Neurotoxicity induced by the non-competative anatagonistof the N- methyl-d-aspartate receptor (NMDA) MK-801 in the rat retrosplenial cortex: A study of sexual dimorphic effects.

DE OLMOS S; BENDER C; DE OLMOS, J.S.

June 16-19, 2006 Scottsdale Arizona, USA.Page 6 poster 5.

Congreso; 2006 NIDA International Forum: International Trends and Needs in Drug Abuse Research; 2006

NID-NIH-CPDD

Noncompetitive antagonists of the N- methyl-D-aspartate receptor (NMDA), like phencyclidine, MK-801 and ketamine are classified as dissociative anesthetics, being MK-801 the most potent of this group. Several studies show that they are of potential therapeutic benefit for several conditions, such as treatment of ischemic brain injury. However, they have limited clinical use due to their ability to induce psychotomimetic effects in humans.  In rats it has been found that under certain conditions they can eventually lead to neurotoxicity. On the other hand, these compounds are also drugs of abuse that induce hallucinations and addiction.  Therefore it is important to elucidate how these side effects and the mechanism underlying them are produced. These studies could result in improving our understanding of psychotic illnesses such as schizophrenia. In this work we studied the extent of the effects produced by MK-801 using acute moderate to high doses (5-10 mg/kgr) in male and female rats, and compared different protocols for detecting degeneration, such as the Amino Cupric Silver Technique (A-CuAg), Fluoro Jade B (FGB) and GFAP immunohistochemistry. Comparing the results obtained by the A-CuAg with the other protocols, it is concluded that A-CuAg was the most sensitive protocol for the detection and accurate appraisal of the neuronal degeneration produced. Thereby, we analysed both divisions of the granular (RSG) and agranular (RSA) Restrosplenial Cortex (RSC), areas that previous reports have shown to be sensitive to the effects of this drug. The somatodendritic degeneration (SD) induced by MK-801  (5 mg/kg) in the female rat was almost completely restricted to layer IV of the RSG. At the same dose,  the male shows much less cell damage (p < 0.0001),but  at higher concentrations (10 mg/kg) the SD invaded layer 5 of the immediately neighbouring RSA. Since RSA and RSG have different afferent and efferent connections, it is probable that the sexually dimorphic neuronal toxicity induced by MK-801 is reflected in mechanisms involving sensorial areas which may lead in turn to behavioural differences between sexes described in the literature. Objectives:1) Analyze sexual dimorphism in the retrosplenial cortex, area that is known to be sensitive to the neurotoxic effects induced by MK-801.2) Analyze the sensitivity of different techniques to the neurotoxic  effect of MK-801.