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 + phe‐nytoin‐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.

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.

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)

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.

Different groups of male and female Wistar rats were exposed to a discrete-trial delayed discrimination procedure, in which subjects were required to discriminate between a continuously or intermittently presented visual (half of the subjects) or auditory (other half of the subjects) stimulus. The opportunity to respond was delayed for 0, 5, 10 or 20 s after stimulus presentation. Both response levers were inserted into the experimental chamber immediately upon the termination of the delay interval. A press on the left lever was followed by food if the continuous stimulus had been presented, while food was presented following a press on the right lever if the intermittent stimulus had been presented. During sessions 1-60, each incorrect response or failure to respond during the 5-s lever presentation was followed by presentation of the same visual or auditory stimulus, and the same delay interval, once the intertrial interval was terminated. This sequence was repeated until a correct response occurred. During sessions 61-90, repeated presentations of the same trial following incorrect responses or a failure to respond on initial trials were no longer presented. All other experimental contingencies remained unchanged. Response accuracy increased with prolonged training. Subjects exposed to the visual delayed discrimination procedure showed less accurate performance than subjects who were exposed to the auditory delayed discrimination procedure. Response accuracy was higher when the delay interval was short than when it was long. Males made more correct responses than females.(ABSTRACT TRUNCATED AT 250 WORDS)

Response perseveration was investigated in an experimental procedure which has previously been shown to be sensitive to pharmacologically induced behavioral perseveration and response stereotypy. Different groups of intact, gonadectomized, and gonadectomized plus chronically testosterone-treated male and female Wistar rats were exposed to this procedure in which reinforcers were randomly assigned to one of two levers in an operant chamber. One response on the lever to which the reinforcer was assigned was sufficient to produce a food pellet. Response perseveration, defined as the percentage of trials on which more than one response on the lever not selected for reinforcement was made prior to switching to the selected lever was highest in testosterone-treated subjects. Females made more responses on the lever which had been selected for food on the preceding trial, suggesting that females may be more sensitive than males to the consequences of their behavior. This behavioral difference between the sexes may be mediated by the male hormone testosterone.

Discrete bilateral lesions were placed into the sexually dimorphic nucleus (SDN) of the medial preoptic area (MPOA) of ovariectomized female Wistar rats, chronically treated with testosterone (T). Effects of these lesions upon masculine and feminine sexual behavior were studied by comparing the results of pre- and postoperative tests, using sham-operated and unoperated females as controls. Bilaterally-lesioned and, to a lesser extent, unilaterally-lesioned females, showed a marked and significant reduction of masculine sexual behavior (i.e., mounting), especially in the first postoperative tests. Feminine sexual responses, i.e., receptive and proceptive behavior, although slightly lower in bilaterally-lesioned females, did not change significantly. Sexual partner preference, operationalized as the choice between a receptive female and a sexually active male, remained unaffected by the lesions. Plasma levels of testosterone were similar in the various groups. It is concluded that the SDN may be functionally implicated in the control of masculine sexual behavior in T-treated females.

The present experiment investigates the activation of aggressive and sexual behaviors by gonadal hormones in female rats of the S3-strain. In the first experiment three doses of testosterone propionate (TP) were chronically injected. In the second experiment effects of TP were compared to those of estradiol benzoate (EB) and methyltrienelone (R1881), a synthetic, unaromatizable androgen. Females of the S3-strain were tested against TP-treated female Wistar rats as opponents, and masculine and feminine sexual responses were assessed in the test for aggression as well as in separate tests with sexually active stimulus animals. The results of the first experiment indicate that TP in all doses, increased aggressive as well as sexual behavior equally, although plasma testosterone levels differed significantly between the groups. In the second experiment, EB significantly decreased overall aggression as compared to control-treatment. TP- and R1881-stimulated fighting, particularly, as the most offensive parameter of aggression, but did not increase overall levels of aggression. Tests for sexual preference in which the choice between a sexually active male or female was given, indicated that TP-treated females stayed near males with longer durations. Scentmarking frequencies, measured in the semiopenfield test, were effectively activated by TP-treatment. EB- and R1881-treatment resulted in intermediate levels of marking behavior.

Intact male and ovariectomized female rats were trained to lever press under a random ratio (RR) schedule of food reinforcement. Effects of different doses of pentobarbital (1–16 mg/kg) and progesterone (10–80 mg/kg) on response output were studied. Low doses of pentobarbital increased responding, high doses decreased responding. Sex differences were observed in the rate-decreasing effects of high doses of pentobarbital. Progesterone increased the response rate of ovariectomized females, but did not affect responding in intact males.

In the present series of experiments, dose-response and time-response relationships between single injections of sex steroids and the display of lordosis behaviour in the female rat, were investigated. When injected 48 h prior to testing, increasing doses of estradiol benzoate (EB) or testosterone propionate (TP) resulted in increasing levels of lordosis behaviour. TP was much less effective than EB in facilitating lordosis behaviour in the female rat. The optimum time interval between hormonal treatment and testing was 48-72 h for TP, but 48 h for EB. Single injections of dihydrotestosterone propionate (DHTP), also injected 48 h prior to testing, inhibited lordosis behaviour in EB-primed female rats. DHTP-inhibition of lordosis behaviour in EB-primed female rats was most effective when given prior to and least effective when given after EB-treatment. Progesterone, injected 4 h prior to testing, facilitated lordosis in EB-, TP- or EB + DHTP-treated female rats.

In order to test the hypothesis that active sleep (AS) is important for the normal development of the central nervous system, 3 different deprivation methods were applied to male Wistar rat pups during the first month of life. Daily injection of clomipramine from 8 to 21 days of age reduced the high level of AS to less than the adult value throughout most of the experimental period. Administration of clonidine from 8 to 21 days of life induced an almost total suppression of AS. Instrumental deprivation, using the 'pendulum' method, led to a significant (but less severe) AS reduction during 2-4 weeks of postnatal age. Open-field behavior testing in adulthood revealed a higher than normal level of ambulation in all 3 experimental groups. Masculine sexual responses were deficient, due to a low level of both mounts and ejaculations, in both clomipramine- and clonidine-treated animals. Neither passive avoidance learning nor dark preference tests revealed any differences between the experimental and control rats. Sleep observations showed that there was an abnormally high incidence of large myoclonic jerks during AS in both clomipramine- and clonidine-treated rats. Subsequent measurement of regional brain weights showed a significant reduction in the cerebral cortex and medulla oblongata, as compared with the respective control groups, in both the clomipramine- and the clonidine-treated rats. In addition, DNA and protein determination in the affected brain areas showed a proportional reduction in the cortex and in the medulla. These results demonstrate that interference with normal functioning either of AS per se or of specific monoaminergic transmitter systems during early development can produce long-lasting behavioral as well as brain morphological and biochemical abnormalities in later life.

The effect of testosterone (testosterone propionate: TP) on intraspecific aggression in males and females of two strains of rats—WEzob and S3—was examined. Pairs of these rats, gonadectomized and treated either with oil or with testosterone propionate (TP), were tested in three different combinations: OIL against OIL, OIL against TP, and TP against TP-treated animals. Subsequently the effects of TP treatment of the subject and for the opponents interaction with sex and strain on the occurrence of diverse social + aggression behavioral parameters were determined. The results of the S3 strain indicate that testosterone treatment of either the subject or the opponent stimulates aggression in both males and females. No sex difference could be determined with respect to the incidence of aggression. In the WEzob strain a stimulatory effect of TP was shown in females but not in males. The absence of a clear stimulatory effect of TP in WEzob males in terms of changes in the total time spent on aggression, however, could wrongly suggest that TP does not affect aggression in these animals. The possibility of TP having an effect on these males in terms of increasing the intensity of fighting is discussed.

In an attempt to study the possible role of active sleep in brain development, male rats were injected twice daily with chlorimipramine, a potent monoamine reuptake blocker, from 1 week to 3 weeks of postnatal age. AS was reduced to less than 10% of total sleep time, the level found in mature rats. Most of the AS reduction was compensated for by quiet sleep but a slight increase in wakefulness also occurred, owing to brief interruptions of sleep at times when AS was expected. In adulthood, the AS-deprived rats showed a higher percentage of AS than did the controls, due to an increase in frequency and duration of AS epochs. Moreover, many of the epochs contained abnormally frequent and strong jerky body movements and rapid-eye-movements, reminiscent of neonatal AS patterns. In addition, the amplitude of hippocampal theta waves during AS was greater than in control rats. The chlorimipramine-treated rats also showed behavioral abnormalities in later life. On the open field test exploratory behavior was much reduced, while increased rearing and defecation occurred. Masculine sexual performance was severely deficient, primarily due to the low level of intromissions and ejaculations. Experimental animals performed less efficiently than controls on a temporal learning task (differential reinforcement of low response rate) and responded more rapidly on a spatial task (left-right alternation learning). These results demonstrate that early interference with the functioning of monoaminergic systems can have long-lasting physiological and behavioral consequences. Furthermore, they are consistent with the hypothesis that AS is an important factor in normal brain development.

A plausible case for supposing the "active" (that is, rapid-eye-movement) sleep (AS) could be an important factor in the normal maturation and maintenance of neural organization was presented earlier by Jouvet. The fact that AS is present for a large percentage of the time at early stages of development, and that its phasic motor manifestations are much more intense and frequent than in adult animals, indeed makes a compelling argument for pursuing this line of reasoning. Furthermore, AS may be physiologically related in certain respects to prenatal spontaneous motility mechanisms, and it has been proposed that the latter too play a significant role in neurogenesis.

Concerning the effects of sex hormones on the development of the central nervous system (CNS) and its functions in controlling behavior, an important distinction is generally made between organizational effects, which take place in early life, and activational effects occurring in adulthood. Because these two factors are interdependent, this chapter deals with both effects of the hormones. It is established that the differentiation of the embryonic gonads during early development into ovaries or testes, and the subsequent release of hormonal products from the testis in the male, drastically affects the brain-pituitary-gonadal axis of the fetus, the newborn, and the adult organism. Because of these effects upon somatic dimorphism and sexual differentiation of hypothalamic-pituitary functioning, some workers postulated that similar processes in the CNS would underlie sex differences in sexual behavior. These ideas stimulated a large amount of research into gonadal hormone-induced sexual differentiation of behavior. This particular history of the research on sex differences in behavior, however, led to biases in the formation of general concepts. The chapter also discusses the current state of the field of sexual behavior, aggression, and learning.