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PubMed1984

Nitrous oxide generalizes to a discriminative stimulus produced by ethylketocyclazocine but not morphine.

The discriminative stimulus properties of nitrous oxide, an analgesic and anesthetic gas, were evaluated in rats trained to discriminate the effects of morphine or ethylketocyclazocine. Administration of nitrous oxide in concentrations as high as 80 percent did not produce generalization to the discriminative cue produced by morphine. Nitrous oxide did, however, generalize in a concentration-dependent manner in rats trained to discriminate ethylketocyclazocine, a psychotomimetic opioid. Naltrexone, a potent narcotic antagonist, did not block the generalization of nitrous oxide to ethylketocyclazocine. These results suggest that the subjective effects of nitrous oxide are similar to those produced by psychotomimetic drugs rather than those produced by morphine. These findings are in close agreement with those generated in man. Thus, nitrous oxide exhibits some pharmacological properties similar to those of morphine, for example, naloxone reversible analgesia. Yet, it has other properties such as subjective effects that are dissimilar from morphine.

Analgesics, Opioid↗
PubMed1982

D-Ala2,D-Leu5-enkephalin generalizes to a discriminative stimulus produced by fentanyl but not ethylketocyclazocine.

Male Sprague-Dawley rats were trained to discriminate between the effects of saline and either fentanyl (0.04 mg/kg) or ethylketocyclazocine (0.32 mg/kg) by responding on a FR 10 schedule of food reinforcement with a lever on one side of a food cup following a subcutaneous saline injection and responding with a lever on the alternate side following the subcutaneous injection of one of those drugs. The effects of an intracerebroventricular injection of either fentanyl (2.89-14.45 nmol) or D-Ala2,D-Leu5-enkephalin (0.172-1.72 nmol) dose-dependently generalized to the discriminative stimulus produced by fentanyl injected subcutaneously. Intracerebroventricular injection of ethylketocyclazocine (15.7-125.8 nmol) but not D-Ala2,D-Leu5-enkephalin (1.72-13.76 nmol) dose-dependently generalized to the discriminative stimulus produced by ethylketocyclazocine injected subcutaneously. These data demonstrate similarities in the discriminative stimulus properties of proposed micron and delta but not kappa and delta opiate receptor agonists.

Animals↗
PubMed1982

A comparison of the behavioral effects of DOM homologs.

Twenty-four rats, trained to discriminate 1.0 mg/kg of (+/-)-DOM, i.e. (+/-)-2,5-dimethoxy-4-methylphenylisopropylamine, from saline under a VI-15 schedule of reinforcement, were challenged with a series of DOM homologs. The agents examined included the 4-ethyl (DOET), -propyl (DOPR), -butyl (DOBU), -tertiary butyl (DOTB) and -amyl (DOAM) derivatives as well as the R(-)- and S(+)-isomers of DOET. The (+/-)-DOM stimulus was found to generalize to all of the agents, except DOTB and DOAM, where only partial generalization occurred. The results suggest that the stimulus properties produced by the latter two compounds may differ from those of the remainder of the series. Furthermore, the ED50 values obtained, for those compounds to which the DOM-stimulus generalized, correlated significantly (r2 = 0.94) with the human hallucinogenic potencies of these agents.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1985

N-Ethyl-17(R,S)-methyl-(6aR,10aR)-delta 8-tetrahydrocannabinol-18-oic amide. Brain pharmacokinetics in mice, triglyceride/phospholipid partitioning and generalization to the discriminative stimulus properties of delta 9-THC in rats.

The title compound, designed as a model for the affinity moiety of a cannabinoid affinity gel was synthesized in tritiated form (sp. act. 7.27 mCi/mmole). To validate the affinity approach to isolate the putative THC receptor, the properties of the amide were studied. Upon i.p. injection in mice the amide reaches peak brain levels of 0.13% of the total dose after 15 min. Following i.v. injection, maximal brain concentrations of 1.9% are observed at 5 min. Compared to delta 9-THC, which distributes almost equally between triglyceride and phospholipid phases (51:49) the amide exhibits a strong preference for phospholipids (5:95) that can be interpreted as high relative membrane affinity. In rats trained in a water maze to discriminate between i.p. injections of 3 mg/kg delta 9-THC (ED50 = 1.8 mg/kg) and its vehicle, the amide was generalized to the training drug, being five times less potent (ED50 = 8.7 mg/kg) than delta 9-THC. This demonstration of cannabis-like activity indicates that the amide retains affinity to the postulated receptor and justifies the choice for the affinity ligand.

Animals↗
PubMed1999

Effects of stimulus preexposure on the generalization of conditioned taste aversions in infant rats.

Generalization of a conditioned taste aversion in infant rats and how this is affected by stimulus preexposure was investigated in a series of experiments. In Experiment 1 generalization of a conditioned aversion between two tastes (sweet and salty) was found, and the effect of tastes preexposure was a reduction in generalization (Experiment 2). However, when these tastes were combined with a common taste (acid) that was less (Experiment 3) or more intense (Experiment 3b), the effect of stimulus preexposure was a stronger generalization of the conditioned aversion. In this case, a reduction on generalization was again observed by increasing the number of preexposure trials to the taste compounds (Experiment 4). In all cases the generalization levels were directly related to the effect of stimulus preexposure on the acquisition rate of conditioning. It can be concluded that, with the appropriate parameters, a reduction of generalization of a conditioned taste aversion can be obtained after taste exposure in preweanling rats.

Animals↗
PubMed1982

The generality of the stimulus-binding hypothesis across drinking behavior and task performance in alcoholics.

This experiment investigated the validity of applying the stimulus-binding hypothesis of obesity to conceptualize drinking and task performance behaviors in alcoholics. Twenty alcoholics and 12 nonalcoholics participated in two counterbalanced experimental sessions. One session involved an assessment of subjects' voluntary consumption of preferred and nonpreferred nonalcoholic beverages. The other session involved their performance of four tasks that involved or manipulated the presence of salient external cues. The prediction of heightened externality in alcoholics was supported on the beverage consumption measures and was marginally supported on the task performance measures. The results are discussed in terms of their implications for models and treatments of alcohol problems.

Adult↗
PubMed1982

Generalization of the discriminative stimulus properties of phencyclidine to other drugs in the pigeon using color tracking under second order schedules.

Pigeons were trained to track the location of a red or green key color under a second order schedule, with reinforcement of responses to each color contingent upon whether 1.5 mg/kg phencyclidine (PCP) or saline had been administered before the session. When cumulative dose-effect curves were determined for other drugs substituted for PCP, pigeons responded predominantly on the PCP key after other doses of PCP, ketamine, pentobarbital, d-cyclazocine and l-cyclazocine, but not after saline, lactic acid solution, d-amphetamine, chlordiazepoxide, scopolamine, morphine, naltrexone, or d-, or l-methadone. l-Cyclazocine was slightly more potent than d-cyclazocine in producing PCP key responding. PCP key responding after the optical isomers of cyclazocine was not blocked by naltrexone.

Animals↗
PubMed1976

Generalization of morphine and lysergic acid diethylamide (LSD) stimulus properties to narcotic analgesics.

The present investigation sought to determine whether the stimulus properties of morphine and lysergic acid diethylamide (LSD) would generalize to several narcotic analgesics which vary in their subjective effects. Morphine and saline served as discriminative stimuli for one group of rats in a 2-lever discrimination task. LSD and saline were discriminative stimuli for a second group. Depression of one lever in an operant chamber resulted in reinforcement following the administration of morphine or LSD and the opposite lever was reinforced after saline. After discriminated responding was stable, stimulus generalization tests with narcotic analgesics and antagonists showed that the stimulus properties of morphine generalized to methadone and meperidine, and partially to pentazocine, all of which produce morphine-like subjective effects in humans. Morphine stimulus properties did not generalize to nalorphine or cyclazocine, which produce dissimilar subjective effects. The stimulus properties of LSD generalized partially to cyclazocine, but not to nalorphine. In humans cyclazocine and nalorphine produce a high incidence of psychotomimetic effects, but the subjective effects of cyclazocine are differentiable from those of LSD.

Analgesics, Opioid↗
PubMed2004

The functions of the orbitofrontal cortex.

The orbitofrontal cortex contains the secondary taste cortex, in which the reward value of taste is represented. It also contains the secondary and tertiary olfactory cortical areas, in which information about the identity and also about the reward value of odours is represented. The orbitofrontal cortex also receives information about the sight of objects from the temporal lobe cortical visual areas, and neurons in it learn and reverse the visual stimulus to which they respond when the association of the visual stimulus with a primary reinforcing stimulus (such as taste) is reversed. This is an example of stimulus-reinforcement association learning, and is a type of stimulus-stimulus association learning. More generally, the stimulus might be a visual or olfactory stimulus, and the primary (unlearned) positive or negative reinforcer a taste or touch. A somatosensory input is revealed by neurons that respond to the texture of food in the mouth, including a population that responds to the mouth feel of fat. In complementary neuroimaging studies in humans, it is being found that areas of the orbitofrontal cortex are activated by pleasant touch, by painful touch, by taste, by smell, and by more abstract reinforcers such as winning or losing money. Damage to the orbitofrontal cortex can impair the learning and reversal of stimulus-reinforcement associations, and thus the correction of behavioural responses when there are no longer appropriate because previous reinforcement contingencies change. The information which reaches the orbitofrontal cortex for these functions includes information about faces, and damage to the orbitofrontal cortex can impair face (and voice) expression identification. This evidence thus shows that the orbitofrontal cortex is involved in decoding and representing some primary reinforcers such as taste and touch; in learning and reversing associations of visual and other stimuli to these primary reinforcers; and in controlling and correcting reward-related and punishment-related behavior, and thus in emotion. The approach described here is aimed at providing a fundamental understanding of how the orbitofrontal cortex actually functions, and thus in how it is involved in motivational behavior such as feeding and drinking, in emotional behavior, and in social behavior.

Animals↗
PubMed1990

American College of Sports Medicine position stand. The recommended quantity and quality of exercise for developing and maintaining cardiorespiratory and muscular fitness in healthy adults.

The combination of frequency, intensity, and duration of chronic exercise has been found to be effective for producing a training effect. The interaction of these factors provide the overload stimulus. In general, the lower the stimulus the lower the training effect, and the greater the stimulus the greater the effect. As a result of specificity of training and the need for maintaining muscular strength and endurance, and flexibility of the major muscle groups, a well-rounded training program including resistance training and flexibility exercises is recommended. Although age in itself is not a limiting factor to exercise training, a more gradual approach in applying the prescription at older ages seems prudent. It has also been shown that endurance training of fewer than 2 d.wk-1, at less than 50% of maximum oxygen uptake and for less than 10 min.d-1, is inadequate for developing and maintaining fitness for healthy adults. In the interpretation of this position statement, it must be recognized that the recommendations should be used in the context of participants' needs, goals, and initial abilities. In this regard, a sliding scale as to the amount of time allotted and intensity of effort should be carefully gauged for both the cardiorespiratory and muscular strength and endurance components of the program. An appropriate warm-up and cool-down, which would include flexibility exercises, is also recommended. The important factor is to design a program for the individual to provide the proper amount of physical activity to attain maximal benefit at the lowest risk. Emphasis should be placed on factors that result in permanent lifestyle change and encourage a lifetime of physical activity.

Cardiovascular Physiological Phenomena↗
PubMed1993

The recommended quantity and quality of exercise for developing and maintaining cardiorespiratory and muscular fitness in healthy adults. Position stand of the American College of Sports Medicine.

The combination of frequency, intensity, and duration of chronic exercise has been found to be effective for producing a training effect. The interaction of these factors provide the overload stimulus. In general, the lower the stimulus the lower the training effect, and the greater the stimulus the greater the effect. As a result of specificity of training and the need for maintaining muscular strength and endurance, and flexibility of the major muscle groups, a well-rounded training program including resistance training and flexibility exercises is recommended. Although age in itself is not a limiting factor to exercise training, a more gradual approach in applying the prescription at older ages seems prudent. It has also been shown that endurance training of fewer than 2 d/wk, at less than 50% of maximum oxygen uptake and for less than 10 min/d, is inadequate for developing and maintaining fitness for healthy adults. In the interpretation of this position statement, it must be recognized that the recommendations should be used in the context of participants' needs, goals, and initial abilities. In this regard, a sliding scale as to the amount of time allotted and intensity of effort should be carefully gauged for both the cardiorespiratory and muscular strength and endurance components of the program. An appropriate warm-up and cool-down, which would include flexibility exercises, is also recommended. The important factor is to design a program for the individual to provide the proper amount of physical activity to attain maximal benefit at the lowest risk. Emphasis should be placed on factors that result in permanent lifestyle change and encourage a lifetime of physical activity.

Adult↗
PubMed1984

Withdrawal from morphine generalizes to a pentylenetetrazol stimulus.

Rats trained to discriminate pentylenetetrazol (PTZ) from saline in a two-lever food-reinforced operant task were given a three-day course of morphine, 15 to 45 mg/kg tid, ip. On the third day naloxone produced dose-dependent generalization to the PTZ stimulus, with 66% of subjects selecting the PTZ lever after the highest dose (0.32 mg/kg). Following termination of morphine injections, generalization of spontaneous withdrawal was tested. Approximately 50% of subjects selected the PTZ lever at 24 and 48 hrs after the last morphine, and by 96 hrs the percentage of subjects selecting the PTZ lever had dropped to 11%. Rats that chose the PTZ lever at 48 hrs were given diazepam, 5.0 mg/kg, which blocked the PTZ-like stimulus. These data demonstrate that morphine withdrawal produces a stimulus with PTZ-like characteristics which can be blocked by an anxiolytic, and they suggest that the PTZ discrimination may have general utility for investigating drug dependence and withdrawal in animals.

Animals↗
PubMed2004

Synaptic dynamics mediate sensitivity to motion independent of stimulus details.

Humans and other animals generally perceive motion independently of the cues that define the moving object. To understand the underlying mechanisms of this generalization of stimulus attributes, we have examined the cellular properties of avian wide-field tectal neurons that are sensitive to a variety of moving stimuli but not to static stationary stimuli. This in vitro study showed phasic signal transfer at the retinotectal synapse and binary dendritic responses to synaptic inputs that interact in a mutually exclusive manner in the postsynaptic tectal neuron. A model of the tectal circuitry predicts that these two cellular properties mediate sensitivity to a wide range of dynamic spatiotemporal stimuli, including moving stimuli, but not to static stationary stimuli in a tectal neuron. The computation that is independent of stimulus detail is initiated by tectal neurons and is completed by rotundal neurons that integrate outputs from multiple tectal neurons in a directionally selective manner.

Animals↗
PubMed1979

Discriminative stimulus properties of pentylenetetrazol and bemegride: some generalization and antagonism tests.

In an operant procedure of lever pressing on a FR 10 schedule of food reinforcement, male hooded rats were trained to respond with a lever on one side of a food cup following a drug injection, and to respond with a lever on the alternate side following a 1 ml/kg saline injection. All of 14 subjects learned to discriminate reliably between the effects of 20 mg/kg pentylenetetrazol (PTZ) and saline. Seven of eight rats learned to discriminate between the effects of bemegride (5 mg/kg) and saline. None of 14 rats learned to discriminate between 5mg/kg PTZ and saline. The bemegride discriminative stimulus generalized to PTZ (20mg/kg) and was antagonized by chlordiazepoxide (10 mg/kg). Chlordiazepoxide, diazepam, flurazepam, clobazam, and meprobamate were all effective antagonist of PTZ in a dose-dependent manner. Bemegride and cocaine generalized to the PTZ discriminative stimulus in a dose-dependent manner, but d-amphetamine, methylphenidate, and nicotine did not. Since bemegride and PTZ are convulsants at higher doses, the discriminative stimulus properties of these drugs might be based on a subtle convulsive brain state. The anxiolytic properties of benzodiazepines and meprobamate suggest that the discriminative stimulus produced by these convulsants is related to an "anxiety-inducing" action.

Animals↗
PubMed1982

The role of fentanyl training dose and of the alternative stimulus condition in drug generalization.

Different groups of rats were trained to discriminate fentanyl (F) (0.03, 0.02, or 0.01 mg/kg) from saline or to discriminate 0.03 mg/kg fentanyl (F) from alternative stimulus conditions (saline, 0.15 mg/kg nicotine, or 0.01 mg/kg F). When percentage of responses on the drug lever and percentage of time spent responding on the drug lever were used as dependent variables, it was found that training dose and alternative stimulus condition both affected the ED50 and the slope of the F generalization gradient. ED50 and slope values based on group data were not significantly different from values based on individual data. Differences between from values based on individual data. Differences between the results of the first and second 2.5-min period of the extinction test were not significant. ED50 and slope values were unaffected by the preceding training session, except in the group trained to discriminate 0.03 from 0.01 mg/kg F. A lever selection measure showed a significant effect of alternative stimulus condition on ED50 values only. Training dose and alternative stimulus condition also affected the generalization to morphine. Under none of the conditions explored in this study did generalization occur to amphetamine or nicotine. The results are discussed in terms of the relative nature of drug generalization.

Amphetamine↗
PubMed1999

Asymmetric generalization between the discriminative stimulus effects of nicotine and cocaine.

The discriminative stimulus effects of nicotine and cocaine were studied, alone and in combination, in rats. Two sets of rats were trained to press one lever when injected intraperitoneally (i.p.) with either nicotine (0.1 mg/kg = 0.6 micromol/kg, Set 1) or cocaine (8.9 mg/kg base = 29.4 micromol/kg, Set 2), and another lever when injected with saline. Rats learned to discriminate drug from saline, and maintained discriminative control throughout the study (at > 85% drug-appropriate responding). In accordance with most previous findings, cocaine only partially substituted for nicotine (maximum = 41% nicotine-lever responding). The nicotinic agonist, nornicotine, produced dose-related, near-full substitution for nicotine (maximum = 76% nicotine-lever responding), whereas the peripherally acting nicotinic agonist, methylcarbamylcholine, did not substitute for nicotine. The muscarinic receptor agonist pilocarpine also failed to substitute for nicotine. However, in the cocaine-trained rats, nicotine substituted fully for cocaine in a dose-dependent manner, demonstrating that cross-generalization between the two drugs is not symmetrical. Finally, administration of each drug as a pre-treatment to the other yielded inconsistent increases in each drug's discriminative stimulus effects. The results are congruent with the view that the discriminative stimulus effects of nicotine and cocaine share common features, but the asymmetric pattern of cross-generalization and the interactions revealed in the combination tests also suggest that there are important differences between them.

Animals↗
PubMed1978

The discriminative stimulus properties of cyclazocine: generalization studies involving nalorphine, morphine and LSD.

Rats learned to discriminate cyclazocine (2 mg/kg, i.p.) from saline using a two-lever operant (FR-4) procedure within 10 sessions under each drug condition. The cyclazocine discriminative stimulus (DS) was both dose- and time-related, being antagonized by naloxone at doses approximately 80 times that necessary to block the discriminative stimulus effect of morphine. Cyclazocine also generalized to nalorphine, but not to morphine, pentazocine or LSD. These data suggest that cyclazocine produced DS control of behavior by acting at CNS sites different from those affected by morphine or LSD.

Animals↗
PubMed1988

Prefrontal representation of stimulus attributes during delay tasks. II. The role of behavioral significance.

Rhesus monkeys were trained to perform two visual discrimination tasks with delayed response. In both tasks, the response depended on the color of the cue, a lighted circle in the center of a panel. Red and green guided one task, yellow and blue the other. In the course of performance, a fifth color (violet), non-relevant and inconsequential, was presented at random in the same location as the cues. All 5 stimuli were of equal brightness. Many cells in the dorsolateral prefrontal cortex (sulcus principalis and superior convexity) treated the relevant cues differently than the irrelevant stimulus. In general, cellular reactions to that stimulus were of lesser magnitude than the reactions to the cues. Cell reaction differences as a function of stimulus significance outnumbered and overshadowed differences as a function of cue-color or any other task variable. The results indicate that, during visual delay tasks, units in the dorsolateral prefrontal cortex differentiate stimuli by their behavioral significance, as well as by other stimulus attributes, including color. Because the motivational evaluation of sensory stimuli is an integral part of the cognitive processes in delay tasks (together with short-term memory and motor set), these results support the notion that the prefrontal cortex integrates motivational inputs into the structure of behavioral action.

Animals↗