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Biomedical subjects

T J Marczynski

Publications and source records attributed to T J Marczynski.

At least 55 records · Page 3Linked to original sources
PubMed1969

Steady potential correlates of positive reinforcement: reward contingent positive variation.

A positive reinforcement with food produced high-voltage bursts of alpha activity over the posterior marginal gyrus in a cat deprived of food and water. This synchronization was always associated with a large (180 to 300 microvolt), positive steady potential shift comparable to that occurring during the onset of sleep. Since this shift was contingent upon the relative appropriateness and desirability of food reward, it was termed reward contingent positive variation.

Animals↗
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Benzodiazepines inhibit neutrophil chemotaxis and superoxide production in a stimulus dependent manner; PK-11195 antagonizes these effects.

Diazepam, which binds both central (neuronal) and peripheral (non-neuronal) benzodiazepine binding sites, and Ro5-4864, a ligand selective for benzodiazepine peripheral binding sites (PBS), both inhibited the FMLP induced chemotaxis in human neutrophils at concentrations as low as 10(-8) M. A selective peripheral benzodiazepine antagonist, PK-11195 (10(-5) M), partially reversed the benzodiazepine inhibition of chemotaxis. Diazepam also inhibited the superoxide production induced by FMLP, NaF, and A23187, but not that induced by PMA whose stimulant action was insensitive even to 10(-4) M diazepam. The FMLP-induced superoxide production was most sensitive to diazepam inhibition (ID50 = 2.25 x 10(-6) M diazepam); the effect of NaF was slightly less sensitive (ID50 = 1.34 x 10(-5) M diazepam); and the effect of A23187 was least sensitive as it was suppressed only at 10(-4) M diazepam concentrations. Like diazepam, Ro5-4864 inhibited the FMLP-induced superoxide production, and PK-11195 (10(-5) M) significantly antagonized both diazepam and Ro5-4864 inhibition. Binding studies showed the presence of a saturable benzodiazepine 'peripheral' type binding site (PBS) on human neutrophils with a Kd of 1.2 +/- 0.06 x 10(-8) M (+/- SEM), and a Bmax of 1028 +/- 86.2 fmol/10(6) cells (+/- SEM) for [3H]Ro5-4864; the binding was displaceable by PK-11195, Ro5-4864 and diazepam but not by clonazepam.

Adult↗
PubMedDate not supplied

Chronic administration of flumazenil increases life span and protects rats from age-related loss of cognitive functions: a benzodiazepine/GABAergic hypothesis of brain aging.

Under barrier condition and with ad lib access to food and water, 20 Fischer-344 rats were chronically treated for 10 months with the benzodiazepine (BDZ) antagonist, flumazenil (FL; 4 mg/kg/day in drinking water acidified to pH = 3.0), beginning at the age of 13 months, while the group of 20 control age-matched rats received plain acidified water. The life span of the first 8 deceased rats treated with FL was significantly longer than that of the first 8 deceased rats in the age-matched control group. In tests for spontaneous ambulation and exploratory behavior in the Holeboard apparatus, conducted during the 3rd and the 8th month of treatment, the FL group, relative to controls, had significantly higher scores for the ambulation and exploratory behavior. In tests for unrewarded spontaneous alternation in the T maze, conducted at days 7, 39, 42, and 47 through 54 after drug withdrawal, i.e., at the age of 24-25 months, the FL-exposed group, compared to age-matched controls, showed a significantly higher percent of alternating choices, a behavior that was statistically comparable to that of the "young" 6-month-old controls. In the Radial Maze tests conducted 2 months after drug withdrawal, the FL group made significantly less "working memory" errors and "reference memory" errors, relative to the age-matched 25-month-old control group, a performance that was comparable to that of the young 7-month-old control group. In conclusion, chronic FL significantly protected rats from age-related loss of cognitive functions. It is postulated that the age-related alterations in brain function may be attributable to the negative metabolic/trophic influences of the "endogenous" benzodiazepine (BDZ) ligands and/or those ingested with food. A BDZ/GABAergic hypothesis of brain aging has been formulated which assumes that age-related and abnormally strong BDZ/GABAergic influences promote neurodegeneration by suppressing trophic functions of the aminergic and peptidergic neurons through opening of chloride channels in soma membrane and axon terminals, causing excessive hyperpolarizing and depolarizing inhibition, respectively. The review of human clinical and animal data indicates that FL has nootropic actions by enhancing vigilance cognitive and habituation processes.

Aging↗
PubMedDate not supplied

Perinatal upregulation of benzodiazepine receptor ontogenesis: "fearless" and more efficient goal-directed behavior of adult rat progenies.

Pregnant and subsequently lactating rats had ad lib access to drinking water which contained either a benzodiazepine antagonist, Ro 15-1788 or diazepam (DZ). On the average, the rats consumed 2.9 mg/kg/day of Ro 15-1788 or 5.3 mg/kg/day of diazepam over the time period of 3 weeks, from gestation day 14 through postpartum day 14. The control group consumed equivalent volumes of the drug vehicle in water. While Ro 15-1788 had no apparent toxic effects, the numbers of viable pups in the DZ group were significantly reduced. The mean weight of the viable pups, and their gross behavior were not different in all three groups. However, the fully mature 4.5-month-old male progenies exposed to Ro 15-1788 were much more efficient in the radial arm maze test than the control or the diazepam-exposed animals; they rapidly habituated to the novel environment, their exploratory activity was uninhibited by distracting visual and auditory stimuli, they made fewer "working memory" errors in collecting baits, had a much better control over their emotional responses and the autonomic nervous system, as shown by very low defecation/urination scores, and, at the age of 5 months, they had a significant (66%) increase in the density of benzodiazepine receptors in the hippocampal formation, as compared to the control or the diazepam-exposed progenies. In conclusion, the upregulation of benzodiazepine receptor ontogenesis is retained in adult animals and resulted in improved "working memory" and better control over emotional responses that were particularly evident when the animals were challenged by novel and "intimidating" environmental stimuli.

Animals↗
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Chronic flumazenil (Ro 15-1788) facilitates acquisition and retention of a swim-escape response in rats.

Since chronic flumazenil treatment was previously found to stimulate exploratory behavior in rodents, the aim of this study was to test the effect of chronic exposure to flumazenil on acquisition and retention of escape behavior. Adult rats were treated with flumazenil (Ro 15-1788; 4 mg/kg/day in drinking water) for 21 days (experiment 1) and for 17 days (experiment 2). In experiment 1 (a round water tank with one escape rope) conducted 24 h after drug/vehicle withdrawal, the time the animals needed to resolve a swim-escape task was significantly shorter in the drug group, compared to the controls. In the retention trial, 24 h later, the control group matched the performance of the drug group. In experiment 2, a water T-maze was used which was equipped with two ropes, one anchored to the bottom and the other unanchored and therefore was more difficult to climb. On day 14 of flumazenil/vehicle treatment, there were no differences between the groups in the time needed to escape from the maze. However, on day 15 and 16 of drug/vehicle treatment, the drug group made highly significant progress, while the control group showed no improvement of the escape behavior. The possible mechanisms of flumazenil-induced facilitation of escape behavior have been discussed.

Animals↗
PubMedDate not supplied

GABAergic deafferentation hypothesis of brain aging and Alzheimer's disease; pharmacologic profile of the benzodiazepine antagonist, flumazenil.

Recent experiments have shown that: 1) A chronic 10 month daily administration to rats of the benzodiazepine (BDZ) receptor antagonist, flumazenil (FL; 4 mg/kg in drinking water), from the age of 13 through 22 months, significantly retarded the age-related loss of cognitive functions, as ascertained by the radial arm maze tests conducted two months after FL withdrawal. 2) An equal number of 8 rats died in the control and FL-treated group before the behavioral tests were completed and the animals were sacrificed; the life span of the FL-treated 8 rats equaled 24.0 (+/- 0.6 SEM) months, while that of the control 8 rats equaled 22.3 months (+/- 0.7 SEM), and the group difference was marginally significant (p = 0.04 Mann-Whitney test). 3) In rats sacrificed 3 months after FL withdrawal and behavioral testing, the protective action of FL, relative to age-matched controls, was revealed by a significant reduction in the age-related loss of neurons in the hippocampal formation. 4) In the time period of 3 months between the drug withdrawal and sacrificing of the animals, stress experienced by the aging rats during behavioral testing, related to excessive daily handling of the animals and partial food deprivation to motivate them to perform in the radial arm maze, apparently had excitotoxic effects on the hippocampal neurons, as indexed by the presence of 30% neurons in a state of moderate pyknosis found both in the FL group and the age-matched controls. In the 6 months "young" control group, the number of pyknotic neurons equaled only 3.5%. It was concluded that the drug withdrawal and stress of behavioral testing unleashed the previously FL-controlled age-related degeneration. On the basis of these results and the literature, showing that the tone of the GABAergic system increases with age, and particularly in Alzheimer's disease (AD), the hypothesis of brain aging was formulated. It postulates that in mammals, with growing age, and prematurely in humans with AD, the increasing tone of the BDZ/GABAergic system interferes with antero- and retrograde axonal transport through a chronic depolarizing block of preterminal axon varicosities of the ascending aminergic and cholinergic/peptidergic systems, which are indispensable for normal metabolic/trophic glial-neuronal relationships. Such a state leads to discrete anatomic deafferentation of forebrain systems, and particularly of the neocortex, where block of the anterograde axonal transport results in induction of the cortical mRNA responsible for synthesis of the beta-amyloid precursor protein (beta APP). The simultaneous block of retrograde transport from chronically depolarized preterminal axon varicosities may account for toxic accumulation in cortex of the nerve growth factor (NGF) and other trophins, without which the basal forebrain cholinergic neurons degenerate. The general pharmacologic profile of FL has been discussed on the basis of FL administration to animals and healthy and diseased humans. This profile shows that FL: 1) increases brain metabolic functions; 2) reduces emotional responses, thereby stabilizing the functions of the autonomic system in both humans and animals challenged by adverse environmental stimuli; 3) improves cognitive and coordinated motor functions in both humans and animals; 4) uniquely combines anxiolytic, vigilance and cognitive enhancing, i.e. nootropic, properties, which may, in part, stem from FL-induced emotional imperturbability (ataraxy); 5) facilitates habituation of healthy humans and animals to novel but inconsequential environmental stimuli, and promotes non-aggressive interactions among animals; 6) in single i.v. doses, and administered chronically to humans, FL has antiepileptic actions in the Lennox-Gastaut syndrome and other forms of epilepsy characterized by "spike-and-dome" EEG patterns; these actions are likely to depend on FL's disinhibition of the serotonin system; 7) administered in single i.v...

Afferent Pathways↗
PubMedDate not supplied

Prenatal diazepam: chronic anxiety and deficits in brain receptors in mature rat progeny.

Pregnant rats were treated with daily doses (5.0 to 7.5 mg/kg, SC) of the benzodiazepine (BDZ) receptor agonist, diazepam (DZ) between day 15 through day 20 of gestation, i.e., during ontogenesis of BDZ receptors in an attempt to alter their development. In the radial arm maze, 6 months old rat progeny showed behavioral anomalies and deficient exploratory behavior. One plausible interpretation of their poor performance is a deficit in short-term spatial "working memory." However, a more detailed evaluation of their behavior suggests a chronic state of hyperarousal/anxiety and thus, poor focus of attention on the task at hand. In addition, the number of brain BDZ receptors in the thalamus, at the age of one year, was significantly reduced. Hence, prenatal exposure to DZ has enduring and detrimental effects on brain function.

Animals↗
PubMedDate not supplied

Prenatal exposure to diazepam: late postnatal teratogenic effect.

During the last 5 days of gestation, pregnant Sprague-Dawley rats were treated daily with SC diazepam (DZ) injections (average dose 6 mg/kg of body weight). The control pregnant rats were treated with corresponding volumes of the vehicle. The progenies were examined for the occurrence of neoplastic and non-neoplastic lesions for up to 20 months. Although there were no early postnatal effects of DZ, 13 neoplasms developed in the 52 DZ-exposed rats (12 mammary fibroadenomas and one uterine sarcoma), while there were not such lesions in 44 control rats (p less than 0.001, Fisher's exact test). The non-neoplastic lesions in the DZ-exposed group, such as infections, arteriosclerosis etc., were also significantly greater in magnitude and incidence, compared to control animals (p = 0.007, Wilcoxon Rank Sum test). Also, the DZ-exposed rats had a significantly lower titre of the plasma immunoglobulin G (IgG), higher levels of white blood cells and lower hematocrit values than the control animals. DZ is known to bind with high affinity to both central nervous system and non-neuronal receptors present in peripheral organs and blood cells, such as monocytes. The monocyte receptors appear to be critical for chemotaxis induced by many agents affecting the normal function of the immune system including antineoplastic defense. We have previously shown that prenatal DZ suppresses ontogenesis of brain benzodiazepine receptors as tested in adult 12 months old cat and rat progenies. If the ontogenesis of "peripheral" receptors is also suppressed, this would provide a plausible explanation for teratogenic effect of DZ.

Animals↗