Neuropathology and behavioral impairments following pyrithiamine-induced thiamine deficiency: Protective effects of glutamate antagonist MK-801

Thirty-six male rats were extensively pretrained on a spatial delayed non-matching to sample (DNMTS) task at 0 sec, 3 sec, 4.5 sec, and 6 sec retention intervals. They were matched by performance and assigned to one of four treatment groups: pyrithiamine-induced thiamine deficiency (PTD), pair-fed control, pyrithiamine-induced thiamine deficiency plus injections of glutamate antagonist MK-801 (PTD + MK-801), or pair-feeding and MK-801 injections. After 16 days of treatment and three weeks recovery, subjects were tested again on nonmatching to sample. Performance was initially assessed at a 3-sec delay for 400 trials, and then memory delay was varied for 100 trials each at 4.5 sec, 6.8 sec, 10 sec, 15 sec and 0 sec delays. Following this, a delay titration procedure was employed for 30 sessions that exposed subjects to increasing delay durations if their performance met a 75% session performance criteria. Finally, performance on an eight radial arm maze procedure was assessed. PTD subjects were impaired relative to subjects in all other groups on reacquisition of DNMTS and were less accurate as the length of delay was varied. PTD subjects fell to 75% accuracy at a significantly shorter delay than all other groups. PTD subjects required more trials to reach both a discrimination and working memory criteria on the eight radial arm maze. Subjects given MK-801 during PTD treatment did not differ significantly from controls on any behavioral measures. When examined histologically, all PTD subjects had lesions of the medial thalamus and showed consistent lesioning of the entire internal medullary lamina site. In contrast, only 1 of 12 PTD + MK-801 subjects showed any lesioning of the medial thalamus. The results indicate that MK-801 protects rats exposed to thiamine deficiency from brain lesions and behavioral impairments, and provides confirmatory evidence that the neuropathology produced by thiamine deficiency is mediated by a glutaminergic excitotoxic process