Serial injections of MK 801 (Dizocilpine) in neonatal rats reduce behavioral deficits associated with X-ray-induced hippocampal granule cell hypoplasia.
MK 801 (NMDA antagonist) has been shown to protect newborns from hypoxia-induced brain damage. Here, we determined if (+)-5-methyl-10,11-dihydroxy-5h-dibenzo (a,d)cyclohepten-5,10-imine (MK 801) could attenuate behavioral deficits associated with early radiation-induced hypoplasia of fascia dentata granule cells. We pretreated neonatal rats (n = 20) with MK 801 (0, 0.1, or 0.2 mg/kg, IP) before each of eight fractionated, head-only doses of X-rays (13 Gy total) administered during the first 16 days postpartum. Other rats (n = 18) received the same drug treatments but were sham irradiated. At age 16 months, water-escape latencies to a submerged platform were measured in a water maze. Irradiated rats with hippocampal damage exhibited impaired learning (longer latencies to find the platform) than did sham-irradiated subjects. Moderate doses of MK 801 (0.1 mg/kg) facilitated the learning of the water maze by irradiated subjects but did not enhance the number of their fascia dentata granule cells. Higher doses (0.2 mg/kg) of MK 801 provided no behavioral benefits. In fact, this dose significantly impaired the learning of the water maze by sham-irradiated rats and potentiated the granule cell hypoplasia observed in irradiated subjects. Thus, early MK 801 treatment produces dose-dependent behavioral protection for rats with radiation-induced hippocampal damage. Future studies may reveal the neurophysiological and neuroanatomic substrates of this behavioral recovery.
Mickley
G A
GA
Behavioral Sciences Department, Armed Forces Radiobiology Research Institute, Bethesda, MD 20889-5145.
Ferguson
J L
JL
Nemeth
T J
TJ
D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D001522:Behavior, Animal / Q000187:drug effects* / Q000528:radiation effects; D001835:Body Weight / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D005260:Female; D006624:Hippocampus / Q000166:cytology* / Q000528:radiation effects; D011247:Pregnancy; D011833:Radiation Injuries, Experimental / Q000523:psychology*; D051381:Rats; D014965:X-Rays
D016291:Dizocilpine Maleate