Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2012 Mar 7.
Published in final edited form as: Anim Behav. 2009 Aug;78(2):279–286. doi: 10.1016/j.anbehav.2009.04.017

Progesterone can enhance consolidation and/or performance in spatial, object and working memory tasks in Long–Evans rats

Cheryl A Frye a,b,c,d,*, Danielle C Llaneza a, Alicia A Walf a
PMCID: PMC3296563  NIHMSID: NIHMS358114  PMID: 22408275

Abstract

Progesterone has a ubiquitous role in reproduction and fitness and may influence cognitive performance. We examined the effects of administration of progesterone (a regimen that facilitates sexual behaviour) on consolidation of complex information in Long–Evans rats, Rattus norvegicus, that may be relevant for social engagement. We also examined the effects of subcutaneous progesterone administration (4 mg/kg versus oil vehicle placebo) on memory of ovariectomized rats during various cognitive tasks. Ovariectomized rats that received progesterone, versus the vehicle, immediately post-training were better able to find a hidden platform in the water maze. In a recognition task, rats that received progesterone spent more time in the novel arm of the Y-maze task than rats that received the vehicle. Ovariectomized rats that received progesterone immediately after training spent significantly more time exploring a novel object (compared to a familiar object) than did vehicle-administered rats. When socially relevant stimuli (i.e. objects with the scent of familiar or novel conspecifics) were used in the social cognition task, ovariectomized rats that received progesterone spent more time exploring the object with the novel conspecifics’ scent than did vehicle-administered rats. Pairing of progesterone, but not the vehicle, conditioned a place preference to the originally nonpreferred side of the conditioning chamber. We found no significant differences in motor activity measures in these tasks due to progesterone treatment. These results suggest that progesterone’s effects to improve cognitive processes with nonsocial and socially relevant stimuli, as well as have reinforcing effects, may underlie some of its salient effects on reproduction-related behaviours.

Keywords: cognition, learning, Long, Evans rat, memory, neurosteroid, progesterone, progestogen, Rattus norvegicus

Increases in ovarian secretion of progesterone (P4) during the oestrous cycle are associated with improved cognitive performance (Walf et al. 2006) and an increase in reproductively relevant behaviours, such as greater attractivity to a male partner through proceptive behaviour (ear wiggling, darting) and sexual receptivity (lordosis) (Beach 1976; Feder 1984). P4 contributes to the onset of maternal behaviour in females (Mann 2006; Lonstein 2007; Frye 2009), and the manifestation of sexual and maternal behaviour in rats both involve approach towards stimuli that have been previously avoided (Numan & Insel 2003). P4 greatly contributes to facilitation of these reproductively motivated behaviours (reviewed in: Mann & Bridges 2001; Olazábal et al. 2004; Frye 2007; Hull & Dominguez 2007). Perhaps one way that P4 exerts these effects is by enhancing consolidation of information relevant for reproductive success through improved cognitive performance.

There is evidence that reproductive and/or hormonal status can influence cognitive function of women. Although the majority of these studies have focused on oestrogen (E2) and cognitive performance, P4, alone or in conjunction with E2, may enhance learning and memory in women. In support, refractory increases in P4 that occur during the luteal and midluteal phase of the menstrual cycle are associated with enhanced attentional, perceptual, visual, implicit (long-term memory of skills and procedures without conscious awareness) and working memory (Broverman et al. 1981; Phillips & Sherwin 1992; Maki et al. 2002; Solis-Ortiz et al. 2004). Transvaginal P4 (400 mg daily) to young women with pharmacological suppression of the ovaries enhances cognition-related neural activity in the prefrontal cortex (PFC; Berman et al. 1997). Thus, to begin characterizing the role of P4 in cognitive processes, an animal model is logical, given the difficulty in examining the role of physiological levels of P4 independent of E2 in women.

In animal models, endogenous increases in P4 also influence cognitive performance. When trained and tested in the same phase of the cycle, rats in behavioural oestrus, with higher physiological P4 levels, perform significantly better in the inhibitory avoidance task (Rhodes & Frye 2004) and more readily acquire trace conditioning (Wood et al. 2001) than do dieostrous rats. Pregnant rats, which have naturally high levels of P4 and its neuroactive metabolites (referred to as progestogens), perform better in the water maze and in object placement compared to nonpregnant rats (Galea et al. 2000; Frye et al. 2007a). In addition, acquisition of conditioned aversive and rewarding stimuli are, respectively, reduced and enhanced during behavioural oestrus, when P4 levels are high, compared to their acquisition during dieostrus, when P4 levels are lower (Everitt 1990; Oldenburger et al. 1992; Paredes & Alonso 1997; Lopez et al. 1999; Diaz-Veliz et al. 2005; Domjan 2005). Thus, when P4 levels are naturally increased, differences in cognitive performance are observed.

Administration of P4 alone, or to E2-primed ovariectomized rats (in regimens that produce physiological levels akin to those seen during behavioural oestrus), may also affect cognitive performance. In a water maze test, P4 administered during pretraining either had no effect (El-Bakri et al. 2004), or improved performance 8 h but not 24 h postinjection (Sandstrom & Williams 2001). In another less physically demanding spatial task, the object placement task, post-training administration of P4 improved performance when ovariectomized rats were tested 4 h later (Frye et al. 2007a). Together, these results suggest that P4 administration can alter cognitive processes in animal models.

Our interest in P4’s effect on memory emerged from our investigation of the influence of progestogens on appetitive and/or consummatory aspects of sexual behaviour in female rodents. Indeed, progestogens increase the display of proceptive behaviours (i.e. hopping, darting, ‘ear wiggling’), enhance the expression of complex appetitive behaviours (i.e. approach, exploration, social interaction) and mediate the consummation of mating by facilitating lordosis (Frye 2007; Frye et al. 2007b). The ubiquitous role of progestogens in reproduction and fitness, along with their effects on memory, led us to examine the effects of P4 on consolidation of complex information that may be relevant for social engagement in Long–Evans rats, Rattus norvegicus. Rats in the wild have to traverse a complex environment to find potential mates, and therefore, consolidation of cues and information within the environment may be important for reproductive success. In the following experiments, we examined the effects of exogenous administration of P4 on female Long–Evans rats’ (1) consolidation of spatial information in the water maze, (2) object recognition in a Y-maze task, (3) object memory in an object recognition task and (4) working memory in a social cognition task. In addition, we examined motivation-related effects of P4 in a conditioned place-preference paradigm, and its effects on motor behaviour. We hypothesized that P4 may have beneficial effects across a variety of cognitive domains, each of which is likely to tap into different brain regions (i.e. hippocampus, PFC and striatum). We predicted that these beneficial effects would occur independently of other behavioural processes, such as motor activity, among young, adult ovariectomized rats.

METHODS

Animal care was in accordance with the Guide for the Care and Uses of Laboratory Animals (National Institute of Health, publication 865-23, Bethesda, MD, U.S.A.). These experiments were approved by the Institutional Animal Care and Use Committee of the University at Albany-SUNY (Protocol no. 06-012).

Subjects and Housing

Female Long–Evans rats (N = 74) were bred and reared in the Laboratory Animal Care Facility at SUNY-Albany from stock obtained from Taconic Farms (Germantown, NY, U.S.A.). Rats were group-housed (3–5 per cage) throughout the study in polycarbonate cages (45 × 24 × 21 cm) in a temperature-controlled room (21 ± 1 °C) in the Laboratory Animal Care Facility. The rats were on a 12:12 h reversed light:dark cycle (lights off at 0800 hours). Rats had continuous access to Purina Rat Chow and tap water in their home cages.

Procedures

Surgical procedures

All rats were anaesthetized with xylazine (Rompum, 12 mg/kg intraperitoneally; Bayer Corp., Shawnee Mission, KS, U.S.A.) and ketamine (Ketaset, 80 mg/kg intraperitoneally; Fort Dodge Animal Health, Fort Dodge, IA, U.S.A.) and ovariectomized 1 week prior to behavioural testing. Female rats had ventral incisions between the ribs and hip, so that the ovaries could be isolated. After a recovery period of 1–2 weeks, rats were P4- or vehicle-treated and behaviourally tested in the tasks described below.

P4 treatment

In all experiments, rats were administered SC sesame oil vehicle (0.2 ml) or P4 (4 mg/kg; Steraloids, Newport, RI, U.S.A.). This P4 regimen produces physiological levels of progestogens akin to those observed during behavioural oestrus (when females are sexually receptive) within 30 min of administration, with effects sustained for up to 4 h but reaching nadir within 24 h (Frye & Lacey 2000; Frye et al. 2007a). We administered the vehicle or the P4 regimen immediately post-training, as a delay in administration during consolidation will not yield enhancing effects of P4 (Walf et al. 2006; Frye et al. 2007a).

Behavioural testing

Water maze

The water maze procedure that we used was as previously implemented in our laboratory (Vongher & Frye 1999), with minor modification described below to assess spatial memory.

Habituation

On day 1, we habituated rats to the task and to the water maze environment by allowing them to swim in the pool without the platform for 120 s. This was necessary so that the novelty of the environment did not interfere with training and consolidation of the platform placement.

Acquisition phase

This phase allowed the animal to consolidate the platform placement within the water maze through spatial cues within the testing room. On day 2, there were two consecutive training trials in which rats were given 120 s to find the hidden platform. Rats that did not find the platform were guided to it and allowed to remain there for 45 s. Immediately after training, rats were administered P4 (N = 8) or vehicle (N = 8).

Intertrial interval

After training, we returned rats to their home cages in their housing room for 24 h to ensure that their circulating progestogen levels would be low when we tested them in the retention trials (see below).

Retention trial

On day 3 (testing), we conducted four test trials to determine whether rats not only consolidate what they have been guided to learn, but also use the information and cues that they learned during training to further demonstrate their spatial learning capacity. We averaged latencies and distances to find the hidden platform, and swim speeds (as an activity measure) across the four test trials.

Y-maze

The Y-maze is a two-trial recognition memory test in which performance does not involve the learning of a rule, because it taps into an innate tendency of rats to explore novel environments. The task was done as per previously reported methods (Conrad et al. 1997, 2004; Frye & Lacey 2000).

Acquisition phase

We blocked one arm of the Y-maze with Plexiglas so that the rats could not enter the maze during acquisition; we refer to this arm as the ‘novel arm’ during the retention trial (see below). We placed rats in the start arm and allowed them to explore this arm and the familiar arm during the 10 min trial. At the end of the trial, rats were given vehicle (n = 8) or P4 (n = 8).

Intertrial interval

Between training and testing, rats remained in a darkened, quiet area for 240 min to allow time for consolidation in a familiar environment and for physiological P4 levels to be concomitant with behavioural oestrus (Frye et al. 2007a).

Retention trial

During the 5 min test trial, in which no arms were blocked, we recorded the entries made and the time spent by each rat in each arm of the maze. We used the percentage of time spent in the novel arm relative to the total trial time as the dependent measure of performance and we used total entries made as an index of motor activity.

Object recognition task

The object recognition task assesses object memory and was implemented according to previously published methods (Ennaceur & Delacour 1988; Luine et al. 2003; Walf et al. 2007).

Acquisition phase

Rats were placed in a white open-field (76 × 57 × 35 cm) in a brightly lit testing room for 3 min with two identical coloured spheres (‘orange’ or ‘lemon’ plastic toys) that were situated by Velcro in adjacent corners (NW and NE). We recorded the time that each rat spent exploring these objects. Immediately after training, rats were given P4 (N = 15) or vehicle (N = 15).

Intertrial interval

Between training and testing, rats remained in individual cages in a darkened, quiet area for 240 min. We used this intertrial interval because P4 levels remain comparable to those observed during behavioural oestrus for up to 4 h following acute administration (Frye et al. 2007a).

Retention trial

During testing, we replaced one sphere with a cone-shaped (blue or red plastic toy ‘buoy’) or a square-shaped (block) object of similar size. Four hours after training, we placed each rat in the open-field with two objects, one that the rats had previously been exposed to during training and one that was novel. During the training and retention trials, we recorded the time that each rat spent exploring the two objects for 3 min. We used the relative percentages of time that each rat spent exploring the novel and familiar objects (time with novel object/(time with novel object + time with familiar object) × 100) as an index of cognitive performance.

Social cognition

The social cognition task assesses working memory for socially relevant stimuli and is similar to the object recognition task (described above) in its basis on preference for novel stimuli. We used a slightly modified version of our previously published object recognition methods (Walf et al. 2006) to include socially relevant target stimuli (Y. Delville, personal communication).

Acquisition phase

Rats were placed in a white open-field with two identical wooden blocks in adjacent corners (NW and NE) that had been placed in the experimental rats’ home cage overnight. As above, we recorded the time that each rat spent exploring these objects. Ovariectomized rats were given P4 (N = 6) or vehicle (N = 6), SC, immediately after training and were tested 3 h later for social cognition.

Intertrial interval

Between training and testing, rats remained in individual cages in a darkened, quiet area for 180 min.

Retention trial

During testing, we replaced one block with another that had been placed in a conspecific’s home cage overnight. Three hours after training, rats were placed back in the open-field with two blocks, one that the rats had previously been exposed to during training (familiar-scented) and one that had been placed in a conspecific’s cage overnight (novel-scented). During the training and retention trials, we recorded the time that each rat spent exploring the two objects for 3 min. We used the relative percentages of time that each rat spent exploring the novel-scented and familiar-scented blocks during testing (time spent with novel-scented block/(time spent with novel-scented block + time spent with familiar-scented block) × 100) as an index of social cognition.

Conditioned place preference

The conditioned place-preference paradigm that we used to assess motivation-related memory is described in Walf et al. (2007) and is a typical place-preference paradigm. The procedure included four phases: habituation (days 1 and 2); baseline preference test (day 3); place-preference conditioning (days 4–11); place-preference test (day 12).

Acquisition phase

Briefly, rats were given P4 (N = 6) or vehicle (N = 7) immediately before being placed on the nonpreferred side of the chamber (as determined on day 3 during the baseline preference test). Pairings of vehicle or P4 and the nonpreferred side occurred on place-preference conditioning days 4–5 and 8–9. On nonconditioning days, all rats received vehicle immediately before being placed on the originally preferred side of the chamber (days 6–7 and 10–11).

Intertrial interval

We conducted retention trials 48 h after the last pairing of vehicle or P4 with the nonpreferred side of the chamber.

Retention trial

For testing, we placed rats in the chamber with free access to both sides and we recorded the time that each rat spent on each side of the chamber for 30 min. We also measured the time (in seconds) that each rat spent on their originally non-preferred side of the chamber (place-preference index) and the number of crossings that each rat made from one side of the chamber to the other as an index of general motor activity.

Activity monitor

To assess motor behaviour following P4 administration, rats were placed in an activity monitor (39 × 39 × 30 cm; Accuscan, Columbus, OH, U.S.A.) immediately after the retention trial in object recognition. The number of beam breaks made in this chamber was mechanically recorded during the 5 min task, as per Frye et al. (2000).

Statistical Analyses

To examine the effects of P4 treatment on cognitive behaviour, we used one-way ANOVA to examine effects of progesterone on performance. Significant main effects of treatment were supported when the α level was P < 0.05.

RESULTS

P4 Enhanced Spatial Performance in the Water Maze

Rats that received exogenous P4 found the hidden platform in the water maze significantly faster (ANOVA: F1,14 = 6.59, P = 0.02) and moved significantly less (ANOVA: F1,14 = 5.03, P = 0.04) than did vehicle-administered rats (Fig. 1). Progesterone also enhanced swim speed (ANOVA: F1,14 = 11.50, P = 0.01; mean ± SE swim speed: vehicle = 27 ± 2 cm/s; P4 = 34 ± 0.5 cm/s).

Figure 1.

Figure 1

Open in a new tab

Mean ± SE (a) latency and (b) distance travelled to find the hidden platform in the water maze for ovariectomized rats injected with vehicle (□) or progesterone (■) post-training. *P < 0.05.

P4 Enhanced Spatial Performance in the Y-maze

Compared to vehicle administration, P4 significantly increased the percentage of time that rats spent in the novel arm of the Y-maze (ANOVA: F1,14 = 5.05, P = 0.04; Fig. 2). P4-administered rats spent more total time in the novel arm (mean ± SE: 120.9 ± 15.1 s) than in the start arm (97.3 ± 16.0 s) or the familiar arm (79.1 ± 16.0 s) of the Y-maze. This pattern was different from that observed in vehicle-administered rats (novel arm: 86.9 ± 8.0 s; start arm: 118.8 ± 12.3 s; familiar arm: 92.8 ± 4.7 s). No differences were observed between groups for total number of entries made in the maze during the retention trial (mean ± SE entries: vehicle: 16.9 ± 1.6; P4: 15.2 ± 1.5).

Figure 2.

Figure 2

Open in a new tab

Mean ± SE percentage of time that ovariectomized rats treated with post-training vehicle (□) or progesterone (■) spent exploring the novel arm of the Y-maze. *P < 0.05.

P4 Enhanced Object Memory in the Object Recognition Task

P4 significantly enhanced object recognition performance (ANOVA: F1,28 = 7.67, P = 0.01) compared to vehicle administration. During training, P4- and vehicle-administered rats spent similar amounts of time exploring both objects (mean ± SE: P4: 5.8 ± 1.6 s; vehicle: 6.3 ± 2.0 s). However, during testing, P4-administered rats spent significantly more time exploring the novel object (mean ± SE: 5.7 ± 1.3 s) than they did the familiar object (1.2 ± 0.3 s), whereas vehicle-administered rats showed no significant difference in time spent exploring either object (novel: 1.8 ± 0.4; familiar: 2.7 ± 0.4 s) (Fig. 3).

Figure 3.

Figure 3

Open in a new tab

Mean ± SE percentage of time that ovariectomized rats treated with post-training vehicle (□) or progesterone (■) spent exploring (a) a novel object in the object recognition task and (b) a novel-scented object in the social cognition task. *P < 0.05.

P4 Enhanced Working Memory in the Social Cognition Task

P4 significantly enhanced performance in the social cognition task (ANOVA: F1,10 = 8.08, P = 0.02) compared to vehicle administration. During training, rats that received P4 or the vehicle did not differ in the time they spent exploring both objects (mean ± SE exploration time: vehicle: 9.2 ± 1.1 s; P4: 10.8 ± 1.1 s). During testing, however, rats that received P4 post-training spent a greater percentage of time exploring the novel-scented object (mean ± SE exploration time: 9.5 ± 1.9 s) than they did the familiar object (4.1 ± 1.2 s) (Fig. 3), whereas rats that received the vehicle did not differ significantly in the time they spent exploring each object (mean ± SE time: novel: 5.6 ± 0.8 s; familiar: 4.8 ± 1.2 s).

P4 Produced a Place Preference

Rats that received P4 spent significantly more time on the nonpreferred side of the conditioning chamber on test day than did vehicle-administered rats (ANOVA: F1,11 = 11.15, P = 0.001; Fig. 4). There were no differences in chamber-crossing activity between groups on test day (ANOVA: F1,11 = 0.01, P = 0.96; mean ± SE crosses: vehicle:14 ± 2; P4: 13 ± 2).

Figure 4.

Figure 4

Open in a new tab

Mean ± SE time that ovariectomized rats administered vehicle (□) or progesterone (■) spent on the nonpreferred side of the conditioned place-preference chamber. *P < 0.05.

P4 Did Not Alter General Motor Behaviour in an Activity Monitor

There were no differences between groups for the number of beam breaks made in an activity monitor (ANOVA: F1,28 = 0.43, P = 0.52; mean ± SE beam breaks: vehicle: 327 ± 27; P4: 304 ± 22).

DISCUSSION

Our results support our hypothesis that P4 enhances cognitive performance of young, ovariectomized rats across a variety of tasks, which may in turn influence reproductive success of the species. P4, but not vehicle, administration enhanced spatial performance in the water maze and the Y-maze. Compared to vehicle, P4 treatment to ovariectomized rats improved object memory in the object recognition task as well as working memory in the social cognition task, a task with socially relevant stimuli. P4 had reinforcing effects and produced a place preference to the originally nonpreferred side of the chamber. P4’s effects on performance were not solely due to differences in motor activity in each of these tasks. Thus, these results suggest that P4 can improve cognitive performance of young, ovariectomized rats across several cognitive domains.

The present results contribute to the limited data reported in the literature regarding P4’s effects on spatial and recognition memory. Enhancing effects of P4 and its metabolites in rats have been shown in other cognitive tasks, such as the water maze, object recognition, object placement and inhibitory avoidance tasks, but these effects are altered by factors such as the timing of treatment (Frye & Sturgis 1995; Frye et al. 2000, 2007a; Sandstrom & Williams 2001; Walf et al. 2006). In the present study, post-training P4 administration improved performance at testing, which occurred 3 h (social cognition), 4 h (Y-maze, object recognition) and 24 h (water maze) later, and it improved performance in the conditioned place preference task 48 h postinjection. Similar effects were observed with a single dosing with P4 in the water maze, Y-maze, object recognition task and social cognition task, and with multiple dosing with P4 in the conditioned place-preference task. Our findings also contribute to the literature on progestogens’ cognitive effects by showing that P4 treatment can significantly improve performance in a cognitive task using socially relevant stimuli. In the social cognition task, post-training administration of P4, compared to vehicle, enhanced recognition of the novel-scented object. This finding indicates that P4 can have positive effects on memory across several cognitive tasks and that the presence of, and/or withdrawal from, P4, probably did not contribute substantially to differences in retention in these tasks. The post-trial learning observed with P4 administration may be adaptive for consolidation of novel rewarding experiences that are associated with mating and subsequent reproductive success.

The present findings that post-training administration of P4 improved learning and memory when rats were tested 4, 24 or 48 h after training (the latter two of which would be associated with P4 levels at nadir) suggest that the improvement in learning and memory in these tasks cannot be solely attributed to the presence of progestogens altering sensory and/or attentional processes and, thereby, performance. Indeed, if a delay in post-training P4 administration is introduced (such that P4 is not on-board during consolidation), enhancing effects of P4 are not observed in the object placement or object recognition task (Walf et al. 2006; Frye et al. 2007a). Thus, these results suggest that P4 may improve performance in these tasks because of its effect on consolidation processes. Future studies need to examine these nuances further and determine how they may be related to progestogens’ effects on mating behaviour.

Our finding that P4 can enhance consolidation adds to the literature showing that progestogens enhance the expression of diverse motivated behaviours (e.g. feeding, fighting, fleeing and mating). The higher levels of progestogen during reproductive cycles also enhance feeding, anticonflict behaviour, wheel-running activity, lever-pressing activity and sexual behaviour (Gerall & Dunlap 1973; Gerall et al. 1973; Kanarek & Beck 1980; Roberts et al. 1989a, b; Canonaco et al. 1990; Roth et al. 2005). Removal of the primary endogenous source of P4, the ovaries, attenuates increases in these motivated behaviours that typically occur during behavioural oestrus. Administration of progestogens, but not vehicle, to ovariectomized rats enhances feeding, affiliation, activity and mating to levels akin to those seen during behavioural oestrus (Marrone et al. 1975; Canonaco et al. 1990; Mascarenhas et al. 1992; Chen et al. 1996; Bless et al. 1997; Frye 2001a, b; Miczek et al. 2003; Pinna et al. 2005).

In rats, cyclic increases in P4 influence mating, enhance exploration of complex environments, suppress fear responses to novel stimuli and enhance approach towards individuals that have previously elicited aggressive behaviours (Carter et al. 1999; Frye & Rhodes 2007). P4 may also enhance consolidation of information that is relevant for reproductive success. In this and previous studies, we have shown that progestogens can enhance conditioned place preference in rodents (Frye & Rhodes 2006b; Frye 2007). Together, these results suggest that P4 can have rewarding effects. Given that progestogens can enhance conditioned place preference, the rewarding/reinforcing effects of progestogens may also mediate other motivated behaviours such as mating, which are associated with concomitant increases in progestogen levels as well as an increase in progestogens following mating.

One limitation of our study is that we investigated the effects of only one P4 concentration (i.e. an acute P4 dose) that produces progestogen levels similar to those that occur during behavioural oestrus, when rats are naturally sexually receptive. However, there are probably regimen-specific effects related to dose and to acute versus chronic exposure. Indeed, exposure to chronic high levels of progestogens, as occurs in rats that have experienced pregnancies, significantly improves cognitive performance and enhances hippocampal plasticity (Kinsley et al. 1999, 2008; Pawluski & Galea 2006, 2007; Pawluski et al. 2006). Furthermore, when rats are in dieostrus and progestogen levels are low, cognitive performance is similar to that of ovariectomized rats that have received vehicle (Walf et al. 2006). However, administration of E2 or selective oestrogen receptor modulators (SERMs) immediately following training in object recognition produces behavioural effects in rats similar to that of P4 (Walf et al. 2006). Of interest is whether the effects of P4 are observed across species. P4 enhances mating and cognitive performance in mice (Frye & Vongher 1999, 2001; Frye et al. 2006; Frye & Walf 2008), and glucose improves memory performance in cognitive tasks (Messier 2004). In addition, paced mating, similar to mating experienced in a naturalistic environment, increases progestin concentrations in the midbrain and/or in the hippocampus of female rats (Frye & Rhodes 2006a). Indeed, similar effects across species would suggest the importance of these effects of P4 for motivated behaviours and for behaviours that support them.

Systematic investigation of P4’s site-specific effects is of interest, given that the tasks used to examine P4’s effects may use different brain regions, such as the hippocampus, PFC and striatum. Indeed, how these findings extend to other tasks that are mediated by these and other brain regions is also of interest. For example, learning of inhibitory avoidance is primarily mediated by changes in the hippocampus and the amygdala (Izquierdo & Medina 1997), and post-training administration of P4 increases latencies to cross-over to the dark, shock-associated side of a chamber (Frye & Lacey 2000). There is clear site specificity even within these brain regions for learning and memory processes and these aspects need to be investigated further with respect to progestogens’ memory effects, because these targeted brain regions may be related to mating and other reproductively relevant behaviours.

It will be important for future studies to investigate the mechanisms of progestogens for the functional effects observed in the present study. Progestin receptors have been localized to the likely brain targets for these memory effects of P4, the hippocampus (Hagihara et al. 1992) and the frontal cortex (Blaustein & Wade 1978), but there may be few in the striatum (MacLusky & McEwen 1980). P4 may be exerting its effects through its metabolite (3α,5α-THP) at GABAA receptors, and this can affect cognitive performance on similar tasks. Some of P4’s effects on memory may involve actions of 3α,5α-THP, which in physiological concentrations is devoid of affinity for intracellular progestin receptors but enhances function of GABAA receptors (Iswari et al. 1986; Majewska et al. 1986). Rats administered 3α,5α-THP perform better in the water maze, in a delayed nonmatching-to-sample Y-maze task and in object recognition/placement tasks than do rats administered vehicle (Frye & Sturgis 1995; Walf et al. 2006; Frye et al. 2007a). Furthermore, 3α,5α-THP enhances conditioned place preference of rodents (Finn et al. 1997; Frye 2007) and can decrease avoidance behaviour in conditioned aversion tasks (Manshio & Gershbein 1975; Farr et al. 1995). Whether the observed effects of P4 in the tasks used in the present study were due to effects of 3α,5α-THP on GABAA receptor function is also of great interest.

Recently, our laboratory has found that P4 administration to ovariectomized 5α-reductase knockout mice, which cannot convert P4 to 3α,5α-THP, does not improve cognitive performance in the object recognition task compared to that of vehicle administration. However, administration of 3α,5α-THP significantly increases the percentage of time that mice spend with a novel object compared with administration of vehicle (unpublished data). This finding suggests that 3α,5α-THP may be important in facilitation of not only sexual behaviour, but also cognitive performance.

In summary, our results indicate that P4 can have positive effects on spatial memory in the water maze, recognition memory in the Y-maze task, object memory in the object recognition task, working memory in the social cognition task and motivation-related behaviour in the conditioned place-preference task in rats. These results lay the framework for further investigation of P4’s effects on specific memory processes and the mechanisms and brain targets for enhanced cognitive performance. How these effects are related to the salient effects of P4 to enhance reproductive behaviours is of interest. Consolidation of novel spatial and recognition cues may be ecologically important for animals that traverse complex environments to find mating opportunities and food, which in turn can influence motivation-related memory necessary for reproduction and survival.

Acknowledgments

This research was supported, in part, by grants from the National Science Foundation (IBN03-16083) and the National Institute of Mental Health (MH06769).

References

  1. Beach FA. Sexual attractivity, proceptivity and receptivity in female mammals. Hormones and Behavior. 1976;7:105–138. doi: 10.1016/0018-506x(76)90008-8. [DOI] [PubMed] [Google Scholar]
  2. Berman KF, Schmidt PJ, Rubinow DR, Danaceau MA, Van Horn JD, Esposito G, Ostrem JL, Weinberger DR. Modulation of cognition-specific cortical activity by gonadal steroids: a positron-emission tomography study in women. Proceedings of the National Academy of Sciences, USA. 1997;94:8836–8841. doi: 10.1073/pnas.94.16.8836. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Blaustein JD, Wade GN. Progestin binding by brain and pituitary cell nuclei and female rat sexual behavior. Brain Research. 1978;140:360–367. doi: 10.1016/0006-8993(78)90469-9. [DOI] [PubMed] [Google Scholar]
  4. Bless EP, McGinnis KA, Mitchell AL, Hartwell A, Mitchell JB. The effects of gonadal steroids on brain stimulation reward in female rats. Behavioural Brain Research. 1997;82:235–244. doi: 10.1016/s0166-4328(96)00129-5. [DOI] [PubMed] [Google Scholar]
  5. Broverman DM, Vogel W, Klaiber EL, Majcher D, Shea D, Paul V. Changes in cognitive task performance across the menstrual cycle. Journal of Comparative Physiology and Psychology. 1981;95:646–654. doi: 10.1037/h0077796. [DOI] [PubMed] [Google Scholar]
  6. Canonaco M, Valenti A, Maggi A. Effects of progesterone on [35S] t-butylbicyclophosphorothionate binding in some forebrain areas of the female rat and its correlation to aggressive behavior. Pharmacology, Biochemistry and Behavior. 1990;37:433–438. doi: 10.1016/0091-3057(90)90008-6. [DOI] [PubMed] [Google Scholar]
  7. Carter C, Lederhendler I, Kirkpatrick B, editors. The Integrative Neurobiology of Affiliation. Cambridge, Massachusetts: MIT Press; 1999. [DOI] [PubMed] [Google Scholar]
  8. Chen SW, Rodriguez L, Davies MF, Loew GH. The hyperphagic effect of 3α-hydroxylated pregnane steroids in male rats. Pharmacology, Biochemistry and Behavior. 1996;53:777–782. doi: 10.1016/0091-3057(95)02142-6. [DOI] [PubMed] [Google Scholar]
  9. Conrad CD, Lupien SJ, Thanasoulis LC, McEwen BS. The effects of type I and type II corticosteroid receptor agonists on exploratory behavior and spatial memory in the Y-maze. Brain Research. 1997;759:76–83. doi: 10.1016/s0006-8993(97)00236-9. [DOI] [PubMed] [Google Scholar]
  10. Conrad CD, Jackson JL, Wieczorek L, Baran SE, Harman JS, Wright RL, Korol DL. Acute stress impairs spatial memory in male but not female rats: influence of estrous cycle. Pharmacology, Biochemistry and Behavior. 2004;78:569–579. doi: 10.1016/j.pbb.2004.04.025. [DOI] [PubMed] [Google Scholar]
  11. Diaz-Veliz G, Butron S, Benavides MS, Dussaubat N, Mora S. Gender, estrous cycle, ovariectomy, and ovarian hormones influence the effects of diazepam on avoidance conditioning in rats. Pharmacology, Biochemistry and Behavior. 2000;66:887–892. doi: 10.1016/s0091-3057(00)00283-5. [DOI] [PubMed] [Google Scholar]
  12. Domjan M. Pavlovian conditioning: a functional perspective. Annual Review of Psychology. 2005;56:179–206. doi: 10.1146/annurev.psych.55.090902.141409. [DOI] [PubMed] [Google Scholar]
  13. El-Bakri NK, Islam A, Zhu S, Elhassan A, Mohammed A, Winblad B, Adem A. Effects of estrogen and progesterone treatment on rat hippocampal NMDA receptors: relationship to Morris water maze performance. Journal of Cellular and Molecular Medicine. 2004;8:537–544. doi: 10.1111/j.1582-4934.2004.tb00478.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Ennaceur A, Delacour J. A new one-trial test for neurobiological studies of memory in rats. 1: behavioral data. Behavioural Brain Research. 1988;31:47–59. doi: 10.1016/0166-4328(88)90157-x. [DOI] [PubMed] [Google Scholar]
  15. Everitt BJ. Sexual motivation: a neural and behavioural analysis of the mechanisms underlying appetitive and copulatory responses of male rats. Neuroscience & Biobehavioral Reviews. 1990;14:217–232. doi: 10.1016/s0149-7634(05)80222-2. [DOI] [PubMed] [Google Scholar]
  16. Farr SA, Flood JF, Scherrer JF, Kaiser FE, Taylor GT, Morley JE. Effect of ovarian steroids on footshock avoidance learning and retention in female mice. Physiology & Behavior. 1995;58:715–723. doi: 10.1016/0031-9384(95)00124-2. [DOI] [PubMed] [Google Scholar]
  17. Feder HH. Hormones and sexual behavior. Annual Review of Psychology. 1984;35:165–200. doi: 10.1146/annurev.ps.35.020184.001121. [DOI] [PubMed] [Google Scholar]
  18. Finn DA, Phillips TJ, Okorn DM, Chester JA, Cunningham CL. Rewarding effect of the neuroactive steroid 3α-hydroxy-5α-pregnan-20-one in mice. Pharmacology, Biochemistry and Behavior. 1997;56:261–264. doi: 10.1016/s0091-3057(96)00218-3. [DOI] [PubMed] [Google Scholar]
  19. Frye CA. The role of neurosteroids and non-genomic effects of progestins and androgens in mediating sexual receptivity of rodents. Brain Research Reviews. 2001a;37:201–222. doi: 10.1016/s0165-0173(01)00119-9. [DOI] [PubMed] [Google Scholar]
  20. Frye CA. The role of neurosteroids and nongenomic effects of progestins in the ventral tegmental area in mediating sexual receptivity of rodents. Hormones and Behavior. 2001b;40:226–233. doi: 10.1006/hbeh.2001.1674. [DOI] [PubMed] [Google Scholar]
  21. Frye CA. Progestins influence motivation, reward, conditioning, stress, and/or response to drugs of abuse. Pharmacology, Biochemistry and Behavior. 2007;86:209–219. doi: 10.1016/j.pbb.2006.07.033. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Frye CA. Neurosteroids: from basic research to clinical perspectives. In: Rubin R, Pfaff D, editors. Hormones, Brain and Behavior. 2. San Diego: Elsevier; 2009. pp. 2709–2748. [Google Scholar]
  23. Frye CA, Lacey EH. Progestins influence performance on cognitive tasks independent of changes in affective behavior. Psychobiology. 2000;28:550–563. [Google Scholar]
  24. Frye CA, Rhodes ME. Progestin concentrations are increased following paced mating in midbrain, hippocampus, diencephalon, and cortex of rats in behavioral estrus, but only in midbrain of diestrous rats. Neuroendocrinology. 2006a;83:336–347. doi: 10.1159/000096051. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Frye CA, Rhodes ME. Administration of estrogen to ovariectomized rats promotes conditioned place preference and produces moderate levels of estrogen in the nucleus accumbens. Brain Research. 2006b;1067:209–215. doi: 10.1016/j.brainres.2005.10.038. [DOI] [PubMed] [Google Scholar]
  26. Frye CA, Rhodes ME. Infusions of 3α,5α-THP to the VTA enhance exploratory, anti-anxiety, social, and sexual behavior and increase levels of 3α,5α-THP in midbrain, hippocampus, diencephalon, and cortex of female rats. Behavioural Brain Research. 2007;187:88–99. doi: 10.1016/j.bbr.2007.08.031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Frye CA, Sturgis JD. Neurosteroids affect spatial/reference, working, and long-term memory of female rats. Neurobiology of Learning and Memory. 1995;64:83–96. doi: 10.1006/nlme.1995.1046. [DOI] [PubMed] [Google Scholar]
  28. Frye CA, Vongher JM. Progesterone has rapid and membrane effects in the facilitation of female mouse sexual behavior. Brain Research. 1999;815:259–269. doi: 10.1016/s0006-8993(98)01132-9. [DOI] [PubMed] [Google Scholar]
  29. Frye CA, Vongher JM. Progesterone and 3α,5α-THP enhance sexual receptivity in mice. Behavioral Neuroscience. 2001;115:1118–1128. [PubMed] [Google Scholar]
  30. Frye CA, Walf AA. Effects of progesterone administration and APPswe+PSEN1Deltae9 mutation for cognitive performance of mid-aged mice. Neurobiology of Learning and Memory. 2008;89:17–26. doi: 10.1016/j.nlm.2007.09.008. [DOI] [PubMed] [Google Scholar]
  31. Frye CA, Petralia SM, Rhodes ME. Estrous cycle and sex differences in performance on anxiety tasks coincide with increases in hippocampal progesterone and 3α,5α-THP. Pharmacology, Biochemistry and Behavior. 2000;67:587–596. doi: 10.1016/s0091-3057(00)00392-0. [DOI] [PubMed] [Google Scholar]
  32. Frye CA, Rhodes ME, Petralia SM, Walf AA, Sumida K, Edinger KJ. 3α–hydroxy – 5α–pregnan – 20–one in the midbrain ventral tegmental area mediates social, sexual, and affective behaviors. Neuroscience. 2006;138:1007–1014. doi: 10.1016/j.neuroscience.2005.06.015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Frye CA, Duffy CK, Walf AA. Estrogens and progestins enhance spatial learning of intact and ovariectomized rats in the object placement task. Neurobiology of Learning and Memory. 2007a;88:208–216. doi: 10.1016/j.nlm.2007.04.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Frye CA, Paris JJ, Rhodes ME. Engaging in paced mating, but neither exploratory, anti-anxiety, nor social behavior, increases 5α-reduced progestin concentrations in midbrain, hippocampus, striatum, and cortex. Reproduction. 2007b;133:663–674. doi: 10.1530/rep.1.01208. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Galea LA, Ormerod BK, Sampath S, Kostaras X, Wilkie DM, Phelps MT. Spatial working memory and hippocampal size across pregnancy in rats. Hormones and Behavior. 2000;37:86–95. doi: 10.1006/hbeh.1999.1560. [DOI] [PubMed] [Google Scholar]
  36. Gerall AA, Dunlap JL. The effect of experience and hormones on the initial receptivity in female and male rats. Physiology & Behavior. 1973;10:851–854. doi: 10.1016/0031-9384(73)90053-x. [DOI] [PubMed] [Google Scholar]
  37. Gerall AA, Dunlap JL, Hendricks SE. Effect of ovarian secretions on female behavioral potentiality in the rat. Journal of Comparative Physiology and Psychology. 1973;82:449–465. doi: 10.1037/h0034113. [DOI] [PubMed] [Google Scholar]
  38. Hagihara K, Hirata S, Osada T, Hirai M, Kato J. Distribution of cells containing progesterone receptor mRNA in the female rat di- and telencephalon: an in situ hybridization study. Brain Research Molecular Brain Research. 1992;14:239–249. doi: 10.1016/0169-328x(92)90179-f. [DOI] [PubMed] [Google Scholar]
  39. Hull EM, Dominguez JM. Sexual behavior in male rodents. Hormones and Behavior. 2007;52:45–55. doi: 10.1016/j.yhbeh.2007.03.030. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Iswari S, Colas AE, Karavolas HJ. Binding of 5 alpha-dihydroprogesterone and other progestins to female rat anterior pituitary nuclear extracts. Steroids. 1986;47:189–203. doi: 10.1016/0039-128x(86)90088-7. [DOI] [PubMed] [Google Scholar]
  41. Izquierdo I, Medina JH. Memory formation: the sequence of biochemical events in the hippocampus and its connection to activity in other brain structures. Neurobiology of Learning and Memory. 1997;68:285–316. doi: 10.1006/nlme.1997.3799. [DOI] [PubMed] [Google Scholar]
  42. Kanarek RB, Beck JM. Role of gonadal hormones in diet selection and food utilization in female rats. Physiology & Behavior. 1980;24:381–386. doi: 10.1016/0031-9384(80)90102-x. [DOI] [PubMed] [Google Scholar]
  43. Kinsley CH, Madonia L, Gifford GW, Tureski K, Griffin GR, Lowry C, Williams J, Collins J, McLearie H, Lambert KG. Motherhood improves learning and memory. Nature. 1999;402:137–138. doi: 10.1038/45957. [DOI] [PubMed] [Google Scholar]
  44. Kinsley CH, Bardi M, Karelina K, Rima B, Christon L, Friedenberg J, Griffin G. Motherhood induces and maintains behavioral and neural plasticity across the lifespan in the rat. Archives of Sexual Behavior. 2008;37:43–56. doi: 10.1007/s10508-007-9277-x. [DOI] [PubMed] [Google Scholar]
  45. Lonstein JS. Regulation of anxiety during the postpartum period. Frontiers in Neuroendocrinology. 2007;28:115–141. doi: 10.1016/j.yfrne.2007.05.002. [DOI] [PubMed] [Google Scholar]
  46. Lopez HH, Olster DH, Ettenberg A. Sexual motivation in the male rat: the role of primary incentives and copulatory experience. Hormones and Behavior. 1999;36:176–185. doi: 10.1006/hbeh.1999.1535. [DOI] [PubMed] [Google Scholar]
  47. Luine VN, Jacome LF, Maclusky NJ. Rapid enhancement of visual and place memory by estrogens in rats. Endocrinology. 2003;144:2836–2844. doi: 10.1210/en.2003-0004. [DOI] [PubMed] [Google Scholar]
  48. MacLusky NJ, McEwen BS. Progestin receptors in the developing rat brain and pituitary. Brain Research. 1980;189:262–268. doi: 10.1016/0006-8993(80)90026-8. [DOI] [PubMed] [Google Scholar]
  49. Majewska MD, Harrison NL, Schwartz RD, Barker JL, Paul SM. Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor. Science. 1986;232:1004–1007. doi: 10.1126/science.2422758. [DOI] [PubMed] [Google Scholar]
  50. Maki PM, Rich JB, Rosenbaum RS. Implicit memory varies across the menstrual cycle: estrogen effects in young women. Neuropsychologia. 2002;40:518–529. doi: 10.1016/s0028-3932(01)00126-9. [DOI] [PubMed] [Google Scholar]
  51. Mann PE. Finasteride delays the onset of maternal behavior in primigravid rats. Physiology & Behavior. 2006;88:333–338. doi: 10.1016/j.physbeh.2006.04.008. [DOI] [PubMed] [Google Scholar]
  52. Mann PE, Bridges RS. Lactogenic hormone regulation of maternal behavior. Progress in Brain Research. 2001;133:251–262. doi: 10.1016/s0079-6123(01)33019-4. [DOI] [PubMed] [Google Scholar]
  53. Manshio DT, Gershbein LL. Avoidance and poke behavior in rats after gonadectomy and hormonal treatment. Research Communications in Chemical Pathology & Pharmacology. 1975;12:473–480. [PubMed] [Google Scholar]
  54. Marrone BL, Roy EJ, Wade GN. Progesterone stimulates running wheel activity in adrenalectomized-ovariectomized rats. Hormones and Behavior. 1975;6:231–236. doi: 10.1016/0018-506x(75)90010-0. [DOI] [PubMed] [Google Scholar]
  55. Mascarenhas JF, Borker AS, Venkatesh P. Differential role of ovarian hormones for taste preferences in rats. Indian Journal of Physiology and Pharmacology. 1992;36:244–246. [PubMed] [Google Scholar]
  56. Messier C. Glucose improvement of memory: a review. European Journal of Pharmacology. 2004;490:33–57. doi: 10.1016/j.ejphar.2004.02.043. [DOI] [PubMed] [Google Scholar]
  57. Miczek KA, Fish EW, De Bold JF. Neurosteroids, GABAA receptors, and escalated aggressive behavior. Hormones and Behavior. 2003;44:242–257. doi: 10.1016/j.yhbeh.2003.04.002. [DOI] [PubMed] [Google Scholar]
  58. Numan M, Insel TR. The Neurobiology of Parental Behavior. New York: Springer; 2003. [Google Scholar]
  59. Olazábal DE, Abercrombie E, Rosenblatt JS, Morrell JI. The content of dopamine, serotonin, and their metabolites in the neural circuit that mediates maternal behavior in juvenile and adult rats. Brain Research Bulletin. 2004;63:259–268. doi: 10.1016/j.brainresbull.2004.02.009. [DOI] [PubMed] [Google Scholar]
  60. Oldenburger WP, Everitt BJ, de Jonge FH. Conditioned place preference induced by sexual interaction in female rats. Hormones and Behavior. 1992;26:214–228. doi: 10.1016/0018-506x(92)90043-u. [DOI] [PubMed] [Google Scholar]
  61. Paredes RG, Alonso A. Sexual behavior regulated (paced) by the female induces conditioned place preference. Behavioral Neuroscience. 1997;111:123–128. doi: 10.1037//0735-7044.111.1.123. [DOI] [PubMed] [Google Scholar]
  62. Pawluski JL, Galea LA. Hippocampal morphology is differentially affected by reproductive experience in the mother. Journal of Neurobiology. 2006;66:71–81. doi: 10.1002/neu.20194. [DOI] [PubMed] [Google Scholar]
  63. Pawluski JL, Galea LA. Reproductive experience alters hippocampal neurogenesis during the postpartum period in the dam. Neuroscience. 2007;149:53–67. doi: 10.1016/j.neuroscience.2007.07.031. [DOI] [PubMed] [Google Scholar]
  64. Pawluski JL, Vanderbyl BL, Ragan K, Galea LA. First reproductive experience persistently affects spatial reference and working memory in the mother and these effects are not due to pregnancy or ‘mothering’ alone. Behavioural Brain Research. 2006;75:157–165. doi: 10.1016/j.bbr.2006.08.017. [DOI] [PubMed] [Google Scholar]
  65. Phillips SM, Sherwin BB. Variations in memory function and sex steroid hormones across the menstrual cycle. Psychoneuroendocrinology. 1992;7:497–506. doi: 10.1016/0306-4530(92)90008-u. [DOI] [PubMed] [Google Scholar]
  66. Pinna G, Costa E, Guidotti A. Changes in brain testosterone and allopregnanolone biosynthesis elicit aggressive behavior. Proceedings of the National Academy of Sciences, USA. 2005;102:2135–2140. doi: 10.1073/pnas.0409643102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Rhodes ME, Frye CA. Estrogen has mnemonic-enhancing effects in the inhibitory avoidance task. Pharmacology, Biochemistry and Behavior. 2004;78:551–558. doi: 10.1016/j.pbb.2004.03.025. [DOI] [PubMed] [Google Scholar]
  68. Roberts DC, Bennett SA, Vickers GJ. The estrous cycle affects cocaine self-administration on a progressive ratio schedule in rats. Psychopharmacology. 1989a;98:408–411. doi: 10.1007/BF00451696. [DOI] [PubMed] [Google Scholar]
  69. Roberts DC, Loh EA, Vickers G. Self-administration of cocaine on a progressive ratio schedule in rats: dose-response relationship and effect of haloperidol pretreatment. Psychopharmacology. 1989b;97:535–538. doi: 10.1007/BF00439560. [DOI] [PubMed] [Google Scholar]
  70. Roth ME, Negus SS, Knudson IM, Burgess MP, Mello NK. Effects of gender and menstrual cycle phase on food-maintained responding under a progressive-ratio schedule in cynomolgus monkeys. Pharmacology, Biochemistry and Behavior. 2005;82:735–743. doi: 10.1016/j.pbb.2005.11.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Sandstrom NJ, Williams CL. Memory retention is modulated by acute estradiol and progesterone replacement. Behavioral Neuroscience. 2001;115:384–393. [PubMed] [Google Scholar]
  72. Solis-Ortiz S, Guevara MA, Corsi-Cabrera M. Performance in a test demanding prefrontal functions is favored by early luteal phase progesterone: an electroencephalographic study. Psychoneuroendocrinology. 2004;29:1047–1057. doi: 10.1016/j.psyneuen.2003.10.007. [DOI] [PubMed] [Google Scholar]
  73. Vongher JM, Frye CA. Progesterone in conjunction with estradiol has neuroprotective effects in an animal model of neurodegeneration. Pharmacology Biochemistry Behavior. 1999;64:777–785. doi: 10.1016/s0091-3057(99)00140-9. [DOI] [PubMed] [Google Scholar]
  74. Walf AA, Rhodes ME, Frye CA. Ovarian steroids enhance object recognition in naturally cycling and ovariectomized, hormone-primed rats. Neurobiology of Learning and Memory. 2006;86:35–46. doi: 10.1016/j.nlm.2006.01.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Walf AA, Rhodes ME, Meade JR, Harney JP, Frye CA. Estradiol-induced conditioned place preference may require actions at estrogen receptors in the nucleus accumbens. Neuropsychopharmacology. 2007;32:522–530. doi: 10.1038/sj.npp.1301124. [DOI] [PubMed] [Google Scholar]
  76. Wood GE, Beylin AV, Shors TJ. The contribution of adrenal and reproductive hormones to the opposing effects of stress on trace conditioning in males versus females. Behavioral Neuroscience. 2001;115:175–187. doi: 10.1037/0735-7044.115.1.175. [DOI] [PubMed] [Google Scholar]

RESOURCES