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Eur J Neurosci. 2002 Nov;16(9):1690-6.
Modulation of secretion by the endoplasmic reticulum in mouse chromaffin cells.

Rigual R, Montero M, Rico AJ, Prieto-Lloret J, Alonso MT, Alvarez J.

Instituto de Biologia y Genetica Molecular (IBGM), Departamento de Bioquimica y Biologia Molecular y Fisiologia, Facultad de Medicina, Universidad de Valladolid and Consejo Superior de Investigaciones Cientificas (CSIC), E-47005 Valladolid, Spain.

The endoplasmic reticulum (ER) has been suggested to modulate secretion either behaving as a Ca2+ sink or as a Ca2+ source in neuronal cells. Working as a Ca2+ sink, through ER-Ca2+ pumping, it may reduce secretion induced by different stimuli. Instead, working as a Ca2+ source through the Ca2+ induced Ca2+ release (CICR) phenomenon, it may potentiate secretion triggered by activation of plasma membrane Ca2+ channels. We have previously demonstrated the presence of CICR in bovine chromaffin cells, but we now find that mouse chromaffin cells almost lack functional caffeine-sensitive ryanodine receptors in the ER and, consistently, no CICR from the ER could be observed. In addition, inhibition of ER Ca2+ pumping with ciclopiazonic acid or thapsigargin strongly stimulated high-K+-evoked catecholamine secretion and cytosolic [Ca2+] ([Ca2+]c) transients. Surprisingly, 5 mm caffeine reduced high-K+-induced [Ca2+]c peaks but considerably potentiated secretion induced by high-K+ stimulation. However, this potentiation was insensitive to ryanodine and additive to that induced by emptying the ER of Ca2+ with thapsigargin, suggesting that it is unrelated to the activation of ryanodine receptors. We conclude that, in mouse chromaffin cells, CICR is not functional and the ER strongly inhibits secretion by acting as a damper of the [Ca2+]c signal.

online pharmacy ref. source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12431221&dopt=Abstract

Eur J Pharmacol. 2000 Oct 20;406(3):345-54.
Lack of tolerance to motor stimulant effects of a selective adenosine A(2A) receptor antagonist.

Halldner L, Lozza G, Lindstrom K, Fredholm BB.

Department of Physiology and Pharmacology, Section of Molecular Neuropharmacology, Karolinska Institutet, S-171 77, Stockholm, Sweden.

It is well known that tolerance develops to the actions of caffeine, which acts as an antagonist on adenosine A(1) and A(2A) receptors. Since selective adenosine A(2A) antagonists have been proposed as adjuncts to 3,4-dihydroxyphenylalanine (L-DOPA) therapy in Parkinson's disease we wanted to examine if tolerance also develops to the selective A(2A) receptor antagonist 5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo-[4,3-e]-1,2, 4-triazolo [1,5-c]pyrimidine (SCH 58261). SCH 58261 (0.1 and 7.5 mg/kg) increased basal locomotion and the motor stimulation afforded by apomorphine. Neither effect was subject to tolerance following long-term treatment with the same doses given intraperitoneally twice daily. There were no adaptive changes in A(1) and A(2A) adenosine receptors or their corresponding messenger RNA or in dopamine D(1) or D(2) receptors. These results demonstrate that the tolerance that develops to caffeine is not secondary to its inhibition of adenosine A(2A) receptors. The results also offer hope that long-term treatment with an adenosine A(2A) receptor antagonist may be possible in man.

online pharmacy ref. source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11040341&dopt=Abstract

J Neurosci Methods. 2000 Oct 30;102(2):117-25.
The plus-maze discriminative avoidance task: a new model to study memory-anxiety interactions. Effects of chlordiazepoxide and caffeine.

Silva RH, Frussa-Filho R.

Departamento de Farmacologia, Escola Paulista de Medicina, Universidade Federal de Sao Paulo, Rua Botucatu, 862-Edificio Jose Leal Prado, CEP 04023-062 Sao Paulo, SP, Brazil.

The plus-maze discriminative avoidance paradigm is a new animal model of learning/memory that provides simultaneous information about anxiety. Mice are conditioned to choose between the two enclosed arms (in one of which light and noise are presented as aversive stimuli) while avoiding the two open arms of the apparatus. The test has the advantage of measuring, at the same time and in the same animals, learning/memory (by the percent time spent in aversive enclosed arm - PTAV) and anxiety (by the percent time spent in the open arms - PTO). The effects of chlordiazepoxide and caffeine on learning/memory and anxiety of mice tested in this paradigm were investigated. Chlordiazepoxide (5 mg/kg) significantly increased and caffeine (20 mg/kg) significantly decreased PTO during the training session, suggesting an anxiolytic and an anxiogenic effect, respectively. In the test session, chlordiazepoxide- or caffeine-treated mice presented higher PTAV, suggesting amnestic effects. Given together, chlordiazepoxide plus caffeine did not alter PTO, and the amnesic effect produced by each drug was no longer observed. It is concluded that learning/memory depends on an optimum emotional level. The plus-maze discriminative avoidance model appears to be a useful test to investigate this critical relationship between learning/memory and anxiety.

online pharmacy ref. source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11040408&dopt=Abstract

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