A mechanism used by cells to regulate their volume under hypo-osmotic conditions is the release of organic osmolytes, one of which is myo-inositol. The possibility that activation of phospholipase-C-linked receptors can regulate this process has been examined for SH-SY5Y neuroblastoma cells. Incubation of cells with hypo-osmolar buffers (160-250 mOsm) led to a biphasic release of inositol which persisted for up to 4 h and could be inhibited by inclusion of anion channel blockersresults which indicate the involvement of a volume-sensitive organic anion channel. Inclusion of oxotremorine-M, a muscarinic cholinergic agonist, resulted in a marked increase (80-100%) in inositol efflux under hypo-osmotic, but not isotonic, conditions. This enhanced release, which was observed under all conditions of hypo-osmolarity tested, could be prevented by inclusion of atropine. Incubation of the cells with either the calcium ionophore, ionomycin, or the phorbol ester, phorbol 12-myristate 13-acetate, partially mimicked the stimulatory effect of muscarinic receptor activation when added singly, and fully when added together. The ability of oxotremorine-M to facilitate inositol release was inhibited by removal of extracellular calcium, depletion of intracellular calcium or down-regulation of protein kinase C. These results indicate that activation of muscarinic cholinergic receptors can regulate osmolyte release in this cell line. Keywords: calcium, muscarinic cholinergic receptors, myoinositol, osmolyte, protein kinase C, volume regulation. Regulation of cell volume is essential for many physiological processes and is of prime importance to the CNS, because of the restricted volume of the skull. Brain cells can swell in response to either changes in plasma osmolarity (hypoosmotic swelling) or from changes in intracellular ion and water distribution (isotonic swelling). The latter is also referred to as cellular or cytotoxic edema (Kimelberg 2000; Pasantes-Morales et al. 2000). Hypo-osmotic swelling frequently occurs as a result of hyponatremia, which is associated with clinical conditions such as congestive heart failure, nephrotic syndrome and hepatic cirrhosis. Water overload may also occur in some psychiatric disorders, such as schizophrenia, or in athletes and in instances of the inappropriate secretion of anti-diuretic hormone. The majority of symptoms observed are neurological and include disorientation, mental confusion and seizures.In response to hypo-osmotic stress, neural cells swell, and to restore osmotic balance a loss of K + and Cl -ions is initially observed. However, as large changes in ion concentrations can adversely impact cell excitability, cells subsequently utilize 'compatible' or 'non-perturbing' osmolytes which are specifically designed to counter changes in osmolarity without compromising cell function. Three distinct classes of osmolytes can be identified, namely (i) amino acids, such as glutamate or taurine, (ii) methylamines, such as betaine and glycerophosphorylcholine, and (iii) polyols, such...
IntroductionAntidepressants that combine serotonergic (SSRI) and noradrenergic (NaRI) actions may have greater efficacy in treating depression than SSRI monotherapy. This theory has not been tested in any trials examining augmentation of SSRIs with a NaRI.ObjectivesDoes augmenting SSRIs with reboxetine, a NaRI, in depressed patients unresponsive to first line treatment, result in improved antidepressant efficacy?MethodsIn a naturalistic observational study, 30 patients with moderate to severe depression (ICD-10) who failed to respond to at least 20 mg of a SSRI, were augmented with reboxetine (4 mg increased to 8 mg if tolerated). BDI-II was measured before and 6 weeks after introduction of reboxetine. Changes in BDI scores were analysed using paired t-test.Results20 out of 30 patients were able to tolerate the combination of SSRI and reboxetine treatment for at least 6 weeks. There was a significant reduction in mean BDI-II scores from 36.6 at baseline to 27.2 at six weeks follow-up (t = 4.13, df = 29, p < 0.001). 13 out of 30 previously unresponsive patients showed a response (reduction in BDI score of at least 10 points) to combination treatment, with 5 patients achieving remission (BDI < 12) over the six weeks.ConclusionsReboxetine augmentation of SSRIs can be tolerated by a majority of patients and results in a significant increase in response rates. It is a treatment strategy that should be considered in patients with moderate to severe depression who fail to respond to first line treatment with an SSRI.
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