Biomedical subjects

R H Porter

Publications and source records attributed to R H Porter.

At least 37 records · Page 2Linked to original sources

PubMed1996

Contrasting effects of electroconvulsive shock on mRNAs encoding the high affinity kainate receptor subunits (KA1 and KA2) and cyclophilin in the rat.

Kainate-preferring glutamate receptors may contribute to the glutamatergic responses to seizures. The cloning of their encoding genes overcomes limitations of the receptor ligands available for their investigation. We have examined the expression of the high affinity kainate receptor subunits KA1 and KA2 mRNAs in the rat hippocampus, using electroconvulsive shock (ECS) as a seizure paradigm not confounded by neurotoxicity. A single shock reduced the levels of KA1 mRNA in the CA3c region, while increasing the expression of KA2 mRNA in the dentate gyrus. Following repeated ECS (5 shocks over 10 days), KA1 mRNA was reduced in CA3c and in CA3a-b but was unchanged in dentate gyrus. KA2 mRNA, on the other hand, significantly increased in dentate gyrus, and to a lesser extent in CA3c and CA1. All changes in KA1 and KA2 mRNAs had returned to baseline 3 weeks after the last shock. We also measured the expression of cyclophilin mRNA, and found it to be reduced in all hippocampal subfields, and in the parietal cortex, after a single ECS. It returned to control levels after repeated ECS but was again reduced following 3 weeks recovery from repeated ECS. These results indicate that the expression of KA1 and KA2 not only change in opposite directions in the rat hippocampus after ECS, but that the alterations are anatomically and temporally regulated. In the respect that cyclophilin is regarded as a housekeeping gene, the reduction in its mRNA suggests that ECS may have more persistent and widespread effects on brain gene expression than previously suspected.

Amino Acid Isomerases↗

PubMed1996

ARL-15896, a novel N-methyl-D-aspartate receptor ion channel antagonist: neuroprotection against mitochondrial metabolic toxicity and regional pharmacology.

ARL-15896 [(+)-alpha-phenyl-2-pyridineethanamine], formerly known as FPL-15896, is a novel N-methyl-D-aspartate (NMDA) receptor ion channel antagonist. Using quantitative receptor autoradiography, we examined the regional binding characteristics of ARL-15896 and compared them to those of MK-801, the prototypical NMDA receptor channel blocker. The affinity of ARL-15896 was much lower (3000-fold) than that of MK-801 in all brain regions examined. In addition, in contrast to MK-801, which has a higher affinity in the forebrain than in the cerebellum (IC50 of 10 nM vs 24 nM), ARL-15896 had a higher affinity in the cerebellum than in the forebrain (IC50 of 17 microM vs 45 microM). The neuroprotective potential of ARL-15896 was investigated in a rat model of excitotoxicity, the intrastriatal injection of malonate. Malonate is a competitive inhibitor of succinate dehydrogenase, and its toxicity has been shown to be mediated largely by the NMDA receptor. Administration of ARL-15896 either intrastriatally (200 nmol) or subcutaneously (9.0 mg/kg) reduced the volume of the lesion produced by 1 mumol of malonate by 80%, a degree similar to that reported for MK-801. ARL-15896 was also protective when administered after the malonate injection. Furthermore, in contrast to MK-801, administration of ARL-15896 was not associated with any apparent behavioral side effects. This report is consistent with previous studies suggesting that drugs with regional pharmacological profiles similar to that of ARL-15896 have better clinical tolerability; it also indicates that ARL-15896 is an effective neuroprotective agent.

Animals↗

PubMed1996

Glutamate and Parkinson's disease.

Altered glutamatergic neurotransmission and neuronal metabolic dysfunction appear to be central to the pathophysiology of Parkinson's disease (PD). The substantia nigra pars compacta--the area where the primary pathological lesion is located--is particularly exposed to oxidative stress and toxic and metabolic insults. A reduced capacity to cope with metabolic demands, possibly related to impaired mitochondrial function, may render nigral highly vulnerable to the effects of glutamate, which acts as a neurotoxin in the presence of impaired cellular energy metabolism. In this way, glutamate may participate in the pathogenesis of PD. Degeneration of dopamine nigral neurons is followed by striatal dopaminergic denervation, which causes a cascade of functional modifications in the activity of basal ganglia nuclei. As an excitatory neurotransmitter, glutamate plays a pivotal role in normal basal ganglia circuitry. With nigrostriatal dopaminergic depletion, the glutamatergic projections from subthalamic nucleus to the basal ganglia output nuclei become overactive and there are regulatory changes in glutamate receptors in these regions. There is also evidence of increased glutamatergic activity in the striatum. In animal models, blockade of glutamate receptors ameliorates the motor manifestations of PD. Therefore, it appears that abnormal patterns of glutamatergic neurotransmission are important in the symptoms of PD. The involvement of the glutamatergic system in the pathogenesis and symptomatology of PD provides potential new targets for therapeutic intervention in this neurodegenerative disorder.

Animals↗

PubMed1996

Attractiveness of amniotic fluid odor: evidence of prenatal olfactory learning?

Human infants are responsive to maternal odors beginning shortly after birth. In several non-human mammals, the fetus is capable of olfactory learning and in some species neonates are attracted to the odor of amniotic fluid (AF). The present study examined the responses of newborn babies to AF in a biologically relevant context, i.e. during their initial attempt to locate the mother's nipple/areola. We observed newborns' spontaneous choice between a breast with the nipple/areola moistened with AF and an untreated breast; 23 of 30 infants chose the AF-treated breast. All babies had been washed before the observations, and only 12/30 sucked their hands/fingers prior to approaching the nipple/ areola. In a previous study with unwashed newborns, the corresponding proportion was 27/30 (p < 0.001). We tentatively suggest that the observed attraction to AF odor may reflect fetal exposure to that substance (i.e. prenatal olfactory learning). Because of the salience of biological odors for neonates, products that eliminate or mask such cues should be avoided during the perinatal period.

Amniotic Fluid↗

PubMed1995

Autoradiographic study of mitochondrial complex I and glutamate receptors in the basal ganglia of rats after unilateral subthalamic lesion.

A unilateral lesion of the subthalamic nucleus (STN) induced, in the short-term (< or = 1 week), an ipsilateral decrease in [3H]dihydrorotenone binding to complex I in entopeduncular nucleus and substantia nigra pars reticulata (SNr). A slight reduction of [3H]MK-801 binding to N-methyl-D-aspartate (NMDA) receptors in the ipsilateral SNr was also found, whereas no changes in [3H]alpha-amino-3-hydroxy-5-methylisoxazole propionic acid binding were observed. The complex I decrease likely reflects a reduction in neuronal activity subsequent to the interruption of excitatory signaling from STN. The unexpected decrease in [3H]MK-801 binding in SNr may be related to presynaptic NMDA receptor modifications.

Animals↗

PubMed1995

Regional variations in the pharmacology of NMDA receptor channel blockers: implications for therapeutic potential.

Quantitative receptor autoradiography was used to examine the regional binding characteristics of a diverse group of N-methyl-D-aspartate (NMDA)-receptor channel blockers that varied in potency 10(5)-fold. Full competition curves were generated in each of six brain regions for 11 different compounds. MK-801 was the most potent compound studied, with an IC50 of approximately 10 nM in the forebrain regions and 24 nM in the cerebellar granule cell layer (p < 0.05). The binding affinities of nine of the 11 compounds examined were significantly different in cerebellar granule cell layer than in forebrain regions. In addition, the apparent Hill slopes of five of the compounds were significantly different in cerebellum compared with forebrain. That the rank order of drug potencies in cerebellar diverges from that in forebrain suggests that cerebellar NMDA-receptor ion channels differ pharmacologically from those in forebrain. There was a general trend that drugs known to be well tolerated in humans (remacemide hydrochloride and its metabolites, amantadine, budipine, and memantine) had lower affinities than compounds with severe neurobehavioral or psychotomimetic effects. Moreover, all of the compounds known to be well tolerated in humans had a significantly higher affinity in the cerebellum than in forebrain regions, in contrast to MK-801, 1-[1-(2-thienyl)cyclohexyl]-piperidine hydrochloride (TCP), phencyclidine (PCP), and ketamine, which had lower affinities in cerebellum. Our results are consistent with the notion that low affinity (rapid kinetics) and, possibly, subunit specificity (as indicated by distinct regional pharmacologies) may be important determinants of the clinical tolerability of NMDA-receptor channel blockers.

Acetamides↗

PubMed1994

Regional variations in the pharmacology of AMPA receptors as revealed by receptor autoradiography.

Using quantitative autoradiography, we examined the ability of NBQX (2,3-dihydro-6-nitro-7-sulfamoyl-benzo(f)-quinoxaline), S-AMPA (alpha-amino-3-hydroxy-5-methylisoxazole propionic acid), L-glutamate and NS-257 (1,2,3,6,7,8-hexahydro-3-(hydroxyimino)- N,N,7-trimethyl-2-oxobenzo[2,1-b:3,4-c']dipyrrole-5-sulfonam ide) to compete for [3H]AMPA binding sites in several forebrain regions and cerebellar cortex. NBQX had a higher affinity (P < 0.0001) in cerebellar molecular layer than in any forebrain region, whereas the opposite was true for AMPA (P < 0.001). L-Glutamate and NS-257 had different regional patterns of displacement. Consequently, cerebellum and forebrain have distinct rank orders of potency for AMPA receptor ligands. These results suggest that there are regional variations in the pharmacological specificity of AMPA receptors.

Animals↗

PubMed1994

Does the newborn baby find the nipple by smell?

We studied the involvement of naturally occurring odours in guiding the baby to the nipple. One breast of each participating mother was washed immediately after delivery. The newborn infant was placed prone between the breasts. Of 30 infants, 22 spontaneously selected the unwashed breast. The washing procedure had no effect on breast temperature. We concluded that the infants responded to olfactory differences between the washed and unwashed breasts.

Breast Feeding↗

PubMed1994

Inhibition of autoradiographic MK-801 binding by an endogenous factor.

In an autoradiographic assay of glutamate/glycine-stimulated [3H]MK-801-binding, a 30-min prewash of tissue sections in buffer resulted in a 40-78% enhancement of binding over that in the absence of a prewash. Inclusion of buffer used for the prewash in the binding assay significantly inhibited binding in prewashed sections. Addition of competitive glutamate and glycine antagonists to the prewash buffer significantly reduced the effect of a prewash except in striatum. The presence of EDTA in the binding assay of unwashed sections did not alter binding, suggesting the prewash effect is not mediated by divalent cations. The results suggest the presence of a differentially distributed endogenous substance that inhibits MK-801-binding.

Animals↗

PubMed1994

Olfactory cues mediate food selection by young chicks.

An illness-induced aversion paradigm was used to assess the possible influence of olfactory cues on food selection by young chicks. At 2-3 days posthatching, chicks were exposed briefly to food scented with a novel odor (orange) followed by an injection of LiCl or saline. LiCl-injected chicks subsequently displayed stronger avoidance of orange-scented food than did the controls. Chicks in a second experiment were preexposed to novel-scented food, then either injected with LiCl or not injected. The LiCl chicks, but not the controls, later avoided food associated with the preexposure odor (relative to food treated with an unfamiliar odorant). Two- to three-day-old chicks are capable of associating specific food odors with negative consequences and modify their feeding behavior as a function of such experience.

Age Factors↗

PubMed1994

Establishment of maternal bonding and its mediation by vaginocervical stimulation in goats.

To investigate the establishment of offspring recognition in mother goats, 11 females were subjected to two successive 5-min tests with their own kid and an alien, 2 h 30 min postpartum. All mothers accepted their own kid, while nine rejected the alien. This suggests that in goats, 2.5 h are sufficient for the development of an exclusive bond with the kid. We also studied the role of physiological factors mediating maternal bonding in this species. Eight of the nine goats that rejected alien kids were, therefore, submitted to 5 min of vaginocervical stimulation (VCS) immediately following the selectivity tests. Of these eight goats, five changed their behavior after VCS and accepted the alien kid (0/8 before VCS vs. 5/8 after VCS, p = 0.031). Thus, VCS appears to reduce rejection behavior towards alien kids while resulting in a significant increase in their rate of acceptance. Underlying physiological mechanisms by which VCS may act are discussed.

Animals↗

PubMed1994

Anatomy and physiology of glutamate in the CNS.

Glutamate is the predominant excitatory neurotransmitter in the mammalian CNS. The neurotransmitter pool of glutamate is stored in synaptic vesicles and, upon depolarization, is released into the synaptic cleft in a Ca(2+)-dependent fashion. Glutamate is cleared from the synaptic cleft by high-affinity, Na(+)-dependent uptake carriers located in both neurons and glia. Glutamate acts on several distinct families of receptors, each of which has multiple subtypes with distinct pharmacologic and physiologic properties. Under some conditions, glutamate and related compounds act as excitotoxins and might participate in the events leading to neuronal damage and death in a variety of acute and chronic neurologic disorders. The potential for glutamate to become an excitotoxin is highly dependent upon neuronal metabolic status. A great deal of interest in developing selective, well-tolerated glutamate receptor antagonists for the treatment of a variety of neurologic disorders exists.

Central Nervous System↗

PubMed1994

Polysynaptic regulation of glutamate receptors and mitochondrial enzyme activities in the basal ganglia of rats with unilateral dopamine depletion.

After nigrostriatal dopaminergic denervation, the output nuclei of the basal ganglia, the medial globus pallidus and substantia nigra pars reticulata (Snr), become overactive, in part, because of increased activity of excitatory afferents from the subthalamic nucleus (STN). Because STN uses glutamate as a transmitter, we examined whether there are regulatory changes in glutamate receptor binding in the basal ganglia. Rats received unilateral 6-hydroxydopamine lesions of the medial forebrain bundle and substantia nigra pars compacta that were confirmed by apomorphine-induced rotation and 3H-GBR-12935 binding. As an indirect index of relative synaptic activity, succinate dehydrogenase and cytochrome oxidase activities were assayed histochemically in sections adjacent to those used for receptor binding. There were increases in enzymatic activity in entopeduncular nucleus (EP; the rodent homolog of medial globus pallidus), SNr, and globus pallidus (GP, the rodent homolog of lateral globus pallidus) in the lesioned hemisphere, suggesting increased synaptic activity, perhaps due to increased firing of the STN. Ipsilateral to the lesion, and postsynaptic to the STN, there were profound decreases in the binding of 3H-AMPA (alpha-amino-3-hydroxy-5-methylisoxazole propionic acid) in EP and SNr (45% and 30%, respectively); there were no alterations in the striatum, globus pallidus, or STN, and binding throughout the unlesioned hemisphere was equivalent to that in unlesioned control animals. In contrast, 3H-MK-801 binding to the NMDA receptor ion channel was not reduced in SNr, and was too low to be measured reliably in EP and STN. 3H-MK-801 binding was reduced by 6% in striatum and 39% in globus pallidus.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

NMDA receptor status in elderly normal individuals and those with Alzheimer's disease.

The status of NMDA receptors in the brains of normal aged individuals and those with Alzheimer's disease was investigated. The binding of [3H]3-((+-)-2-carboxypiperazin-4-yl)propyl phosphonic acid ([3H]CPP) to NMDA antagonist-preferring sites on frontal and temporal cortical synaptic membranes was assessed. Binding could be resolved into two components, one of high and the other of low affinity. Pharmacologically, the two sites were qualitatively similar. Considerable intersubject variation in binding parameters was detected, but no significant differences were found between the mean values for the control and Alzheimer's disease groups. This study indicates that, when changes in receptor integrity occur in individual patients, these may be occluded because of the large variations between individuals.

Aged↗

PubMed1993

Glutamate metabotropic receptor activation in neonatal rat cerebral cortex by sulphur-containing excitatory amino acids.

The sulphur-containing acidic amino acids (SAAs) display neuroexcitatory actions similar to those of L-glutamate and are widely regarded as bona fide transmitter candidates. In this study, L-cysteine sulphinic acid, L-cysteic acid, DL-homocysteic acid and L-homocysteine sulphinic acid were investigated for their ability to stimulate phosphatidylinositol hydrolysis in rat pup cerebrocortical slices and compared with L-glutamate and the selective agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid ((1S,3R)-ACPD). Each of the SAAs possessed agonist activity at metabotropic glutamate receptors (mGluRs) and, although they exhibited lower efficacy than L-glutamate, they were more potent (EC50s of 401-487 microM compared with 791 microM for L-glutamate). These data are consistent with the possibility that SAAs may have a physiological role as endogenous activators of metabotropic (and presumably ionotropic) excitatory amino acid receptors.

Amino Acids, Sulfur↗

PubMed1993

Competitive antagonism at metabotropic glutamate receptors by (S)-4-carboxyphenylglycine and (RS)-alpha-methyl-4-carboxyphenylglycine.

Two phenylglycine derivates, (S)-4-carboxyphenylglycine and (RS)-alpha-methyl-4-carboxyphenylglycine, competitively antagonised (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (ACPD)-stimulated phosphoinositide hydrolysis in rat cerebral cortical slices. The same phenylglycine derivatives selectively antagonized ACPD-induced depolarization in neonatal rat spinal motoneurones and rate thalamic neurones relative to depolarization or excitation induced by N-methyl-D-aspartate (NMDA) or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA). Both phenylglycine derivatives also selectively depressed synaptic excitation in thalamic neurones evoked by noxious thermal stimuli, without affecting the synaptic stimulation of the same cells by non-noxious stimuli.

Animals↗

PubMed1993

Phenylglycine derivatives as new pharmacological tools for investigating the role of metabotropic glutamate receptors in the central nervous system.

The possible roles of G-protein coupled metabotropic glutamate receptors in central nervous function are currently the focus of intensive investigation. The complexity of effects produced by agonists at these receptors probably reflects the activity of a range of sub-types. The metabotropic glutamate receptors first described are linked to phospholipase C, mediating phosphoinositide hydrolysis and release of Ca2+ from intracellular stores. A substance generally considered to be a selective agonist for these receptors is (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD). This substance not only stimulates phosphoinositide hydrolysis, but also inhibits cyclic AMP formation. A family of metabotropic glutamate receptors, incorporating both phospholipase C- and adenylcyclase-linked sub-types has been cloned. Various effects of metabotropic glutamate receptor agonists on membrane ion fluxes and synaptic events have been reported, including neuronal depolarization and/or excitation, hyperpolarization, inhibition of Ca(2+)-dependent and voltage-gated K+ currents, potentiation of N-methyl-D-aspartate-induced responses, depression of synaptic excitation and either induction or augmentation of long-term potentiation. To clarify the role of metabotropic glutamate receptors in central nervous activity and to aid the characterization of the various receptor types that may be involved, a range of highly selective agonists and antagonists is required. To date, currently available antagonists such as L-2-amino-3-phosphonopropionate and L-aspartic acid-beta-hydroxamate appear to be unselective and insufficiently potent. We report here the actions of three phenylglycine derivatives, the particular agonist and/or antagonist properties of which may help to elucidate the roles of metabotropic glutamate receptors in central nervous activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Inhibition of succinate dehydrogenase by malonic acid produces an "excitotoxic" lesion in rat striatum.

Excitotoxicity and defects in neuronal energy metabolism have both been implicated in the pathogenesis of neurodegenerative disease. These two mechanisms may be linked through the NMDA receptor, activation of which is dependent on neuronal membrane potential. Because the ability to maintain membrane potential is dependent on neuronal energy metabolism, bioenergetic defects may affect NMDA receptor-mediated excitotoxicity. We now report that reversible inhibition of succinate dehydrogenase (SDH), an enzyme central to both the tricarboxylic acid cycle and the electron transport chain, produces an "excitotoxic" lesion in rat striatum that can be blocked by the NMDA antagonist MK-801. Male Sprague-Dawley rats received intrastriatal stereotaxic injections of the SDH inhibitor malonic acid (1 or 2 mumol) in combination with intraperitoneal injections of vehicle or MK-801 (5 mg/kg) 30 min before and 210 min after malonic acid. Animals were killed 72 h after surgery, and brains were processed for histology, cytochrome oxidase activity, and [3H]MK-801 and [3H]AMPA autoradiography. The higher dose of malonic acid (2 mumol) produced large lesions that were markedly attenuated by treatment with MK-801 (28.1 +/- 3.6 vs. 4.7 +/- 2.6 mm3; p < 0.001). [3H]MK-801 and [3H]AMPA binding were reduced in the lesions by 60 and 63%, respectively. One micromole of malonic acid produced smaller lesions that were almost completely blocked by MK-801 treatment (9.6 +/- 1.3 vs. 0.06 +/- 0.04 mm3; p < 0.0001). The toxic effects of malonic acid were due specifically to inhibition of SDH inasmuch as coinjection of a threefold excess of succinate with the malonic acid blocked the striatal lesions (p < 0.002).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗