Acute and chronic effects of nicotine in rats and evidence for a noncholinergic site of action.
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Biomedical subjects
Publications and source records attributed to K Lowy.
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In an effort to investigate the possibility of noncholinergic nicotine sites within the brain, psychopharmacological, biochemical and eletrophysiological studies were undertaken with nicotine and various newly synthesized derivatives of nicotine and piperidine. When 1-10 micrograms of (-)-nicotine was injected into the region of the lateral ventricle of rats through implanted cannulae, there resulted a characteristic prostration immobilization syndrome, which was accompanied by seizures and tremors at the higher dose range. The (+)-isomer possessed 1/100 the activity of the natural (-)-isomer. The syndrome could be prevented by pre-treatment, intraventricularly, with the N-benzyl and N-p-nitrophenylazido derivates of either nicotine or piperide. A variety of neurotransmitters and psychotropic agents, including acetylcholine and anticholinergic drugs, were without antagonistic action. After nicotine, recordings of spontaneous electrical activity from electrodes chronically implanted into the region of the dorsal hippocampus showed a marked decrease in the amplitude and number of 6-8 sec discharges, and the change was correlated with the behavioral syndrome. Receptor binding studies were performed with rat brain slices and various neural preparations using 3H-nicotine, 125I-alpha-bungarotoxin and 14C-d-tubocurarine as ligands; and only with 3H-nicotine was it possible to demostrate any competitive effect with the various nicotine and piperidine antagonists. It was possible to demonstrate stereospecific or specific nicotine binding to only glass fiber filters and, to a lesser extent, brain slices, but not to cell-free preparations. It was concluded that there existed specific noncholinergic sites for nicotine's action which have not been hitherto described.
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A comparison was made of the behavioral effects in cats of the dextro and levo isomers of 3-quinuclidinyl benzilate (QB), using a special computer-controlled program. Such psychophysical parameters as rate of response and tendency to use the left or right paw for lever pressing were used primarily to evaluate drug efficacy. The drug did not alter auditory threshold or the percentage of errors in lever pressing. The l-isomer was found to be at least 100 times as potent as the d-isomer, the effects of both being qualitatively similar. After a single dose of 5 mug/Kg of 1-QB, the cats' performance did not return to normal until 5-7 days later. Pretreatment of the cats with a dose of 2 mg/Kg of atropine, an antimuscarinic agent, did not prevent the behavioral effects of 1-QB. The binding affinity of two isomers for synaptic membranes and phosphatidyl serine was identical.
Two cases of malignant external otitis are presented and the literature is reviewed. The disease seems to occur exclusively in elderly diabetic patients. Diagnosis is mostly a clinical one, and requires a high index of suspicion. The characteristic clinical manifestations are pain and severe tenderness of the tissues around the ear and mastoid, persistent drainage and the presence of granulation tissue at the junction of the osseus and cartilagenous portions of the external ear. Roentgenographic findings are not helpful in the early stages. The pathogenesis of this disease depends on the presence of clefts in the cartilage forming the floor of the external auditory canal at its junction with the osseus portion through which infection can spread from the external ear to the deep soft tissues. Serious and often fatal complications may ensue. The most common and earliest symptom to appear if facial nerve palsy. Pseudomonas aeruginosa has been isolated uniformly, in pure or mixed cultures. This entity, therefore, should be borne in mind whenever an elderly diabetic patient presents with external otitis not amenable to the usual methods of therapy. Ps. aeruginosa should be strongly suspected, and its isolation should prompt vigorous systemic treatment with gentamicin and carbenicillin before extensive necrosis of cartilage and bone takes place. Any delay in diagnosis and management will lead to a serious and often fatal complications.
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