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 17β-estradiol (E) or testosterone propionate (TP). Rats received four acquisition trials, four trials 24 h 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 1 week. 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.

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.

Most adults consume alcohol with relative impunity, but about 10–20% of users persist (or progress) in their consumption, despite mounting and serious repercussions. Identifying at-risk individuals before neuroadaptative changes associated with chronic use become well ingrained is thus a key step in mitigating and preventing the end stage disease and its devastating impacts. Explaining liability has been impeded, in part, by the absence of animal models for assessing initial sensitivity to the drug's reinforcing properties, an important endophenotype in the trajectory toward excessive drinking. Here we assess the initial rewarding effects of the drug in a novel application of the conditioned place preference paradigm. In contrast to previous studies that have all employed repeated drug administration, we demonstrated a robust preference for a context paired with a single exposure to 1.5 g/kg EtOH in male and female subjects of three strains. This model validates an assay of initial sensitivity to the subjective rewarding effects of alcohol, a widely used drug with multifarious impacts on both brain and society, and provides a new tool for theory-driven endophenotypic pharmacogenetic approaches to understanding and treating addiction.

The mesocortical and mesolimbic dopamine systems regulate cognitive and motivational processes and are strongly implicated in neuropsychiatric disorders in which these processes are disturbed. Sex differences and sex hormone modulation are also known for these dopamine-sensitive behaviours in health and disease. One relevant mechanism of hormone impact appears to be regulation of cortical and subcortical dopamine levels. This study asked whether this regulation of dopamine tone is a consequence of sex or sex hormone impact on the firing modes of ventral midbrain dopamine neurons. To address this, single unit extracellular recordings made in the ventral tegmental area and substantia nigra were compared among urethane-anaesthetized adult male, female, gonadectomized male rats. These comparisons showed that gonadectomy had no effect on nigral cells and no effects on pacemaker, bursty, single-spiking or random modes of dopamine activity in the ventral tegmental area. However, it did significantly and selectively increase burst firing in these cells in a testosterone-sensitive, estradiol-insensitive manner. Given the roles of prefrontal cortex (PFC) in modulating midbrain dopamine cell firing, we next asked whether gonadectomy's effects on dopamine cell bursting had correlated effects on the activity of ventral tegmentally projecting prefrontal cortical neurons. We found that gonadectomy indeed significantly and selectively increased burst firing in ventral tegmentally projecting but not neighbouring prefrontal cells. These effects were also androgen-sensitive. Together, these findings suggest a working model wherein androgen influence over the activity of PFC neurons regulates its top-down modulation of mesocortical and mesolimbic dopamine systems and related dopamine-sensitive behaviours.

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 glutamate receptor (NMDAR) antagonist D(-)-2-amino-5-phosphonopentanoic acid (APV) was combined with Barnes maze testing, gonadectomy 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, gonadectomy-induced deficits in spatial working memory and androgen-sensitive, gonadectomy-induced deficits in spatial search strategy. Here we found that bilateral infusion of APV into the medial prefrontal cortex 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 hours 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.