BACKGROUND The brain glutamate neurotransmitter system and its NMDA (N-methyl-D-aspartate) receptors in the nucleus accumbens play an important role in the incidence of sensitivity and addiction. The present study examined the inhibitory effect of glutamate NMDA receptors in the nucleus accumbens in response to chronic stress. METHODS After the unilateral and bilateral placement of cannula(e) in the nucleus accumbens, one group of the animals received different doses of intra-accumbens memantine (0.1, 0.5 and 1 μg/mouse) 5 minutes before receiving the electric shock stress at their soles (using a Communication Box) and the other group received intraperitoneal memantine (doses of 0.1, 0.5 and 1mg/kg) 30 minutes before receiving the same shock. Chronic stress increased the animals' weight, plasma corticosterone, food and water intake, but reduced their defecation rates and eating latency. RESULTS The intraperitoneal administration of memantine increased plasma corticosterone, water intake, fecal weight, and eating latency, but had no effect on food intake or weight. The dose and site-dependent intra-accumbens administration of memantine either exacerbated the effects of stress on plasma corticosterone levels, water and food intake, or had no effect on these parameters. Furthermore, the administration of memantine had no effect on animal's weight and inhibited the effects of stress on fecal weight and eating latency. CONCLUSIONS The inhibition of glutamate NMDA receptors in the nucleus accumbens can inhibit and/or exacerbate the dose and site-dependent effects of chronic stress, and gender plays a significant role in producing this effect too.