Association of peripartum synthetic oxytocin administration and depressive and anxiety disorders within the first postpartum year.

BACKGROUND: Due to its potent effects on social behavior, including maternal behavior, oxytocin has been identified as a potential mediator of postpartum depression and anxiety. The objective of this study was to examine the relationship between peripartum synthetic oxytocin administration and the development of depressive and anxiety disorders within the first year postpartum. We hypothesized that women exposed to peripartum synthetic oxytocin would have a reduced risk of postpartum depressive and anxiety disorders compared with those without any exposure. METHODS: Population-based data available through the Massachusetts Integrated Clinical Academic Research Database (MiCARD) were used to retrospectively (2005-2014) examine this relationship and calculate the relative risk of peripartum synthetic oxytocin for the development of postpartum depressive and anxiety disorders in exposed (n = 9,684) compared to unexposed (n = 37,048) deliveries. RESULTS: Among deliveries to women with a history of prepregnancy depressive or anxiety disorder, exposure to peripartum oxytocin increased the risk of postpartum depressive or anxiety disorder by 36% (relative risk (RR): 1.36; 95% confidence interval (95% CI): 1.20-1.55). In deliveries to women with no history of prepregnancy depressive or anxiety disorder, exposure to peripartum oxytocin increased the risk of postpartum depressive or anxiety disorder by 32% compared to those not exposed (RR: 1.32; 95% CI: 1.23-1.42). CONCLUSIONS: Contrary to our hypothesis, results indicate that women with peripartum exposure to synthetic oxytocin had a higher relative risk of receiving a documented depressive or anxiety disorder diagnosis or antidepressant/anxiolytic prescription within the first year postpartum than women without synthetic oxytocin exposure.

Chronic social instability in adult female rats alters social behavior, maternal aggression and offspring development.

We investigated the consequences of chronic social instability (CSI) during adulthood on social and maternal behavior in females and social behavior of their offspring in a rat model. CSI consisted of changing the social partners of adult females every 2-3 days for 28 days, 2 weeks prior to mating. Females exposed to CSI behaved less aggressively and more pro-socially towards unfamiliar female intruders. Maternal care was not affected by CSI in a standard testing environment, but maternal behavior of CSI females was less disrupted by a male intruder. CSI females were quicker to attack prey and did not differ from control females in their saccharin consumption indicating, respectively, no stress-induced sensory-motor or reward system impairments. Offspring of CSI females exhibited slower growth and expressed more anxiety in social encounters. This study demonstrates continued adult vulnerability to social challenges with an impact specific to social situations for mothers and offspring.

Social stress during lactation, depressed maternal care, and neuropeptidergic gene expression.

Depression and anxiety can be severely detrimental to the health of both the affected woman and her offspring. In a rodent model of postpartum depression and anxiety, chronic social stress exposure during lactation induces deficits in maternal care and increases anxiety. Here, we extend previous findings by expanding the behavioral analyses, assessing lactation, and examining several neural systems within amygdalar and hypothalamic regions involved in the control of the stress response and expression of maternal care that may be mediating the behavioral changes in stressed dams. Compared with control dams, those exposed to chronic social stress beginning on day 2 of lactation show impaired maternal care and lactation and increased maternal anxiety on day 9 of lactation. Saccharin-based anhedonia and maternal aggression were increased and lactation was also impaired on day 16 of lactation. These behavioral changes were correlated with a decrease in oxytocin mRNA expression in the medial amygdala, and increases in the expressions of corticotrophin-releasing hormone mRNA in the central nucleus of the amygdala, glucocorticoid receptor mRNA in the paraventricular nucleus, and orexin 2 receptor mRNA in the supraoptic nucleus of stressed compared with control dams. The increase in glucocorticoid receptor mRNA in the paraventricular nucleus was negatively correlated with methylation of a CpG site in the promoter region. In conclusion, the data support the hypothesis that social stress during lactation can have profound effects on maternal care, lactation, and anxiety, and that these behavioral effects are mediated by central changes in stress and maternally relevant neuropeptide systems.

Habituation of hypothalamic-pituitary-adrenocortical axis hormones to repeated homotypic stress and subsequent heterotypic stressor exposure in male and female rats.

Understanding potential sex differences in repeated stress-induced hypothalamic-pituitary-adrenocortical (HPA) axis habituation could provide insight into the sex-biased prevalence of certain affective disorders such as anxiety and depression. Therefore in these studies, male and female rats were exposed to 30 min of either audiogenic or restraint stress daily for 10 days in order to determine whether sex regulates the extent to which HPA axis hormone release is attenuated upon repeated homotypic stressor presentation. In response to the initial exposure, both stressors robustly increased plasma concentrations of both adrenocorticotropic hormone (ACTH) and corticosterone (CORT) in both sexes. Acutely, females displayed higher ACTH and CORT concentrations following restraint stress, whereas males exhibited higher hormone concentrations following loud noise stress. HPA axis hormone responses to both stressors decreased incrementally over successive days of exposure to each respective stressor. Despite the differential effect of sex on acute hormone responses, the extent to which HPA axis hormone response was attenuated did not differ between male and female animals following either stressor. Furthermore, ACTH and CORT responses to a novel environment were not affected by prior exposure to stress of either modality in either male or female rats. These experiments demonstrate that despite the acute stress response, male and female rats exhibit similar habituation of HPA axis hormones upon repeated homotypic stressor presentations, and that exposure to repeated stress does not produce exaggerated HPA axis hormone responses to a novel environment in either female or male rats.

Transgenerational effects of social stress on social behavior, corticosterone, oxytocin, and prolactin in rats.

Social stressors such as depressed maternal care and family conflict are robust challenges which can have long-term physiological and behavioral effects on offspring and future generations. The current study investigates the transgenerational effects of an ethologically relevant chronic social stress on the behavior and endocrinology of juvenile and adult rats. Exposure to chronic social stress during lactation impairs maternal care in F0 lactating dams and the maternal care of the F1 offspring of those stressed F0 dams. The overall hypothesis was that the male and female F2 offspring of stressed F1 dams would display decreased social behavior as both juveniles and adults and that these behavioral effects would be accompanied by changes in plasma corticosterone, prolactin, and oxytocin. Both the female and male F2 offspring of dams exposed to chronic social stress displayed decreased social behavior as juveniles and adults, and these behavioral effects were accompanied by decreases in basal concentrations of corticosterone in both sexes, as well as elevated juvenile oxytocin and decreased adult prolactin in the female offspring. The data support the conclusion that social stress has transgenerational effects on the social behavior of the female and male offspring which are mediated by changes in the hypothalamic-pituitary-adrenal axis and hypothalamic-pituitary-gonadal axis. Social stress models are valuable resources in the study of the transgenerational effects of stress on the behavioral endocrinology of disorders such as depression, anxiety, autism, and other disorders involving disrupted social behavior.

Stressor-specific effects of sex on HPA axis hormones and activation of stress-related neurocircuitry.

Experiencing stress can be physically and psychologically debilitating to an organism. Women have a higher prevalence of some stress-related mental illnesses, the reasons for which are unknown. These experiments explore differential HPA axis hormone release in male and female rats following acute stress. Female rats had a similar threshold of HPA axis hormone release following low intensity noise stress as male rats. Sex did not affect the acute release, or the return of HPA axis hormones to baseline following moderate intensity noise stress. Sensitive indices of auditory functioning obtained by modulation of the acoustic startle reflex by weak pre-pulses did not reveal any sexual dimorphism. Furthermore, male and female rats exhibited similar c-fos mRNA expression in the brain following noise stress, including several sex-influenced stress-related regions. The HPA axis response to noise stress was not affected by stage of estrous cycle, and ovariectomy significantly increased hormone release. Direct comparison of HPA axis hormone release to two different stressors in the same animals revealed that although female rats exhibit robustly higher HPA axis hormone release after restraint stress, the same effect was not observed following moderate and high intensity loud noise stress. Finally, the differential effect of sex on HPA axis responses to noise and restraint stress cannot readily be explained by differential social cues or general pain processing. These studies suggest the effect of sex on acute stress-induced HPA axis hormone activity is highly dependent on the type of stressor.

Estrous cycle dependent expression of oxycodone conditioned reward in rats.

Oxycodone is one of the most widely prescribed and misused opioid painkillers in the United States. Evidence suggests that biological sex and hormonal status can impact drug reward in humans and rodents, but the extent to which these factors can influence the rewarding effects of oxycodone is unclear. The purpose of this study was to utilize place conditioning to determine the effects of sex and female hormonal status on the expression of oxycodone conditioned reward in rats. Gonadally intact adult Sprague-Dawley male and female rats were used to test: (1) whether both sexes express conditioned reward to oxycodone at similar doses, (2) the impact of conditioning session length on oxycodone conditioned reward expression in both sexes, and (3) the influence of female estrous cycle stage on oxycodone conditioned reward expression. Both sexes expressed conditioned reward at the same doses of oxycodone. Increasing the length of conditioning sessions did not reveal an effect of sex and resulted in lower magnitude conditioned reward expression. Importantly however, female stage of estrous cycle significantly influenced oxycodone conditioned reward expression. These results suggest that female hormonal status can impact the rewarding effects of opioids and thus have important implications for prescription opioid treatment practices.

Disturbances in fear extinction learning after mild traumatic brain injury in mice are accompanied by alterations in dendritic plasticity in the medial prefrontal cortex and basolateral nucleus of the amygdala.

Mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) have emerged as the signature injuries of the U.S. veterans who served in Iraq and Afghanistan, and frequently co-occur in both military and civilian populations. To better understand how fear learning and underlying neural systems might be altered after mTBI, we examined the acquisition of cued fear conditioning and its extinction along with brain morphology and dendritic plasticity in a mouse model of mTBI. To induce mTBI in adult male C57BL/6J mice, a lateral fluid percussive injury (LFP 1.7) was produced using a fluid pulse of 1.7 atmosphere force to the right parietal lobe. Behavior in LFP 1.7 mice was compared to behavior in mice from two separate control groups: mice subjected to craniotomy without LFP injury (Sham) and mice that did not undergo surgery (Unoperated). Following behavioral testing, neural endpoints (dendritic structural plasticity and neuronal volume) were assessed in the basolateral nucleus of the amygdala (BLA), which plays a critical sensory role in fear learning, and medial prefrontal cortex (mPFC), responsible for executive functions and inhibition of fear behaviors. No gross motor abnormalities or increased anxiety-like behaviors were observed in LFP or Sham mice after surgery compared to Unoperated mice. We found that all mice acquired fear behavior, assessed as conditioned freezing to auditory cue in a single session of 6 trials, and acquisition was similar across treatment groups. Using a linear mixed effects analysis, we showed that fear behavior decreased overall over 6 days of extinction training with no effect of treatment group across extinction days. However, a significant interaction was demonstrated between the treatment groups during within-session freezing behavior (5 trials per day) during extinction training. Specifically, freezing behavior increased across within-session extinction trials in LFP 1.7 mice, whereas freezing behavior in control groups did not change on extinction test days, reflecting a dissociation between within-trial and between-trial fear extinction. Additionally, LFP mice demonstrated bilateral increases in dendritic spine density in the BLA and decreases in dendritic complexity in the PFC. The translational implications are that individuals with TBI undergoing fear extinction therapy may demonstrate within-session aberrant learning that could be targeted for more effective treatment interventions.

Ranking the contribution of behavioral measures comprising oxycodone self-administration to reinstatement of drug-seeking in male and female rats.

Introduction: Rates of relapse to drug use during abstinence are among the highest for opioid use disorder (OUD). In preclinical studies, reinstatement to drug-seeking has been extensively studied as a model of relapse-but the work has been primarily in males. We asked whether biological sex contributes to behaviors comprising self-administration of the prescription opioid oxycodone in rats, and we calculated the relative contribution of these behavioral measures to reinstatement in male and female rats. Materials and methods: Rats were trained to self-administer oxycodone (8 days, training phase), after which we examined oxycodone self-administration behaviors for an additional 14 days under three conditions in male and female rats: short access (ShA, 1 h/d), long access (LgA, 6 h/d), and saline self-administration. All rats were then tested for cue-induced reinstatement of drug-seeking after a 14-d forced abstinence period. We quantified the # of infusions, front-loading of drug intake, non-reinforced lever pressing, inter-infusion intervals, escalation of intake, and reinstatement responding on the active lever. Results: Both male and female rats in LgA and ShA conditions escalated oxycodone intake to a similar extent. However, males had higher levels of non-reinforced responding than females under LgA conditions, and females had greater levels of reinstatement responding than males. We then correlated each addiction-related measure listed above with reinstatement responding in males and females and ranked their respective relative contributions. Although the majority of behavioral measures associated with oxycodone self-administration did not show sex differences on their own, when analyzed together using partial least squares regression, their relative contributions to reinstatement were sex-dependent. Front-loading behavior was calculated to have the highest relative contribution to reinstatement in both sexes, with long and short inter-infusion intervals having the second greatest contribution in females and males, respectively. Discussion: Our results demonstrate sex differences in some oxycodone self-administration measures. More importantly, we demonstrate that a sex- dependent constellation of self-administration behaviors can predict the magnitude of reinstatement, which holds great promise for relapse prevention in people.

Evidence for intact 5-HT1A receptor-mediated feedback inhibition following sustained antidepressant treatment in a rat model of depression.

Serotonin (5-HT) neurons are strongly implicated in mood disorders such as depression and are importantly regulated by feedback inhibition mediated by 5-HT1A receptors. These receptors may play a role, albeit a poorly understood one, in the generation of mood disorders, treatment response to antidepressants and delayed therapeutic efficacy. Here we sought to gain insight into the role of 5-HT1A receptor-mediated feedback inhibition in these processes by studying Fos protein expression within serotonin neurons in a rat model of stress-related mood disorder, early life maternal separation (MS), combined with two-week treatment with the antidepressant fluoxetine (FLX) in adulthood. We gauged 5-HT1A receptor-mediated feedback inhibition by the ability of the antagonist, WAY-100635 (WAY), to disinhibit Fos expression in 5-HT neurons. We found that two-week FLX treatment dramatically inhibited Fos expression in serotonin neurons and that this effect was reversed by blocking 5-HT1A receptors with WAY. Together these observations reveal that after prolonged exposure to SSRIs, endogenous 5-HT1A receptors continue to exert feedback inhibition of serotonin neurons. Furthermore we found unique effects of pharmacological treatments after MS in that the WAY effect was greatest in MS rats treated with FLX, a phenomenon selective to the rostral 2/3 of the dorsal raphe nucleus (B7). These results indicate that the balance between activation and feedback inhibition of serotonin neurons in B7 is altered and uniquely sensitive to FLX after early-life stress.

Sensorimotor gating and dopamine function in postpartum rats.

There is much speculation regarding the effects of estrogen withdrawal at the end of pregnancy on forebrain dopamine, however, few studies have directly examine changes in this system postpartum. The present work sought to determine what changes in forebrain dopamine function occur in the postpartum rat. Specifically, prepulse inhibition of the acoustic startle response (PPI) was measured in primiparous female rats on postpartum day 2 (PPD2) or 14 (PPD14) following treatment with saline or the dopamine D2 agonist, quinpirole. Diestrus (DI) females served as controls. Dopamine content and turnover as well as cyclic AMP (cAMP) accumulation were determined within the nucleus accumbens and dorsal striatum in these same females. In addition, circulating levels of plasma corticosterone, estradiol and progesterone were measured. PPI was significantly disrupted in both postpartum groups. This effect was associated with decreased cAMP content within the nucleus accumbens. Quinpirole treatment (0.1 and 0.5 mg/kg) dose-dependently disrupted PPI in DI controls while PPD2 and PPD14 animals demonstrated reduced sensitivity to the D2 agonist. PPD14 animals demonstrated increased startle amplitude, an effect that was attenuated by quinpirole treatment. PPD14 females were also less sensitive to quinpirole-mediated reductions in DA turnover within the nucleus accumbens and both PPD2 and PPD14 females had an attenuated response to the stimulatory effects of quinpirole on corticosterone secretion. Collectively these findings suggest that the postpartum period is associated with reduced sensorimotor gating and altered forebrain DA systems, which may be related to shifts in circulating hormones.

The Rodent Forced Swim Test Measures Stress-Coping Strategy, Not Depression-like Behavior.

The forced swim test (FST) measures coping strategy to an acute inescapable stress and thus provides unique insight into the neural limb of the stress response. Stress, particularly chronic stress, is a contributing factor to depression in humans and depression is associated with altered response to stress. In addition, drugs that are effective antidepressants in humans typically promote active coping strategy in the FST. As a consequence, passive coping in the FST has become loosely equated with depression and is often referred to as "depression-like" behavior. This terminology oversimplifies complex biology and misrepresents both the utility and limitations of the FST. The FST provides little construct- or face-validity to support an interpretation as "depression-like" behavior. While stress coping and the FST are arguably relevant to depression, there are likely many factors that can influence stress coping strategy. Importantly, there are other neuropsychiatric disorders characterized by altered responses to stress and difficulty in adapting to change. One of these is autism spectrum disorder (ASD), and several mouse genetic models of ASD exhibit altered stress-coping strategies in the FST. Here we review evidence that argues a more thoughtful consideration of the FST, and more precise terminology, would benefit the study of stress and disorders characterized by altered response to stress, which include but are not limited to depression.

Transgenerational Social Stress, Immune Factors, Hormones, and Social Behavior.

A social signal transduction theory of depression has been proposed that states that exposure to social adversity alters the immune response and these changes mediate symptoms of depression such as anhedonia and impairments in social behavior The exposure of maternal rats to the chronic social stress (CSS) of a male intruder depresses maternal care and impairs social behavior in the F1 and F2 offspring of these dams. The objective of the present study was to characterize basal peripheral levels of several immune factors and related hormone levels in the adult F2 offspring of CSS exposed dams and assess whether changes in these factors are associated with previously reported deficits in allogrooming behavior. CSS decreased acid glycoprotein (α1AGP) and intercellular adhesion molecule-1 (ICAM-1) in F2 females, and increased granulocyte macrophage-colony stimulating factor (GM-CSF) in F2 males. There were also sex dependent changes in IL-18, tissue inhibitors of metalloproteinases 1 (TIMP-1), and vascular endothelial growth factor (VEGF). Progesterone was decreased and alpha melanocyte stimulating hormone (α-MSH) was increased in F2 males, and brain-derived neurotrophic factor (BDNF) was decreased in F2 females. Changes in α1AGP, GM-CSF, progesterone, and α-MSH were correlated with decreased allogrooming in the F2 offspring of stressed dams. These results support the hypothesis that transgenerational social stress affects both the immune system and social behavior, and also support previous studies on the adverse effects of early life stress on immune functioning and stress associated immunological disorders, including the increasing prevalence of asthma. The immune system may represent an important transgenerational etiological factor in disorders which involve social and/or early life stress associated changes in social behavior, such as depression, anxiety, and autism, as well as comorbid immune disorders. Future studies involving immune and/or endocrine assessments and manipulations will address specific questions of function and causation, and may identify novel preventative measures and treatments for the growing number of immune mediated disorders.

Neural steroid hormone receptor gene expression in pregnant rats.

Estrogen and progesterone play important roles during pregnancy in stimulating the onset of maternal behavior at parturition. The status of receptor expression of these hormones during pregnancy in neural regions that regulate maternal behavior is unclear. The objective of the present study is to characterize changes in neural gene expression of the estrogen receptors alpha and beta (ERalpha and ERbeta) and the progesterone receptor (PR) during the latter part of pregnancy. Brains from primigravid Sprague-Dawley rats were collected on days 15 and 21 of pregnancy. Micropunches of the olfactory bulb (OB), medial preoptic area (MPOA), bed nucleus of the stria terminalis (BnST), hypothalamus (HYP), medial amygdala (MeA), and the temporal cortex (TCx) were analyzed by real-time RT-PCR (Taqmantrade mark) for levels of gene expression. No changes in either ERalpha or ERbeta mRNA levels were detected in any brain region between days 15 and 21 of pregnancy: however, the MPOA had higher levels of both ERalpha and ERbeta than other brain regions. Progesterone receptor mRNA levels, in contrast, declined significantly in the MPOA, HYP, and TCx, between days 15 and 21 of pregnancy (P < 0.05). In addition, the levels of PR mRNA were significantly higher in the HYP and TCx compared to both the OB and MeA. These data indicate that there is a downregulation of PR prepartum and suggest that this decrease may play a role in the disinhibition of maternal behavior at parturition.

Peripartum depression and anxiety as an integrative cross domain target for psychiatric preventative measures.

Exposure to high levels of early life stress has been identified as a potent risk factor for neurodevelopmental delays in infants, behavioral problems and autism in children, but also for several psychiatric illnesses in adulthood, such as depression, anxiety, autism, and posttraumatic stress disorder. Despite having robust adverse effects on both mother and infant, the pathophysiology of peripartum depression and anxiety are poorly understood. The objective of this review is to highlight the advantages of using an integrated approach addressing several behavioral domains in both animal and clinical studies of peripartum depression and anxiety. It is postulated that a greater focus on integrated cross domain studies will lead to advances in treatments and preventative measures for several disorders associated with peripartum depression and anxiety.

Disinhibition of maternal behavior following neurotoxic lesions of the hypothalamus in primigravid rats.

Virgin female rats do not respond maternally to foster pups due to an endogenous neural circuit that actively inhibits the display of maternal behavior. Once pregnant, primigravid rats will continue to avoid foster pups until just prior to or at parturition. Anosmia or lesions of the olfactory tract, medial amygdala, and areas of the hypothalamus will stimulate virgin females to display maternal behavior rapidly, but little is known of the effect of these lesions in primigravid rats. The objective of the present study was to determine if neurotoxic lesions of the dorsomedial (DMH) and ventromedial nuclei (VMH) of the hypothalamus will advance the onset of maternal behavior in primigravid rats. Nulliparous Sprague-Dawley female rats were mated and then on day 8 of gestation bilaterally infused with N-methyl-d-aspartic acid (NMDA; 8 microg/0.2 microl/side) or vehicle directed toward either the DMH or VMH. Beginning on day 15 of gestation until parturition, females were tested daily for maternal responsiveness. DMH and VMH lesions significantly advanced the onset of maternal behavior (5-6 days vs. 0-1 day before parturition) in first-time pregnant rats. These results indicate that the DMH and VMH are involved in the regulation of maternal behavior and may be part of an endogenous neural circuit that inhibits maternal behavior during pregnancy.

Auditory cortex lesions do not disrupt habituation of HPA axis responses to repeated noise stress.

Previous research has suggested that sensory areas may play a role in adaptation to repeated stress. The auditory cortex was the target of the present studies because it is a major projection area of the auditory thalamus, where functional inactivation disrupts stress habituation to repeated loud noise. Large bilateral excitotoxic lesions of the auditory cortex were made in male rats 2 weeks prior to (Experiment 1) or a few days after (Experiment 2) a 5 day 30 min repeated 95 dBA noise or no noise regimen. Blood was collected immediately after exposure on days 1, 3, and 5. Two weeks after the 5th exposure, the rats were retested with 30 min noise or no noise to determine retention of the habituated responses. Animals were killed immediately after the retest and trunk blood and brains collected for lesion verification. Plasma adrenocorticotropic hormone (ACTH) and corticosterone levels were determined. In both experiments, significant between-subjects effects were found for noise (95 dBA or no noise) but not for surgery (lesion, sham, or no surgery control rats), with lesion groups exhibiting similar levels of ACTH and corticosterone across days as the sham and no surgery control groups. All noise exposed groups displayed similar habituation rates and retention levels. A third experiment indicated that similar auditory cortex lesions significantly disrupted background noise gap detection in an acoustic startle paradigm. Overall, these data suggest that the information mediating hypothalamic-pituitary-adrenal axis response habituation to repeated loud noise exposures is not derived from the auditory cortex.

Sex and estradiol influence glial pro-inflammatory responses to lipopolysaccharide in rats.

There is a greater prevalence of neuroinflammatory diseases in females than males. Microglia, the major immunocompetent cells of the central nervous system, play a key role in neuroinflammation. We aimed to determine if inherent differences in toll-like receptor 4 mediated pro-inflammatory response in glia could possibly contribute to the skewed female prevalence of neuroinflammatory disorders. In addition, in order to identify if estradiol (E2), the major female sex steroid contributes to a heightened pro-inflammatory response, estradiol was added both in vivo and in vitro. Microglia and astrocytes were isolated from neonatal pups and stimulated with lipopolysaccharide (LPS) in the presence and absence of E2. Hippocampal microglia were isolated from adult male and female rats and stimulated ex vivo with LPS. Male neonatal microglia and astrocytes produced greater IL-1ß mRNA than females. However, when co-incubated with varying doses of estradiol (E2), the E2 produced anti-inflammatory effects in the male microglia but a pro-inflammatory effect in female microglia. LPS-induced IL-1ß mRNA was attenuated by E2 in female but not male adult hippocampal microglia. However, females supplemented with E2 in vivo produced a potentiated IL-1ß mRNA response. TLR4 mRNA was decreased by LPS in both microglia and astrocytes but was not affected by sex or E2. CD14 mRNA was increased by LPS and may be elevated more in females than males in microglia but not astrocytes. Therefore, sexual dimorphic differences do occur in both neonatal and adult microglia though maturity of the microglia at the time of isolation influences the pro-inflammatory response.

Adolescent opioid exposure in female rats: transgenerational effects on morphine analgesia and anxiety-like behavior in adult offspring.

The use of narcotics by adolescent females is a growing problem, yet very little is known about the long-term consequences for either the user or her future offspring. In the current study, we utilized an animal model to examine the transgenerational consequences of opiate exposure occurring during this sensitive period. Female rats were exposed to increasing doses of morphine or its saline vehicle twice daily during adolescent development (postnatal days 30-40), after which they remained drug free. At 60 days of age, all females were mated and their adult offspring were tested for anxiety-like behavior and sensitivity to morphine. Specifically, offspring of adolescent morphine (MOR-F1)- or saline (SAL-F1)-exposed mothers were tested for acute locomotor responses in an open field, followed by testing of acute or chronic morphine analgesia on the hot plate. Open field testing indicated alterations in anxiety-like behavior in MOR-F1 female offspring, with effects dependent upon the stage of the estrus cycle. Hot plate testing revealed sex differences in baseline pain threshold and morphine sensitivity in all offspring, regardless of maternal exposure. However, when compared to their SAL-F1 counterparts, MOR-F1 male offspring demonstrated significantly increased sensitivity to the analgesic effects of acute morphine, and developed analgesic tolerance more rapidly following chronic morphine treatment. The findings indicate that prior opiate exposure during early adolescence in females produces sex-specific alterations of both emotionality and morphine sensitivity in their progeny.

Stress rapidly increases alpha 1d adrenergic receptor mRNA in the rat dentate gyrus.

The hippocampal formation is a highly plastic brain region that is sensitive to stress. It receives extensive noradrenergic projections, and noradrenaline is released in the hippocampus in response to stressor exposure. The hippocampus expresses particularly high levels of the alpha(1D) adrenergic receptor (ADR) and we have previously demonstrated that alpha(1d) ADR mRNA expression in the rat hippocampus is modulated by corticosterone. One of the defining features of a stress response is activation of the hypothalamic pituitary adrenal (HPA) axis, resulting in the release of corticosterone from the adrenal glands. However, the effect of stress on hippocampal expression of alpha(1d) ADR mRNA has not been determined. In this study, male rats were exposed to inescapable tail shock, loud noise or restraint, and the effect on alpha(1d) ADR mRNA expression in the hippocampus was determined by semi-quantitative in situ hybridization. All three stressors resulted in a rapid upregulation of alpha(1d) ADR mRNA in the dentate gyrus, with expression peaking at approximately 90min after the start of the stressor. Physical activity has previously been reported to counteract some of the effects of stress that occur within the dentate gyrus. However, 6weeks of voluntary wheel running in rats did not prevent the restraint stress-induced increase in alpha(1d) ADR mRNA expression in the dentate gyrus. Although the function of the alpha(1D) ADR in the dentate gyrus is not known, these data provide further evidence for a close interaction between stress and the noradrenergic system in the hippocampus.