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.

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.

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.

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.

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.

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.

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.

Enhanced dendritic cell antigen uptake via alpha2 adrenoceptor-mediated PI3K activation following brief exposure to noradrenaline.

Although noradrenaline (NA), a stress-associated neurotransmitter, seems to affect the immune system, the precise mechanisms underlying NA-mediated immunoregulation are not fully understood. We examined the effect of NA on Ag uptake (endocytosis) by dendritic cells (DCs) using murine bone marrow-derived DCs and fluorescence-labeled endocytic tracers (dextran and OVA). Ag uptake by DCs notably increased following a very brief treatment (3 min) with NA. NA-induced endocytosis was completely blocked by treatment with α(2)-adrenoceptor antagonist yohimbine. Neither α(1)-adrenoceptor antagonist prazosin nor ß-adrenoceptor antagonist propranolol affected NA-induced endocytosis by DCs. A selective α(2)-adrenoceptor agonist, azepexole (B-HT 933), also significantly increased endocytosis by DCs. Thus, the α(2)-adrenoceptor seems to be responsible for NA-induced DC endocytosis. In parallel, NA markedly activated intracellular signaling pathways of PI3K and ERK1/2 in DCs. NA-mediated activation of these pathways was completely inhibited by yohimbine treatment. Blocking PI3K activation significantly reduced NA-induced endocytosis by DCs. Based on these results, NA rapidly enhances Ag capture by DCs via α(2) adrenoceptor-mediated PI3K activation, which may be associated with immune enhancement following acute stress.

Retrieval of conditioned fear activates the basolateral and intercalated nucleus of amygdala.

The amygdala is one of the crucial brain structures for conditioned fear, in which conditioned stimuli are received by the basolateral nucleus of the amygdala (BLA), inducing a fear reaction via the central nucleus of the amygdala (CeA). Whereas BLA sends glutamatergic projections into CeA, the intercalated nucleus of the amygdala (ITC) sends GABAergic projections into CeA, which is doubly regulated by BLA and ITC. In the present study, we investigated the characteristics of the neural cells activated by retrieval of conditioned fear in BLA and ITC using immunohistochemistry, in situ hybridization, and Western blot analysis of transcription factors and neural cell markers. Because most conditioned fear-induced c-Fos-positive cells in BLA were glutaminase positive and 67-kDa isomer of glutamic acid decarboxylase (GAD67) negative, these cells are speculated to be glutamatergic. Seventy-eight percent of the phosphorylated CREB (pCREB)-positive cells were glutaminase double positive and 13% of the pCREB-positive cells were GAD67 double positive, indicating that many of the conditioned fear-induced pCREB-positive cells in BLA were glutamatergic, but at least some of the pCREB-positive cells were GABAergic. These results suggested that CREB phosphorylation was increased both in glutamatergic and in GABAergic neurons, but c-Fos expression was increased mainly in glutamatergic neurons in BLA. CREB phosphorylation but not c-Fos expression in ITC was specifically increased by retrieval of conditioned fear. It is therefore speculated that ITC GABAergic neurons were activated by retrieval of conditioned fear and that transcription factors other than c-Fos were relevant to the activation.

The role of tumor necrosis factor-α for interleukin-10 production by murine dendritic cells.

In the present study, we examined the role of tumor necrosis factor (TNF) in interleukin (IL)-10 production by dendritic cells (DCs) using bone-marrow derived DCs from wild type (WT) and TNF-α knockout (TNF-α(-/-)) mice. Toll-like receptor (TLR) stimulation induced substantial level of IL-10 production by WT DCs, but significantly low level of IL-10 production by TNF-α(-/-) DCs. In contrast, no significant difference was detected in IL-12 p40 production between WT and TNF-α(-/-) DCs. Addition of TNF-α during TLR stimulation recovered the impaired ability of TNF-α(-/-) DCs for IL-10 production. This recovery appeared to be associated with an activation of extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, and phosphatidylinositol 3-kinase/Akt following the TNF-α addition. Blocking these kinases significantly inhibited IL-10 production by TNF-α(-/-) DCs stimulated with TLR ligands plus TNF-α. Thus, TNF-α may be a key molecule to regulate the balance between anti-inflammatory versus inflammatory cytokine production in DCs.

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.

Dendritic cell-derived TNF-alpha is responsible for development of IL-10-producing CD4+ T cells.

Immature dendritic cells (DCs) appear to be involved in peripheral immune tolerance via induction of IL-10-producing CD4(+) T cells. We examined the role of TNF-alpha in generation of the IL-10-producing CD4(+) T cells by immature DCs. Immature bone marrow-derived DCs from wild type (WT) or TNF-alpha(-/-) mice were cocultured with CD4(+) T cells from OVA specific TCR transgenic mice (OT-II) in the presence of OVA(323-339) peptide. The WT DCs efficiently induced the antigen-specific IL-10-producing CD4(+) T cells, while the ability of the TNF-alpha(-/-) DCs to induce these CD4(+) T cells was considerably depressed. Addition of exogenous TNF-alpha recovered the impaired ability of the TNF-alpha(-/-) DCs to induce IL-10-producing T cells. However, no difference in this ability was observed between TNF-alpha(-/-) and WT DCs after their maturation by LPS. Thus, TNF-alpha appears to be critical for the generation of IL-10-producing CD4(+) T cells during the antigen presentation by immature DCs.

Diazepam-induced increases of synaptic efficacy in the hippocampal-medial prefrontal cortex pathway are associated with its anxiolytic-like effect in rats.

The medial prefrontal cortex (mPFC) has recently been shown to be an important brain region for emotional function as well as cognitive ability. In previous experiments, we studied the population spike amplitude (PSA) in the mPFC induced by stimulation of the CA1/subicular region as an index of synaptic efficacy in the hippocampal-mPFC pathway. In the present study, we investigated the relationship between the anxiolytic effect of diazepam and the changes of synaptic efficacy in this pathway. In contextual fear conditioning tests, diazepam (0.1 mg/kg) was not effective for fear-related freezing behavior. At a dose of 0.5 mg/kg, diazepam decreased freezing behavior 20 min after administration, with no discernible effect 30 min after administration. In electrophysiological experiments, 0.1 mg/kg diazepam had no effect on the PSA in the mPFC. In contrast, 0.5 mg/kg diazepam increased the PSA in the mPFC within 30 min of administration; however, this PSA increase was attenuated over the 30-min period. Based on these results, we propose that the diazepam-induced PSA increase in the mPFC is associated with its anxiolytic-like effect.

Alteration of synaptic transmission in the hippocampal-mPFC pathway during extinction trials of context-dependent fear memory in juvenile rat stress models.

The medial prefrontal cortex (mPFC) has been proposed to be essential for extinction of fear memory, but its neural mechanism has been poorly understood. The present study examined whether synaptic transmission in the hippocampal-mPFC pathway is related to extinction of context-dependent fear memory in freely moving rats using electrophysiological approaches combined with behavioral analysis. Population spike amplitude in the mPFC was decreased during the first extinction trial by exposure to contextual fear conditioning. This synaptic inhibition was reversed by repeated extinction trials, accompanied by decreases in fear-related freezing behavior. These results suggest that alteration of synaptic transmission in the hippocampal-mPFC pathway is associated with the extinction processes of context-dependent fear memory. Further experiments were performed to elucidate whether early postnatal stress alters the synaptic response in the mPFC during extinction trials using a juvenile stress model, based on our previous findings that early postnatal stress affects the behavioral response to emotional stress. Adult rats that previously were exposed to five footshocks (FS) (shock intensity, 0.5 mA; intershock interval, 28 seconds; shock duration, 2 seconds) at postnatal day 21 to 25 (week 3; 3W-FS) exhibited impaired reversal of both inhibitory synaptic transmission and freezing behavior induced by repeated extinction trials. The neuronal and behavioral deficits observed in the 3W-FS group were prevented by pretreatment with the serotonin(1A) receptor agonist tandospirone (1 mg/kg, i.p.). These results indicate the possiblity that aversive stress exposure during the third postnatal week impaired extinction processes of context-dependent fear memory. The deficits in extinction observed in the 3W-FS group might be attributable to dysfunction of hippocampal-mPFC neural circuits involving 5-HT(1A) receptor mechanisms.

Possible relationship between the stress-induced synaptic response and metaplasticity in the hippocampal CA1 field of freely moving rats.

Hippocampal long-term potentiation (LTP) is suppressed not only by stress paradigms but also by low frequency stimulation (LFS) prior to LTP-inducing high frequency stimulation (HFS; tetanus), termed metaplasticity. These synaptic responses are dependent on N-methyl-D-aspartate receptors, leading to speculations about the possible relationship between metaplasticity and stress-induced LTP impairment. However, the functional significance of metaplasticity has been unclear. The present study elucidated the electrophysiological and neurochemical profiles of metaplasticity in the hippocampal CA1 field, with a focus on the synaptic response induced by the emotional stress, contextual fear conditioning (CFC). The population spike amplitude in the CA1 field was decreased during exposure to CFC, and LTP induction was suppressed after CFC in conscious rats. The synaptic response induced by CFC was mimicked by LFS, i.e., LFS impaired the synaptic transmission and subsequent LTP. Plasma corticosterone levels were increased by both CFC and LFS. Extracellular levels of gamma-aminobutyric acid (GABA), but not glutamate, in the hippocampus increased during exposure to CFC or LFS. Furthermore, electrical stimulation of the medial prefrontal cortex (mPFC), which caused decreases in freezing behavior during exposure to CFC, counteracted the LTP impairment induced by LFS. These findings suggest that metaplasticity in the rat hippocampal CA1 field is related to the neural basis of stress experience-dependent fear memory, and that hippocampal synaptic response associated stress-related processes is under mPFC regulation.

GABAergic mechanism mediated via D receptors in the rat periaqueductal gray participates in the micturition reflex: an in vivo microdialysis study.

The periaqueductal gray (PAG) is critically involved in the micturition reflex, but little is known about the neuronal mechanisms involved. The present study elucidated dynamic changes in dopamine (DA), glutamate and gamma-aminobutyric acid (GABA) in the rat PAG during the micturition reflex, with a focus on dopaminergic modulation using in vivo microdialysis combined with cystometrography. Extracellular levels of DA and glutamate increased, whereas levels of GABA decreased, in parallel with the micturition reflex. Application of a D(1) receptor antagonist into the PAG produced increases in maximal voiding pressure (MVP) and decreases in intercontraction interval (ICI), suggesting that the micturition reflex was facilitated by D(1) receptor blockade. The D(1) receptor antagonist prevented micturition-induced decreases in GABA efflux but had no effect on DA or glutamate. Neither a D(2) receptor antagonist nor a D(1)/D(2) receptor agonist affected these neurochemical and physiological parameters. Micturition-induced inhibition of GABA was not observed in 6-hydroxydopamine (6-OHDA)-lesioned rats, an animal model of Parkinson's disease. 6-OHDA-lesioned rats exhibited bladder hyperactivity evaluated by increases in MVP and decreases in ICI, mimicking facilitation of the micturition reflex induced by D(1) receptor blockade. These findings suggest that the micturition reflex is under tonic dopaminergic regulation through D(1) receptors, in which a GABAergic mechanism is involved. Bladder hyperactivity observed in 6-OHDA-lesioned rats may be caused by dysfunction of GABAergic regulation underlying the micturition reflex. The present findings contribute to our understanding not only of the neurophysiology of the micturition reflex but also of the pathophysiology of lower urinary tract dysfunction in patients with Parkinson's disease.

Characterization of stress-induced suppression of long-term potentiation in the hippocampal CA1 field of freely moving rats.

Several lines of evidence have shown that exposure to stress impairs long-term potentiation (LTP) in the CA1 field of the hippocampus, but the detailed mechanisms for this effect remain to be clarified. The present study elucidated the synaptic mechanism of stress-induced LTP suppression in conscious, freely moving rats using electrophysiological approaches. Open field stress (i.e., novel environment stress) and elevated platform stress (i.e., uncontrollable stress) were employed. Basal synaptic transmission was significantly reduced during exposure to elevated platform stress but not during exposure to open field stress. LTP induction was blocked by elevated platform stress but not influenced by open field stress. Significant increases in serum corticosterone levels were observed in the elevated platform stress group compared with the open field stress group. Furthermore, LTP suppression induced by elevated platform stress was prevented by pretreatment with an anxiolytic drug diazepam (1 mg/kg, i.p.). These results suggest that stress-induced LTP suppression depends on the relative intensity of the stressor. The inhibitory synaptic response induced by an intense psychological stress, such as elevated platform stress, may be attributable to LTP impairment in the CA1 field of the hippocampus.

Characterization of clozapine-induced changes in synaptic plasticity in the hippocampal-mPFC pathway of anesthetized rats.

Synaptic plasticity expressed as long-term potentiation (LTP) in the hippocampal-medial prefrontal cortex (mPFC) pathway is considered to be involved in cognitive function and learning and memory processes, but its synaptic mechanism remains unknown. The present study characterized LTP in the mPFC using the atypical antipsychotic clozapine, with a focus on dopaminergic modulation. The magnitude of LTP was facilitated by pretreatment with clozapine (20 mg/kg, i.p.), but not by the typical antipsychotic haloperidol (1 mg/kg, i.p.). Clozapine-induced LTP augmentation was blocked by the dopamine D(1) receptor antagonist SCH-23390 (10 microg/rat, i.c.v.), but not by the D(2) receptor antagonist remoxipride (10 microg/rat, i.c.v.) or the 5-HT(1A) receptor antagonist WAY-100635 (20 microg/rat, i.c.v.). SCH-23390 (10 microg/rat, i.c.v.) by itself did not affect LTP induction. The D(1) receptor agonist SKF-38393 (10 microg/kg, i.c.v.) facilitated LTP, mimicking the clozapine-induced response. Furthermore, in vivo microdialysis showed that transient increases in mPFC dopamine levels induced by tetanic stimulation sustained facilitation following clozapine administration (20 mg/kg, i.p.). These results demonstrate the importance of the D(1) receptor as a mediator of clozapine-induced LTP augmentation through enhanced dopaminergic activity. Augmentation of synaptic plasticity in the hippocampal-mPFC pathway via D(1) receptors appears to be responsible for the therapeutic effects of clozapine.

Corticotropin releasing factor in the median raphe nucleus is involved in the retrieval of fear memory in rats.

In the present study, we examined the role of corticotropin releasing factor (CRF) in the median raphe nucleus (MRN) on fear-related behaviors in rats. We employed the contextual fear conditioning test and the elevated plus maze test as memory-dependent and -independent tasks, respectively. Human/rat CRF (10 ng) in 0.5 microl saline was injected into the MRN. Administration of CRF significantly increased memory dependent, but not independent, fear expression. These results suggest that CRF release in the MRN is involved in the retrieval of fear memory.