Local N-methyl-d-aspartate receptor antagonism in the prefrontal cortex attenuates spatial cognitive deficits induced by gonadectomy in adult male rats

• NMDA receptor block in the prefrontal cortex impairs Barnes maze performance in male rats.
• NMDA receptor block in the prefrontal cortex improved cognition in gonadectomized rats.
• Estrogen and androgen modulate cognition through NMDA receptors in the prefrontal cortex.

Gonadectomy in adult male rats significantly impairs spatial working memory, behavioral flexibility and other functions associated with the prefrontal cortex (PFC). However, the mechanisms through which this occurs are largely unknown. In this study, intracortical drug challenge with the selective N-methyl-d-aspartate receptor (NMDAR) antagonist D(−)-2-amino-5-phosphonopentanoic acid (APV) was combined with Barnes maze testing, gonadectomy (GDX) and hormone replacement (17β-estradiol, testosterone propionate) to explore the contributions of NMDAR-mediated activity within the PFC to hormone effects on spatial cognition in adult male rats. Previous studies have shown that Barnes maze testing reveals significant estrogen-dependent, GDX-induced deficits in spatial working memory and androgen-sensitive, GDX-induced deficits in spatial search strategy. Here we found that bilateral infusion of APV into the medial PFC prior to testing significantly improved both sets of behaviors in gonadectomized rats and significantly worsened performance measures in gonadally intact controls. In hormone-replaced cohorts, we further found that behaviors that are normally similar to controls were significantly disrupted by APV, and those that are normally similar to gonadectomized rats were rescued by intracortical APV infusion. There were, however, no residual effects of APV on retention testing conducted 24 h later. Together these findings suggest that hormone regulation of NMDAR-mediated activity specifically within the PFC may be fundamental to the effects of gonadal steroids on spatial cognition in males. Our findings further identify NMDAR antagonists as potentially novel, non-steroidal means of attenuating the cognitive deficits that can accompany gonadal hormone decline in human males in aging, clinical cases of hypogonadalism and in certain neurologic and psychiatric illnesses. Accordingly, it may be important to obtain in males the kind of detailed knowledge concerning hormone effects on, for example, the channel and electrophysiological properties of NMDAR that currently exists for the female brain.