2,4-DITHIOBIURET IN RATS - COGNITIVE FACILITATION AFTER ACUTE INJECTION PRECEDES MOTOR IMPAIRMENT AFTER REPEATED DAILY INJECTIONS

2,4-Dithiobiuret (DTB) is a sulfonated derivative of urea that is used as a reducing agent in chemical manufacture. Its low acute toxicity t o rodents belies a peripherally mediated, delayed-onset muscle weaknes s which develops during repeated daily exposure. In experiment 1, a st andard dose regimen of DTB (0.5 mg/kg per day IP for 5 days) was used to induce motor dysfunction as a way to dissociate peripheral and cent ral influences on a test of cognitive and motor function in rats. Sixt een male rats were trained to perform a Delayed Matching-to-Position/V isual Discrimination (DMTP/VD) task which permits quantification of wo rking memory (matching accuracy), reference memory (discrimination acc uracy), and motor function (choice response latency and nosepoke inter -response time, IRT). The first dose of DTB significantly increased ma tching accuracy; during the following week, DTB reduced matching accur acy, increased choice response latency and nosepoke IRT, and reduced t rial completion. Discrimination accuracy remained unaffected. Experime nt 2 explored the effects of single administrations of DTB on DMTP/VD. Sixteen other trained rats were divided into two groups with equal ma tching accuracy. One group received DTB (0.5, 1.0, and 2.0 mg/kg, IF) in separate injections at least 1 week apart; the other group received vehicle at the same times. Matching accuracy increased significantly in the treated rats and not in the controls following each dose of DTB . The magnitude of this increase was dose-dependent, and lasted from 1 to 8 weeks after each injection. Discrimination accuracy, response la tency, nosepoke IRT and trial completion remained unaffected throughou t the study. After DTB, matching accuracy was less easily disrupted by scopolamine (0.1-0.3 mg/kg, IF). However, DTB did not alter the rats' response to reducing the distance between the response levers, to rev ersal of the matching rule to a nonmatching rule, or to challenge with MK-801 (0.05-0.10 mg/kg, IP). These data indicate that acute DTB caus es a long-lasting facilitation of working memory in rats in the absenc e of any of the indications of motor impairment which follow repeated, daily injections of the chemical.