The alpha7 subunit of the neuronal nicotinic acetylcholine receptor (nAChR) is abundantly expressed in hippocampus and is implicated in modulating neurotransmitter release and in binding alpha-bungarotoxin (alpha-BGT). A null mutation for the alpha7 subunit was prepared by deleting the last three exons of the gene. Mice homozygous for the null mutation lack detectable mRNA, but the mice are viable and anatomically normal. Neuropathological examination of the brain revealed normal structure and cell layering, including normal cortical barrel fields; histochemical assessment of the hippocampus was also normal. Autoradiography with [3H]nicotine revealed no detectable abnormalities of high-affinity nicotine binding sites, but there was an absence of high-affinity [125I]alpha-BGT sites. Null mice also lack rapidly desensitizing, methyllycaconitine-sensitive, nicotinic currents that are present in hippocampal neurons. The results of this study indicate that the alpha-BGT binding sites are equivalent to the alpha7-containing nAChRs that mediate fast, desensitizing nicotinic currents in the hippocampus. These mice demonstrate that the alpha7 subunit is not essential for normal development or for apparently normal neurological function, but the mice may prove to have subtle phenotypic abnormalities and will be valuable in defining the functional role of this gene product in vivo.

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Notaspid snails are known for their defensive skin secretion of sulfuric acid (pH 1–2) in response to noxious stimuli. We observed acid secretion and behavior in five notaspid species, and studied them in detail in Pleurobranchaea californica. All species secreted acid in response to skin abrasion or compression. Moreover, all species showed stereotypic avoidance behavior to acidified sea water less acidic (pH 2–3) then their own secretions. In Pleurobranchaea, secretion could also be stimulated by dilute solutions of taurine, 10−5-10−2moll−1. Secretion began at the stimulated region and spread slowly for about a minute following stimulation. Local contraction and transient edema of the skin were associated with acid secretion. In de-ganglionated preparations secretion could be caused by orthodromic stimulation of body wall nerves, by mechanical stimulation or by taurine. These data suggest that acid secretion is a positive feedback process modulated by inhibitory paths and coordinated by both central and peripheral nervous systems. A picture emerges of a defensive secretory response that provides an additional noxious stimulus initiating or potentiating avoidance behavior. The data also suggest a potential role for taurine release from injured tissue and the existence of specific nociceptive neural pathways regulating complex behavior. In addition to deterring extraspecific predation, acid secretion could regulate interactions between animals of the same species.

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1. TAS-103, a novel condensed quinoline derivative, has been developed as an anticancer drug targeting topoisomerases I and II. 2. The purpose of the present study was to characterize the metabolism and urinary excretion of TAS-103 after the intravenous infusion of a single dose to patients in Phase I clinical trials. 3. Five metabolites were detected using high-performance liquid chromatography (HPLC) photodiode array and a precursor scan by liquid chromatography mass spectrometry mass spectrometry (LC/MS/MS). 4. Structures of the five metabolites were determined using the results of enzymatic hydrolysis and the analysis of production mass spectra obtained by LC/MS/MS, and by comparing HPLC retention times and UV, mass and production mass spectra of authentic standards. 5. The metabolites were identified as demethyl-TAS-103 glucuronide (DM-TAS-103-G), TAS-103 glucuronide (TAS-103-G), TAS-103 glucuronide N-oxide (NO-TAS-103-G), demethyl-TAS-103 (DM-TAS-103) and TAS-103 N-oxide (NO-TAS-103). 6. The mean total amount of TAS-103 and TAS-103-G in urine was only 6.03% of the dose, suggesting that urine is not the main elimination route. TAS-103 was extensively metabolized, and a small percentage of the parent drug (0.41%) was found in urine.