Nociceptive sensitivity to a long-term stimulus in the formalin test in female and male rats in postnatal ontogenesis

In Wistar rats, a comparative study of pain sensitivity to the long-term stimulus in the formalin test was carried out at different age periods—the prepubertal (25 days), pubertal (40 days), and sex maturity (90 days) periods. The pain sensitivity was evaluated by standard indexes of the biphasic behavioral response (BBR)—patterns of flexing, shaking, licking of the leg injected by formalin, and by duration of the first and second response phases and of the interphase interval. It is found that with development of the central nervous system the pain sensitivity changed, with differences in the first, acute and the second, tonic BBR phases: in the tonic phase of response the pain sensitivity increased in males by the indexes organized at the spinal, while in females, at the supraspinal level, whereas in the acute phase it decreased essentially at the supraspinal level in individuals of both sexes. The greater number of age differences in the pain sensitivity is revealed in females by the response patterns organized at the supraspinal level. At the same level, essential readjustments in hormonal and neurotransmitter systems are reflected in the high BBR indexes. In adult individuals the sex dimorphism is detected in duration of the interphase intervals. Activity of the bulbospinal descending inhibitory monoaminergic systems is shown to continue increasing for the first three months of life, with predominance of this process in females. The obtained data allow concluding that the BBR characteristics depend on age and sex of individuals and are determined by the organization level in CNS of the response patterns characterizing the pain sensitivity in the formalin test.Translated from Zhurnal Evolyutsionnoi Biokhimii i Fiziologii, Vol. 41, No. 1, 2005, pp. 76–81.Original Russian Text Copyright © 2005 by Butkevich, Vershinina.     

Sex Differences in Effects of Prenatal Stress on Specific Biphasic Behavioral Response in Nociceptive Formalin Test in Adult Rats

Remote effects of stress (immobilization) in pregnant females at critical stages of fetal development on pain sensitivity to a long-term nociceptive stimulus (formalin test) were studied in their female and male off-spring at the age of 90 days. Prenatal stress produced changes of the standardized specific biphasic behavior response (BBR), whose intensity was evaluated by the number of flexion and shakings and by duration of licking of thee extremity injected with formalin. Apart from intensity of the BBR, duration of its both phases and of interphase interval was determined. It was found that the response intensity by the licking pattern increased significantly at the first response phase reflecting acute pain in males, whereas at the second phase reflecting tonic pain, both in females and males; duration of the phases and interphase interval increased statistically significantly only in females. Thus, in the prenatally stressed adult rats, an increase of pain sensitivity to a long-term nociceptive stimulus producing inflammation has been revealed by the BBR patterns organized at the supraspinal, but not at the spinal CNS level. Sex differences were found in the acute phase intensity and in duration both of acute and of tonic response phase. The data obtained indicate different effects of prenatal stress on the nociceptive systems involved in realization of the BBR in the formalin test in adult females and males and are an essential argument in favor of the concept of different characteristics of the acute and tonic pain.     

Differences in Behavioral Parameters of Long-Term Pain in Formalin Test at the Period of Sex Maturation in Prenatally Stressed Female and Male Rats

The effect of immobilization of pregnant rats was studied on parameters of the specific biphasic behavioral response (BBR) (patterns of flexion, shaking, licking, duration of the phases and of the interphase interval), of which the first phase characterizes the acute, while the second, he long-term pain in a nociceptive formalin test in the 40-day old female and male off-spring. The following was found: (1) an increase of intensity of patterns of flexion and shaking in the extremity injected with formalin at the second response phase and of the phase duration both in males and in females, (2) an increase of the licking pattern during the second phase and of the phase duration in males. Thus, the prenatal stress produced an increase of the pain sensitivity only at the long-term BBR phase; this increase was revealed in males from the patterns organized at the spinal and supraspinal levels, whereas in females, only at the spinal level. It was concluded that at the period of sex maturation, before the onset of sex maturity, the prenatally stressed males had more expressed damages in the behavioral parameters of the long-term pain in the formalin test, as compared with the prenatally stressed females. The comparative analysis of the response parameters allows suggesting the greater damage in males, then in females, of the inhibition process in the descending inhibitory system modulating nociceptive signals at the spinal cord level.     

Consequences of the prenatal depletion of serotonin and stress on nociceptive sensitivity in rats

The long-term effects of serotonin (5-HT) synthesis alteration and of restraint stress experienced by pregnant Wistar rats on pain sensitivity (evaluated by the indices of the biphasic behavioral response in the formalin test) were studied in their 90-day-old offspring. Prenatal 5-HT depletion decreased pain sensitivity in one third of the rats and failed to change it in the rest of the rast. In these later, however, an obvious tendency for an increase of interphase duration in females and its decrease in males were revealed that indicates changing of the activity of the descending serotoninergic system modulating nociceptive signals at the level of the spinal dorsal horns. Prenatal stress decreased pain sensitivity in 50% of the rats with prenatal deficiency of 5-HT but increased it in the rest of the animals. Increase of pain sensitivity also occurred in the control rats but to a lesser extent (significantly in flexing + shaking behavior during the second phase) compared to the animals with prenatal 5-HT depletion. In the latter, sex differences were found in effects of prenatal stress on pain sensitivity. The present data point an important role of 5-HT in: 1) embryonic development of tonic nociceptive system which is modulated in the CNS by mechanisms differing from those of acute pain; 2) mediation of the prenatal stress influence on pain sensitivity in the formalin test in adult rats.     

Long-term effects of stress in critical periods of development on reactivity of adult female rats

Effects of stress during different periods of ontogeny, namely, the prenatal, prepubertal, or their combination (prenatal+prepubertal), on the indices of psychoemotional and tonic pain-related behaviors, as well as corticosterone reactivity after pain behavior were investigated in adult 90-day-old female Wistar rats. Our data show for the first time, the similarity of effects of prenatal (immobilization stress of a rat dam during the last week of pregnancy) and prepubertal (forced swimming, pain-related response in the formalin test) stresses on the indices under study, an increase in the time of immobility and in licking duration, but the difference between effects of combined stress on these indices. Pain-related response increased corticosterone in prepubertally stressed rats while in prenatally stressed rats, decreased it. In rats experienced combined stress, formalin-induced pain increased corticosterone as compared with that in prenatally, but not in prepubertally stressed rats. A positive correlation between pain-related reaction and stressed hormonal response was revealed in prepubertally stressed animals. So, long-term effects of stress during critical periods of ontogeny determine stress reactivity of behavioral and hormonal responses in adult female rats.     

Sex-dependent differences in parameters of long-term pain caused by inflammatory focus in prenatally stressed newborn rats

In experiments on the 7-day old female and male Long-Evans rat pups, for the first time, there was studied effect of prenatal (immobilization) stress on dynamics of nociceptive behavioral response caused by an inflammatory focus. The nociceptive sensitivity was evaluated for 1 h by the number of the flexion-shaking patterns organized at the spinal level in response to injection of formalin (10%, 10 μl) to the posterior leg sole. Control rat pups were not submitted to any prenatal stress; in these animals the response in the formalin test was found to be represented by one phase. It the prenatally stressed rat pups the studied patterns were organized into two phases characteristic of the definitive type of response. At the period between them (during interphase), the nociceptive behavior was absent. At the second, tonic phase the number of flexion-shakings in the prenatally stressed males was statistically significantly higher than in the prenatally stressed females, which indicates a sensitization of the neurons involved in the tonic pain chains in male individuals. Thus, the data obtained on prenatally stressed animals confirm the previous data about immaturity of the mechanisms mediating the second phase of response in the formalin test in the 7-day old rat pups. An important fact is revealed which indicates that in the prenatally stressed rat pups of the same age the second phase of response is already obvious. Mechanisms underlying the behavioral response caused by the inflammatory focus in the formalin test in the one-week old stressed rat pups are characterized by sexual dimorphism: the pain sensitivity in males at the second phase of response is statistically significantly higher than in females.     

Sex-dependent differences in parameters of a long-term pain caused by inflammatory focus in prenatally stressed newborn rats

In experiments on the 7-day-old female and male Long-Evans rat pups, for the first time, there was studied effect of prenatal (immobilization) stress on dynamics of nociceptive behavioral response caused by an inflammatory focus. The nociceptive sensitivity was evaluated for 1 h by the number of 7-day-old organized at the spinal level in response to injection of formalin (10%, 10 microl) to the posterior leg sole. Control rat pups were not submitted to any prenatal stress; in these animals the response in the formalin test was found to be represented by one phase. It the prenatally stressed rat pups the studied patterns were organized into two phases characteristic of the definitive type of response. At the period between them (during interphase), the nociceptive behavior was absent. At the second, tonic phase the number of flexes+shakes in the prenatally stressed males was statistically significantly higher than in the prenatally stressed females, which indicates a sensitization of the neurons involved in the tonic pain chains in male individuals. Thus, the data obtained on prenatally stressed animals confirm the previous data about immaturity of the mechanisms mediating the second phase of response in the formalin test in the 7-day-old rat pups. An important fact is revealed which indicates that in the prenatally stressed rat pups of the same age the second phase of response is already obvious. Mechanisms underlying the behavioral response caused by the inflammatory focus in the formalin test in the number flexes + shakes old stressed rat pups are characterized by sexual dimorphism: the pain sensitivity in males at the second phase of response is statistically significantly higher than in females.     

Effects of Decrease of Serotonin Synthesis and Subsequent Stress in Embryogenesis on Rat Pain Sensitivity during the Prepuberty Period of Development

In the 25-day old rats there were studied effects of prenatal serotonin (5-HT) depletions and stress on pain sensitivity evaluated using formalin test by indexes of the biphasic behavioral response (BBR)-the number of flexions and shakings as well as duration of licking of the formalin injected leg, duration of the first and second response phases and on morphofunctional characteristics of the brain structures involved in BBR. The 5-HT depletion (a single intraperitoneal injection of parachlorophenylalanine, an inhibitor of 5-HT synthesis, to pregnant females at the initial period of development of the serotoninergic system) produced morphological lesions in the neocortex areas and hippocampus and raphe nuclei, which were accompanied by an essential decrease of the pain sensitivity (until its complete inhibition) during the second, tonic, BBR phase. In the prenatally stressed rats (immobilization of pregnant females for the last pregnancy week) with prenatal 5-HT depletion the nerve cell death in the above brain structures was accompanied by an increase of the pain sensitivity revealed by all response indexes during the second, tonic phase, whereas in the prenatally stressed rats developed without the intervention into the serotoninergic system, only one index was found to increase. The obtained results indicate that 5-HT participates in formation of the tonic nociceptive system and in mediation of effects of the prenatal stress on the pain sensitivity to the long-term nociceptive stimulus.__________Translated from Zhurnal Evolyutsionnoi Biokhimii i Fiziologii, Vol. 41, No. 2, 2005, pp. 168–175.Original Russian Text Copyright © 2005 by Butkevich, Mikhailenko, Khozhai, Otellin.     

Decreased serotonin level during pregnancy alters morphological and functional characteristics of tonic nociceptive system in juvenile offspring of the rat

Serotonin (5-HT) contributes to the prenatal development of the central nervous system, acting as a morphogen in the young embryo and later as a neurotransmitter. This biologically active agent influences both morphological and biochemical differentiation of raphe neurons, which give rise to the descending serotonergic paths that regulate the processing of acutely evoked nociceptive inputs. The involvement of 5-HT in the prenatal development of tonic nociceptive system has not been studied. In the present study we evaluated the effects of a single injection (400 mg/kg, 2 ml, i.p.) of the 5-HT synthesis inhibitor, para-chlorophenylalanine (pCPA), given to pregnant rats during the critical period fetal serotonin development. The functional integrity of the tonic nociceptive response was investigated in 25 day old rats using the classic formalin test. Morphological analysis of brain structures involved in formalin-induced pain and 5-HT levels in the heads of 12-day embryos were also evaluated. Embryonic levels of 5-HT were significantly lowered by the treatment. The juvenile rats from pCPA-treated females showed altered brain morphology and cell differentiation in the developing cortex, hippocampus, raphe nuclei, and substantia nigra. In the formalin test, there were significant decreases in the intensity and duration of the second phase of the formalin-induced response, characterizing persistent, tonic pain. The extent of impairments in the brain structures correlated positively with the level of decrease in the behavioral responses. The data demonstrate the involvement of 5-HT in the prenatal development of the tonic nociceptive system. The decreased tonic component of the behavioral response can be explained by lower activity of the descending excitatory serotonergic system originating in the raphe nuclei, resulting in decreased tonic pain processing organized at the level of the dorsal horn of the spinal cord.     

Prenatal melatonin influences developmental changes of tachykinins in response to estradiol benzoate

The developmental changes of hypothalamic, pituitary, striatum and pineal gland tachykinin concentrations, as well as the response to estradiol-benzoate (EB) administration, were studied in offspring of control and melatonin (MEL) treated mother rats. Female rats were studied throughout different phases of the sexual development: infantile, prepubertal and pubertal periods, in the four following groups; control-offspring+vehicle; control-offspring+EB; MEL-offspring+vehicle; MEL-offspring+EB. Hypothalamic NKA in control-offspring+ vehicle was significantly increased only at 27 days of age and in control-offspring+EB at 27 days of age and during the infantile period. Hypothalamic SP levels increased similarly in control-offspring+EB during the infantile period but the EB influence was more pronounced with significantly increased concentrations at 32 days of age. Prenatal melatonin treatment produced major alterations in these patterns of postnatal development. In MEL-offspring+EB tachykinins concentrations in the hypothalamus during infantile and prepubertal periods did not increase, however at 37 days of age, they showed significantly higher values than in control-offspring+EB groups. The developmental pattern of pituitary NKA and SP concentrations in both; control-offspring+vehicle and control-offspring+EB groups, showed similar values from the infantile period to puberty, indicating that NKA and SP concentrations remained at similar levels independently of the sexual stage, only at 27 days of age in control-offspring+EB significantly increased values were found as compared to MEL-offspring+EB. Prenatal melatonin did not produce marked modifications, only significantly lower NKA and SP concentrations in MEL-offspring+EB group were observed at 25 days of age in comparison to control-offspring+EB group. Striatal NKA and SP concentrations showed a similar developmental pattern. In control-offspring, EB treatment produced NKA and SP decreased concentrations at the infantile period than in control-offspring+vehicle and significantly increased concentrations during the prepubertal period, then during the pubertal period NKA and SP concentrations decreased in control-group+EB. However, prenatal melatonin treatment reduced the levels of striatal NKA and SP during the prepubertal period after EB treatment and delayed until pubertal period the increase previously observed in control group during the prepubertal period. In MEL-offspring+vehicle group striatal concentrations of both tachykinins remained at low levels from infantile period until pubertal period. Prenatal melatonin and EB did not produce major alterations in SP pineal concentrations throughout sexual development. Plasma estradiol concentrations were significantly higher in the groups that received EB treatment than in those that received vehicle during prepubertal and juvenile periods in control-offspring+EB group and during the pubertal period in MEL-offspring+EB group. These data indicate that prenatal MEL treatment may influence NKA and SP developmental pattern from the infantile period until adulthood in the female rat.     

Delayed puberty in lambs chronically treated with oestradiol

Intact female lambs were chronically treated with low levels of oestradiol by Silastic implant from 20 weeks of age. Reproductive cycles were initiated in only 33% of these lambs (3 of 9) compared to 80% of untreated females (11 of 14) by 45 weeks when the study was terminated. Moreover, in the 3 oestradiol-treated lambs which began cycles, the age at first oestrus was delayed 3 weeks (37 +/- 1 weeks of age vs 34 +/- 1 weeks of age for untreated controls). Retardation of the pubertal process was not due to absence of the pubertal rise in circulating LH. At about 32 weeks of age, chronic oestradiol treatment was no longer able to suppress tonic LH secretion and serum LH increased in intact, oestradiol-treated lambs. These results indicate that a maturational decrease in responsiveness to oestradiol inhibition of tonic LH secretion can be demonstrated in the intact female, as in the ovariectomized female. However, chronic oestradiol suppression of prepubertal LH secretion also delays onset of reproductive cycles. This finding raises the possibility that low tonic LH secretion, presumably in the form of slow pulses, is necessary for development or maintenance of ovarian function before puberty. In the absence of LH during the last part of sexual maturation, the ability of the ovary to respond to the high frequency LH pulses during the pubertal gonadotrophin rise may be delayed.     

Antinociceptive properties of the 5-HT3 receptor antagonist in the model of inflammatory pain in rats of different age with prenatal deficit of serotonine and under stress

The role of peripheral 5-HT3 receptors in the nociceptive behavioral response and the effect of the 5-HT3 antagonist ondansetron on indices of acute and tonic pain were investigated in the formalin test in 25- and 90-day-old Wistar male rats. The experimental rats were prenatally exposed to 5-HT depletion (a single injection ofparachlorophenilalanine 400 mg/kg/2 ml, i. p.; ICN, USA to the dams on day 9 of pregnancy) and to stress (dams immobilization during the last week of pregnancy). Antinociceptive effects of ondansetron in the rats with both prenatal 5-HT deficiency and stress (experimental rats) and prenatal injection of saline solution and stress (control rats) were more obvious in the younger animals. Prenatal 5-HT deficiency attenuated the antinociceptive effect of ondansetron in licking patterns in the younder age group in acute pain, and in adults--in tonic pain. Thus, the data obtained in the rats with prenatal 5-HT deficiency and stress indicate involvement of 5-HT3 receptors in mediation of prolonged pain in the formalin test, and antinociceptive effect of ondansetron which is attenuated in animals with prenatal 5-HT deficiency and specifically depends on rat's age.     

Possible organizational effect of sex steroids on the stabilization of manual preference in female common marmosets (<Emphasis Type="Italic">Callithrix jacchus</Emphasis>)

Handedness has been widely studied in nonhuman primates. However, few studies investigate this behavior throughout ontogenetic development. To determine the influence of developmental stage in common marmoset (Callithrix jacchus) females, we used six animals, which were observed in food-reaching tests involving hand-use preference from the infantile to the adult phase. During this period, fecal samples were collected for sexual hormone analysis (estrogen and progesterone). The results point to correlations between age and stabilization of manual preference across the developmental phases. A relationship between progesterone and the intensity of hand use asymmetry was observed during the pubertal period, when the data was grouped into three phases: prepubertal, pubertal, and postpubertal. These data show increasing strength of hand preference during ontogenetic development and that sexual hormones may be involved in females.     

Functional maturation of the gonads of Turkish hamsters under various photoperiods

The golden hamster, Mesocricetus auratus, is the only photoperiodic rodent to date that has been shown to fail to respond to inhibitory (i.e., short, less than 12.5 h/day) photoperiods until after pubertal onset. In other photoperiodic hamsters, mice, and voles, short photoperiods greatly retard gonadal maturation. The Turkish hamster, Mesocricetus brandti, is a photoperiodic rodent that as an adult is reproductively competent only on photoperiods of 15-17 h of light per day; photoperiods of less than 15 or greater than 17 h of light promote gonadal regression. In this report we addressed two questions: a) are prepubertal M. brandti photoperiodic, and b) if so, is gonadal maturation enhanced or suppressed by exposure to photoperiods of greater than 17 h of light per day? Turkish hamsters were raised on photoperiods of 12, 16, 20, or 24 (= LL) h of light per day. Testicular growth was retarded for 16 wk by 12L:12D. Very long days, 20L:4D, or LL did not retard testicular development. In females, pubertal onset, as indicated by first vaginal estrus, was delayed in young raised on 12L:12D and in 2 of 18 and 4 of 19 young raised on 20L:4D and LL, respectively. These results demonstrate that prepubertal Turkish hamsters are photoperiodic, but respond differently from adults to photoperiods greater than 17 h of light per day.     

Perigestational suppression of weight gain with central leptin gene therapy results in lower weight F1 generation

The efficacy of central leptin therapy on weight homeostasis through various phases of reproduction, pregnancy outcome and postnatal, prepubertal and pubertal growth of offspring was assessed. Enhanced leptin transgene expression after a single intracerebroventricular injection of recombinant adeno-associated virus vector encoding the leptin gene (rAAV-lep) decreased calorie intake and weight in adult nulliparous female rats. rAAV-lep treated rats conceived normally, displayed unremarkable pregnancy rate, parturition and delivered normal sized litters. Significantly lower weight was maintained through gestation, lactation, and post-lactation periods. The maintenance of a modest weight reduction was accompanied by voluntarily reduced calorie intake, increased thermogenic energy expenditure, decreased adiposity as reflected by drastically reduced leptin levels, and suppressed insulin and insulin-like growth factor 1 levels through lactation and post-lactation in rAAV-lep treated dams. The offspring at birth weighed significantly less than those of controls and this lower weight range was sustained during postnatal, prepubertal, pubertal and adult (3 months old) periods, contemporaneous with metabolic circulating hormones in the normal range. For the first time we show the persistent efficacy of central leptin gene therapy to suppress weight gain through all phases of reproduction, lactation and post-lactation in dams and reveal the potential imprinting link to producing lower weight in the F1 generation.     

Tonic pain response in mice: effects of sex,season and time of day

Seasonal and diurnal variations in tonic pain reactions were examined in female and male CBA/J mice maintained in a 12/12 dark/light cycle, at controlled temperature and humidity conditions. Animals were injected into the dorsum of one hindpaw with a dilute (20 microl, 1%) formalin solution. Pain-related behaviors were quantified as the time spent licking the injected paw and the number of flinching episodes. The experiments were performed during the first part of the light phase (Light: from 7 to 10 a.m.) or during the first part of the dark phase of the diurnal cycle (Dark: from 7 to 10 p.m.), in two different periods of the year: Spring (March-June) and Winter (November-January). Considering all data, females showed a slightly enhanced licking response, as well as an increase in the time spent in self-grooming, in comparison with males. In Spring, the licking and flinching responses were higher during the Dark phase than during the Light phase. This held for both sexes and for both phases of the behavioral response to formalin injection. By contrast, no significant diurnal variation in pain reactions was found in Winter. These seasonal and diurnal differences were not due to nonspecific changes in motor behavior, inasmuch as locomotor activity and self-grooming showed a different pattern: during the second phase after formalin, self-grooming was higher in the Light period in the experiments performed in Spring, whereas locomotor activity showed no significant seasonal changes. These results show that the behavioral reactions to prolonged noxious input, integrated both at spinal and supraspinal sites, undergo similar seasonal and diurnal variations in both sexes, strengthening the importance of chronobiological factors in the modulation of nociception.     

Pubertal maturation and time of day differentially affect behavioral and neuroendocrine responses following an acute stressor

Puberty markedly influences stress responsiveness such that prepubertal animals show a more protracted corticosterone (CORT) and progesterone response following acute stress compared to adults. In both adult and juvenile rats, circadian time modulates adrenocortical steroids with basal CORT and progesterone levels rising prior to the onset of the dark phase of the light-dark cycle (i.e., active period). How time of day affects the pubertal difference in stress responsiveness and if the behaviors of prepubertal and adult animals are differentially affected by stress and time of testing remain unknown. Thus, we exposed group housed (3 per cage) prepubertal (28d) and adult (77d) male rats to 30 min of restraint in either the early portion of the behaviorally inactive, light (circadian nadir of CORT and progesterone) or behaviorally active, dark (circadian peak) phase of their light-dark cycle and measured ACTH, CORT, progesterone, and home cage behavior before and after the stressor. We found that the extended hormonal stress response demonstrated by prepubertal males occurred at both times of day. However, differences in post-stress behavior were dependent on time of testing. Specifically, although pre- and post-stress behaviors were similarly affected by the stressor in the light phase in prepubertal and adult males, during the dark phase, stress suppressed play behavior in the prepubertal males, and increased their time spent resting together (huddling), while these behaviors were unaffected by stress in the adults. These data indicate that pubertal development and time of day interact to modulate post-stress behavior and demonstrate a dissociation between post-stress hormonal and behavioral responses.     

Prenatal SSRI alters the hormonal and behavioral responses to stress in female mice: Possible role for glucocorticoid resistance

Life time prevalence of major depression disorder (MDD) is higher in women compared to men especially during the period surrounding childbirth. Women suffering from MDD during pregnancy use antidepressant medications, particularly Selective Serotonin Reuptake Inhibitors (SSRI). These drugs readily cross the placental barrier and impact the developing fetal brain. The present study assessed the effects of prenatal exposure to fluoxetine (FLX), an SSRI antidepressant drug, on corticosterone and behavioral responses to stress in female mice. In young females, prenatal FLX significantly elevated corticosterone response to continuous stress. In adults, prenatal FLX augmented corticosterone response to acute stress and suppressed the response to continuous stress. Additionally, prenatal FLX significantly augmented stress-induced increase in locomotion and reduced anxiety- and depressive-like behaviors in adult, but not young mice. The dexamethasone suppression test revealed that prenatal FLX induced a state of glucocorticoid resistance in adult females, indicating that the negative feedback control of the hypothalamic-pituitary-adrenal axis response to stress was disrupted. These findings provide the first indication of altered hormonal and behavioral responses to continuous stress and suggest a role for the development of glucocorticoid resistance in these effects. According to these findings, prenatal environment may have implications for stress sensitivity and responsiveness to life challenges. Furthermore, this study may assist in understanding the limitations and precautions that should be taken in the use of SSRIs during pregnancy.     

Hormone responses to clomiphene citrate in young chimpanzees

The responses of gonadotropin and gonadal steroids to the administration of clomiphene citrate were studied in male and female chimpanzees, aged 3.6 to 9.9 years. Follicle-stimulating hormone (FSH) was significantly reduced after treatment in the prepubertal females (n = 4) and in early pubertal males (n = 2) but not in prepubertal males (n = 5). FSH was unchanged or increased in early pubertal females (n = 2) and late pubertal males (n = 2). There was no consistent response to treatment with clomiphene citrate by luteinizing hormone (LH) in either males or females, nor by 17 beta-estradiol in the females. Testosterone levels were reduced in the early pubertal males only. These results support the hypothesis that negative feedback by gonadal steroids is operative in prepubertal chimpanzees and that puberty is accompanied by a reduction in the sensitivity to such feedback.     

Neuroactive steroids in the brain and age and sex specificity of behavior and anxiety: An experimental study

Changes in the brain’s neuroactive steroid levels, behavior in the open field, and the anxious-phobic status of male and female rats in the course of development have been studied. An increase in the motor and exploratory activity and emotionality in rats of both sexes in the pubertal period and a decrease in their values in mature and old animals have been detected. Anxiety has no sexual dimorphism in adult animals; it is significantly higher in males than in females in the prepubertal and pubertal periods of development and is higher in old females than in males of the same age. An increase in the level of corticosterone in some brain structures in maturing and old rats has been found; the testosterone concentration increases in one-month-old and adult animals but decreases in old individuals, while the estradiol concentration in all studied brain structures of male and female rats was low in all periods of postnatal life. Correlation analysis has shown modulation by steroid hormones of the changes in behavioral responses during development.