PubMed Health⌕ Search

Biomedical subjects

J C Hackman

Publications and source records attributed to J C Hackman.

At least 37 records · Page 2Linked to original sources
PubMed1989

NMDA antagonists and potentiation of NMDA-induced motoneuron depolarizations in the isolated frog spinal cord.

The action of N-methyl-D-aspartate (NMDA) antagonists on motoneurons was studied in the isolated, hemisected frog spinal cord using sucrose gap techniques. NMDA-evoked motoneuron depolarizations were depressed by application of APV, APH, kynurenate, Mg2+ ions, ketamine, and MK-801. Upon returning to normal Ringer's solution after exposure to all antagonists (except MK-801). NMDA responses were significantly potentiated. Kainate- and quisqualate-induced depolarizations were unchanged. The facilitation appeared to result, at least in part, from a direct action on motoneuron membranes since it persisted in the presence of tetrodotoxin which eliminated interneuronal firing. However, indirect actions involving interneurons also contributed to the potentiation because NMDA-evoked changes in K+ release were increased following exposure to NMDA antagonists and return to normal medium. Reduction of temperature (7 degrees C) which should reduce amino acid uptake did not affect results with APV. In addition, desensitization of NMDA responses was not altered by application of APV. The results indicate that NMDA antagonists have complex and long-lasting effects on the function of the NMDA receptor complex.

2-Amino-5-phosphonovalerate↗
PubMed1989

Excitotoxicity, reflex responses, and evoked changes in extracellular potassium in the frog spinal cord.

1. The effects of the excitatory amino acid agonists kainate (KA), quisqualate (QUIS), and N-methyl-D-aspartate (NMDA) were studied in vitro on the hemisected frog spinal cord. 2. Prolonged (1.0 hr) application of excitatory amino acid agonists (KA, 50 or 300 microM; QUIS, 30 microM; NMDA, 300 microM) significantly reduced the ventral root potentials (VRPs) and [K+]0 evoked by a dorsal root tetanus (10 sec, 25 Hz), by brief (10 sec) applications of the same agonists (KA, 30 microM; QUIS, 30 microM; NMDA, 300 microM), and by GABA (10 sec, 1.0 mM). 3. The effect was essentially irreversible and persisted despite 2-4 hr of washing. 4. Excitatory amino acid antagonists (APV, 30 microM and kynurenate, 2 mM) blocked the neurotoxic effects of the excitatory agonists NMDA and KA respectively, an observation which indicates the observed effects of the agonists require the activation of specific excitatory receptors. 5. TTX did not alter the neurotoxic effects of KA suggesting that interneuronal firing does not contribute to the observed changes. 6. Addition of high K+ did not duplicate the effect of prolonged excitatory amino acid agonist exposure, an indication that elevation of K+ does not cause the decreased responses. 7. Light microscopy did not provide any evidence of gross tissue damage. 8. The parallel reduction of postsynaptic responses and delta [K+]0 support the idea that elevation of extracellular [K+] by afferent stimuli results from interneuronal activity.

Amino Acids↗
PubMed1988

Excitatory transmitters, ventral root potentials and [K+]o in the isolated frog leg-spinal cord preparation.

Motoneuron depolarizations and changes in [K+]o were studied in the isolated frog spinal cord in response to non-nociceptive (touch/pressure) and nociceptive (acetic acid, heat, pinch) stimulation of the skin of the leg. Kynurenate, APV (D(-)-2-amino-5-phosphonovalerate), and 1.0 mM Mg2+ blocked or substantially reduced responses produced by all types of stimuli. Spantide was minimally effective in reducing nociceptive responses and had insignificant effects on responses to innocuous stimuli. These observations are consistent with the notion that excitatory amino acids activating both N-methyl-D-aspartate (NMDA) and non-NMDA receptors participate in the reflex responses to cutaneous stimuli in the frog spinal cord.

2-Amino-5-phosphonovalerate↗
PubMed1988

Primary afferent activity, putative excitatory transmitters and extracellular potassium levels in frog spinal cord.

1. Changes in extracellular K+ activity were measured with ion-selective microelectrodes in the grey matter of the isolated hemisected frog spinal cord. The magnitude of the elevation of [K+]o (delta[K+]o) produced by repetitive stimulation (25 Hz, 10 s) of afferent fibres in the sciatic nerve was monotonically related to the strength of the electrical stimuli applied to the sciatic nerve. Repetitive stimulation of the largest diameter A alpha and A beta fibres, which were found histologically to comprise only 11% of the afferent axons in the dorsal root, elevated [K+]o to approximately 60% of the maximum level seen when all afferent fibres were stimulated. 2. Addition of Mg2+ (20 mM) to Ringer solution devoid of Mg2+ reduced delta[K+]o by over 85% suggesting that about 15% of delta[K+]o results from action potentials in presynaptic primary afferents. When 20 mM-Mg2+ was added to spinal cords bathed in Ringer solution containing a physiological (i.e. 1.0 mM) concentration of Mg2+, delta[K+]o was reduced by ca. 65-75% indicating that in spinal cords bathed in medium containing 'physiological' concentrations of Mg2+ about 25-35% of the K+ is released from primary afferent fibres. 3. Application of excitatory amino acids and agonists increased [K+]o with the following potency pattern: quisqualate greater than kainate greater than NMDA (N-methyl-D-aspartate) greater than glutamate greater than aspartate. 4. D(-)-2-Amino-5-phosphonovalerate (APV), an NMDA antagonist, reduced [K+]o by only about 50%, but kynurenate, an NMDA and non-NMDA antagonist, reduced [K+]o by approximately 85%; i.e. the same levels observed when synaptic transmission was blocked with 20 mM-Mg2+. These findings support the idea that synaptic release of excitatory amino acids such as L-glutamate and/or L-aspartate and subsequent activation of specific receptors by these putative transmitters are necessary for the postsynaptic component of delta[K+]o. 5. Addition of tachykinins elevated [K+]o but the effect appeared to require the participation of excitatory amino acids because it was blocked by APV and by kynurenate. 6. The finding that tetrodotoxin substantially reduced the ability of excitatory amino acid agonists and tachykinins to elevate [K+]o suggests that discharges in interneurones as a result of excitatory amino acid receptor activation are responsible for the postsynaptic component of delta[K+]o.

Action Potentials↗
PubMed1987

After-hyperpolarizations produced in frog motoneurons by excitatory amino acid analogues.

After-hyperpolarizations (AHPs) produced in frog motoneurons by applications of the excitatory amino acid analogues quisqualate (QUIS), N-methyl-D-aspartate (NMDA), and kainate (KA) were studied in the isolated hemisected frog spinal cord using sucrose gap techniques. AHPs were present following 98% of QUIS-induced depolarizations, but were seen in only 35% and 15% of NMDA- and KA-evoked responses respectively. AHPs produced by QUIS are produced both by direct effects of QUIS on motoneuron membranes and by indirect effects mediated through a synaptic process involving interneurons. Thus, application of Mg2+, Mn2+, or tetrodotoxin (TTX) in concentrations sufficient to block synaptic transmission and interneuronal firing, reduced, but did not abolish the AHPs produced by QUIS. In contrast, NMDA- and KA-AHPs appear to be entirely mediated by indirect means as block of synaptic transmission and interneuronal firing eliminated AHPs produced by these substances. Exposure of the cord to Mn2+ after addition of TTX did not affect the size of QUIS-AHPs. In the presence of TTX, QUIS-AHPs were reduced or completely blocked by addition of dinitrophenol (DNP) and sodium cyanide, by dihydro-ouabain, by removal of K+ from the superfusate, by cooling, and by replacement of 50% of the external Na+ with Li+. The results suggest that the QUIS-AHPs are largely the result of the direct effect of the excitatory amino acid agonist on motoneuron membranes and is caused by activation of an electrogenic Na+ pump. AHPs following depolarizations evoked by NMDA and KA are presumably the result of indirect actions of these latter analogues on interneurons.

2,4-Dinitrophenol↗
PubMed1987

Epinephrine and norepinephrine modulate neuronal responses to excitatory amino acids and agonists in frog spinal cord.

The interaction of the catecholamines epinephrine (E) and norepinephrine (NE) (1.0-100 microM) and excitatory amino acids on motoneurons of the isolated superfused frog spinal cord was investigated by sucrose gap recordings from ventral roots. Exposure of the cord to E or NE 30 sec prior to application of L-aspartate or L-glutamate reduced the motoneuron depolarizations produced by the amino acids. The reduction of responses to the mixed receptor agonists L-glutamate and L-aspartate may be the result of opposite actions of the catecholamines on the activation of specific excitatory receptors by the amino acids. Thus, E and NE facilitated depolarizations caused by application of N-methyl-D-aspartate (NMDA) and depressed those produced by quisqualate. The effect on NMDA responses appeared to be beta-adrenoceptor mediated because it was mimicked by the beta-agonist isoproterenol and blocked by propranolol. The effect on quisqualate depolarizations appeared to require activation of alpha 2-adrenoceptors; it was mimicked by the alpha 2-agonists clonidine and alpha-methylnorepinephrine and antagonized by yohimbine and piperoxan. These results are important in understanding the actions of catecholamines on reflex transmission in spinal pathways which use excitatory amino acids as transmitters.

Amino Acids↗
PubMed1986

Analysis of the responses of frog motoneurons to epinephrine and norepinephrine.

Epinephrine and norepinephrine were applied to the isolated superfused frog spinal cord hyperpolarized motoneurons. The hyperpolarization was related to both direct and indirect actions and the indirect effects were produced by activation of alpha 2-adrenoceptors. In about half of the spinal cords a slow depolarization caused by activation of beta-receptors was seen and was largely attributable to direct actions of the catecholamines on motoneuron membranes. In a small number of preparations an early alpha 1-mediated depolarization was noted. The results suggest that catecholamines released from terminals in the frog ventral horn could exert a modulatory action on the motoneuron output from the spinal cord.

Adrenergic Antagonists↗
PubMed1986

Effects of barium on isolated frog spinal cord.

The effects of Ba2+ were studied in vitro on the isolated frog spinal cord. Ba2+ (25 microM-5 mM) caused a concentration-dependent depolarization of ventral (VR) and dorsal (DR) roots. TTX and Mg2+ substantially reduced the depolarization suggesting that interneuronal effects were involved. Ba2+ (25-500 microM) markedly increased the frequency and duration of spontaneous VR and DR potentials and substantially enhanced the duration (and frequently the amplitude) of VR and DR potentials evoked by DR stimulation. Higher concentrations of Ba2+ (1-5 mM) reduced both spontaneous and evoked potentials. Ba2+ (25-500 microM) enhanced the amount of K+ released by a DR volley and by application of L-glutamate and L-aspartate. The cation reduced VR and DR root depolarizations produced by elevated [K+]0. VR potentials induced by L-glutamate, L-aspartate, GABA and glycine and DR depolarizations caused by GABA were reduced by Ba2+. These results show that Ba2+ has complex actions on reflex transmission, interneuronal activity, the postsynaptic actions of excitatory and inhibitory amino acids and the evoked release of K+.

Action Potentials↗
PubMed1985

Potential changes of frog afferent terminals in response to dopamine.

The actions of dopamine on the membrane potential of afferent fibers of the isolated hemisected frog spinal cord were studied by sucrose gap techniques. The most prominent effect seen after addition of dopamine to the superfusing Ringer's solution was a slow reversible hyperpolarization at concentrations as low as 0.01 microM; its amplitude and duration were dependent upon concentration and length of application. Biphasic responses with an initial dominant hyperpolarization and a much smaller, later depolarization were also noted and were particularly prominent when dopamine was applied at higher concentrations. Exposure of the cord to apomorphine, a non-selective agonist, to SKF 38393A, a D-1 selective agonist, or to LY-14186, a D-2 selective agonist, hyperpolarized the dorsal root in a manner similar to that of dopamine, but only when the former compounds were applied at higher concentrations (100 microM or greater). Apomorphine also elicited a late depolarization. The non-selective dopamine antagonists, fluphenazine and haloperidol, reversibly reduced dopamine's actions. Similar effects were produced by the selective D-2 antagonists, sulpiride and metoclopramide, which had no effect on hyperpolarizations evoked by norepinephrine. Dopamine did not appear to activate adrenergic or serotonergic receptors, for its effects were not affected by yohimbine, corynanthine, propranolol, or methysergide. The effect of dopamine appeared to result from an action of the amine on both afferent fibers and interneurons. This inference was drawn because the potential changes produced by dopamine were substantially reduced, but never eliminated, by superfusion of the cord with solutions containing Mn2+ ions, tetrodotoxin or mephenesin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Epinephrine- and norepinephrine-evoked potential changes of frog primary afferent terminals: pharmacological characterization of alpha and beta components.

The effects of superfused epinephrine (E) and norepinephrine (NE) on the membrane potential of primary afferent fibers of the isolated frog spinal cord were studied by sucrose gap recordings from the dorsal root. In all preparations both E and NE, applied in concentrations ranging from 0.1 microM to 1.0 mM, produced a hyperpolarization of afferent terminals. In many instances this was followed by a slow depolarization and, in a small number of cords, a small depolarization preceded the increase in membrane potential. E- and NE-induced hyperpolarizations were blocked by the selective alpha 2-antagonists yohimbine and piperoxan, but not by the selective alpha 1-antagonists prazosin and corynanthine or by the beta-blockers propranolol and sotalol. The alpha 2-agonists clonidine, alpha-methylnorepinephrine and guanabenz also hyperpolarized terminals, causing a change in potential that was reduced by yohimbine and piperoxan. Taken together, these results suggest that alpha 2-receptors mediate the hyperpolarizing effects of E and NE. The beta-agonist isoproterenol evoked a slow depolarization similar to that produced by E and NE. The isoproterenol-depolarization was antagonized by propranolol. Sometimes, application of E and NE after superfusion with yohimbine produced only a depolarization of the dorsal root and this depolarization was sensitive to propranolol. It would appear therefore that the late depolarization seen after the application of E and NE is produced by activation of beta-receptors. In contrast, the alpha 1-agonist phenylephrine elicited a short latency, short duration depolarization similar to those seen preceding approximately 10% of the E- and NE-hyperpolarizations. Such short-latency depolarizations were blocked by prazosin and corynanthine. The major component of the response to both E and NE is indirectly mediated through a synaptic process: application of Mn2+, Mg2+, procaine or tetrodotoxin in concentrations sufficient to block synaptic transmission substantially reduced, but never eliminated, the actions of the catecholamines. Interneurons are probably involved because mephenesin, which reduces interneuronal transmission, significantly decreased the E and NE effects. Furthermore, interneurons which secrete excitatory amino acids and/or GABA may mediate the indirect effects of the catecholamines on afferent terminals because (-)baclofen and D.L-alpha-aminoadipate decrease, and picrotoxin and bicuculline increase, the dorsal root (DR) effects of E and NE.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenergic Agonists↗
PubMed1984

Spontaneous dorsal root potentials arise from interneuronal activity in the isolated frog spinal cord.

Spontaneous dorsal root potentials (sDRPs) were recorded from the dorsal roots of the isolated frog spinal cord using sucrose gap techniques. sDRPs were always negative (depolarizing) in sign and ranged in size from about 100 microV to 6.0 mV. The largest sDRPs were 25-40% of the amplitude of DRPs evoked by stimulation of adjacent dorsal roots. Hypoxia or accumulation of extracellular K+ ions did not appear responsible for the generation of this spontaneous activity since exposing the cord to unoxygenated Ringer's solution decreased sDRPs and K+-sensitive microelectrodes indicated that only small changes in extracellular K+ (approximately 0.15 mM) were produced coincidently with the largest sDRPs. Chemically-mediated synaptic transmission was found to be necessary for the production of sDRPs because the addition of Mn2+ or Mg2+ ions or tetrodotoxin to the Ringer's solution or reduction of its Na+ concentration blocked sDRPs, whereas application of 4-aminopyridine enhanced them. It did not seem that a direct action of GABA on afferent fiber terminals was responsible for the generation of spontaneous potentials since an increase in sDRPs was seen after: application of the GABA antagonists, bicuculline and picrotoxin; exposure to the glutamic acid decarboxylase inhibitor, semicarbazide (which significantly reduced the concentration of GABA in the cord); and lowering of the external Cl- concentration. Similarly taurine is probably not significant since the taurine antagonist, TAG, increased the amount of spontaneous activity. On the other hand, (--)-baclofen, which is thought to reduce excitatory amino acid release, D,L-alpha-aminoadipic acid, alpha, epsilon-diaminopimelic acid, and 2-amino-4-phosphonobutyric acid, which are believed to be selective postsynaptic excitatory amino acid antagonists, and [D-Pro2-D-Phe7-D-Trp9]-substance P, a postsynaptic blocker of the action of substance P, markedly and reversibly reduced sDRPs. Experiments were performed on isolated cords without supraspinal or afferent input; therefore sDRPs must be generated by intraspinal structures. It would seem that interneurons are responsible because addition of mephenesin or pentobarbital--compounds which inhibit polysynaptic reflex transmission involving interneurons--reduced the production of sDRPs. sDRPs may result from the action of excitatory transmitters such as L-glutamate, L-aspartate, or substance P released by interneuronal firing in the spinal cord. Moreover, because sDRPs were increased by application of yohimbine, corynanthine and propanolol and reduced by haloperidol, such interneurons may be under descending control of adrenergic and dopaminergic fibers.

Afferent Pathways↗
PubMed1984

Spinal seizures and excitatory amino acid-mediated synaptic transmission.

In the isolated frog spinal cord penicillin or strychnine produced spinal seizures with spontaneous slow paroxysmal ventral root depolarizations (pVRDs) and superimposed motoneuron spikes. Mn2+, tetrodotoxin, mephenesin and low [Na+]o suppressed pVRDs, an indication that paroxysmal activity requires intact excitatory synaptic transmission involving interneurons. Compounds reducing the release of amino acids [-)baclofen) or interfering with the activation of N-methyl-D-aspartic acid (NMDA) receptors (D,L-alpha-aminoadipate, D-2-amino-5-phosphonovalerate, gamma-D-glutamylglycine) eliminated pVRDs. The results suggest that synaptic release of excitatory amino acids (e.g. L-glutamate, L-aspartate) and subsequent activation of specific receptors sensitive to the action of NMDA underlie spinal convulsions.

Afferent Pathways↗
PubMed1983

Catecholamine effects on frog dorsal root terminals.

Dopamine, norepinephrine and epinephrine applied to the isolated superfused frog spinal cord had complex effects on the terminals of primary afferent fibers. The most consistent finding was a slow hyperpolarization of terminals with lower concentrations (10 microM or lower), but depolarizations either following or admixed with the hyperpolarizations were seen. These were particularly prominent when the catecholamines were applied in high concentrations or for prolonged periods of time. A part of the response of afferent terminals appears to be indirect since the potential changes were reduced following exposure of the cord to tetrodotoxin, Mn2+, or mephenesin. The hyperpolarizations were augmented by imipramine, a known inhibitor of catcholamine uptake. These observations are consistent with a role of catecholamines in the processing of sensory input in the spinal cord.

Animals↗
PubMed1982

GABA 'desensitization' of frog primary afferent fibers.

GABA (gamma-aminobutyric acid) depolarizes the terminals of primary afferent fibers of the in vitro hemisected frog spinal cord. During sustained or repetitive exposure to GABA or to muscimol, the amplitude of the depolarization is characterized by a rapid and exponential decline to a steady plateau level (desensitization). Desensitization to muscimol was eliminated by removal of Ca2+ and addition of Mn2+ to the superfusate--a finding consistent with the presence of 'receptor' ('true') desensitization (i.e., receptor inactivation). GABA desensitization was significantly reduced by exposure of the cord to either low Na+, low temperature, ouabain, dinitrophenol, (+/-)-nipecotic acid, or cis-1,3-aminocyclohexanecarboxylic acid. These treatments also significantly decreased the high affinity uptake of GABA when the latter process was studied by incubating frog spinal slices in Ringer's solution containing a low concentration of [3H]GABA. These results suggest that cellular transport processes can influence the form of GABA responses and indicate that neuronal removal of GABA is responsible in part for GABA desensitization.

Afferent Pathways↗
PubMed1982

Excitatory amino acids and potassium release in the frog spinal cord.

Synaptic release of excitatory amino acids such as L-glutamate and/or L-aspartate and subsequent activation of specific receptors by these putative transmitters appears necessary for the release of K+ by afferent stimulation in the isolated frog spinal cord. This conclusion is based on the findings that (-)baclofen, which is thought to reduce the presynaptic release of putative excitatory amino acid transmitters, and some amino dicarboxylic amino acids (D, L-alpha-aminoadipic acid, 2-amino-4-phosphonobutyric acid, and D, L-alpha, epsilon-diaminopimelic acid), which are believed to interfere with the activation of receptors by these same excitatory amino acids, significantly attenuate the increment in extracellular K+ evoked by tetanic dorsal root stimulation.

Afferent Pathways↗
PubMed1981

The presynaptic effects of valproic acid in the isolated frog spinal cord.

The effects of the anticonvulsant valproic acid (n-dipropylacetate, DPA) on frog primary afferent fibers was examined with sucrose gap recordings from the dorsal roots. Addition of DPA to the superfusate consistently reduced the amplitude and duration of the dorsal root potential. In contrast, DPA augmented the depolarization of dorsal roots produced by GABA, beta-alanine and taurine. It also decreased afferent fiber 'desensitization' to GABA. DPA depressed the ability of K+ and the excitatory amino acids glutamate and aspartate to depolarize afferent fibers. In addition, the compounds decreased the amount of K+ released by tetanic stimulation of the dorsal root. The K+-evoked release of tritiated GABA from cord slices was initially reduced by exposure to DPA, but was then unaffected after a longer application of the anticonvulsant. On the other hand, the high affinity uptake of tritiated GABA and glycine were almost totally blocked by the addition of DPA to the incubating medium. In sum, DPA has complex effects on neuronal membranes. Some of these effects may serve to explain the anticonvulsant actions of this drug.

Afferent Pathways↗