N-methyl-d-aspartate receptor dysfunction in the prefrontal cortex of stroke-prone spontaneously hypertensive rat/Ezo as a rat model of attention deficit/hyperactivity disorder.

AIM: We previously reported that stroke-prone spontaneously hypertensive rat/Ezo (SHRSP/Ezo) has high validity as an attention deficit/hyperactivity disorder (AD/HD) animal model, based on its behavioral phenotypes, such as inattention, hyperactivity, and impulsivity. Fronto-cortical dysfunction is implicated in the pathogenesis of AD/HD. In this study, we investigated prefrontal cortex (PFC) function in SHRSP/Ezo rats by electrophysiological methods and radioreceptor assay. METHODS: We recorded excitatory postsynaptic potential in layer V pyramidal neurons in the PFC by intracellular recording method to assess synaptic plasticity in the form of long-term potentiation (LTP). We also performed N-methyl-d-aspartate acid (NMDA) receptor binding assay in the PFC and hippocampus using radiolabeled NMDA receptor antagonist [3 H]MK-801. RESULTS: Theta-burst stimulation induced LTP in the PFC of genetic control, WKY/Ezo, whereas failed to induce LTP in that of SHRSP/Ezo. The Kd value of [3 H]MK-801 binding for NMDA receptors in the PFC of SHRSP/Ezo was higher than in the WKY/Ezo. Neither the Bmax nor Kd of [3 H]MK-801 binding in the SHRSP/Ezo hippocampus was significantly different to WKY/Ezo. CONCLUSION: These results suggest that the AD/HD animal model SHRSP/Ezo has NMDA receptor dysfunction in the PFC.

Enhanced transglutaminase 2 expression in response to stress-related catecholamines in macrophages.

Transglutaminase 2 (TG2) is a multifunctional protein that contributes to inflammatory disease when aberrantly expressed. Although macrophages express TG2, the factor stimulating TG2 expression remains poorly characterized in these cells. In the present study, we examined the effects of the stress-related catecholamines adrenaline and noradrenaline on macrophage expression of TG2 in RAW264.7 murine macrophages and murine bone marrow-derived macrophages. Treatment with adrenaline markedly increased TG2 mRNA expression and increased TG2 protein levels. While the ß2-adrenoceptor-selective antagonist ICI 118,551 completely blocked adrenaline-induced TG2 mRNA expression, the ß2-adrenoceptor specific agonist salmeterol increased TG2 expression. Noradrenaline also increased TG2 mRNA expression at higher doses than the effective doses of adrenaline. The effect of adrenaline on TG2 mRNA expression was mimicked by treatment with the membrane-permeable cAMP analog 8-Br-cAMP. Thus, increased intracellular cAMP following stimulation of ß2-adrenoceptors appeared to be responsible for adrenaline-induced TG2 expression. Because stress events activate the sympathetic nervous system and result in secretion of the catecholamines, adrenoceptor-mediated increase in macrophage TG2 expression might be associated with stress-related inflammatory disorders.

Metaplastic regulation of the median raphe nucleus via serotonin 5-HT1A receptor on hippocampal synaptic plasticity is associated with gender-specific emotional expression in rats.

Gender differences in psychiatric disorders are considered to be associated with the serotonergic (5-HTergic) system; however the underlying mechanisms have not been clearly elucidated. In this study, possible involvement of the median raphe nucleus (MRN)-hippocampus 5-HTergic system in gender-specific emotional regulation was investigated, focusing on synaptic plasticity in rats. A behavioral study using a contextual fear conditioning (CFC) paradigm showed that the females exhibited low anxiety-like behavior. Extracellular 5-HT levels in the hippocampus were increased by CFC only in the males. Long-term potentiation (LTP) in the hippocampal CA1 field was suppressed after CFC in the males, which was mimicked by the synaptic response to MRN electrical stimulation. In the MRN, 5-HT immunoreactive cells significantly increased in the females compared with those in the males. Pretreatment with the 5-HT1A receptor agonists tandospirone (10 mg/kg, i.p.) and 8-OH DPAT (3 mg/kg, i.p.) significantly suppressed LTP induction in the males. Synaptic responses to CFC and 5-HT1A receptor interventions were not observed in the females. These results suggest that the metaplastic 5-HTergic mechanism via 5-HT1A receptors in the MRN-hippocampus pathway is a key component for gender-specific emotional regulation and may be a cause of psychiatric disorders associated with vulnerability or resistance to emotional stress.

Aberrant CaMKII activity in the medial prefrontal cortex is associated with cognitive dysfunction in ADHD model rats.

Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurobehavioral disorder accompanied by cognitive and learning deficits, which is prevalent among boys. Juvenile male stroke-prone spontaneously hypertensive rats (SHRSP) exhibit ADHD-like behaviors including cognitive deficits and represent one animal model of ADHD. Here, we define a mechanism underlying cognitive dysfunction observed in SHRSP. Acute methylphenidate (MPH: 1mg/kg, p.o.) administration to SHRSP significantly improved not only inattention in a Y-maze task but also cognitive dysfunction in a novel object recognition test. Interestingly, Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) activity, which is essential for memory and learning acquisition, was excessively elevated in the medial prefrontal cortex (mPFC) but not in the hippocampal CA1 region of SHRSP compared with Wistar-Kyoto (WKY) rats. We also confirmed that elevated CaMKII autophosphorylation in the mPFC causes increased phosphorylation of the CaMKII substrate α-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid-type glutamate receptor subunit 1 (GluR1) (Ser-831). Ca(2+)-dependent phosphorylation levels of factors such as extracellular signal-regulated kinase (ERK) and protein kinase C (PKC) were unchanged in the SHRSP mPFC. Also, protein levels of the dopamine D2 receptor (D2R) but not the dopamine D1 receptor (D1R) were increased in the SHRSP mPFC. Acute MPH (1mg/kg, p.o.) administration attenuated aberrant CaMKII activity and increased GluR1 phosphorylation observed in SHRSP. Taken together, we propose that cognitive impairment in SHRSP is associated with aberrant CaMKII activity in the mPFC.

Rapid induction of REDD1 gene expression in macrophages in response to stress-related catecholamines.

In the present study, we examined the effect of stress-related catecholamines adrenaline and noradrenaline on macrophage expression of a new host defense factor REDD1 using murine macrophage cell line RAW264.7 and murine peritoneal macrophages. Short-term adrenaline exposure (15-60 min) upregulated REDD1 mRNA expression and its protein synthesis in macrophages. This adrenaline-induced REDD1 expression was completely blocked by ß2-adrenoceptor selective antagonist ICI 118,551, whereas ß2-adrenoceptor specific agonist salmeterol markedly enhanced REDD1 expression. Moreover, noradrenaline increased REDD1 mRNA expression at doses higher than the effective doses of adrenaline. The effect of adrenaline on REDD1 mRNA expression was mimicked by treatment with membrane-permeable cAMP analog 8-Br-cAMP. Thus, increased intracellular cAMP level resulting from ß2-adrenoceptor stimulation appeared to be responsible for adrenaline-induced REDD1 mRNA expression. However, inhibiting protein kinase A (PKA) activity had no significant effect on REDD1 mRNA expression after ß2-adrenoceptor stimulation. In addition, exchange protein activated by cAMP (Epac) agonist 8-CPT-20-O-Me-cAMP had no effect on REDD1 mRNA expression. Thus, ß2-adrenoceptor-mediated increase in cAMP levels seems to induce REDD1 mRNA expression in macrophages through a PKA- and Epac-independent pathway.

Subanalgesic ketamine enhances morphine-induced antinociceptive activity without cortical dysfunction in rats.

PURPOSE: Ketamine, a noncompetitive N-methyl-D-aspartate receptor antagonist, has been used for the treatment of cancer pain as an analgesic adjuvant to opioids. However, ketamine is known to produce psychotomimetic side effects including cognitive impairments under a high-dose situation, presumably as the result of cortical dysfunction. Here, we investigated whether low-dose ketamine was useful as an analgesic adjuvant to morphine for pain control, focusing on frontocortical function. METHODS: To assess the analgesic effects of ketamine with or without morphine, we performed behavioral and histochemical experiments, using the hot plate test and c-Fos expression analysis in rats. The effect on cortical function was also determined by prepulse inhibition (PPI) of the acoustic startle and evoked potentials in the hippocampal CA1-medial prefrontal cortex (mPFC) synapses as measures of synaptic efficacy. RESULTS: Coadministration of ketamine as a subanalgesic dose significantly enhanced intraperitoneal morphine-induced antinociceptive response, which was measured as the increased reaction latency in the hot plate test. In addition, the noxious thermal stimulus-induced c-Fos expression in the ventrolateral periaqueductal gray matter was significantly suppressed by concomitant ketamine and morphine. In contrast, the subanalgesic dose of ketamine did not impair PPI and synaptic efficacy in the mPFC. CONCLUSION: The present results indicate that the morphine-induced analgesic effect is enhanced by a concomitant subanalgesic dose of ketamine without affecting cortical function. Our findings possibly support the clinical notion that low-dose ketamine as an analgesic adjuvant has therapeutic potential to reduce opioid dosage, thereby improving the quality of life in cancer pain patients.

Synaptic modulation via basolateral amygdala on the rat hippocampus-medial prefrontal cortex pathway in fear extinction.

The present study elucidated the functional role of modulatory effects of basolateral amygdala (BLA) on synaptic transmission in the rat hippocampus-medial prefrontal cortex (mPFC) pathway, compared with the hippocampal dentate gyrus (DG). Exposure to conditioned fear stress (CFS) or prior BLA activation enhanced tetanus-induced long-term potentiation (LTP) in DG. A similar synaptic response was found by low frequency stimulation (LFS) prior to tetanus. In mPFC, they did not affect LTP, but prior BLA activation, as well as pretreatment with the N-methyl-d-aspartate (NMDA)-receptor antagonist MK-801 (0.1 mg/kg, i.p.), suppressed LFS-primed LTP. This BLA-mediated synaptic pattern was mimicked by synaptic changes observed in the fear extinction process; prior BLA activation suppressed the synaptic potentiation responsible for extinction retrieval and attenuated decreases in fear-related freezing behavior. These data suggest that LFS-primed LTP in mPFC is related to the neural basis of extinction. Extinction-related synaptic potentiation did not occur in a juvenile stress model that exhibited extinction deficit. In addition, LFS-primed LTP was suppressed in this model, which was reversed by the NMDA-receptor agonist d-cycloserine (15 mg/kg, i.p.). These findings suggest that modulatory effects of BLA on synaptic function in the hippocampus-mPFC pathway play a significant role in fear extinction in rats.

Early life stress affects the serotonergic system underlying emotional regulation.

Traumatic events in early life are implicated in an increased risk of psychiatric diseases, such as depression and anxiety disorders. Serotonin is thought to play a central role in stress-induced psychiatric diseases. Serotonergic systems, including neural organization and receptor function, could dramatically change with each developmental stage. Here, we reviewed the persistent influence of early life stress on emotional regulation, focusing on the serotonergic system in rats. An aversive stimulus, foot shock (FS), during the early postnatal period (2-3 weeks after birth) produced behavioral, neuroanatomical and electrophysiological changes accompanied by serotonergic dysfunction, especially functional impairment of the serotonin (5-hydroxytryptamine; 5-HT)1A receptor in the cortico-limbic area. These findings suggest that normalization of the cortico-limbic serotonergic function has therapeutic potential for early stress-induced emotional disturbance.

Behavioural effects of monoamine reuptake inhibitors on symptomatic domains in an animal model of attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurobehavioural disorder. Several lines of evidence have implicated monoamine signalling systems, including transporters and receptors, in the pathogenesis of ADHD. We explored the heterogeneity of neural mechanisms that may possibly underlie symptomatic abnormalities in ADHD, by investigating the effects of monoamine reuptake inhibitors with differential spectrums for each monoamine transporter on ADHD-like behaviours in an animal model of ADHD, i.e. juvenile (6-week-old) male stroke-prone spontaneously hypertensive rats (SHRSP/Ezo). The impaired spontaneous alternation performance in a Y-maze task, demonstrated the inattentive features of SHRSP/Ezo, was improved by a selective DA reuptake inhibitor GBR-12909 (1 and 3mg/kg, i.p.). Desipramine (1, 3 and 10mg/kg, i.p.) and milnacipran (30mg/kg, i.p.), which possess a noradrenaline (NA) reuptake inhibitory activity, also ameliorated inattentive behaviour. Increased locomotor activity in open-field apparatus and total arm entries in a Y-maze task, which demonstrate the hyperactive features of SHRSP/Ezo, were improved by desipramine and milnacipran, but impaired by a high dose of GBR-12909 (10mg/kg, i.p.). A selective serotonin (5-HT) reuptake inhibitor fluvoxamine (10 and 30mg/kg, i.p.), did not affect inattention but significantly suppressed hyperactivity at a high dose (30mg/kg, i.p.). Moreover, a low dose of fluvoxamine (3mg/kg, i.p.) ameliorated the increased open arm spent time in an elevated plus-maze without affecting total arm entries, indicating an effect on impulsive features based on the anxiolytic characteristics of SHRSP/Ezo. These behavioural effects of monoamine reuptake inhibitors support the heterogeneity of monoaminergic systems, which are responsible for ADHD-like behaviours in SHRSP/Ezo. These findings may provide pharmacological evidence for the development of ADHD treatments that target more appropriate monoamine transporters.

Enhanced depressive-like behaviors after Toll-like receptor 7 stimulation in mice.

Toll-like receptor (TLR) 7 recognizes viral single-stranded RNA and triggers anti-viral immune responses through the production of type I interferons (IFNs) IFN-alpha and IFN-beta. IFN-alpha is known to induce various psychiatric changes such as depressive symptoms; however, the correlation with TLR7 activation remains to be determined. In this study, we examined the effect of imiquimod, a TLR7 specific ligand, on depressive-like behaviors evaluated by the forced swim test (FST) and the tail suspension test (TST) in mice. Immobility durations were significantly prolonged in both FST and TST by 2 h after imiquimod treatment (50 microg/body, i.p.), indicating that TLR7 activation enhanced depressive-like behaviors in mice. In addition, imiquimod induced IFN-alpha mRNA expression in the hippocampus, whereas it prevented long-term potentiation in the Schaffer-CA1 pathway (i.e., hippocampal synaptic plasticity). Moreover, TLR7 mRNA expression in the hippocampus was higher than that in the whole brain. These findings suggest that TLR7 activation enhances depressive-like behaviors in mice, possibly through increasing IFN-alpha expression and altering synaptic plasticity in the hippocampus.

Facilitation of fear extinction by the 5-HT(1A) receptor agonist tandospirone: possible involvement of dopaminergic modulation.

Fear extinction-based exposure treatment is an important component of psychotherapy for anxiety disorders such as posttraumatic stress disorder (PTSD). Recent studies have focused on pharmacological approaches combined with exposure therapy to augment extinction. In this study, we elucidated the therapeutic potential of the serotonin 1A (5-HT(1A) ) receptor agonist tandospirone compared with the effects of the N-methyl-D-aspartate partial agonist D-cycloserine (DCS), focusing on the possible involvement of dopaminergic mechanisms. We used a rat model of juvenile stress [aversive footshock (FS)] exposure during the third postnatal week (3wFS). The 3wFS group exhibited extinction deficit reflected in sustained fear-related behavior and synaptic dysfunction in the hippocampal CA1 field and medial prefrontal cortex (mPFC), which are responsible for extinction processes. Tandospirone administration (5 mg/kg, i.p.) before and after the extinction trials ameliorated both the behavioral deficit and synaptic dysfunction, i.e., synaptic efficacy in the CA1 field and mPFC associated with extinction training and retrieval, respectively, was potentiated in the tandospirone-treated 3wFS group. Extracellular dopamine release in the mPFC was increased by extinction retrieval in the non-FS control group. This facilitation was not observed in the 3wFS group; however, tandospirone treatment increased cortical dopamine levels after extinction retrieval. DCS (15 mg/kg, i.p.) also ameliorated the extinction deficit in the 3wFS group, but impaired extinction in the non-FS control group. These results suggest that tandospirone has therapeutic potential for enhancing synaptic efficacy associated with extinction processes by involving dopaminergic mechanisms. Pharmacological agents that target cortical dopaminergic systems may provide new insights into the development of therapeutic treatments of anxiety disorders, including PTSD.

Toll-like receptor 7-mediated enhancement of contextual fear memory in mice.

Toll-like receptor (TLR) 7 recognizes viral single-stranded RNA and triggers production of the type I interferons (IFNs) IFN-α and IFN-ß. Imiquimod, a synthetic TLR7 ligand, induces production of type I IFNs and is used clinically as an antiviral and antitumor drug. In the present study, we examined the effect of imiquimod on conditioned and innate fear behaviors in mice. Imiquimod was administered 2, 4, or 15 h before contextual fear conditioning. Imiquimod treatment 4 or 15 h before fear conditioning significantly enhanced context-dependent freezing behavior. This imiquimod-induced enhancement of fear-related behaviors was observed 120 h after fear conditioning. In contrast, imiquimod failed to enhance context-dependent freezing behavior in TLR7 knockout mice. Imiquimod had no significant effect on pain threshold or on innate fear-related behavior, as measured by the elevated plus-maze. The levels of type I IFN mRNA in the brain were significantly increased at 2 h after imiquimod treatment. Imiquimod also increased interleukin (IL)-1ß mRNA expression in the brain at 4 h following administration, while mRNA expression of F4/80, a macrophage marker, was unaffected by imiquimod treatment. Our findings suggest that TLR7-mediated signaling enhances contextual fear memory in mice, possibly by inducing the expression of type I IFNs and IL-1ß in the brain.

Possible modulation of the amygdala on metaplasticity deficits in the hippocampal CA1 field in early postnatally stressed rats.

Several lines of evidence have shown that early life experiences have a profound impact on fear-related behavior, but the detailed mechanisms are unknown. The present study examined the possible involvement of the amygdala in behavioral deficits associated with fear memory in a juvenile stress model, with a focus on hippocampal synaptic function. Adult rats exposed to footshock (FS) stress during the second postnatal period (2wFS group) exhibited low levels of freezing in response to contextual fear conditioning (CFC). The CFC-induced suppression of long-term potentiation (LTP) in the CA1 field was not found in the 2wFS group. Additionally, synaptic metaplasticity, that is, low-frequency stimulation-induced suppression of subsequent LTP, did not occur in the 2wFS group; instead, LTP was induced. These synaptic changes mimicked the impairment in metaplasticity induced by reversible inactivation of the basolateral amygdala (BLA). Inactivation of the BLA markedly decreased freezing behavior in non-FS controls, similar to the 2wFS group. Furthermore, extracellular signal-regulated kinase activation in the BLA in response to CFC did not occur in the 2wFS group. These findings suggest that early postnatal stress may cause long-term dysfunction of the modulatory effect of the amygdala on hippocampal function associated with fear memory.

Phase-dependent synaptic changes in the hippocampal CA1 field underlying extinction processes in freely moving rats.

Recent studies focus on the functional significance of a novel form of synaptic plasticity, low-frequency stimulation (LFS)-induced synaptic potentiation in the hippocampal CA1 area. In the present study, we elucidated dynamic changes in synaptic function in the CA1 field during extinction processes associated with context-dependent fear memory in freely moving rats, with a focus on LFS-induced synaptic plasticity. Synaptic transmission in the CA1 field was transiently depressed during each extinction trial, but synaptic efficacy was gradually enhanced by repeated extinction trials, accompanied by decreases in freezing. On the day following the extinction training, synaptic transmission did not show further changes during extinction retrieval, suggesting that the hippocampal synaptic transmission that underlies extinction processes changes in a phase-dependent manner. The synaptic potentiation produced by extinction training was mimicked by synaptic changes induced by LFS (0.5 Hz) in the group that previously received footshock conditioning. Furthermore, the expression of freezing during re-exposure to footshock box was significantly reduced in the LFS application group in a manner similar to the extinction group. These results suggest that LFS-induced synaptic plasticity may be associated with the extinction processes that underlie context-dependent fear memory. This hypothesis was supported by the fact that synaptic potentiation induced by extinction training did not occur in a juvenile stress model that exhibited extinction deficits. Given the similarity between these electrophysiological and behavioral data, LFS-induced synaptic plasticity may be related to extinction learning, with some aspects of neuronal oscillations, during the acquisition and/or consolidation of extinction memory.

Early postnatal stress alters extracellular signal-regulated kinase signaling in the corticolimbic system modulating emotional circuitry in adult rats.

The present study elucidated whether early life stress alters the extracellular signal-regulated kinase (ERK) pathway that underlies fear retrieval and fear extinction based on a contextual fear conditioning paradigm, using a juvenile stress model. Levels of phospho-ERK (pERK), the active form of ERK, increased after fear retrieval in the hippocampal CA1 region but not in the medial prefrontal cortex (mPFC). ERK activation in the CA1 following fear retrieval was not observed in adult rats who received aversive footshock (FS) stimuli during the second postnatal period (2wFS), which exhibited low levels of freezing. In fear extinction, pERK levels in the CA1 were increased by repeated extinction trials, but they were not altered after extinction retrieval. In contrast, pERK levels in the mPFC did not change during extinction training, but were enhanced after extinction retrieval. These findings were compatible in part with electrophysiological data showing that synaptic transmission in the CA1 field and mPFC was enhanced during extinction training and extinction retrieval, respectively. ERK activation in the CA1 and mPFC associated with extinction processes did not occur in rats that received FS stimuli during the third postnatal period (3wFS), which exhibited sustained freezing behavior. The repressed ERK signaling and extinction deficit observed in the 3wFS group were ameliorated by treatment with the partial N-methyl-D-aspartate receptor agonist D-cycloserine. These findings suggest that early postnatal stress induced the downregulation of ERK signaling in distinct brain regions through region-specific regulation, which may lead to increased behavioral abnormalities or emotional vulnerabilities in adulthood.

Prostaglandin E(2) enhances IL-33 production by dendritic cells.

While interleukin (IL)-33, a novel member of the IL-1 family, seems to promote T helper type 2 (Th2)-associated inflammations and allergic diseases, the stimulating factors for IL-33 production are less well characterized. Prostaglandin E(2) (PGE(2)) has been shown to suppress immune cell functions. However, the immune enhancement by this mediator is not well understood. In the present study, we examined the effect of PGE(2) on IL-33 production by dendritic cells (DCs). Bone marrow-derived DCs were stimulated with lipopolysaccharide (LPS) in the presence or absence of PGE(2). LPS increased mRNA expression of the IL-1 family members, IL-1, IL-18, and IL-33 in DCs. PGE(2) alone showed slight effect on IL-1, IL-18, and IL-33 mRNA expression in DCs. Of note, LPS combined with PGE(2) caused in a synergistic enhancement of mRNA expression of IL-33 but not IL-1 and IL-18. In addition, PGE(2) dramatically enhanced IL-33 protein production by DCs upon LPS stimulation. The protein kinase A (PKA) inhibitor H89 significantly inhibited the PGE(2)-mediated enhancement of IL-33 production by DCs. Thus, PGE(2) appears to enhance IL-33 mRNA expression and its protein synthesis via PKA pathway in DCs. PGE(2) may promote Th2-mediated inflammations through the enhancement of IL-33 production by DCs, which might be associated with the pathogenesis of allergic diseases.

Adrenoceptor-mediated enhancement of interleukin-33 production by dendritic cells.

While noradrenaline and adrenaline suppress some aspects of immune functions, the immune enhancement via these catecholamines is not well understood. Interleukin (IL)-33, a novel member of the IL-1 family, promotes T helper type 2 (T(h)2)-associated inflammations and plays a role in allergic diseases. However, the precise immune cell source and the stimulating factors for IL-33 production are less well characterized. In the present study, we examined the effects of noradrenaline and adrenaline, stress-related catecholamines, on IL-33 production by dendritic cells (DCs). Murine bone marrow-derived DCs were stimulated with lipopolysaccharide (LPS) in the presence or absence of these catecholamines. LPS alone slightly increased IL-33 production by DCs. Noradrenaline or adrenaline dramatically enhanced IL-33 mRNA expression and its protein synthesis by DCs upon LPS stimulation. The noradrenaline-induced enhancement of IL-33 production was completely blocked by ß(2)-adrenoceptor specific antagonist ICI 118,551, while ß(2)-adrenoceptor specific agonist salmeterol enhanced DC production of IL-33. Protein kinase A (PKA) specific inhibitor H89 blocked the noradrenaline-induced IL-33 production. Cyclic adenosine monophosphate (cAMP) and its analogue enhanced DC production of IL-33 upon LPS stimulation. Thus, ß(2)-adrenoceptor-mediated cAMP-PKA pathway appears to enhance DC production of IL-33. The adrenoceptor-mediated enhancement of IL-33 production by DCs might be associated with the stress-related progression of T(h)2-associated disorders.

Serotonin(1A) receptor-mediated synaptic response in the rat medial prefrontal cortex is altered by early life stress: in vivo and in vitro electrophysiological studies.

Serotonin (5-HT)(1A) receptors play a critical role in the 5-HTergic mechanism associated with fear memory. Previously we showed that adult rats exposed to early postnatal stress, i.e. footshock (FS) stress experienced during the second week (PND 14-18, 2W-FS), exhibited low levels of fear expression. The present study explored whether aversive stress exposure in the second and/or the third week (PND 21-25, 3W-FS) affects the function of cortical 5-HT(1A) receptors, using in vivo and in vitro experiments. A 5-HT(1A) receptor agonist, 8-OH-DPAT (0.5 mg/kg, i.p.), slightly decreased the evoked potential in the mPFC in Non-FS control and 3W-FS group. In contrast, the evoked potential increased after 8-OH-DPAT in the 2W-FS group. The in vitro experiment using patch-clamp recording showed that application of 8-OH-DPAT (10 microM) elicited membrane hyperpolarization of pyramidal neurons in the mPFC in the Non-FS and 3W-FS groups, whereas no changes in membrane potential were observed in the 2W-FS group. These results suggest that synaptic facilitation induced by 8-OH-DPAT resulted from functional changes in cortical 5-HT(1A) receptors. Thus, aversive stress exposure during the second postnatal period appears to cause persistent changes mediated via 5-HT(1A) receptors, presumably involving signal transduction regulating the development of synaptic connectivity underlying fear circuits.