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F F Weight

Publications and source records attributed to F F Weight.

At least 19 recordsLinked to original sources
PubMed1992

Ethanol dependence and withdrawal selectively alter localized cerebral glucose utilization.

The 2-deoxyglucose technique was used to determine local cerebral glucose utilization (LCGU) in over 50 brain regions of rats physically dependent upon ethanol and compared to those of acutely intoxicated and those undergoing an overt ethanol-withdrawal syndrome. Dependent-intoxicated rats (average blood ethanol concentration 64 mM) had decreased LCGU in 13/54 regions, including those associated with the limbic system, cerebellum, and motor system. The ethanol withdrawal syndrome was associated with 17/50 gray regions showing an increase, including regions involved with motor function, auditory system, and mammillary bodies-anterior thalamus-cingulate cortex pathway. The most pronounced differences between these groups occurred in regions associated with motor function, cerebellar function, anterior thalamus, and median raphe. Comparisons between dependent-intoxicated and acutely intoxicated rats (average blood ethanol concentration 66 mM) revealed that acute intoxication was associated with a relatively greater reduction in LCGU in regions involved with sensory-related functions, mammillary bodies, and median raphe. With the development of dependence, adaptation occurred in these regions except for inferior colliculus and median raphe. Dependence was also associated with a relative decrease in LCGU in white matter, limbic system, and extrapyramidal motor system.

Animals↗
PubMed1992

Ethanol inhibition of N-methyl-D-aspartate-activated ion current in rat hippocampal neurons is not competitive with glycine.

The interaction of ethanol with glycine at the N-methyl-D-aspartate (NMDA)-activated ion channel was investigated in voltage-clamped rat cultured hippocampal neurons. As shown previously, glycine increased, and ethanol inhibited, the NMDA-activated current in these cells. Concentration-response data for glycine (0.1-100 microM) indicate that the inhibition of NMDA-activated current by ethanol does not involve a competitive interaction with glycine. Thus, ethanol appears to inhibit NMDA-activated current at a locus different from the glycine modulatory site.

Animals↗
PubMed1992

Labelling and recording from dissociated target-specific rat superior cervical ganglion neurons.

A population of neurons was retrogradely labelled in the superior cervical ganglia (SCG) of the adult rat following the injection of the fluorescent dye Fast blue into the submandibular salivary glands (SMG). The neurons retained the fluorescent label following dissociation and culture. Electrical and chemosensitive properties of the labelled neurons were studied with the whole-cell patch-clamp technique.

Acetylcholine↗
PubMed1992

GABA- and glutamate-gated ion channels as molecular sites of alcohol and anesthetic action.

The evidence presented above indicates that GABA- and glutamate-activated ion channels are molecular sites of alcohol and anesthetic action. In view of the important role that these channels play in CNS excitability, it seems likely that the actions of alcohol and anesthetics on these channels contribute significantly to the behavioral effects of these agents. Although the behavioral effects of alcohol and anesthetics may well result from a combination of actions on different ion channels and other molecular sites in the CNS, it is of interest to consider whether the actions of these agents on particular types of ion channels may contribute to particular behavioral effects. In this regard, it should be noted that benzodiazepines potentiate GABAA responses, but do not produce intoxication or general anesthesia in their clinical dose range. Benzodiazepines are widely used clinically, primarily for their anxiolytic actions (26), suggesting that the potentiation of GABAA responses by ethanol and barbiturates may contribute to the anxiolytic effects of these agents. Since kainate and quisqualate channels mediate fast excitatory transmission in the CNS, inhibition of kainate and quisqualate receptor-activated responses would be expected to result in general CNS depression. This suggests that inhibition of kainate and quisqualate receptor-mediated responses may contribute to the general anesthetic effects of ethanol, trichloroethanol and barbiturates. NMDA channels are thought to mediate complex excitatory neural phenomena and cognitive function. In view of this, the observation that ethanol inhibits NMDA receptor-mediated responses over the concentration range that produces intoxication and the correlation between the potency of different alcohols for inhibiting NMDA-activated current and their potency for producing intoxication suggest that ethanol-induced inhibition of NMDA receptor-mediated responses may contribute to the intoxicating effects of ethanol. Although these speculations are no doubt oversimplifications, the recognition that GABA- and glutamate-gated ion channels are molecular sites of alcohol and anesthetic action provides a basis for investigating the molecular mechanisms involved in the action of these agents and the behavioral significance of those actions.

Alcohols↗
PubMed1991

TTX-sensitive action potentials and excitability of adult rat sensory neurons cultured in serum- and exogenous nerve growth factor-free medium.

The excitability of adult rat dorsal root ganglion (DRG) neurons cultured in the absence of serum and exogenously added nerve growth factor (NGF) was studied. Current-clamp recordings revealed the presence of tetrodotoxin (TTX)-sensitive action potentials. Voltage-clamp recordings demonstrated the presence of both inward and outward currents. The inward Na+ current had a maximal amplitude near -10 mV and was completely blocked by TTX. A sustained Ca2+ inward current and a slowly activating outward K+ current were also observed. TTX-sensitive and TTX-resistant action potentials have been observed in previous studies in DRG neurons cultured in the presence of serum. By contrast, in the study reported here, only TTX-sensitive action potentials and Na+ currents were found in the neurons cultured in the absence of serum and nerve growth factor.

Action Potentials↗
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

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↗
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

Cerebral glucose utilization during diazepam withdrawal in rats.

The diazepam withdrawal syndrome in rats was characterized behaviorally by an increase in spontaneous motor activity, slight body tremor and a lack of convulsions. The 2-deoxyglucose (2-DG) technique was used to measure quantitatively cerebral glucose utilization during diazepam withdrawal and revealed changes in glucose utilization in 30% of the 54 structures evaluated. Areas of increased glucose utilization included medial geniculate, inferior colliculus, visual cortex, mammillary body, dorsal hippocampus, cerebellar flocculus, and zona reticulata and globus pallidus, olfactory cortex, nucleus accumbens and internal capsule. There was no single or consistent relationship between reported benzodiazepine receptor densities and glucose utilization.

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

Effect of adrenalectomy on ethanol-associated immunosuppression.

The alterations in lymphoid cell numbers and lymphocyte function due to administration of ethanol was found to be associated with high levels of circulating corticosteroids. The role of corticosteroids in the ethanol-induced alterations in the immune system was studied by administering ethanol to adrenalectomized rats. The results of these experiments showed that the ethanol-induced loss of cells from the thymus was not completely prevented by adrenalectomy and the ethanol-induced loss of cells from the spleen was not affected by adrenalectomy. Likewise the ethanol-induced decrease in antibody production to the T-cell-dependent antigen sheep erythrocytes were not affected by adrenalectomy. The ability of animals to produce antibodies of the T-cell-independent antigen, TNP-Ficoll, was not affected by ethanol regardless of whether the animals had adrenal glands or not. These data indicate that adrenal corticosteroids are responsible for some but not all of the thymic involution due to ethanol intoxication. Also, adrenalectomized rats did not show as much impairment in lymphocyte proliferation as sham adrenalectomized animals after ethanol administration. However, this loss of cells from peripheral lymphoid organs such as the spleen and the decreased ability to respond to T-cell-dependent antigens is not influenced by adrenalectomy indicating mechanisms other than corticosteroids mediate these effects of ethanol.

Adrenalectomy↗
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

Cerebral glucose utilization in rat brain during phenobarbital withdrawal.

The phenobarbital withdrawal syndrome in rats is characterized by tremors, arched back, weight loss and hyperactivity. This syndrome is shown to be associated with both general and localized increases in cerebral glucose utilization. An increase in glucose utilization (significant at the P less than or equal to 0.001 level) was observed in 72% of the 57 structures examined. Increases in glucose utilization of greater than or equal to 180% of control values were noted in structures associated with the motor system (columns in the frontal sensorimotor cortex, globus pallidus, dentate nucleus of the cerebellum and ovoid areas in the cerebellar vermis), thalamic nuclei (lateral and posterior), dorsal lateral geniculate, mammillary body, cingulate cortex, locus ceruleus, and cerebellar flocculus and paraflocculus. The structures showing the greatest increase in glucose utilization were cerebellar paraflocculus (257% of control), columns in the frontal sensorimotor cortex (247% of control) and ovoid areas in the cerebellar vermis (223% of control). Areas of the brain that have been described as cell body areas for serotonergic (raphe), noradrenergic (locus ceruleus), dopaminergic (substantia nigra, zona compacta) and GABAergic (globus pallidus) neurons also showed increases in glucose utilization. The pattern of cerebral glucose utilization accompanying the phenobarbital withdrawal syndrome in rats contrasts with that for morphine withdrawal and exhibits both similarities and differences with respect to ethanol withdrawal.

Animals↗
PubMed1989

Quinine potently blocks single K+ channels activated by dopamine D-2 receptors in rat corpus striatum neurons.

In single channel recordings from acutely dissociated neurons of the rat corpus striatum, a membrane K+ channel which is activated by dopamine D-2 receptors was blocked by nanomolar concentrations of quinine. An intermittent partial blockade was observed at 4-10 nM quinine, with a voltage dependence consistent with quinine binding to the channel near the extracellular surface of the membrane. A nearly complete blockade of channel current was observed at 100 nM quinine and above. Such concentrations are known to be too low to block various other ion channels, and may be attained in human brain at antimalarial dosages of quinine. Blockade of this channel by quinine may provide a useful experimental probe of dopaminergic function, as an alternative to D-2 receptor binding site blockade by neuroleptics.

Animals↗
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↗