The pharmacological characterization of attentional processes using a two-lever choice reaction time task in rats

Activating the noradrenergic and cholinergic systems is known to enhance attentional processes, while stimulating dopaminergic, serotonergic, and GABAergic systems suppresses them. The objective of the present study was to investigate the pharmacological characterization in the attentional processes of a two-lever choice reaction time (CRT) task using different centrally acting drugs. We designed seven parameters in this task: the correct response (CR) rate; error response rate; nonresponse (NR) rate; differential reinforcement of other behavior (DRO) responses; number of incorrect lever pressings during both the intertrial interval and DRO periods; the mean CRT of CR; and activity during 30 trials. The compounds produced different profiles at each dose. 1) Facilitative and disruptive effects on attentional processes occurred with changes in CRT alone. Scopolamine (0.1 mg/kg) and prazosin (0.3-1 mg/kg) prolonged the CRT, whereas methamphetamine (0.3 mg/kg) shortened the CRT. 2) Attentional deficits occurred with abnormal behavior showing premature response or perseverative behavior. Scopolamine (0.2-1 mg/kg), methamphetamine (3 mg/kg), delta(9)-tetrahydrocannabinol (10 mg/kg), and MK-801 (0.1-0.3 mg/kg) produced a marked increase in the number of total lever pressings. 3) Motor function deficits rather than attentional deficits occurred. 8-OH DPAT (1 mg/kg) and muscimol (1 mg/kg) produced a decrease in CR and an increase in NR with a marked decrease in activity and prolonged the CRT. Activating noradrenergic alpha(1) receptors was found to enhance the attentional processes, while blocking muscarinic receptors, alpha(1) receptors, and NMDA receptors, and stimulating cannabinoid receptors and the dopaminergic systems impaired the attentional processes in the two-lever CRT task.     

Expression of cIAP1, a target for 11q22 amplification,correlates with resistance of cervical cancers to radiotherapy

Inhibition of, or increased resistance to, apoptosis is a common property of cancer cells. This means that a constitutive activation of antiapoptotic molecules via genetic or epigenetic mechanisms, including gene amplification, may well be involved in carcinogenesis. Recently we reported that cIAP1, an inhibitor of apoptosis, is overexpressed through 11q22 amplification in cell lines derived from esophageal squamous cell carcinomas and is associated with resistance of esophageal squamous cell carcinomas to drug-induced apoptosis (I. Imoto et al. Cancer Res., 61: 6629-6634, 2001). Because amplification of 11q22 has been implicated in other malignancies also, including cervical squamous cell carcinomas (CSCCs), we attempted to correlate amplification and overexpression of cIAP1 with radiation sensitivity in CSCC-derived cell lines and primary CSCC tumors. In the nine cell lines we examined, two showed amplification and consistent overexpression of cIAP1, as well as significant resistance to radiation-induced cell death as compared with lines showing no cIAP1 amplification. Immunohistochemical analysis of 70 primary CSCCs from patients treated only with radiotherapy demonstrated that both overall survival and local recurrence-free survival was significantly poorer among patients with tumors showing high levels of nuclear cIAP1 staining than among patients whose tumors revealed little or no nuclear cIAP1. Multivariate analysis showed nuclear cIAP1 staining to be an independent predictive factor for local recurrence-free survival after radiotherapy among patients with CSCC. These findings demonstrate that cIAP1 may play an important role in the development/progression of this disease and that cIAP1 could be a novel predictive marker for resistance to radiotherapy in individual CSCC patients.     

Pathologic features of superficial esophageal squamous cell carcinoma with lymph node and distal metastasis

BACKGROUND: Endoscopic mucosal resection (EMR) is a less invasive localized treatment for patients with esophageal carcinoma. However, indications for EMR use in cases of superficial esophageal carcinoma are controversial. The authors evaluated histopathologic risk factors for lymph node metastasis and recurrence. METHODS: In the specimens resected, the authors examined depth, the superficial area and the area attached to or infiltrating the lamina muscularis mucosa. RESULTS: The authors found that the superficial area and the attached or infiltrated area reflected the depth of the tumor. However, there was a recurrence of esophageal carcinoma even in m3 cases attached only to the lamina muscularis mucosa. CONCLUSIONS: The authors concluded that ml and m2 esophageal carcinoma had almost no risk of lymph node metastasis and recurrence no matter how extensive the superficial area. In addition, sm2 and sm3 carcinoma have a high frequency of lymph node metastasis and recurrence. M3 and sm1 carcinoma run the risk of lymph node metastasis and recurrence however small the superficial area and the area attached to or infiltrating the lamina muscularis mucosa. Treatment strategies for patients with superficial esophageal carcinoma, including EMR, should take the above findings into account.     

Vasopressin receptor knockout mice as an animal model of psychiatric disorders]

Arginine vasopressin (AVP) is a neurohypophyseal peptide best known as an antidiuretic hormone. AVP receptors have been classified into three subtypes: V1a, V1b, and V2 receptors. The V1a receptor (V1aR) and V1b receptor (V1bR) are widely distributed in the central nervous system, including the cortex and hippocampus. In the present study, we examined the performance of V1aR or V1bR knockout (KO) mice compared to wild-type (WT) mice in behavioral tests. V1aR KO mice exhibited impairments of spatial learning (eight-arm radial maze), prepulse inhibition (PPI) and social behavior in comparison to WT mice. On the other hand, V1bR KO mice also displayed impairments of PPI and social behavior. These results suggest that V1aR and V1bR may be involved in psychiatric disorders associated with impairments of sensorimotor gating and social behavior such as schizophrenia and autism.     

Memory and learning-enhancing effect of Daikenchuto, a traditional Japanese herbal medicine, in mice

The effect of Daikenchuto (DKT), a traditional Japanese herbal medicine (Kampo medicine), and its constituents (ginger rhizome, ginseng root, rice gluten and Zanthoxylum fruit) on the memory formation process was examined in mice by means of a Morris water maze test. The administration of DKT [300–4000 mg/kg, administered orally (p.o.)] for 3 consecutive days dose-dependently shortened the time required by the mice to find the platform in the water maze test relative to the control. Among the four constituents of DKT, the extract of Zanthoxylum fruit (70 mg/kg, the dose equivalent to 4000 mg/kg DKT) administered p.o. for 3 consecutive days significantly promoted the memory and learning rate. The memory- and learning-enhancing effect was potently elicited by 5 mg/kg (p.o., 2 days) hydroxy-sanshool, the active component of the ethyl acetate fraction of Zanthoxylum fruit. In another series of experiments with the water maze test, the administration of scopolamine [1 mg/kg, intraperitoneally (i.p.)] for 3 consecutive days significantly prolonged the time needed by the mice to find the platform. The subsequent administration of DKT (4000 mg/kg, p.o.) for 3 consecutive days possessed an abatement effect on the scopolamine-induced dementia. The present results indicate that DKT and, more specifically, its constituent Zanthoxylum fruit and the active component of Zanthoxylum fruit, hydroxy-sanshool, all have a memory- and learning-enhancing effect and are probably associated with the release of acetylcholine from neuronal terminals in the brain.     

Effects of estrogen on female mouse thymus, with special reference to ER-mRNA and T cell subpopulations

The effect of estrogen (E), a female sex steroid, on the thymus tissues from castrated female mice treated with E was examined by molecular biologic, microscopic and flowcytometric techniques.

First, using an oligoprobe for E receptor (ER)-messenger RNA (ER-mRNA), one hybridized band was found at 6.2 kilobase (kb) in mouse thymus tissue, as was also the case in the human breast cancer MCF-7 cell line. ER-mRNA level in the E-treated animals was almost 3 times that in oil-treated controls.

Secondly, an electron microscopic observation indicated E treatment to bring about apoptosis of thymocytes (T cell) which were embraced by thymic stromal cells (possibly phagocytic in nature) and/or ballooning of the endoplasmic reticulum in the epithelial cells with abundant lipid droplets.

Thirdly, flow cytometric analysis demonstrated E to induce the change of T cell subpopulations: an increase in helper/inducer (L₃T⁺₄Lyt⁻₂) cells with decrease in the double positive (L₃T⁺₄Lyt⁺₂) cells.

It follows from the above findings that E may cause morphologic changes in the thymus closely related to T cell differentiation. In addition, these changes appear to derive mainly from E-induced tissue-specific gene expression including that of ER-mRNA.