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Biomedical subjects

C J Price

Publications and source records attributed to C J Price.

At least 91 records · Page 5Linked to original sources
PubMed1996

Evaluation of the developmental toxicity of methacrylonitrile in Sprague-Dawley rats and New Zealand white rabbits.

Timed-pregnant Sprague-Dawley (CD) outbred rats and New Zealand White rabbits were dosed by gavage with methacrylonitrile (MACR) in distilled water during major organogenesis. Rats were dosed on Gestational Days (GD) 6 through 15 (0, 5, 25, or 50 mg MACR/kg/day) and rabbits on GD 6 through 19 (0, 1, 3, or 5 mg MACR/kg/day). Maternal clinical status was monitored daily during treatment. At termination (GD 20, rats; GD 30, rabbits), confirmed-pregnant females (25-26 per group, rats; 17-22 per group, rabbits) were evaluated for clinical status and gestational outcome; each live fetus was examined for external, visceral, and skeletal malformations. In rats, no treatment-related maternal clinical signs or mortality were observed, nor was there any adverse effect on maternal body weight or food or water consumption. At necropsy, absolute, relative, and adjusted maternal liver weight was increased at the mid- and high-dose groups, an effect that may be indicative of induction of hepatic enzymes rather than toxicity. In the absence of any indication of maternal toxicity, the no-observed-adverse-effect level (NOAEL) for maternal toxicity in this study was >/=50 mg MACR/kg/day. The NOAEL for developmental toxicity in rats was also >/=50 mg MACR/kg/day. There was no effect of treatment on postimplantation loss, mean fetal body weight per litter, or morphological development. In rabbits, maternal mortality and clinical signs were not dose related. Maternal food consumption, body weight, and liver weight were not adversely affected by treatment. Thus, the maternal NOAEL was >/=5 mg MACR/kg/day. Maternal toxicity, including death, was observed >/=7.5 mg/kg/day in preliminary studies. The developmental NOAEL was also >/=5 mg MACR/kg/day. There was no adverse effect of treatment on postimplantation loss or fetal body weight. A significant decrease in the percentage male fetuses per litter was observed, although there was no effect on total live litter size, suggesting that the reduction in the ratio of live male fetuses in the high-dose group was not biologically significant. MACR had no adverse effect on morphological development. In summary, oral administration of MACR to rats and rabbits during organogenesis, at doses that did not cause persistent maternal toxicity (50 mg MACR/kg/day, rats; 5 mg MACR/kg/day, rabbits), also did not cause any adverse developmental effects.

Abnormalities, Drug-Induced↗
PubMed1996

The effect of varying stimulus rate and duration on brain activity during reading.

The effect of the presentation rate and exposure duration of visually presented words on brain activity was investigated using positron emission tomography. Subjects either read aloud or silently mouthed the names of words. In regions associated with early visual analysis, activity increased with both rate and duration; in regions associated with response generation, activity increased with increasing rate but was unaffected by duration; and in regions associated with word recognition, activity decreased with increasing duration. The variable responses of different brain regions illustrate the functional segregation of these regions. Of particular interest was the dissociation between activity in the posterior fusiform gyri and that in the medial lingual gyrus--in the former, activity increased with rate and duration but the latter was unaffected by either variable. This finding suggests that word processing in the lingual gyrus during reading is distinct from that in the posterior fusiform gyri. A further observation was that during reading aloud, when subjects can hear the sound of their own voice, the response in the primary auditory cortices increased with stimulus rate, demonstrating that subjects process the sound of their own voice in a qualitatively similar way to words spoken by another.

Adult↗
PubMed1996

The trouble with cognitive subtraction.

In this paper we present a critique of pure insertion. Pure insertion represents an implicit assumption behind many (but not all) studies that employ cognitive subtraction. The main contention is that pure insertion is not valid in relation to the neuronal instantiation of cognitive processes. Pure insertion asserts that there are no interactions among the cognitive components of a task. It is possible to evaluate and refute this assumption by testing explicitly for interactions using factorial experimental designs. It is proposed that factorial designs are more powerful than subtraction designs in characterizing cognitive neuroanatomy, precisely because they allow for interactions and eschew notions like pure insertion. In particular we suggest that the effect of a cognitive component (i.e., an effect that is independent of other components) is best captured by the main (activation) effect of that component and that the integration among components (i.e., the expression of one cognitive process in the context of another) can be assessed with the interaction terms. In this framework a complete characterization of cognitive neuroanatomy includes both regionally specific activations and regionally specific interactions. To illustrate our point we have used a factorial experimental design to show that inferotemporal activations, due to object recognition, are profoundly modulated by phonological retrieval of the object's name. This interaction implicates the inferotemporal regions in phonological retrieval, during object naming, despite the fact that phonological retrieval does not, by itself, activate this region.

Attention↗
PubMed1996

Detecting activations in PET and fMRI: levels of inference and power.

This paper is about detecting activations in statistical parametric maps and considers the relative sensitivity of a nested hierarchy of tests that we have framed in terms of the level of inference (voxel level, cluster level, and set level). These tests are based on the probability of obtaining c, or more, clusters with k, or more, voxels, above a threshold u. This probability has a reasonably simple form and is derived using distributional approximations from the theory of Gaussian fields. The most important contribution of this work is the notion of set-level inference. Set-level inference refers to the statistical inference that the number of clusters comprising an observed activation profile is highly unlikely to have occurred by chance. This inference pertains to the set of activations reaching criteria and represents a new way of assigning P values to distributed effects. Cluster-level inferences are a special case of set-level inferences, which obtain when the number of clusters c = 1. Similarly voxel-level inferences are special cases of cluster-level inferences that result when the cluster can be very small (i.e., k = 0). Using a theoretical power analysis of distributed activations, we observed that set-level inferences are generally more powerful than cluster-level inferences and that cluster-level inferences are generally more powerful than voxel-level inferences. The price paid for this increased sensitivity is reduced localizing power: Voxel-level tests permit individual voxels to be identified as significant, whereas cluster-and set-level inferences only allow clusters or sets of clusters to be so identified. For all levels of inference the spatial size of the underlying signal f (relative to resolution) determines the most powerful thresholds to adopt. For set-level inferences if f is large (e.g., fMRI) then the optimum extent threshold should be greater than the expected number of voxels for each cluster. If f is small (e.g., PET) the extent threshold should be small. We envisage that set-level inferences will find a role in making statistical inferences about distributed activations, particularly in fMRI.

Brain↗
PubMed1996

Noun and verb retrieval by normal subjects. Studies with PET.

PET activation studies identify significant local changes in regional cerebral blood flow (rCBF) in contrasts of behavioural tasks with control states, and these local changes identify net changes in local synaptic activity. A number of studies on word retrieval have all demonstrated left frontal (dorsolateral and medial) involvement in the task. However, there have been differences in the responses observed in the left temporal lobe, with variously a deactivation (significant decrease in rCBF), no response and an activation (significant increase in rCBF). In the four studies described here, we have examined word (verbs and nouns) retrieval contrasted with a number of different control states. The studies confirmed extensive activation of the left dorsolateral prefrontal cortex and, medially, the anterior cingulate cortex and the supplementary motor area (SMA). Activations of the left posterior temporal lobe and the inferior parietal lobe were consistently demonstrated when word retrieval was contrasted with a rest state. Contrasts with other single word tasks controlled out the activation in the perisylvian part of the left posterior temporal lobe, suggesting a role for this region in lexical processing. The left inferolateral temporal cortex and the posterior part of the inferior parietal lobe were only activated by word retrieval, particularly verbs. It is proposed that these activated regions reflect access to semantic fields.

Adult↗
PubMed1996

Hearing and saying. The functional neuro-anatomy of auditory word processing.

The neural systems involved in hearing and repeating single words were investigated in a series of experiments using PET. Neuropsychological and psycholinguistic studies implicate the involvement of posterior and anterior left perisylvian regions (Wernicke's and Broca's areas). Although previous functional neuroimaging studies have consistently shown activation of Wernicke's area, there has been only variable implication of Broca's area. This study demonstrates that Broca's area is involved in both auditory word perception and repetition but activation is dependent on task (greater during repetition than hearing) and stimulus presentation (greater when hearing words at a slow rate). The peak of frontal activation in response to hearing words is anterior to that associated with repeating words; the former is probably located in Brodmann's area 45, the latter in Brodmann's area 44 and the adjacent precentral sulcus. As Broca's area activation is more subtle and complex than that in Wernicke's area during these tasks, the likelihood of observing it is influenced by both the study design and the image analysis technique employed. As a secondary outcome from the study, the response of bilateral auditory association cortex to 'own voice' during repetition was shown to be the same as when listening to "other voice' from a prerecorded tape.

Auditory Perception↗
PubMed1996

Evans blue antagonizes both alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate and kainate receptors and modulates receptor desensitization.

The biphenyl derivative of 1,3-naphthalene disulfonic acid, known as Evans blue (EB), has been shown previously to specifically antagonize currents mediated by the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) subtype of glutamate receptors (1). In contrast, we demonstrate herein that EB potently inhibits glutamate-evoked currents mediated by the kainate-type receptor GluR6 (IC50 150 nM) as well as the AMPA-type receptor GluR1 (IC50 = 220 nM) in whole-cell patch clamp recordings from transfected human embryonic kidney 293 cells. In addition to diminishing GluR6-mediated peak current amplitude, EB significantly altered receptor desensitization by slowing the rate of onset by approximately 2-fold (1 microM EB), slowing the rate of recovery by approximately 2-fold (0.1 microM EB), and increasing the steady state to peak current amplitude ratio by approximately 50-fold (1 microM EB). Interestingly, relatively little EB inhibition of GluR6 currents was observed in recordings from cells pretreated with the lectin concanavalin A, which eliminates kainate receptor desensitization. Similarly, currents recorded from GluR1-transfected cells were also relatively insensitive to EB inhibition if desensitization was first blocked by cyclothiazide. Moreover, for both GluR6 and GluR1, EB inhibition of agonist-evoked current was largely reversed if transfected cells were subsequently exposed to concanavalin A or cyclothiazide, respectively. Although EB may not be as selective an antagonist as previously believed, the relationship between EB-induced peak current inhibition and effects on receptor desensitization may be useful in further elucidating structures or mechanisms involved in the rapid desensitization of AMPA- and kainate-type glutamate receptors.

Cell Line↗
PubMed1995

The evaluation of the developmental toxicity of hydrochlorothiazide in mice and rats.

Timed-pregnant CD-1 outbred albino Swiss mice and CD Sprague-Dawley rats were administered hydrochlorothiazide (HCTZ, USP) in corn oil by gavage during major organogenesis, Gestational Days (GD) 6 through 15. The doses administered were 0, 300, 1000, or 3000 mg/kg/day for mice and 0, 100, 300, or 1,000 mg/kg/day for rats. Maternal clinical status was monitored daily during treatment. At termination (GD 17, mice; GD 20, rats), confirmed pregnant females (20-27 per group, mice; 36-39 per group, rats) were evaluated for clinical status and gestational outcome; each live fetus was examined for external, visceral, and skeletal malformations. In mice, no maternal mortality was observed. However, clinical signs including dehydration, piloerection, lethargy, and single-day weight loss appeared to be dose-related. HCTZ had no effect on maternal weight gain or water consumption, gravid uterine weight, relative maternal liver weight, or relative maternal kidney weight. There was no definitive evidence of embryotoxicity or fetal toxicity for mice on GD 17. Thus, the no observed adverse effect level (NOAEL) for both maternal and developmental toxicity was 3000 mg/kg/day. In rats, HCTZ had no effect on maternal survival, clinical signs, or water consumption. Clinical signs were not dose-related. Maternal weight gain during treatment was depressed at 1000 mg/kg/day. Gravid uterine weight and relative maternal liver weight were unaffected. Relative maternal kidney weight was slightly (7-8%) increased at all dose levels, but there was no evidence of a dose response. Thus, the maternal NOAEL for rats was 300 mg/kg/day, based on decreased maternal weight gain during treatment at 1000 mg/kg/day.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Contrasting effects of letter-spacing in alexia: further evidence that different strategies generate word length effects in reading.

The reading behaviour of two alexic patients (SA and WH) is reported. Both patients are severely impaired at reading single words, and both show abnormally strong effects of word length when reading. These two symptoms are characteristic of letter-by-letter reading. Experiment 1 examined the pattern of errors when the patients read large and small words. Further experiments examined the effects of inter-letter spacing on word naming (Experiments 2a and 2b) and the identification of letters in letter strings (Experiment 3). For both patients, letter identification was better for widely spaced letters in letter strings, and this effect was most pronounced for the central letters in the strings. This is consistent with abnormally strong flanker interference in letter identification. However, inter-letter spacing affected word reading behaviour in the two patients in different ways. SA's word reading improved with widely spaced letters; WH's word reading was disrupted. This suggests that these patients adopted different strategies when reading words. We conclude that several reading behaviours can elicit word length effects, and that these different behaviours can reflect strategic adaptation to a common functional deficit in patients. We discuss the implications both for understanding alexia and for models of normal word identification.

Adult↗
PubMed1994

Assessment of the reproductive and developmental toxicity of pesticide/fertilizer mixtures based on confirmed pesticide contamination in California and Iowa groundwater.

Pesticides and fertilizers, as used in modern agriculture, contribute to the overall low-level contamination of groundwater sources. In order to determine the potential of pesticide and fertilizer mixtures to produce reproductive or developmental toxicity at concentrations up to 100 x the median level found in groundwater, we prepared and studied two mixtures of pesticides and a fertilizer (ammonium nitrate). One mixture containing aldicarb, atrazine, dibromochloropropane, 1,2-dichloropropane, ethylene dibromide, and simazine plus ammonium nitrate was considered to be a representative of groundwater contamination in California (CAL). The other, containing alachlor, atrazine, cyanazine, metolachlor, metribuzin, and ammonium nitrate, simulated groundwater contamination in Iowa (IOWA). Each mixture was administered in the drinking water of either Swiss CD-1 mice during a Reproductive Assessment by Continuous Breeding study or pregnant Sprague-Dawley rats (gd 6-20) at three dose levels (1x, 10x, and 100x) where 1x was the median concentration of each pesticide component as determined in the groundwater surveys in California or Iowa. Unlike conventional toxicology studies, the purpose of this study was to evaluate the health effects of realistic human concentrations. Thus, the testing concentrations are probably well below the maximally tolerated dose. Propylene glycol was used as the solubilizer for the pesticides in drinking water formulations in both studies. In the reproductive study, neither mixture caused any clinical signs of toxicity, changes in food or water consumption, or body weight in either F0 or F1 mice at doses up to 100x the median groundwater concentrations. There were no treatment-related effects on fertility or any measures of reproductive performance of either the F0 or the F1 generation mice exposed to either CAL or IOWA at up to 100x. Similarly, measures of spermatogenesis, epididymal sperm concentration, percentage motile sperm, percentage abnormal sperm, and testicular and epididymal histology were normal. In the developmental study, CAL- or IOWA-exposed females did not exhibit any significant treatment-related clinical signs of toxicity. No adverse effects of CAL or IOWA were observed for measures of embryo/fetal toxicity, including resorptions per litter, live litter size, or fetal body weight. CAL or IOWA did not cause an increased incidence of fetal malformations or variations. In summary, administration of these pesticide/fertilizer mixtures at levels up to 100-fold greater than the median concentrations in groundwater supplies in California or Iowa did not cause any detectable reproductive (mice), general, or developmental toxicity (rats).

Animals↗
PubMed1994

Brain activity during reading. The effects of exposure duration and task.

Brain activity during reading tasks was investigated using PET. The aim was to account for differences in the results of two previous studies [those of Petersen et al. (Science 1990; 249: 1041-4) and Howard et al. (Brain 1992; 115: 1769-82)] by systematically varying the type of reading task and the exposure duration of the word stimuli. Both variables strongly influenced patterns of brain activity. There were three types of task: (i) reading aloud; (ii) reading silently; and (iii) lexical decision on visually presented words and pseudowords. Reading aloud and reading silently engaged the left middle and superior temporal regions, confirming the important role of these areas in visual word processing. The areas principally engaged during lexical decision were the left inferior and middle frontal cortices and the supplementary motor area; activity in these areas suggests that the subjects were using a phonological strategy to perform the task. There was also a significant effect of exposure duration, with activity being greater for short (150 ms) exposure durations than for long (1000 ms or 981 ms) exposure durations. We conclude that until we understand how subtle variations in experimental design influence brain activity during reading tasks, the association of specific processing functions with individual anatomical areas activated during reading is premature.

Adult↗
PubMed1994

The developmental toxicity of boric acid in mice, rats, and rabbits.

Boric acid (BA) is a naturally occurring agent used in manufacturing processes and numerous consumer products. Because of the potential for both industrial and consumer exposure to boron-containing compounds, and the lack of developmental toxicity data, the National Toxicology Program evaluated the potential for boric acid to cause developmental toxicity in pregnant Swiss (CD-1) mice, Sprague-Dawley rats (n = 26-28/group), and New Zealand rabbits (n = 18-23/group). BA was provided in the feed to mice and rats at 0, 0.1, 0.2, or 0.4% throughout gestation to attain steady-state exposure as early as possible during development. Average doses (mg/kg/day) were 248, 452, or 1003 for mice, and 78, 163, or 330 in rats. A separate group of rats received 0.8% BA in the feed, or 539 mg/kg/day only on gestation days (gd) 6 to 15. Rabbits were given BA (0, 62.5, 125, or 250 mg/kg) by gavage administration on gd 6 to 19. Maternal body weight, food and/or water consumption and signs of toxicity were monitored at regular intervals. At termination, gd 17 (mice), 20 (rats), or 30 (rabbits), the uterus was examined to determine the number of resorptions, dead, or live fetuses. Fetuses were weighed and live fetuses were examined for external, visceral, and skeletal defects. Mouse dams exhibited mild renal lesions (> or = 248 mg/kg/day BA), increased water intake and relative kidney weight (1003 mg/kg/day BA), and decreased weight gain during treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities, Drug-Induced↗
PubMed1993

Presence and biological activity of a GnRH-like factor in the nervous system of Helisoma trivolvis.

Gonadotropin-releasing hormone (GnRH) constitutes a family of neuropeptides found throughout the vertebrates. Although a GnRH-like peptide has also been isolated from yeast (alpha-mating factor), the presence of GnRH has not been clearly demonstrated in invertebrate phyla. In this study, we tested the hypothesis that GnRH-like peptides are present and functional in the central nervous system (CNS) of the gastropod mollusc, Helisoma trivolvis. The presence of a GnRH-like peptide was examined by three methods: (1) in immunofluorescence studies with four different antibodies generated against several GnRH peptides, select neurons and putative neurosecretory cells were specifically and consistently labelled throughout the CNS; (2) reverse-phase high performance liquid chromatography (HPLC) and radioimmunoassay (RIA) analysis revealed a GnRH-like factor which co-migrates with mammalian (m)GnRH; and (3) in bioactivity experiments, extracts of Helisoma trivolvis CNS mimicked GnRH in stimulating gonadotropin release from dispersed goldfish pituitary cells in static culture. Two functional assays were carried out to examine the potential biological roles of GnRH-like peptides in Helisoma. (1) Intracellular recordings of left-parietal and visceral ganglion neurons revealed diverse electrophysiological responses to mGnRH. These effects were attenuated by a mGnRH antagonist. (2) Addition of mGnRH arrested neurite outgrowth in a subpopulation of dissociated embryonic Helisoma neurons in culture. Taken together, these results strongly suggest that a mGnRH-like peptide is an important neuropeptide in Helisoma. A hypothesis is presented that GnRH-like peptides may be ancient factors that are conserved both structurally and functionally in the evolution of animals.

Animals↗
PubMed1993

Developmental toxicity evaluation of diethyl and dimethyl phthalate in rats.

Diethyl phthalate (DEP) and dimethyl phthalate (DMP), phthalic acid ester (PAE) plasticizers, were evaluated for developmental toxicity because of reports in the literature that some PAE were embryotoxic and teratogenic. A previous study (Singh et al., '72) suggested that an increased incidence of skeletal defects in rats might result from gestational exposure to DEP (0.6-1.9 g/kg) or DMP (0.4-1.3 g/kg), ip, on gestational days (gd) 5, 10, and 15. In the current study DEP (0, 0.25, 2.5, and 5%) or DMP (0, 0.25, 1, and 5%) in feed (approximately 0.2-4.0 g/kg/day) were supplied to timed-mated rats from gd 6 to 15. Treatment with 5% DMP resulted in increased relative maternal liver weight. Also, animals exhibited reduced body weight gain during treatment (5% DEP or DMP) and during gestation (5% DEP). Weight gain corrected for gravid uterine weight was also reduced in animals fed 5% DEP. However, high-dose treatment with either DEP or DMP resulted in changes in food and water consumption paralleling the body weight reductions, suggesting that apparent toxic effects on maternal body weight may reflect PAE/feed unpalatability. Treatment with 2.5% DEP resulted in only transient changes in body weight during early treatment. The only maternal effects at 0.25 or 1% DMP were minor changes in food and/or water consumption, and there were no effects at 0.25% DEP. Thus, the NOAELs for maternal toxicity were 1% DMP and 0.25% DEP. In contrast to the observed maternal toxicity, there was no effect of DEP or DMP treatment on any parameter of embryo/fetal development, except an increased incidence of supernumerary ribs (a variation) in the 5% DEP group. These results do not support the conclusion of other investigators that DEP and DMP are potent developmental toxicants. Rather, they suggest that the short-chain PAE are less developmentally toxic than PAE with more complex substitution groups, e.g., di(2-ethylhexyl) phthalate, mono(2-ethylhexyl) phthalate, and butyl benzyl phthalate.

Abnormalities, Drug-Induced↗
PubMed1993

Developmental toxicity evaluation of ethylene glycol by gavage in New Zealand white rabbits.

Artificially inseminated New Zealand white (NZW) rabbits were administered ethylene glycol (EG) by gavage on Gestational Days (GD) 6 through 19 at doses of 0, 100, 500, 1000, or 2000 mg/kg/day, with 23-24 inseminated animals per group. Clinical signs were recorded and water consumption was measured daily; does were weighed on GD 0, 6-19, 25, and 30. At necropsy (GD 30), maternal liver, kidney, and gravid uterine weights were recorded. Histopathologic examination was performed on kidneys from 10 does/dose and for all unscheduled deaths. Ovarian corpora lutea were counted and uterine implantation sites (total sites, resorptions, dead and live fetuses) were recorded. All live fetuses were weighed, sexed, and examined for external, visceral, and skeletal malformations and variations. EG resulted in profound maternal toxicity at 2000 mg/kg/day (42% mortality; three early deliveries and one spontaneous abortion) associated with renal pathology and unaccompanied by any other indicators of maternal toxicity. Renal lesions at 2000 mg/kg/day involved the cortical renal tubules and included intraluminal oxalate crystals, epithelial necrosis, and tubular dilatation and degeneration. No dose-related maternal toxicity occurred at 100-1000 mg/kg/day. There was no indication of developmental toxicity at any dose tested, including no effects on pre- or postimplantation loss, number of fetuses, fetal body weight, or sex ratio (% male fetuses) per litter, and no evidence of teratogenicity. The "no observable adverse effect level" (NOAEL) for maternal toxicity was therefore 1000 mg/kg/day and the NOAEL for developmental toxicity was at least 2000 mg/kg/day in this study. The sensitivity of NZW rabbits relative to that of Sprague-Dawley rats and Swiss mice for maternal and developmental toxicity from gavage administration of EG during organogenesis can be determined for maternal toxicity: rabbits > mice > rats, and for developmental toxicity, mice >> rats >> rabbits.

Animals↗
PubMed1993

Voltage-activated ionic currents in goldfish pituitary cells.

The release of gonadotropin and growth hormone from goldfish pituitary cells has been shown to be dependent on the entry of extracellular Ca2+ through voltage-sensitive Ca2+ channels by pharmacological studies. As a first step to further investigate the involvement of voltage-dependent ion channels in the regulation of anterior pituitary hormone release in the goldfish, cell excitability and voltage-dependent ion currents were characterized using tight-seal whole-cell recordings in dispersed goldfish pituitary cells. Cultured goldfish pituitary cells had an average membrane potential of -36 +/- 3 mV. When held at membrane potentials more negative than -60 mV, these cells were excitable, responding to depolarizing current pulses or anode break with the firing of single action potentials. Results from total current voltage-clamp recordings suggested that all goldfish pituitary cells possess voltage-dependent Na+, Ca2+, and K+ currents. These currents were further characterized independently under isolated current recording conditions. The rapid, transient Na+ current activated at voltages more positive than -40 mV and was sensitive to tetrodotoxin. The steady state inactivation of this Na+ current was also voltage-dependent; at the measured resting potential, > or = 50% of the Na+ current was not available for activation. The voltage-dependence and activation kinetics of the tetraethylammonium-sensitive K+ current resembled those of the delayed rectifier K+ current. The K+ current activated slowly at potentials more positive than -40 mV, and showed little inactivation over the duration of a 1-sec depolarizing pulse. Steady-state inactivation characteristics indicated that < 50% of the K+ current was inactivated at resting potentials. Experiments with 4-aminopyridine indicated the presence of an early transient K+ current that activated in a similar voltage range as the delayed rectifier current. Using barium as the charge carrier to measure Ca2+ currents, a high-voltage activated, long-lasting Ca2+ current was revealed. This "L-type" Ca2+ current activated at potentials more positive than -30 mV and was inhibited by verapamil and nifedipine. This study indicates that goldfish pituitary cells possess the electrophysiological properties required for the participation of voltage-sensitive ion channels in the regulation of hormone release.

4-Aminopyridine↗
PubMed1993

Serotonin activation of a cyclic AMP-dependent sodium current in an identified neuron from Helisoma trivolvis.

The mechanisms by which neurotransmitters regulate neurite extension and growth cone motility have been extensively studied using identified Helisoma neurons regenerating in cell culture. Specific neurons, such as buccal neuron B19, display a complex response to the addition of 5-HT involving the generation of action potentials, influx of extracellular calcium, and cessation of neurite extension and growth cone motility. While several studies have addressed the role of calcium in this cascade, little is known about the mechanism underlying the 5-HT-induced excitation of neuron B19. Therefore, we have begun to characterize the ion currents, receptors, and second messengers involved in the 5-HT-dependent depolarization of B19. Exposure of B19 to 5-HT resulted in the activation of a maintained inward current. Ion substitution experiments revealed that this current was carried mainly by sodium ions. The use of 8-bromo-cAMP, forskolin, or the phosphodiesterase inhibitor isobutyl methylxanthine (IBMX) to increase intracellular cAMP levels all resulted in inward current activation in the absence of 5-HT. Moreover, preloading the neuron with 8-bromo-cAMP was sufficient to prevent further current activation by 5-HT. In addition, the IBMX-activated current was greatly enhanced when induced in the presence of 5-HT. Protein kinase inhibitors failed to prevent 5-HT activation of sodium current, suggesting that cAMP may directly activate the current, independent of phosphorylation. Pharmacological experiments showed the B19 5-HT receptor has an EC50 of approximately 10(-7) M and can be activated by various indole analogs of 5-HT. Furthermore, methysergide displayed partial agonist activity.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-3-isobutylxanthine↗