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PubMed2004

Interactions in the tumor-promoting activity of carbon tetrachloride, trichloroacetate, and dichloroacetate in the liver of male B6C3F1 mice.

Interactions between carcinogens in mixtures found in the environment have been a concern for several decades. In the present study, male B6C3F1 mice were used to study the responses to mixtures of dichloroacetate (DCA), trichloroacetate (TCA), and carbon tetrachloride (CT). TCA produces liver tumors in mice with the phenotypic characteristics common to peroxisome proliferators. DCA increases the growth of liver tumors with a phenotype that is distinct in several respects from those produced by TCA. These chemicals are effective as carcinogens at doses that do not produce cytotoxicity. Thus, they encourage clonal expansion of initiated cells through subtle, selective mechanisms. CT is well known for its ability to promote the growth of liver tumors through cytotoxicity that produces a generalized growth stimulus in the liver that is reflected in a reparative hyperplasia. Thus, CT is relatively non-specific in its promotion of initiated cells within the liver. The objective of this study was to determine how the differing modes of action of these chemicals might interact when given as mixed exposures. The hypothesis was that the effects of two selective promoters would not be more than additive. On the other hand, CT would be selective only to cells not sensitive to its effects as a cytotoxin. Thus, it was hypothesized that neither DCA nor TCA would add significantly to the effects produced by CT. Mice were initiated by vinyl carbamate (VC), and then promoted by DCA, TCA, CT, or the pair-wised combinations of the three compounds. The effect of each treatment or treatment combination on tumor number per animal and mean tumor volume was assessed in each animal. Dose-related increases in mean tumor volume were observed with 20 and 50mg/kg CT, but each produced equal numbers of tumors at 36 weeks. As the dose of CT was increased to >/=100mg/kg substantial increases in the number of tumors per animal were observed, but the mean tumor size decreased. This finding suggests that initiation occurs as doses of CT increase to >/=100mg/kg, perhaps as a result of the inflammatory response that is known to occur with high doses of CT. When administered alone in the drinking water at 0.1, 0.5 and 2g/l, DCA increased both tumor number and tumor size in a dose-related manner. With TCA treatment at 2g/l in drinking water a maximum tumor number was reached by 24 weeks and was maintained until 36 weeks of treatment. DCA treatment did not produce a plateau in tumor number within the experimental period, but the numbers observed at the end of the experimental period were similar to TCA and doses of 50mg/kg CT. The tumor numbers observed at the end of the experiment are consistent with the assumption that the administered dose of the tumor initiator, vinyl carbamate, was the major determinant of tumor number and that treatments with CT, DCA, and TCA primarily affected tumor size. The results with mixtures of these compounds were consistent with the basic hypotheses that the responses to tumor promoters with differing mechanisms are limited to additivity at low effective doses. More complex, mutually inhibitory activity was more often observed between the three compounds. At 24 weeks, DCA produced a decrease in tumor numbers promoted by TCA, but the numbers were not different from TCA alone at 36 weeks. The reason for this result became apparent at 36 weeks of treatment where a dose-related decrease in the size of tumors promoted by TCA resulted from DCA co-administration. On the other hand, the low dose of TCA (0.1g/l) decreased the number of tumors produced by a high dose of DCA (2g/l), but higher doses of TCA (2g/l) produced the same number as observed with DCA alone. DCA inhibited the growth rate of CT-induced tumors (CT dose = 50mg/kg). TCA substantially increased the numbers of tumors observed at early time points when combined with CT, but this was not observed at 36 weeks. The lack of an effect at 36 weeks was attributable to the fact that more than 90% of the livers consisted of tumors and the earlier effect was masked by coalescence of tumors. Thus, the ability of TCA to significantly increase tumor numbers in CT-treated mice was probably real and contrary to our original hypothesis that CT was non-specific in its effects on initiated cells. It is probable that the interaction between CT and TCA is explained through stimulation of the growth of cells with differing phenotypes. These data suggest that the outcome of interactions between the mechanisms of tumor promotion vary based on the characteristics of the initiated cells. The interactions may result in additive or inhibitory effects, but no significant evidence of synergy was observed.

Administration, Oral↗
PubMed1997

Vicarious learning revisited: a contemporary behavior analytic interpretation.

Beginning in the 1960s, social learning theorists argued that behavioral learning principles could not account for behavior acquired through observation. Such a viewpoint is still widely held today. This rejection of behavioral principles in explaining vicarious learning was based on three phenomena: (1) imitation that occurred without direct reinforcement of the observer's behavior; (2) imitation that occurred after a long delay following modeling; and (3) a greater probability of imitation of the model's reinforced behavior than of the model's nonreinforced or punished behavior. These observations convinced social learning theorists that cognitive variables were required to explain behavior. Such a viewpoint has progressed aggressively, as evidenced by the change in name from social learning theory to social cognitive theory, and has been accompanied by the inclusion of information-processing theory. Many criticisms of operant theory, however, have ignored the full range of behavioral concepts and principles that have been derived to account for complex behavior. This paper will discuss some problems with the social learning theory explanation of vicarious learning and provide an interpretation of vicarious learning from a contemporary behavior analytic viewpoint.

Cognition↗
PubMed1998

Three-dimensional object recognition based on the combination of views.

Visual object recognition is complicated by the fact that the same 3D object can give rise to a large variety of projected images that depend on the viewing conditions, such as viewing direction, distance, and illumination. This paper describes a computational approach that uses combinations of a small number of object views to deal with the effects of viewing direction. The first part of the paper is an overview of the approach based on previous work. It is then shown that, in agreement with psychophysical evidence, the view-combination approach can use views of different class members rather than multiple views of a single object, to obtain class-based generalization. A number of extensions to the basic scheme are considered, including the use of non-linear combinations, using 3D versus 2D information, and the role of coarse classification on the way to precise identification. Finally, psychophysical and biological aspects of the view-combination approach are discussed. Compared with approaches that treat object recognition as a symbolic high-level activity, in the view-combination approach the emphasis is on processes that are simpler and pictorial in nature.

Depth Perception↗
PubMed1998

Recovery of 3D volume from 2-tone images of novel objects.

In 2-tone images (e.g., Dallenbach's cow), only two levels of brightness are used to convey image structure-dark object regions and shadows are turned to black and light regions are light regions are turned white. Despite a lack of shading, hue and texture information, many 2-tone images of familiar objects and scenes are accurately interpreted, even by naive observers. Objects frequently appear fully volumetric and are distinct from their shadows. If perceptual interpretation of 2-tone images is accomplished via bottom-up processes on the basis of geometrical structure projected to the image (e.g., volumetric parts, contour and junction information) novel objects should appear volumetric as readily as their familiar counterparts. We demonstrate that accurate volumetric representations are rarely extracted from 2-tone images of novel objects, even when these objects are constructed from volumetric primitives such as generalized cones (Marr, D., Nishihara, H.K., 1978. Proceedings of the Royal Society London 200, 269-294; Biederman, I. 1985. Computer Vision, Graphics, and Image Processing 32, 29-73), or from the rearranged components of a familiar object which is itself recognizable as a 2-tone image. Even familiar volumes such as canonical bricks and cylinders require scenes with redundant structure (e.g., rows of cylinders) or explicit lighting (a lamp in the image) for recovery of global volumetric shape. We conclude that 2-tone image perception is not mediated by bottom-up extraction of geometrical features such as junctions or volumetric parts, but may rely on previously stored representations in memory and a model of the illumination of the scene. The success of this top-down strategy implies it is available for general object recognition in natural scenes.

Adult↗
PubMed1998

Evidence accumulation in cell populations responsive to faces: an account of generalisation of recognition without mental transformations.

In this paper we analyse the time course of neuronal activity in temporal cortex to the sight of the head and body. Previous studies have already demonstrated the impact of view, orientation and part occlusion on individual cells. We consider the cells as a population providing evidence in the form of neuronal activity for perceptual decisions related to recognition. The time course on neural responses to stimuli provides an explanation of the variation in speed of recognition across different viewing circumstances that is seen in behavioural experiments. A simple unifying explanation of the behavioural effects is that the speed of recognition of an object depends on the rate of accumulation of activity from neurones selective for the object, evoked by a particular viewing circumstance. This in turn depends on the extent that the object has been seen previously under the particular circumstance. For any familiar object, more cells will be tuned to the configuration of the object's features present in the view or views most frequently experienced. Therefore, activity amongst the population of cells selective for the object's appearance will accumulate more slowly when the object is seen in an unusual view, orientation or size. This accounts for the increased time to recognise rotated views without the need to postulate 'mental rotation' or 'transformations' of novel views to align with neural representations of familiar views.

Attention↗
PubMed1998

Do viewpoint-dependent mechanisms generalize across members of a class?

Evidence for viewpoint-specific image-based object representations have been collected almost entirely using exemplar-specific recognition tasks. Recent results, however, implicate image-based processes in more categorical tasks, for instance when objects contain qualitatively different 3D parts. Although such discriminations approximate class-level recognition. they do not establish whether image-based representations can support generalization across members of an object class. This issue is critical to any theory of recognition, in that one hallmark of human visual competence is the ability to recognize unfamiliar instances of a familiar class. The present study addresses this questions by testing whether viewpoint-specific representations for some members of a class facilitate the recognition of other members of that class. Experiment 1 demonstrates that familiarity with several members of a class of novel 3D objects generalizes in a viewpoint-dependent manner to cohort objects from the same class. Experiment 2 demonstrates that this generalization is based on the degree of familiarity and the degree of geometrical distinctiveness for particular viewpoints. Experiment 3 demonstrates that this generalization is restricted to visually-similar objects rather than all objects learned in a given context. These results support the hypothesis that image-based representations are viewpoint dependent, but that these representations generalize across members of perceptually-defined classes. More generally, these results provide evidence for a new approach to image-based recognition in which object classes are represented as cluster of visually-similar viewpoint-specific representations.

Adult↗
PubMed2002

Can free-viewing perceptual asymmetries be explained by scanning, pre-motor or attentional biases?

Judgments of relative magnitude between the left and right sides of a stimulus are generally weighted toward the features contained on the left side. This leftward perceptual bias could be the result of, (a) left-to-right scanning biases, (b) pre-motor activation of the right hemisphere, or (c) a left hemispatial attentional bias. The relative merits of these explanations of perceptual asymmetry were investigated. In Experiment 1, English and Hebrew readers made luminance judgements for two left/right mirror-reversed luminance gradients (greyscales task). Despite different reading/scanning habits, both groups exhibited a leftward perceptual bias. English and Hebrew readers also performed a line bisection task. Scanning biases were controlled by asking participants to follow a marker as it moved left-to-right or right-to-left and then stop it as it reached the midpoint of the line. Despite controlling scanning, a leftward bias was observed in both groups. In Experiment 2, peripheral spatial cues were presented prior to the greyscales stimuli. English readers showed a reduction in the leftward bias for right-sided cues as compared to left-sided and neutral cues. Right-side cues presumably overcame a pre-existing leftward attentional bias. In both experiments, pre-motor activation was controlled using bimanual responses. Despite this control, a leftward bias was observed throughout the study. The data support the attentional bias account of leftward perceptual biases over the scanning and pre-motor activation accounts. Whether or not unilateral hemispheric activation provides an adequate account of this attentional bias is discussed.

Adolescent↗
PubMed1999

Discriminative effects of CGS 15943, a competitive adenosine receptor antagonist, have a dopamine component in monkeys.

9-Chloro-2-(2-furyl)[1,2,4]triazolol[1,5-c]quinazolin-5-amin e (CGS 15943), like caffeine, is an antagonist at adenosine A1 and A2A receptors and a behavioral stimulant in animals. The two drugs have overlapping discriminative effects. Enhancement of dopamine-mediated neurotransmission appears to contribute to the behavioral effects of caffeine. This study was conducted to determine if there is a dopamine component to the discriminative effects of CGS 15943. Squirrel monkeys discriminating between i.m. injections of 1.0 mg/kg CGS 15943 and vehicle generalized dose-dependently and completely to eight dopamine receptor agonists that encompass a variety of mechanisms and sites of action, both pre- and postsynaptic. The discriminative effects of the training dose of CGS 15943 were blocked dose-dependently and completely by the dopamine receptor antagonists R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzaz epine (SCH 23390; D1) and eticlopride (D2). Thus, the discriminative effects of CGS 15943 have a dopamine component that appears to be mediated by both the D1 and D2 families of dopamine receptors. The monkeys also generalized to selective inhibitors of the neuronal transporters of norepinephrine (nisoxetine) and serotonin (fluoxetine), indicating that monoamines other than dopamine also contribute to the discriminative effects of CGS 15943.

Animals↗
PubMedDate not supplied

Effects of ketanserin on the discrimination of electrical stimulation of the dorsal raphé nucleus in rats.

The electrical stimulation of the dorsal raphé nucleus was used as a training cue in a discrimination paradigm. Sprague-Dawley rats were trained to discriminate between electrical stimulation (ES; 200 microA) of the dorsal raphé nucleus (DRN) and non-stimulation. This was accomplished by associating ES with intraperitoneal (i.p.) injection of lithium chloride (LiCl), following the session with electrical stimulation. This made the drinking of saccharin during ES aversive by conditioned taste aversion. Following training, rats decreased saccharin consumption in ES sessions. This discrimination was learned within three pairings of the ES with LiCl. Lowering the ES current to 50-100 microA resulted in levels of saccharin consumption similar to non-stimulation levels, whereas 150 microA showed a response intermediate between the stimulation response at 200 microA and non-stimulation. The discrimination of ES of the DRN (200 microA) was not affected by prior administration of the 5-HT2 antagonist ketanserin (1 or 2 mg/kg, i.p.), suggesting that activation of 5-HT2 receptors is not the primary discriminative cue generated by ES. However, the 5-HT2A/2C agonist DOI (0.25-0.5 mg/kg, i.p.), substituted for ES of the DRN, i.e. animals reduced saccharin consumption following DOI administration. This substitution of DOI for ES was antagonized by the administration of ketanserin (1 mg/kg, i.p.). These results suggest that ES of the DRN has properties that are similar to the activation of 5-HT2A/2C receptors by DOI. However, other stimuli such as activation of other 5-HT receptors are also involved, given that the discriminative cues of ES are not blocked by the 5-HT2A/2C antagonist ketanserin.

Amphetamines↗
PubMed1998

Visual discrimination in pigeons impaired by glutamatergic blockade of nucleus accumbens.

The nucleus accumbens septi (Acc) is thought to be involved in the control of cognitive processes and to be implicated in the pathophysiology of schizophrenia. Because perceptual-cognitive distortions are a core symptom in schizophrenia, any evidence that the Acc intervenes in a sensory recognition task in an animal species would be of interest. Pigeons were instrumentally trained to discriminate visual shapes. The acute effects of drug microinjections into the Acc on the discrimination of the training shapes, on the correction responding after errors, and on the generalisation to different shapes were examined. The effects of conduction blockade with lidocaine, glutamatergic blockade with 7-aminophosphonoheptanoic acid, and dopaminergic stimulation with apomorphine on behavioural performance were tested. No effects were observed with lidocaine and apomorphine. A significant and reversible performance disruption to near chance levels was obtained after aminophosphonoheptanoic acid injections into the Acc. It appears that a glutamatergic blockade of the Acc interferes with the visual discrimination processes of pigeons.

2-Amino-5-phosphonovalerate↗
PubMed1999

Behavioral responses to aliphatic aldehydes can be predicted from known electrophysiological responses of mitral cells in the olfactory bulb.

For a better understanding of the encoding of odor quality in the olfactory system, it is critical to determine how electrophysiological responses to odorants are reflected in the behavioral responses to these odorants. In this article, we use a simple behavioral paradigm to show that the behavioral responses to similar odorants can be predicted from the electrophysiological responses of neurons in the olfactory bulb. Carbon chain length in aliphatic aldehydes has been used as a model for graded similarity among odorants. Recent electrophysiological experiments have shown that mitral cells in the rabbit olfactory bulb respond with similar response patterns to aliphatic aldehydes of similar chain length. On average, mitral cells responded with increased spiking activity to stimulation with two to three different aldehydes of neighboring chain length. We here show that the perception of these odorants can be predicted from the electrophysiological responses: rats that are conditioned to a given aldehyde generalize to aldehydes with one to two carbon differences in chain length from the conditioned aldehyde. When asked to discriminate between aldehydes of different chain lengths, rats learned to discriminate between any two odorants, but the rate of acquisition depended on the degree of similarity between the two odorants.

Aldehydes↗
PubMed1999

Generalization between binary odor mixtures and their components in the rat.

We have adopted a conditioning paradigm to investigate generalization between odor mixtures and components. Rats were conditioned to find a reward buried in odor-scented cups. The conditioned odor was either a mixture (O1 + O2) or a pure component (O1). Once they learned the task to criterion, they were tested in random sequence for response to that O1, O1 + O2 and to an unrelated odor (O3). Generalization was consistently the strongest from O1 to O1 + O2 or from O1 + O2 to O1. Furthermore. the degree of generalization depended on the odorants used as O1, O2, and O3. This latter finding in a particular indicates that this assay can be used to assess properties of mixtures, which could arise at either peripheral or more central locations.

Animals↗
PubMed2006

Building the gist of a scene: the role of global image features in recognition.

Humans can recognize the gist of a novel image in a single glance, independent of its complexity. How is this remarkable feat accomplished? On the basis of behavioral and computational evidence, this paper describes a formal approach to the representation and the mechanism of scene gist understanding, based on scene-centered, rather than object-centered primitives. We show that the structure of a scene image can be estimated by the mean of global image features, providing a statistical summary of the spatial layout properties (Spatial Envelope representation) of the scene. Global features are based on configurations of spatial scales and are estimated without invoking segmentation or grouping operations. The scene-centered approach is not an alternative to local image analysis but would serve as a feed-forward and parallel pathway of visual processing, able to quickly constrain local feature analysis and enhance object recognition in cluttered natural scenes.

Generalization, Stimulus↗
PubMed2001

Increased sensitivity of dopamine systems following reproductive experience in rats.

Several studies have suggested that alterations in forebrain dopamine activity during the postpartum period may result in the onset of postpartum psychosis in women [J. Psychosom. Obstet. Gynecol. 19 (1998) 104; Prog. Neuro-Psychopharmacol. Biol. Psychiatry 17 (1993) 571; J. Clin. Psychiatry 51 (1990) 365.]. The present study investigated whether increased dopamine activity in these forebrain regions is a normal consequence of reproductive experience in rodents. Both intact and ovariectomized parous and nulliparous females were tested for their responses to the dopamine agonist apomorphine using two behavioral measures, prepulse inhibition (PPI) and oral stereotypy. In addition, dopamine and DOPAC levels were measured in tissue from the striatum and nucleus accumbens together with circulating plasma prolactin levels. The results of the behavioral studies demonstrate an increased response to apomorphine in parous females. Parous subjects also had increased levels of dopamine and DOPAC in striatal tissue and lower levels of circulating prolactin. Ovariectomy in nulliparous females resulted in a potentiated response to apomorphine with regard to the disruption of PPI, as well as a significant decrease in the plasma prolactin levels, as compared with intact nulliparous females. These data suggest that increased dopamine activity in forebrain regions occurs as a consequence of parity, which persists for a minimum of several weeks postpartum. These findings support the hypothesis that increased dopamine sensitivity in forebrain dopamine regions may be one potential mechanism underlying the development of postpartum psychosis in women.

Animals↗
PubMed1998

Drug discrimination analysis of pseudoephedrine in rats.

Rats were trained to discriminate amphetamine, 1 mg/kg given intraperitoneally, from saline injection in a two-lever operant drug discrimination task. Pseudoephedrine (a sympathomimetic drug with central and peripheral actions) at doses of 10 mg/kg failed to substitute for amphetamine, at 20 mg/kg partial substitution occurred, while at a 40 mg/kg full substitution was seen. The specificity of the amphetamine cue at the training dose used (1 mg/kg) was shown by the finding that a peripherally acting sympathomimetic drug phenylephrine at doses from 0.2 to 0.8 mg/kg failed to substitute for amphetamine. The potential for abuse of pseudoephedrine administered at high doses is discussed.

Adrenergic alpha-Agonists↗