Aripiprazole ameliorates phencyclidine-induced impairment of recognition memory through dopamine D1 and serotonin 5-HT1A receptors.

RATIONALE: Cognitive deficits, including memory impairment, are regarded as a core feature of schizophrenia. Aripiprazole, an atypical antipsychotic drug, has been shown to improve disruption of prepulse inhibition and social interaction in an animal model of schizophrenia induced by phencyclidine (PCP); however, the effects of aripiprazole on recognition memory remain to be investigated. OBJECTIVES: In this study, we examined the effect of aripiprazole on cognitive impairment in mice treated with PCP repeatedly. MATERIALS AND METHODS: Mice were repeatedly administered PCP at a dose of 10 mg/kg for 14 days, and their cognitive function was assessed using a novel-object recognition task. We investigated the therapeutic effects of aripiprazole (0.01-1.0 mg/kg) and haloperidol (0.3 and 1.0 mg/kg) on cognitive impairment in mice treated with PCP repeatedly. RESULTS: Single (1.0 mg/kg) and repeated (0.03 and 0.1 mg/kg, for 7 days) treatment with aripiprazole ameliorated PCP-induced impairment of recognition memory, although single treatment significantly decreased the total exploration time during the training session. In contrast, both single and repeated treatment with haloperidol (0.3 and 1.0 mg/kg) failed to attenuate PCP-induced cognitive impairment. The ameliorating effect of aripiprazole on recognition memory in PCP-treated mice was blocked by co-treatment with a dopamine D1 receptor antagonist, SCH23390, and a serotonin 5-HT1A receptor antagonist, WAY100635; however, co-treatment with a D2 receptor antagonist raclopride had no effect on the ameliorating effect of aripiprazole. CONCLUSIONS: These results suggest that the ameliorative effect of aripiprazole on PCP-induced memory impairment is associated with dopamine D1 and serotonin 5-HT1A receptors.

Upside-down gliding of Lymnaea.

The pond snail Lymnaea stagnalis can often be observed moving upside down on its back just below the surface of the water. We have termed this form of movement "upside-down gliding." To elucidate the mechanism of this locomotion, we performed a series of experiments involving behavioral analyses and microscopic observations. These experiments were designed (1) to measure the speed of this locomotion; (2) to determine whether the mucus secreted from the foot of Lymnaea repels water, thereby allowing the snail to exploit the surface tension of the water for upside-down gliding; and (3) to observe the beating of foot cilia in this behavior. The beating of these cilia is thought to be the primary driving force for upside-down gliding. Our results demonstrate that upside-down gliding is an efficient active process involving the secretion of mucus that floats up to the water surface to serve as a substrate upon which cilia beat to cause locomotion at the underside of the water surface.

Speed of back-swimming of Lymnaea.

The pond snail, Lymnaea stagnalis, can locomote on its back utilizing the surface tension of the water. We have called this form of movement 'back-swimming'. In order to perform this behavior, the snail must flip itself over on its back so that its foot is visible from above. Little is known about the mechanism of this back-swimming. As a first step for the elucidation of this mechanism, we measured the speed of back-swimming of Lymnaea at the different times of the day. They back-swam significantly faster in the morning than just before dark. These data are consistent with our earlier findings on circadian-timed activity pattern in Lymnaea. Lymnaea appear to secrete a thin membrane-like substance from their foot that may allow them to back-swim. To confirm the existence of this substance and to examine whether this substance is hydrophobic or hydrophilic, we applied a detergent onto the foot during back-swimming. A single drop of 1% Tween 20 drifted Lymnaea away that were still kept at the water surface. These results suggest that Lymnaea secrete a hydrophobic substance from their foot that floats to the water surface allowing Lymnaea to back-swim.

Hypofunctional glutamatergic neurotransmission in the prefrontal cortex is involved in the emotional deficit induced by repeated treatment with phencyclidine in mice: implications for abnormalities of glutamate release and NMDA-CaMKII signaling.

In the present study, we investigated the involvement of prefrontal glutamatergic neurotransmission in the enhancement of immobility (emotional deficit) in a forced swimming test in mice treated with phencyclidine (PCP: 10mg/kg/day for 14 days) repeatedly, which is regarded as an animal model for negative symptoms. A decrease in spontaneous extracellular glutamate release and increase in levels of the glutamate transporter GLAST, were observed in the prefrontal cortex (PFC) of PCP-treated mice, compared to saline-treated mice. NMDA receptor subunit 1 (NR1) and Ca(2+)/calmoduline kinase II (CaMKII) were markedly activated in the PFC of saline-treated mice, but not PCP-treated mice, immediately after the forced swimming test. The facilitation of the function of NMDA receptors by d-cycloserine (30mg/kg i.p.), an NMDA receptor glycine-site partial agonist, reversed the enhancement of immobility in the forced swimming test and impairment of CaMKII activation in the PCP-treated mice. Microinjection of dl-threo-beta-benzyloxyaspartate (10nmol/site/bilaterally), a potent blocker of glutamate transporters, into the PFC of PCP-treated mice also had an attenuating effect. In addition, activation of glial cells and a decrease of neuronal cell size were observed in the PFC of PCP-treated mice. These results suggest that repeated PCP treatment disrupts pre- and post-synaptic glutamatergic neurotransmission and induces morphological changes in the PFC and that such changes cause the emotional deficits exhibited in PCP-treated mice.

Immunological evaluation of peptide vaccination for patients with gastric cancer based on pre-existing cellular response to peptide.

There is no standard treatment modality for advanced gastric cancer (GC) at the present time. To develop a new treatment modality, we investigated the immunological responses of advanced GC patients (n = 13, 9 non-scirrhous and 4 scirrhous types) vaccinated with peptides to a regimen under which pre-vaccination peripheral blood mononuclear cells (PBMCs) were screened for their reactivity in vitro to each of 14 peptides on HLA-A24 or 16 peptides on -A2 allele, then only the reactive peptides (maximum: 4) were administered in vivo. This regimen was generally well tolerated, although grade I levels of fever and local skin reactions were observed in several patients. Delayed-type hypersensitivity (DTH) to the vaccinated peptides was observed in 4 patients. Increased cellular and humoral immune responses to the vaccinated peptides were observed in post-vaccination PBMCs from 4 of 8 patients and in post-vaccination sera of 8 of 10 patients tested, respectively. Prolonged survival was observed in patients showing cellular and humoral immune responses to the vaccinated peptides in the post-vaccination samples, including all 4 patients with the scirrhous type. These results encourage further development of peptide-based immunotherapy for GC patients.