Alleviation of x-irradiation-based deficit in memory-based learning by D-amphetamine: suggestions for attention deficit-hyperactivity disorder

Abstract

Selective exposure to x-irradiation during infancy, from postnatal days (PND) 2-11 in the rat, results in severe hippocampal granule cell hypoplasia. Preweanling (PND 17-18) rats, which suffer such hippocampal granule-cell agenesis, show deficits in patterned single alternation (PSA), a form of memory-based learning. Deficits in short-term memory along with increased arousal have been suggested as characteristic of children diagnosed with attention deficit-hyperactivity disorder (ADHD). We report here on the ameliorating effects of D-amphetamine, a drug commonly used in the treatment of ADHD, before Ritalin, on PSA, after infantile (PND 2-15) exposure to x-irradiation. After i.p. injections of 0.3 mg/kg D-amphetamine, the onset and magnitude of the PSA memory-based discrimination in the x-irradiated preweanling rats was restored to about the level of controls. These results, showing alleviation of x-irradiation-related deficits in short-term memory by D-amphetamine injections, along with our earlier and present results, showing substantial deficits after x-irradiation alone, encourage the hypothesis that hippocampal granule-cell hypoplasia, which would occur in humans prenatally and is Altman's model of "minimal brain dysfunction" [Altman, J. (1986) in Learning Disabilities and Prenatal Risk, ed. Lewis, M. (Univ. of Illinois Press, Urbana), pp. 241-304], may be a factor in at least some forms of ADHD and may provide a basis for an animal model of the disease.

Figure 1

Photomicrographs of the 21-day-old hippocampus. (Upper) A sham-irradiated animal shows no damage to the dentate gyrus. (Lower) X-irradiated hippocampus with an approximately 80% decrease in dentate gyrus granule cells.

Figure 2

(A) X-irradiated animals receiving saline injections begin to pattern late (blocks 21–24). (B) Amphetamine (0.3 mg/kg) restores PSA in x-irradiated animals to the level of sham-treated animals. They start patterning as early as block 16. Sham-irradiated animals receiving saline (C) and sham-irradiated animals receiving d-amphetamine (D) also pattern much earlier than x-irradiated animals receiving saline. These groups also show PSA as early as block 16.