You're supposed to feel abnormal.
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Aged↗
Biomedical subjects
E G Anderson
Publications and source records attributed to E G Anderson.
Reversal of the antinociceptive effects of intrathecally administered serotonin in the rat by a selective 5-HT3 receptor antagonist.
The ability of the highly selective 5-HT3 receptor antagonist ICS 205-930 (3 alpha-tropanyl-1H-indole-3-carboxylic acid ester) to block the increase in tail flick (TFL) and hot plate latencies (HPL) produced by intrathecally (i.t.) administered serotonin (5-HT) was examined in pargyline pretreated rats. ICS 205-930 (0.1 microgram, i.t.) blocked the ability of 5-HT (200 micrograms) to increase TFL and HPL. Significant hyperalgesia, as measured by a decrease in TFL and HPL compared to saline controls, also resulted from either the coadministration of ICS 205-930 (10 micrograms) and 5-HT (200 micrograms) or from ICS 205-930 (100 micrograms) alone. These data suggest an important role for 5-HT3 receptors in modulating spinal nociceptive responses.
Animals↗
Identification of 5-HT3 binding sites in rat spinal cord synaptosomal membranes.
The 5-HT3 receptor antagonists, ICS 205-930 and MDL 72222, displace 47-55% of the specific [3H]serotonin (100 nM) binding to synaptosomal membranes derived from the dorsal, but not ventral, spinal cord of rats with IC50s less than 1.0 nM. Methiothepin (10 microM) increased displacement to 86-94% without shifting these IC50s. Scatchard plots of [3H]5-HT binding in the presence of methiothepin (10 microM) reveal a single population of sites (KD = 11.5 nM, Bmax = 282 fmol mg-1 protein). These results indicate the presence of 5-HT3 binding sites in dorsal spinal cord.
Binding Sites↗
Three putative 5-HT1A agonists act as 5-HT antagonists in frog sensory neurons.
The putative 5-HT1A agonists 8-hydroxy-dipropylaminotetralin (DPAT), buspirone and p-aminophenylethyl-m-trifluoromethylphenyl piperazine (PAPP) were tested for their ability to narrow the action potentials of bullfrog sensory neurons, a serotonergic response observed to be blocked by the 5-HT1A antagonists spiperone and spiroxitrine. Given alone, DPAT, buspirone, and PAPP were ineffective 5-HT agonists. When applied concomitantly with 5-HT, however, they significantly antagonized the original response. Thus, in some systems these putative 5-HT1A agonists function as antagonists.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Serotonin-induced reduction of the calcium-dependent plateau in frog dorsal root ganglion cells is blocked by serotonergic agents acting at 5-hydroxytryptamine1A sites.
Intracellular recordings from the dorsal root ganglion cells of adult frogs in the presence of tetraethylammonium display action potentials with a prominent calcium-dependent plateau. These action potentials can be altered by serotonergic agents in one of two ways. The superfusion of 5-HT (0.1-1 microM) usually produces a dose-dependent reduction of the action potential duration, whereas 8-hydroxy dipropylaminotetralin (8-OH-DPAT) (10-50 microM) produces a dose-dependent increase in duration. A series of 5-HT antagonists were tested for their ability to block either the 5-HT or the 8-OH-DPAT effect. The antagonists were chosen for their reported selectivity in distinguishing receptors of the 5-HT1A, 5-HT2 and 5-HT3 subtypes. The antagonists' action on 5-HT narrowing [blockade by methiothepin, spiperone and spiroxitrine, but not by ketanserin or 3-tropyl-indole-3-carboxylate (ICS 205-930)] suggests that this response is mediated by 5-HT1A receptors. The widening effect produced by 8-OH-DPAT (a putative 5-HT1A agonist) was not blocked by any antagonist tested. At lower concentrations (0.1-2.5 microM) 8-OH-DPAT exhibited no agonist actions, but antagonized the 5-HT-induced narrowing. These results suggest the 5-HT receptors mediating 5-HT action potential narrowing in these cells are of the 5-HT1A subtype, but that they differ from the 5-HT1A receptors described in other tissues in which 8-OH-DPAT is an agonist or a partial agonist.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Reflections on taking the geriatrics 'special competence' boards.
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Geriatrics↗
Long-term potentiation induced by physiologically relevant stimulus patterns.
Single pulse stimuli were delivered to the Schaffer collaterals in the in vitro hippocampal slice preparation. Local application of bicuculline to the CA3 region resulted in a series of population cell bursts in CA3, resembling the neuronal patterns which occur in the normal, freely moving rat during hippocampal sharp waves. These bicuculline-induced cell bursts in CA3 resulted in long-term potentiation (LTP) of the CA1 response. These findings suggest that the naturally occurring hippocampal sharp waves may reflect events analogous to artificially induced LTP.
Animals↗
Tumour induced hypophosphataemia associated with small cell carcinoma of the bronchus.
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Adult↗
Action of hallucinogens on raphe-evoked dorsal root potentials (DRPs) in the cat.
The dorsal root potential (DRP) evoked by stimulation of the inferior central nucleus (ICN) of the cat is affected by administration of a variety of hallucinogenic agents. It has been previously shown that a single low dose of LSD is unique in that it potentiates this DRP, while injections of 5-methoxy-N,N- dimethyltryptamine (5-MeODMT), ketamine or phencyclidine (PCP) inhibit its production. Tolerance develops to the facilitatory effect of low doses of LSD on the DRP, but not to the inhibitory action of 5-MeODMT. Repeated injections of ketamine every 30 minutes also fail to produce tachyphylaxis to the inhibitory effect of this dissociative anesthetic. The raphe-evoked DRP is a long latency potential that is inhibited by a wide variety of putative serotonin antagonists and has therefore been traditionally thought to be mediated by serotonin. However, in light of the inability of either tryptophan or fluoxetine to potentiate this DRP, and the resistance of this DRP to blockade by parachlorophenylalanine, reserpine or intrathecally administered 5,7-dihydroxytryptamine, it appears that this potential may in fact be mediated, at least in part, by a non-serotonergic transmitter.
Action Potentials↗
Serotonin decreases the duration of action potentials recorded from tetraethylammonium-treated bullfrog dorsal root ganglion cells.
Neurotransmitter effects on calcium currents activated by sensory neuron action potentials have been previously studied in embryonic or neonatal dorsal root ganglion (DRG) cells in culture. In the present study we examined the effects of serotonin (5-HT) on the shape of action potentials recorded from fully differentiated primary afferent neurons in isolated DRG of adult bullfrogs. Intracellular recordings were obtained from cell bodies of type A and C neurons. Concentrations of 5-HT that had no effect on membrane potential or input resistance had little or no effect on action potential shape. Treatment with 5-20 mM tetraethylammonium ion (TEA) led to the appearance of a plateau phase on the falling limb of the spike. This plateau phase appears to result from calcium influx, as it was dramatically reduced in amplitude and duration by solutions containing low concentrations of calcium or the calcium channel blocker, manganese. In preparations treated with 7.5 mM TEA, low concentrations of 5-HT (10 nM-1 microM) produced a dose-dependent narrowing of the calcium-dependent plateau phase of the mixed sodium/calcium spike. A decrease in spike afterhyperpolarization was also noted. The decrease in spike duration was recorded from 74% of type A neurons and 57% of type C neurons, and was not secondary to a change in resting potential or input resistance. The 5-HT receptor antagonists methysergide and metergoline did not block the response to 5-HT. Instead, they exhibited weak agonist-like actions. Serotonin also reduced the rate of rise and peak amplitude of calcium spikes recorded in the presence of tetrodotoxin and TEA.(ABSTRACT TRUNCATED AT 250 WORDS)
Action Potentials↗
Serotonin depolarizes type A and C primary afferents: an intracellular study in bullfrog dorsal root ganglion.
Intracellular recordings were obtained from the somata of type A and C primary afferents in the isolated bullfrog dorsal root ganglion (DRG) preparation. Bath application of serotonin (5-HT) in concentrations of 0.25-1.0 mM led to slow and fast depolarizing responses. Slow, maintained 5-HT depolarizations were observed in 47% of type A and 70% of type C neurons. These slow depolarizations were associated with an underlying increase in input resistance (Rin). In some type A neurons, the Rin increase was masked by a decrease in Rin due to depolarization-induced rectification. The slow 5-HT depolarization of type A, but not type C neurons showed pronounced tachyphylaxis to repeated 5-HT applications. In type C afferents, serotonin's slow action was often accompanied by spontaneous firing. Manganese decreased slow 5-HT depolarizations of both cell types. A slow depolarization and excitation of type C afferents by methysergide and cinanserin was also observed. Fast transient 5-HT depolarizations accompanied by a rapid decrease in Rin were observed in 7% of type A and 24% of type C neurons. In some DRG cells the fast and slow depolarizations combined to form a biphasic response. The actions of 5-HT reported here resemble in some ways 5-HT responses recorded extracellularly from the spinal terminations of primary afferents.
Animals↗
The actions of serotonin on frog primary afferent terminals and cell bodies.
The actions of serotonin (5-HT) were studied in the isolated frog spinal cord and dorsal root ganglion preparations. In the spinal cord, 5-HT increased the spontaneous activity recorded from dorsal roots, facilitated evoked spinal reflexes and produced fast and slow primary afferent depolarization (PAD). A direct action of 5-HT on primary afferent terminals is likely since 5-HT induced PAD remained in the presence of 1 microM tetrodotoxin and 2 mM Mn2+. The direct action of 5-HT on primary afferent terminals was blocked by methysergide and attenuated by concentrations of Mn2+ in excess of that required to block transmitter release. Cell bodies of the dorsal root ganglion were also depolarized by 5-HT. A slow hyperpolarization occasionally followed the initial depolarization. The depolarizing action of 5-HT in the dorsal root ganglion was also attenuated by treatment with Mn2+. It is concluded that 5-HT acts directly on frog primary afferents and that this influence may involve a calcium sensitive process. The dorsal root ganglion response to 5-HT appears to be a suitable model of the afferent terminal response.
Animals↗
Single unit studies of identified bulbospinal serotonergic units.
Non-serotonergic bulbospinal neurons were identified by conduction velocities greater than 6 m/s. These units were found to fire at rates from 0 to 22 Hz, to respond to sensory stimuli with either excitation or inhibition, and to have unremarkable spike shapes. In iontophoretic experiments, both excitation and inhibition were observed in response to acetylcholine, norepinephrine and serotonin. Serotonergic bulbospinal neurons were identified by their conduction velocities below 6 m/s. These neurons, (which have been shown to be destroyed by 5,7-dihydroxytryptamine), exist as two groups: a a slower-conducting group with conduction velocities below 1.2 m/s, and a faster-conducting group with conduction velocities between 2 and 6 m/s. The neurons of the faster-conducting group were found to be similar to the non-serotonergic group in their firing, spike shapes and responses to sensory stimuli; while the units of the slower-conducting group were consistently found to fire between 0.03 and 6 Hz, to respond to sensory stimuli only with excitation, and to have distinctive spike shapes. Despite these differences, both groups of serotonergic units were found to be consistently inhibited by ACh, NE and 5-HT. In contrast to reports of serotonergic neurons in the midbrain, these units were not generally found to be inhibited by i.v. LSD. It is concluded that the serotonergic neurons of the medullary raphe are distinct both from the non-serotonergic neurons, and from serotonergic neurons in other parts of the brain.
Acetylcholine↗
Pre-steady state beta-lactamase kinetics. The trapping of a covalent intermediate and the interpretation of pH rate profiles.
The hydrolysis of sodium 3-dansylamidomethyl-7-beta (thienyl-2')-acetamido-ceph-3-em-4-oate, catalyzed by the beta-lactamase of Staphylococcus aureus PC1, has previously been shown (Anderson, E. G., and Pratt, R. F. (1981) J. Biol. Chem. 256, 11401-11404) to follow the reaction scheme Formula; see text. where ES' is an enzyme-substrate complex in which the substrate has undergone nucleophilic attack at the beta-lactam carbonyl group and P is product. Acid quenching of the reaction mixture has now been shown to yield, in amounts predicted by the rate constants, a covalent enzyme-substrate complex. The liability of this complex in alkaline solution is suggestive of that of an ester. Together, all of these results prove that the turnover of this apparently normal substrate by a class A beta-lactamase involves an acyl-enzyme intermediate. In the case of another fluorescent substrate, dansylcephalexin, no intermediate analogous to ES' accumulated during catalysis; presumably here, acylation of the enzyme is rate-determining. The pH profiles (pH 4-9) of the pre-steady state rate constants for hydrolysis of the former substrate have also been determined. Binding (1/K8) is pH invariant except at low pH where it weakens, probably because of substrate protonation and/or a protein conformational change. The rate constants, k2, k-2, and k3, are pH invariant at low pH but decrease at higher pH in a way which can be described by ionization of an essential acid of pKa around 7.7. This may be the same acid for each constant, being either an active participant at the active site, or a more distant acid which controls an essential conformational change.
Cephalosporins↗
Pre-steady state beta-lactamase kinetics. Observation of a covalent intermediate during turnover of a fluorescent cephalosporin by the beta-lactamase of STaphylococcus aureus PC1.
The pre-steady state kinetics of the hydrolysis of sodium 3-dansylamidomethyl-7-beta (thienyl-2')-acetamidoceph-3-em-4-oate, catalyzed by the beta-lactamase of Staphylococcus aureus PC1, has been studied by the stopped flow method. Fluorescence measurements indicated the presence of two intermediate enzyme-substrate complexes, i.e. at least a three-step mechanism. The disappearance of the characteristic cephem chromophore, which reflects nucleophilic attack at the beta-lactam carbonyl group, correlated with the second step. These results show that an intermediate species with a covalently altered substrate occurs on the reaction path prior to the last step which includes release of product. This intermediate is most likely an acyl-enzyme. The data have been analyzed numerically and the derived rate constants are in accord with the steady state parameters.
Cephalosporins↗
The identification of serotonergic neurons in the nucleus raphe magnus by conduction velocity.
Histochemical studies have described serotonergic neurons in the nucleus raphe magnus, and since their axons are small, they would be expected to have low conduction velocities. However, previous studies have reported few slow-conducting units in the nucleus. In these studies, raphe-spinal neurons, detected by antidromic activation, were found to exhibit a wide range of conduction velocities, including numbers of slow-conducting units. In a second set of experiments, the number of raphe-spinal units found in control rats and those treated with 5,7-dihydroxytryptamine, a serotonin neurotoxin, were compared. Two groups of slow-conducting units were reduced in treated animals and those units, conducting between 0.7-1.0 m/sec and 3.1-6.0 m/sec, were presumed to be serotonergic. These neurons comprised about 40% of the total found in the nucleus.
Animals↗
Aqua vitae: the health spas of Europe.
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Balneology↗
Dual actions of lysergic acid diethylamide tartrate (LSD), 2-bromo-D-lysergic acid diethylamide bitartrate (BOL) and methysergide on dorsal root potentials evoked by stimulation of raphe nuclei.
A variety of drugs reported to antagonize serotonin were found to affect spinal cord potentials evoked by electrical stimulation of the caudal raphe nuclei of the cat. These brain stem-evoked dorsal root potentials (DRPs) consisted of a short latency depolarization (DRP-1), which was evoked by stimulation of a wide variety of sites in the medial brain stem and a long latency potential (DRP-2), which was elicited only when stimuli were applied near the raphe. The ability of serotonergic antagonists to increase or decrease these DRPs was dependent on the dose of the drug administered. High doses of lysergic acid diethylamide tartrate (LSD), 2-bromo-D-lysergic acid diethylamide bitartrate (BOL), methysergide and cinanserin each produced an immediate inhibition of DRP-2 and a simultaneous enhancement of DRP-1, both of which recovered by approximately 30 min. Each of the drugs produced a dose-related inhibition of DRP-2 at high doses, with LSD being the most potent and cinanserin the least potent. In contrast, low doses of LSD, BOL and methysergide elicited little or no immediate change in either DRP-2 or DRP-1, but produced an enhancement of DRP-2 which developed slowly over a period of 60 to 90 min. This increase in DRP-2 was most dramatic after administration of LSD and was not accompanied by changes in DRP-1. The inhibition of DRP-2 by high doses of LSD, BOL, methysergide and cinanserin may result primarily from inhibition of postsynaptic serotonergic receptors located on the primary afferent terminals. The increase in DRP-2 produced by low doses of LSD, BOL and methysergide is postulated to result from an interaction with receptors distinct from those which produced the inhibition of DRP-2 at higher doses.
Animals↗