围生期双酚A暴露对不同性别子代小鼠行为的影响

探讨围生期母体双酚A(bisphenol A, BPA)暴露对幼年期(生后21~30天, postnatal day 21~30, PND 21~30)和青年期(生后56~63天, PND 56~63)不同性别子代小鼠行为的影响。母鼠从妊娠第7天至断乳前(产后21天)进行BPA(0.05、0.5、5、50 mg/kg/day)灌胃染毒, 同时设对照组。每个剂量组分别在PND 21和PND 56开始测试雌雄子代小鼠各项行为。以旷场行为检测小鼠的自发活动及探究行为, 以高架十字迷宫检测小鼠的焦虑行为, 以水迷宫检测小鼠的空间学习记忆能力, 以跳台检测小鼠的被动回避记忆行为。结果表明, BPA使PND 21雌雄子鼠和PND 56雄性子鼠自发活动减少(p<0.05或p<0.01), 理毛和站立行为发生性别分化(p<0.05或p<0.01); PND 21子鼠的3分钟跑动格数有明显的剂量效应关系, 其中5~50 mg/kg/day组特别显著。BPA显著增加PND 21雌雄子鼠和PND56雌性子鼠在高架十字迷宫中进入开放臂次数和停留时间(p<0.05或p<0.01)并减少封闭臂的进入时间, 但没有明显的剂量效应关系; BPA减少PND 56雄性子鼠开放臂的进入并增加其封闭臂的进入, 干扰了幼年期和青年期小鼠焦虑行为的性别分化。BPA剂量依赖性地延长PND 21和PND 56雄性子鼠在水迷宫搜索平台的平均距离, 其中5~50 mg/kg/day剂量组具有差异显著性(p<0.05或p<0.01), 但对雌性子鼠空间学习记忆行为没有影响。此外, 5~50 mg/kg/day BPA增加PND 21雄性子鼠在跳台实验中的错误次数并缩短其跳下平台潜伏期, PND 56雌雄子鼠的被动回避记忆仅被50 mg/kg/day BPA减弱。以上结果提示, 围生期BPA暴露可影响子代小鼠幼年期和青年期的多种行为及行为的性别差异, 不同行为对BPA的敏感程度不同, 其中以自发活动和探究行为最敏感。     

Differential Effects of Short- and Long-Term Early Maternal Separation on Subsequent Maternal Behavior in Rats

Female Sprague-Dawley pups were separated from mothers every other day for 8 hr (long-term separation/LTS), 4 hr (short-term separation/STS), or 0 hr (no separation/NS) from postnatal day 2–20. In adulthood, they were mated and tested for maternal behaviors during two lactations. It was expected that females separated from mothers as pups would show deficits in maternal behavior as adults. Contrary to expectations, LTS showed better nest building and grouped young faster during both lactations. LTS were first to display aggression and displayed more aggression during the second lactation. Notably, while some measures decreased from first to second lactation in NS and STS, LTS maintained levels of maternal care. These results suggest that extended periods of maternal separation may exaggerate some aspects of maternal behavior.     

生命早期双酚A暴露对子代成年小鼠焦虑和抑郁行为的影响及其神经机制

双酚A (bisphenol A, BPA)对脑和行为发育的影响已引起关注, 本研究探讨围生期不同发育阶段母体BPA暴露对仔鼠成年后焦虑和抑郁行为的影响。分别在妊娠期(妊娠第7天~出生)和哺乳期(出生第1~14天) 将母鼠暴露于BPA (0.4、4 mg/kg/day), 以旷场、明暗箱、镜子迷宫、高架十字迷宫等多种模型检测生后56天(postnatal day 56)仔鼠的焦虑行为, 以强迫游泳模型检测其抑郁行为。结果显示, 妊娠期BPA暴露的成年雌性仔鼠在所有4种模型中均检测到促焦虑作用, 而哺乳期BPA暴露的雌鼠、妊娠期或哺乳期BPA暴露的雄鼠仅在2种模型中检测到促焦虑作用。妊娠期BPA暴露显著加重雌雄仔鼠的抑郁行为, 而哺乳期仅高剂量BPA加重仔鼠的抑郁行为。进一步的Western blot分析显示, 妊娠期或哺乳期BPA暴露显著下调成年后雌雄仔鼠海马和杏仁核AMPA受体GluR1亚基的表达, 但对NMDA受体NR1亚基的影响不一致。以上结果提示, 妊娠期或哺乳期BPA暴露对成年雌雄仔鼠均有不同程度的促焦虑和抑郁作用, 其中妊娠期暴露对雌鼠的作用最显著, 海马和杏仁核AMPA受体活动的减弱可能与围生期BPA暴露加重仔鼠成年后的焦虑和抑郁行为有关。     

Factors influencing sexual performance in male rhesus monkeys.

A 5-yr retrospective study of the sexual behavior of eight adult male rhesus monkeys showed that sexual vigor declined over the years but testosterone levels in peripheral vein plasma did not. Two prospective experiments were then carried out on these males during the sixth year. (a) The four poorest performers were injected daily for 28 days with testosterone propionate (1 mg/kg of body weight). There was no significant increase in level of performance, and behavior was not correlated with plasma levels of testosterone either before or 24 hr after the last hormone injection. (b) All eight males were exposed to novel nonspecific sensory stimulation during tests of sexual behavior. Eight different adult male rhesus strangers-present in the room but not in the test cage-were used as stimuli, one for each experimental test. Sexual behavior during experimental and control tests did not differ.     

Early maternal separation has mild effects on cardiac autonomic balance and heart structure in adult male rats

Early life adverse experiences have long-term physiologic and behavioral effects and enhance stress sensitivity. This study examined the effects of maternal separation (MS) on cardiac stress responsivity and structure in adulthood. Male Wistar rats were separated from the dams for 3?h per day from postnatal days 2 through 15. When exposed to 5-day intermittent restraint stress (IRS) as adults, MS, and control rats showed similar acute modifications of cardiac sympathovagal balance, quantified via heart rate variability analysis. In addition, MS had no effect on cardiac pacemaker intrinsic activity (as revealed by autonomic blockade with scopolamine and atenolol) and did not affect the circadian rhythmicity of heart rate, neither before nor after IRS. However, MS differed from control rats in cardiac parasympathetic drive following IRS, which was heightened in the latter but remained unchanged in the former, both during the light and dark phases of the daily rhythm. The evaluation of adult cardiac structure indicated that stress experienced during a crucial developmental period induced only modest changes, involving cardiomyocyte hypertrophy, increased density of vascular structures, and myocardial fibrosis. The mildness of these functional-structural effects questions the validity of MS as a model for early stress-induced cardiac disease in humans.     

Maternal behavior of rats is affected by hormonal condition of pups

Previous research has found that maternal rats discriminate male from female offspring and provide more anogenital licking to males. Two experiments were performed to determine whether this discrimination is based on hormonal condition of young. It was found that 500 micrograms of testosterone, estradiol, or dihydrotestosterone injected on the day of birth into female pups led to their receiving an equivalent amount of maternal anogenital licking as males and significantly more than either oil or untreated females. The different steroids had similar effects. Maternal nonanogenital licking was not affected by sex or hormonal condition of pups, but it was significantly increased by injection per se. Effects on maternal behavior of hormonal condition or neonatal injection of young were apparent 1 and 9 days after injection.     

Role of neonatal androgens in sexual differentiation of brain structure, scent marking, and gonadotropin secretion in gerbils

Gerbils display a sexually dimorphic scent marking behavior that responds to testosterone (T) in adulthood and develops under the influence of testosterone perinatally. A complex of cell groups between the preoptic area and anterior hypothalamus of the gerbil brain is also sexually dimorphic and responsive to testosterone. One of these cell groups, the sexually dimorphic area pars compacta (SDApc), usually exists only in males. Even when given testosterone, adult female gerbils rarely have an SDApc. To determine if the SDApc develops under the influence of testosterone, male gerbils were castrated or given sham operations on the day they were born or 1 day later, or were not manipulated. Female gerbils were injected subcutaneously with 0, 50, or 100 micrograms testosterone propionate (TP) on the day after birth. When given ovarian transplants as adults, neonatally castrated males scent marked at low levels typical of females. Neonatally androgenized females given testosterone as adults scent marked at high levels typical of males. Neonatal castration did not affect the probability that the SDApc would develop, but neonatal androgenization did. Half the females given either dose of TP as neonates had SDApcs bilaterally. The sizes of the SDApcs present in females depended on the dose of testosterone given neonatally. The larger dose produced larger SDApcs. The 100-micrograms dose of TP also defeminized gonadotropin secretion, but the 50-micrograms dose did not. The castration of males neonatally prevented the defeminization normally caused by endogenous testosterone. Both groups of neonatally castrated males formed corpora lutea in their ovarian transplants, but control males did not.     

Agonistic rank,aggression, social context,and testosterone in male pigtail monkeys

Two groups of pigtail monkeys were merged, a third was formed, and individual males were introduced into a group in a series of experiments examining the effects of social context upon agonistic rank, aggressive expression, and testosterone levels. In the first experiment, two heterosexual groups, containing adult males unfamiliar to the other group, were merged. The two groups fought, and the smaller group was defeated. The alpha and beta males of the defeated group were singled out for repeated attack and both showed significant drops in circulating levels of testosterone. Both males were removed from the group during the first day, but testosterone levels did not recover to baseline levels for several days. The alpha male of the victorious group, on the other hand, showed a significant rise in testosterone, which was apparent only on the day following the merger. In order to study the influence of previous social familiarity on male reception into a group, another group was formed by removing males from the victorious group and placing them in a separate enclosure. The males in the new group established a dominance hierarchy unrelated to their previous social ranks with one another. Three months later, each of the six adult males remaining in the parent group was individually introduced into the new group for one day or less. Each of the males introduced into the new group accepted a social position at the lower end of the dominance hierarchy without regard to his previous rank relationships with the host males when they were all in the parent group. Even the alpha and beta males of the parent group were relegated to low rank positions in the new group, despite having ranked over each of the host males since birth. In contrast to the aggression directed at the unfamiliar males in the first experiment, a minimum of aggression was directed to the familiar males introduced into the new group in the second experiment. Although the males introduced accepted low social ranks, it appeared that each was readily integrated into the group with a minimum of aggressive interaction during the time he was scheduled to remain in the group. There were no significant changes in circulating levels of testosterone in any of the males during the introductions of familiar males to one another.     

Effects of motherless rearing on basal and stress-induced corticosterone secretion in rat pups

Rearing of rat pups without a mother, artificial rearing (AR), produces substantial changes in the pups' behavior in later life. These changes are similar to those produced by the stress of repeated mother-pup separations. The predominant interpretation is that the long-term effects of disruptions to the mother-pup relationship are mediated by exposure to elevated levels of corticosterone which affect the development of neurobiological systems underlying cognition and behavior. Indeed, repeated separation of pups from the mother sensitizes the pups' corticosterone response to stress. This study examined basal and stress-induced corticosterone release in AR pups. Corticosterone levels were increased immediately following implantation of feeding cannulae. One day after the start of AR, circulating concentrations of corticosterone were not increased unless AR pups were challenged with an additional stressor (injection). Corticosterone levels were lowest when cannulation and AR started on postnatal day (PND) 5 compared with earlier PNDs. On PND 12, there was no evidence of increased corticosterone levels in AR pups at baseline or in response to stress, indicating that AR did not result in persistent sensitization of corticosterone release. The long-term effects of motherless rearing on rat behavior are mediated by mechanisms that are independent of sustained early corticosterone exposure.     

Testosterone prevents synaptic loss in the perineal motoneuron pool in the spinal cord in male rats exposed to chronic stress

Chronic stress is known to induce disorders of reproductive neuroendocrine functions. Motoneurons of the spinal nucleus of the bulbocavernosus (SNB) in male rats play an important role in copulatory behavior. In the present study, it was examined whether chronic stress would alter synaptic organization of the SNB motoneurons and whether androgen would modify the changes under chronic stress. Five male rats were under restraint stress for 5 days per week for 3 weeks, and five males implanted subcutaneously with Silastic capsules containing testosterone were also exposed to stress. Five males served as unstressed controls. After 3 weeks of restraint stress, cholera toxin-horseradish peroxidase (CT-HRP) was injected into the bulbocavernosus muscles and animals were killed 2 days later. The spinal cords containing the SNB were dissected, processed with a modified tetramethylbenzidine (TMB) method for visualization of retrogradely transported CT-HRP, and examined ultrastructurally. Neuronal structures apposing the membranes of 150 SNB motoneurons (total for three groups) were analyzed by measuring the percentage of somatic membranes covered by synaptic contacts. The mean percentage of somatic membranes covered by synapses in males exposed to chronic stress was significantly less than that in controls or stressed males treated with testosterone. Size and number of synaptic contacts per unit length of somatic membranes in males exposed to stress were also significantly less than those in controls or stressed males treated with testosterone. There was no significant difference in any of the parameters between controls and stressed males treated with testosterone. Changes in plasma levels of testosterone showed the same profile as changes in the synaptic contacts. These results suggest that the SNB motoneurons of male rats exposed to chronic stress retain a considerable synaptic plasticity in response to androgen, and that androgen treatment can rescue the SNB system in male rats when under chronic restraint stress.     

Sex differences in behavioral consequences of defeat in the rat are not organized by testosterone during early development

Male and female rats react differently to losing an aggressive encounter, the presence of testosterone (at the time of confrontation) being a critical factor in the manifestation of this sex difference. Female rats were androgenized by 250 μg testosterone propionate sc on days 1 and 5 after birth. When adult they received a sc testosterone proprionate (TP) implant and were subjected to repeated defeats by being placed in the cage of an aggressive resident female. In contrast to males, which freeze and become permanently submissive, androgenized females showed no freezing or other signs of submission. The sex difference in response to defeat is therefore not dependent on the presence of testosterone during the period of post-natal sexual differentiation.     

Learning strategy is influenced by trait anxiety and early rearing conditions in prepubertal male, but not prepubertal female rats

Rodents solve dual-solution tasks that require navigation to a goal by adopting either a hippocampus-dependent place strategy or a striatum-dependent stimulus-response strategy. A variety of factors, including biological sex and emotional status, influence the choice of learning strategy. In these experiments, we investigated the relationship between learning strategy and anxiety level in male and female rats prior to the onset of puberty, before the activational effects of gonadal hormones influence these processes. In the first experiment, prepubertal male rats categorized as high in trait anxiety at 26days of age exhibited a bias toward stimulus-response strategy at 28days of age, whereas age-matched females exhibited no preference in strategy regardless of anxiety level. In the second experiment, male and female rats were separated from their dams for either 15 or 180min per day during the first 2weeks of life and tested on a battery of anxiety and cognitive tasks between 25 and 29days of age. Prolonged maternal separations for 180min were associated with impaired spatial memory on a Y-maze task in both prepubertal males and females. Furthermore, prolonged maternal separations were linked to elevated anxiety and a bias for stimulus-response strategy in prepubertal males but not females. Alternatively, brief separations from dams for 15min were associated with intact spatial memory, lower levels of anxiety, and no preference for either learning strategy in both sexes. These results provide evidence of sex-specific effects of trait anxiety and early maternal separation on the choice of learning strategy used by prepubertal rodents.     

Neonatal tactile stimulation enhances spatial working memory, prefrontal long-term potentiation, and D1 receptor activation in adult rats

Environmental stimuli during neonatal periods play an important role in the development of cognitive function. In this study, we examined the long-term effects of neonatal tactile stimulation (TS) on spatial working memory (SWM) and related mechanisms. We also investigated whether TS-induced effects could be counteracted by repeated short periods of maternal separation (MS). Wistar rat pups submitted to TS were handled and marked transiently per day during postnatal days 2–9 or 10–17. TS/MS pups were stimulated in the same way as TS pups and then individually separated from their mother for 1 h/day. Their nontactile stimulated (NTS) siblings served as controls. In adulthood, TS and TS/MS rats showed better performance in two versions of the delayed alternation task and superior in vivo long-term potentiation of the hippocampo–prefrontal cortical pathway when compared with controls. Furthermore, there were more doses of A77636 (a selective dopamine D1 agonist) to significantly improve SWM performance in TS and TS/MS rats than in NTS rats, suggesting that activation of prefrontal D1 receptors in TS and TS/MS rats is more optimal for SWM function than in NTS rats. MS did not counteract TS-induced effects because no significant difference was found between TS/MS and TS animals. These data indicate that in early life, external tactile stimulation leads to long-term facilitative effects in SWM-related neural function.     

Intergenerational effects of cocaine on maternal aggressive behavior and brain oxytocin in rat dams

Gestational cocaine treatment results in significantly increased maternal aggression towards an intruder by postpartum day six, while acute postpartum treatment dose dependently decreases maternal aggressive (MA) behavior. Both increased and decreased aggression in the cocaine-treated dams are correlated with either decreased or increased levels of oxytocin in the amygdala, respectively. The current study was an effort to determine whether the effect of gestational cocaine on maternal aggression is transient or would continue into the postpartum period; whether an intermittent cocaine treatment regimen, which incorporates gestational and postpartum intermittent cocaine treatment, would differ from chronic daily gestational treatment; and finally, whether next generation female offspring of cocaine-treated or control dams would have altered MA behavior and oxytocin system changes attributable to either prenatal drug exposure, rearing condition or both. We now report no increase in maternal aggression following chronic gestational treatment and significantly lower levels of aggression in intermittently treated dams on postpartum day eight, with no significant effects in either group on postpartum day 12. Young adult female offspring of the cocaine-treated and control dams, who reared their own natural litters and were tested on postpartum day eight for maternal aggression, had higher levels of maternal aggression towards an intruder attributable to both prenatal cocaine exposure and rearing condition. Higher aggression in cocaine-reared next generation dams was associated with lower levels of oxytocin in the amygdala. Intergenerational effects of cocaine were apparent with respect to aggression and oxytocin system changes.     

Effects of neonatal treatment with cyproterone acetate on aggressive behavior induced by footshock in adult male rats

High levels of androgens are required to organize aggressive behavior in adult male rats. Footshock-induced aggression was tested in Wistar rats allocated to one of three experimental groups: control (oil-injected) males (M), males neonatally injected with the antiandrogen cyproterone acetate (CA), and males treated as in the CA group but gonadectomized just before puberty (CAG). An antiaggressive effect of CA in those adult male rats neonatally treated with this compound was found. Neonatal exposure to cyproterone acetate exerts an antiandrogenic effect over the expression of shock-induced aggressive behavior. The behavioral effects of CA were not countered by adult treatment with testosterone propionate.     

Testosterone,aggressiveness, and antisocial personality

Testosterone levels were examined in prisoners convicted of violent crimes (n = 13), in men previously convicted of violent crimes but currently not in prison (n = 15), in nonviolent alcoholics (n = 15), and in randomly selected control males (n = 16). Morning, afternoon, and evening testosterone levels were assessed after a minimum alcohol abstinence period of 24 hr. Violent and nonviolent men did not differ in plasma total testosterone level on any sampling occasion. In violent men, however, testosterone levels were significantly correlated with hostility, as measured by the Derogatis Symptom Check List. Most violent men were diagnosed with Antisocial Personality Disorder (ASP) [DSM‐III‐R; 301.70], and the unweighted ASP symptom count also correlated significantly with testosterone levels in these subjects. We suggest that individuals whose life histories involve numerous antisocial behaviors tend to have high testosterone levels even when interpersonal violence is excluded. This, however, does not eliminate the possibility that males who are characterized by high hostility may also have elevated testosterone levels. Violent predisposition and antisocial conduct beginning in early adolescence predict adult aggressive behaviors, which are augmented by power‐related alcohol expectancies and alcohol abuse. Aggr. Behav. 25:113–123, 1999. © 1999 Wiley‐Liss, Inc.     

Developmental expression of defensive responses during exposure to conspecific adults in preweanling rats (Rattus norvegicus).

I examined preweanling rats' (Rattus norvegicus) expression of ultrasounds and secretion of ACTH when exposed to unfamiliar adult male rats or to their mothers. Pups at 7 days of age produced similar levels of ultrasonic vocalization near both unfamiliar males and mothers. However, these pups could discriminate familiar from unfamiliar adults because ACTH was significantly higher in pups near adult males than in those near mothers. At 14 days of age, pups avoided adult males but not their mothers; therefore, adult males represented a significant threat. Importantly, 14-day-old rats significantly reduced ultrasound production only when near adult males. Pups at 21 days of age no longer emitted ultrasounds when socially isolated or when near conspecific adults. In addition, 14- and 21-day-old rats produced similar elevated ACTH levels across stimulus conditions. Results show significant changes in preweanling rats' responses to conspecific adults.     

Long-term consequences of early experience on adult avoidance learning in female rats: role of the dopaminergic system

Following our hypothesis that juvenile emotional and/or cognitive experience should affect learning performance at preweaning age as well as adulthood, the present study in female Wistar rats aimed to examine the impact of (i) avoidance training at preweaning age, (ii) exposure to repeated maternal separation, (iii) the combination of both, and (iv) the blockade of dopaminergic neurotransmission on adult two-way active avoidance learning in rats. We found that preweaning, i.e. three week old, rats were less capable of avoidance learning compared to adults. Our main findings revealed that preweaning avoidance training alone improved avoidance learning in adulthood. Furthermore, maternal separation alone also improved avoidance learning in preweaning and in adult rats, but this effect of maternal separation did not add up to the beneficial effect of preweaning avoidance training on adult learning. In addition, the pharmacological blockade of dopamine receptors during preweaning avoidance training via systemic application of haloperidol impaired preweaning avoidance performance in a dose-dependent manner. Testing the haloperidol-treated preweaning presumed "non-learners" as adults revealed that they still showed improved learning as adults. Taken together, our results strongly support the hypothesis that emotional as well as cognitive experience at preweaning age leaves an enduring "memory trace," which can facilitate learning in adulthood. Our pharmaco-behavioral studies suggest that unlike the adult brain, preweaning learning and memory formation is less dependent on dopaminergic mechanisms, which raises the intriguing question of possible alternative pathways.     

早期剥夺所致大鼠抑郁样行为与海马BDNF mRNA表达变化

为探讨早期剥夺对大鼠行为与海马脑源性神经营养因子(BDNF)mRNA表达的影响,将新生的SD大鼠随机分为正常对照组与早期剥夺组,早期剥夺组在出生后1～14d每天孤养4h。监测体重,在出生后36?64天进行液体消耗试验,每周一次。12w龄时,进行穿梭箱试验,酶联免疫法检测海马BDNF含量,原位杂交法观察海马BDNF mRNA的表达。早期剥夺组大鼠体重显著低于正常对照组(p0.01),糖水摄入量与糖水偏爱显著低于正常对照组(p0.05或p0.01)。穿梭箱试验中,早期剥夺组大鼠在训练时的穿梭反应次数显著少于正常对照组(p0.05),在测试时,两组大鼠的被动逃避行为、主动逃避行为与逃避错误次数无显著差异。早期剥夺组大鼠海马BDNF含量、CA1区和CA3区BDNF mRNA表达显著低于正常对照组(p=0.05或p0.05)。提示早期剥夺可导致大鼠生长减慢,表现出快感缺失的抑郁样行为,但未诱导成年大鼠表现出明显的习得性无助倾向,早期剥夺能下调成年大鼠海马BDNFmRNA的表达。     

Simple disturbance of the dam in the neonatal period can alter haloperidol-induced catalepsy in the adult offspring

Three experiments were performed to determine whether apparently minimal disturbances of dams and litters would influence haloperidol-induced akinesia. In Experiment I, Long-Evans hooded rats (a) were left unmanipulated, (b) received nestcage relocation and observation, (c) received nestcage relocation/observation and maternal separation, or (d) received nestcage relocation/observation and pup handling. The male adult offspring received open-field testing and later received forepaw-on-dowel catalepsy testing following saline, morphine (20 mg/kg), or haloperidol (2 mg/kg). In Experiment II, hooded rats received (a) no manipulation, (b) nestcage relocation, (c) maternal separation, or (d) pup handling. At weaning, dams were tested in the open-field. Activity wheel locomotion of the offspring was assessed following saline or haloperidol for 3 days/week for 3 weeks; then, 5 and 7 days later, rats received haloperidol (0.5 mg/kg) and catalepsy testing. In both experiments, manipulations involving the dam reduced the offsprings' haloperidol-induced catalepsy, but, in Experiment II, a history of haloperidol administration distinguished between the effects of nestcage relocation and maternal separation. In Experiment III, Swiss albino mice received (a) no treatment, (b) nestcage relocation and maternal separation, (c) relocation/separation and mild cold stress of pups, (d) relocation/separation and pup handling, or (e) relocation/separation and severe cold stress of pups. Adult male mice received saline or haloperidol (2.5 mg/kg) and inclined grid catalepsy testing. Mice receiving relocation/separation and mice receiving relocation/separation and severe cold stress showed enhanced catalepsy versus control mice. Thus, it was concluded that seemingly innocuous events in infancy can influence the intensity of extrapyramidal side effects of neuroleptics in adulthood.