Biomedical subjects

D M Lovinger

Publications and source records attributed to D M Lovinger.

At least 73 records · Page 4Linked to original sources

PubMed1991

Trans-1-aminocyclopentane-1,3-dicarboxylic acid (t-ACPD) decreases synaptic excitation in rat striatal slices through a presynaptic action.

Excitatory synaptic transmission was decreased in the presence of trans-1-aminocyclopentane-1,3-dicarboxylic acid (t-ACPD) during whole-cell recordings from striatal slices. This effect of t-ACPD increased in a concentration-dependent manner at drug concentrations from 5-100 microM. Decreased transmission appeared to result from a presynaptic effect as indicated by the observations that: (1) t-ACPD decreased the amplitude of excitatory postsynaptic potentials (EPSPs) mediated by either quisqualate alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) or N-methyl-D-aspartate (NMDA) receptors, but did not block responses to agonist application; indicating that t-ACPD is not a glutamate receptor antagonist; (2) t-ACPD decreased transmission in the absence of changes in postsynaptic cell properties. The t-ACPD-activated receptor appears to differ from previously identified presynaptic receptors. These findings indicate that t-ACPD activates a presynaptic receptor; most likely a glutamate receptor.

Animals↗

PubMed1991

Ethanol potentiation of 5-HT3 receptor-mediated ion current in NCB-20 neuroblastoma cells.

The effect of acute ethanol (EtOH) exposure on 5-HT3 receptor-mediated ion current was examined in whole-cell patch-clamp recordings from NCB-20 neuroblastoma cells. The physiologic and pharmacologic properties of 5-HT-activated ion current in NCB-20 cells indicated that it was mediated by 5-HT3 receptors. EtOH potentiated 5-HT3 receptor-mediated current in a concentration-dependent manner at concentrations (25-100 mM) which are achieved during EtOH intoxication in vivo.

Ethanol↗

PubMed1991

Alcohol and anesthetic actions on excitatory amino acid-activated ion channels.

The actions of alcohol and anesthetics have been studied on excitatory amino acid activated ion channels in mammalian neurons. Ethanol inhibits NMDA-activated current over a concentration range that produces intoxication, and the potency of several alcohols for inhibiting the NMDA-activated current is correlated with their intoxicating potency, suggesting that alcohol-induced inhibition of responses to NMDA receptor activation may contribute to the neural and cognitive impairments associated with intoxication. Studies on the mechanism of ethanol inhibition of NMDA-activated current indicate that ethanol does not appear to block the ion channel, alter the ion selectivity of the channel, or interact with previously described binding sites on the NMDA receptor/ionophore complex. The linear relation between the potency of several alcohols for inhibiting the NMDA-activated current and the hydrophobicity of the alcohols suggests that ethanol may inhibit the NMDA-activated ion current by a novel type of interaction with a hydrophobic site associated with the NMDA channel. In addition, different types of general anesthetic agents exhibit different inhibitory actions on NMDA-, kainate-, and quisqualate-activated currents, suggesting that differences in the profile of inhibition of excitatory amino acid neurotransmission in the CNS among different classes of general anesthetics may contribute to the differences in their behavioral and physiological effects.

Alcohols↗

PubMed1991

Inhibition of 5-HT3 receptor-mediated ion current by divalent metal cations in NCB-20 neuroblastoma cells.

1. The effect of micromolar concentrations of divalent metal cations on ion current activated by 5-hydroxytryptamine (5-HT) was investigated in NCB-20 neuroblastoma cells by the use of the whole-cell, patch-clamp technique. 2. Ion current activated by 5-HT in these cells was mimicked by 5-HT3 receptor agonists, blocked by nanomolar concentrations of selective 5-HT3 receptor antagonists and reversed polarity at approximately 0 mV. These properties indicate that this current is carried primarily if not exclusively by the nonspecific cation channel activated by the 5-HT3 receptor. 3. The Group IIb metal cations Cd2+ and Zn2+ and the Group Ib cation Cu2+ inhibited 5-HT-activated current with inhibition increasing in a concentration-dependent manner over micromolar concentrations of the ions. The order of potency of the ions for inhibiting 5-HT-activated current was Zn2+ (IC50 = 20 microM) greater than or equal to Cu2+ (IC50 = 25 microM) greater than Cd2+ (IC50 = 75 microM) at -50 mV. The other divalent metal cations tested (Ba2+, Co2+, Mg2+, Mn2+, and Ni2+) produced little or no inhibition of 5-HT-activated current at concentrations up to 200 microM. 4. Inhibition of 5-HT-activated current by Cd2+ and Zn2+ was dependent on membrane potential with the Kd increasing e-fold per 72 and 52 mV, respectively. Inhibition by Cu2+ was much less voltage dependent with the Kd increasing e-fold per 233 mV. 5. Inhibition by all three cations decreased with increasing concentration of agonist over a range of 5-HT concentrations from 1 to 10 microM.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Ethanol potentiation of 5-hydroxytryptamine3 receptor-mediated ion current in neuroblastoma cells and isolated adult mammalian neurons.

Recent studies indicate that ethanol (EtOH) potentiates ion current through the channel associated with the 5-hydroxytryptamine3 (5-HT3)-type serotonin receptor. The present study was designed to determine 1) whether such potentiation occurs in adult mammalian neurons expressing 5-HT3 receptors; 2) whether potentiation is selective for the 5-HT3 receptor, relative to other ligand-gated ion channels; and 3) possible mechanisms by which EtOH potentiates this response. EtOH potentiated 5-HT3 receptor-mediated ion current in freshly isolated nodose ganglion neurons at concentrations similar to those previously reported to be effective in neuroblastoma cells (25-100 mM). Current was blocked by the selective 5-HT3 antagonist ICS 205-930 even in the presence of EtOH, and current activated by a 5-HT3 agonist (2-methyl-5-HT) was potentiated by EtOH. Thus, EtOH appears to produce potentiation via an alteration in the function of 5-HT3 receptors and not through an independent effect. gamma-Aminobutyric acidA receptor-mediated Cl- current was not potentiated by EtOH in neurons in which potentiation of responses to 5-HT was observed. Methanol potentiated 5-HT3 receptor-mediated current with a potency lower than that of EtOH. Potentiation by EtOH decreased with increasing 5-HT concentration. In addition, EtOH increased the decay rate of current. EtOH did not alter the reversal potential of the 5-HT3 receptor-mediated current. These observations indicate that intoxicating concentrations of EtOH selectively potentiate 5-HT3 receptor-mediated responses by increasing the apparent potency of 5-HT for activating ion current.

Animals↗

PubMed1991

Alcohol inhibition of NMDA channel function.

In mammalian central neurons, intoxicating concentrations of ethanol inhibit the ion current activated by the glutamate agonist N-methyl-D-aspartate (NMDA). Electrophysiologic analysis of the molecular mechanism involved in this inhibition indicates that ethanol does not inhibit NMDA-activated ion current by voltage-dependent block of the channel, altering the ion selectivity of the channel, or altering the affinity of binding sites for NMDA, glycine or substances known to regulate the function of this channel (Mg2+, Zn2+ and ketamine). The potency for inhibiting the NMDA-activated current by different alcohols is linearly related to their hydrophobicity, suggesting that alcohols may inhibit the NMDA-activated current by a novel type of interaction with a hydrophobic region of the channel.

Alcohols↗

PubMed1991

Ethanol potentiates ion current mediated by 5-HT3 receptors on neuroblastoma cells and isolated neurons.

Effects of ethanol on receptor/channel complexes appear to play an important role in acute intoxication. One such receptor that has not previously been investigated for ethanol sensitivity is the 5-HT3 receptor for the neurotransmitter serotonin. Ethanol potentiates ion current mediated by 5-HT3 receptors in NCB-20 neuroblastoma cells and isolated Nodose ganglion neurons examined with whole-cell patch-clamp recording. Potentiation increases in a concentration-dependent manner over a range of concentrations (25-100 mM) achieved during acute intoxication. Potentiation appears to be due to a direct effect on the 5-HT3 receptor. Ethanol's effect on 5-HT3 receptor-mediated current decreases with increasing agonist concentration, providing an initial clue as to the mechanism of ethanol's action. These data are discussed in light of recent behavioral data suggesting a role for 5-HT3 receptors in the discriminative stimulus and reinforcing properties of ethanol.

Animals↗

PubMed1990

Inhibition of N-methyl-D-aspartate activated ion current by desmethylimipramine.

The tricyclic antidepressant desmethylimipramine (DMI) interacts with the NMDA receptor/ionophore complex; however, the site of the interaction has not been clearly established. Although evidence from receptor binding assays suggests that DMI interacts with the Zn2+ binding site, other binding studies and electrophysiological studies suggest otherwise. Using the whole-cell patch clamp technique to record from cultured hippocampal neurons, we report that recovery of NMDA-activated current from block by DMI is time-dependent and this time-dependent component was not observed following preexposure of neurons to Zn2+. These observations favor the hypothesis that DMI interacts at a binding site within the NMDA receptor/complex channel pore and not at the Zn2+ binding site.

Animals↗

PubMed1990

The actions of 2-hydroxy-saclofen at presynaptic GABAB receptors in the rat hippocampus.

The actions of 2-hydroxy-saclofen (2-OH-S), a recently developed analog of baclofen, were studied at presynaptic GABAB receptors in the rat hippocampal slice. Baclofen (0.5-20 microM) reduces the amplitude of excitatory postsynaptic potentials (EPSPs) recorded from hippocampal CA1 pyramidal neurons. In the presence of 200-500 microM 2-OH-S, the synaptic depressant action of baclofen is significantly reduced. These data show that 2-OH-S is an effective antagonist at presynaptic GABAB receptors on excitatory terminals in the hippocampus.

Animals↗

PubMed1990

Ethanol inhibits NMDA-activated current but does not alter GABA-activated current in an isolated adult mammalian neuron.

The effects of ethanol (EtOH) on membrane ion currents activated by N-methyl-D-aspartate (NMDA) and gamma-aminobutyric acid (GABA) were studied under voltage-clamp conditions in isolated sensory neurons within hours of being dissociated from adult rats. The amplitude of the ion current activated by NMDA was decreased in the presence of 2.5-100 mM EtOH (IC50, 10 mM or 0.05% EtOH), a concentration range that produces intoxication. The amplitude of the GABA-activated Cl- current, on the other hand, was not significantly affected by this concentration range of EtOH. The observations suggest that some of the neural and cognitive impairments associated with EtOH intoxication may result from inhibition of the NMDA-activated ion current.

Animals↗

PubMed1990

Ethanol inhibition of neuronal glutamate receptor function.

Acute ethanol intoxication is associated with changes in the activity of neurons in the central nervous system. However, the cellular and molecular mechanisms underlying these changes are poorly understood. We have examined the acute effects of ethanol on excitatory synaptic mechanisms in neurons from mammalian central nervous system, and observed that intoxicating concentrations of ethanol can inhibit the ion current activated by the glutamate receptor agonist N-methyl-D-aspartate in cultured neurons from mouse hippocampus, cortex and spinal cord. This inhibition is seen under a variety of experimental recording conditions. On the other hand, ethanol is less effective in inhibiting ion current produced by activation of non-N-methyl-D-aspartate glutamate receptors. Intoxicating concentrations of ethanol also inhibit excitatory synaptic transmission mediated by N-methyl-D-aspartate receptors in hippocampal slices from adult rodents. These observations support the hypothesis that the N-methyl-D-aspartate receptor/ionophore complex is a target for the neural actions of ethanol, and that inhibition of N-methyl-D-aspartate receptor-mediated responses might contribute to acute ethanol intoxication. The possibility that other receptor-gated ion channels may also be sensitive to ethanol is discussed.

Action Potentials↗

PubMed1990

NMDA receptor-mediated synaptic excitation selectively inhibited by ethanol in hippocampal slice from adult rat.

The effect of ethanol (EtOH) on synaptic transmission mediated by N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptors was investigated in slices from adult rat hippocampus. Synaptic responses were elicited by stimulation of stratum radiatum and were recorded in CA1 stratum radiatum or stratum pyramidale. Population EPSPs (pEPSPs) mediated by NMDA receptor activation were isolated by application of a solution containing the kainate/quisqualate receptor antagonist 6,7-dinitroquinoxaline-2,3-dione and either low (0.1 mM) Mg2+ or 100 microM bicuculline. Increasing concentrations of EtOH produced increasing inhibition of NMDA receptor-mediated pEPSPs with EtOH concentrations between 1 and 50 mM. At a concentration of 50 mM, EtOH inhibited NMDA receptor-mediated pEPSPS by 43%; the inhibition by 100 mM EtOH was not significantly different from that produced by 50 mM. Methanol and 1-butanol also inhibited the NMDA receptor-mediated pEPSPs; the potency of the alcohols for inhibition of NMDA receptor-mediated pEPSPs was 1-butanol greater than ethanol greater than methanol. pEPSPs mediated by non-NMDA glutamate receptors were isolated by the application of the NMDA receptor antagonist d,1-2-amino-5-phosphonovaleric acid in the presence of 1.5 mM Mg2+. These pEPSPs were not significantly affected by 50 mM EtOH, whereas 100 mM EtOH reduced the amplitude of these pEPSPs by 9%. The observations indicate that synaptic excitation mediated by NMDA receptors in tissue from adult rat is inhibited by intoxicating concentrations of EtOH. The data are consistent with the hypothesis that EtOH-induced inhibition of EPSPs mediated NMDA receptors may contribute to the intoxicating effects of EtOH.

Animals↗

PubMed1989

Post-natal development of burst firing behavior and the low-threshold transient calcium current examined using freshly isolated neurons from rat dorsal root ganglia.

Burst firing was triggered by an afterdepolarizing potential (ADP) in whole-cell recordings from neurons recently isolated from dorsal root ganglia (DRG) of adult rats, less frequently in neurons from 12-day-old rats, and not at all in neurons from 1-day-old rats. Both the ADP and voltage-activated transient (T-type) Ca2+ current which generates the ADP were present in neurons at all postnatal ages; however, the amplitude of the ADP and of the T-type current were greatest in neurons from adults, smaller in neurons from 12-day animals, and smallest in neurons from 1-day animals. These observations suggest that the increase in amplitude of the T-type current with age leads to the generation of an ADP of increased amplitude and those properties of the ADP which develop with age may contribute to or generate burst firing behavior.

Action Potentials↗

PubMed1989

Ethanol inhibits NMDA-activated ion current in hippocampal neurons.

The ion current induced by the glutamate receptor agonist N-methyl-D-aspartate (NMDA) in voltage-clamped hippocampal neurons was inhibited by ethanol (EtOH). Inhibition increased in a concentration-dependent manner over the range 5 to 50 mM, a range that also produces intoxication. The amplitude of the NMDA-activated current was reduced 61 percent by 50 mM EtOH; in contrast, this concentration of EtOH reduced the amplitude of current activated by the glutamate receptor agonists kainate and quisqualate by only 18 and 15 percent, respectively. The potency for inhibition of the NMDA-activated current by several alcohols is linearly related to their intoxicating potency, suggesting that alcohol-induced inhibition of responses to NMDA receptor activation may contribute to the neural and cognitive impairments associated with intoxication.

1-Butanol↗

PubMed1989

Transient low-threshold Ca2+ current triggers burst firing through an afterdepolarizing potential in an adult mammalian neuron.

In a variety of mammalian neurons, a brief depolarization generates an afterdepolarizing potential that triggers the firing of a short series or burst of action potentials. Although such burst firing is thought to contribute to the processing of neural information, the ionic currents that underlie this phenomenon have not been established. In whole-cell patch-clamp experiments on dorsal root ganglion neurons, we have found that the current that underlies this type of burst firing is a transient low-threshold (T-type) Ca2+ current. The data suggest that the T-type Ca2+ current may play an important role in the processing of information in the nervous system by virtue of its ability to elicit burst firing in neurons.

Action Potentials↗

PubMed1988

Glutamate induces a depolarization of adult rat dorsal root ganglion neurons that is mediated predominantly by NMDA receptors.

The effects of glutamate, glutamate receptor agonists and substances that affect glutamate responses were studied, using the whole-cell patch-clamp technique, on neurons isolated from adult rat dorsal root ganglia. In current-clamp, glutamate (100 microM) or the excitatory amino acid receptor agonist N-methyl-D-aspartate (NMDA; 10 or 100 microM) induced membrane depolarization. Under voltage-clamp, these compounds induced an inward current that was voltage-dependent in the presence of Mg2+. The NMDA-induced current was inhibited by the NMDA receptor antagonist D,L-2-amino-5-phosphono-valerate (APV; 100 microM), and potentiated by 100 nM glycine. Few neurons responded to the receptor agonists kainate (100 microM), or quisqualate (1-10 microM). These observations suggest that glutamate-induced depolarization of primary sensory neurons is mediated predominantly by NMDA receptors.

2-Amino-5-phosphonovalerate↗

PubMed1988

Synapse-specific protein kinase C activation enhances maintenance of long-term potentiation in rat hippocampus.

1. Protein kinase C (PKC) stimulators, 12-O-tetradecanoyl-phorbol-13-acetate (TPA) or cis-unsaturated fatty acid (UFA), have been shown to prolong synaptic enhancement induced by long-term potentiation (LTP). This observation suggests a role for PKC in the biochemical mechanisms underlying maintained enhancement. 2. To determine if PKC stimulators prolong LTP by acting selectively at synapses given high-frequency stimulation or by actions that are not synapse-specific (e.g. increased postsynaptic excitability) we examined the effect of TPA or UFA on input-selective enhancement. Population EPSPs, evoked in the same granule cell population by either the medial (MPP) or lateral (LPP) perforant path, can be selectively enhanced leaving the other perforant path input which receives only low-frequency stimulation as an internal control for PKC stimulator effects not specific to enhanced synapses. 3. Synapse-specific effects were in fact observed, as UFA or TPA selectively prolonged MPP enhancement following two trains of high-frequency MPP stimulation, without affecting responses evoked by the LPP. A similar synapse selectivity of PKC stimulator action was seen following high-frequency LPP stimulation. 4. These findings suggest that PKC stimulators prolong enhancement by acting specifically at high-frequency-stimulated synapses. PKC stimulators do not appear to affect either postsynaptic neurone excitability or synapses given only low-frequency stimulation. This provides further evidence that PKC acts synergistically with the consequences of repetitive synaptic activation to maintain enhancement.

Action Potentials↗

PubMed1987

Protein kinase C inhibitors eliminate hippocampal long-term potentiation.

Recent findings suggest that protein kinase C (PKC) regulates the persistence of long-term potentiation (LTP). To test the hypothesis that PKC inhibition would decrease persistence of potentiation we applied PKC inhibitors (mellitin, polymyxin B, H-7) by micropressure ejection to the intact hippocampus either before or after LTP induction. When inhibitor was given 15 min before LTP, initial potentiation was unaffected, yet responses decayed to baseline levels by 60 min after the onset of potentiation. PKC inhibitor treatment 10 min after LTP onset induced decay of responses to pre-LTP baseline levels within 50 min of ejection. Inhibitor applied 60 min after LTP onset induced substantial decay but not to baseline levels. Potentiation was unaffected by inhibitor treatment 4 h after the induction of LTP. Measurement of PKC subcellular distribution revealed that inhibitor significantly reduced the proportion of PKC associated with the membrane. These findings represent the first demonstration that PKC inhibitors prevent persistence of potentiation. They also suggest that PKC regulates the persistence of synaptic enhancement beginning after its onset, and that PKC's role decreases with time after the induction of enhancement.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗