Neonatal pain modulates in adolescent rats the antinociceptive effects of fluoxetine and buspirone administrated to their depressive dams during gestation.

Previously, we have shown that the administration of a selective serotonin reuptake inhibitor fluoxetine or a 5-HT1A receptor agonist buspirone to stressed rats during gestation causes in the offspring alleviation of formalin-induced pain, strengthened by prenatal stress. We have also found that neonatal inflammatory pain strengthens formalin-induced pain in prenatally unstressed rats in later life. In the present study, we investigated the effect of neonatal inflammatory pain on the time-course of the biphasic pain response in the formalin test in prenatally stressed adolescent rats of both sexes to evaluate whether neonatal pain affects the antinociceptive properties of these drugs administered to their depressed mothers during gestation. Our findings demonstrate that neonatal pain modulates in prenatally stressed rats the antinociceptive effect of fluoxetine and buspirone depending on the level of organization of pain response in the central nervous system, the phase of the time-course of the formalin-induced pain, and sex of the rat.

Effects of neonatal pain, stress and their interrelation on pain sensitivity in later life in male rats.

Neonatal pain and stress induce long-term changes in pain sensitivity. Therefore their interrelation is a topical subject of clinical and basic research. The present study investigated the effects of inflammatory peripheral pain and stress of maternal deprivation (MD)-isolation in 1-2- and 7-8-day-old Wistar rats (P1,2 and P7,8 respectively, ages comparable to preterm and full-term human babies) on basal pain and pain sensitivity in conditions of inflammatory pain (formalin test) during adolescence. The neonatal impacts were: pain (formalin injection, FOR in the paw), stress (a short 60-min MD), or pain+stress combination (FOR+MD), and appropriate controls. We found that stress of short-term maternal deprivation-isolation and inflammatory pain on P1,2 and P7,8 significantly increased the vulnerability of the nociceptive system to inflammatory pain. Maternal deprivation-isolation on P1,2 as compared with a similar impact on P7,8 had a greater effect on pain sensitivity of the adolescent rats, but the influence of early pain was independent of the injury age. Only adolescent rats with an early combination of pain and maternal deprivation-isolation showed hypoalgesia in the hot plate (HP) test. However licking duration (reflecting pain sensitivity) in these rats did not exceed licking duration in animals exposed only to maternal deprivation-isolation or pain. This study adds new data to the growing body of work demonstrating that early noxious impacts have long-term consequences for the functional activity of the nociceptive system. Our new findings may help to understand the impact of pain and maternal separation in the neonatal intensive care unit.

Inflammatory pain and corticosterone response in infant rats: effect of 5-HT1A agonist buspirone prior to gestational stress.

Our researches have shown that gestational stress causes exacerbation of inflammatory pain in the offspring; the maternal 5-HT1A agonist buspirone before the stress prevents the adverse effect. The serotonergic system and hypothalamo-pituitary-adrenal (HPA) axis are closely interrelated. However, interrelations between inflammatory pain and the HPA axis during the hyporeactive period of the latter have not been studied. The present research demonstrates that formalin-induced pain causes a gradual and prolonged increase in plasma corticosterone level in 7-day-old male rats; twenty-four hours after injection of formalin, the basal corticosterone level still exceeds the initial basal corticosterone value. Chronic treatments of rat dams with buspirone before restraint stress during gestation normalize in the offspring pain-like behavior and induce during the acute phase in the formalin test the stronger corticosterone increase as compared to the stress hormonal elevation in animals with other prenatal treatments. Negative correlation between plasma corticosterone level and the number of flexes+shakes is revealed in buspirone+stress rats. The new data enhance the idea about relativity of the HPA axis hyporeactive period and suggest that maternal buspirone prior to stress during gestation may enhance an adaptive mechanism of the inflammatory nociceptive system in the infant male offspring through activation of the HPA axis peripheral link.

The Long-Term Effects of Neonatal Inflammatory Pain on Cognitive Function and Stress Hormones Depend on the Heterogeneity of the Adolescent Period of Development in Male and Female Rats.

Exposure to stress at an early age programs the HPA axis which can lead to cognitive deficits in adults. However, it is not known whether these deficits emerge in adulthood or are expressed earlier in life. The aims of the study were to investigate (1) the immediate effects of early injury-induced stress in one-day-old (P1) and repeated stress on at P1 and P2 rat pups on plasma corticosterone levels; and (2) examine the subsequent long-term effects of this early stress on spatial learning and memory, and stress reactivity in early P26-34 and late P45-53 adolescent male and female rats. Intra-plantar injection of formalin induced prolonged and elevated levels of corticosterone in pups and impaired spatial learning and short- and long-term memory in late adolescent males and long-term memory in early adolescent females. There were sex differences in late adolescence in both learning and short-term memory. Performance on the long-term memory task was better than that on the short-term memory task for all early adolescent male and female control and stressed animals. Short-term memory was better in the late age control rats of both sexes and for formalin treated females as compared with the early age rats. These results are consistent with an impaired function of structures involved in memory (the hippocampus, amygdala, prefrontal cortex) after newborn pain. However, activation of the HPA axis by neonatal pain did not directly correlate with spatial learning and memory outcomes and the consequences of neonatal pain remain are likely multi-determined.

Success of Hand Movement Imagination Depends on Personality Traits, Brain Asymmetry, and Degree of Handedness.

Brain-computer interfaces (BCIs), based on motor imagery, are increasingly used in neurorehabilitation. However, some people cannot control BCI, predictors of this are the features of brain activity and personality traits. It is not known whether the success of BCI control is related to interhemispheric asymmetry. The study was conducted on 44 BCI-naive subjects and included one BCI session, EEG-analysis, 16PF Cattell Questionnaire, estimation of latent left-handedness, and of subjective complexity of real and imagery movements. The success of brain states recognition during imagination of left hand (LH) movement compared to the rest is higher in reserved, practical, skeptical, and not very sociable individuals. Extraversion, liveliness, and dominance are significant for the imagination of right hand (RH) movements in "pure" right-handers, and sensitivity in latent left-handers. Subjective complexity of real LH and of imagery RH movements correlates with the success of brain states recognition in the imagination of movement of LH compared to RH and depends on the level of handedness. Thus, the level of handedness is the factor influencing the success of BCI control. The data are supposed to be connected with hemispheric differences in motor control, lateralization of dopamine, and may be important for rehabilitation of patients after a stroke.

Early lexical development of children raised in institutional care in Russia.

Children abandoned to institutions display a host of developmental delays, including those involving general cognition and language. The majority of published studies focus on children over 3 years of age; little is known about whether these delays may be detected earlier when children undergo rapid lexical development. To investigate the early language development of children raised in institutional settings in the Russian Federation, we compared a group of children in institutional care (n = 36; 8-35 months) to their age-matched peers raised in biological families, who have never been institutionalized (n = 72) using the Russian version of the CDI. The results suggest that institutionalization is associated with pronounced delays in children's early language development with large and robust effect sizes. Among children with a history of institutionalization, these delays are also associated with difficulties in Daily Living skills, communication, and socialization.

Family and Child Characteristics Associated with Foster Care Breakdown.

Studies examining the experience of children returned from foster care can reveal its causes and the severity of the psychological consequences, as well as the positive effect of psychological support on family functioning. Our research was aimed at the features of children and characteristics of foster families who refuse to continue parenting foster children. The study participants were comprised of families raising a foster child (Group One-182 families), and families who refused to continue parenting and returned the child (Group Two-19 families). The study was conducted using the "standardized interview for parents" and the "list of traumatic experiences of the child." The results show that the strongest contributor to foster family breakdown was the degree of the child's traumatic experience before placement (for Group One, 3.9 (1.15); Group Two, 6.1 (1.31), U = 395.0, p < 0.001) and the minimal participation of the family in an intervention program (the total number of program activities the family did not participate in; for Group One, 48.5 (28.27)%, Group Two, 95.5 (2.58)%, U = 67.5, p < 0.001). Our data expand ideas about the functioning of foster families who have taken children with significant traumatic experience and indicate the need to improve the quality of psychological and social support to foster families as an important factor in preventing secondary returns.

Differences Between the Prenatal Effects of Fluoxetine or Buspirone Alone or in Combination on Pain and Affective Behaviors in Prenatally Stressed Male and Female Rats.

The selective serotonin reuptake inhibitor fluoxetine and the 5-HT1A receptor agonist buspirone are used to treat depression and anxiety. Previously we demonstrated that chronic stress during pregnancy (prenatal stress) in rats, used as a model of maternal depression risk, increased inflammatory pain and depressive-like behavior in the offspring; buspirone injected to pregnant dams was protective. Clinically, the addition of buspirone to fluoxetine increases the latter's efficacy in treating depression in patients. Here, we investigated the influence of repeated prenatal injections of fluoxetine, buspirone or their combination on pain- and depressive-like behaviors in prenatally stressed young male and female rats. Prenatal stress augmented depressive-like behavior and both thermal and inflammatory pain (formalin test), replicating our prior findings, and increased basal levels of corticosterone in the blood plasma. Both drugs and their combination reduced the effects of prenatal stress on thermal pain and depressive-like behavior independently of sex. The combination of fluoxetine and buspirone, compared with fluoxetine, was more antinociceptive in the hot plate test in both sexes, and when compared with buspirone, was more antinociceptive only in males. A detailed study of the time-course of formalin-induced pain showed a nuanced effect of these drugs that was sex-dependent. The combination of the two drugs was less effective in females than males during the initial acute phase of nociceptive behavior in flexing + shaking behaviors, whereas that combination was more effective than fluoxetine alone in the first acute phase of licking behavior in females. The antinociceptive effect of buspirone dominated that of the drug combination and of fluoxetine alone, especially during the interphase of the formalin test in both sexes for both flexing + shaking and licking, suggesting a more effective prenatal action of buspirone on the development of a descending serotonergic inhibitory system modulating pain in the spinal cord dorsal horn neurons. Our results indicate that inflammatory pain-like responses integrated at the spinal level in males were more vulnerable to prenatal stress than females. In licking, the antinociceptive effect of fluoxetine and drug combination in the interphase was more in males than females. The data underscore the importance of considering sexual dimorphism when using drug therapy.

Maternal para-chlorophenylalanine exposure modifies central monoamines and behaviors in the adult offspring.

We reported a perspective animal model of neurodevelopmental disorders using rats prenatally exposed to an inhibitor of serotonin (5HT) synthesis, para-chlorophenylalanine (PCPA). Earlier, we demonstrated that prenatal exposure to PCPA caused fetal 5HT depletion and changes both in open field activity and in depression-related behavior, as well as impairments in spatial learning in the adult offspring (Vataeva et al., 2007). The present study revealed that prenatal PCPA treatment resulted in the offspring's significantly reduced anxiety-related behavior in the elevated plus-maze and reduced neophobia to intake fluids in a novel environment. These effects are accompanied by hedonic changes in the form of an appropriate increase in saccharin preference. We confirmed our earlier finding that prenatal PCPA exposure affected the open field locomotor activity. In the present study we have shown that the selective 5HT reuptake inhibitor (SSRI) paroxetine decreases locomotor activity in the prenatally PCPA-treated offspring. It was also found that in the PCPA-treated fetal brain, 5HT depletion was associated with a significant decrease in the level of dopamine (DA) metabolite dihydroxyphenylacetic acid (DOPAC) and with a reduction of DOPAC/DA and homovanillic acid (HVA)/DA ratios. An assay of adult offspring brain revealed that the prenatal PCPA produced different effects on monoamines in the studied brain structures. The relationships between behavioral abnormalities and alterations in brain monoamine levels consequent on the prenatal PCPA treatment are discussed.

Behavioral alteration in the adult rats prenatally exposed to para-chlorophenylalanine.

In the present work, effects of maternal administration of para-chlorophenylalanine (PCPA), a serotonin synthesis inhibitor, on behavior of adult offspring were studied. Pregnant rats were injected intraperitoneally with PCPA (200/100/100/50 mg/kg) either on the gestational days (GD) 8-11 or 14-17, or with vehicle at the same days. Behavioral parameters, in an open field, the Porsolt forced swim test and the Morris water maze test were evaluated at the age of 3-3.5 months in the male and female offspring. The prenatal PCPA increased activity in an open field in the offspring treated on either GD 8-11 or 14-17. The highest levels of the activity were revealed in the male and female offspring treated on GD 14-17. Besides, the PCPA treatment on GD 8-11 or 14-17 facilitated the intersession habituation of activity to repeated exposures to an open field in the male offspring. Both male and female offspring treated on GD 14-17 showed an increased immobility in the Porsolt forced swim test and a significant learning impairment in the Morris water maze. Thus, it has been shown that administration of PCPA to pregnant rats might cause significant changes in the adult offspring behavior. These results provide further evidence that unfavorable influence may have more adverse effects on the behavioral development of rats when exposed during the final trimester of pregnancy than during the second trimester.

Sex differences in formalin-induced pain in prenatally stressed infant rats.

The aim of this work was to study the effects of prenatal stress on nociceptive responses in the formalin test in female and male infant (7-day-old) Long-Evans hooded rats. Prenatally stressed infant rats displayed biphasic flinching+ shaking behavior whereas non-stressed animals showed only a weak second phase. Pain sensitivity in prenatally stressed males was significantly greater than that of prenatally non-stressed males during the second phase only; there were no differences in pain sensitivity between prenatally stressed and non-stressed females. Moreover prenatally stressed male rats pups demonstrated that the second phase of the response to formalin was enhanced relative to the second phase in stressed females. The current and previous data [Butkevich IP, Barr GA, Mikhailenko VA, Otellin VA. Increased formalin-induced pain and expression of fos neurons in the lumbar spinal cord of prenatally stressed infants rats. Neurosci Lett 2006a;403:222-226] show increased tonic pain in prenatally stressed infant rats and a large increase in the number of formalin-induced fos-like immunoreactivity in the spinal cord dorsal horn. There is a concomitant decrease in serotonin-like immunoreactivity in the lumbar spinal cord dorsal horn [Butkevich IP, Barr GA, Otellin VA. Effect of prenatal stress on behavioral and neural indices of formalin-induced pain in infant rats. Abstracts, 35th Annual Meeting of Soc. For Neurosci. 2005a. Program No. 512.4 Washington, DC: Society for Neuroscience]. Given the decreased level of perinatal testosterone in prenatally stressed rats to which infant males are more sensitive than females, we suggest that these hormonal, behavioral and neuronal indices are strongly interrelated in prenatally stressed 7-day-old rat pups and that the decreased surge of testosterone may contribute to the increased behavioral response in the second phase in male rat pups. Mechanisms underlying the behavioral pain response induced by inflammation in prenatally stressed rat pups are characterized by sexual dimorphism even prior to the activational effects of sex hormones.

Long-Term Effects of Chronic Buspirone during Adolescence Reduce the Adverse Influences of Neonatal Inflammatory Pain and Stress on Adaptive Behavior in Adult Male Rats.

Neonatal pain and stress induce long-term changes in pain sensitivity and behavior. Previously we found alterations in pain sensitivity in adolescent rats exposed to early-life adverse events. We tested whether these alterations have long-lasting effects and if those effects can be improved by the 5-hydroxytryptamine 1A (5-HT1A) receptor agonist buspirone injected chronically during the adolescent period. This study investigates: (1) effects of inflammatory pain (the injection of formalin into the pad of a hind paw) or stress (short maternal deprivation-isolation, MI), or their combination in 1-2-day-old rats on the adult basal pain, formalin-induced pain, anxiety and depression; (2) effects of adolescent buspirone in adult rats that experienced similar early-life insults. Changes in nociceptive thresholds were evaluated using the hot plate (HP) and formalin tests; levels of anxiety and depression were assessed with the elevated plus maze and forced swim tests respectively. Both neonatal painful and stressful treatments induced long-term alterations in the forced swim test. Other changes in adult behavioral responses were dependent on the type of neonatal treatment. There was a notable lack of long-term effects of the combination of early inflammatory pain and stress of MI on the pain responses, anxiety levels or on the effects of adolescent buspirone. This study provides the first evidence that chronic injection of buspirone in adolescent rats alters antinociceptive and anxiolytic effects limited to adult rats that showed behavioral alterations induced by early-life adverse treatments. These data highlight the role of 5-HT1A receptors in long-term effects of neonatal inflammatory pain and stress of short MI on adaptive behavior and possibility of correction of the pain and psychoemotional behavior that were altered by adverse pain/stress intervention using buspirone during critical adolescent period.

Electrostatic Switch Function in the Mechanism of Protein Kinase A Iα Activation: Results of the Molecular Dynamics Simulation.

We used molecular dynamics to find the average path of the A-domain H → B conformational transition in protein kinase A Iα. We obtained thirteen productive trajectories and processed them sequentially using factor and cross-correlation analyses. The conformational transition is presented as partly deterministic sequence of six events. Event B represents H → B transition of the phosphate binding cassette. Main participants of this event form electrostatic switch cAMP(O6)-A202(N-H)-G199(C=O). Through this switch, cAMP transmits information about its binding to hydrophobic switch L203-Y229 and thus triggers conformational transition of A-domain. Events C and D consist in N3A-motif displacement towards phosphate binding cassette and B/C-helix rotation. Event E involves an increase in interaction energy between Y229 and ß-subdomain. Taken together, events B, E, and D correspond to the hinge movement towards ß-barrel. Transition of B/C-helix turn (a.a. 229-234) from α-form to π-form accounts for event F. Event G implies that π-helical turn is replaced by kink. Emerging in the resulting conformation, electrostatic interaction R241-E200 facilitates kink formation. The obtained data on the mechanism of cAMP-dependent activation of PKA Iα may contribute to new approaches to designing pharmaceuticals based on cAMP analogs.

Role of arginine 209 in the conformational transition of the protein kinase A regulatory subunit RIα A-domain.

Using the combination of molecular dynamics (MD) simulations and geometric clustering we analyzed the role of arginine at 209 position in the transition of protein kinase A Iα (PKA Iα) regulatory subunit A-domain from H- to B-conformation and stabilization of the latter. The mechanism underlying the role of the residue at position 209 in the realization of B-conformation includes: (1) possibility to bind the ligand tightly (if transition happens in the presence of cAMP), (2) capability to hold ß2ß3-loop in the correct conformation, (3) tendency of residue at 209 position to stabilize B-conformation in the absence and in presence of the ligand. In terms of the effect produced on transition of A-domain from H- to B-conformation in the presence of cAMP, mutational substitutions for R209 can be arranged in the following order: Glu(Gly)>Lys>Ile. In the absence of cAMP the order is different Lys>Gly>Glu>Ile. Thus, our results allow us to presume that the role of arginine at 209 position can be important though not crucial.

Evidence of active regulation of cerebral venous tone in individuals undergoing embolization of brain arteriovenous malformations.

Cerebral venous drainage is generally believed to be regulated primarily by hydrodynamic forces. To gain further insight into the regulation of this process, we investigated the response of blood flow velocity and cross-sectional area (CSA) of the internal jugular veins (IJVs) to local hemodynamic shifts. All procedures and assessments were performed on patients (n = 30) undergoing embolization of brain arteriovenous malformations (AVMs). The procedure efficiency was verified by the postembolization reduction in time-averaged maximum blood flow velocities, as well as the elevation of pulsatility index and resistance index in the arterial feeders. In cerebral veins, the dominant IJV pressure remained unchanged during the procedure. At the same time, AVM embolization caused a significant reduction in maximal CSA (84 ± 7.6 to 68 ± 7.7 mm(2), P < 0.05) and minimal CSA (68 ± 7.0 to 51 ± 7.0 mm(2), P < 0.01) of the IJV located ipsilateral to the AVM, while the maximal linear blood flow velocity in the IJV remained unchanged (71 ± 4.9 and 85 ± 8.4 cm/s, P = 0.098). Consistent with previously published studies, the data obtained provide further evidence of active regulation of the venous outflow, probably mediated by certain neurogenic and/or endothelium-dependent mechanisms.

Buspirone before prenatal stress protects against adverse effects of stress on emotional and inflammatory pain-related behaviors in infant rats: age and sex differences.

Prenatal stress strengthens tonic pain and provokes depression. The serotoninergic system is involved in these processes. We recently showed that maternal buspirone, a 5-HT1A receptor agonist, protects against the adverse effects of in utero stress on depression and pain in adult rat offspring. Using a similar maternal treatment with buspirone, we focus here on the infant stage, which is important for the correction of prenatal abnormalities. Maternal buspirone before restraint stress during the last week of pregnancy decreased the time of immobility in the forced swim test in the infant offspring. Prenatal stress increased formalin-induced pain in the second part of the time-course of the response to formalin in males of middle infancy but in the first part of the response in males of late infancy. The effect was reversed by maternal buspirone. Pain dominated in males of both middle and late infancy but the time-course of formalin pain in infant females revealed a slower development of the processes. The results show that the time-course of formalin-induced pain in infant rats reacts to prenatal stress in an age-dependent and sexually dimorphic manner. Our finding of opposite influences of prenatal stress and buspirone before prenatal stress on formalin-induced pain during the interphase indicates that functional maturity of the descending serotonergic inhibitory system occurs in late infancy males (11-day-olds), and 5-HT1A receptors participate in this process. The data provide evidence that maternal treatment with buspirone prior to stress during pregnancy alleviates depression-like and tonic pain-related behaviors in the infant offspring.

Heterogeneity of the infant stage of rat development: inflammatory pain response, depression-related behavior, and effects of prenatal stress.

The infant stage of rat development is a very important period for potential correction of adverse consequences produced by negative prenatal events. However the age limit for this correction needs to be investigated. The last prenatal and first two weeks after birth are "critical" for maturation of the nociceptive and emotional systems. Clinical observations suggest a correlation between persistent pain response and emotional behavior. In infant male rats of different ages, we studied indices of the inflammatory pain response (the number of flexes+shakes in the formalin test), depression-related behavior (immobility in the forced swim test) and the relations between them, as well as the effects of prenatal stress on these indices. Furthermore, we assessed the trend of body weight and the relations between body weight and the depression- and pain-related behaviors. We demonstrate heterogeneity of the infant stage: control prenatally non-stressed rat pups showed significantly lower immobility at 7 days of age than at 10 days; prenatal stress caused an increase of immobility and the number of flexes+shakes in 7-8-day-old pups but not in 10-11-day-olds. These findings should be taken into account in the treatment of abnormalities of emotional and inflammatory pain-related behaviors produced by prenatal stressful events. The present data and our previous findings indicate that the deficiency of body weight in prenatally stressed newborns may predict the development of abnormalities in inflammatory pain-related responses during postnatal ontogeny.