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PubMed1989

Phosphodiesterase inhibitors potentiate opiate-antagonist discrimination by morphine-dependent rats.

This study was performed to examine the relevance of the quasi-withdrawal syndrome in nondependent rats to the syndrome precipitated by naltrexone in rats physically dependent upon morphine. Morphine-dependent rats trained to discriminate between SC injections of naltrexone (0.1 mg/kg) and saline were pretreated with 10 mg/kg of a phosphodiesterase inhibitor: 3-isobutyl-1-methylxanthine (IBMX), Ro 20-1724, or papaverine. The naltrexone stimulus-generalization curve and dose-response curve for loss of body weight were shifted to the left by IBMX and Ro 20-1724, which produce quasi-withdrawal, but not by papaverine, which does not. IBMX also potentiated the naltrexone-like discriminative effects and loss of body weight induced by cyclazocine, an opioid agonist-antagonist. Butorphanol, another agonist-antagonist, occasioned choice responding appropriate for saline when tested alone but engendered more than 50% naltrexone-appropriate choice responses in rats pretreated with IBMX. Thus, phosphodiesterase inhibitors that produce an opiate quasi-withdrawal syndrome potentiate interoceptive stimuli and weight loss associated with the withdrawal syndrome precipitated by naltrexone in morphine-dependent rats. Furthermore, they appear to enhance the opiate-antagonist activity of opioids with mixed agonist and antagonist properties.

1-Methyl-3-isobutylxanthine↗

PubMed1990

Stimulus properties of a new designer drug: 4-methylaminorex ("U4Euh").

Like other phenylisopropylamine derivatives, 4-methylaminorex is a central stimulant. The cis isomer of 4-methylaminorex ("U4Euh"; "ICE") has appeared on the clandestine market as a novel designer drug and was recently classified as a Schedule I substance. In the present investigation, the stimulus properties of racemic cis, racemic trans, and all four individual optical isomers of 4-methylaminorex were examined in rats trained to discriminate 1 mg/kg of S(+)amphetamine sulfate from saline. The S(+)amphetamine stimulus generalized to all of the agents investigated and the relative potencies of the optical isomers (followed by ED50 values) were as follows: trans(4S,5S) (0.25 mg/kg) greater than cis(4S,5R) (1.2 mg/kg) = cis(4R,5S) (1.5 mg/kg) greater than trans(4R,5R). The trans(4R,5R) isomer did not completely substitute for S(+)amphetamine unless a longer (i.e., 60-min) presession injection interval was used, suggesting that it has a longer duration of onset than the other isomers of 4-methylaminorex. The results, which are consistent with established structure-activity relationships, suggest that the trans(4S,5S) isomer (which has not been scheduled) is similar in potency to (+)amphetamine (ED50 = 0.4 mg/kg) and is more potent than either of the cis isomers.

Amphetamines↗

PubMed1992

Enhancement of sensory preconditioning by a moderate dose of ethanol in infant and juvenile rats.

Little is known regarding the effects of acute ethanol on learning and memory among infant and juvenile rats. Two experiments were designed to evaluate the influence of various doses of ethanol administration on sensory preconditioning and primary conditioning in preweanling (16-day-old) and postweanling (28-day-old) rats. Moderate doses of ethanol facilitated conditioning at both ages. In the absence of ethanol, sensory preconditioning was not statistically significant among postweanlings in Experiment 1, although the phenomenon was clear and robust among preweanlings. Sensory preconditioning was facilitated by administration of doses of 0.8 and 1.2 g/kg ethanol in preweanlings and a dose of 1.6 g/kg ethanol in postweanlings, whereas sensory preconditioning was impaired in preweanlings by a high dose (2.4 g/kg) of ethanol. This reflected a shift to the right, between the preweaning and the postweaning periods, in the dose-response curve. It was determined in Experiment 2 that the effect of ethanol on sensory preconditioning could not be explained by stimulus generalization or an effect of ethanol on first-order conditioning, confirming the effect of ethanol on learning of the odor-odor association in the preexposure phase. The basis for a dose-dependent biphasic effect of ethanol on sensory preconditioning is discussed.

Animals↗

PubMed1989

Conditioned response models of placebo phenomena: further support.

Following our earlier research, we further investigated a model that conceptualizes placebo phenomena as the result of conditioning and attempted to extend and replicate the finding that placebo responses can be conditioned in human subjects. Two groups of 10 subjects were told that they were receiving an analgesic which was in fact a placebo. During the conditioning, placebo administration was surreptitiously paired with an increase in the painful stimulus for half of the subjects and with a decrease for the other half. Subjects were tested pre and post conditioning for a placebo response. A second type of experimental pain was also used to determine stimulus generalization. The results confirmed a previous finding that placebo responses can be conditioned in human subjects. The implications for clinical practice of a learning model of placebo behavior are discussed.

Adult↗

PubMed1992

Analytic listening by the goldfish.

A stimulus generalization paradigm was used with classical respiratory conditioning to study analytic listening in the goldfish. Animals were first conditioned to suppress respiration upon the presentation of a long-duration complex sound comprised of two sinusoidal components, 166 and 724 Hz. Conditioned animals were then presented with a set of eight novel test tones with frequencies between 95 and 1514 Hz, and including 166 and 724 Hz. Response magnitudes were greatest at the frequencies of the components making up the complex to which the animals were initially conditioned. This is a demonstration that the goldfish had acquired independent information about the frequencies of the individual sinusoidal components making up a complex sound, and thus had listened to the complex analytically. To my knowledge, this is the first demonstration of simultaneous frequency analysis and analytic listening by a nonhuman animal, and suggests that this fundamental aspect of human hearing may be a primitive character shared with the fishes and perhaps with all living vertebrates.

Acoustic Stimulation↗

PubMed1995

Perception of spectrally and temporally complex sounds by the goldfish (Carassius auratus).

Behavioral studies on complex sound perception in goldfish were carried out in order to help determine what, if any, differences exist between the sense of hearing of fishes and other vertebrates. A stimulus generalization paradigm was used with classical conditioning in three experiments to determine: (1) the perceptual relations between a pure tone and harmonic complexes having a fundamental frequency equal to that of the tone; (2) the combined effects on perception of pulse repetition rate and spectral envelope; and (3) whether goldfish can be shown to identify a complex source when presented simultaneously with another complex source. Experiment 1 showed that the perceptions of tones and harmonic complexes differ profoundly even for the cases in which they have common periodicities and frequency components. Experiment 2 demonstrated that pulse repetition rate and spectral location simultaneously control behavior, and that repetition rate exerts behavioral control independent of spectral location. Experiment 3 indicates that goldfish did not 'hear out' or analyze a complex target source within a mixture of complex sources. In general, goldfish appear to be aware of multiple acoustic dimensions of complex sounds, suggesting both pitch-like and timbre-like perceptual dimensions. These results do not permit a qualitative distinction between the sense of hearing of goldfish and that of other vertebrates.

Acoustic Stimulation↗

PubMed2005

How do pigeons represent numbers? Studies of number scale bisection.

Pigeons' bisection of two number scales, 1-16 and 2-32, was examined in two experiments. In Experiment 1, pigeons learned to choose different comparison keys following 1 or 16 key pecks and 2 or 32 key pecks and then were tested with intermediate numbers of key pecks on nonreinforced probe trials. Psychophysical curves that plotted choice of the large number key against number of pecks showed superposition of the two number scales and indifference between the two keys at the geometric means of each scale. The same procedures were used in Experiment 2, but pigeons were trained to bisect each scale at its arithmetic mean. Two asymmetries appeared in curves that plotted discrimination performance against number: near the midpoints of the scales, accuracy was higher for high numbers than for low numbers, but this relationship reversed at the ends of the scales, with low numbers discriminated more accurately than high numbers. An associative model that assumed stimulus generalization between numbers was used to predict the findings of these two experiments. The model showed a good qualitative fit to the obtained data when it was assumed that number was represented on a log scale and generalization was constant at all numbers but not when it was assumed that number was represented on a linear scale and generalization was scalar.

Animals↗

PubMed2005

Caffeine induces differential cross tolerance to the amphetamine-like discriminative stimulus effects of dopaminergic agonists.

The purpose of this study was to determine if caffeine induces cross tolerance to the amphetamine-like discriminative stimulus effects of dopaminergic drugs that act through distinct mechanisms (e.g., release, uptake inhibition, direct activation of dopamine D(1)- or D(2)-family receptors). Rats were trained to discriminate 1.0 mg/kg d-amphetamine from saline in a two-choice discrete-trial procedure. Stimulus-generalization curves were generated by cumulative dosing for d-amphetamine (0.1-1.0 mg/kg), methylphenidate (0.3-5.6 mg/kg), SKF 81297 (0.3-3.0 mg/kg), and R-(-)-propylnorapomorphine (NPA; 0.001-1.78 mg/kg), as well as for caffeine (3.0-56 mg/kg); curves were re-determined after twice daily injections of caffeine (30 mg/kg) for 3.5 days. The rats generalized dose dependently to the four dopaminergic drugs, but only to a limited extent to caffeine. Twice daily injections of caffeine induced significant cross tolerance (i.e., increased ED(50)) to the amphetamine-like discriminative effects of methylphenidate and SKF 81297, attenuated non-significantly the effects of NPA, and did not alter the effects of amphetamine. Thus, caffeine produces differential cross tolerance to the amphetamine-like discriminative effects of dopaminergic drugs, a phenomenon in which the dopamine D(1) receptor appears to have an important role.

Amphetamine↗

PubMed2005

Perception of pitch by goldfish.

Classical conditioning and stimulus generalization methods have revealed much about the sense of hearing in non-human animals, and are now used here to investigate how goldfish perceive a variety of complex sounds, including multi-harmonic complexes and rippled noise (RN). In several experiments, animals were conditioned to respond to one type of complex sound, and were then tested for generalization to other sounds differing along one or more acoustic dimensions from the conditioning sounds. Overall, generalization occurred only to the extent that the conditioning and test sounds were essentially similar in spectral range and, in most cases, waveform periodicity. For example, goldfish showed inverted V-shaped generalization gradients to harmonic complexes varying in fundamental frequency after conditioning to complexes having a fundamental frequency of 100 Hz. In several cases, similar gradients were observed whether the fundamental frequency component was present or absent in conditioning and testing complexes, indicating that goldfish, like other vertebrate listeners, do not "miss the fundamental" when it is missing. This generalization pattern tended to disappear when harmonic complexes were used that had random phase relations among the components, or slight mistuning of all components. In a few cases, patterns of generalization were determined by as yet unidentified acoustic features. Goldfish did not generalize to RN or harmonic complexes after conditioning to tones, and vice versa, in spite of the three signal types having fundamental frequency components and periodicity in common. Moreover, goldfish did not generalize robustly to infinitely iterated rippled noise after conditioning to harmonic complexes with a prominent periodic envelope, and vice versa, in spite of the two signal types having similar spectra and pitches as judged by human listeners. These and other results suggest that the pitch of harmonic complexes is prominent in goldfish generalization behavior and that this pitch-like dimension arises primarily from the signal's periodicity. The perceptions of single tones, RNs, and harmonic complexes having the same fundamental frequency are fundamentally different. It is concluded that the different perceptions of these signals arise in part from differences in periodic envelope prominence and spectral envelope, and possibly in the stochastic versus deterministic natures of their respective waveforms.

Acoustic Stimulation↗

PubMed2002

Functional diversity among 5-substituted nicotine analogs; in vitro and in vivo investigations.

Two 5-substituted derivatives of nicotine (nicotinic acetylcholine receptor: K(i)=2.4 nM) were synthesized and evaluated: 5-bromonicotine (K(i)=6.9 nM) and 5-methoxynicotine (K(i)=14.3 nM). Despite their high affinity, neither 5-bromonicotine nor 5-methoxynicotine mimicked nicotine in producing antinociceptive (tail-flick, hotplate), hypolocomotor, or hypothermic effects in mice. Neither agent antagonized the hypolocomotor actions of nicotine, whereas 5-methoxynicotine, but not 5-bromonicotine, antagonized the antinociceptive (tail-flick) activity of nicotine in a dose-related manner. In tests of stimulus generalization using rats trained to discriminate 0.6 mg/kg of (-)-nicotine from vehicle, 5-bromonicotine substituted for nicotine. Further evaluation of 5-bromonicotine indicated that it might be a partial agonist at alpha4beta2 receptors (stimulation of Rb(+) efflux; alpha4beta2 receptors expressed in oocytes) and at alpha3-containing nicotinic acetylcholine receptors (synaptosomal dopamine release). Thus, 5-bromonicotine might be acting as a partial agonist at alpha4beta2 receptors and/or some of its effects might be related to interactions with non-alpha4beta2 receptors. Clearly, the effects of 5-bromonicotine and 5-methoxynicotine are different from those of nicotine, and from one another. These actions demonstrate that substitution at the 5-position of nicotine exerts a profound influence on the pharmacological profile as well as agonist/antagonist properties of nicotine.

Analgesics↗

PubMed1996

Phentermine+fenfluramine produce cocaine-like discriminative cues.

Drug discrimination studies were conducted in six male Sprague-Dawley rats trained to discriminate the interoceptive cues produced by 10 mg/kg cocaine in an effort to investigate if there is stimulus generalization to phentermine or phentermine + fenfluramine. Once having reached criterion performance, these rats were tested with lower doses of cocaine and generated a typical dose-response curve allowing for calculation of an ED50 value: 2.798 mg/kg. Testing of phentermine in doses of 1.25-5.0 mg/kg indicated generalization with the highest dose producing 80% cocaine-appropriate responding and allowing for an ED50 value of 2.356 mg/kg. When the phentermine doses were tested in combination 2.0 mg/kg fenfluramine, however, there was an increase in the discriminability of the highest phentermine dose and a slight decrease in the ED50 value of the combination. Thus, administration of phentermine + fenfluramine, having both dopamine-releasing and serotonin-releasing properties, respectively, may mimic the neurochemical activity by which cocaine acts in the central nervous system and may possibly allow for cocaine-like effects as these two drugs see increased use in obesity control.

Animals↗

PubMed2000

The psychophysics of visual search.

Most theories of visual search emphasize issues of limited versus unlimited capacity and serial versus parallel processing. In the present article, we suggest a broader framework based on two principles, one empirical and one theoretical. The empirical principle is to focus on conditions at the intersection of visual search and the simple detection and discrimination paradigms of spatial vision. Such simple search conditions avoid artifacts and phenomena specific to more complex stimuli and tasks. The theoretical principle is to focus on the distinction between high and low threshold theory. While high threshold theory is largely discredited for simple detection and discrimination, it persists in the search literature. Furthermore, a low threshold theory such as signal detection theory can account for some of the phenomena attributed to limited capacity or serial processing. In the body of this article, we compare the predictions of high threshold theory and three versions of signal detection theory to the observed effects of manipulating set size, discriminability, number of targets, response bias, external noise, and distractor heterogeneity. For almost all cases, the results are inconsistent with high threshold theory and are consistent with all three versions of signal detection theory. In the Discussion, these simple theories are generalized to a larger domain that includes search asymmetry, multidimensional judgements including conjunction search, response time, search with multiple eye fixations and more general stimulus conditions. We conclude that low threshold theories can account for simple visual search without invoking mechanisms such as limited capacity or serial processing.

Discrimination, Psychological↗

PubMed1997

Clobenzorex: evidence for amphetamine-like behavioral actions.

Clobenzorex, an optically active N-substituted derivative of (+)amphetamine, has been identified on the illicit market. Because so little is known regarding the pharmacology or abuse potential of this agent, it was examined in tests of stimulus generalization in rats trained to discriminate 1 mg/kg of (+)amphetamine from vehicle to determine if it would produce amphetamine-appropriate responding. Clobenzorex (ED50 = 6.6 mg/kg) substituted for (+)amphetamine (ED50 = 0.3 mg/kg) but was approximately twenty times less potent than the training drug. Clobenzorex was also compared with (+)amphetamine and cocaine for its ability to induce locomotor stimulation and rearing frequency in mice. Clobenzorex was active in both assays but was less potent than either (+)amphetamine or cocaine. It is concluded that, although weaker than (+)amphetamine, clobenzorex constitutes an agent with amphetamine-like central stimulant behavioral properties.

Amphetamine↗

PubMed1997

Antagonism of morphine-like discriminative effects by beta-funaltrexamine.

beta-Funaltrexamine (beta-FNA), an irreversible antagonist at the mu-opioid receptor, was administered intracisternally to rats discriminating between subcutaneous injections of saline and 3.0 mg/kg of morphine in order to reduce the size of the receptor reserve. beta-FNA alone (10 micrograms) occasioned substantial morphine-appropriate responding for at least 6 h but mainly saline-appropriate responding 24 h after administration, the pretreatment interval for most experiments. beta-FNA (3.0-30 micrograms) dose-dependently shifted to the right stimulus-generalization curves for morphine and fentanyl; 10 micrograms also shifted to the right the curves for meperidine and buprenorphine. In all cases, antagonism was fully surmounted by higher doses of the agonist, even after inactivation of more than 75% of mu-opioid receptors. This antagonist effect of beta-FNA is smaller than that reported previously in tests of analgesia, suggesting that the receptor reserve for the discriminative effects of morphine-like drugs is larger than the receptor reserve for their analgesic effects. beta-FNA produced larger rightward displacements of the morphine and buprenorphine curves than of the fentanyl curve and inactivated a larger fraction of the receptors acted upon by those drugs compared to fentanyl. Results with meperidine were intermediate. This suggests that the receptor population mediating morphine-like discriminative effects of fentanyl is not identical to the receptor population mediating these effects of morphine and buprenorphine.

Analgesics, Opioid↗

PubMed2001

Drug discrimination studies with ibogaine.

The results of the studies described here support the hypothesis that ibogaine produces its effects via selective interactions with multiple receptors. It appears that 5-HT2A, 5-HT2C, and sigma 2 receptors are involved in mediating the stimulus effects of ibogaine. In addition, opiate receptors may also be involved. In contrast, sigma 1, PCP/MK-801, 5-HT3, and 5-HT1A receptors do not appear to play a major role. Ibogaine's hallucinogenic effects may be explained by its interactions with 5-HT2A and 5-HT2C receptors, while its putative antiaddictive properties may result from its interactions with sigma 2 and opiate receptors. Alternatively, the possibility that ibogaine's hallucinogenic properties underlie its antiaddictive effects, as previously suggested (34), would support a role for 5-HT2 receptors in mediating the reported therapeutic effects of ibogaine. Certainly many questions remain regarding ibogaine's mechanism of action. Although drug discrimination will be useful for answering some of those questions, the true potential of this technique is realized whin it is combined with other techniques. The next few years promise to be fruitful with respect to our understanding of this agent. Reasons supporting this belief include advances in the study of sigma receptors, interest in ibogaine's effects on second messenger systems, and the development of ibogaine congeners such as 18-methoxycoronaridine (35). In conclusion, the aforementioned studies should serve to guide further endeavors. Pertinent questions have been generated: What is the role of sigma receptors in the effects of ibogaine, especially with regard to addiction? How does ibogaine affect opiate neurotransmission? What effects, if any, do the Harmala alkaloids have on addiction phenomena? What is the mechanism of action of harmaline? Can 10-hydroxyibogamine serve as a discriminative stimulus and, if so, what receptor interactions mediate its stimulus effects? Does the ibogaine-trained stimulus generalize to novel agents, including 18-methoxycoronaridine?

Animals↗

PubMed1998

Perception of two-tone complexes by the goldfish (Carassius auratus).

Previous experiments on the sense of hearing in goldfish have used a stimulus generalization paradigm to investigate the perceptual dimensions evoked by spectrally and temporally complex sounds. The present experiments investigated the effects on perception of the frequency separation between two tones. In the first set of experiments, six groups of goldfish were classically conditioned to a single tone and then tested for generalization to two-tone complexes having one frequency component equal to the conditioning tone, and the other differing by 2-256 Hz. Generalization declined with increasing frequency differences up to about 32 Hz, and then increased for wider frequency separations. These functions indicate that a restricted range of beat rates produces a perceptual quality that is quite unlike that of a single tone. The generalization function of frequency separation resembles the inverse of the 'fluctuation strength' and 'roughness' functions for human listeners. The second experiment investigated the effects of spectral location on the perception of a 32 Hz beat rate. Goldfish were conditioned to a two-tone complex (500 and 532 Hz) and then tested for generalization to single tones at various frequencies between 200 and 1200 Hz, and to two-tone complexes having a 32 Hz beat rate but with the lower tone component at various frequencies. For single-tone stimuli, generalization was relatively weak but showed a peak at 500 Hz. For the two-tone stimuli, generalization was more robust, but showed a similarly shaped gradient centered on 500 Hz. Thus, goldfish behaved as if they had acquired information about both temporal modulation and the frequency location of the tone components. These perceptual behaviors appear to be shared with humans and other vertebrates.

Acoustic Stimulation↗

PubMed1991

Effects of ectostriatal lesions on natural concept, pseudoconcept, and artificial pattern discrimination in pigeons.

Pigeons were trained on four different visual discrimination tasks: (1) concept of natural stimuli (food vs. non-food object discrimination); (2) arbitrary classification of natural stimuli (pseudoconcept); (3) concept of artificial stimuli (triangles generated by computer graphics); and (4) discrimination of one pair of artificial stimuli. Then, lesions of the ectostriatum were carried out. The ectostriatal lesions impaired the arbitrary classification of natural stimuli and the concept of artificial pattern but did not impair the natural concept or the simple discrimination of fixed two stimuli. Lesions in the neostriatum did not cause deficits in any discrimination task. The birds had to learn individual stimuli for the arbitrary classification of stimuli and the stimulus generalization test after the artificial pattern concept discrimination indicated that the pigeons formed a concept more complicated than "triangle" in human language. These results suggest that the ectostriatum plays a role in task discrimination that requires much visual processing to classify stimuli.

Animals↗

PubMed1991

Synthesis and pharmacological examination of 1-(3-methoxy-4-methylphenyl)-2-aminopropane and 5-methoxy-6-methyl-2-aminoindan: similarities to 3,4-(methylenedioxy)methamphetamine (MDMA).

The racemate and the enantiomers of 1-(3-methoxy-4-methyphenyl)-2- aminopropane (6) and racemic 5-methoxy-6-methyl-2-aminoindan (11) were tested for stimulus generalization in the two-lever drug-discrimination paradigm. Both 6 and 11 were found to substitute with high potency in 3,4-(methylenedioxy)methamphetamine (1) and (S)-1-(1,3-benzodioxol-5-yl)-2-(methylamino)butane (2) trained rats. In the latter assay, both enantiomers of 6 had identical potencies, but their dose-response curves were not parallel. Racemic 6, but not 11, partially substituted for LSD. Racemic 6 and 11 did not substitute in (S)-amphetamine-trained rats. All of the test compounds were potent inhibitors of [3H]-5-HT uptake into synaptosomes in vitro, with the S enantiomer of 6 being most active. Rat brain monoamine levels were unaltered 1 week following a single high dose (10 or 20 mg/kg, sc) of 6 or 11, or two weeks following a subacute dosing regimen (20 mg/kg, sc, twice a day for 4 days). In addition, radioligand-binding parameters in rat brain homogenate with the 5-HT uptake inhibitor [3H]paroxetine were unchanged after subacute dosing with either racemic 6 or 11. The results indicate that compounds 6 and 11 have animal behavioral pharmacology similar to the methylenedioxy compounds 1 and 2, but that they do not induce the serotonin neurotoxicity that has been observed for the latter two drugs.

3,4-Methylenedioxyamphetamine↗