Sex Differences Distinguish Intracortical Glutamate Receptor-Mediated Regulation of Extracellular Dopamine Levels in the Prefrontal Cortex of Adult Rats.

Executive functions of the prefrontal cortex (PFC) are sensitive to local dopamine (DA) levels. Although sex differences distinguish these functions and their dysfunction in disease, the basis for this is unknown. We asked whether sex differences might result from dimorphisms in the glutamatergic mechanisms that regulate PFC DA levels. Using antagonists selective for α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) receptors, we compared drug effects on in vivo microdialysis DA measurements in the PFC of adult male and female rats. We found that baseline DA levels were similar across sex, AMPA antagonism decreased PFC DA in both sexes, and NMDA antagonism increased DA in males but decreased DA in females. We also found that, at subseizure-producing drug levels, γ-aminobutyric acid (GABA)-A antagonism did not affect DA in either sex but that GABA-B antagonism transiently increased PFC DA in both sexes, albeit more so in females. Finally, when NMDA antagonism was coincident with GABA-B antagonism, PFC DA levels in males responded as if to GABA-B antagonism alone, whereas in females, DA effects mirrored those induced by NMDA antagonism. Taken together, these data suggest commonalities and fundamental differences in the intracortical amino acid transmitter mechanisms that regulate DA homeostasis in the male and female rat PFCs.

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

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 (17ß-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 24h 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.

Assessment of the effects of sex and sex hormones on spatial cognition in adult rats using the Barnes maze.

Although sex differences and hormone effects on spatial cognition are observed in humans and animals, consensus has not been reached regarding exact impact on spatial working or reference memory. Recent studies in rats suggest that stress and/or reward, which are often different in tasks used to assess spatial cognition, can contribute to the inconsistencies in the literature. To minimize the impact of these sex- and sex hormone-sensitive factors, we used the Barnes maze to compare spatial working memory, spatial reference memory and spatial learning strategy in adult male, female, gonadectomized (GDX) male, and GDX male rats supplemented with 17ß-estradiol (E) or testosterone propionate (TP). Rats received four acquisition trials, four trials 24h later, and a single retention trial one week after. Males and females acquired the task during the first four trials and retained the task thereafter. In contrast, GDX rats took longer to acquire the task and showed retention deficits at 1week. All deficits were attenuated similarly by TP and E. Assessment of search patterns also showed that strategies in the males transitioned from random to spatially focused and eventually direct approaches to the goal. However, this transition was faster in control and GDX-TP than in GDX and GDX-E rats. In contrast, the females almost invariantly followed the maze edge in thigmotactic, serial searches. Thus, while Barnes maze reveals activational, in part estrogenic effects on spatial cognition in males, its amenability to animals' use of multiple strategies may limit its ability to resolve mnemonic differences across sex.