The use of antidepressants for bipolar depression.

Clinical Dilemma: You have diagnosed a 33-year-old male with bipolar disorder and initiated lithium treatment and psycho-social therapy. Two months later his lithium level is within the therapeutic range but his symptoms and function level correlate with moderate depressive episode. Is there a place for adjunctive antidepressant medication?

Membrane depolarization combined with Gq-activated G-protein-coupled receptors induce transient receptor potential channel 1 (TRPC1)- dependent potentiation of catecholamine release.

Agonists of the Gq/11-activated G-protein-coupled receptors (GPCRs) combined with strong membrane depolarization (high KCl) induce a synergistic amplification of transmitter release. The molecular basis for the synergy is unknown. Here, we investigated this potentiated transmitter release (PTR) phenomenon at the single cell level by monitoring catecholamine (CA) release in chromaffin cells using amperometry. We found that the 60 mM KCl (K60)-triggered release in bovine chromaffin cells synergizes with bradykinin (BK) or histamine (Hist) to potentiate CA release. PTR was independent of Ca2+ influx through voltage-gated calcium channels (VGCC), but required Ca2+ at the extracellular medium and was abolished by inhibitors of phospholipase Cß (PLCß). The∼four-fold PTR induced in mouse chromaffin cells by BK and K60, was not observed in chromaffin cells prepared from TRPC1 KO mice and was restored by expressing hTRPC1. The synergy between strong voltage perturbation (K60) in the presence of VGCC blockers, and the activation of the Gq/11-PLCß signal-transduction cascade generates unique and fundamental amplified signaling machinery. The concerted activation of two independent cellular pathways could reinforce physiological signals that impinge on regulation of secretory events during repeated sequence of high-frequency excitation, hyperpolarization, and relief of inhibition such as long-term potentiation (LTP), that lead to neuronal synaptic plasticity.

Selective inhibition of Ras-dependent cell growth by farnesylthiosalisylic acid.

S-trans,trans-Farnesylthiosalicylic acid (FTS) is a novel farnesylated rigid carboxylic acid derivative. In cell-free systems, it acts as a potent competitive inhibitor (Ki = 2.6 microM) of the enzyme prenylated protein methyltransferase (PPMTase), which methylates the carboxyl-terminal S-prenylcysteine in a large number of prenylated proteins including Ras. In such systems, FTS inhibits Ras methylation but not Ras farnesylation. Inhibition of the PPMTase by FTS in homogenates or membranes of a variety of tissues and cell lines is inferred from a block in the methylation of exogenously added substrates such as N-acetyl-S-trans,trans-farnesyl-L-cysteine and of endogenous substrates including small GTP-binding proteins. FTS can also inhibit methylation of these proteins in intact cells (e.g. in Rat-1 fibroblasts, Ras-transformed Rat-1, and B16 melanoma cells). Unlike in cell-free systems, however, relatively high concentrations of FTS (50-100 microM) are required for partial blocking (10-40%) of protein methylation in the intact cells. Thus, FTS is a weak inhibitor of methylation in intact cells. Because methylation is the last step in the processing of Ras and related proteins, FTS is not likely to affect steps that precede it, e.g. protein prenylation. This may explain why the growth and gross morphology of a variety of cultured cell types (including Chinese hamster ovary, NIH3T3, Rat1, B16 melanoma, and PC12) is not affected by up to 25 microM FTS and is consistent with the observed lack of FTS-induced cytotoxicity. Nevertheless, FTS reduces the levels of Ras in cell membranes and can inhibit Ras-dependent cell growth in vitro, independently of methylation. It inhibits the growth of human Ha-ras-transformed cells (EJ cells) and reverses their transformed morphology in a dose-dependent manner (0.1-10 microM). The drug does not interfere with the growth of cells transformed by v-Raf or T-antigen but inhibits the growth of ErbB2-transformed cells and blocks the mitogenic effects of epidermal and basic fibroblast growth factors, thus implying its selectivity toward Ras growth signaling, possibly via modulation of Ras-Raf communication. Taken together, the results raise the possibility that FTS may specifically interfere with the interaction of Ras with a farnesylcysteine recognition domain in the cell membrane.(ABSTRACT TRUNCATED AT 400 WORDS)

Farnesyl derivatives of rigid carboxylic acids-inhibitors of ras-dependent cell growth.

Inhibitors of the enzyme that methylates ras proteins, the prenylated protein methyltransferase (PPMTase), are described. They are farnesyl derivatives of rigid carboxylic acids that recognize the farnesylcysteine recognition domain of the enzyme but do not serve as substrates. They also inhibit ras-dependent cell growth by a mechanism that is probably unrelated to inhibition of ras methylation, even though their potencies as PPMTase inhibitors and cell-growth inhibitors correlate well. The most potent inhibitor is S-trans,trans-farnesylthiosalicylic acid (FTS) (2). FTS (2) selectively inhibits the growth of human Ha-ras-transformed Rat1 cells in vitro (EC50 = 7.5 microM).

Changes in serum, liver and kidneys of cisplatin-treated rats; effects of antioxidants.

Cisplatin, a nephrotoxic chemotherapeutic agent, was injected into Sprague Dawley rats, alone or together with cysteine, vitamin E and clonidine. The effects on erythrocyte fragility, serum composition, and kidney and liver enzymes were studied. Cisplatin was administered as two i.p. injections (6 mg/kg body weight) at an interval of 120 hours. The animals were sacrificed 24 hours after the second injection. Erythrocytes were prepared from blood collection with anticoagulant. Serum was prepared from clotted blood, collected without anticoagulant. Kidneys and liver were removed and homogenized, and a supernatant prepared by high speed centrifugation. In cisplatin-treated rats, the serum activities of aspartate aminotransferase, alanine aminotransferase, lactic dehydrogenase and alkaline phosphatase were significantly decreased, whereas the activities of isocitric dehydrogenase and glutathione reductase were increased. Also, concentrations of blood urea nitrogen, creatinine, total lipids and magnesium increased while albumin and glucose decreased. Mean osmotic fragility of erythrocytes from cisplatin-treated rats was decreased, while the haematocrit was increased. In the liver, the only change seen was an increased activity of isocitric dehydrogenase. Much greater changes were found in the kidneys, with increased activity of glucose-6-phosphate dehydrogenase and decreased activities of aspartate and alanine aminotransferases, alkaline phosphatase, malic dehydrogenase, sorbitol dehydrogenase and gamma-glutamyltransferase, as well as a decreased phosphorylation to oxidation ratio in the mitochondria, indicating reduced adenosine triphosphate production. Administration of cysteine and vitamin E together with cisplatin partially reversed the uraemia and many of the biochemical changes induced by cisplatin.(ABSTRACT TRUNCATED AT 250 WORDS)

Lack of correlation between 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and lovastatin resistance in nerve growth factor treated PC-12 cells.

1. The relationships among the mevalonic acid (MVA) forming enzyme, 3-hydroxy-3-methylglutaryl coenzyme A (CoA) reductase, cell growth and differentiation, and the cytotoxic effects of the reductase inhibitor lovastatin were studied in PC-12 cells, exposed to growth factors. 2. When added individually, nerve growth factor (NGF), basic fibroblast growth factor, and epidermal growth factor induce an increase in HMG-CoA reductase activity in cells grown in serum-containing medium. In the presence of serum, the effect of NGF on HMG-CoA reductase is persistent. 3. Short-term serum starvation and long-term NGF treatment, in combination, have an additive effect, resulting in a high reductase activity. 4. Unlike serum and MVA, which downregulate levels of HMG-CoA reductase by accelerating its degradation, NGF upregulates reductase by slowing the rate of its degradation. This mechanism, however, appears to operate only in the presence of serum, as after prolonged growth with NGF in serum-free medium, cells have a low reductase activity. 5. PC-12 cells grown in the absence of NGF are highly sensitive to lovastatin (25 microM) and more than 70% of the cells die after 48 hr. NGF confers lovastatin resistance on cells grown in the presence or in the absence of serum (only 30-40% cell death after 48 hr with lovastatin). 6. NGF-induced resistance on lovastatin develops with time and is apparent only in the well-differentiated PC-12 cells whether or not the cells express a high reductase activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Training teachers as facilitators of mental health: 'Psychotherapy of the Role'.

This paper describes an attempt to stimulate positive mental health in the classroom. It was carried out by a group of psychologists who experimented with mental health consultation ideas and techniques and developed a model of working with groups of teachers. This model focuses on discussion topics chosen by the teachers (such as envy). The psychologist provides relevant psychological knowledge. Teachers discuss the issues experientially, clarifying their feelings and often uncovering disruptive personal biases in their work. An attempt is made to understand the point of view of teacher and child, both developmentally and interpersonally. Practical implications for the classroom are discussed. In evaluating the project teachers expressed satisfaction with the groups and reported improvement in their ability to cope with the emotional problems of their students. The authors call this approach 'Psychotherapy of the Role'.