Neuroscience& BiobeharioralReviews. Vol. 14. pp. 23-33. e Pergamon Press plc, 1990. Printed in the U.S.A.

0149-7634/90 $3.00 + .00

Behavioral Differences Between Male and Female Rats: Effects of Gonadal Hormones on Learning and Memory F R A N S vAN H A A R E N

Department o f Psychology, UniversiO, o f Florida, Gainesville, FL 32611 ANNEMIEKE

vAN H E S T

Department o f Pharmacology, DUPHAR, B.V., Weesp, The Netherlands AND R O B P. W. H E I N S B R O E K

Netherlands hzstitute f o r Brain Research, Amsterdam, The Netherlands R e c e i v e d 1 N o v e m b e r 1988

VANHAAREN, F., A. vat,' HEST AND R. P. W. HEINSBROEK. Behavioral differences between male and female rats: Effects of gonadal hormones on learning and memory. NEUROSCI BIOBEHAV REV 14(1) 23-33, 1990.--The organizational, activational and reorganizational effects of gonadal hormones have been extensively investigated with respect to sexual, aggressive and maternal behavior. It has thus been established that manipulations of gonadal hormones during critical periods in development functionally affect reproductive behavior. The effects of gonadal hormones on nonreproductive behavior are not immediately obvious because of the fact that the behavioral effects of gonadal hormones on learning and memory have been investigated in a large number of unrelated experimental procedures. The present paper provides an organized overview of these different experimental procedures, summarizes the most important findings and discusses some of the variables which determine the effects of manipulations in gonadal hormones on learning and memory in male and female rats. Passive avoidance Active avoidance Taste aversion Maze learning Schedules of reinforcement Delayed matching procedures Gonadal hormones Gonadectomy Male and female rats

continued functional flexibility of neuronal systems and behavior which previously had been thought to be permanently organized. The organizational, activational or reorganizational effects of hormonal state on behavior are most likely to be evident in those behavioral functions which are directly dependent upon the early or current hormonal status of the organism. It is therefore reasonable to assume that the effects of manipulations of gonadal hormones may be more or less evident dependent upon the behavior under investigation. Behavior which is directly relevant for the survival of the species (such as sexual and aggressive behavior) more obviously reflects the effects of manipulations of gonadal hormones than other forms of behavior which are much more important for the immediate survival of individual members of a species (39). The latter categories of behavior are called nonreproductive and include those behaviors which tend to vary dependent upon changes in immediate environmental contingencies. The experimental analysis of the organization, activational and reorganizational effects of gonadal hormones on learning and

THE effects of gonadal hormones on reproductive and nonreproductive behavior are the result of a complex interaction between hormonal and environmental variables. It has previously been proposed that gonadal hormones exert their influence on the reproductive and nonreproductive behavior of individual organisms along an organizational-activational continuum [(7, 74, 88, 139) but see (69,70)]. Organizational effects of gonadal hormones, which are most likely to occur during prenatal and perinatal sensitive periods, are more or less permanent and irreversible. Gonadal hormones may thus be involved in the structural and functional organization of the central nervous system. Activational effects of gonadal hormones include the transient effects of momentary hormonal state at the time of occurrence of a particular behavior. These activational effects may affect the form or intensity of the behavior executed under different environmental contingencies. Recent insights have suggested that reorganizational effects of gonadal hormones may also be observed in adulthood (3). Reorganizational effects define the

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van HAAREN, VAN HEST AND HEINSBROEK

memory has resulted in a large amount of interesting data, but has been hampered by the fact that these effects have been studied in a great variety of unrelated experimental procedures. This review of sex differences in learning and memory is an attempt to integrate the available evidence on the basis of: 1) the different experimental procedures in which sex differences have been investigated and 2) the manipulations of gonadal hormones which have been conducted. Although such an approach may seem to be rather mechanistic and atheoretical, it is important to present this overview because of the fact that only then an attempt may be made to derive more general principles describing the effects of gonadal hormones on learning and memory. A distinction will be made between sex differences observed in aversively and positively motivated experimental procedures. This distinction is appropriate because of the fact that available evidence strongly suggests that the behavioral effects of manipulations in gonadal hormones may differ as a function of the consequences which follow the occurrence of behavior. Differences between intact male and female rats will be the focus of attention. In addition, the effects of hormonal manipulations during the neonatal period or in adulthood will be reviewed for those experimental paradigms for which they are available. AVERSIVELYMOTIVATEDBEHAVIOR Reactivi~" to Shock and Adulterated Substances

Active avoidance, passive avoidance and taste aversion procedures have been employed to investigate behavioral reactivity of male and female rats in response to the presentation or removal of mild to moderate electrical shocks on the one hand, and reactivity to the presentation of quinine-adulterated substances on the other hand. In the absence of other contingencies, female rats generally have lower thresholds for, and shorter escape latencies from, shock presentation than males (9, 14, 15, 77, 85). Beatty and Holzer (17) have shown that shock intensity thresholds did not vary with the day-night cycle in males, but that females were more sensitive to shock intensity during the dark than during the light portion of the day-night cycle. The role of gonadal hormones in modifying reactivity to electrical shock presentation has not yet clearly been established. Gonadectomy increases flinch and jump thresholds in females (76,77), while it reduces these thresholds and escape latencies in males (34). However, threshold changes were only observed when changes in body weight as a result of gonadectomy were also allowed to develop. Beatty and Beatty (9) and Beatty and Fessler (13) observed the effects of gonadectomy and hormone replacement on flinch-jump thresholds in male and female rats. Ovariectomy increased the body weight of females, but did not affect shock sensitivity. Castration reduced weight gain in males, but only affected shock sensitivity when subjects were castrated during the neonatal period. Castration in adulthood did not alter flinch-jump thresholds. These investigators also showed that testosterone administration increased shock intensity thresholds in neonatally castrated rats, suggesting that sex differences in sensitivity to shock intensity are not solely due to the organizational effects of gonadal hormones, or mediated by changes in body weight. Marks and Hobbs (77) set out to investigate whether or not males and females differed with respect to quinine-induced suppression of water intake. Females consumed less water than males after the water had been adulterated with quinine. It was also noted that the effects of gonadectomy on quinine-induced suppression of water intake were dependent on changes in body weight (76,77). Differences between intact and gonadectomized subjects were not observed prior to the development of weight changes as a result of gonadectomy. When weight changes were allowed to develop the heavier subjects within each sex showed less quinine-induced

suppression of water intake than other groups of subjects. Wade and Zucker (136) failed to observe sex differences in quinineinduced suppression of water intake in intact male and female rats. Water intake was much more reduced in intact female rats than in rats which previously had been ovariectomized. Changes in water intake were not observed in ovariectomized rats after treatment with either estradiol or progesterone. However, when both estradiol and progesterone were administered, ovariectomized rats decreased the intake of quinine-adulterated water, suggesting that these hormones may act synergetically to produce the decrease in water intake. Active Avoidance Conditioning

Shuttle box avoidance, lever press-signalled avoidance and Sidman avoidance procedures have been employed to study the behavioral effects of gonadal hormones on active avoidance learning. In shuttle box avoidance conditioning subjects avoid the presentation of an aversive event by moving from one compartment into another during the presentation of a stimulus which precedes the presentation of an aversive event (usually a mild electric shock). Escape behavior is observed when subjects move from one compartment into the other one once the aversive event has been initiated. In signalled avoidance procedures, subjects avoid the presentation of the aversive event by pressing a lever during the presentation of a stimulus which precedes presentation of the aversive event. Subjects may also escape presentation of the aversive event by pressing the lever during its presentation. In Sidman avoidance procedures (95) unsignalled presentation of the aversive event occurs regularly when lever presses do not occur, while shock-free periods are scheduled when subjects engage in lever pressing. Intact female rats acquire shuttle box avoidance behavior more rapidly than males (9, 37, 38, 73, 92). Extinction of shuttle box avoidance behavior occurs slower in females than in males (11, 24, 61). Limited evidence is available to suggest that these behavioral differences between the sexes may be dependent upon the time of testing. Beatty (6) has reported that sex differences are observed when testing occurs during the light period of the day-night cycle, but not when subjects are tested during the dark period. Gonadectomy in adulthood did not affect shuttle box avoidance behavior. However, exposure to exogenous androgens during the neonatal period, combined with testosterone in adulthood, produced females whose shuttle box avoidance behavior very much resembled that of intact males (9). Beatty and Beatty (10) also treated female rats with testosterone or placebo injections at 3 days of age. All subjects were ovariectomized in adulthood and received either placebo, estrogen or testosterone treatment. Only those females who received testosterone treatment both during the neonatal period and in adulthood showed shuttle box avoidance behavior which was indistinguishable from that of intact males. Scouten et al. (92) performed a number of experiments in which they investigated shuttle box avoidance behavior after gonadectomy in adulthood, after neonatal castration and after prenatal exposure to the antiandrogen cyproterone acetate combined with neonatal castration. Only the latter treatment produced males whose active avoidance behavior was indistinguishable from that of intact females, suggesting that prenatal exposure to endogenous androgens is sufficient to organize characteristic male active avoidance behavior. Denti and Negroni (38) showed that neonatal castration of male rats did not affect shuttle box avoidance behavior, but neonatal androgenization of females decreased avoidance response efficiency. Several investigators have observed active avoidance behavior of female rats while controlling their reproductive status. Sfikakis et al. (94), for instance, showed that shuttle box avoidance behavior of female rats was specifically

SEX DIFFERENCES IN LEARNING AND MEMORY

facilitated during the proestrus phase of the reproductive cycle. Canizarro et al. (25) observed that ovariectomy of female rats resulted in shuttle box avoidance behavior which was inferior to that of female rats which had been ovariectomized and simultaneously treated with a combination of progesterone and estrogen. Finally, Telegdy (103) and Telegdy and Stark (104) studied the effects of different steroids in male and female rats during extinction of pole-jump active avoidance responding. In such procedures rats may avoid or escape the presentation of an aversive event by jumping from the grid floor into a pole or onto a platform. Telegdy (103) reported that castration of male and female rats before puberty delayed extinction of pole-jump avoidance responding when compared to intact male and female rats. Telegdy and Stark (104) noted that neonatal androgenization of female rats shortened extinction of this avoidance response, while estrogen and progesterone treatment of ovariectomized females prior to extinction prolonged extinction of pole-jump avoidance behavior. Van Oijen et al. (134) and Heinsbroek et al. (57) showed that females acquired a signalled active avoidance response more efficiently than males. They also observed that ovariectomy did not affect discriminated lever press avoidance whereas castration tended to improve it (134). Similar observations were reported by Davis et al. (34) who showed that lever press shock escape behavior of castrated males resembled that of intact females whereas the performance of ovariectomized females came to resemble that of intact males. It was also reported that females behaved more efficiently than males in an experimental procedure in which unsignalled shock presentation could be terminated by a lever press; shorter escape latencies were recorded in females than in males (34). Behavioral differences between the sexes have also been observed during the acquisition of Sidman avoidance behavior (4). Females were more likely than males to acquire efficient avoidance responding. Others have provided evidence to show that gonadectomy impairs acquisition of behavior in Sidman avoidance procedures in male and female rats (81]. McCord et al. (79) studied the effects of different gonadal hormones on the acquisition of Sidman avoidance behavior in male rats only. Different groups were castrated and received injections of either estradiol, estradiol plus progesterone, progesterone alone, testosterone or saline. After eight days of hormone treatment, the Sidman avoidance behavior of these rats was compared with that of other rats who had received a sham operation and saline treatment. Although significant differences between groups were not observed, estradiol treatment following castration seemed to facilitate the acquisition of Sidman avoidance behavior (79).

Passive A v o i d a n c e Conditioning

During step-through passive avoidance conditioning (1) subjects are exposed to a brightly lit platform or a brightly lit compartment of a two compartment apparatus. They are also allowed access to a dark compartment: males and females usually enter the dark compartment with very short entrance latencies. After a number of trials during which they are allowed to leave the brightly lit compartment and to enter the dark compartment, a mild unavoidable footshock is presented once the subjects have entered the dark compartment. Some time later subjects are reexposed to the brightly lit compartment and tested to see whether or not they leave the illuminated compartment to enter the dark compartment. Latencies to reenter are usually also recorded. A number of experiments have shown that females are more likely than males to reenter the dark compartment in which they previously have been shocked (16, 21, 56). Recent experiments have shown that

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behavioral differences between the sexes in this procedure are observed when subjects are exposed to 1 or 3, but not when they are exposed to 9 preshock trials (111). In other experiments different groups of subjects were exposed to the passive avoidance procedure under different luminance conditions. More females than males entered the dark compartment when reexposed to the apparatus one hour after shock presentation irrespective of the intensity of the light stimulus during the preshock trials (112). Van Oijen et al. ( 131 ) showed that the number of males reentering the dark compartment in which they had been shocked increased as shock intensity was decreased, but females reentered the dark compartment irrespective of shock intensity. In other experiments, van Oijen et al. (132) varied the duration of the interval between shock presentation and reexposure to the passive avoidance apparatus from a few minutes to several days for different groups of subjects. The number of subjects which reentered the dark compartment increased systematically as a function of the duration of the interval between shock presentation and reexposure to the passive avoidance apparatus. More females than males entered the dark compartment once the duration of the interval exceeded 15 min. Sex differences were also observed when subjects were reexposed to the apparatus immediately after shock presentation (0 rain), but not when the duration of the interval was 15 rain. Heinsbroek et al. (56) observed sex differences after a shock-retest interval of 60 rain or more, but not when subjects were tested after 0 or 15 min. Similar observations have been reported by Drago et al. (40]. Van Haaren and van de Poll (110) employed a passive avoidance procedure similar to the one previously described by Carew (26) and trained male and female rats to enter two distinctively different dark compartments during the preshock trials. Shock was only presented in one of the two compartments. One hour after shock presentation females were more likely than males to reenter the compartment in which they had not been shocked. Heinsbroek et al. (51 ) exposed different groups of male and female rats to a step-through passive avoidance procedure in which some subjects were shocked and others were not. These authors observed that female rats were more likely than males to reenter the dark compartment with shorter latencies when they were reexposed to the passive avoidance apparatus 1 hour after shock presentation. Separate groups of male and female rats were also trained in the passive avoidance procedure, but not reexposed to the passive avoidance apparatus 1 hour later. Instead, they were tested in an open-field to investigate whether the behavioral inhibition observed after reexposure to the passive avoidance apparatus would generalize to another environment, which was completely novel for all groups of subjects. Heinsbroek et al. (51) observed that shock presentation reduced locomotor activity in the open-field in both sexes, but the locomotor activity of males was reduced to a greater extent than that of females. Whether or not sex differences in the reactivity of the serotonergic system, as have been observed by Heinsbroek et al. (50), are involved in the observation of behavioral differences between the sexes in the passive avoidance procedure was evaluated in an experiment in which administration of the neurotoxin para-chloramphetamine (PCA) was used to reduce the activity of the central serotonergic system before subjects were exposed to the choice passive avoidance procedure (49,110). One hour after shock presentation more females than males reentered the dark compartment in which they had not been shocked. These behavioral differences between the sexes were not observed in the PCA-treated groups as a result of the fact that more males reentered the compartment in which they had not been shocked. Some experiments have been reported in which the effects of hormonal manipulations on passive avoidance behavior were investigated. Negroni and Denti (83) showed that neonatal castra-

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tion decreased response efficiency in a one-trial passive avoidance procedure, while neonatal androgenization of female rats failed to affect the behavior of these females relative to that of intact controls. Van Oijen et al. (132) observed that ovariectomy did not affect the behavior of female rats, but castration significantly increased the number of males which reentered the dark compartment. Finally, Phillips and Deol (87) showed that neonatal treatment of intact male rats with testosterone propionate did not affect step-down avoidance behavior when compared with the behavior of subjects who had only been injected with vehicle solution. Taste Aversion Conditioning

Garcia et al. (45) first described an experiment in which subjects learned to avoid a saccharin solution which previously had been paired with an illness-inducing agent. In the typical taste aversion procedure, subjects are allowed daily access to water for a limited period of time. On day 1 of the experiment, the water is replaced by a sucrose or saccharin solution. Immediately after the session subjects are exposed to an illness-inducing agent (gamma radiation or intraperitoneal injections with lithium chloride). The next day, subjects are again allowed access to the saccharin solution. Subjects treated with radiation or lithium chloride avoid contact with the saccharin solution for some time. The number of times that subjects are exposed to the solution until extinction of the taste aversion is usually the dependent variable of interest. Chambers and her colleagues have repeatedly shown that taste aversions are slower to extinguish in male than in female rats (27-32, 93). Social isolation of male rats leads to a more rapid extinction of a taste aversion than when subjects are housed in social groups (30). Behavioral differences between the sexes are also not observed when subjects are water deprived (29). Weinberg et al. (137) failed to observe behavioral differences between the sexes when nondeprived male and female rats were exposed to a milk solution and subsequently injected with lithium chloride. These investigators suggest that the failure to find differences similar to those reported by Chambers and co-workers may have been due to differences in experimental procedures. Finally, Chambers et al. (32) have shown that male rats are more likely than female rats to acquire a taste aversion but only when subjects are not deprived. Another experiment employed a procedure which might be considered an operant lever press analogue of the conditioned taste aversion procedure, Van Oijen et al. trained male and female rats to hold down a lever in order to obtain food (133). Once consistent lever holding had been established, presentation of a short-duration shock occurred concurrently with food presentation. This manipulation decreased lever hold activity in both males and females. When the original reinforcement conditions (food, but no shock) were reinstated in subsequent sessions females were more likely than males to resume lever hold activity (133). Several experiments have shown that behavioral differences between the sexes in taste aversion extinction are dependent upon the subjects' hormonal status. Castration produced a reduction in the duration of taste aversion extinction, while ovariectomy did not affect the behavior of females. Administration of testosterone propionate, however, increased the duration of extinction in both sexes (27, 32, 137). Chambers and Sengstake (30,31) confirmed these observations in other experiments in which they showed that social isolation of males (which led to a reduction in the availability of endogenous testosterone) shortened the duration of taste aversion extinction. When different groups of castrated male and female rats were given testosterone either during the acquisition or during the extinction phase of the experiment, slower rates of

VAN HAAREN, VAN HEST AND HEINSBROEK

extinction were only observed in those subjects given testosterone during extinction. Chambers (28) showed that the duration of taste aversion extinction can be extended by the administration of corticotropin in intact, but not in castrated male rats. Early and Leonard (41) extended these observations across a range of different hormonal manipulations in male rats. Castrated male rats were not treated or were treated with testosterone, estradiol or dihydrotestosterone. The testosterone-treated group maintained the taste aversion for the longest period of time, followed by the dihydrotestosterone, sham, castrated and estradiol-treated groups. When estradiol was combined with dihydrotestosterone, the duration of taste aversion extinction was dependent upon the ratio of estradiol to dihydrotestosterone. Summalw. : Sex Differences in Aversively Motivated Behavior

The results of the experiments reviewed above suggest that consistent behavioral differences between the sexes may be observed when behavior is acquired and maintained by the presentation or removal of an aversive event. Available evidence shows that presentation of an aversive event results in behavioral inhibition in intact males, but not in intact females (9, 11, 16, 21, 24, 49, 56, 57, 92, 98, 110-112, 131, 132, 134). Evidence is available to suggest that, organizational, more than activational effects of gonadal hormones play an important role in mediating behavioral differences between the sexes in active avoidance procedures. Gonadectomy in adulthood does not affect active avoidance behavior of males and females in shuttlebox avoidance procedures. However, neonatal castration of males, or neonatal androgenization of females has been shown to reverse the behavioral differences observed in intact males and females in shuttlebox avoidance procedures ( 10, 38, 92). Results of other experiments, however, suggest that the effects of gonadectomy in adulthood may vary dependent upon the experimental procedure in which they are investigated. Van Oijen et al. (134) and Davis et al. (34) have shown that castration in adulthood may result in lever press avoidance behavior which resembles that of intact females. It should be noted, however, that these investigators employed signalled lever press avoidance procedures and not shuttlebox avoidance procedures. It may very well be the case that response topography plays an important role in the explanation of these discrepancies. Experiments in which gonadal hormones were manipulated, either during the neonatal period or in adulthood, have not provided enough evidence to substantiate claims of organizational or activational effects of gonadal hormones which might mediate behavioral differences between the sexes in passive avoidance procedures (21, 83, 87, 132). On the other hand, it has repeatedly been shown that taste aversion extinction occurs much slower in intact male than in intact female rats (27, 29, 30). Manipulation of gonadal hormones has provided rather consistent results in taste aversion procedures. Several experiments have shown that testosterone plays an activating role in the observation of this behavioral difference between the sexes. When males are castrated in adulthood, taste aversion extinction behavior becomes comparable to that of intact females. Administration of testosterone to ovariectomized females results in taste aversion extinction behavior which resembles that of intact males. The presence of testosterone is critical during extinction training, but not during the acquisition of the taste aversion (28, 32, 41, 137). POSITIVELYMOTIVATEDBEHAVIOR ActiviD' and Food Motivation

Behavioral differences between the sexes have also been observed in procedures in which behavior is acquired and main-

SEX DIFFERENCES IN LEARNING AND MEMORY

tained by the presentation of a positive event. Food or water deprivation plays an important role in most positively motivated experimental procedures. The influence of gonadal hormones on body weight regulation will therefore be reviewed, before behavioral differences between the sexes observed in positively motivated experimental procedures will be discussed. Wade (135) has previously reviewed the evidence available in this area of research. Male rats eat more and weigh more than female rats. Males only show small irregular changes in body weight and eating habits, while female rats have been observed to exhibit large, predictable changes (20). Males have also been observed to grow faster than females (97,135). Van Hest et al. (125) exposed food-deprived (59) male and female rats to different progressive-ratio schedules in order to establish the effects of food deprivation on food motivation in an operant conditioning environment. Van Hest et al. (125) manipulated the increment value of the ratio as well as increment variability and observed intact and gonadectomized male and female rats to reach the same final completed ratio in all experimental conditions. It can thus be tentatively concluded that, even though sex differences in body weight regulation exist, such differences are not likely to be responsible for behavioral differences observed in food-motivated experimental procedures. A large number of experiments have shown that female rats are more active than males in the open-field and running wheel (2, 4, 13, 18, 35, 46, 47, 52, 58, 60, 71, 72, 78, 83, 86, 89, 90, 96.99, 138). Several experiments have shown that the behavioral difference between the sexes is not dependent on the presence of gonadal hormones at the time of testing (21,23). However, neonatal androgen treatment of intact female rats produces females who ambulate significantly less than intact vehicle-treated female rats, while ambulation scores are comparable to those of intact males (101). Other experiments have produced evidence to suggest that neonatal exposure to testosterone, dihydrotestosterone or estradiol produces male-like open-field behavior in female rats (22, 24, 102). Stewart and Cygan (100) have shown that gonadectomy at 1 or 8 days, but not at 23 days of age disrupted the normal female activity score in the open-field, while exposure to low doses of exogenous estradiol between days 10 and 20 led to higher levels of activity as compared to oil-treated controls. Schedule-Controlled Behavior

Van Haaren et al. (116) and van Hest and van Haaren (120) employed different autoshaping procedures to investigate whether or not sex differences would be observed in the acquisition of lever press behavior. These investigators observed higher lever contact rates in males than in females, both when lever presentations were followed by response-independent food and when they were not. Other experiments have shown that female rats behave more efficiently than males when behavior is maintained by a differential reinforcement of low rate (DRL) schedule (5, 12, 19, 64, 109, 122, 124, 140). Sex differences in DRL response efficiency in adulthood are not observed when subjects are trained to respond on this schedule during the adolescent period (19). Van Hest et al. (122) investigated the possibility that sex differences in DRL efficiency might be due to the fact that females are more likely than males to engage in activities other than lever pressing in an operant environment. It was argued that high activity levels make it less likely that subjects will only engage in one relatively localized activity (lever pressing). Van Hest et al. (122) thus tested male and female rats in different DRL procedures in which stimuli were presented to facilitate the development of collateral behavior (66,67). As expected, females behaved more efficiently than males when these stimuli were not presented. The addition of stimuli to the experimental environment facilitated the execution

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of efficient DRL performance in males but not in females. Other experiments have confirmed that behavioral differences between the sexes in DRL efficiency might be mediated by differences in the extent to which subjects engage in activities other than lever pressing. Van Hest et al. (123) required male and female rats to hold down a lever for a specific period of time in order for food to be presented. Females spent less time than males holding down the lever. Van Haaren et al. (109,121) investigated the existence of sex differences in schedules which explicitly reinforced high rates of behavior. When exposed to a differential reinforcement of high rate (DRH) schedule, males responded at higher rates than females. Similar results were obtained when males and females were exposed to different random-ratio schedules by Heinsbroek et al. (53,54). A number of experiments have been conducted to investigate the effects of manipulations of gonadal hormones on autoshaping, DRL and random-ratio behavior. The autoshaping efficiency of gonadectomized male and female rats does not differ from that observed in intact males and females, but chronic testosterone suppletion to gonadectomized males and females produced autoshaping behavior which resembled that observed in intact males (120). Beatty (5) showed that ovariectomy abolished sex differences in DRL acquisition, but neonatal castration did not affect the acquisition of DRL performance in male rats (12). Lentz et al. (68) implanted ovariectomized female rats with estradiol, progesterone or a combination of estrogen and progesterone. Ovariectomized subjects which did not receive supplemental hormones responded faster than intact subjects during 30 days of DRL acquisition, but the efficiency of DRL acquisition or the number of earned reinforcers did not differ between any of the groups of subjects. Finally, Moss (82) measured bar press duration of intact female rats and showed that it covaried with regular cyclic changes in female ovarian hormones. Both bar press duration and sexual receptivity varied together, disappeared after ovariectomy and were not observed in male rats. Heinsbroek et al. (54) compared response rates during random ratio acquisition in gonadectomized male and female rats. Castration greatly reduced response rates in males, while ovariectomy did not affect the behavior of female rats. Van Hest et al. (127) investigated whether or not behavioral differences between males and females might also be observed in experimental procedures specifically designed to investigate response perseveration. In these procedures, two levers are available in the experimental environment, while reinforcement is randomly assigned to be delivered after the occurrence of a lever press on only one of the two levers. Response perseveration (continued responding on the lever to which delivery of reinforcement was not assigned) occurred more often in male than in female rats. These investigators also analyzed the behavior of gonadectomized and gonadectomized plus testosterone-treated male and female rats in the same experimental procedure. Gonadectomy did not influence response perseveration, but chronic testosterone suppletion to gonadectomized female rats resulted in response perseveration which resembled that of intact males. Thompson and Wright (105) defined response perseveration in terms of difficulty in shifting from one to another discrimination. These investigators injected intact male rats with either a low (25 mg/100 g body weight) or a high dose (55 mg/100 g body weight) of testosterone, while other animals were treated with cyproterone acetate or vehicle solution. Increased persistence was observed in subjects treated with the low dose of testosterone, while cyproterone acetate resulted in decreased perseveration compared to the control group. Memo~3'

In memory procedures subjects are required to behave under

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the discriminative control of stimuli which are no longer physically present at the time of response execution. Thus, correct responses at time X can only occur when subjects behave under the control of stimuli which were present at time X - t . Memory for recent or past events can be inferred from the accuracy with which subjects perform the task at hand. A number of different experimental procedures have been used to assess memory functioning. Maze procedures in which rats are required to reach a goal box in order to obtain food have been employed. The complexity of the mazes has varied from simple T-mazes to complex Hebb-Williams arrangements. Frequently, T-maze alternation procedures are used, in which subjects have to enter one of the two arms of the maze during different trials in order to gain access to food. In operant spatial delayed alternation procedures, subjects usually have access to two levers in a Skinner box. Correct alternation performance (alternating between pressing the left and right levers) is reinforced with the presentation of food or water. Other experimental procedures employ the presentation of a sample stimulus (spatially. visually or auditorially defined) to which correct responses have to be subsequently matched (matching-to-sample proceduresl (108, 113-115, 117, 126, 129). Perfornlance in different memory procedures is very much dependent upon the way in which males and females are able to discriminate one stimulus condition from another one. Gandelman (44) has reviewed evidence which shows that gonadal hormones may affect sensory functioning in a number of different ways [see also (36)]. Van Haaren and van Hest ( l l 3 ) thus investigated whether or not differences between male and female Wistar rats would be observed when they were required to discriminate between the presentation of two different visual or auditory stimuli in order for food to be presented. The acquisition of the visual or auditory discrimination occurred at the same rate in male and female rats, while discrimination performance improved with prolonged training. Guillamon et al. (48) have shown that males and females did not differ in the acquisition of a black-white discrimination in the T-maze, but that females were more likely than males to acquire the discrimination reversal. Similar observations had previously been reported by Millar (80), who investigated discrimination reversal performance in an operant experimental procedure. Guillamon et al. (48) also exposed androgenized females and neonatally castrated males to the black-white T-maze discrimination task and showed that the behavior of androgenized females resembled that of intact males, while the behavior of neonatally castrated males was comparable to that of intact females. Behavioral differences between the sexes have been observed in complex mazes which resemble a large open-field. Females usually make more errors than males [(4, 33, 64, 91, 101L but see (75)]. It has previously been suggested that activity differences between the sexes mediate the observation of sex differences in these mazes. Van Haaren et al. (I 19) explicitly tested this notion by investigating the behavior of male and female rats in an eight-arm radial maze (841, which is considered to be relatively complex, hut which does not resemble a large open-field. Male and female rats required an equal number of choices and an equal amount of time to attain a stable level of correct choices, in concordance with results of other experiments (42, 63, 119). In contrast to these findings, Beatty (8) has reported the results of an experiment in which male and female rats were trained to obtain food from only 6 baited arms in an eight-arm radial maze. He showed that females made more reference and working memory errors than males. The results of experiments conducted in standard complex mazes and radial mazes thus suggest that the

VAN HAAREN, VAN HEST AND HEINSBROEK

spatial arrangement of a maze may determine whether or not behavioral differences between the sexes are observed. Behavioral differences between male and female rats in different maze procedures seem to be a function of neonatal hormonal status. It has been shown that neonatal castration of male rats or neonatal androgenization of female rats results in maze learning efficiency in adulthood which resembles that of the opposite sex (35). These observations were confirmed by Stewart et al. (101L who showed that Lashley lII maze performance of neonatally testosterone-treated female rats resembled that of intact males when testing occurred in adulthood. Joseph et al. (62) investigated maze learning efficiency of males who had been castrated at birth, males and females which were treated with cyproterone acetate and females treated with testosterone within l0 days after birth. Neonatal castration and treatment with cyproterone acetate reversed the behavioral differences which are usually observed, while gonadectomy in adulthood was ineffective. Similar conclusions were reached by Schenk and Slob (91), who treated gonadectomized male and female rats with testosterone propionate, estradiol benzoate or oil vehicle before training in a HebbWilliams maze. Behavioral differences between the sexes were observed in subjects which had been treated with the oil vehicle, but not in subjects treated with exogenous hormones. Several investigators have examined the behavior of male and female rats in different spatial alternation and matching-to-sample procedures (43, 107, 108, l l4, l l5, 126, 129, 130). Male and female rats responded less efficiently as the delay interval between stimulus presentation and response opportunities was increased, but male and female rats reached similar levels of accuracy independent of the duration of the delay interval. Some experiments have shown, however, that the acquisition of an operant spatial delayed response alternation task may occur faster in males than in females (126,130). The behavior of males, on the other hand, is more easily disrupted than that of females when response noncontingent stimuli are presented during the delay interval (126). Van Hest et al. (129) also examined the effects of gonadectomy on the acquisition of efficient performance in the operant delayed spatial alternation procedure. These investigators showed that all subjects (whether intact or gonadectomized) reached similar levels of accuracy, but that intact males reached efficient performance faster than any of the other groups of subjects. Van Haaren and van Hest (114) trained male and female rats in a spatial delayed matching-to-position procedure in which subjects were required to engage in nosepoke behavior in the feeder tray during the delay interval. Response accuracy of male and female rats decreased as the duration of the delay interval was increased, but differences between the sexes in final response accuracy or response acquisition were again not observed. Summao': Sex Differences in Positively Motivated Behavior

Intact female rats are more active than intact male rats in the open-field. This behavioral difference between the sexes is a function of the organizational effects of gonadal hormones as experiments have shown that gonadectomy of adult male and female rats does not influence behavioral differences observed in the open-field (21,23). In addition, neonatal androgenization of female rats resulted in ambulation scores in adulthood which were comparable to those of intact males (22, 101, 102). Neonatal ovariectomy also disrupted the normal female-like open-field behavior in adulthood ( 1001. Intact male rats are more likely than intact female rats to exhibit lever press behavior in an operant environment. Male rats thus acquire lever pressing more efficiently than female rats (116,120), respond at higher rates in

SEX DIFFERENCES IN LEARNING AND MEMORY

free-operant experimental procedures (53, 54, 109, 118), but are less efficient when required to temporally space responding (5, 109, 122, 124, 1401. Males are also more likely than females to engage in lever press behavior which is no longer reinforced (105, 116, 127/. Some experiments have shown that behavioral differences between the sexes in free-operant experimental procedures may be influenced by the manipulation of gonadal hormones in adulthood. Van Hest and van Haaren (1201 showed that gonadectomy did not affect response acquisition of male and female rats in autoshaping procedures, but gonadectomy plus chronic testosterone suppletion to females resulted in male-like acquisition of lever press behavior. Response perseveration is also not affected by gonadectomy in adulthood, but chronic testosterone suppletion to ovariectomized females resulted in perseverative responding which resembled that of intact males (127). It has been shown, on the other hand, that ovariectomy greatly reduced efficient DRL performance in female rats, while castration did not affect the males' behavior (5,68). Since neonatal castration did not result in more efficient DRL behavior in adulthood (121, it remains unclear to what extent organizational or activational effects of gonadal hormones contribute to the behavioral differences between the sexes in DRL experiments. Males behave more efficiently than females in maze procedures designed to measure different aspects of memory functioning. Some experiments, however, have shown that differences between the sexes are only observed when the maze resembles a large open-field and when activity differences between the sexes are allowed to interfere with the assessment of memory functioning (7, 8, 42, 63, 119). Behavioral differences between the sexes in complex maze procedures seem to be very much determined by the activity of gonadal hormones during the neonatal period. Joseph et al. (62) have shown that gonadectomy in adulthood does not affect the maze performance of male and female rats, while other investigators have presented evidence to suggest that neonatal castration or neonatal androgenization may result in maze learning efficiency which resembles that of the intact opposite sex (35,101). These results thus support the generalization that behavioral differences between the sexes in mazes which resemble an open-field are most likely due to the organizational effects of gonadal hormones, very much like the effects observed in the open-field itself. When male and female rats are trained to respond in operant procedures designed to investigate memory functioning, behavioral differences in final response accuracy are not observed, even though males reach final accuracy levels faster than females (113, 114, 126, 129, 1301. Gonadectomy in adulthood does not affect final response accuracy in these procedures (1301. CONCLUSIONS The load of evidence presented above strongly suggests that the type of environmental event maintaining behavior is of utmost importance when experiments are designed to investigate the role of gonadal hormones in learning and memory. The presentation of aversive stimulation in active and passive avoidance procedures, as in taste avoidance experiments, produces behavioral inhibition in intact male, but not in intact female rats. This behavioral inhibition in male rats is reflected in delayed acquisition of active avoidance learning, delayed extinction of taste aversions and a tendency to remain immobile on a platform in passive avoidance experiments. The behavior maintained by aversive events is also relatively insensitive to manipulations in experinaental contingencies, as manipulations of different environmental variables do not

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affect sex differences. Manipulations of gonadal hormones during the neonatal period produce impressive behavioral effects: neonatal castration of males produces behavioral effects in adulthood which are comparable to those of intact females, while neonatal administration of testosterone to females results in behavioral effects in adulthood which are comparable to those of intact males. Gonadectomy in adulthood does not affect sex differences observed in these procedures, but other experiments have shown that castration in adulthood may alter lever press active avoidance behavior such that the behavior of castrated males comes to resemble that of intact females. To complicate the picture, but to attest to the notion that the effects of manipulations of gonadal hormones are very much dependent upon the experimental procedure in which they are investigated, the available evidence is inconclusive with respect to the organizational and activational role of gonadal hormones in passive avoidance procedures. Female rats make more errors than males in complex mazes which resemble an open-field, but not in mazes in which activity differences are less likely to play an important role. Neonatal castration or neonatal androgenization effectively alters open-field activity as well as maze learning efficiency such that it comes to resemble open-field activity and maze learning efficiency of the opposite untreated sex. In addition, manipulation of gonadal hormones in adulthood does not influence open-field behavior or maze learning efficiency. These are the only informative observations with respect to the role of gonadal hormones in procedures in which behavior is maintained by the presentation of a positive event. It has also been observed that male rats are more likely than female rats to exhibit lever press behavior in free-operant schedules of reinforcement. Behavioral differences between the sexes are usually not observed in discrete-trial experiments in which the availability of the response manipulandum is limited. Evidence is available to suggest that the presence of the male gonadal hormone testosterone at the time of testing is crucial for the observation of behavioral differences between the sexes in free-operant experiments; testosterone administration to gonadectomized male and female rats usually produces behavior which resembles that of intact males. Whether or not organizational effects of gonadal hormones play an important role is presently unknown, these experiments have not yet been conducted. The results of the experiments reviewed above strongly suggest that the effects of manipulations of gonadal hormones on learning and memory are very much dependent upon parameters of the experimental procedure in which these adaptive processes are investigated. This observation, obviously, is not very surprising, because of the fact that learning naturally occurs under many different sets of environmental circumstances, each of which may. require a different adaptive response from individual organisms. Even though a large number of experinaents have investigated the effects of manipulations of gonadal hormones in a multitude of different experimental paradigms, the role of gonadal hormones in modifying learning and memory has not been firmly established, simply because of the fact that the effects of manipulations of gonadal hormones have not been investigated in many of the experimental protocols which have been and which might be used to investigate behavioral differences between male and female individuals.

ACKNOWLEDGEMENTS A number of the experiments discussed in this paper were conducted while Annemieke van Hest was supported by a grant from the Dutch

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VAN H A A R E N , VAN H E S T A N D H E I N S B R O E K

Organization for the Advancement of Basic Research (NWO 560-258-024, F. van Haaren, principal investigator). Preparation of this manuscript was

facilitated by grants DA-04074 and DA-04940 from the National Institute on Drug Abuse.

REFERENCES 1. Ader, R.; Weijnen, J. A. W. M.; Moleman, P. Retention of a passive avoidance response as a function of the intensity and the duration of electric shock. Psychon. Sci. 26:125-128; 1972. 2. Archer, J. Sex differences in the emotional behavior of three strains of laboratory rats. Anim. Learn. Behav. 2:43-48; 1974. 3. Arnold, P. M.; Breedlove, S. M. Organizational and activational effects of sex steroids on brain and behavior: a reanalysis. Horm. Behav. 19:469-498: 1985. 4. Barret, R. J.; Ray, O. S. Behavior in the open-field, Lashley III maze, shuttle-box and Sidman avoidance as a function of strain, sex and age. Dev. Psychol. 3:73-77; 1970. 5. Beatty, W. W. Effects of gonadectomy on sex differences in DRL behavior. Physiol. Behav. 10:177-178; 1973. 6. Beatty, W. W. Sex differences in DRL and active avoidance behaviors in the rat depend upon the day-night cycle. Bull. Psychon. Soc. 10:95-97; 1977. 7. Beatty, W. W. Gonadal hormones and sex differences in nonreproductive behaviors in rodents: organizational and activational influences. Horm. Behav. 12:112-163; 1979. 8. Beatty, W. W. Hormonal organization of sex differences in play fighting and spatial behavior. In: de Vries, G. J.; de Bruin, J. P. C.; Uylings, H. B. M.; Comer, M. A., eds. Sex differences in the brain. Amsterdam: Elsevier Science Publishers; 1984. (Prog. Brain Res., vol. 61.) 9. Beatty, W. W.; Beatty, P. A. Hormonal determinants of sex differences in avoidance behavior and reactivity to electric shock in the rat. J. Comp. Physiol. Psychol. 73:446--455; 1970. 10. Beatty, W. W.; Beatty, P. A. Effects of neonatal testosterone on the acquisition of an active avoidance response in genotypically female rats. Psychon. Sci. 19:315-316; 1970. 11. Beatty, W. W.; Beatty, P. A.; Bowman, R. A sex difference in the extinction of avoidance behavior in the rat. Psychon. Sci. 23: 213-214; 1971. 12. Beatty, W. W.; Bierley, C. M.; Gerth, J. M. Effects of neonatal gonadectomy on DRL behavior. Bull. Psychon. Soc. 6:615; 1975. 13. Beatty, W. W.; Fessler, R. G. Ontogeny of sex differences in open-field behavior and sensitivity to electric shock in the rat. Physiol. Behav. 16:413-417; 1976. 14. Beatty, W. W.- Fessler, R. G. Gonadectomy and sensitivity to electric shock in the rat. Physiol. Behav. 19:1-6; 1977. 15. Beatty, W. W.; Fessler, R. G. Sex differences in sensitivity to electric shock in rats and hamsters. Bull. Psychon. Soc. 10:189-190; 1977. 16. Beatty, W. W.; Gregoire, K. C.; Parmiter, L. L. Sex differences in retention of passive avoidance behavior in rats. Bull. Psychon. Soc. 2:99-100; 1973. 17. Beatty, W. W.; Holzer, G. H. Sex differences in shock thresholds in rats and gerbils and the day-night cycle. Bull. Psychon. Soc. 11:71-72; 1978. 18. Beatty, W. W.; Siders, W. A. Effects of small lesions in the globus pallidus on open-field and avoidance behavior in male and female rats. Bull. Psychon. Soc. 10:98-100; 1977. 19. Beatty, W. W.; Studelska, D. R.; Gerth, .1. M. Some aspects of the development of sex differences in DRL behavior. Bull. Psychon. Soc. 6:622-624; 1975. 20. Bell, D. D.; Zucker, I. Sex differences in bodyweight and eating: Organization and activation by gonadal hormones in the rat. Physiol. Behav. 7:27-34; 1971. 21. Bengelloun, W. A.; Nelson, D. J.; Zent, H. M.; Beatty, W. W. Behavior of male and female rats with septal lesions: Influence of prior gonadectomy. Physiol. Behav. 16:317-330; 1976. 22. Blizard, D.; Denef, C. Neonatal androgen effects on open-field activity and sexual behavior in the female rat: The modifying influence of ovarian secretions during development. Physiol. Behav.

11:65--69; 1973. 23. Blizard, D. A.; Lippman, H. R.; Chen, J. J. Sex differences in open-field behavior in the rat: The inductive and activational role of gonadal hormones. Physiol. Behav. 14:601-608; 1975. 24. Brush, F. R.; Baron, S.; Froehlich, J. C.; Ison, J. R.; Pellegrino, L. J.; Phillips, D. S.; Sakellaris, P. C.; Williams, V. N. Genetic differences in avoidance learning by rattus norvegicus: escape/ avoidance responding, discrimination learning and open-field behavior. J. Comp. Psychol. 99:60-73; 1985. 25. Canizzaro, G.; Provenzano, P. M.; Nigito, S. The effects of castration and of progestin-oestrogen combinations upon avoidance conditioning in female rats. Pharmacol. Res. Commun. 2:267-276; 1970. 26. Carew, T. J. Do passive avoidance tasks permit assessment of retrograde amnesia in rats? J. Comp. Physiol. Psychol. 72:267-271; 1970. 27. Chambers, K. C. Hormonal influences on sexual dimorphism in rate of extinction of a conditioned taste aversion in rats. J. Comp. Physiol. 90:851-856; 1976. 28. Chambers, K. C. Failure of ACTH to prolong extinction of a conditioned taste aversion in the absence of the testes. Physiol. Behav. 29:915-919; 1982. 29. Chambers, K. C.; Sengstake, C. B. Sexually dimorphic extinction of a conditioned taste aversion in rats. Anim. Learn. Behav. 4:181-185; 1976. 30. Chambers, K. C.; Sengstake, C. B. Pseudo-castration effects of social isolation on extinction of a taste aversion. Physiol. Behav. 21:29-32; 1978. 31. Chambers, K. C.; Sengstake, C. B. Temporal aspects of the dependency of a dimorphic rate of extinction on testosterone. Physiol. Behav. 22:53-56; 1979. 32. Chambers, K. C.; Sengstake, C. B.; Yoder, R. L.; Thornton, J. E. Sexually dimorphic acquisition of a conditioned taste aversion in rats: Effects of gonadectomy, testosterone replacement and water deprivation. Physiol. Behav. 27:83-88; 1981. 33. Davenport, J.; Hagquist, W.; Rankin, G. The symmetrical maze: an automated closed field test series for rats. Behav. Res. Methods Instr. 2:112-118; 1970. 34. Davis, H.; Porter, J. W.; Burton, J.; Levine, S. Sex and strain differences in leverpress shock escape behavior. Physiol. Psychol. 4:351-356; 1976. 35. Dawson, J. L. M.; Cheung, Y. M.; Lau, R. T. S. Developmental effects of neonatal sex hormones on spatial and activity skills in the white rat. Biol. Psychol. 3:213-229; 1975. 36. Delay, E. R. Effects of cross-modal transfer on direct and reversal learning in the rat. Anim. Learn. Behav. 14:427-434; 1986. 37. Denti, A.; Epstein, A. Sex differences in the acquistion of two kinds of avoidance in rats. Physiol. Behav. 8:611-615; 1972. 38. Denti, A.; Negroni, J. A. Activity and learning in neonatally hormone treated rats. Acta Physiol. Latinoam. 25:99-106; 1975. 39. de Vries, G. J.; de Bruin, J. P. C.; Uylings, H. B. M.; Comer, M. A., eds. Sex differences in the brain. Amsterdam: Elsevier Science Publishers; 1984. (Prog. Brain Res., vol. 61.) 40. Drago, F.; Bohus, B.; Scapagnini, U.; de Wied, D. Sexual dimorphism in passive avoidance behavior of rats: Relation to bodyweight, age, shock intensity and retention interval. Physiol. Behav. 24:1164-1167; 1980. 41. Early, C. J.; Leonard, B. E. Effects of prior exposure on conditioned taste aversions in the rat: androgen and estrogen-dependent events. J. Comp. Physiol. Psychol. 93:793-805; 1979. 42. Einon, D. Spatial memory and response strategies in rats: age, sex and rearing differences in performance. Q. J. Exp. Psychol. 32: 473-489; 1980. 43. Ellis, M. E.; Clegg, D. K.; Kesner, R. P. Exhaustive memory

SEX D I F F E R E N C E S IN L E A R N I N G A N D M E M O R Y

44. 45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59. 60.

61.

62.

63.

64.

scanning in rattus norvegicus: recognition of food items. J. Comp. Psychol. 98:194-200; 1984. Gandelman, R. Gonadal hormones and sensory functioning. Neurosci. Biobehav. Rev. 7:1-17; 1983. Garcia. J.; Kimrneldorf, D. J.; Koelling, R. A. Conditioned taste aversion to saccharin resulting from exposure to gamma irradiation. Science 122:157-158; 1955. Gray, J. A. Sex differences in emotional behavior in mammals including man: endocrine bases. Acta Psychol. (Amst.) 35:29-46; 1971. Gray, J. A.; Lean, J.; Keynes, A. Infant androgen treatment and adult open-field behavior: Direct effects and effects of injections to siblings. Physiol. Behav. 4:177-181; 1969. Guillamon, A.; Valencia, A.; Cales, J. M.; Segovia, S. Effects of early postnatal steroids on the successive conditional discrimination reversal learning in the rats. Physiol. Behav. 38:845-849; 1986. Heinsbroek, R. P. W.; Feenstra, M. G. P.; Boon, P.; van Haaren, F.; van de Poll, N. E. Sex differences in passive avoidance depend on the integrity of the central serotonergic system. Pharmacol. Biochem. Behav. 31:499-503; 1988. Heinsbroek, R. P. W.; van Haaren, F.; Feenstra, M. G. P.; van Galen, H.; van de Poll, N. E. Sex differences in the effects of uncontrollable footshock stress on central catecholaminergic and serotonergic activity. Submitted; 1989. Heinsbroek, R. P. W.; van Haaren, F.; van de Poll, N. E. Sex differences in passive avoidance behavior of rats: Sex-dependent susceptibility to shock-induced behavioral depression. Physiol. Behav. 43:201-206; 1988. Heinsbroek, R. P. W.; van Haaren, F.; van de Poll, N. E. Open-field behavior of food-deprived ovariectomized rats: The effects of progesterone mimic those of central depressants. Physiol. Behav. 43:779-782; 1988. Heinsbroek, R. P. W.; van Haaren, F.; Zantvoord, F.; van de Poll, N. E. Effects of pentobarbital and progesterone on random-ratio responding in male and female rats. Psychopharmacology (Berlin) 93:178-181; 1987. Heinsbroek, R. P. W.; van Haaren, F.: Zantvoord, F.; van de Poll, N. E. Sex differences in response rates during random-ratio acquisition: Effects of gonadectomy. Physiol. Behav. 39:269-272; 1987. Heinsbroek, R. P. W.; van Haaren, F.; Zantvoord, F.; van de Poll, N. E. Discriminative stimulus properties of pentobarbital and progesterone in male and female rats. Pharmacol. Biochem. Behav. 28:371-374; 1987. Heinsbroek, R. P. W.; van Oijen, H. G.; van de Poll, N. E. The pituitary-adrenocortical system is not involved in the sex difference in passive avoidance. Pharmacol. Biochem. Behav. 20:663-668; 1984. Heinsbroek, R. P. W.; van Oijen, H. G.; van de Poll, N. E.; Boer. G. J. Failure of dexamethasone to influence sex differences in the acquisition of discriminated leverpress avoidance. Pharmacol. Biochem. Behav. 19:599-604; 1983. Hendley, E. D.; Wessel, D. J.; Atwater, D. G.; Gellis, J.; Whitehorn, D.; Low, W. C. Age, sex and strain differences in activity in SHR and WKY rats. Physiol. Behav. 34:379-383; 1985. Hurwitz, H. B. M.; Davis, H. Depriving rats of food: a reappraisal of two techniques. J. Exp. Anal. Behav. 40:211-213; 1983. Hyde, J. F.; Jerussi, T. P. Sexual dimorphism in rats with respect to locomotor activity and circling behavior. Pharmacol. Biochem. Behav. 18:725-729; 1983. Ikard. W. L.; Bennett, W. C.; Lundin, R. W.; Trost, R. C. Acquisition and extinction of the conditioned avoidance response: a comparison between male rats and estrus and nonestrus female rats. Psychol. Rec. 22:249-254; 1972. Joseph, R.; Hess, S.; Birecree, E. Effects of hormone manipulations and exploration on sex differences in maze learning. Behav. Biol. 24:364-377; 1978. Juraska, J. M.; Henderson, C.; Muller, J. Differential rearing experience, gender and radial maze performance. Dev. Psychobiot. 17:209-215; 1984. Kearley, R. C.; van Hartesveldt, C.; Woodruff, M. L. Behavioral and hormonal effects of hippocampal lesions on male and female

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rats. Physiol. Psychol. 2:187-196; 1974. 65. Krasnoff, A.; Weston, L. M. Puberal status and sex differences: activity and maze behavior in rats. Dev. Psychobiol. 9:261-269; 1976. 66. Laties, V. G.; Weiss, B.; Clarke, R. L.; Reynolds, M. D. Overt "mediating' behavior during temporally spaced responding. J. Exp. Anal. Behav. 8:107-116; 1965. 67. Laties, V. G.; Weiss, B.; Weiss, A. B. Further observations on overt "mediating' behavior and the discrimination of time. J. Exp. Anal. Behav. 12:43-57; 1969. 68. Lentz, F. E.; Pool, G. E.; Milner, J. S. Effects of ovariectomy and hormone replacement on DRL behavior in the rat. Physiol. Behav. 20:477--480; 1978. 69. Leshner, A. I. An introduction to behavioral endocrinology. New York: Oxford UniversityPress; 1978. 70. Leshner, A. I. Kinds of hormonal effects on behavior: A new view. Neurosci. Biobehav. Rev. 3:69-73; 1979. 71. Lester, D. Sex differences in exploration: toward a theory of exploration. Psychol. Rec. 17:55-62; 1967. 72. Lester. D. Sex differences in the exploration of a familiar locale. Psychol. Rec. 17:63-64; 1967. 73. Levine, S.; Broadhurst. P. L. Genetic and ontogenetic determinants of adult behavior in the rat. J. Comp. Physiol. Psychol. 56:423-428; 1963. 74. Maclusky, N. S.; Naftolin, F. Sexual differentiation of the nervous system. Science 211:1294-1303; 1981. 75. Magalhaes, H. M.: de Araujo Carlini, E. L. Effects of perinatal testosterone treatment on bodyweight, open-field behavior and Lashley HI maze performance of rats. Acta Physiol. Latinoam. 24: 317-327; 1974. 76. Marks, H. E.; Fargason. B. D.; Hobbs, S. H. Reactivity to aversive stimuli as a function of alterations in bodyweight in normal and gonadectomized female rats. Physiol. Behav. 9:539-544; 1972. 77. Marks, H. E.; Hobbs, S. H. Changes in stimulus reactivity following gonadectomy in male and female rats of different ages. Physiol. Behav. 8:1113-1119; 1972. 78. Masur, J. Sex differences in "emotionality' and behavior of rats in the open-field. Behav. Biol. 7:749-754; 1972. 79. McCord, D. M.; Hamlin, E. D.; Pool, G. L.: Milner, J. S. Castration, gonadal hormones and Sidman avoidance acquisition. Physiol. Behav. 22:601-603; 1979. 80. Millar, R. D. Free-operant comparisons of wild and domestic Norway rats. J. Comp. Physiol. Psychol. 89:913-922; 1975. 81. Milner, J. S. Castration and amphetamine effects on acquisition of a Sidman avoidance task in rats. Physiol. Behav. 17:545-548: 1976. 82. Moss, R. L. Changes in bar-press duration accompanying the estrous cycle. J. Comp. Physiol. Psychol. 66:460-466; 1968. 83. Negroni. J. A.; Denti, A. One-trial passive avoidance learning in neonatally hormone treated rats. Its relation with activity. Acta Physiol. Latinoam. 27:281-287; 1977. 84. Olton. D. S.; Samuelson. R. J. Remembrance of places past: spatial memory in rats. J. Exp. Psychol. [Anim. Behav.] 2:97-116; 1976. 85. Pare, W. P. Age, sex and strain differences in the aversive threshold to grid shock in the rat. J. Comp. Physiol. Psychol. 69:214-218; 1969. 86. Pfaff, D. W.; Zigmond. R. E. Neonatal androgen effects on sexual and non-sexual behavior of adult rats tested under various hormone regimens. Neuroendocrinology 7:129-145: 1971. 87. Phillips, A. G.; Deol, G. S. Neonatal androgen levels and avoidance learning in prepubescent and adult male rats. Honn. Behav. 8:22-29; 1977. 88. Phoenix, C.; Goy, R.; Geralh A.; Young, W. Organizing action of prenatally administered testosterone propionate on the tissues mediating mating behavior in the female guinea pig. Endocrinology 65:369-382; 1959. 89. Russell. P. A. Sex differences in rats' stationary cage activity measured by observation and automatic recording. Anim. Learn. Behav. 1:278-282; 1973. 90. Russell, P. A. Sex differences in rats" stationary exploration as a function of stimulus and environmental novelty. Anim. Learn.

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Behav. 5:297-302: 1977. 91. Schenk, P. E.; Slob, A. K. Sex differences and gonadal hormones in Hebb-Williams Maze performance in adult rats. J. Endocrinol. 64:31; 1975. 92. Scouten. C. W.; Grotelueschen, L. K.: Beatty, W. W. Androgens and the organization of sex differences in active avoidance behavior in the rat. J. Comp. Physiol. Psychol. 88:264-270: 1975. 93. Sengstake, C. B.; Chambers, K. C.; Thrower, J. H. Interactive effects of fluid deprivation and testosterone on the expression of a sexually dimorphic conditioned taste aversion. J. Comp. Physiol. Psychol. 92:1150-1156; 1978. 94. Sfikakis, A.; Spyraki. C.: Sitaras. N.; Varonos, D. Implication of the estrous cycle on conditioned avoidance behavior in the rat. Physiol. Behav. 21:'441-446; 1978. 95. Sidman, M. Two temporal parameters in the maintenance of avoidance behavior by the white rat. J. Comp. Physiol. Psychol. 46: 253-261: 1953. 96. Slob. A. K.; Bogers, H.; van Stolk. M. A. Effects of gonadectomy and exogenous gonadal steroids on sex differences in open-field behavior of adult rats. Behav. Brain Res. 2:347-362; 1981. 97. Slob, A. K.; van der Werff ten Bosch, J. J. Sex differences in body-growth in the rat. Physiol. Behav. 14:353-361; 1975. 98. Steenbergen, H. L.; Heinsbroek, R. P. W.; van Haaren, F.; van de Poll, N, E. Sex-dependent effects of inescapable shock administration on behavior and subsequent escape performance in rats. Physiol. Behav. 45:781-787; 1989. 99. Stevens, R,; Goldstein, R. Effects of neonatal testosterone and progesterone on open-field behavior in the rat. Q. J. Exp. Psychol. 30:157-166; 1978. 100. Stewart, J.; Cygan, D. Ovarian hormones act early in development to feminize adult open-field behavior in the rat. Horm. Behav. 14: 20-32; 1980. 101. Stewart, J.; Skvarenina, A.; Pottier, J. Effects of neonatal androgens on open-field behavior and maze learning in the prepubescent and adult rats. Physiol. Behav. 14:291-295: 1975. 102. Stewart, J.: Vallentyne, S.; Meany, M. J. Differential effects of testosterone metabolites in the neonatal period on open-field behavior and lordosis in the rat. Horm. Behav. 13:282-292; 1979. 103. Telegdy. G. Effects of gonadotrophin and sexual steroids on avoidance behavior in rats. In: Lorenza, L.; Pancheri, P.; Zichella, L., eds. Clinical psychoneuroendocrinology in reproduction. New York: Academic Press; 1978. 104. Telegdy, G.: Stark, A. Effects of sexual steroids and androgen sterilization on avoidance and exploratory behavior in the rat. Acta Physiol. Acad. Sci. Hung. 43:55--63; 1973. 105. Thompson. W. R.; Wright. J. S. 'Persistence' in rats: effects of testosterone. Physiol. Psychol. 7:291-294; 1979. 106. Valle, F. P. Effects of strain, sex and illumination on open field behavior of rats. Am. J. Psychol. 83:103-11 l; 1970. 107. van de Poll, N. E.; de Bruin, J. P. C.; van Dis, H.: van Oijen, H. G. Gonadal hormones and the differentiation of sexual and aggressive behavior and learning in the rat. In: Corner, M. A., ed. Maturation of the nervous system. Amsterdam: Elsevier Science Publishers: I978. (Prog. Brain Res., vol. 48.1 108. van Haaren, F.: de Bruin, J. P. C.; Heinsbroek. R. P. W.; van de Poll, N. E. Delayed spatial response alternation: effects of delay interval duration and lesions of the medial prefrontal cortex on response accuracy of male and female Wistar rats. Behav. Brain Res. 18:41--49; 1985. 109. van Haaren, F.: Heinsbroek, R. P. W.; Louwerse, A.; van de Poll, N. E. d-Amphetamine differentially affects low, but not high response rates of male and female Wistar rats. Psychopharmacology (Berlin) 89:73-76; 1986. 110. van Haaren, F.: van de Poll, N. E. The effects of a choice alternative on sex differences in passive avoidance behavior. Physiol. Behav. 32:211-215; 1984. I I 1. van Haaren, F.; van de Poll, N. E. The number of pre-shock trials affects sex differences in passive avoidance behavior. Physiol. Behav. 33:269-272; 1984. 112. van Haaren. F.; van de Poll, N. E. Effects of light intensity on

VAN H A A R E N , VAN HEST A N D H E I N S B R O E K

113.

114.

115.

116.

117. 118.

119.

120.

121. 122.

123.

124.

125.

126.

127.

128.

129.

130.

131.

132.

133.

passive avoidance behavior of male and female Wistar rats. Physiol. Behav. 36:123-125; 1986. van Haaren. F.: van Hest, A. The acquisition of visual and auditory discriminations in male and female Wistar rats. Behav. Brain Res. 32:191-195; 1989. van Haaren, F.: van Hest, A. Spatial matching and non-matching in male and female Wistar rats: effects of delay interval duration. Anim. Learn. Behav. 17:355-360; 1989. van Haaren, F.; van Hest, A. The effects of scopolamine and methylscopolamine on visual and auditory discriminations in male and female Wistar rats. Pharmacol. Biochem. Behav. 32:707-710; 1989. van Haaren, F.; van Hest. A.; van de Poll, N. E. Acquisition and reversal of a discriminated autoshaped response in male and female rats: effects of long or short and fixed or variable intertrial interval duration. Learn. Motiv. 18:220-233: 1987. van Haaren, F.: van Hest, A.: van de Poll, N. E. Self-control in male and female rats. J. Exp. Anal. Behav. 49:201-212; 1988. van Haaren, F.; van Hest, A.; van Hattum. T. Scopolamine and methylscopolamine differentially affect fixed-consecutive-number performance of male and female Wistar rats. Pharmacol. Biochem. Behav. 33:361-365; 1989. van Haaren, F.; Wouters, M.; van de Poll, N. E. Absence of behavioral differences between male and female rats in different radial-maze procedures. Physiol. Behav. 39:409-412; 1987. van Hest, A.; van Haaren, F. The effects of gonadectomy and chronic testosterone suppletion on the autoshaped response of male and female Wistar rats. Bull. Psychon. Soc. 27:45--48; 1989. van Hest, A.: van Haaren, F. Cooperative behavior in female, but not in male Wistar rats. Submitted. van Hest, A.; van Haaren. F.; van de Poll, N. E. Behavioral differences between male and female Wistar rats on DRL schedules: Effects of stimuli promoting collateral activities. Physiol. Behav. 39:255-261; 1987. van Hest, A.; van Haaren, F.; van de Poll, N. E. Behavioral differences between male and female Wistar rats in food-rewarded lever holding. Physiol. Behav. 39:263-267; 1987. van Hest, A.; van Haaren, F.; van de Poll, N. E. Haloperidol, but not apomorphine differentially affects low response rates of male and female Wistar rats. Pharmacol. Biochem. Behav. 29:529-532; 1988. van Hest, A.; van Haaren, F.; van de Poll, N. E. The behavior of male and female Wistar rats pressing a lever for food is not affected by sex differences in food motivation. Behav. Brain Res. 27: 215-221: 1988. van Hest, A.; van Haaren, F.; van de Poll, N. E. Delayed response alternation: effects of stimulus presentations during the delay interval on response accuracy of male and female Wistar rats. Bull. Psychon. Soc. 26:141-144: 1988. van Hest, A.; van Haaren, F.; van de Poll, N. E. Perseverative responding in male and female Wistar rats: effects of gonadal hormones. Horm. Behav. 23:57~7; 1989. van Hest, A.: van Haaren, F.: van de Poll, N. E. Operant conditioning of response variability in male and female Wistar rats. Physiol. Behav. 45:551-555; 1989. van Hest, A.: van Haaren, F.; van de Poll, N. E. The acquisition of delayed visual and auditory discriminations in male and female Wistar rats. Behav. Brain Res., in press; 1989. van Hest. A.; van Kempen, M.; van Haaren, F.; van de Poll. N. E. Memory in male and female Wistar rats: effects of gonadectomy and stimulus presentations during the delay interval. Behav. Brain Res. 29:103-110; 1988. van Oijen. H. G.: van de Poll, N. E.; de Bruin, J. P. C. Sex, age and shock intensity as factors in passive avoidance behavior. Physiol. Behav. 23:915-918; 1979. van Oijen, H. G.: van de Poll, N. E.: de Bruin. J. P. C. Effects of retention interval and gonadectomy on sex differences in passive avoidance behavior. Physiol. Behav. 25:859-862; 1980. van Oijen, H. G.; van der Zwan, S. M.; van de Poll, N. E.; Walg, H. Punishment of food rewarded leverholding in male and female rats. Physiol. Behav. 26:1037-1040; 1981.

SEX D I F F E R E N C E S IN L E A R N I N G A N D M E M O R Y

134. van Oijen,'H. G.; Walg, H.; van de Poll. N. E, Discriminated leverpress avoidance conditioning in rnale and female rats. Physiol. Behav. 26:313-317; 1981. 135. Wade. G. N. Gonadal hormones and behavioral regulation of body weight. Physiol. Behav. 8:523-534; 1972. 136. Wade, G. N.; Zucker. 1, Hormonal modulation of responsiveness to an aversive taste stimulus in rats. Physiol. Behav. 5:269-273; 1970. 137. Weinberg, J.: Gunnar, M. R.; Brett, L. P.; Gonzalez, C. A.: Levine, S. Sex differences in biobehavioral responses to conflict in a taste

33

aversion paradigm. Physiol. Behav. 29:201-210: 1982. 138. Wollnik, F. Sex differences in the daily pattern of locomotor activity in laboratory rats. Naturwissenschaften 72:S 158: 1985. 139, Young, W. C.; Goy, R. W.; Phoenix, C, H. Hornlones and sexual behavior. Science 143:212-218; 1964. 140. Zeier, H.: Baettig, K.; Driscoll, P. Acquisition of DRL-20 behavior in male and female, Roman High- and Low-avoidance rats. Physiol. Behav. 20:791-793; 1978.