Biomedical subjects

A A Larson

Publications and source records attributed to A A Larson.

At least 109 records · Page 6Linked to original sources

PubMed1986

Quantification of tryptamine in brain using high-performance liquid chromatography.

The concentration of endogenously formed tryptamine in central nervous system tissue was determined after extraction into ethyl acetate, purification on a weak cation-exchange resin and analysis using high-performance liquid chromatography with fluorometric detection. Final chromatographic separation of this indoleamine was achieved using a muBondapak C18 reversed-phase column under isocratic conditions. Using this method, the concentration of tryptamine in the whole brain of normal rats was found to be 0.60 +/- 0.06 ng/g of tissue, while pretreatment with dl-p-chlorophenylalanine, tranylcypromine and l-tryptophan increased the concentration to 96.7 +/- 21.9 ng/g.

Acetylation↗

PubMed1986

Immunocytochemical localization of glutamate-, glutaminase- and aspartate aminotransferase-like immunoreactivity in the rat deep cerebellar nuclei.

Although the anatomy and the connectivity of the deep cerebellar nuclei have been well documented, little is known about the neurotransmitter systems mediating cerebellar efferent pathways. The present study utilizes immunohistochemical procedures in conjunction with a novel monoclonal antibody specific for carbodiimide-fixed glutamate and polyclonal antisera against glutaminase (GLNase) and aspartate aminotransferase (AATase) to examine the presence of putative excitatory amino acid transmitters in neurons of the deep cerebellar nuclei. Carbodiimide-fixed glutamate-like, GLNase-like and AATase-like immunoreactivities were observed in neurons of the lateral, posterior interpositus, anterior interpositus and medial deep cerebellar nuclei. More neurons were stained with AATase antiserum than with the GLNase antiserum or the monoclonal antibody. These results suggest glutamate, GLNase and AATase are present in neurons of the deep cerebellar nuclei and raise the possibility that glutamate may be an excitatory transmitter in these structures.

Animals↗

PubMed1986

Pain threshold changes in adjuvant-induced inflammation: a possible model of chronic pain in the mouse.

A chronic hyperalgesic condition was induced in mice by the injection of Freund's complete adjuvant (FCA) into the lower lumbar region or directly into the hind footpads. Although little or no visible inflammation was observed after a single intradermal injection of FCA into the lower lumbar area of rats or mice, significant alterations in nociceptive thresholds occurred in each species as determined by decreases in response latency in tail-flick and hot-plate assays. Unilateral intraplantar administration of FCA in mice resulted in visible inflammation in the area of the tibiotarsal (ankle) joint. Changes in the response latency to a noxious stimulus in the areas surrounding the inflamed joint were similar to those observed in non-inflamed limbs, suggesting that changes in sensitivity to noxious stimuli were not merely the result of local hypersensitivity of the inflamed tissue, but may also be due to alterations in nociception at the level of the central nervous system (CNS). When the chronic inflammatory condition induced in the mouse tibiotarsal joint was evaluated by histological and morphological techniques, it was found to have the same characteristics as described in the early stages of FCA-induced arthritis in rats. The similarities between the response to FCA in rat and mouse suggest that injection of FCA in mice may prove to be a useful model for the study of chronic pain in mice as well as in rats.

Adjuvants, Immunologic↗

PubMed1986

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↗

PubMed1986

Immunohistochemical localization of glutamate, glutaminase and aspartate aminotransferase in neurons of the pontine nuclei of the rat.

The pontine nuclei form the key relay nuclei in the cerebropontocerebellar pathway. Although a great deal of information is available regarding the anatomy of this region, the identity of the neurotransmitter(s) contained in the neurons of the pontine gray are not known. The aim of the present investigation is to utilize immunohistochemical techniques to determine whether glutamate, a putative excitatory transmitter, and the enzymes responsible for its metabolism, are found in pontine neurons. Both glutaminase, an enzyme which converts glutamine to glutamate, and aspartate aminotransferase, an enzyme which is involved in the interconversion between glutamate and aspartate, have been proposed to be markers of neurons which use excitatory amino acids as neurotransmitters. The present study utilizes a monoclonal antibody against carbodiimide-fixed glutamate and polyclonal antisera against glutaminase and aspartate aminotransferase in conjunction with the indirect peroxidase technique or the peroxidase-labeled biotin-avidin procedure to localize glutamatergic neurons in the pontine nuclei of the rat. Numerous neurons in all subdivisions of the pontine nuclei were found to contain carbodiimide-fixed glutamate-like immunoreactivity, glutaminase-like immunoreactivity or aspartate aminotransferase-like immunoreactivity. Horseradish peroxidase was injected into the cerebellum of four rats for use with a combined retrograde transport-immunohistochemical procedure. Double-labeled neurons were observed in all subdivisions of the pontine nuclei, indicating that pontine neurons which contain glutamate-like immunoreactivity project to the cerebellum. Based on the hypothesis that increased levels of glutamate, glutaminase and aspartate aminotransferase reflect a transmitter role for glutamate, the present data raise the possibility that glutamate may be a major neurotransmitter of pontocerebellar fibers.

Animals↗

PubMed1986

Monoclonal antibody specific for carbodiimide-fixed glutamate: immunocytochemical localization in the rat CNS.

Glutamate is widely distributed in the central nervous system (CNS) and is present in greater amounts than any other putative neurotransmitter. To study its distribution in the CNS, a monoclonal antibody was raised against gamma-L-glutamyl-L-glutamic acid (gamma-Glu-Glu) conjugated to keyhole limpet hemocyanin (KLH) using glutaraldehydeborohydride. By use of this antibody, indirect immunoperoxidase staining was observed in CNS tissue fixed with carbodiimide to form gamma-Glu-Glu from glutamate and post-fixed with glutaraldehyde or paraformaldehyde. In contrast, immunoreactivity was quite low in tissues fixed only with glutaraldehyde. Absorption controls indicated that the staining of carbodiimide-fixed tissue could be inhibited by micromolar concentrations of gamma-Glu-Glu but not by other small molecules. Using ELISA, the antibody reacted strongly with the gamma-Glu-Glu/KLH conjugate used to immunize the mouse, but not with other small molecules conjugated to KLH. The reactivity of the antibody with the gamma-Glu-Glu/KLH conjugate on ELISA was inhibited by free gamma-Glu-Glu in micromolar concentrations, but not by similar dipeptides or amino acids. Dense immunocytochemical staining was observed in cortical pyramidal cells, cerebellar granule cells, and the cochlear nuclei. Staining with this monoclonal antibody correlated well with other methods of localizing glutamate in the CNS.

Animals↗

PubMed1986

Autoradiographic localization of tryptamine binding sites in the rat and dog central nervous system.

Tryptamine, an endogenous trace amine, is currently postulated to be a neuromodulator or neurotransmitter in the mammalian CNS. High-affinity binding sites have been described for tryptamine in rat brain homogenate preparations. The present study further characterizes tryptamine binding throughout the CNS and delineates its distribution using in vitro receptor binding in conjunction with autoradiographic techniques. Saturation studies on 20-micron-thick brain sections suggest a single class of binding sites (Hill coefficient = 0.97 +/- 0.04) with a high affinity (KD = 4.79 +/- 1.55 nM). In competition studies, kynuramine and tetrahydrobetacarboline significantly inhibited H3-tryptamine binding while serotonin, dopamine, and phenylethylamine failed to significantly inhibit it. The most potent inhibitor of H3-tryptamine binding was tryptamine (KI = 4.19 +/- 2.13 nM). In rat brain sections processed for in vitro autoradiography, highest binding occurred in the following limbic structures: the accumbens nucleus, the amygdalohippocampal area, the lateral septal nucleus, the entorhinal cortex, and the anterior olfactory nucleus. At diencephalic levels, the highest binding was observed in the reuniens thalamic nucleus, the paraventricular thalamic nucleus, the medial habenular nucleus, the central medial thalamic nucleus, and the arcuate hypothalamic nucleus. In the midbrain of the rat, binding was most notable in the interpeduncular nucleus, the superficial layer of the superior colliculus, the periaqueductal gray, and the paranigral nucleus. In the lower brain stem of the dog, binding was evident in the external cuneate nucleus, the spinal trigeminal nucleus, and in the region of the solitary nucleus. Binding was also present in both the ventral and dorsal horns of the canine spinal cord.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1985

Inhibition of intrathecally administered picrotoxin- and bicuculline-induced convulsions in mice by pipecolic acid or GABA.

Pipecolic acid (PA) is an alicyclic amino acid and putative neurotransmitter which may modulate GABAergic transmission in the central nervous system. The present study was designed to investigate the anticonvulsant effect of intrathecally (i.t.) injected PA on picrotoxin- and bicuculline-induced convulsions which are thought to be produced by interactions with GABAergic systems. Intrathecal injections of picrotoxin and bicuculline in mice produced convulsions which were characterized by a rapid onset and short duration. Coadministration of GABA with either bicuculline or picrotoxin, but not strychnine, attenuated the severity of the convulsions. Coadministration of PA also protected against bicuculline- and picrotoxin-induced convulsions. Intrathecal injections of PA produced a dose-related increase in the latency to the onset of these convulsions as well as a decrease in their duration, however PA failed to inhibit the duration of strychnine-induced seizures. The D isomer of PA was found to be more effective than the L isomer as an anticonvulsant in this study. When administered in a high dose (500 micrograms i.t.), the D isomer produced flaccid paralysis while injection of high doses (100-500 micrograms i.t.) of the L isomer actually elicited convulsions. These results further support an interaction between PA and GABAergic activity.

Animals↗

PubMed1984

Acute and chronic effects of LSD and 5-MeODMT on raphe-evoked dorsal root potentials in the cat.

Both acute and chronic effects of lysergic acid diethylamide (LSD) and 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) on the dorsal root potential (DRP), evoked by stimulation of the nucleus raphe magnus of the cat, were examined. Single injections of LSD potentiated while those of 5-MeODMT inhibited the raphe-evoked DRP. The electrophysiologic response produced by each drug correlates well in dosage and time-course with their reported behavioral effects. Following four consecutive daily injections of LSD, complete tolerance developed to the potentiating effect of LSD on this potential. A similar pretreatment schedule with 5-MeODMT failed to alter its acute inhibitory effect on the DRP. These results correlate well with the development of tolerance to the behavioral effects of LSD and 5-MeODMT. This system may thus provide a unique electrophysiological model to examine the effects of these drugs.

Action Potentials↗

PubMed1984

Synergistic behavioral effects of serotonin and tryptamine injected intrathecally in mice.

The endogenous compounds, serotonin (5-HT) and tryptamine (TA), have been found to alter function in the CNS, supporting the hypothesis that they serve as neurotransmitters. It is reported here that intrathecal injections of either 5-HT or tryptamine elicited similar behavioral syndromes consisting of caudally-directed biting, or licking and scratching. Serotonin was found to be considerably more potent than tryptamine. However, administration of both indoleamines produced synergistic interactions with respect to this behavioral syndrome. Administration of fluoxetine with either 5-HT or tryptamine potentiated the scratching behavior produced by either indoleamine, but failed to enhance the effect of an injection of 5-HT plus tryptamine. Administration of methysergide blocked the effects of both indolamines. The results are discussed in terms of a possible mechanism of the synergism between 5-HT and tryptamine.

Animals↗

PubMed1984

Interactions between ketamine and phencyclidine and dorsal root potentials (DRPs), evoked from the raphe nuclei.

Dorsal root potentials (DRPs) are thought to reflect presynaptic inhibition of primary afferent activity. Electrical stimulation of sites near the nucleus raphe magnus evokes two such potentials (DRP-1 and DRP-2) along dorsal roots of the lumbar and sacral spinal cord in the anaemically decerebrated cat. Dorsal root potential-2 is thought to be serotonergically mediated, while the neurochemical mediator of dorsal root potential-1 is not known. Serotonin antagonists selectively inhibit dorsal root potential-2 while the shorter latency dorsal root potential-1, which can be elicited anywhere in the brain stem, is potentiated by these drugs. The present study showed that most general anesthetics, such as ether or barbiturates, uniformly depressed both dorsal root potentials 1 and 2. The present studies indicate that two dissociative anesthetics, ketamine and phencyclidine, selectively inhibited dorsal root potential-2. This inhibitory effect of ketamine was dose-related, such that a dose of 11 mg/kg completely blocked dorsal root potential-2, but had no effect on dorsal root potential-1. Time-course studies indicated that the effect of phencyclidine on dorsal root potential-2 lasted much longer than that of ketamine. These results suggest that the effect of dissociative anesthetics on the descending pathways is unique compared to that of other anesthetic agents and that their effect correlates well in time-course and dose-range to their sedative/anesthetic effects.

Animals↗

PubMed1984

Response of great horned owls given the optical isomers of ketamine.

The relative anesthetic effects of the 2 purified isomers and the racemic mixture of ketamine were compared in 6 great horned owls (Bubo virginianus), a species in which racemic ketamine is poorly tolerated. Other investigators have reported that the L(-) form is only a 3rd as potent as the D(+) form with respect to analgesic action in mammals. Accordingly, the racemic and the - forms were given at 2 X and 3 X, respectively, the dose of the + form in an attempt to achieve a potentially equivalent state of anesthesia. At these dose levels, there was no difference observed in the average duration of anesthesia with the 3 ketamine preparations. The - isomer yielded a poorer anesthetic response characterized by inadequate muscle relaxation, cardiac arrhythmias, and marked excitatory behavior during recovery. With the dosages used, the + form and the racemate were comparable in degree of muscle relaxation produced. The + form yielded smoother inductions and less cardiac arrhythmia than did the racemate.

Analgesia↗

PubMed1983

Hyperalgesia produced by the intrathecal administration of tryptamine to rats.

Tryptamine was applied directly into the spinal subarachnoid space of rats via permanently indwelling cannulas. Changes in pain-perception were measured by changes in the latency of the tail-flick in response to a radiant heat source of low intensity. While an intrathecal injection of serotonin has been previously shown to be analgesic, exogenous tryptamine produced dual effects on the pain-threshold, depending on the dose of tryptamine injected. Low doses of tryptamine (100 and 200 micrograms/rat) injected intrathecally onto the sacral area of the spinal cord appeared to be hyperalgesic by significantly decreasing the average tail-flick latency by 5 min after injection. Administration of the serotonin antagonist methysergide alone was without effect on the average tail-flick reaction time when injected either intrathecally or subcutaneously. However, pretreatment with either methysergide or cinanserin not only failed to inhibit tryptamine's potentiation of nociception, but actually enhanced the hyperalgesia produced by tryptamine. In contrast, a dose of 400 micrograms of tryptamine significantly increased the average tail-flick latency, suggesting an analgesic effect at this higher dose. This analgesic effect of 400 micrograms of tryptamine was completely inhibited by subcutaneously administered methysergide, while intrathecally injected methysergide produced even greater decreases in the tail-flick latencies after this high dose of tryptamine. These results suggest that tryptamine, although it differs from serotonin by only one hydroxyl group, may play a role in nociception which is opposite that played by serotonin.

Animals↗

PubMed1983

Pharmacokinetics of gentamicin in birds of prey.

The pharmacokinetics of gentamicin, including half-life, apparent volume of distribution, total body clearance, and fraction of drug absorbed from IM injection sites, were determined in 3 species of birds of prey (red-tailed hawks, great horned owls, and golden eagles). Significant differences (P less than 0.05) between species were found for the half-life and total body clearance values for this broad-spectrum antibiotic. The values for apparent volume of distribution and fraction absorbed did not differ among species and were similar to those reported in mammals. Rapid and relatively complete absorption from IM injection sites resulted in high bioavailability. After IV administration of 10 mg of gentamicin/kg of body weight, serum concentrations greater than 12 micrograms/ml were present for at least 2 hours and greater than 2 micrograms/ml for 4 to 6 hours. On the basis of the various determinations, an IM dose of 2.5 mg of gentamicin/kg given every 8 hours should provide therapeutic serum concentrations of gentamicin in the 3 species.

Animals↗

PubMed1982

Nociception is enhanced by the intrathecal injection of 5-methoxy-N,N-dimethyltryptamine in the rat.

The effect of 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) at the spinal cord level on nociceptive reflexes was tested using the tail-flick assay in rats. 5-MeODMT was injected directly into the spinal subarachnoid space of conscious rats via a permanently indwelling intrathecal cannula. Administration of 100 micrograms/rat of 5-MeODMT into the thoracic region, using a 4 cm long cannula, reduced the average percent of control reaction time by 14%. The injection of the same dose of 5-MeODMT into the lumbosacral region, via an 8.6 cm long cannula, decreased the average percent of control reaction time by 25%. The ability of 5-MeODMT to mimic the facilitatory (hyperalgesic) effect on nociception of similar doses of tryptamine, in contrast to the antinociceptive (analgesic) effect of serotonin, suggests an interaction of 5-MeODMT with tryptaminergic rather than serotonergic receptors in the spinal cord.

Animals↗

PubMed1982

Nociception in mice after chronic stress and chronic narcotic antagonists during maturation.

The effects of chronic, mild stress and chronic narcotic antagonism during maturation of mice on the sensitivity to pain and to the analgesic effect of morphine were examined. Analgesia was measured using the tail-flick assay. Chronic stress, produced simply by the subcutaneous injection of mice twice daily with saline starting day 5 postpartum, produced an increased in the sensitivity of these mice, when mature, to the analgesic effect of morphine. A similar schedule of saline injections for 4 weeks in adult mice did not alter the sensitivity of those mice to the analgesic effects of morphine. Chronic injections of narcotic antagonists during maturation did not produce an effect on morphine analgesia different from that after chronic injections of saline. However chronic exposure to narcotic antagonists since conception, compared to chronic injections since day 5 postpartum in the offspring, did produce differential effects on the control tail-flick latencies such that naloxone during gestation decreased, while naloxone during gestation and postpartum increased tail-flick latencies. These data suggest that exposure to chronic stress during early development is responsible for an altered sensitivity to narcotic analgesics while exposure to naloxone during maturation affects pain perception.

Aging↗

PubMed1982

Serotonin-induced gnawing in rats: comparison with tail pinch-induced gnawing.

The intrathecal (IT) injection of serotonin in the rat was found to produce a variety of behavioral signs of the serotonin "syndrome" as well as intense gnawing. Serotonin-induced gnawing is qualitatively similar to that evoked by tail pinch. Paradoxically, tail pinch-induced gnawing has been previously shown to be inhibited by serotonergic activity while we found a positive dose-related correlation between the IT administration of serotonin and gnawing. Pretreatment with methysergide IT completely blocked gnawing produced by intrathecally injected serotonin but not that evoked by tail pinch. In contrast, naloxone, reported to inhibit tail pinch-induced hyperphagia, failed to affect serotonin-induced gnawing. The parenteral injection of haloperidol inhibited both tail pinch-induced and serotonin-induced gnawing. Failure of intrathecally injected haloperidol to inhibit serotonin-induced gnawing indicates that dopamine mediates this behavior at a supraspinal level. The ability of serotonin to elicit gnawing when injected at the spinal cord level, but to inhibit the same behavior when evoked by tail pinch, suggest that this neurotransmitter plays opposite roles depending on which part of the CNS is involved.

Animals↗

PubMed1981

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↗