Characterization of Disulfoton-Induced Behavioral and Neurochemical Effects Following Repeated Exposure

These experiments examined the relationship between behavioralalterations and neurochemical changes in rats exposed repeatedlyto disulfoton, an organophosphate cholinesterase inhibitor.Male Long-Evans rats were injected ip for 30 days with 0, 0.5,1, or 2 mg/kg of disulfoton in corn oil. Clinical signs andmotor activity were measured during the course of repeated exposure.Cognitive function, as measured in the Morris water maze, andpassive avoidance procedures were assessed near the end of thedosing regimen. Regional brain acetylcholinesterase (AChE) activitywas measured during the course of dosing while the total numberof muscarinic receptors was measured at the end of the dosingregimen. Tolerance developed rapidly to the clinical signs producedby disulfoton, but not to the disulfoton-induced decrease inmotor activity. Disulfoton affected the acquisition of watermaze performance, but had no effect on passive avoidance acquisitionor retention. Repeated exposure to disulfoton decreased brainAChE activity and the number of [³H]quinuclidinyl benzilatebinding sites. These data indicate that, in spite of muscarinicreceptor down-regulation that followed repeated exposure todisulfoton, animals become tolerant to only some of the functionaleffects produced by this chemical.     

STUDIES ON THE MECHANISMS OF SOMATOSTATIN RELEASE AFTER INSULIN INDUCED HYPOGLYCAEMIA IN MAN

Insulin-induced hypoglycaemia, which stimulates gastric acid secretion, is associated with an increase in circulating somatostatin levels in man. In order to assess the mechanisms involved in this rise, six normal volunteers connected to a Biostator for continuous glucose monitoring were studied, on three separate occasions. On each occasion after basal blood sampling, 0.15 i.u./kg body weight of insulin was administered i.v. and further samples were obtained intermittently over 150 min. On one occasion, dextrose was infused by the Biostator to prevent hypoglycaemia, while on the other two, a constant infusion of either normal saline or the specific H2 antagonist cimetidine was administered. Insulin plus dextrose caused no significant changes in circulating somatostatin levels, whereas insulin plus saline was associated with a marked, sustained and significant rise in all subjects; insulin plus cimetidine also produced a rise but it was delayed; the area under the curve was significantly (P less than 0.05) greater with insulin plus saline than with insulin plus cimetidine. These results show that in man insulin itself does not stimulate somatostatin secretion directly, but indirectly via hypoglycaemia. Further, the inhibition of gastric acid secretion with cimetidine reduces somatostatin release during insulin-induced hypoglycaemia. This suggests that gastric acid may mediate somatostatin secretion associated with insulin-induced hypoglycaemia.