/kg of PCP in a two-choice discrete-trial avoidance paradigm. Behavior was considered to be under stimulus control when a rat reliably completed at least 18 trials of a 20-trial session on the appropriate choice lever after receiving PCP or saline. Tests of stimulus generalization were performed over an 8- to 32-fold range of doses with ketamine, a PCP analog, and eight opioids. Dose- and time-dependent stimulus control of behavior comparable to that produced by 2.0 mg/kg of PCP (defined by the number of trials completed on the PCP-appropriate choice lever) were produced by ketamine and the opioids cyclazocine, SKF 10,047 and dextrorphan. These drugs also produced orderly increases in responses during the interval between trials suggestive of a relationship between this effect and PCP-like stimulus control. In contrast, after ethylketocyclazocine, ketocyclazocine, pentazocine and dextromethorphan trials were completed primarily on the saline-appropriate lever and responding between trials produced did not change. Neither the PCP-like stimulus control of behavior nor the increased responding between trials produced by cyclazocine were prevented by pretreatment with naltrexone (1.0 mg/kg). These results provide further evidence that PCP and certain opioids share a common component of action that is probably mediated by neuronal substrates not usually associated with the activity of opioids.

Analgesics, Opioid↗

PubMed1986

Discriminative stimulus effects of the opioid antagonist diprenorphine in the squirrel monkey.

Squirrel monkeys were trained in a discrete-trial avoidance paradigm to discriminate i.m. injections of the opioid antagonist diprenorphine (0.1 mg/kg) from vehicle. When the monkeys could complete reliably at least 22 trials of a 25-trial session on the choice level appropriate for the substance injected before the session (i.e., diprenorphine or vehicle), tests of stimulus generalization to novel drug conditions were conducted. Mu receptor agonists (morphine, etorphine and buprenorphine) and kappa receptor agonists (ethylketocyclazocine, nalorphine and I-N-allylnormetazocine) produced dose-dependent diprenorphine-like discriminative effects. The dextrorotatory isomer of N-allynormetazocine was almost two-orders of magnitude less potent than the levorotatory isomer in this respect and phenycyclidine generalized to diprenorphine only partially, suggesting that the phencyclidine/sigma site does not have a prominent role in the discriminative effects of diprenorphine. Other nonopioid drugs (d-amphetamine, mescaline and pentobarbital) also did not produce discriminative effects comparable to those of the training drug. The pure opioid antagonists, naloxone, naltrexone, and WIN 44,441-3 [(2-alpha-6 alpha, 11S)-(-)-1-cyclopentyl-5-(1,2,3,4,5,6-hexahydro-8-hydroxy-3,6,11-trim eth yl-2, 6-metheno-3-benzazocin-11-yl)-3-pentanone] occasioned responding primarily on the lever appropriate for vehicle. Naloxone (1.0 mg/kg) blocked surmountably the diprenorphine-like discriminative effects of the mu and kappa agonists, displacing generalization curves to the the right by 10- to 100-fold; however, naloxone failed to shift the curve for diprenorphine itself. Thus, in the squirrel monkey diprenorphine has discriminative stimulus effects in common with mu- and kappa-opioid agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1983

Discriminative stimulus effects of dextrorphan in pigeons.

Pigeons were trained to discriminate between dextrorphan (10 mg/kg) and saline in a task in which 20 consecutive key pecks on either the left or right key, depending on whether dextrorphan or saline had been administered, produced food. During sessions in which stimulus generalization to other drugs was evaluated, 20 consecutive responses on either the dextrorphan- or saline-appropriate key produced food. Dextromethorphan and dexoxadrol produced dose-related stimulus control of behavior similar to that produced by dextrorphan. In contrast, the l-isomers of these compounds, levomethorphan, levoxadrol and levorphanol, at doses up to and including those that markedly decreased the rate of responding, produced responding primarily on the saline-appropriate key. In addition, both the d- and l-isomers of methadone, codeine, morphine, butorphanol and profadol resulted in predominantly saline-appropriate responding. l-Cyclorphan, dl-, l- and d-SKF-10,047 and l- and d-cyclazocine produced dose-related dextrorphan-appropriate responding, whereas, l-oxilorphan (the 14-hydroxymorphinan analog of cyclorphan), dl-, l- and d-pentazocine, l- and d-ethylketazocine and l-naltrexone resulted in either responding exclusively on the saline-appropriate key or responding that was intermediate between that appropriate for saline and dextrorphan. Although levorphanol alone produce little or no dextrorphan-appropriate responding, the coadministration of naltrexone (1.0 mg/kg) and high doses of levorphanol, but not levoxadrol, resulted in responding similar to that produced by dextrorphan.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1986

Differential modification of pentobarbital stimulus control by d-amphetamine and ethanol.

The ability of d-amphetamine and ethanol to alter discriminative stimulus control by pentobarbital was examined in pigeons. Saline and pentobarbital (5.6 mg/kg) were established as discriminative stimuli for food-maintained responding in six birds. Dose-response functions for stimulus control and response rate were determined for pentobarbital alone and in combination with selected doses of d-amphetamine or ethanol. In tests of stimulus generalization, d-amphetamine alone did not exert pentobarbital-like stimulus control, while ethanol alone evoked variable degrees of pentobarbital-like stimulus control. d-Amphetamine attenuated pentobarbital stimulus control. Doses of 1.0 or 3.2 mg/kg d-amphetamine increased the dose of pentobarbital required for stimulus control in five of six birds. Combinations of high d-amphetamine and pentobarbital doses yielded less than additive rate suppression. Ethanol produced variable effects on pentobarbital stimulus control, with moderate doses generally decreasing, and high doses increasing, the dose of pentobarbital required for stimulus control. A high ethanol dose decreased the pentobarbital dose required for rate suppression. Taken together, these data demonstrate that pentobarbital stimulus control can be altered by drugs within or without the sedative hypnotic class.

Animals↗

PubMed1975

Contradiction of auditory and visual information by brain stimulation.

Cats with permanently implanted electrodes were trained to discriminate between trains of flashes or clicks at two different repetition frequencies. After substantial overtraining with these sensory stimuli, high levels of stimulus generalization were obtained to electrical stimulation of the reticular formation at either frequency stimultaneously with contradictory flicker or click stimulation at the opposite frequency resulted in control of the behavior by the reticualr stimulus. Lateral geniculate stimulation failed to show this effect.

Acoustic Stimulation↗

PubMed1994

Discriminative stimulus effects of melatonin in the rat.

To provide initial information on the potential mechanisms underlying the discriminative stimulus effects of melatonin, rats were trained to discriminate melatonin (150 mg/kg, IP) from saline in a two-choice discrete-trial avoidance paradigm. Stimulus generalization curves for melatonin were steep; complete generalization with melatonin occurred at 100-150 mg/kg. Triazolam generalized completely with melatonin (n = 7). Flurazepam generalized completely with melatonin in only two out of six rats; however, partial generalization was produced in the remaining four animals. The melatonin-appropriate responding produced by triazolam was antagonized completely (in six out of seven rats) by 0.3-10 mg/kg flumazenil (Ro 15-1788). In contrast, the dose of flumazenil sufficient to block completely the melatonin-like discriminative effects of triazolam failed to block the stimulus effects of the training dose of melatonin. Pentobarbital produced primarily melatonin-appropriate responding, with complete generalization with melatonin in five out of seven rats. Diphenhydramine generalized completely with melatonin in two out of seven rats; however, little or no partial generalization was observed in the remaining five rats. These results suggest that melatonin may produce its discriminative effects through sites on the GABAA-benzodiazepine receptor complex distinct from the benzodiazepine binding sites.

Animals↗

PubMed1992

Discriminative stimulus properties of the serotonergic compound eltoprazine.

The 5-hydroxytryptamine-1a/1b (5-HT1a/1b) agonist eltoprazine is the main representative of the so-called "serenics," a group of drugs sharing a specific antiaggressive activity. Rats were trained to discriminate an i.p. dose of 0.5 mg/kg of eltoprazine from saline in a two-lever operant drug discrimination task using a fixed ratio 10 schedule of food reinforcement. The cue of eltoprazine was found to be dose and time dependent. The eltoprazine stimulus generalized to the structurally related experimental drug fluprazine, the mixed 5-HT1a/1b agonist 5-methoxy-3-(1,2,3,6-tetrahydropyridinyl)-1H indole, (RU 24969), the 5-HT1b/1c agonist 1-[3-(trifluoromethyl)phenyl]piperazine, (TFMPP), the 5-HT1a agonist 8-hydroxy-2-(di-n-propylamino)tetralin-HB, (8-OH-DPAT), and the beta adrenergic/5-HT1 antagonists (+/-)-pindolol and (+/-)-propranolol. The eltoprazine cue partially generalized to the cues of the 5-HT1a agonists flesinoxan and buspirone, (m-CPP), the 5-HT1b/1c agonist 1,3-chlorophenyl-piperazine dihydrochloride and the 5-HT1c/2 antagonist mesulergine, and did not generalize to the 5-HT2/1c agonist DOI. During tests of antagonism, neither mesulergine, the nonspecific 5-HT antagonist methysergide, the 5-HT2 antagonist ketanserin, the 5-HT3 antagonist tropisetron (ICS 205-930), nor (+/-)-pindolol and (+/-)-propranolol attenuated the stimulus effect of eltoprazine. The specific beta adrenergic antagonist timolol did not substitute for eltoprazine. The present data show that eltoprazine can serve as a discriminative stimulus in rats and suggest that specifically 5-HT1 (i.e., 5-HT1a and 5-HT1b) receptors are involved in the stimulus properties of eltoprazine.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1985

Discriminative stimulus properties of xylazine in rat: discriminability and effects of putative alpha-2 adrenoceptor agonists and antagonists.

In a first experiment, rats were trained initially to discriminate i.p. injections of 2.5 mg/kg of xylazine from saline in a two-lever, food-reinforced, fixed-ratio 10 drug discrimination procedure. The animals were then retrained on progressively lower doses of the training drug. The stimulus generalization gradient of xylazine was established each time the animals had reached criterion on successive training doses; the criterion required that lever selection be appropriate to the saline or xylazine injection on 10 consecutive sessions. The findings indicate the lowest xylazine training dose at which individual rats can reach criterion to range from 2.5 to less than or equal to 0.31 mg/kg; the median lowest discriminable dose was 0.89 mg/kg. The distribution of lowest discriminable dose accommodated a Gaussian shape. The slope of the xylazine gradient did not in a systematic manner vary as a function of training dose, and the ED50 value of xylazine was an almost constant fraction of training dose (1:2.0) at training doses ranging from 2.5 to 0.63 mg/kg. A second experiment examined the xylazine-like agonist and the xylazine-antagonist effects of clonidine, yohimbine, piperoxan and idazoxan in rats discriminating xylazine from saline at a training dose of 2.5 mg/kg. Clonidine produced generalization in all animals and antagonized the xylazine stimulus in one. Idazoxan produced near complete antagonism, and was generalized in one animal. Yohimbine and piperoxan produced magnitudes of agonist and antagonist effects that were intermediate between those of clonidine and idazoxan. Lisuride and d-lysergic acid diethylamide produced up to 71 and 29% generalization, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗

PubMed1987

Discriminative stimulus effects of caffeine: tolerance and cross-tolerance with methylphenidate.

Twice daily injection of caffeine (30 mg/kg) for 3-1/2 days shifted the caffeine stimulus generalization curve to the right by 3-fold in rats trained to discriminate saline from 30 mg/kg of caffeine, and by 4-fold in rats trained to discriminate saline from 10 mg/kg of caffeine. The latter group was also tested for cross-tolerance with methylphenidate, a drug that generalizes completely with caffeine. Twice daily injection of caffeine (30 mg/kg) for 3-1/2 days increased the ED50 of methylphenidate for caffeine-appropriate responding from 1.5 to 5.5 mg/kg. Conversely, injections of methylphenidate (3.0 mg/kg) increased the ED50 of caffeine from 5.2 to 15 mg/kg. The development of symmetrical cross-tolerance to the discriminative effects of caffeine and to the caffeine-like discriminative effects of methylphenidate supports previous observations suggesting commonalities in the cellular bases of the stimulus properties of these drugs.

Animals↗

PubMedDate not supplied

Generalization of habituation and intrinsic sensitization in the leech.

Using the shortening reflex of the medicinal leech Hirudo medicinalis we examined stimulus generalization of habituation learning. Preparations received mechanosensory stimulus at two positions on the leech body wall, one site used to carry out habituation training and a second novel site to test for generalization of habituation. After training, the specific mechanosensory neurons activated by each stimulus were assessed using intracellular recordings. As expected, the closer the two sites were to each other, the greater the degree of generalization of habituation at the novel site and the more sensory cells were shared. However, a form of behavioral facilitation was observed at the trained site that resembled behavioral sensitization, but differed from the standard sensitization process in several respects. (1) Facilitation was induced by stimulation of the novel site before habituation training at the trained site, although the stimulus intensity at the novel site was equivalent to the training stimuli and was not the strong, noxious stimuli that normally induce sensitization. (2) The magnitude of the facilitating effect was proportional to the proximity of the novel and trained stimulation sites. (3) Although behavior at the trained site was facilitated, behavior at the novel site was habituated, indicating that the induced behavioral facilitation did not generalize throughout the animal, as normally occurs during sensitization, but was limited to a single stimulus-response pathway.

Analysis of Variance↗

PubMedDate not supplied

Pavlovian conditioning in human skilled motor behavior.

The role of Pavlovian contingencies in human skilled motor behavior was investigated in three experiments by means of a new conditioning preparation. In Experiment 1 the present method was shown to be appropriate for the study of associative learning. Subjects who experienced a standard delay configuration performed significantly more conditioned responses than subjects who received either backward conditioning or random pairings. Stimulus generalization was shown to be slight in two additional groups. Subsequent experiments examined conditioning with multiple conditioned stimuli (CSs). In particular, in Experiment 2 some reciprocal overshadowing was demonstrated when two conditional stimuli (tone and vibration) were compounded. Experiment 3 investigated blocking. Blocking was less than expected, however. Subjects' perceptions of the stimuli and reaction time data suggest that a certain proportion had shifted their attention to the added element of the CS compound. Results are discussed in relation to other studies on Pavlovian learning in humans and animals, which are concerned with "stimulus selection."

Acoustic Stimulation↗

PubMed1987

Toluene, halothane, 1,1,1-trichloroethane and oxazepam produce ethanol-like discriminative stimulus effects in mice.

Drug discrimination procedures were used to compare the discriminative stimulus properties of ETOH and volatile inhalants. Mice were trained to discriminate between i.p. injections of ETOH (1 g/kg) and saline in a two-lever operant task. Stimulus generalization was examined after 20-min inhalation exposures to toluene (300-5400 ppm), halothane (500-8000 ppm) and 1,1,1,-trichloroethane (TCE; 125-14000 ppm). Oxazepam (10-30 mg/kg i.p.) also was tested. Concentration- or dose-related increases in ETOH-lever responding were observed with toluene, halothane, TCE and oxazepam. Shared discriminative stimulus properties among toluene, halothane, TCE and ETOH indicate that some volatile inhalants share pharmacological properties with ETOH. Previous research has shown that these inhalants also produce pentobarbital-like discriminative stimulus effects in mice. Thus, at least some inhaled anesthetics and abused solvents have behavioral effects in common with abused central nervous system depressant drugs such as ETOH and barbiturates.

Animals↗

PubMed2005

Discriminative stimulus effects of gamma-hydroxybutyrate (GHB) and its metabolic precursor, gamma-butyrolactone (GBL) in rats.

RATIONALE: Gamma-hydroxybutyrate (GHB) is becoming an increasingly popular drug of abuse. Metabolic precursors of GHB, gamma-butyrolactone (GBL) and 1,4-butanediol (BDL), are commercially available industrial solvents that may also present potential health risks. Relatively little is known about the neurobehavioral effects of GHB and its precursors. OBJECTIVE: The aim of the present investigation was to characterize the discriminative stimulus effects of GHB and its precursor, GBL. METHODS: Male Sprague-Dawley rats were trained to discriminate GHB [300 mg/kg, i.g.; n=16] or GBL (150 mg/kg, i.p.; n=8) from vehicle under a fixed ratio 20 (FR 20) schedule of food reinforcement. Stimulus generalization tests were then conducted with several compounds. RESULTS: GHB and GBL produced cross-generalization and BDL was fully substituted for both GHB and GBL. Two benzodiazepines, alprazolam and diazepam, and the 5-HT1A agonist, buspirone, did not substitute for either training drug nor did ethanol or the NMDA antagonists, PCP and ketamine. The GHB antagonist, NCS-382, and the GABA(B) antagonist, CGP-35348, blocked the discriminative stimulus effects of GHB but not those of GBL. CONCLUSIONS: These findings suggest that GHB and its metabolic precursors produce similar subjective effects that differ from those of other sedative-hypnotic drugs. Further investigations into the neurochemical actions underlying the subjective effects of these drugs are warranted.

4-Butyrolactone↗

PubMed1986

A psychophysical measure of pitch discrimination loss resulting from a frequency range constraint in European starlings (Sturnus vulgaris).

Earlier research (Hulse & Cynx, 1985) revealed that a number of species of songbirds acquired a pitch discrimination between rising and falling sequences in an arbitrarily defined training range of frequencies, but then failed to generalize the discrimination to new frequency ranges--a frequency range constraint. The two experiments here provide a psychophysical estimate of how pitch discrimination deteriorated in one species as sequences were stepped out from the training range. The gradient showing loss of discrimination was much sharper than would have been anticipated by stimulus generalization or the training procedures, and appeared unaffected by the removal of rising and falling frequency information. The frequency range constraint and its psychophysical properties have implications both for the analysis of birdsong and the study of animal cognition.

Animals↗

PubMed1972

Modification of consonant speech-sound articulation in young children.

A series of three experiments was performed in a classroom setting with small groups of young children with severe articulation problems. Variations on a basic token reinforcement procedure were demonstrated in each experiment. A combined multiple baseline/reversal design showed effective experimenter control of rates of correct and incorrect consonant sound articulation in all cases. In addition, the data in each experiment showed the problems of obtaining stimulus generalization of the high rates of correct articulation to non-training settings. The third experiment demonstrated a procedure for producing such generalization by making each child a discriminative stimulus for correct articulaton by the other child, thus maintaining high levels of correct articulation for each child when in the presence of the other.

Journal Article↗

PubMed1992

A comparison of generalization functions and frame of reference effects in different training paradigms.

Six experiments were carried out to compare go/no-go and choice paradigms for studying the effects of intradimensional discrimination training on subsequent measures of stimulus generalization in human subjects. Specifically, the purpose was to compare the two paradigms as means of investigating generalization gradient forms and frame of reference effects. In Experiment 1, the stimulus dimension was visual intensity (brightness); in Experiment 2, it was line orientation (line-angle stimuli). After learning to respond (or to respond "right") to stimulus value (SV) 4 and not to respond (or to respond "left") to SV2 (in Experiment 1) or SV1 (in Experiment 2), the subjects were tested for generalization (recognition) with an asymmetrical set of values ranging from SV1 to SV11. Go/no-go training produced peaked gradients, whereas choice training produced sigmoid gradients. The asymmetrical testing resulted in a gradual shift of the peak of responding (go/no-go group) or in the point of subjective indifference (PSI; choice group) toward the central value of the test series; thus, both paradigms revealed a frame of reference effect. The results were comparable for the quantitative (intensity) and the qualitative (line-angle) stimulus dimensions. Experiment 3 compared the go/no-go procedure with a yes/no procedure in which subjects responded "right" to SV4 and "left" to all other intensities and found no differences between these procedures. Thus the difference in gradient forms in go/no as opposed to (traditional) choice paradigms depends on whether one or two target stimuli are used in training. In Experiment 4, in which visual intensity was used, the shift in the PSI following choice training varied positively with the range of asymmetrical test stimuli employed. In Experiment 5, also with visual intensity, the magnitude of the peak shift following go/no-go training varied as a function of overrepresenting a high or a low stimulus value during generalization testing. Experiment 6, with line angles, showed that the PSI following choice training varies in a similar way. The frame of reference effects obtained in these experiments are consistent with an adaptation-level model.

Discrimination Learning↗

PubMed1985

The effect of drugs on the acquisition of stimulus control in a conditioned suppression procedure.

Rats were trained to press a lever under a variable-interval (VI) schedule of water reinforcement. After stable responding had developed, a 4.5-KHz tone (CS) was conditioned classically to a 2.5-mA electric shock (US) in groups of animals which had been given various psychoactive drugs or saline. Twenty-four hours later, a stimulus generalization test was conducted in the absence of drug; during this session, tones that varied in frequency around 4.5 KHz were presented while the animals were responding under the VI schedule. In animals conditioned under saline, all tones (non-differentially) suppressed responding which, however, recovered gradually over time. This suppressive effect was eliminated by lysergic acid diethylamide (LSD; 0.2 and 0.32 mg/kg), cocaine (20 mg/kg), diazepam (2.5 mg/kg), lisuride (0.08 mg/kg), mescaline (20 mg/kg) and 5-methoxy-N,N-dimethyltryptamine (4 mg/kg), and was attenuated by amphetamine (4 mg/kg), pentobarbital (15 mg/kg) and morphine (4 mg/kg). Atropine (10 mg/kg), scopolamine (1 mg/kg), clonazepam (0.5 mg/kg), and chlorpromazine (4 mg/kg) did not alter the suppressive effect of the tone. The serotonin antagonist BC-105 (6 mg/kg) reversed the effect of 0.2 mg/kg of LSD. These results suggest (1) that drug-induced stimuli may "overshadow" other (e.g., external) stimuli during classical conditioning and, (2) that drugs might affect behavior by altering processes (stimulus control or others) that do not simultaneously involve response or motor control.

Animals↗