Diferenças sexuais no efeito tipo-anticompulsivo da memantina : envolvimento da via do óxido nítrico, mas não dos receptores AMPA

Abstract

The Obsessive-Compulsive Disorder (OCD) is a neuropsychiatric disorder characterized by the occurrence of unwanted and intrusive thoughts (obsessions) and repetitive behaviors, considered compulsions. The standard treatment of OCD consists of a pharmacological intervention combined with psychotherapeutic management, but only a portion of the affected population presents an adequate response. Memantine is an NMDA antagonist drug that has been evaluated for the treatment of OCD, but little is known about its anticompulsive mechanism and there are no studies that compare its effect in men and women, or in male and female rodents. In this study, we investigated whether there are differences in the anticompulsive effect of memantine after acute treatment in adult male and female Swiss mice, as well as investigated a possible involvement of the nitric oxide (NO) pathway and AMPA receptors in this effect. First, we evaluated the effect of acute intraperitoneal administration of memantine (3, 5 and 10 mg/kg) on the open field test (OFT) and the marble-burying test (MBT), a predictive test of anticompulsive effect. The 3 different doses of memantine reduced the marble-burying behavior in the MBT in males and females, in addition to not causing impairment to the animals' motor activity in the OFT. Therefore, we used a second predictive test of anticompulsive effect, the nest-building test (NBT). In this test, memantine at 10 mg/kg also reduced nest-building behavior with no difference between the sexes. The third experiment aimed to evaluate the participation of the NO pathway in the anticompulsive effect of memantine. Thus, we observed that L-arginine, an NO precursor, did not prevent the decrease in the number of marbles buried by females also treated with memantine, but it was successful in males. Finally, it was assessed whether the anticompulsive-like effect of memantine could also be mediated by AMPA receptors. However, NBQX, an AMPA receptors antagonist, did not block the effect of memantine, suggesting that this effect does not depend on the participation of such receptors. In this line, the anticompulsive-like effect of memantine in the TEE was shown not to be sex-dependent, not to be mediated for AMPA receptors, and to involve the NO pathway only in male mice. Therefore, more studies are needed to confirm the anticompulsive effect of memantine in other predictive tests or models of compulsion