Biomedical subjects

M A Cierpial

Publications and source records attributed to M A Cierpial.

At least 19 recordsLinked to original sources

PubMed1998

Selective breeding of rats for high and low motor activity in a swim test: toward a new animal model of depression.

Because low motor activity ina swim test has been found to represent "depression-like" behavior in the rat, Sprague-Dawley (SD) albino rats were selectively bred for low motor activity (low struggling time/high floating time) in a swim test, while others were bred for high motor activity (high struggling time/low floating time). Eighty-four male and 42 female SD rats were initially purchased from Charles-River Breeding Laboratories in 1987, their behavior assessed in a 15-min swim test, and selective breeding carried out by mating those male and female rats that showed either low or high levels of motor activity in the test; results from behavioral testing of the first 18 generations produced by this selective breeding process are reported here. Two rat lines have been obtained, Swim Low-Active (SwLo) and Swim High-Active (SwHi) rats, which differ dramatically in swim-test behavior--SwLo rats show little struggling and much floating, while SwHi rats show the reverse. Activity scores of individual SwLo and SwHi rats now show no overlap. Selective breeding has produced bidirectional changes; that is, SwLo rats are considerably less active than randomly bred Sprague-Dawley albino rats, while SwHi rats are considerably more active than randomly bred rats. Measuring activity of SwLo and SwHi rats in other situations--ambulation in the home cage, open-field activity, exploratory activity in a novel, home cage-like situation, and immobility in the Porsolt swim test--revealed that differences are most pronounced when animals respond to acute challenges; under these conditions, SwHi rats show active, assertive behavior, whereas SwLo rats show a distinct absence of this type of response. When SwLo rats from the 8th to the 11th generations were given antidepressant medication [desipramine, (DMI), a tricyclic, or phenelzine, an MAO inhibitor], chronic but not acute administration of both drugs increased swim-test activity of SwLo rats. Buspirone, an anxiolytic, did not increase activity of SwLo rats. Use of animals selectively bred for high and low activity in the swim test may represent a new tool for studying physiological processes relevant to affective disorders and for testing antidepressant drugs/treatments.

Animals↗

PubMed1997

Sudden unexplained death in epilepsy: observations from a large clinical development program.

PURPOSE: The present study was conducted to determine the rate of sudden unexplained death in epilepsy (SUDEP) in a well-defined cohort of patients included in the lamotrigine (LTG) clinical development database. METHODS: A panel of scientists experienced in the area of SUDEP was assembled and provided with case summaries on all deaths (n = 45) reported during the initial clinical development of LTG. The panel developed a set of criteria for classifying cases as SUDEP (definite or highly probable), possible SUDEP, or non-SUDEP. This classification algorithm was then applied to the LTG cases, and SUDEP rates were calculated using patient-years of exposure as the denominator. RESULTS: At the time of the study, 4,700 patients (5,747 patient-years of exposure) were included in the worldwide LTG clinical trials database. In this cohort, 45 deaths were reported. Eighteen were judged by the panel to be SUDEP, 6 were defined as possible SUDEP, 20 were judged to be due to other causes (non-SUDEP), and 1 lacked sufficient data from which to make a classification. The overall SUDEP rate (definite/ highly probable SUDEP and possible SUDEP combined) was calculated to be 3.5 in 1,000 patient-years of exposure to LTG. CONCLUSIONS: The rate of SUDEP in this cohort of patients was comparable to the rate that would be expected in young adults with severe epilepsy (the subgroup of patients believed to be at highest risk of SUDEP). The data suggest that the rate of SUDEP in the LTG clinical development program is a function of the clinical trial population and is unrelated to drug treatment.

Adolescent↗

PubMed1996

Susceptibility and resistance of rats to stress-induced decreases in swim-test activity: a selective breeding study.

In this study, selective breeding was used to generate two populations of rats that differed in their susceptibility to showing decreased struggling activity in a swim test after being exposed to uncontrollable electric tail-shock. After five generations of selective breeding, we obtained a population that displayed large decreases in swim-test struggling after shock (swim-test susceptible) and a population that displayed no decrease in struggling after shock (swim-test resistant). Males of this fifth generation from the two selectively-bred populations were then compared for differences in non-swim behavioral measures (home-cage 24-h spontaneous ambulatory activity and food/water intake) and several aspects of brain catecholaminergic activity, including electrophysiological activity of locus coeruleus (LC) neurons, catecholamine/metabolite concentrations in various brain regions, and in vivo tyrosine hydroxylase activity. Interestingly, swim-test resistant rats displayed larger decreases in home-cage ambulatory activity and water intake after exposure to shock than did swim-test susceptible animals. Marked differences were also seen in measures of brain noradrenergic activity. Compared to the susceptible rats, resistant rats showed higher levels of evoked activity of LC neurons, larger shock-induced depletions of norepinephrine (NE) and 3-methoxy-4-hydroxyphenylglycol (MHPG) in the LC, lower in vivo tyrosine hydroxylase (TH) activity in ventral bundle projection areas such as the hypothalamus, and larger amounts of NE in dorsal bundle projection areas. Finally, swim-test resistant rats had much higher concentrations of dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) in striatum and nucleus accumbens than susceptible rats. These results appear to be explainable on the basis that differences in swim-test struggling behavior for which the two populations were selectively bred were a consequence of differences in forebrain DA whereas stress-induced differences in other behavioral measures (i.e. spontaneous ambulation and intake) occurred because swim-test resistant animals showed greater disturbance of the LC-NE system after uncontrollable shock.

Animals↗

PubMed1992

Maternal involvement in the development of cardiovascular phenotype.

Over the past 20 years, laboratory studies of genetically defined animal models of human essential hypertension have provided valuable information on the pathophysiology of this disturbance in cardiovascular regulation. Relatively fewer studies have examined the impact of preweaning factors on the developing cardiovascular system of hypertensive animals. In our laboratory studies, we have utilized two inbred genetically hypertensive models: the spontaneously hypertensive (SHR) rat and its Wistar/Kyoto (WKY) normotensive control strain as well as the Dahl hypertension-sensitive (SS/Jr) and hypertension-resistant (SR/Jr) strains. To manipulate the preweaning maternal environment, we have employed the technique of reciprocal cross-fostering of litters between hypertensive and matched normotensive mothers. Our findings to date point to the maternal environment as a powerful influence on the development of high blood pressure in genetically hypertensive rats. In general, hypertensive rats reared by normotensive foster mothers have significant reductions in arterial blood pressure in adulthood. Thus, the progression of hypertensive disease is not strictly predetermined by genotypic factors. Rather, a genetic predisposition to hypertension interacts with preweaning environmental factors to determine an animal's cardiovascular phenotype in adulthood.

Animals↗

PubMed1991

Human immunodeficiency virus glycoprotein (gp120) infused into rat brain induces interleukin 1 to elevate pituitary-adrenal activity and decrease peripheral cellular immune responses.

Intracerebroventricular (i.c.v.) infusion of glycosylated recombinant gp120, the envelope protein of human immunodeficiency virus, in various doses (100 ng to 4 micrograms) resulted in detection of interleukin 1 (IL-1) activity in a high percentage (61%; 33 of 54) of rat brains, whereas IL-1 was very rarely detected in brains of animals infused with several control substances (4%; 1 of 28). To detect IL-1, clarified glial lysate of diencephalon plus brainstem was subjected to gel exclusion chromatography and fractions were assessed for thymocyte stimulation. IL-1 was seen 2, 6, and 24 hr postinfusion. i.c.v. gp120 also produced known effects of IL-1 in brain, elevating steroid concentration in plasma and decreasing cellular immune responses [natural killer (NK) cell activity and mitogenic response to Con A] of blood and splenic lymphocytes. When gp120 was infused together with alpha-melanocyte-stimulating hormone (20 ng), which blocks many biological actions of IL-1, gp120 no longer elevated steroids or decreased NK cell activity. After intravenous gp120, IL-1 was not found in brain or plasma, indicating that stimulation of IL-1 in brain by i.c.v. gp120 was not due to gp120 affecting infiltrating cells from blood or to elevated circulating IL-1. That induction of IL-1 in brain might have resulted from lipopolysaccharide (LPS) in the gp120 solution was ruled out by studies showing that (i) heating of the infusion solution, which does not affect the capacity of LPS to induce IL-1, eliminated the ability of gp120 infusion to induce brain IL-1, and (ii) gp120 induced IL-1 in brains of LPS-resistant C3H/HeJ mice. Injection of gp120 directly into the hippocampus stimulated IL-1 more readily than i.c.v. infusion. Thymocyte stimulation produced by active fractions of gp120-infused brains was blocked by monoclonal antibody to IL-1 receptors. These findings indicate that elevation of IL-1 in brain can result from infection with human immunodeficiency virus and may be responsible for certain abnormalities (e.g., elevated activity of pituitary-adrenal axis) seen in AIDS patients.

Animals↗

PubMed1991

Effects of interleukin-1 infused into brain are antagonized by alpha-MSH in a dose-dependent manner.

Interleukin-1 (IL-1) in the brain stimulates the pituitary-adrenal axis and markedly suppresses cellular immune responses. alpha-Melanocyte-stimulating hormone (alpha-MSH) introduced into the ventricular system simultaneously with IL-1 blocked these effects of IL-1 in a dose-dependent manner, with 10 ng of alpha-MSH totally blocking the elevation of plasma ACTH and corticosterone and suppression of Natural Killer (NK) cell activity produced by a dose of IL-1 (100 pg) that otherwise causes maximal effects. In that IL-1 has been shown to promote production of alpha-MSH, these results suggest that actions of IL-1 in brain are under negative feedback control and, consequently, that the effects of this cytokine in brain are of biological significance.

Adrenocorticotropic Hormone↗

PubMed1991

Adult blood pressure reduction in spontaneously hypertensive rats reared by normotensive Sprague-Dawley mothers.

Spontaneously hypertensive (SHR), Wistar-Kyoto (WKY) normotensive, and Sprague-Dawley (SD) normotensive rats were either reared by their natural mothers (controls) or fostered to a mother of one of the other strains. The effects of rearing environment were assessed by measures of body weight at weaning and adult resting mean arterial blood pressure (MAP) and heart rate (HR). At weaning, SHR control rats weighed less than WKY controls which in turn weighed less than SD controls. SHR and WKY rats reared by SD mothers weighed significantly more than their respective controls, whereas SD rats reared by either SHR or WKY mothers weighed less than SD control rats. Manipulation of the maternal environment was attended by a change in adult resting MAP in only one group. SHR rats reared by SD mothers had MAPs which were significantly lower than SHRs reared by their natural mothers. No within-strain adult HR differences were observed between control and cross-fostered groups. These data indicate that the effects of cross-fostering on adult resting MAP previously reported for SHR and WKY animals are generalizable to another normotensive strain. That is, genetically hypertensive (SHR) animals exposed to a normotensive (WKY or SD) maternal environment display a reduction in adult resting MAP, whereas hypertension or an increase in adult MAP is not induced in normotensive rats (WKY or SD) as a consequence of exposure to a hypertensive maternal environment.

Animals↗

PubMed1990

Maternal behavior of spontaneously hypertensive and Wistar-Kyoto normotensive rats: effects of reciprocal cross-fostering of litters.

Maternal behavior of spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) normotensive dams rearing either their natural pups or pups of the opposite strain was assessed when pups were 4-6 days of age. Consistent with previous reports, SHR dams caring for their natural pups were observed nursing and licking their pups more often than WKY dams and were away from their pups less often. The behavior of dams rearing cross-fostered pups demonstrated that this strain difference in patterns of maternal behavior is dependent on pup type. Mothers of both strains shifted their behavior in the direction of the opposite strain's maternal behavior pattern when caring for cross-fostered pups. This shift was most pronounced in SHR dams caring for WKY pups. These data suggest that alterations in patterns of maternal behavior produced by cross-fostering may play an important role in cross-fostering effects on the physiological development of SHRs previously reported.

Animals↗

PubMed1990

Maternal influences on sympathetic-adrenal medullary system in spontaneously hypertensive rats.

The technique of reciprocal cross fostering was used to assess the influence of the maternal environment on the functioning of the sympathetic-adrenal medullary system in the spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) normotensive rats. Control, in-fostered, and cross-fostered rats were tested in adulthood to assess 1) the neural contribution to resting mean arterial blood pressure (MAP) and 2) sympathetic-adrenal medullary responses to acute footshock stress. Adult resting MAP was significantly lower in cross-fostered SHRs (139.6 mmHg) compared with control or in-fostered SHRs (162.1 and 159.3 mmHg). In addition, the decrease in MAP after sympathetic blockade (40.6 mmHg) was significantly less in cross-fostered SHRs compared with controls (50.1 mmHg). Sympathetic-adrenal medullary responses to foot-shock were greater in SHR than WKY rats; however, cross-fostered SHRs showed exaggerated responses compared with control and in-fostered SHRs. Altering the maternal environment did not produce any measurable effects on the neural contribution to resting MAP or sympathetic-adrenal medullary responsivity to acute stress in the WKY strain. These results indicate that the blood pressure-lowering effect of cross fostering in the SHR strain is caused in part by a dampening of the neural contribution to resting MAP; however, these animals retain their strain's characteristic adrenergic hyperreactivity to stressful stimulation.

Adrenal Medulla↗

PubMed1990

Brain IL-1-induced immunosuppression occurs through activation of both pituitary-adrenal axis and sympathetic nervous system by corticotropin-releasing factor.

Intracerebroventricular infusion of femtomolar quantities of interleukin-1 (IL-1) or stimulated release of endogenous IL-1 in the brain suppresses various cellular immune responses, decreasing natural killer cell (NK) activity, response to mitogen, and interleukin-2 production of splenic and blood lymphocytes (an effect hereafter called "brain IL-1-induced immunosuppression"). The present study examines mechanisms by which IL-1 produces this effect. First, because IL-1 in the brain activates the pituitary-adrenal axis by stimulating release of corticotropin-releasing factor (CRF), the role of CRF was investigated. To block CRF, affinity-purified antibody to CRF was infused into the lateral ventricle 30 min before introduction of IL-1. When this was done, suppression of cellular immune responses that normally follow IL-1 infusion was completely prevented. Infusion with an equal quantity of non-CRF IgG prior to IL-1 was without effect. Second, the role of sympathetic nervous activity was examined. To block neural transmission at sympathetic ganglia, chlorisondamine (3.0 mg/kg) was injected intraperitoneally 60 min before IL-1 infusion. When this was done, suppression of immune responses by IL-1 was partially blocked. These results indicate that IL-1 in the brain suppresses various cellular immune responses by activating both the pituitary-adrenal axis and the sympathetic nervous system, and that these systems are both activated through the influence of IL-1 on CRF.

Animals↗

PubMed1989

Open-field behavior of spontaneously hypertensive and Wistar-Kyoto normotensive rats: effects of reciprocal cross-fostering.

The influence of the maternal environment on the development of open-field behavior in spontaneously hypertensive (SHR) rats was investigated using the technique of reciprocal cross-fostering. Entire litters of SHR and Wistar-Kyoto (WKY) normotensive rats were either reared by their natural mothers, in-fostered to dams of the same strain, or cross-fostered to dams of the opposite strain on the day after birth. Open-field behavior was assessed in male and female rats from the six groups (2 strains x 3 rearing conditions) at 30, 60, 90, and 120 days of age. Animals were observed in the open-field during a 5-min test period and the number of squares entered and hindlimb rears were recorded. At all ages tested, SHR rats were more active in the open field, entering more squares and rearing more frequently than WKYs. SHR females were more active than age-matched SHR males, while no sex differences were apparent in the WKY strain. At each age, open-field behavior was similar across WKY rearing groups. SHR control and in-fostered animals responded similarly in the open field; however, SHR cross-fostered rats (particularly females) tended to be more active than controls. Although cross-fostering has profound effects on cardiovascular development and functioning in the SHR, it appears that altering the early maternal environment experienced by SHR pups does not grossly affect the development of open-field behavior.

Animals↗

PubMed1989

Intracerebroventricular infusion of interleukin 1 rapidly decreases peripheral cellular immune responses.

Low doses (50-200 pg or 3.1-12.4 fmol) of interleukin 1 (IL-1) infused into the brain of rats produced rapid suppression of various cellular immune responses in peripheral lymphocytes of rats. Fifteen minutes after infusion of purified IL-1 beta into the lateral ventricle, natural killer cell activity, response to phytohemagglutinin stimulation, and interleukin 2 production were markedly suppressed in lymphocytes isolated from blood and spleen. These effects were due to infusion of IL-1 into brain since they did not occur when IL-1 was infused into the cisterna magna (essentially posterior to brain) or was injected intraperitoneally. Effects of IL-1 in brain could be blocked by simultaneous infusion of alpha-melanocyte-stimulating hormone, which is known to block the biological actions of IL-1. To stimulate release of endogenous IL-1 in brain, lipopolysaccharide was infused; this produced similar effects as IL-1, and these effects also were blocked by alpha-melanocyte-stimulating hormone. At longer intervals after infusion of IL-1 and lipopolysaccharide (3, 6, and 24 hr), immune responses returned to baseline or remained suppressed; i.e., "rebound" immunopotentiation did not occur. Finally, IL-1 infusion suppressed cellular immune responses in adrenalectomized animals, thereby showing that the effects of central IL-1 on peripheral cellular immune responses were, at least in part, independent of the stimulatory effect of IL-1 on secretion of adrenal hormones. These results indicate a link from brain to peripheral immune responses by means of action of a cytokine acting in the brain.

Animals↗

PubMed1989

Behavioral and neural influences on cellular immune responses: effects of stress and interleukin-1.

A series of experiments examined effects of stressful conditions on several cellular immune responses and attempted to elucidate the physiological mechanisms underlying these effects. Initial studies showed that stressful conditions can profoundly suppress immune responses of blood and splenic lymphocytes, including T-cell mitogenesis, natural killer cell activity, production of interleukin-2 (IL-2) and interferon and IL-2 receptor expression. Subsequent studies found that (1) multiple physiological pathways mediate stress-induced suppression of these responses; (2) stress-induced suppression of these responses is produced, at least in part, by a peptide with molecular weight greater than 10 kilodaltons, which stressed animals release into circulation; (3) whereas most stressful conditions suppress immune responses, stressful conditions of moderate intensity can enhance cellular immune responses; and (4) extremely small quantities of interleukin-1 (IL-1) acting in the brain (e.g., 3.1-12.4 X 10(-15) moles) bring about suppression of cellular immune responses very rapidly and for a prolonged period of time. The relationship between the newly-discovered immunosuppressive influence of IL-1 in the brain and immunosuppression produced by stressful conditions remains to be determined.

Animals↗

PubMed1988

Pertussis toxin blocks the effects of alpha 2-agonists and antagonists on locus coeruleus activity in vivo.

This study assessed the effects of pertussis toxin, which is known to inactivate G proteins and therefore to block receptors linked to G proteins, on electrophysiological activity of the locus coeruleus in vivo. Pertussis toxin was injected into the lateral cerebral ventricle of rats, and locus coeruleus activity was then recorded. Compared to vehicle-injected control animals, pretreatment with pertussis toxin markedly increased the spontaneous firing rate of locus coeruleus neurons. In addition, the alpha 2-antagonist idazoxan was no longer able to augment either spontaneous or evoked locus coeruleus activity after pretreatment with pertussis toxin. Finally, pretreatment with pertussis toxin made locus coeruleus neurons resistant to inhibition by the alpha 2-agonist clonidine. These results are consistent with the view that pertussis toxin blocks alpha 2-receptors, receptors linked to G proteins, in vivo.

Adrenergic alpha-Agonists↗

PubMed1988

Sympathetic-adrenal medullary response to stress in hyperactive and hypertensive rats.

Sympathetic-adrenal medullary hyperreactivity to acute stress, measured as an exaggerated elevation of plasma epinephrine and norepinephrine levels in response to footshock, was examined in four genetically related, inbred rat strains, all derived from the Wistar-Kyoto rat (WKY). These four strains are endowed with the traits of hypertension and behavioral hyperactivity, expressed either together (in SHR), or separately in two new strains (Wistar-Kyoto hyperactive rats, WK-HA, and Wistar-Kyoto hypertensive rats, WK-HT), or not at all (in WKY). Male rats of the SHR, WKY, WK-HA and WK-HT strains were subjected to acute footshock stress in order to determine whether the previously reported hyperreactivity of the SHR is attributable to the hypertensive trait, or to the behavioral hyperactivity trait, both of which are characteristic of the SHR. Plasma catecholamine levels were determined prior to, immediately following, and 5 min following acute footshock stress. We report here that the WK-HA strain (hyperactive but not hypertensive) exhibited the hyperreactivity characteristic of SHRs, and not the WK-HT strain (hypertensive but not hyperactive). We conclude that the exaggerated sympathetic-adrenal medullary response to acute stress is associated with the hyperactivity trait and not with hypertension among these congenic rat strains.

Adrenal Medulla↗

PubMed1988

Maternal effects on the development of spontaneous hypertension.

Cross-fostering spontaneously hypertensive rat (SHR) pups to Wistar-Kyoto (WKY) normotensive mothers influenced physical development, resting mean arterial pressure and heart rate, open-field behavior, and sympathetic-adrenal medullary responses to stressors. In contrast, cross-fostering WKY pups to SHR mothers at birth did not affect these developmental processes.

Animals↗

PubMed1987

Preweanling behavioral development in spontaneously hypertensive, borderline hypertensive, and Wistar-Kyoto normotensive rats.

Preweanling physical and behavioral development was studied in spontaneously hypertensive (SHR), borderline hypertensive (BHR), and Wistar-Kyoto normotensive (WKY) rat pups. Measures of physical development included body weight, onset of various morphological landmarks, and speed of surface righting. Behavioral tests assessed locomotor development, exploratory behavior, and cliff avoidance in pups of the 3 groups. On all measures employed, SHR pups exhibited a delay in physical maturation compared to age-matched BHR and WKY pups. Results from the locomotor development test revealed that young WKY pups (ages 1-7 days) spent more time locomoting than SHR pups, with BHR times being intermediate. In contrast, older SHR pups (ages 17-30 days) displayed greater activity in an exploratory maze than WKY pups, with BHR values again intermediate. Finally, SHR pups were more behaviorally reactive in the cliff avoidance task compared to BHR and WKY pups. These group differences may be useful in understanding the development of genetic hypertension and may serve as early behavioral markers of a predisposition to cardiovascular disease.

Animals↗

PubMed1987

Patterns of maternal behavior in the spontaneously hypertensive rat.

Maternal behavior of spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) normotensive rats was assessed over the preweanling period (days 1-21). Ten litters of each strain were observed during the dark phase of the light:dark cycle using a scan sampling technique. Cages were observed periodically throughout the day and the momentary behavior of the dam was recorded on a checklist of 9 different behaviors. These behaviors included: nursing entire litter, nursing part of litter, contact with entire litter, contact with part of litter, pup carrying/retrieval, licking pups, sniffing pups, nest building, and away from litter. A second set of ten litters per strain was observed in the same manner during the light phase of the light:dark cycle thus providing around the clock data throughout the entire preweanling period. For purposes of data analysis, the 21-day preweanling period was divided into 7 3-day blocks. The mean relative frequency with which each behavior was observed from SHR and WKY mothers was determined for each block and for each phase of the light:dark cycle separately. SHR mothers were with their pups and nursing them more frequently than WKY mothers during the light phase of the circadian cycle. Complimentary to this finding, WKY mothers were observed away from their pups more frequently than SHR mothers during both light and dark phases. Finally, SHR mothers were observed to lick their pups more often than WKY mothers during both phases of the light:dark cycle. These findings were consistent across the entire preweanling period.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗