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PubMedDate not supplied

The phenomenology of limbic kindling.

Kindling is a model of epilepsy whereby repeated administration of brief low-intensity trains of electrical stimulation come to elicit electrographic and behavioral manifestations of seizure. In the absence of overt tissue damage, an animal that has been kindled is rendered in a permanent state of increased susceptibility to seizures. A number of persistent biochemical and physiological alterations in function accompany kindling, some of which may impact upon behavior of the organism for a long period of time despite the absence of further seizure activation. The sensitivity of limbic structures to kindling may contribute to the behavioral categories of cognition and affect that are particularly impacted by the kindling process. The increased proclivity for seizure disorders that characterizes kindling is not restricted to the initial kindling stimulus, but generalizes to other agents with convulsive properties. This paper provides an overview of the phenomenology of kindling, describes some of the conditions necessary for its induction, and some of the functional alterations that accompany its development and endure when overt convulsive behavior has subsided. Finally, a series of studies in our laboratory is presented which provides evidence of chemically induced kindling by repeated low-level exposure to some pesticides, namely those of the chlorinated hydrocarbon class.

Animals↗
PubMed1994

Effect of various partial separations of the litters from their mother on plasma prolactin levels of lactating rats.

Removal of the pups results in an abrupt and marked depression in plasma prolactin (PRL) level of the lactating mother. The present studies were undertaken to investigate what kind of sensory input (smell, sound, visual, touch etc.) from the pups is essential for the mother to avoid the pituitary PRL response to pup-removal. Therefore, various partial separations were made and their effect on plasma PRL levels tested: a. The pups were placed into a small glass having holes on its cover; b. they were put into a long measuring tube not covered; c. the pups were placed into the feeding trough made of a wireframe; d. a dividing wall made of glass or metal was slowly let down when the mother spontaneously went away from her pups; e. the nipples were covered by a cotton plaster. Pituitary PRL responses were almost identical after all these separations and similar to that one obtained after removal of the pups from the cage. In addition, separation of the mother resulted in a rise in plasma corticosterone concentrations. The findings suggest that the pup-removal induced inhibition of PRL secretion is a very complex event for the mother and cannot be prevented by partial separations when the mother can see, smell her pups, or hear them or even can touch them with her nose. We assume that separation of the pups is a stress for the mother and cannot simply be due to the lack of just one kind of sensory input from the pups. This assumption is in line with our recent observations indicating that in lactating rat stress causes a decrease in plasma PRL level.

Animals↗
PubMed1976

Behavior of the lysosomal system during organ perfusion. An inquiry into the mechanism of hepatic proteolysis.

In this chapter we have attempted to provide some insight into a mechanism(s) of protein degradation in liver which we believe is implicated in the physiological regulation of free amino acid pools. The association we have observed between regulatory effects of insulin and amino acids in the perfused rat liver and physical alterations of the lysosomal system in similarly treated livers suggests that the final stage of the process is localized within the lysosomal-vacuolar system. The present studies show that perfusion of the isolated rat liver is in itself a potent stimulus to general proteolysis, an effect which is associated with increases in lysosomal size, density and sensitivity to osmotic shock. Since the osmotic and density alterations can be prevented or reversed by the provision of insulin or amino acid mixtures, we believe these agents normally act to restrain some inherent proteolytic process. Although the attendant lysosomal alterations are similar in many respects to those induced by glucagon, they differ sharply from the latter in having no sequestered organelles or evident membrane structures and the fact that they rise in the absence of any increase in the tissue level of cyclic AMP. Aside from the obvious problem of evaluating the quantitative importance of the lysosomal system in hepatic proteolysis, three interesting problems remain to be solved: (1) the nature of the proteins involved, (2) their mode of acquisition by the lysosome, and (3) the relationship of this inherent proteolytic process to glucagon or cyclic AMP-induced cellular autophagy. With regard to the former it seems reasonably clear from our studies and those of others that protein substrate does not gain access to lysosomal proteases by the direct penetration of lysosomal membranes, but more likely by fusion of a preexisting lysosome with some, as yet undefined, membrane-bound element. Whether such an element is formed in a manner analogous to that of the precursor vacuoles in autophagy (Ericsson 1969) or by some other process is not known. Closely related to this is the question of the nature of the substrate and the factors determining its uptake by the lysosome. Space does not permit us to review evidence from a number of laboratories which suggests that the turnover of intracellular protein may be a function of size (Dehlinger and Schimke 1971; Dice et al. 1973), charge (Dice and Goldberg 1975), or conformational stability (Li and Knox 1972; Ballard et al. 1974). We have no idea at the moment whether the mechanism we have outlined will eventually be shown to encompass a wide range of turnover of intracellular proteins or, alternatively, whether it will be limited to a certain class of proteins that turnover as a unit. While there is undoubtedly far more specificity in the regulation of intracellular proteins than our present data indicate, we do not view this as an incompatibility, but rather as another aspect of a complex problem we are only beginning to understand.

Acid Phosphatase↗
PubMed1993

[Visual evoked potentials and functional asymmetry in children with with different degrees of intellectual retardation].

Visual evoked potentials (VEP) to flash and patterned visual stimuli have been recorded from occipital and central brain regions in 7-8-year-old boys with normal intellect (20 cases), with mental retardation (15 cases) and with oligophrenia of a debile degree (27 cases). A significant elongation of late-component latency has been revealed in motor brain areas VEP in oligophrenia group compared to normal subjects. A negative correlation between P190 component latency of motor area VEP to patterned visual stimulus and general and non-verbal intellectual indices has been stated in full right-handed subjects with intellectual deficiency. Such a relation was absent in right-handed patients with left dominant eye.

Child↗
PubMed1993

[Myoclonic hyperkinesis induced by repeated administration of picrotoxin into rat neostriatum].

The effects of three-week daily intrastriatal 45 mcg GABA, 5 and 15 mcg picrotoxin and 5 bicuculline microinjections in rats were investigated. The inhibition of avoidance conditioning in shuttle box was registered in first days of GABA microinjection; stereotyped behaviour and paradoxal freezing in further GABA effects were developed. After the short orofacial dyskinesia as the acute picrotoxin effects, the choreo-myoclonic limb jerks, with the distinct generalization stage were observed. Picrotoxin dose increasing in toxic convulsive status results. No any dystonia, but strong avoidance conditioning inhibition in all three weeks of bicuculline treatment were observed only. The novel functional and controlled model of choreo-myoclonic hyperkinesis is proposed. The role of the striatal GABA system in human neuro-motor dyskinesias were discussed.

Animals↗
PubMedDate not supplied

[Hyperparathyroidism with lithium].

Lithium has proved to be a highly effective preventive measure in mood disorders and an increasing number of patients are receiving long-term lithium carbonate therapy. Among other biologically and clinically important effects of lithium, the possible induction of hyperparathyroidism was first suggested in 1973 by Garfinkel et al. About thirty other case reports have since been described, but they could simply have represented the coincidental occurrence of primary hyperparathyroidism and lithium carbonate treatment in the same patients. Eleven cross-sectional studies of calcium metabolism in patients treated with lithium carbonate have been reported. Evidence of a causal relationship of lithium to hyperparathyroidism can lead to a loss of effectiveness of lithium in controlling the affective symptoms. Interestingly, coexistence with hypothyroidism is not uncommon. Low serum phosphate, high serum chloride are also observed. Bone mineral content may decrease. In addition, several studies have shown that lithium treatment increases serum magnesium level. Unusual metabolic features are associated with hyperparathyroidism and long-term lithium treatment: low urinary calcium excretion, absence of nephrolithiasis, and normal urinary cyclic AMP excretion. Lithium inhibition of PTH sensitive adenylcyclase in the kidney would explain these features. In vitro studies suggested that lithium is a potent inhibitor of several hormone responsive adenylcyclase systems. It is possible that the tissue susceptibility to adenylcyclase inhibition in an individual may decide the nature of endocrine dysfunction seen during lithium treatment. Information about the time course with which abnormalities may develop is derived from longitudinal studies. Several months to several years are needed for lithium inducing primary hyperparathyroidism. In vitro studies provide strong evidence that lithium can induce a shift in the set-point for inhibition of PTH secretion by calcium and a direct stimulation of PTH secretion. The extent to which we can extrapolate these data to the clinical situation is discussed. In vivo data from Shen an Seely are compatible with these two mechanisms. These alterations should cause parathyroid hyperplasia. The possibility that a generalized parathyroid stimulus might lead to formation of a single adenima is not proved. Several recommendations regarding parathyroid function in patients receiving lithium have been suggested. Measurement of total calcium and serum proteins or of serum calcium ion values when available should be performed before therapy is begun. If elevated values are obtained, lithium treatment should be deferred and evaluation for hyperparathyroidism performed. Serum calcium should be monitored periodically during lithium treatment. Sustained hypercalcemia or true hyperparathyroidism require parathyroidectomy. If hypercalcemia is mild without complication and psychiatric symptoms well controlled, perhaps surgery should not be employed.

Adult↗
PubMedDate not supplied

[Generalized and signal-specific long-term nociceptive sensitization in the snail Helix lucorum].

Neurophysiological and behavioural correlates of the long-term sensitization were investigated in Helix lucorum small. Application of 10% quinine solution on the snail's head initiated a long-term (for more than 24 hours) facilitation of defensive reactions. The behavioural effects correlated with the changes in evoked and spontaneous activity of L-PP11 neurons, i.e., facilitation of synaptic components in responses to testing stimulation, increase in membrane excitability and depolarization. Efficacy of sensitization depended on the duration of the experimental procedure. After daily training site-specific and modality-specific effects dominated (i.e., more expressed facilitation of responses to testing stimulation of the sensitized body site than that of the other sites or to testing stimulation of the same modality as sensitizing stimulation). After 3 days of training the effects of general sensitization were predominantly observed, i.e., facilitation of neuronal responses to stimulation of different modalities and body sites, depolarization of the membrane and increase in its excitability.

Animals↗
PubMed1995

What can be learned from something's not being named.

A new word-learning phenomenon is demonstrated and a new word-learning principle is proposed to account for it. In Study 1, 60 3-year-olds were shown a pair of objects and heard a novel label used repeatedly for one, but not for the other. In a forced-choice test of generalization of the label, the latter object was selected less often by the children than one that had not been present during training. This so-called Nominal Passover Effect was the same whether the speaker had completely ignored the comparison object during training or had referred to it with pronouns. The performance of a no-word control group (N = 24) indicated that the effect was not due to a preference for the less exposed of the two choice objects. The effect is consistent with the Exhaustive Reference Principle, which stipulates that whenever a new generic word is used to name something, expect it to be extended to all entities in a situation that the speaker perceives and believes to be exemplars of the name. In Study 2 (N = 48), the Nominal Passover Effect was replicated with 3 new sets of objects and with training language that contained only indefinite forms of reference. The passover experience was often sufficient to counteract children's tendency to generalize a novel label on the basis of perceptual similarity. The passover effect was not evident in free-choice name generalization tests in either study.

Attention↗
PubMed1977

Differential effects of dorsomedial prefrontal lesions on active and passive avoidance in young and adult rats.

In Experiment I, four weanling and four adult rats had dorsomedial prefrontal lesions administered prior to initial 2-way avoidance acquisition, while in Experiment II surgical procedures for eight subjects were interpolated between acquisition and a first generalization test along CS tonal frequency. Results indicated impairment of initial avoidance acquisition following lesions, which recovered after a 30-day interval, permitting generalization testing in extinction. When DM lesions were interpolated between acquisition and testing, the effects on avoidance responding were comparatively minimal, but after 30 days lesioned subjects could not reacquire criterion avoidance levels. In all generalization tests there was little evidence of frequency control in lesioned subjects compared to eight sham operated controls of each age. Age effects in both experiments were confined to somewhat greater deficits and less recovery of responding in the pups. Two additional experiments examined passive avoidance acquisition and retention in 144 rats of 18-20, 30-32 and 100+ days of age after dorsomedial prefrontal lesions administered either prior to (Experiment III) or following (Experiment IV) initial training and testing. These data suggested rather minimal lesion effects since variability in retention was readily attributed to age differences. Data were related to prefrontal deficits that are specific to age and task requirements.

Age Factors↗
PubMed1997

PNU-96415E, a potential antipsychotic agent with clozapine-like pharmacological properties.

The atypical antipsychotic drug clozapine interacts with multiple transmitter systems, among them the D4 subtype of dopamine receptors. PNU-96415E is chemically unrelated to clozapine and has its highest binding affinity for the D4 and 5-HT2A receptors. In comparison to clozapine, PNU-96415E is weaker in binding to D1, D2, alpha1 and muscarinic receptors. PNU-96415E inhibited exploratory locomotor activity in mice and rats, and antagonized d-amphetamine-induced locomotor stimulation in rats. It antagonized apomorphine-induced cage climbing, and blocked head and body twitch produced by 5-HTP in mice. Like clozapine, but unlike haloperidol, PNU-96415E did not antagonize stereotypic behaviors produced by a high dose of d-amphetamine or methylphenidate in rats and mice. PNU-96415E blocked conditioned avoidance in rats but produced no catalepsy, a pattern similar to clozapine but different from haloperidol. In rats trained to discriminate clozapine from saline injections, the stimulus effect generalized completely with PNU-96415E, but not haloperidol. This profile of pharmacological activities is consistent with that of an atypical antipsychotic and, as in the case with clozapine, the behavioral effects of PNU-96415E cannot be ascribed to a single receptor mechanism.

Animals↗
PubMed1976

Recognition gradients for random shapes following distinctive or equivalent verbal association training.

The effect of distinctive and equivalent verbal label training on a subsequent test of recognition memory for random shapes were assessed. Shape continua, systematically relating the labeled shapes, were used in the memory test so that gradients of recognition memory were obtained. Distinctive-nonrepresentative-label training produced symmetrical recognition gradients with a single mode at the correct target shape. Equivalent-label training produced symmetrical gradients that were as steep as the distinctive-label gradients, but the mode of the equivalent-label gradients was shifted to a distractor shape that varied from the target in the direction of the equivalent-label shape. The results offered support to a Gestalt/configurational account of the effects of verbal labels on memory for form, but the data were also consistent with an extension of Ellis' conceptual coding hypothesis. It was concluded that, rather than being a competing alternative account, the conceptual coding hypothesis may be viewed as an updated, more analytic statement of the older Gestalt view.

Association Learning↗
PubMed1997

Effect of CYP2D1 inhibition on the behavioural effects of d-amphetamine.

In rats, amphetamine (AMP) conversion to 4-OH-AMP is metabolized by CYP2D1, the rat equivalent of the human enzyme CYP2D6. To determine the impact of impaired AMP metabolism on its behavioural effects, AMP-induced hyperactivity, AMP discrimination and AMP self-administration were examined in male Wistar rats with or without pretreatment with the CYP2D1 inhibitors quinine and budipine. In vivo, quinine (20 mg/kg) and budipine (10 mg/kg) increased the plasma area under the curve of AMP 4-fold and 3.6-fold respectively, and decreased the plasma levels of 4-OH-AMP, 3-fold and 8.6-fold, confirming that the doses used suppressed CYP2D1 activity. Both inhibitors prolonged AMP-induced hyperactivity (0.3 mg/kg) and prolonged the duration of AMP-appropriate responding for periods of up to 90 min post-AMP administration in a drug discrimination procedure. In rats given a preload dose of AMP (0.8 mg/kg) 3 h prior to the self-administration test session, CYP2D1 inhibition resulted in fewer AMP infusions being taken compared with rats receiving the AMP preload dose alone. These studies indicate that AMP is responsible for the behavioural effects seen in rats and that a rat phenocopy model of the human CYP2D6 deficiency state can be produced by CYP2D1 inhibitors.

Alcohol Oxidoreductases↗
PubMed1998

Contextual quick-learning and generalization by humans and machines.

In a previous study (1994 Network: Comput. Neural Syst. 5 203-27) we compared human quick-learning and generalization (quick modelling) with that of neural nets (feedforward architectures), symbolic algorithms (decision tree procedures), and pattern classifiers (truth-set descriptors). Those studies raised the question of the role of context in the nature and rapidity of human learning. Here we address that issue in the setting of the same basic experiment (Quinlan classification problem) used for the previous studies. A major implication of our findings is that humans overwhelmingly seek, create, or imagine context in order to provide meaning when presented with abstract or apparently incomplete or contradictory or otherwise untenable situations.

Adolescent↗