Fulminant ascending paralysis as a delayed sequela of diethylene glycol (Sterno) ingestion.

The authors report a 57-year-old man who survived 18 days after swallowing an 8-oz. can of Sterno in a suicide attempt. Two days after ingestion, he developed confusion and acute renal failure requiring hemodialysis, followed on day 8 by a delayed but rapidly evolving ascending paralysis. Pathologic examination showed severe demyelination, with lesser axonal damage, of virtually all cranial and peripheral nerves sampled and sparing of central myelin. The diethylene glycol in the Sterno was considered responsible for this intoxication.

Acetylcholine activates an alpha-bungarotoxin-sensitive nicotinic current in rat hippocampal interneurons, but not pyramidal cells.

The effects of acetylcholine on both pyramidal neurons and interneurons in the area CA1 of the rat hippocampus were examined, using intracellular recording techniques in an in vitro slice preparation. In current-clamp mode, fast local application of acetylcholine (ACh) to the soma of inhibitory interneurons in stratum radiatum resulted in depolarization and rapid firing of action potentials. Under voltage-clamp, ACh produced fast, rapidly desensitizing inward currents that were insensitive to atropine but that were blocked by nanomolar concentrations of the nicotinic alpha7 receptor-selective antagonists alpha-bungarotoxin (alphaBgTx) and methyllycaconitine. Nicotinic receptor antagonists that are not selective for alpha7-containing receptors had little (mecamylamine) or no effect (dihydro-beta-erythroidine) on the ACh-induced currents. Glutamate receptor antagonists had no effect on the ACh-evoked response, indicating that the current was not mediated by presynaptic facilitation of glutamate release. However, the current could be desensitized almost completely by bath superfusion with 100 nM nicotine. In contrast to those actions on interneurons, application of ACh to the soma of CA1 pyramidal cells did not produce a detectable current. Radioligand-binding experiments with [125I]-alphaBgTx demonstrated that stratum radiatum interneurons express alpha7-containing nAChRs, and in situ hybridization revealed significant amounts of alpha7 mRNA. CA1 pyramidal cells did not show specific binding of [125I]-alphaBgTx and only low levels of alpha7 mRNA. These results suggest that, in addition to their proposed presynaptic role in modulating transmitter release, alpha7-containing nAChRs also may play a postsynaptic role in the excitation of hippocampal interneurons. By desensitizing these receptors, nicotine may disrupt this action and indirectly excite pyramidal neurons by reducing GABAergic inhibition.

Nicotinic receptors, smoking and schizophrenia.

Neuronal nicotinic acetylcholine receptor expression was examined in schizophrenia. The incidence of smoking in schizophrenia is remarkably high and nicotine has been found to normalize an auditory evoked potential deficit seen in most subjects who suffer from this disease. Antagonists and agonists of a specific subset of this receptor family, the alpha7 nicotinic receptor, were found to regulate the gating of filtering of auditory information in both humans and in an animal model. The alpha7 gene has been cloned and a polymorphic dinucleotide repeat near the gene was used for linkage analysis, showing the alpha7 locus to be linked to the P50 deficit. Expression of the alpha7 receptor, which binds nicotine with low affinity, is reduced in the hippocampus of schizophrenics. [3H]-nicotine binding, a measure of the high affinity nicotinic receptors, was also decreased in schizophrenics and does not increase in response to tobacco use, as is seen in control subjects. The results of these studies suggest the presence of abnormal expression and function of the neuronal nicotinic receptor gene family in schizophrenia.

Comparison of the regional expression of nicotinic acetylcholine receptor alpha7 mRNA and [125I]-alpha-bungarotoxin binding in human postmortem brain.

Neuronal nicotinic acetylcholine receptors are expressed in the human central nervous system. A specific subtype of this receptor family, the alpha7 nicotinic acetylcholine receptor, is thought to be the principal alpha-bungarotoxin (alphaBTX)-binding protein in mammalian brain. Although the expression of this receptor subtype has been characterized in rat, no study has specifically compared the expression of both the alpha7 gene and the localization of BTX binding sites in human brain. Expression of alpha7 mRNA and receptor protein in human postmortem brain tissue was examined by in situ hybridization and [125I]-alpha-bungarotoxin autoradiography, respectively, with particular emphasis on regions associated with sensory processing. Regions with high levels of both alpha7 gene expression and [125I]-alphaBTX binding include the nucleus reticularis of the thalamus, the lateral and medial geniculate bodies, the basilar pontine nucleus, the horizontal limb of the diagonal band of Broca, the nucleus basalis of Meynert, and the inferior olivary nucleus. High-to-moderate levels of alpha7 probe hybridization were also seen in the hippocampus and the cerebral cortex; however, there was a reduced or variable degree of [125I]-alphaBTX binding in these regions compared with the level of probe hybridization. In most brain regions, [125I]-alphaBTX binding was localized to neuronal cell bodies similar in morphology to those that exhibited alpha7 hybridization, suggesting that the high-affinity [125I]-alphaBTX binding sites in the human brain are likely to be principally composed of alpha7 receptor subtypes.

Cholinergic deafferentation enhances rat hippocampal pyramidal neuron responsiveness to locally applied nicotine.

We tested whether cholinergic denervation of the hippocampus of young rats would result in an enhancement of CA1 pyramidal cell responsiveness to nicotine. Electrolytic lesions of the medial septal area were performed in young male Fisher 344 rats. One month later the rats were anesthetized with pentobarbital and nicotine was locally applied to CA1 pyramidal neurons using pressure microejection. The dose of nicotine required to excite the pyramidal neurons was significantly lower for cells recorded from rats with septal lesions. However, no changes in hippocampal cytisine or alpha-bungarotoxin binding were found.

Expression of insulin-like growth factor-1 (IGF-1) and IGF-binding protein 2 (IGF-BP2) in the hippocampus following cytotoxic lesion of the dentate gyrus.

Receptor binding and gene expression of several members of the IGF gene family were examined in the rat brain following lesion of the hippocampal dentate gyrus granular cells by intradentate colchicine injection. Dentate granular cell loss was accompanied by extensive reactive gliosis in the lesioned hippocampus and damaged overlying cortex, as verified by the increase in GFAP mRNA and BS-1 lectin binding. At 4 days post-lesion, 125I-IGF-2 binding was dramatically increased within the lesioned dentate gyrus and damaged overlying cortex, and corresponded temporally and anatomically with increased IGF-BP2 gene expression following the lesion. Increased IGF-BP3 gene expression was only observed in the overlying cortex at 10 days post-lesion, and corresponded with an increase in 125I-IGF-1 binding at the injured surface of the cortex. Type-2 IGF receptor mRNA expression was reduced to background levels in the lesioned dentate gyrus, suggesting that IGF-BP2 was a major component of the observed increase in 125I-IGF-2 binding. In situ hybridization also revealed a prominent increase in IGF-1 mRNA expression by 4 days post-lesion, which was localized within the lesioned dentate gyrus and damaged cortical areas, and was shown to be expressed by microglia. While no IGF-2 mRNA expression was observed within the CNS, either prior to, or following the lesion, IGF-2 mRNA expression was observed in the choroid plexus, meningeal membranes, and in blood vessel endothelium, providing a potential source for the transport of IGF-2 into the CNS. In the injured CNS, increased IGF-BP2 expression may act to maintain or transport IGF-1 or IGF-2, as well as modulate the local autocrine and paracrine actions of the IGFs. Increased microglial IGF-1 expression following colchicine treatment correlates with the timing of a number of post-traumatic events within the CNS, suggesting that IGF-1 may have a role as a neuroprotectant for surviving neurons and signal for local neuronal sprouting, as well as a role in reactive astrogliosis.

Nicotinic receptor function in schizophrenia.

Schizophrenia can be partially characterized by deficits in sensory processing. Biochemical, molecular, and genetic studies of one such endophenotype, the P50 auditory-evoked potential gating deficit, suggest that one of the neuronal nicotinic receptors, the alpha 7 nicotinic receptor, may function in an inhibitory neuronal pathway involved in this phenotype. The P50 deficit is normalized in nongating subjects by nicotine. Although most schizophrenia patients are heavy smokers, the effects of nicotine may be transient, as alpha 7 receptors are known to desensitize rapidly. In an animal model of the P50 gating deficit, antagonists of the alpha 7 nicotinic receptor block normal gating of the second of paired auditory stimuli. Regional localization of receptor expression includes areas known to function in sensory filtering. An inhibitory mechanism, in the hippocampus, may involve nicotinic stimulation of gamma-aminobutyric acid (GABA)ergic interneurons, resulting in decreased response to repetitive stimuli. Expression of the alpha 7 receptor is decreased in hippocampal brain tissue, dissected postmortem, from schizophrenia subjects. The P50 deficit is inherited in schizophrenia pedigrees, but it is not sufficient for disease development and thus represents a predisposition factor. Linkage analysis between the P50 deficit in multiplex schizophrenia pedigrees and deoxyribonucleic acid (DNA) markers throughout the genome yielded positive lod scores to DNA markers mapping to a region of chromosome 15 containing the alpha 7 nicotinic receptor gene. Elucidation of possible interactions of the P50 with other factors, known to be important in the etiology of the disease, is important in determining an overall pathobiology of schizophrenia.