Sex differences and influence of gonadal hormones on MK801-induced neuronal degeneration in the granular retrosplenial cortex of the rat.

MK801, PCP, and ketamine are non-competitive NMDA receptor-antagonists drugs that in humans produce psychomimetic effects and neurocognitive disturbances reminiscent to those of schizophrenia. The administration of these drugs in animals has been used as a pharmacological model to study the NMDA receptor hypofunction-hypothesis of schizophrenia. In animals, the biological effect of MK801 is dose-dependent. Low doses induce behavioral disturbances and higher doses, in addition, promote neurotoxicity in many brain regions, particularly the granular retrosplenial cortex (RSG). The neurotoxic effect of MK801 is sexually dimorphic, being females markedly more sensitive than males; however, the involvement of gonadal hormones is elusive. Here we show that a single intraperitoneal injection of 5 mg/kg of MK801 induced overt neurodegeneration in RSG of female rats, including abundant somatic degeneration in layer 4, and somatodendritic and terminal degeneration in layers 1, 4, and 5. MK801-degeneration in males was scarce and mainly evidenced by the presence of few argirophilic somas in layer 4. Ovariectomized rats were not significantly different than intact females, while orchiectomized rats showed robust MK801-toxicity. Testosterone and dihydrotestosterone (DHT) inhibit MK801-toxicity in orchiectomized rats. In ovariectomized rats only DHT, but not testosterone, prevented MK801-induced degeneration, while in intact females, DHT was only partially protective. Treatment of intact males with estradiol benzoate significantly enhanced MK801-toxicity. Altogether, our experiments indicate that non-aromatizable androgens protect RSG from MK801-toxicity, while estrogens counteract this protection. Thus, the balance of androgens and estrogens delineate the sexual dimorphism of the RSG to the toxic effect of MK801.