Biomedical subjects

D F Papolos

Publications and source records attributed to D F Papolos.

22 records · Page 2Linked to original sources

PubMed1991

Lithium augments pilocarpine-induced fos gene expression in rat brain.

Lithium salts are considered the most effective agents used in treating manic-depression. Previous studies in PC12 pheochromocytoma cells indicate that lithium has a dramatic augmenting effect on expression of the fos proto-oncogene, a component of the AP-1 transcription factor. Although fos expression is activated by agonists that function through different signal transduction pathways, the lithium augmenting effect appears to be specific for receptor and post-receptor stimulators of protein kinase C (PKC). In particular, fos induction mediated by the m1 muscarinic receptor linked to PKC activation was found to be exquisitely sensitive to lithium enhancement. We now show that a similar augmenting effect can be demonstrated in rat brain. Following treatment with the muscarinic agonist pilocarpine, fos mRNA accumulates in the cortex, an effect that is blocked by the m1 antagonist pirenzepine. Rats treated with a single intraperitoneal injection of lithium chloride exhibited a substantial increase in pilocarpine-mediated fos expression. In contrast, fos expression induced in several brain regions by a single electroconvulsive shock is not augmented by lithium. The finding that short-term treatment with lithium enhances fos expression in the brain suggests a mechanism for its therapeutic action.

Animals↗

PubMed1991

Differential effect of lithium on fos protooncogene expression mediated by receptor and postreceptor activators of protein kinase C and cyclic adenosine monophosphate: model for its antimanic action.

Lithium salts are the most effective agents used in treating manic-depressive illness. It has been suggested that lithium's therapeutic efficacy could be due to an inhibitory effect on either inositol phospholipid (IP) and/or cyclic nucleotide metabolism. We have investigated the effect of lithium on these two signal transduction pathways in PC12 pheochromocytoma cells by studying a common effector target, expression of the fos protooncogene. We find that lithium, at therapeutic doses, has an augmenting effect on phosphatidylinositol (PI)-mediated fos expression induced by activating a muscarinic cholinergic pathway, whereas it has no effect, at tenfold the therapeutic dose, on fos expression induced by receptor or postreceptor activators of cyclic adenosine monophosphate (cAMP). The lithium augmenting effect is also observed when the cells are treated with phorbol esters, which directly activate protein kinase C (PKC), suggesting that the level of lithium's interaction with the IP pathway is at the postreceptor level. We also show that phorbol esters induce extensive down regulation of subsequent cholinergic and phorbol ester responsiveness as well as heterologous down regulation of cAMP responses. Treatment of down-regulated cells with lithium leads to an enhanced responsiveness when cells are rechallenged with agonists that activate PKC but not by agonists that stimulate cAMP. We also show that carbamazepine, another antimanic agent, has an inhibitory effect on cAMP-mediated fos but no effect on the IP pathway. The opposite effects of lithium and carbamazepine on two critical transducing systems suggest a model for the antimanic action of these agents.

Adrenal Gland Neoplasms↗

PubMed1990

Lithium augments fos protoonocogene expression in PC12 pheochromocytoma cells: implications for therapeutic action of lithium.

It has been proposed that lithium's antimanic action is due to an effect on phosphoinositide metabolism. Second messengers generated by this pathway regulate calcium mobilization and the activity of the serine and threonine kinase, protein kinase C (PKC). Included among the targets of PKC is activation of fos protooncogene expression, a well-established component of the AP-1 transcription factor. Because of these interactions, we investigated the effect of lithium on fos gene expression in PC12 pheochromocytoma cells. We find that lithium increases the level of fos mRNA that occurs in response to receptor and postreceptor activation of PKC. Treatment with lithium also leads to an augmentation of muscarinic cholinergic-mediated fos gene expression in cells that are down-regulated as a result of excessive cholinergic stimulation. The ability of lithium to enhance the response of a down-regulated cholinergic system suggests a model for its therapeutic efficacy in affective disorders.

Adrenal Gland Neoplasms↗

PubMed1989

Abnormal signal transduction: a hypothetical model for bipolar affective disorder.

The molecular basis of bipolar affective disorder is poorly understood at this time. The episodic nature of the condition in which relatively euthymic periods of variable duration separate periods of mania and depression, and the specificity of lithium therapy suggests that a molecular target of the illness may be a system that bidirectionally influences neurotransmission and is affected by lithium. Signal transduction pathways, which are important mediators of neurotransmitter generated signals, may represent such a system because they: 1) generate second messenger molecules that stimulate neurotransmission and also mediate negative feedback mechanisms, and 2) appear to be a direct target of lithium's action on cells. In this paper, we present a model in which abnormal regulation of signal transduction could lead to the episodic accumulation of biologically active transducers or second messengers. These alterations may result in prolonged effector stimulation which may underlie mania, followed by excessive receptor desensitization, which may result in depression. Using our model we suggest a plausible hypothesis that can explain the clinical spectrum of the disorder and the therapeutic action of lithium.

Bipolar Disorder↗