Postnatal injection of homocysteic acid leads to the development of behaviors consistent with major‐depressive disorder in female, but not male, Sprague Dawley rats (803.11)

Abstract

Recent evidence suggests that hyperfunction of N‐methyl‐D‐aspartate receptors (NMDA) may be an important factor in the pathophysiology of major depressive disorder (MDD). The NMDA receptor agonist, homocysteic acid (HCA), is an endogenous compound that is formed from the oxidation of homocysteine. Since hyperhomocysteinemia is a risk factor for several disorders, including MDD, we sought to test the hypothesis that elevated HCA levels in developing rats may lead to changes in NMDA receptor expression and the development of behaviors associated MDD. To test this hypothesis, we performed daily intraperitoneal injections of either HCA or saline in postnatal male and female rats for 14 days beginning at day P2. Six weeks later, we observed that female, HCA‐treated rats displayed increased risk‐taking behavior, anhedonia, deficits in pre‐pulse inhibition, and increased sensitivity to pain compared to control and male‐HCA treated rats, but no difference in motor performance or weight gain over the course of the experiment. Consistent with these findings, we observed that HCA exposure led to an increase in the expression of the NMDA E2 subunit and GAD‐67 in the cortex of female, but not male, rats. Given that MDD is sexually dimporphic and observed more often in females compared to males, these data suggest that early postnatal exposure to HCA may serve as an excellent animal model for MDD. This research was supported by the Hope College Neuroscience Program, Biology Department and Chemistry Department, and NSF‐REU # 0851194.Grant Funding Source: NSF‐REU # 0851194