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J S Kelly

Publications and source records attributed to J S Kelly.

At least 19 recordsLinked to original sources
PubMed1992

Action potential waveforms reveal simultaneous changes in ICa and IK produced by 5-HT in rat dorsal raphe neurons.

Action potentials were recorded from serotonergic dorsal raphe (DR) neurons acutely isolated from the adult rat brain. Action potential waveforms were used as command potentials for whole-cell patch-clamp studies to investigate the Ca2+ and K+ currents underlying action potentials and the modulatory effects of 5-Hydroxytryptamine (5-HT) on them. These data were compared with currents elicited by using rectangular voltage steps of the type commonly used in voltage-clamp experiments. In the same cell, 5-HT simultaneously augmented K+ currents and inhibited Ca2+ currents. Experimental conditions were chosen which allowed us to examine the action of 5-HT on K+ and Ca2+ currents simultaneously or in isolation; 5-HT produced a larger inhibition of calcium current during an action potential waveform compared with that measured by using rectangular steps of voltage. A possible explanation for this finding is that the maximal inhibition is seen immediately after a voltage jump and then decreases with time. Action potentials are, in general, so brief that little time-dependent relief of block is observed. Most of the inhibition of Ca2+ current resulted from a direct effect on Ca2+ channels rather than a shortening of the action potential. The inhibition of Ca2+ current by 5-HT also decreased the Ca(2+)-activated K+ currents. These results suggest that 5-HT reduces DR neuron excitability by the simultaneous activation of K+ channel currents open at the resting potential and the suppression of Ca2+ channel currents.

Action Potentials↗
PubMed1992

An intracellular study of the action of NAN-190 on neurons in the dorsal raphe nucleus of the rat.

Intracellular recordings have been made from neurons in the dorsal raphe (DR) nucleus of the rat to determine the mechanism of action of the arylpiperazine compound NAN-190. Application of NAN-190 (50 microM) alone most frequently caused a hyperpolarization accompanied by a fall in RM and reduced the response to 5-HT and 8-OH-DPAT. After pretreatment of the preparation with the 5-HT-uptake blocker citalopram (10 microM) NAN-190 exerted an excitatory effect. It is concluded that NAN-190 is a partial agonist in the DR nucleus.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1992

Ionic mechanisms mediating 5-hydroxytryptamine- and noradrenaline-evoked depolarization of adult rat facial motoneurones.

1. The actions of 5-hydroxytryptamine (5-HT) and noradrenaline (NA) on the membrane properties of facial motoneurones in slices from the adult rat brainstem in vitro were examined using intracellular recording techniques. 2. In voltage clamp recording, hyperpolarizing voltage steps (> 20 mV), from holding potentials at or close to the resting potential, induced a slowly activating, voltage-dependent inward current possessing properties similar to the hyperpolarization-activated current (Ih) seen in other cell types. From tail current analysis two groups of facial motoneurones can be distinguished in terms of the activation range for Ih, one with a half-maximal activation at -81 mV and the other at -94 mV but with similar shapes. 3. 5-HT (120/126) and NA (21/21) depolarized facial motoneurones. The reversal potentials (Em) obtained from peak voltage amplitude I-V plots in varying extracellular potassium concentrations suggested mechanisms involving a decrease in K+ conductance. 4. Under voltage clamp, close to the resting potential, both 5-HT (39/41) and NA (13/13) evoked inward currents. 5. I-V plots and plots of 5-HT-sensitive current at different membrane potentials, obtained from currents evoked by voltage steps and measured before the development of Ih (instantaneous current), indicated that the 5-HT-evoked inward current was predominately associated with a decrease in conductance but with a range of reversal potentials for 5-HT (E5-HT) from close to, to much more negative than the reversal potential for a potassium conductance (EK). In some cases no change or increases in instantaneous conductance were observed. 6. Steady-state I-V relationships and plots of 5-HT-sensitive current, measured after development of Ih, indicated a 5-HT-associated conductance increase with a time and voltage dependence close to that of Ih, which could be abolished by extracellular caesium (2-5 mM). 7. The NA-evoked inward current was always associated with a decrease in conductance. Instantaneous and steady-state I-V relationships as well as plots of NA-sensitive current indicated a reversal potential at EK. 8. The activation curve for Ih was shifted to more positive potentials in the presence of 5-HT. The time constant for activation of Ih showed a similar shift. 9. 5-Carboxamidotryptamine (5-CT), a 5-HT receptor agonist, was selective for the enhancement of Ih and only evoked an inward current when the holding potential was within the activation range of Ih.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Efficacy of the FEF colorimetric end-tidal carbon dioxide detector in children.

Direct laryngoscopy and observation of endotracheal tube (ETT) passage between the vocal cords remain the criterion standard for verifying endotracheal intubation. Detection of end-tidal carbon dioxide (ETCO2) serves as an invaluable adjunct to confirm endotracheal intubation, detect inadvertent esophageal intubation, and monitor for accidental tracheal extubation. Capnography, however, is often unavailable outside the operating suite. A commercially available, disposable, colorimetric ETCO2 detector (FEF, Fenem, Inc., New York, N.Y.), in which color changes using a numerical scale semiquantitatively measure percent carbon dioxide in exhaled gases, has proved effective in confirming endotracheal intubation in adults, but has not been thoroughly investigated in children. We studied 20 otherwise healthy children, aged 6 mo to 8 yr, with simultaneous infrared and colorimetric ETCO2 measurements during elective general anesthesia to evaluate the efficacy of the colorimetric detector. Two hundred of 200 tracheally intubated positive-pressure breaths and 198 of 200 breaths under spontaneous mask ventilation demonstrated a yellow color change (color level 5 or 6), signifying an ETCO2 greater than or equal to 15 mm Hg (2.0 kPa). Repeated-measures analysis of variance revealed no significant differences in infrared ETCO2 values between the two yellow color levels throughout the study period. The associations among color level, infrared ETCO2 determinations, ETT size, and ETT "leak" pressures estimated by Spearman rank correlation analysis were significant only for higher infrared ETCO2 values with higher ETT leak pressures (P less than 0.05). No complications were observed. The Fenem disposable colorimetric ETCO2 detector effectively confirms clinical signs of endotracheal intubation in children when capnography is unavailable.(ABSTRACT TRUNCATED AT 250 WORDS)

Carbon Dioxide↗
PubMed1991

Serotonin receptor heterogeneity and the role of potassium channels in neuronal excitability.

Intracellular recordings in vitro from a variety of central neuronal types have shown both inhibition and excitation to be modulatory consequences of serotonin (5-HT) receptor activation. These responses can be seen in isolation or in some cases (e.g. hippocampal pyramidal cells) as a complex biphasic combination of hyperpolarisation followed by depolarisation, suggesting overall control of neuronal excitability may be dependent on the interaction between activation of more than one post-synaptic receptor and/or mechanism. Our studies have confirmed the 5-HT evoked depolarisation of rat facial motorneurones (FM's) and the hyperpolarisation seen in presumed serotonergic neurones of the dorsal raphe nucleus (DRN) to be the result of opposite effects on K+ ion permeability. Suppression of a resting K+ conductance leads to depolarisation while activation leads to hyperpolarisation. The same mechanisms appear to be responsible for the 5-HT evoked responses in hippocampal pyramidal cells but in addition there is also a suppression of a Ca++ dependent K+ conductance responsible for the long spike after hyperpolarisation (AHP). Data from the hippocampus and DRN indicate the 5-HT induced hyperpolarisation to be sensitive to Pertussis Toxin (PTX) and irreversibly mimicked by GTP gamma S, a non-hydrolysable analogue of GTP, suggesting the involvement of a G protein in K+ channel activation. The mechanism of K+ channel closure is less clear as it is unaffected by PTX or activation of adenylate cyclase, however there is indirect evidence that the phosphoinositide pathway may be involved from the cloned 5-HT1C receptor which also closes a K+ channel in cell lines. The results show that hyperpolarisation evoked by 5-HT in the hippocampus and DRN to be mimicked and blocked by 5-HT1A agonists and antagonists. However, the depolarisations in the hippocampus and FM's are mediated by site-dependent receptors with profiles which do not fit into the current 5-HT receptor subtype classification.

Animals↗
PubMed1991

A study of the mechanism of Ca2+ current inhibition produced by serotonin in rat dorsal raphe neurons.

Calcium currents and their modulation by 5-HT were studied using both whole-cell and single-channel patch-clamp techniques in acutely isolated adult rat dorsal raphe neurons. Evidence for three types of Ca channels (T, N, L) was obtained in both whole-cell and single-channel experiments. Approximately 4% of the total high-threshold Ca current (L-type) was sensitive to dihydropyridines (DHPs) while approximately 40% of the Ca current (N-type) was sensitive to omega-conotoxin (omega-CgTx). About 56% of the whole-cell current was insensitive to either DHPs or omega-CgTx and may thus represent a different kind of Ca current. 5-HT reduced raphe neuron Ca currents by approximately 50%, while slowing activation. 5-HT inhibited both omega-CgTx-sensitive and -insensitive Ca current. Inhibition by 5-HT was voltage dependent; prepulses to +80 mV lasting for 20 msec almost completely abolished the 5-HT-mediated inhibition. The voltage dependence of the response to 5-HT suggested that trains of action potentials might overcome the inhibition due to 5-HT. Trains of brief depolarizations were used to simulate action potentials; only about 5% of the 5-HT-induced inhibition was relieved by the trains. These results suggest that while large depolarizations could restore the Ca current inhibited by 5-HT, physiological stimuli, such as trains of action potentials, could not. The action of 5-HT was made irreversible by inclusion of GTP-gamma-S in the patch pipette, suggesting a G-protein mediation of the response to 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Serotonin receptor activation reduces calcium current in an acutely dissociated adult central neuron.

The release of serotonin (5-HT) from the terminals of serotonergic (raphe) neurons is under inhibitory feed-back control. 5-HT, acting on raphe cell body autoreceptors, also mediates inhibitory postsynaptic potentials as a result of release from collaterals from neighboring raphe neurons. This may involve a ligand (5-HT)-gated increase in the membrane potassium conductance, leading to a decrease in action potential frequency, which could indirectly reduce calcium influx into nerve terminals. In this report we demonstrate that 5-HT can also directly reduce calcium influx at potentials including and bracketing the peak of calcium current activation. Using acutely isolated, patch-clamped dorsal raphe neurons, we found that low concentrations of 5-HT and the 5-HT1A-selective agonist 8-OH-DPAT reversibly decrease whole-cell calcium current. This effect is antagonized by the putative 5-HT1A-selective antagonist NAN 190. Hence, the inhibition of calcium current may serve a physiological role in these cells and elsewhere in the brain.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1990

Effects of selective monoamine oxidase inhibitors on the in vivo release and metabolism of dopamine in the rat striatum.

Brain microdialysis was used to examine the in vivo efflux and metabolism of dopamine (DA) in the rat striatum following monoamine oxidase (MAO) inhibition. Relevant catecholamines and indoleamines were quantified by HPLC coupled with a electrochemical detection system. The MAO-B inhibitor selegiline only affected DA deamination at a dose shown to inhibit partially type A MAO. Alterations in DA and metabolite efflux were not observed when using the MAO-B-selective dose of 1 mg/kg of selegiline. At 10 mg/kg, selegiline reduced the efflux of DA metabolites to approximately 70% of basal values without affecting DA efflux. K(+)- and veratrine-stimulated DA efflux was not affected by selegiline. Experiments using amphetamine and the DA uptake inhibitor nomifensine demonstrated that the effect of selegiline on DA metabolism was unlikely to be mediated either by inhibition of DA uptake or by an indirect effect of its metabolite amphetamine. The possibility that the effect of selegiline is mediated via a nonspecific inhibition of MAO is discussed. In contrast, the MAO-A inhibitor clorgyline inhibited basal DA metabolism and increased basal and depolarisation-induced DA efflux. A 1 mg/kg dose of clorgyline reduced basal DA metabolite efflux (40-60% of control values) without affecting DA efflux. At 10 mg/kg of clorgyline, DA efflux increased to 253 +/- 19% of basal values, whereas efflux of DA metabolites was reduced to between 15 and 26% of control values. The release of DA induced by K+ and veratrine was not affected by 1 mg/kg of clorgyline but was increased by approximately 200% following pretreatment with 10 mg/kg of clorgyline. The nonselective MAO inhibitor pargyline caused similar but more pronounced alterations in these parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphetamine↗
PubMed1990

In vivo mechanisms underlying dopamine release from rat nigrostriatal terminals: I. Studies using veratrine and ouabain.

The in vivo mechanisms underlying the dopamine (DA)-releasing actions of veratrine and ouabain in the striatum of halothane-anaesthetised rats have been investigated using brain microdialysis. Relevant catecholamines and indoleamines were separated and quantified using HPLC combined with an electrochemical detection system. Veratrine (10 micrograms/ml-1 mg/ml) and ouabain (10 microM-1 mM) were added to the medium perfusing the dialysis probes. Both compounds increased dialysate DA content in a dose-related manner. Dialysate levels of the DA metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid and the serotonin metabolite 5-hydroxyindoleacetic acid were reduced by both veratrine and ouabain. Veratrine-induced DA efflux was maximal in the first 20-min sample collected after drug infusion began, whereas the maximal effect of ouabain was not observed until 20-40 min after administration began. Veratrine-induced DA efflux was unaffected by systemic injection of the DA uptake inhibitor nomifensine but was inhibited by either coperfusion of tetrodotoxin (TTX) or removal of calcium from the perfusing buffer. These data suggest that veratrine induces release of DA via a carrier-independent mechanism, perhaps involving an exocytotic release process. In contrast, ouabain-induced DA release was reduced by nomifensine but was inhibited to a lesser degree by calcium depletion and TTX. Detailed analyses of these data suggest that although ouabain initially induces release of DA via a carrier-dependent mechanism, an exocytotic process may also be involved. The finding that ouabain-induced DA efflux exhibits a degree of TTX and calcium sensitivity suggests that membrane depolarisation caused by Na+,K(+)-ATPase blockade opens voltage-gated sodium channels and initiates an exocytotic release of DA. The intracellular pools of DA involved in the release of DA induced by veratrine and ouabain were also examined. Depletion of vesicular pools of DA by pretreatment with reserpine reduced the amount of DA release induced by both agents, although this effect was only significant in the case of veratrine. However, in reserpinised animals the residual amount of DA release induced by veratrine was inhibited by nomifensine, a result suggesting that DA may be released via a carrier-dependent process in the absence of vesicular DA. Newly synthesised pools of DA were also depleted by pretreatment with the DA synthesis inhibitor alpha-methyl-p-tyrosine. Under these conditions, both veratrine- and ouabain-induced DA efflux was reduced.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

In vivo mechanisms underlying dopamine release from rat nigrostriatal terminals: II. Studies using potassium and tyramine.

The brain microdialysis technique has been used to examine the in vivo effects of potassium and tyramine on dopamine (DA) release and metabolism in the striatum of halothane-anaesthetised rats. Increasing the concentration of potassium perfusing the dialysis probe (30-120 mM) induced a dose-related efflux of DA. A dose-related release of DA was also observed following addition of tyramine (1-100 microM) to the perfusing buffer. High concentrations of potassium were found to reduce the dialysate content of the DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid and the serotonin metabolite 5-hydroxyindoleacetic acid. No such effect was observed even when using the highest concentration of tyramine tested. Potassium-evoked DA release was facilitated by pretreatment with the DA uptake inhibitor nomifensine, was inhibited by depletion of extracellular calcium, and was not significantly affected by tetrodotoxin (TTX). The effect of tyramine on DA efflux was inhibited by nomifensine and was insensitive to both TTX and calcium depletion. These data suggest that potassium and tyramine induce release of DA via different mechanisms. Potassium-induced DA release involves a carrier-independent process and may utilise an exocytotic release mechanism. On the other hand, tyramine-induced DA release would appear to involve a carrier-dependent process. Depletion of vesicular stores of DA by pretreatment with reserpine did not significantly affect potassium-induced DA release, whereas a marked inhibition of the effects of tyramine was noted. However, in reserpinised animals the potassium-induced release of DA was inhibited by nomifensine, a result suggesting that a carrier-dependent release mechanism operates in the absence of vesicular DA.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

An intracellular study of grafted and in situ preoptic area neurones in brain slices from normal and hypogonadal mice.

1. Intracellular recordings have been obtained from forty-one preoptic area (POA) neurones at times up to 14 months after they were grafted into the third ventricle of the mouse. Thirty-one neurones were in grafts from hypogonadal (hpg) mice in which a reversal of the hypogonadism was seen (responders), six were in grafts from hpg mice in which no such reversal occurred (non-responders) and four were in grafts from normal mice. 2. The grafted neurones had a mean resting potential (Em) of -57 mV, a mean apparent input resistance (Rm) of 136 M omega and a mean membrane time constant (tau m) of 7.7 ms. The slopes of the current-voltage (I-V) relations were linear. Approximately a quarter of neurones in responders fired action potentials spontaneously either singly or in bursts. Such activity could underlie the release of gonadotrophin hormone-releasing hormone (GnRH) which is known to occur from such grafts. 3. Two types of response were seen when these neurones were depolarized to firing threshold from Em, in one group a single action potential was discharged; in the other group one or more action potentials arising from a transient, slowly rising and falling depolarization (low-threshold response, LTR) was recorded. Some cells in the former category exhibited a LTR when depolarized from a potential more negative than Em. 4. The commonest response to stimulation of the median eminence in responders was an EPSP either alone or in combination with an IPSP. Antidromic action potentials were seen in four neurones and in two of these cells excitatory synaptic inputs could be demonstrated when the host hypothalamus adjacent to the graft was stimulated. It is suggested that these responses may represent activation of an afferent input from the host to neurones in the graft. 5. The morphology of neurones in POA grafts was determined by intrasomatic injection of horseradish peroxidase (HRP). A variety of profiles were seen and although some neurones extended over distances of up to 635 microns and branched extensively only one appeared to enter the host tissue at the ventrolateral edge of the graft. 6. A comparison was made between grafted POA neurones and cells in the medial preoptic area (MPOA), a region which constituted a significant component of the grafted tissue. No significant difference was noted between neurones in the graft and neurones in the MPOA in terms of their passive membrane properties. With regard to the active properties MPOA neurones could also be classified according to whether or not a LTR was elicited when the neurone was depolarized from Em. The major difference between the grafted neurones and those in the MPOA lay in the proportion of cells which exhibited a LTR under such conditions, being significantly greater in the latter group.

Animals↗
PubMed1989

In vivo studies on the enhancement of cholecystokinin release in the rat striatum by dopamine depletion.

The release of cholecystokinin-8-like (CCK) immunoreactivity from the rat striatum has been studied in vivo using brain microdialysis. A basal efflux of CCK-like immunoreactivity was not detectable in the majority of experiments. Intrastriatal infusion of veratrine (100 micrograms/ml) increased striatal dialysate levels of CCK-like immunoreactivity above detection limits, representing an overflow into the interstitial fluid. High concentrations of potassium caused similar but less consistent effects. Extracellular dopamine depletion using alpha-methyl-p-tyrosine or reserpine also increased the dialysate content of CCK-like immunoreactivity. In contrast, inhibition of peptidases reported to hydrolyse CCK in vitro did not affect either basal or evoked efflux of CCK-like immunoreactivity. These data demonstrate that CCK-like immunoreactivity may be released from neuronal elements within the striatum by depolarizing stimuli in vivo, and suggest that increased overflow of CCK-like immunoreactivity is associated with dopamine depletion.

Animals↗
PubMed1989

Electrophysiology of adult rat facial motoneurones: the effects of serotonin (5-HT) in a novel in vitro brainstem slice.

Studies of adult rat motoneurones using in vitro slice preparations are rare. We here describe a novel brainstem slice of the adult rat containing the facial motor nucleus (FMN). Data obtained for facial motoneurones (FM) by intracellular recording indicate that they display several passive and active properties seen in other rat cranial and spinal motoneurones. Bath application of serotonin (5-HT) evokes a reversible depolarization of FMs which is associated with an increase in input resistance due to a reduction in potassium permeability. This effect is unaffected by tetrodotoxin indicating a postsynaptic site of action.

Action Potentials↗
PubMed1989

3H-imipramine binding to freshly prepared platelet membranes in depression.

3H-Imipramine binding was measured in freshly prepared platelet membranes from 47 drug-free major depressives and 46 healthy controls. Where possible, platelet binding in depressed subjects was repeated following treatment. A significant negative correlation was found between Bmax and assay protein concentration and Bmax values were corrected for this effect. Adjusted Bmax was significantly lower (by 14%) in female depressed patients than in female control subjects, and the difference was of similar magnitude premenopausally and postmenopausally. No such difference was found in males. Kd did not differ significantly between depressed and control subjects. Multiple regression analysis confirmed significant effects on Bmax of presence of depressive illness, age (positive correlation), and season (higher in summer). Within the depressed sample, Bmax was significantly lower in those subjects with obsessional features. Endogenicity (Research Diagnostic Criteria or Newcastle), dexamethasone suppression test result, drug-free interval, family history of depression, depressive psychosis, suicidal ideation, and past history of suicide attempts were not significantly related to Bmax. Paired comparisons revealed no significant effect on Bmax of 6 weeks' treatment with imipramine, maprotiline, or BRL 14342 or of a course of electroconvulsive therapy.

Adult↗
PubMed1989

Efficacy of noninvasive transcutaneous cardiac pacing patients undergoing cardiac surgery.

Noninvasive transcutaneous cardiac pacing (NTP) is a rapid, safe, and easily utilized form of emergency cardiac pacing, with hemodynamics similar to right ventricular endocardial pacing. Although the technique has proven effective for hemodynamically significant bradycardias and early use during cardiopulmonary resuscitation, NTP under anesthetic conditions has been poorly characterized. In particular, it is unknown to what degree the multiple physiologic perturbations of cardiac surgery and cardiopulmonary bypass (CPB) affect myocardial thresholds and the efficacy of the unit itself. Patients undergoing procedures utilizing CPB (n = 23) were studied in an effort to address these issues. All patients were able to be paced at all points throughout the 24-h study interval, although four patients developed hemodynamic instability during this period causing their exclusion from additional investigation. Only one patient requested discontinuation from the study due to discomfort. A statistically significant increase in mean current requirements for capture was demonstrated over time (P less than 0.0001), with baseline thresholds being significantly less than other study points (P less than or equal to 0.05). Thresholds following chest wall closure were significantly greater than all other study points (P less than or equal to 0.05), possibly due to accumulation of pericardial and mediastinal air. Multiple measured variables changed significantly during the study, but only increases in cardiac output and core temperature were related to statistically significant increases in current thresholds (P less than or equal to 0.05). Increasing age and pump time were of borderline importance. NTP represents an effective pacing alternative in cardiac surgical patients.

Adult↗