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Transcranial direct current stimulation (tDCS) has been reported to modify cortical function by inducing alterations in the underlying brain function. P50auditory evoked potentials, as assessed using a paired auditory stimulus (S1 and S2) paradigm, are thought to reflect a sensory gating process in which the functional involvement of the dorsolateral prefrontal cortex (DLPFC) is suggested. P50 sensory gating has also been reported to be associated with the pathogenesis of psychiatric diseases such as schizophrenia and anxiety-related disorders. Here we investigated whether the tDCS over the DLPFC could modulate the cortical function leading to alteration of the P50 sensory gating. P50 gating indices (the S2/S1 ratio and S1-S2 difference) were measured during the tDCS (current 1.0 mA, duration 15 min) over the DLPFC with different conditions (anodal, cathodal and sham). Ten male healthy volunteers were studied on separate days in a single blinded paradigm. We observed that the cathodaltDCS significantly altered the mean P50 gating indices compared to the other two conditions. Our results suggest that sensory gating could be modulated by cathodaltDCS on the left DLPFC but not by anodal/sham tDCS.

In the human palm/sole, mental or physical stimuli induce an increase in sweat secretion and a decrease in skin blood flow (SkBF). However, the central pathways of these responses remain unclear. We measured sweat secretion and SkBF in the cat footpad by electrically stimulating the raphe. Stimulation of the rostral raphe magnus/pallidus elicited a reduction in SkBF without affecting sweat secretion. Stimulation of the mid to caudal raphe magnus/pallidus elicited an increase in both sweat secretion and SkBF. The raphe magnus/pallidus may play a crucial role in skin vasomotor and sudomotor responses in the cat footpad.

Increased oxyradical production and membrane lipid peroxidation (MLP) occur under physiological and degenerative conditions in neurons. We investigated whether 4-hydroxynonenal (4HN), one of the membrane lipid peroxidation products, affects long-term potentiation (LTP) in the rat dentate gyrus in vitro. Treatment of hippocampal slices with 4HN (10 microM) enhanced LTP without affecting basal evoked potentials. The enhancement was completely inhibited by 2 microM nifedipine, a blocker of L-type Ca2+ channels. In cultured dentate gyrus neurons, treatment of the cells with 4HN for 24 h resulted in a significant amount of cell death that was detoxified by glutathione, whereas short-term treatment with 4HN (< or = 6 h) had no effect. Nifedipine partially but significantly suppressed the 4HN-induced cell death. These results suggest that 4HN modulates LTP and induces delayed cell death through L-type Ca2+ channel activation in the dentate gyrus. 4HN thereby plays an important role in both physiological and pathophysiological events in the hippocampus.

Modification of voltage-gated Ca(2+) channels by hydrogen peroxide, a membrane-permeable form of reactive oxygen species, in cultured dentate granule cells was examined using the whole cell patch clamp technique. Pretreatment with hydrogen peroxide (1 and 10 microM) for 2 h enhanced the Ca(2+) current without affecting its voltage dependence. The enhancement was completely cancelled by 1 mM glutathione, an antioxidant, and 2 microM nifedipine, an L-type Ca(2+) channel blocker. In contrast, the enhancement of the Ca(2+) current was not mimicked by pretreatment with 10 microg/ml tunicamycin, an endoplasmic reticulum stressor. These results suggest that oxidative stress induced by hydrogen peroxide selectively regulates the activity of L-type Ca(2+) channels.

The role of a tryptophane residue (Trp(256)) in the extracellular loop of a neuronal P2X receptor clone (P2X(2) receptor/channel) was investigated using site-directed mutagenesis and Xenopus oocyte expression. When Trp(256) was replaced with leucine, serine or phenylalanine (W256L, W256S or W256F), a current response to adenosine triphosphate (ATP) mediated through the P2X2 receptor/channel was abolished. When replaced with tyrosine (W256Y), the response was not abolished, but a reduced current response to ATP was observed. The insertion of a tryptophane residue in W256L at positions close to position 256 failed to recover the responsiveness to ATP. These results suggest that an amino acid residue with a side chain of an aromatic ring with a hydroxy group (tryptophane or tyrosine) is necessary exactly at position 256 for P2X(2) receptor/channel activation.

Fifteen pre-inspiratory (pre-I) neurons were extracellularly recorded in the pre-Botzinger complex and their involvements in vestibular (VN) and superior laryngeal (SLN) nerve reflexes and in fictive swallowing and vomiting were tested in decerebrated and artificially ventilated cats. Both type I (1 of 9) and type II (1 of 6) pre-I neurons could project to the contralateral ventral respiratory group region. Pre-I neurons changed their firing during VN and SLN respiratory reflexes and fictive swallowing and vomiting; different response properties were observed among individual pre-I neurons. These results suggest that pre-I neurons are a population of heterogeneous and multifunctional propriobulbar neurons.

We previously demonstrated that 5-hydroxytryptamine (5-HT) enhances the cationic current activated by extracellular ATP in rat pheochromocytoma PC12 cells. We report here that pertussis toxin (PTX) modulates this 5-HT-dependent enhancement in these cells. 5-HT potentiated ATP-evoked intracellular Ca 2+ concentration ([Ca] i ) rise and dopamine release over a concentration range from 1 to 100 μM. When cells were pre-treated with PTX, this potentiation was accentuated. Pretreatment with PTX also accentuated the 5-HT dependent enhancement of the ATP-activated current. These results suggest that the enhancement by 5-HT of the ATP-evoked responses is negatively regulated by a mechanism mediated through PTX-sensitive GTP-binding protein.

The interaction between ATP-activated channels and the nicotinic receptor-channels has been reported in neuronal cells. To elucidate the mechanisms underlying the interaction, the currents activated by ATP and acetylcholine (ACh) were recorded from cell-free membrane patches excised from rat sympathetic neurons. When ATP or ACh (30–300 μM) was applied, the current consisting of multiple channels was observed in most outside-out patches. The amplitude of the ATP-activated current and that of the ACh-activated current in the same patches were highly correlated ( r = 0.89). In a part of the patches, the current activated by ACh (300 μM) with ATP (300 μM) was smaller than the current successively activated by ACh alone, indicating that ATP did not add the current but rather inhibited the ACh-activated channels. In addition, the decay of the current activated by ACh with ATP was faster than the current activated by ACh alone. The coexistence of the two types of channels in the same patches and the interaction of ATP with the ACh-activated current in the cell-free condition may support our previous hypothesis, namely, the activation by ATP of a subpopulation of the nicotinic receptor-channels.

Characteristics of extracellular ATP-evoked electrical responses in rat hippocampal neurons were investigated. Extracellular ATP (100 microM) induced a rapid depolarization followed by repetitive firings of spikes in these cells under whole-cell current-clamp. In whole-cell voltage-clamp experiments, ATP activated 2 types of inward currents that were inhibited by P2-purinoceptor blocker suramin (300 microM). One is a small (about -20 pA) sustained current which is insensitive to tetrodotoxin (TTX), and the other is a large (-100 to -300 pA) transient current which abolished in the presence of 3 microM TTX. The ATP-induced transient current was blocked by 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX; 30 microM), a non-N-methyl-D-aspartate (non-NMDA) receptor antagonist. ATP failed to induce the transient current in the cell which showed the desensitization to quisqualic acid (QA; 10 microM), a non-NMDA receptor agonist. These findings suggest that ATP directly activates small sustained currents, and indirectly induces the transient currents by evoking glutamate release.

The forebrain is one of the important suprapontine micturition centres. Previous studies have shown that electrical stimulation of the frontal lobe and the anterior cingulate gyrus elicited either inhibition or facilitation of bladder contraction. Patients with frontal lobe tumours and aneurysms showed micturition disorders. Functional brain imaging studies showed that several parts of the forebrain are activated during bladder filling. We aimed to examine neuronal activities of forebrain structures with respect to bladder contraction in cats. In 14 adult male cats under ketamine anaesthesia in which a spontaneous isovolumetric bladder-contraction/relaxation cycle had been generated, we carried out extracellular single-unit recording in forebrain with respect to the contraction/relaxation cycles in the bladder. We recorded 112 neurons that were related to the bladder-contraction/relaxation cycles. Ninety-four neurons were found to be tonically activated during the bladder-relaxation phase, whereas the remaining 18 neurons were tonically activated during the bladder-contraction phase. Both types of neuron were widely distributed around the cruciate sulcus. Most were located medially (medial and superior frontal gyrus) and the rest were located laterally (middle and inferior frontal gyrus). Neurons recorded in forebrain structures were activated with respect to the contraction/relaxation cycles in the bladder. Forebrain structures may have a significant role in regulating bladder contraction in cats.

Based on NMDA hypofunction hypothesis for negative symptoms and cognitive deficits in schizophrenia, MK-801-induced animal models of schizophrenia may help us understand the different effects between typical and atypical antipsychotics. On the other hand, the mitogen-activated protein kinase (MAPK) signaling pathways may participate in antipsychotic actions. The aim of this study was to investigate the effects of aripiprazole on MK-801-induced prepulse inhibition (PPI) disruption and MAPK phosphorylation in mice. To clarify the effects of aripiprazole on MK-801-induced PPI disruption, we measured PPI of 51 ddY male mice after aripiprazole was administered 15 min prior to the injection of MK-801, and measured activation of cytosol and nuclear MAPK phosphorylation by western blotting. Aripiprazole (4.0 mg/kg) significantly reversed the MK-801 (0.15 mg/kg)-induced PPI deficits. Pretreatment of aripiprazole (40 mg/kg) had a tendency to suppress MK-801 (1.0 mg/kg)-induced pMEK/MEK (Ser218/222) activation. In addition, aripiprazole treatment showed a significant decrease of pERK/ERK. Our data suggested that aripiprazole may reverse MK-801-induced PPI deficits through regulation of MAPK phosphorylation in the same way as the atypical antipsychotic drug, clozapine.

Effects of imipramine on the cloned P2X 2 receptor/channel and its mutants expressed in Xenopus oocytes were examined. Imipramine (100 μ M) partially blocked an ionic current mediated through the wild-type P2X 2 receptor/channel. With a higher concentration (300 μ M) of imipramine, the current block was attenuated, suggesting that the second, lower affinity, `unblocking' binding-site for imipramine exists in addition to the `blocking' binding-site. These profiles of the modulation by imipramine were influenced by the substitution of negatively charged or polarized amino acid residues near the outer mouth of the channel pore (Asp 315 , Thr 330 and Asn 333 ) with neutral amino acid residues (Val or Ile). With the neutralization of Asp 315 , the current `block' by 100 μ M imipramine was attenuated. With the neutralization of Thr 330 , the current `block' by 100 μ M imipramine was enhanced. With the neutralization of Asn 333 , the `unblock' by 300 μ M imipramine disappeared. The results suggest that imipramine modulates P2X 2 receptor/channels by interacting these amino acid residues.

Single-channel recordings were made using cell-free membrane patches (outside-out configuration) isolated from pheochromocytoma PC12 cells. ATP (50 μM) activated single channel currents in the isolated patches and the currents inactivated with a half-decay time of about 5 s. The single channel conductance was about 13 pS in external solution with 140 mM Na. The amplitudes of the single-channel currents were decreased when external Ca was increased from 1.8 to 16.2 mM, suggesting that Ca blocks ion permeation through the channel. These properties of single-channel currents may underlie those of the macroscopic current.

Characteristics of extracellular ATP-stimulated norepinephrine (NE) secretion were investigated by the batch method in relation to membrane current measured with the whole cell voltage-clamp technique. Extracellular ATP stimulated [ 3 H]NE secretion from PC12 cells in a concentration range from 10 μM to 1 mM. The maximal effect of ATP was about 5 times larger than that of nicotine. ATP-stimulated secretion was extracellular Ca-dependent, but it was not inhibited by the Ca-channel blockers, cadmium (300 μM) or nicardipine (10 μM). Extracellular ATP activated an inward current in PC12 cells and the peak amplitude of the current was about 5 times larger than that activated by nicotine. These findings suggest that extracellular ATP activates receptor-operated channels and causes NE secretion.