Association of prenatal phenobarbital and phenytoin exposure with small head size at birth and with learning problems.

UNLABELLED: Small head size has been observed in prenatally anticonvulsant-exposed neonates. In infancy, cognitive impairments were revealed. It is presently unknown whether these impairments are permanent or disappear after puberty. We studied the link between the prenatal influence of anticonvulsants on brain development and cognitive functioning in adulthood: a retrospective study on head size and a follow-up assessing cognitive capacities among adults who had been included in the retrospective study. The retrospective study comprised 172 exposed and 168 control neonates, matched with respect to age, sex and their mothers' age. Prenatally phenobarbital + phenytoin-exposed neonates had a significantly smaller occipitofrontal circumference (OFC) than prenatally phenobarbital-monotherapy-exposed and control neonates (mean difference of 0.7 cm). In the follow-up, no difference in cognitive functioning was found between the exposed and the control groups. Most of the prenatally anticonvulsant-exposed subjects had normal intellectual capacity. However, 12% of the exposed subjects versus 1% of the controls had persistent learning problems. In addition, more of the exposed subjects were mentally retarded. There was no clear relationship between learning problems and small OFC, maternal epilepsy or unfavourable family climate. CONCLUSIONS: We conclude that the combination of phenobarbital + phenytoin affects the fetal OFC. The smaller OFC does not seem to be related to cognitive functioning in adulthood, but learning problems and mental retardation proved to be more prevalent among exposed subjects. Phenobarbital and phenytoin may therefore affect cognitive capacity but only in infants who are susceptible to this particular influence of the drugs.

Psychoendocrinological assessment of the menstrual cycle: the relationship between hormones, sexuality, and mood.

The role of sex hormones in sexuality and mood across the menstrual cycle was investigated. Twenty-one normal health women were followed for one menstrual cycle. Blood samples were taken frequently, and analyzed for estradiol, progesterone, testosterone, androstenedione, dehydroepiandrosterone sulfate, cortisol, and sex hormone-binding globulin. A diary concerning sexual interest and behavior, and different moods, was completed daily. Although the sample was not large, a clear effect of menstrual cycle phase on levels of testosterone and the free testosterone index was demonstrated. In a preliminary screening interview, 11 of the 21 women had reported that they suffered from premenstrual complaints (PC), the other 10 had reported no complaints in the premenstrual phase (NPC). Significant differences between the two groups were established in estradiol and the estradiol-progesterone ratio, with the NPC group having higher levels of both endocrine parameters across different menstrual samples. Psychologically, a cycle effect on tension and sexual interest was demonstrated. The NPC group reported a peak in sexual interest in the premenstrual phase, whereas the PC group reported a peak in the ovulatory phase. There was a difference between the two groups in feelings of fatigue but not in other moods across the menstrual cycle. The study provides further evidence of the importance of androgen levels in women's sexuality and shows again that the relationship between menstrual cycle phase and sexuality is much clearer than between phase and mood.

The premenstrual phase and reactions to aversive events: a study of hormonal influences on emotionality.

Fifty-eight normal cycle, healthy women were confronted with an aversive, anger-provoking situation in the laboratory. Eighteen women were tested in their follicular phase. A further 40 women were tested in the premenstrual phase, half of whom reported suffering from complaints of premenstrual emotional lability and irritation, the other half reported being without premenstrual problems. Apart from a strong effect of emotion induction on cardiovascular arousal and anger-related moods in the follicular and premenstrual groups, a premenstrual phase effect was also demonstrated, with premenstrual women showing evidence of being more affected by the manipulations on systolic blood pressure and intensity of angry behaviour during anger provocation. Furthermore, some differences were found between those subjects who reported suffering from premenstrual complaints and those free of such complaints, among the most interesting ones being differences in cortisol level preceding the experimental session, in intensity of angry behaviour, and in report of anger intensity at debriefing. The study indicates that the premenstrual phase may have the effect of making women more susceptible to responding emotionally to negative life events.

Gender differences in behaviour: activating effects of cross-sex hormones.

The relative contribution of organizing and activating effects of sex hormones to the establishment of gender differences in behaviour is still unclear. In a group of 35 female-to-male transsexuals and a group of 15 male-to-female transsexuals a large battery of tests on aggression, sexual motivation and cognitive functioning was administered twice: shortly before and three months after the start of cross-sex hormone treatment. The administration of androgens to females was clearly associated with an increase in aggression proneness, sexual arousability and spatial ability performance. In contrast, it had a deteriorating effect on verbal fluency tasks. The effects of cross-sex hormones were just as pronounced in the male-to-female group upon androgen deprivation: anger and aggression proneness, sexual arousability and spatial ability decreased, whereas verbal fluency improved. This study offers evidence that cross-sex hormones directly and quickly affect gender specific behaviours. If sex-specific organising effects of sex hormones do exist in the human, they do not prevent these effects of androgen administration to females and androgen deprivation of males to become manifest.

Studies on long-lasting consequences of prenatal exposure to anticonvulsant drugs.

Based on neonatal examination at birth, it has been estimated that epileptic women have a 2-3 times greater risk of giving birth to an infant with congenital anomalies. But anticonvulsant drugs may also have more subtle influences on the developing foetus which are not visible at birth but only emerge later in life. Evidence for these functional teratogenic influences has been provided by animal research and follow-up studies in young children. This article discusses these findings in human and animal studies. In addition, the outline of a study carried out at the Department of Obstetrics and Neonatology, Academic Medical Centre, Amsterdam, is described. In this study cognitive functioning, fertility and gender role behaviour of young adults, who had been prenatally exposed to barbiturates and/or hydantoins was examined.

Activating effects of androgens on cognitive performance: causal evidence in a group of female-to-male transsexuals.

It is still unclear whether sex differences in cognitive functioning are mainly due to perinatal organizing effects of sex hormones on the brain, or to activating effects in adulthood. In a group of 22 female-to-male transsexuals a battery of visuospatial and verbal ability tests was administered twice: shortly before and 3 months after the start of androgen treatment. The administering of androgens was clearly associated with an increase in spatial ability performance. In contrast, it had a deteriorating effect on verbal fluency tasks. This study offers preliminary evidence that androgens directly and quickly affect cognitive performance in females.

SDN-POA volume, sexual behavior, and partner preference of male rats affected by perinatal treatment with ATD.

The present study investigated 1) the importance of the aromatization process during the perinatal period for the development of the sexually dimorphic nucleus in the preoptic area of the hypothalamus (SDN-POA) of male rats, and 2) the relationship between SDN-POA volume and parameters of masculinization in male rats that were treated perinatally with the aromatase-inhibitor ATD. Males were treated with ATD either prenatally or pre- and neonatally, or with the vehicle. Masculine sexual behavior and partner preference were investigated in adulthood. Thereafter, animals were sacrificed and SDN-POA volume was measured. The SDN-POA volume was reduced in both the prenatally and the pre- and neonatally treated group, with a larger reduction in the latter than in the former group. Combined pre- and neonatal ATD treatment resulted in reduced frequency of mounts, intromissions, and ejaculations, as well as a reduced preference for a female over a male. The SDN-POA size was significantly and positively correlated with frequency of masculine sexual behavior, as well as preference for a female over a male.

Sex-dependent effects of restraint on nociception and pituitary-adrenal hormones in the rat.

The sex-dependent effects of acute restraint (RT) on nociceptive and pituitary-adrenal responses were investigated in the rat. In a first experiment, the effect of 30 min RT on pain sensitivity was evaluated through repeated use of the tail withdrawal test during and after treatment. RT induced an increase in the nociceptive threshold, i.e., analgesia, in males and females, but the duration and time-course of this effect varied between sexes. The latencies returned to approximately control values in females in the second half of RT, but in males they remained higher for the whole period of RT and immediately afterwards. Twenty-four hours later, males displayed longer latencies than controls in response to simple reexposure to the environment. In a second experiment, ACTH and corticosterone plasma levels were measured immediately after 15 or 30 min of RT. ACTH and corticosterone were higher in restrained animals than in controls after both periods of treatment, and in both sexes; however, females showed higher basal and stress corticosterone levels than males. The role played by corticosteroids in the nociceptive responses of the two sexes is discussed.

Cerebral glucose utilization during conditioned sexual arousal.

Local cerebral glucose utilization was investigated in male rats during conditioned sexual arousal. Increased glucose utilization was found in three amygdaloid nuclei after exposure to a stimulus associated with exposure to a sexually active female. No changes were observed in areas known to be of crucial importance for the expression of consummatory aspects of sexual behavior. These results corroborate and extend previous results showing a dissociation between the expression of appetitive and consummatory aspects of sexual behavior at a neural level.

Intracerebroventricular LHRH may serve as a discriminative stimulus in male rats.

Male Wistar rats (N = 16) were trained to discriminate 5 micrograms/kg LHRH, injected intraperitoneally, from saline in a two-lever, food-reinforced drug discrimination procedure, with an injection-session interval of 45 min. Reliable discrimination of LHRH was acquired within 60 training sessions. Subsequent generalization tests in brain-cannulated animals showed dose-dependent and time-related partial substitution of intracerebroventricular LHRH for intraperitoneal LHRH (ventricle doses ranged from 25-400 ng, and the injection-session intervals ranged from 10-40 min). These results indicate that centrally administered LHRH may serve as a dose- and time-dependent discriminative stimulus in male rats.

Testosterone as appetitive and discriminative stimulus in rats: sex- and dose-dependent effects.

Stimulus properties of subcutaneously injected testosterone were studied in male and female rats. In a conditioned place preference procedure, dose-dependent effects (doses: 0, 0.5, and 1 mg/kg) were observed in males. In females, no place preference could be established (doses: 0, 1, and 3 mg/kg). In addition, 1 mg/kg testosterone acquired discriminative stimulus control in male rats in a taste aversion procedure. Animals injected with this hormone prior to saccharin-LiCl pairings and with its vehicle prior to saccharin-NaCl pairings suppressed fluid intake following the administration of testosterone and not following the administration of the vehicle. Subsequent generalization tests revealed dose-dependent stimulus control of this hormone (range of substitution doses: 0.125-2 mg/kg). It is concluded from the results that at least pharmacological (supraphysiological) doses of testosterone may act as appetitive stimuli in male rats, but not in female rats. Furthermore, in male rats (pharmacological doses of) testosterone also possess discriminative stimulus properties.

Changes in male copulatory behavior after sexual exciting stimuli: effects of medial amygdala lesions.

A paradigm was developed to investigate how precoital sexual arousal affects parameters of sexual behavior in male rats. Estrous females in a wire mesh cage were used to induce sexual arousal before the sexual interaction test. In control procedures, males were presented in a wire mesh cage or else there was no stimuli at all. The results indicate that ejaculation latency is consistently reduced after preexposure to a female, but not after preexposure to a male, showing that the effect is specific for precoital sexual arousal. Other parameters were affected by precoital sexual arousal in some, but not in all experiments. Reductions in intromission latency moreover, were observed after both preexposure to a male and preexposure to a female, indicating that general social excitement affects this parameter. Preexposure to females for 10 minutes or 3 hours produced similar results. It was subsequently found that medial amygdala-lesioned (AME) animals differed from sham-lesioned (SHAM) controls with respect to their reaction to precoital sexual arousal. The results show that AME-lesioned animals, in contrast to SHAM-animals, do not show reduced ejaculation latencies after preexposure to an estrous female. The results are in line with the idea that AME-lesioned animals are deficient in the assimilation of information on sexual exciting stimuli.

Temporal characteristics of appetitive stimulus effects of luteinizing hormone-releasing hormone in male rats.

Conditioned place preference, induced by intraperitoneal injections of 5 micrograms/kg luteinizing hormone-releasing hormone (LHRH), was studied by varying the interval between the injection of LHRH and the conditioning sessions. Place preference was investigated for five presession intervals (0, 15, 45, 75, and 120 min) in separate groups of gonadectomized male rats provided with a subcutaneous testosterone implant. It was shown that the presession interval is an important parameter in the development of LHRH-induced conditioned place preference. Place preference was not observed after conditioning with intervals of 0, 75, and 120 min. With 15 and 45 min, however, a reliable preference was induced by LHRH. This study provides insight into the onset and offset of the appetitive stimulus properties of LHRH in male rats.

Hypothalamic involvement in sexuality and hostility: comparative psychological aspects.

Evidence presented in this article shows the representation of sexual and aggressive behaviors at the level of the hypothalamus to be more prominent than in all other brain areas involved. Indeed, there are good arguments to attribute a central position to the hypothalamus within larger structural systems encompassing the limbic system, where aspects of the behaviors involved can be influenced. So far, however, the arguments are purely descriptive and factual and do not contribute much to answering questions about hypothalamic function: the grounds for and consequences of this massive representation of apparently almost all emotionally relevant social behavioral complexes, so universally established in a diversity of species, still has to be detected. A second and equally important aspect of hypothalamic function obviously has to be related to its central position within various hormonal systems. The present article concentrated on the acute dynamics and behavioral significance of activation of the pituitary-adrenocortical and pituitary-gonadal axes. Evidence indicates that the unconditioned behavioral stimuli or the consequences of behavior, but also stimuli conditioned to emotionally relevant events, may drastically alter hypothalamic hormonal regulation. Most importantly, these hormonal consequences in themselves again seem to determine further behavior and responses in relevant situations. The evidence presented with respect to reward and aversion, associated with alterations of specific hormones of the gonadal axis, may add a new dimension to our understanding of psychoendocrine functions of the hypothalamus (see also Gary, 1975; Leshner et al., 1981; Carey, 1987). Psychologically, such data can be taken as an argument for a more thorough study of the relation between memory processes and emotion (Bower et al., 1981). However fragmentary and incomplete this review may be, it will be clear that hypothalamic substrates and directly related areas, as well as affiliated hormonal mechanisms, play a central role in many of the most complex motivational and emotional syndromes and disorders. The prime idea in this is that the psychological concomitants of hypothalamic (dys)function are as much output as input, and as much the consequences as the cause within related syndromes. Such a view places the hypothalamus at the core of psychological theories of emotion and motivation, which from their most early origin have been heavily set towards hormonal and humoral changes and their relationships with psychological experience.(ABSTRACT TRUNCATED AT 400 WORDS)

Dose-dependent and time-related stimulus properties of LHRH in male but not in female rats.

Male and female rats (N = 32) were trained to discriminate 5 micrograms/kg LHRH from saline in a two-lever, food-reinforced drug discrimination procedure with injection-session intervals of 15 min or 45 min. When the interval was 15 min, neither males nor females were able to discriminate the stimulus conditions. With an interval of 45 min, LHRH showed sex-dependent stimulus properties. Male, but not female, rats reliably discriminated LHRH from saline within 50 training sessions. In males, generalization tests showed dose-dependent and time-related stimulus effects of LHRH (doses ranged from 62.5 ng/kg to 8 micrograms/kg, and intervals ranged from -15 min to -120 min). The results indicate that LHRH may be an essential part of the stimulus complex in male rats but could not gain control over operant behavior in female rats.

Discriminative stimulus properties of estradiol in male and female rats revealed by a taste-aversion procedure.

Gonadectomized male and female rats were trained to discriminate 50µg/kg estradiol-17B(E(2)) from its vehicle in a one-bottle forced-drinking discriminative taste-aversion procedure. The animals were injected SC with E(2) or arachidic oil, 60min prior to daily training sessions during which they had access to a saccharin (Sac) solution for 10min. Animals injected with E(2) prior to Sac-LiCl pairings and with arachidic oil prior to Sac-NaCl pairings acquired hormone discrimination, only suppressing Sac intake following the administration of E(2) and not following the administration of arachidic oil. Both males and females reliably discriminated E(2) from arachidic oil within 28 training sessions. Subsequent generalization tests revealed dose-dependent stimulus control of Sac intake by E(2) in both sexes (range of substitution doses: 0.4-250µg/kg). The results show that E(2) may act as a discriminative stimulus in male and female rats.

Estradiol-induced conditioned taste aversion and place aversion in rats: sex- and dose-dependent effects.

Effects of various doses (0-250 micrograms/kg, SC) of estradiol-17 beta (E2) in a two-bottle choice conditioned taste aversion and a two-compartment conditioned place preference procedure were studied in male and female rats. Dose-dependent taste aversion and place aversion effects of E2 were established, and the conditioned taste aversion procedure was found to be more sensitive in detecting aversive properties of E2 than the conditioned place preference procedure. Although aversive properties of E2 were found in both sexes, the effects were clearly more prominent in males as compared to females. From this study, it was concluded that E2 acts as an unconditioned aversive stimulus in both male and female rats capable of gaining control over different types of behavior by associative learning.

Controllable and uncontrollable footshock and monoaminergic activity in the frontal cortex of male and female rats.

Effects of controllable and uncontrollable footshock on monoaminergic activity in the frontal cortex and plasma corticosterone levels were studied in male and female rats. Subjects were exposed to a shuttle-box procedure for a period of either 30 min (60 shocks) or 90 min (180 shocks). A shuttle response ended shock presentation for escape subjects, whereas their yoked, same-sex, counterparts were unable to escape from shock presentation. A third group was exposed to the experimental environment, but did not receive any shocks. Concentrations of noradrenaline, serotonin and dopamine and their major metabolites were measured in the frontal cortex by high performance liquid chromatography with electrochemical detection. Plasma corticosterone was measured by radioimmunoassay. Results of this experiment show that: (1) exposure to the experimental environment without shock already increased the activity of all 3 transmitter systems. In particular, serotonin was very responsive to mere confinement to the shuttle-box. Changes induced by exposure to the experimental environment were similar for males and females. (2) Presentation of footshocks further increased transmitter activity. The activation of noradrenaline and dopamine was larger after uncontrollable shock than after controllable shock. Moreover, uncontrollable shock resulted in higher serotonin levels than controllable shock. (3) Sex-dependent effects of controllability were found for noradrenaline and dopamine, but not for serotonin. Differences in catecholaminergic activity between controllable and uncontrollable shock were larger in females than in males. (4) In both males and females, corticosterone levels in plasma were increased by exposure to the experimental environment. A further elevation was found in response to footshock presentation, which was independent of the controllability of shock.

Sex differences in the behavioral consequences of inescapable footshocks depend on time since shock.

In two experiments, the effects of inescapable shock on subsequent shuttle-box escape performance were studied in male and female rats. Effects of treatment with short-duration shocks (2 s) were studied after 1- and 24-hour intervals (Experiment 1), and effects of long-duration shocks (6 s) were studied after 24- and 72-hour intervals (Experiment 2). Experience with inescapable shock resulted in a serious disruption of escape performance in both males and females. A large increment in escape latencies was found both during fixed ratio 1 and fixed ratio 2 escape training; however, effects of inescapable shock were more pronounced in males than in females. In Experiment 1, sex differences were most obvious after the short 1-hour interval whereas, in Experiment 2, sex differences were only present after 24 hours and not after 72 hours. Shuttle activity during 2-min adaptation prior to shock-escape training was reduced in both males and females treated with IS, and this effect was somewhat stronger in males than in females. The data of these experiments show that male rats are more sensitive to the consequences of exposure to inescapable aversive stimulation than female rats. It is proposed that the time-dependency of the sex differences in behavioral consequences of treatment with inescapable shock may be related to sex differences in transient neurochemical or hormonal changes induced by inescapable shock.

Sex- and time-dependent changes in neurochemical and hormonal variables induced by predictable and unpredictable footshock.

Previous experiments have revealed sex-dependent effects of inescapable shock in rats. Behavior of male rats was more severely disrupted by inescapable shock than behavior of female rats. These sex differences were found after 1- and 24-hour intervals but not after a 72-hour interval. The present experiment was designed to study various physiological parameters at 1-, 4- and 24-hour intervals after inescapable footshock. The predictability of shock was manipulated by adding a compound light and tone stimulus that preceded shock presentation for one group but was not correlated with shock presentation for another group of subjects. Noradrenaline, dopamine, serotonin, and metabolites of these 3 transmitters were measured in the frontal cortex. Transient shock-induced increments in dopamine and metabolites of dopamine and serotonin were found, but the sex of the animal did not differentially affect this neurotransmitter response. In addition to neurotransmitter concentrations in the frontal cortex, levels of corticosterone were measured in plasma. The pituitary-adrenal axis was activated for a longer period in females than males after shock. The present data do not provide evidence that behavioral sex differences induced by inescapable shock are paralleled by sex differences in neurotransmitter activity. In addition, sex-dependent effects of predictability of shock on neurotransmitter activity were not detected. The relevance of the observed sex-dependent responses in the pituitary-adrenal system is discussed.