Kaori Tachibana

Fluvoxamine suppresses the long-term potentiation in the hippocampal CA1 field of anesthetized rats: an effect mediated via 5-HT1A receptors

A selective 5-HT reuptake inhibitor, fluvoxamine (10 and 30 mg/kg, i.p.) suppressed long-term potentiation (LTP) in the hippocampal CA1 field of anesthetized rats. Fluvoxamine (30 mg/kg, i.p.)-induced suppression of LTP was completely reversed by the 5-HT(1A) receptor antagonist NAN-190 (0.5 mg/kg, i.p), but not by the 5-HT(4) receptor antagonist GR 113808 (20 microg/rat, i.c.v.) and the 5-HT(7) receptor antagonist DR 4004 (10 microg/rat, i.c.v.). These data suggest that the inhibitory effect of fluvoxamine on LTP induction is mediated via 5-HT(1A) receptors.

Milnacipran, a serotonin and noradrenaline reuptake inhibitor, suppresses long-term potentiation in the rat hippocampal CA1 field via 5-HT1A receptors and α1-adrenoceptors

Pharmacological characteristics of a serotonin (5-HT) and noradrenaline reuptake inhibitor (SNRI), milnacipran, in modulation of the synaptic plasticity were investigated. Milnacipran (30 mg/kg, i.p.) suppressed the long-term potentiation (LTP) in the hippocampal CA1 field of anesthetized rats. Milnacipran-induced suppression was reversed by pretreatment with the selective 5-HT1A receptor antagonist WAY 100635 (0.1 mg/kg, i.v.) or the alpha1-adrenoceptor antagonist prazosin (1 and 10 microg/rat, i.c.v.). The alpha2-adrenoceptor antagonist idazoxan (5 mg/kg, i.p.) did not influence the milnacipran-induced synaptic responses. These data suggest that the inhibitory effects of milnacipran on LTP induction are mediated via both 5-HT1A receptors and alpha1-adrenoceptors. In other words, functional interaction between the serotonergic and noradrenergic neuronal systems is involved in alteration of the hippocampal synaptic plasticity, which may be implicated in the SNRI-induced therapeutic effect on psychiatric disorders.

Neonatal exposure to sevoflurane causes significant suppression of hippocampal long-term potentiation in postgrowth rats.

BACKGROUND: The inhaled anesthetic sevoflurane is commonly used for neonates in the clinical setting. Recent studies have indicated that exposure of neonatal rodents to sevoflurane causes acute widespread neurodegeneration and long-lasting neurocognitive dysfunction. Although acute toxic effects of sevoflurane on cellular viability in the hippocampus have been reported in some studies, little is known about the effects of neonatal sevoflurane exposure on long-term hippocampal synaptic plasticity, which has been implicated in the processes of learning and memory formation. Our study is the first to examine the long-term electrophysiological impact of neonatal exposure to a clinically relevant concentration of sevoflurane. METHODS: On postnatal day 7, rats were exposed to sevoflurane (1% or 2% for 2 hours) with oxygen. To eliminate the influence of blood gas abnormalities caused by sevoflurane-induced respiratory suppression, a group of rats were exposed to a high concentration of carbon dioxide (8% for 2 hours) to duplicate respiratory disturbances caused by 2% sevoflurane exposure. RESULTS: Exposure of neonatal rats to 2% sevoflurane for 2 hours caused significant suppression of long-term potentiation (LTP) induction in the postgrowth period. There was no significant difference between the control group and the CO2-exposed group in LTP induction, indicating that sevoflurane-induced LTP suppression was not caused by blood gas abnormalities. CONCLUSION: Our present findings indicate that neonatal exposure to sevoflurane at a higher concentration can cause alterations in the hippocampal synaptic plasticity that persists into adulthood.

Neonatal administration with dexmedetomidine does not impair the rat hippocampal synaptic plasticity later in adulthood

Background and objective:  The use of dexmedetomidine (DEX), a selective alpha‐2 agonist, in pediatric practice is expanding as a result of its desirable properties. To clarify the long‐term neurological consequences of neonatal administration of DEX, we investigated the long‐term effects of neonatal administration of DEX on hippocampal synaptic activity.

Serotonergic modulation of psychological stress-induced alteration in synaptic plasticity in the rat hippocampal CA1 field.

In order to elucidate possible involvement of the serotonergic neuronal system in the stress-induced alteration in synaptic plasticity, the effects of contextual fear conditioning (CFC) on long-term potentiation (LTP) in the hippocampal CA1 field were examined in 5-HT-depleted rats by pretreatment with 5,7-dihydroxytryptamine (5,7-DHT, 200 microg/rat, i.c.v.). LTP induction was suppressed by footshock (FS) stimulation in 5-HT-lesioned rats and vehicle-treated controls. When rats were exposed to CFC, which was received 24 h after FS stimulation, LTP was also blocked in both-treated groups. CFC-induced impairment of LTP, however, significantly attenuated in 5-HT-lesioned rats when compared with that in controls. Fear-related freezing behavior after FS stimulation occurred similarly in both treated groups, whereas the behavior observed during exposure to CFC significantly reduced in 5-HT-lesioned rats. These results suggest that the serotonergic mechanism is involved in the psychological stress-induced alteration in synaptic plasticity, which appears to be associated with fear-related behavior.

Electrophysiological and neurochemical characterization of the effect of repeated treatment with milnacipran on the rat serotonergic and noradrenergic systems

The present study was undertaken to elucidate the effects of repeated treatment with milnacipran, a serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor (SNRI), on the synaptic plasticity in the hippocampal CA1 field, focusing on the interaction between the serotonergic and noradrenergic system. Repeated treatment with milnacipran (30mg/kg, i.p. after 30mg/kg, p.o. 14 days) completely restored the suppression of the long-term potentiation (LTP) induced by single milnacipran treatment (30mg/kg, i.p.). Single and repeated milnacipran increased to a similar extent extracellular NA in the hippocampus. Single milnacipran increased extracellular 5-HT and this effect tended to be enhanced by repeated treatment. The restoration of LTP and facilitation of the 5-HT level were not shown after repeated treatment with a selective 5-HT reuptake inhibitor (SSRI) fluvoxamine (30mg/kg, p.o. 14 days). These results suggest that milnacipran-induced restoration of LTP suppression is responsible for the enhancement of 5-HT neurotransmission, which appears to be associated with noradrenergic neuronal activity. In addition, the 5-HT1A receptor agonist tandospirone-induced suppression of LTP was completely blocked by repeated treatment with milnacipran, indicating the possibility that this reversal effect is due to the functional changes in postsynaptic 5-HT1A receptors. Taken together, the present data suggest that the interaction between the serotonergic and noradrenergic mechanism play an important role in the modulation of synaptic plasticity caused by repeated treatment with milnacipran, which may be implicated in the therapeutic effects of SNRI on psychiatric disorders.

Neonatal exposure to high concentration of carbon dioxide produces persistent learning deficits with impaired hippocampal synaptic plasticity

Although respiratory complications with blood gas abnormalities contribute significantly to neurodevelopment in the immature brain, little is known about the mechanisms via which blood gas abnormalities, such as hypoxic hypercapnia, impair neurocognitive outcomes. To investigate the possible long-term consequences of neonatal exposure to hypoxic hypercapnia regarding learning ability, we investigated the effect of neonatal hypoxic hypercapnia on later functions in the hippocampus, which is a structure that has been implicated in many learning and memory processes. Neonatal rat pups (postnatal day 7; P7) were exposed to a high concentration of carbon dioxide (CO2; 13%) for 2 or 4h. Exposure to CO2 in P7 rat pups caused blood gas abnormalities, including hypercapnia, hypoxia, and acidosis, and disrupted later learning acquisition, as assessed in 10-week-old adult rats subjected to a Morris water maze test. Induction of long-term potentiation (LTP) in the synapses of the hippocampal CA1 area was also impaired, whereas the paired-pulse responses of population spikes exhibited a significant increase, in CO2-exposed rats, suggesting decreased recurrent inhibition in the hippocampus. Such long-lasting modifications in hippocampal synaptic plasticity may contribute to the learning impairments associated with perinatal hypoxic hypercapnia and acidosis.

Isoflurane bidirectionally modulates the paired-pulse responses in the rat hippocampal CA1 field in vivo.

BACKGROUND:We studied the effects of isoflurane on hippocampal synaptic transmission and paired-pulse plasticity, under in vivo intact interneuron circuitry. METHODS:Using rats chronically implanted with electrodes, excitatory postsynaptic potential (EPSP) and population spike amplitude (PSA) were measured in the hippocampal CA1 field by stimulating Schaffer collaterals. The lungs of the rats were mechanically ventilated with 0.25–1.5 minimum alveolar anesthetic concentration (MAC) isoflurane. A control value was obtained in the absence of isoflurane. RESULTS:Isoflurane depressed EPSP responses and enhanced synaptic efficacy. PSA was not depressed except under high concentrations, presumably reflecting a well-balanced combination with the decreased EPSP and enhanced synaptic efficacy. Low concentrations of isoflurane (0.25 and 0.5 MAC) increased paired-pulse facilitation (PPF), whereas a high concentration of isoflurane (1.5 MAC) prolonged the paired-pulse depression. CONCLUSIONS:Isoflurane appeared to affect multiple sites of CA1 synapses: 1) the depression of presynaptic glutamatergic transmission as shown by depressed EPSP and increased PPF; 2) the depression of pyramidal neurons as shown by prolonged PPF and depressed PSA under high concentration; and 3) the depression of interneurons as shown by the greater synaptic efficacy. The degree of each of these inhibitory effects seemed to vary at different concentrations, and the overall direction of the synaptic properties may depend on the balances between these inhibitory effects in vivo.

Altered synaptic transmission in rat anterior cingulate cortex following peripheral nerve injury.

BACKGROUND Patients with neuropathic pain present not only with persistent pain but also a complex set of additional symptoms, including mood disorders and cognitive disturbance. Given the important roles of the anterior thalamic nuclei (ATN) and anterior cingulate cortex (ACC) in the cognitive and emotional aspects of pain, investigation of the properties of ATN-ACC synapses will help us to understand the mechanisms underlying neuropathic pain. METHODS We studied changes in ATN-evoked ACC excitatory postsynaptic potentials (EPSPs) induced by neuropathic pain in a rat model under halothane anaesthesia. RESULTS Neuropathic pain caused significant suppression of EPSPs in the ACC compared with rats subjected to sham surgery. Similar to previous evidence, acute inflammatory pain induced by formalin injection into the hind paw significantly increased synaptic efficacy in the ACC compared with naive rats. Neither of the pain paradigms altered the paired-pulse responses. CONCLUSIONS A possible explanation for the neuropathic pain-related suppression of EPSPs is that the ACC was already sufficiently active at baseline as a result of neuropathic pain, and ATN stimulation could not further increase the already elevated level of ACC activity. This abnormal excitability of the ATN-ACC synapse may be important in understanding the mechanism underlying neuropathic pain, particularly with respect to the affective and cognitive aspects.

Gastric intramucosal perfusion during descending aortic repair under femoro-femoral bypass.

The changes in gastric mucosal perfusion during distal aortic perfusion with femoro-femoral bypass (F-F bypass) were assessed by air-automated gastric tonometry. A prospective study was performed in six patients who underwent descending aortic surgery for aortic aneurysm under F-F bypass with mild hypothermia (34°C). Gastric intramucosal pH (pHi) and PaCO2-PgCO2 gap (PCO2 gap) were measured. Data are presented as means and standard deviations and analyzed by using one-way analysis of variance followed by Scheffe test. Perioperative variables of hepatorenal functions are also evaluated. The PCO2 gap significantly increased during F-F bypass (3.0 ± 2.1 mm Hg at control, 14.2 ± 5.5 mm Hg during F-F bypass; p = 0.004), indicating abnormal gastric mucosal perfusion during F-F bypass. Significantly low pHi was found at weaning from F-F bypass (7.35 ± 0.05 at control, 7.21 ± 0.10 at weaning; p = 0.009), which might be related to progressing systemic metabolic acidosis. No impairment of hepatorenal functions was observed after the surgery. Distal perfusion with F-F bypass during descending aortic surgery could impair the gastric mucosal perfusion, but may have little effect on postoperative visceral dysfunction.