Search PubMed⌕ Search

Biomedical subjects

P Boksa

Publications and source records attributed to P Boksa.

At least 19 recordsLinked to original sources
PubMed1998

Caesarean section birth with general anesthesia increases dopamine-mediated behavior in the adult rat.

Schizophrenia is associated with both increased dopaminergic activity and perinatal complications. To test whether dopamine-mediated behavior can be altered by birth complications, we investigated effects of amphetamine (AMPT) on activity levels in adult rats that had been born vaginally or by Caesarean section (C-section) from isoflurane-anesthetized dams with or without addition of 10 min global anoxia. For comparison with our previous results, we also included rats born by C-section from decapitated dams. The main finding is that rats born by C-section from isoflurane-anesthetized dams, either with or without added anoxia, showed greater AMPT-induced activity as adults compared to vaginally born controls. C-section from decapitated dams also enhanced AMPT-induced activity, however the time course differed from that following maternal anesthesia. Thus subtle alterations in birth procedure can produce long-lasting increases in dopamine-mediated behavior, supporting a role for birth complications in the pathophysiology of schizophrenia.

Administration, Inhalation↗
PubMed1998

Birth insult alters ethanol preference in the adult rat.

While genetic factors clearly play a role in regulating ethanol intake, the present study considered the possibility that early environmental factors which influence central nervous system development and long-term function might also alter ethanol intake. The specific aim of the study was to test whether alterations in birth condition, namely Caesarean section (C-section) birth and C-section birth with an added period of global anoxia, can affect subsequent ethanol preference in the adult rat. At 5 months of age, groups of experimental and vaginally born control rats were offered free choice between drinking water or various concentrations of ethanol (1-10% v/v) in water across 36 days of testing. Rats that had been born by C-section with 10 or 15 min of added global anoxia showed significant reductions in ethanol preference scores, in comparison to vaginally born controls. For the 10-min anoxia group, ethanol intake was decreased, water intake was increased and total fluid intake remained unchanged relative to values for vaginally born controls, across the entire test period. Although total fluid intake by the 15-min anoxia group also did not differ from that of vaginally born controls, the decreased ethanol preference scores in the 15-min anoxia group were mainly due to increased water intake during some test periods and a combination of reduced ethanol intake and increased water intake during others. Animals born by rapid C-section alone, with no added period of global anoxia, showed reduced ethanol preference only during a few early periods of testing, a much less pronounced effect than that observed for animals with added global anoxia. When animals were given the choice between drinking water vs. solutions of sucrose or NaCl, no group differences due to birth condition were found on measures of sucrose or NaCl preference. Together with reduced ethanol preference, the 10-min anoxia group showed a transient depression of locomotor activity in response to a low dose (0.25 g/kg) of intraperitoneal ethanol, which had no effect on locomotion in vaginally born controls. These results indicate that a relatively subtle alteration in birth condition, compatible with grossly normal development and behavior, is sufficient to alter ethanol preference in the adult rat.

Animals↗
PubMed1998

Birth insult increases amphetamine-induced behavioral responses in the adult rat.

We have previously reported that an apparently uncomplicated Caesarean section birth produces long-term alterations in steady-state levels of dopamine in the central nervous system of the rat. In addition, adult rats that had been born by Caesarean section, either with or without acute global anoxia, showed markedly greater dopamine release from the nucleus accumbens in response to repeated stress, in comparison to vaginally born controls. The aim of the present study was to test whether these birth complications also result in long-term changes in behavior mediated by dopamine systems. For this, we investigated effects of a low dose (0.5 mg/kg) of amphetamine on activity levels in three-month-old rats that had been born vaginally (control), by rapid Caesarean section, or by Caesarean section with 15 min of global anoxia. Amphetamine induced a significantly greater increase in locomotor activity in animals born by Caesarean section or by Caesarean section+ 15 min anoxia, in comparison to the drug's effects in vaginally born controls. Behavioral responses were further analysed from video recordings of the animals' behavior. In confirmation of automated activity counts, both animals born by Caesarean section and by Caesarean section + 15 min anoxia showed a significant increase in the duration and frequency of moving and a decrease in the duration and frequency of standing, in comparison to vaginally born controls. Animals delivered by Caesarean section showed a significant increase in the duration of sniffing and a decrease in the duration and frequency of grooming when compared to vaginally born controls. Animals delivered by Caesarean section + 15 min anoxia showed a significant increase in the duration and frequency of rearing, in comparison to controls. The pattern of behavioral changes observed indicates that, as adults, animals born by Caesarean section and by Caesarean section with added global anoxia both show heightened behavioral responses to amphetamine, in comparison to vaginally born animals. These findings highlight the sensitivity of dopamine pathways to variations in birth procedure and add experimental support to epidemiological evidence implicating birth complications in the pathophysiology of disorders involving central dopaminergic neurons, such as schizophrenia.

Animals↗
PubMed1998

Responses to stress and novelty in adult rats born vaginally, by cesarean section or by cesarean section with acute anoxia.

The aim of this study was to test the hypothesis that alterations in birth conditions, specifically vaginal birth vs. birth by Cesarean section (C-section) vs. birth by C-section with an added period of acute global anoxia, produces long-term differences in behavioral responses to stress or novelty in the rat at adulthood. In comparison to animals born by rapid C-section alone, animals born by C-section with 10 or 15 min of added anoxia were significantly more immobile during forced swim stress administered for 6 trials over several weeks. In a step-down passive avoidance task, there were no group differences in acquisition or retention of the avoidance response. However, when initially placed in the passive avoidance apparatus before delivery of shock, animals born by C-section with 15 min of anoxia required significantly more pretrials to step down from the wooden platform, than did vaginally born or C-sectioned animals. No group differences were observed on measures of exploratory behavior in an elevated plus-maze or of approach behavior either to food or to a novel object in an open field. These findings suggest that birth conditions which include a degree of perinatal hypoxia can contribute to variability in selective responses to stress and novelty in the adult rat.

Acute Disease↗
PubMed1997

Long-term reciprocal changes in dopamine levels in prefrontal cortex versus nucleus accumbens in rats born by Caesarean section compared to vaginal birth.

Epidemiological evidence indicates a higher incidence of pregnancy and birth complications among individuals who later develop schizophrenia, a disorder linked to alterations in mesolimbic dopamine (DA) function. Two birth complications usually included in these epidemiological studies, and still frequently encountered in the general population, are birth by Caesarean section (C-section) and fetal asphyxia. To test the hypothesis that birth complications can produce long-lasting changes in DA systems, the present study examined the effects of Caesarean birth, with or without an added period of anoxia, on steady state monoamine levels and metabolism in various brain regions in a rat model. Pups born vaginally served as controls. At 2 months of age, in animals born by rapid C-section, steady state levels of DA were decreased by 53% in the prefrontal cortex and increased by 40% in both the nucleus accumbens and striatum, in comparison to the vaginally born group. DA turnover increased in the prefrontal cortex, decreased in the nucleus accumbens, and showed no significant change in the striatum, in the C-section group. Thus, birth by a Caesarean procedure produces long-term reciprocal changes in DA levels and metabolism in the nucleus accumbens and prefrontal cortex. This is consistent with the known inhibitory effect of increased prefrontal cortex DA activity on DA release in the nucleus accumbens. By contrast to birth by rapid C-section alone, young adult animals, that had been born by C-section with 15 min of added anoxia, showed no change in steady state DA levels in the prefrontal cortex, nucleus accumbens, or striatum and a significant decrease in DA turnover only in the nucleus accumbens, in comparison to the vaginally born group. Levels of norepinephrine, serotonin, and its metabolite, 5-hydroxyindole acetic acid, were unchanged in all groups, indicating relatively specific effects on DA systems. Although appearing robust at birth on gross observation, more subtle measurements revealed that rat pups born by C-section show altered respiratory rates and activity levels and increased levels of whole brain lactate, suggestive of low grade brain hypoxia, during the first 24 h of life, in comparison to vaginally born controls. Pups born by C-section with 15 min of added acute anoxia were pale, hypotonic, and inactive at birth and showed reduced respiration and high brain lactate levels. However, these alterations resolved by 1-5 h after birth and, with few exceptions, animals in the anoxic group remained normal with respect to these parameters during the remainder of the first 24 h of life. Immediately after birth, levels of plasma epinephrine, a hormone known to play a role in neonatal adaptation to extrauterine life and protection against hypoxia, were decreased in pups born by C-section but increased in pups born by C-section with 15 min added anoxia, in comparison to levels measured in vaginally born controls. These early developmental alterations could contribute to long-term alterations in dopaminergic parameters observed in rats born by C-section, with or without added anoxia. It is concluded that C-section birth is sufficient perturbation to produce long-lasting effects on DA levels and metabolism in the central nervous system of the rat. These findings highlight the sensitivity of DA pathways to variations in birth procedure and support the notion that birth complications might contribute to the pathophysiology of disorders involving central dopaminergic neurons, such as schizophrenia.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1997

Effects of perinatal anoxia on the acute locomotor response to repeated amphetamine administration in adult rats.

We examined the possibility that anoxia at birth can alter behavioral sensitization to amphetamine during adulthood. Male rats born either vaginally or by Cesarean section with or without an additional 15-min period of anoxia received five once-daily injections of either d-amphetamine (2.0 mg/kg, i.p.) or vehicle or no pretreatment. One week later, all animals received a challenge injection of amphetamine (0.5 mg/kg, i.p.). The data indicate that all three birth groups of animals pretreated with amphetamine had sensitized equally to the drug's behavioral effect. Of animals pretreated with saline, however, only those born by Cesarean section with added anoxia displayed a sensitized response to amphetamine, suggesting that the stress of daily injection was sufficient to sensitize these animals to amphetamine. These findings provide experimental support for clinical evidence implicating obstetric complications, such as perinatal anoxia, in the pathophysiology of schizophrenia.

Animals↗
PubMed1997

Influence of perinatal factors on the nucleus accumbens dopamine response to repeated stress during adulthood: an electrochemical study in the rat.

Evidence from animal studies suggests that a period of anoxia to the fetus, a consequence common to many birth complications, results in long-term alterations in ventral mesencephalic dopamine function. Long-term functional changes in these dopamine neurons, in particular those that innervate the nucleus accumbens, also occur when animals are repeatedly stressed. In the present study, we examined the possibility that a period of anoxia during a Cesarean section birth can later alter the development of stress-induced sensitization of dopamine transmission in the nucleus accumbens. Dams were decapitated on the last day of gestation and the entire uterus was removed by Cesarean section. Pups were then delivered either immediately (Cesarean section group) or were immersed in a 37 degrees C saline bath for 3.5 or 13.5 min (Cesarean section+anoxia groups) before delivery of the pups. A fourth group of pups that were born vaginally served as controls (Vaginal group). Three to four months postnatally, animals from each group were implanted with monoamine-selective carbon-fiber electrodes into the nucleus accumbens. Voltammetry was used to monitor the dopamine response to each of five consecutive, once daily, 15-min exposures to tail-pinch stress. The results show that the first exposure to stress elicited dopamine signal increases of comparable amplitudes and durations in all animals. However, when compared to the initial stress response, the fourth and fifth exposures to tail-pinch elicited significantly longer-lasting dopamine responses in animals born by Cesarean section, either with or without added anoxia. In contrast, there was no significant day-to-day enhancement of the stress response in control, vaginally born animals. The findings reported here provide experimental support for the idea that birth complications may contribute to the pathophysiology of psychiatric disorders, in particular those that involve central dopamine dysfunction, such as schizophrenia. Specifically, our results suggest that subtle alterations in birth procedure may be sufficient to increase the sensitivity of mesolimbic dopamine neurons to the effects of repeated stress in the adult animal.

Age Factors↗
PubMed1997

Early developmental profiles of plasma corticosterone are altered by birth condition in the rat: a comparison of vaginal birth, cesarean section, and cesarean section with added anoxia.

Circulating glucocorticoids play a role during the immediate postnatal period in adapting the neonate to extrauterine life and are also thought to influence tissue development and function in the later postnatal period. In the present study we have used a rat model to test whether birth by cesarean section (C-section), either alone or with an added period of acute anoxia, affects the development profile of basal corticosterone secretion during the first 5 wk of life. Plasma levels of total corticosterone and of corticosteroid-binding globulin were measured at various times after birth in rats born vaginally, by C-section, or by C-section with 15 min of added anoxia. These measures allowed for calculation of levels of free, biologically active, corticosterone. Under all conditions, total corticosterone appeared to accurately reflect levels of free corticosterone. Plasma corticosterone levels measured immediately (< 5 min) after birth were similar in male rat pups born vaginally, by C-section, or by C-section with added anoxia, whereas female pups born by C-section showed a significant increase in free corticosterone at birth, in comparison with vaginally born females. Both male and female animals born by C-section showed a reduction in plasma corticosterone at 1 h (male: 31% of control, p < 0.01; female: 45% of control, p < 0.05) and at 7 d (male: 61% of control, p < 0.01; female: 55% of control, p < 0.05) after birth, in comparison with vaginally born controls. In animals born by C-section with added anoxia, significant reductions in plasma corticosterone were observed for males at 1 h (58% of control; p < 0.05) and for females at 7 d (62% of control; p < 0.05) after birth. At 14 d of age, corticosterone levels were higher in male rats born by C-section either with (227% of control; p < 0.05) or without (239% of control; p < 0.05) added anoxia, in comparison with vaginally born controls. Thus C-section birth produces an early rise in plasma corticosterone on d 14 away from the low values associated with the adrenal quiescent period in the first 1-2 wk in the rat. By 35 d of age, there were no differences in plasma corticosterone attributable to C-section birth and/or acute birth anoxia, in either male or female rats. It is concluded that, in a rat model, birth by C-section has significant effects on the profile of plasma corticosterone during the early weeks of development, a period though to be critical for effects of corticosteroids on developing tissues. Because the rat at birth is developmentally less mature than is the term human neonate, these findings may have implications for development of the premature human neonate.

Animals↗
PubMed1996

Hippocampal and hypothalamic type I corticosteroid receptor affinities are reduced in adult rats born by a caesarean procedure with or without an added period of anoxia.

Brief periods of hypoxia during labour and birth are a frequent occurrence. Within the CNS, the hippocampus is known to be particularly vulnerable to the damaging effects of hypoxia/ischaemia in both adult and immature animals. The hippocampus also contains the highest concentration of corticosteroid receptors of any brain region and both mineralocorticoid (type I) receptors and glucocorticoid (type II) receptors in the hippocampus play a role in the regulation of basal diurnal and stress-induced glucocorticoid secretion. Given this background, the aim of this study was to test whether an acute period of anoxia during the birth process may have lasting effects on CNS corticosteroid receptor levels and/or pituitary-adrenocortical function. Type I and type II corticosteroid receptor binding sites in the hippocampus and hypothalamus were compared in adult rats that had been born vaginally, born by a Caesarean procedure or born by a Caesarean procedure with 5, 10 or 15 min of added anoxia. Using 14 nM [3H]corticosterone as radioligand, mineralocorticoid receptor binding was reduced by approximately 50% in the hippocampus and hypothalamus of adult rats that had been born by the Caesarean procedure either with or without an added period of anoxia, in comparison to vaginally born controls. Saturation analysis revealed that these reductions resulted from decreases in affinity of the mineralocorticoid receptor for [3H]corticosterone, with no change in numbers of receptors. Birth condition had no effect on glucocorticoid receptor binding capacities in the hippocampus or hypothalamus. A small increase in basal corticosterone secretion during the diurnal trough was observed in adult animals that had been born by Caesarean section with 5 or 15 min of added anoxia. The plasma corticosterone response to a 20-min restraint stress was reduced in adult animals born by Caesarean section with or without an added period of anoxia, in comparison to vaginally born controls. However the adrenocorticotropin response to stress was largely unaffected by birth condition. The results indicate that an acute birth insult is sufficient to produce long-lasting alterations in hippocampal and hypothalamic mineralocorticoid receptor sites, accompanied by changes in basal and stress-induced glucocorticoid secretion.

Adrenocorticotropic Hormone↗
PubMed1995

Increased levels of statin, a marker of cell cycle arrest, in response to hippocampal neuronal injury.

Injured neurons in the CNS are known to synthesize high levels of proliferation related oncogene products and heat shock proteins without dividing. Statin is a cell cycle regulated nuclear phosphoprotein, selectively associated with the non-proliferative state in a wide variety of cell types. In the present study, neuronal statin was examined following lethal or sublethal neuronal injuries in the hippocampus of Alzheimer's disease patients, in rats receiving kainate lesions to the dorsal hippocampus and in entorhinal cortex lesioned rats. Immunolabelling of nuclear statin showed that statin immunoreactivity increased preferentially in CA1 pyramidal neurons of the hippocampus in Alzheimer's disease. In kainate lesioned rats, statin immunoreactivity was markedly induced in the CA3 hippocampal region in association with neuronal loss. Entorhinal cortex lesioned rats showed a transient induction of statin between 2 and 6 days post lesion in CA1 neurons. However, cell counts in entorhinal cortex lesioned rats remained unaltered in the CA1 and granule cell layers during the entire 30 day time course, indicating that increased statin levels are not secondary to neuronal degeneration and are not necessarily accompanied by irreversible neuronal death. It is concluded that, in addition to proliferation related gene products, neuronal injury induces an increase in levels of statin, a nuclear marker of cell cycle arrest. Furthermore, statin may be a potentially useful marker of injurious neuronal stress, even under conditions that do not necessarily lead to irreversible cell death.

Alzheimer Disease↗
PubMed1995

Effects of chronic intermittent cold stress on pituitary adrenocortical and sympathetic adrenomedullary functioning.

Basal and stress-induced pituitary-adrenocortical (PA) and sympathetic adrenomedullary (SAM) function was investigated in rats exposed to chronic intermittent cold stress (4 degrees C for 4 h a day for 21 days; CHR). We found that basal plasma levels of corticosterone (B), corticosteroid-binding-globulin, ACTH, epinephrine (E) and norepinephrine (NE) were similar in CHR and control (CTL) animals. In contrast, activity of the adrenal catecholamine-synthesizing enzyme tyrosine hydroxylase, but not phenylethanolamine-N-methyl transferase, was significantly elevated in CHR compared to CTL. Following exposure to a heterotypic stressor (20 min restraint), plasma levels of B were significantly higher in CHR than CTL, but the stress-induced levels of E and NE were not different between groups. These data suggest that, although basal PA function is not altered by exposure to chronic intermittent cold stress, components of the SAM system are affected by this paradigm, and that co-ordinate facilitation of both PA and SAM responses to a novel stressor is not a necessary consequence of exposure to chronic intermittent stress.

Adrenal Medulla↗
PubMed1995

Effects of a period of asphyxia during birth on spatial learning in the rat.

The present study aimed to test whether an acute period of asphyxia during birth in the rat results in long-term alterations in CNS function. Morphologic studies have indicated that the hippocampus is particularly vulnerable to perinatal anoxia. Thus, the present study tested adult rats, which had undergone acute birth asphyxia, for their performance in spatial learning and memory tasks associated with the hippocampus. Rat fetuses on the day of birth were submitted to an acute period of complete asphyxia by submersion of the isolated uterus into a water bath for 5-20 min before delivery of the pups. Control animals were either born vaginally or delivered by rapid cesarean section. At 1.5 mo of age, rats that had undergone 15 min of birth asphyxia showed no deficit in acquisition of spatial learning, measured as latency to find a hidden platform in the Morris water maze. However, at 4 mo of age, separate groups of rats, which had undergone 10, 15, or 20 min of birth asphyxia, showed a deficit in initial acquisition of the spatial learning task compared with vaginally born controls, whereas the 5-min group performed similarly to controls. After overtraining, there was no difference among groups on short-term (1 wk) retention of the spatial navigation task; however, asphytic animals tested at 1.5 mo and retested at 4 mo showed a slight deficit in retention on retest. Animals that had undergone 15 min of birth asphyxia weighed less than did vaginally born animals, but showed no deficit in swimming ability, spontaneous alternation in a T maze, or other sensorimotor indices.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

GABAA receptor-mediated inhibition of N-methyl-D-aspartate-evoked [3H]dopamine release from mesencephalic cell cultures.

Direct activations of both GABAA and GABAB receptors are known to hyperpolarize dopaminergic neurons. However systemic or intra-ventral tegmental administration of a GABAA receptor agonist produces paradoxical depolarization of mesencephalic dopaminergic neurons and increases dopamine release. Thus indirect excitation appears to preclude observation of inhibitory GABAA effects on dopamine release in intact tissue. The present study used cultures of isolated cells from rat ventral mesencephalon to characterize effects of GABAA and GABAB receptor activation on evoked dopamine release. The GABAA receptor agonist, muscimol, produced a potent and complete inhibition of N-methyl-D-aspartate (NMDA)-evoked [3H]dopamine release. This effect was blocked by the GABAA receptor antagonist, picrotoxin, and enhanced by flunitrazepam. Omission of Mg2+ greatly reduced the inhibitory effect of muscimol on NMDA-evoked [3H]dopamine release. Muscimol had little or no effect on [3H]dopamine release evoked by the non-NMDA receptor agonists, quisqualate and kainate. The GABAB receptor agonist, baclofen, slightly inhibited NMDA-evoked [3H]dopamine release and had no effect on release evoked by quisqualate or kainate. Endogenous GABA released by the mesencephalic cells also appeared to inhibit NMDA-evoked [3H]dopamine release mainly via a GABAA receptor-mediated mechanism. This is suggested by the observations that NMDA-evoked [3H]dopamine release was potentiated by picrotoxin but not by the GABAB receptor antagonist, phaclofen, and that blockade of extracellular GABA removal, with amino-oxyacetic acid and beta-alanine, inhibited NMDA-evoked [3H]dopamine release in a picrotoxin-sensitive manner.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Statin, a marker of cell cycle arrest, is overexpressed during the early phase of delayed NMDA toxicity in hippocampal cell cultures.

Statin is a 57-kDa protein exclusively expressed in nuclei of nonproliferating mammalian cells. Recent studies have suggested that statin may play a role in the maintenance of growth arrest. Several lines of evidence also support the notion that a variety of genes and gene products are modulated during cell proliferation and cell death. The present study examined the possibility that statin expression could be modulated during neuronal injury using N-methyl-Daspartate (NMDA)-induced toxicity to rat embryonic hippocampal cultures as a model. Immunocytochemical studies using a monoclonal antibody to statin revealed a prominent nuclear localization of statin in cultured hippocampal cells. Western blot analysis showed that this antibody recognizes a 57-kDa protein band, indicative of the presence of statin in this preparation. Brief exposure of hippocampal neurons to NMDA (500 microM) produced severe neuronal degeneration over the subsequent hours. NMDA-treated neurons markedly overexpressed statin. Both NMDA-induced neuronal toxicity and statin overexpression were prevented by the NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohept-5,10-imine hydrogen maleate (MK-801). Interestingly, time course studies indicate that the increased expression of statin observed following NMDA exposure clearly preceded the appearance of the first signs of neuronal death as determined by vital staining. In addition, exposure of hippocampal neurons to the Ca2+ ionophore, A23187, produced a marked increase in statin immunodetection, indicating that statin expression is likely regulated in a Ca(2+)-dependent manner. Thus, these results show that statin, which is expressed at low levels in embryonic rat cultured hippocampal neurons, is rapidly overexpressed following a toxic insult produced by the activation of the NMDA receptor. The observation that statin overexpression occurs prior to neuronal death raises the possibility that the up-regulation of statin could be used as an early index of neuronal injury.

Animals↗
PubMed1994

The pharmacology of the nicotinic antagonist, chlorisondamine, investigated in rat brain and autonomic ganglion.

1. A single administration of the ganglion blocker, chlorisondamine (10 mg kg-1, s.c.) is known to produce a quasi-irreversible blockade of the central actions of nicotine in the rat. The mechanism of this persistent action is not known. It is also unclear whether chlorisondamine can block neuronal responses to excitatory amino acids and whether chronic blockade of nicotinic responses also occurs in the periphery. 2. Acute administration of chlorisondamine (10 mg kg-1, s.c.) to rats resulted in a blockade of central nicotinic effects (ataxia and prostration) when tested 1 to 14 days later, but caused no detectable cell death in tissue sections sampled throughout the rostrocaudal extent of the brain which were stained in order to reveal neuronal degeneration. 3. Long-term blockade of central nicotinic effects by chlorisondamine was not associated with significant alterations in the density (Bmax) of high-affinity [3H]-nicotine binding to forebrain cryostat-cut sections. 4. In cultured dissociated mesencephalic cells of the foetal rat, chlorisondamine and mecamylamine inhibited [3H]-dopamine release evoked by N-methyl-D-aspartate (NMDA, 10(-4) M), but only at high concentrations (IC50 approx. 600 and 70 microM, respectively). A high concentration of chlorisondamine (10(-3) M) had no effect on responses to quisqualate (10(-5) M) and only slightly reduced responses to kainate (10(-4) M). Mecamylamine (10(-3) M) was ineffective against both agonists. 5. In adult rat hippocampal slices, chlorisondamine depressed NMDA receptor-mediated synaptically-evoked field potentials, but again only at high concentrations (10(-4)-10(-3) M). Synaptic responses that were mediated by non-NMDA excitatory amino acid receptors were less affected. 6. In rat isolated superior cervical ganglion, electrically-evoked synaptic transmission was reduced 1 h after acute in vivo administration of chlorisondamine (0.1 mg kg-1, s.c.). However, in vivo administration of a higher dose (10 mg kg-1, s.c.) did not significantly affect ganglionic transmission when tested two weeks later, despite the continued presence of central nicotinic blockade.7. These results indicate that the persistent CNS nicotinic blockade by chlorisondamine is not accompanied by changes in nicotinic [3H]-nicotine binding site density or by neuronal degeneration in the brain; that at doses sufficient to produce nicotinic receptor blockade, chlorisondamine acts in a pharmacologically selective manner; and that chronic central blockade is not accompanied by long-term peripheral ganglionic blockade.

Amino Acids↗
PubMed1994

Regulation of the adrenomedullary catecholaminergic system after mild, acute stress.

The time course of regulation of rat adrenomedullary phenylethanolamine N-methyltransferase (PNMT) and tyrosine hydroxylase (TH) activity was studied after a single episode of 20-min restraint stress. Significant increases in PNMT and TH activity were observed 18 h after the beginning of the stress. The time course of acute stress-induced regulation of PNMT and TH was examined for the influence of neural and hormonal input. Unilateral denervation was performed, and the animals were exposed to a single episode of restraint. PNMT activity increased similarly in both the innervated and denervated adrenals, with a significant increase observed at 36 h after the stress. TH activity was similar in both denervated and innervated adrenals, with a significant increase observed at 24 and 36 h after stress. Finally, suppression of endogenous corticosterone with dexamethasone delayed the stress-induced increase in activity of PNMT but not TH. The present study indicates that increases in catecholamine biosynthetic enzymes can be observed after a single episode of mild, acute stress. In addition, glucocorticoids appear to be important in the time course of the stress-induced increase in PNMT but not TH activity, whereas neural input does not seem to affect the time course of these increases.

Acute Disease↗