Brain from lithium

Of as yet unknown consequence to the brain and nervous system, there are many studies indicating that valproic acid promotes a variety of potentially dangerous viruses (e.g., Fan et al., 2005). Both valproic acid and carbamazepine cause a small increase in the rate of major congenital malformations in infants (Wide et al., 2004). Acute and potentially fatal pancreatitis has been reported with valproic acid (e.g., Grauso-Eby et al., 2003). Liver failure is a known problem as well. Valproic acid is known to cause hyperammonemia with encephalopathy (e.g., McCall et al., 2004). Severe and even lethal skin disorders can occur with all of the antiseizure medications now used as mood stabilizers. The various adverse effects of valproic acid and other mood stabilizers are not nearly as benign as physicians believe in their eagerness to switch patients from lithium. 

Fig. 3. (A) Autoradiograms of Northern blots (top), and mRNA levels normalized to mRNA for P-actin (bottom) for cPLA and iPLA in brains of control rats and rats treated with lithium for 6 wk. Means SEM ( = 5). p < 0.001. (B) Autoradiograms of Western blots (top) and levels of cPLAj protein (bottom) in brains from control and chronic lithium-treated rats. Means SEM (n = 8). p < 0.001. (From Rintala et al., 1999).

To date, there have only been a limited number of studies directly examining PKC in bipolar disorders [77], Although undoubtedly an oversimplification, particulate (membrane) PKC is sometimes viewed as the more active form of PKC, and thus an examination of the subcellular partitioning of this enzyme can be used as an index of the degree of activation. Friedman etal. [78] investigated PKC activity and PKC translocation in response to serotonin in platelets obtained from bipolar-disorder patients before and during lithium treatment. They reported that the ratios of platelet-membrane-bound to cytosolic PKC activities were elevated in the manic patients. In addition, serotonin-elicited platelet PKC translocation was found to be enhanced in those patients. With respect to brain tissue, Wang and Friedman [74] measured PKC isozyme levels, activity and translocation in postmortem brain tissue from patients with bipolar disorder, and reported increased PKC activity and translocation in the brains of bipolar patients compared with controls, effects which were accompanied by elevated levels of selected PKC isozymes in cortices of bipolar disorder patients. 

Lithium. Lithium has also been used in an attempt to circumvent craving. Like alcohol dependence, cocaine-dependent craving is believed by some, based on limited data, to result from a kindling effect that begins in one area of the brain and spreads to induce an intense desire to use. Lithium s success in treating bipolar disorder, another purportedly kindling-dependent illness, led to its use for cocaine dependence. Unfortunately, lithium has not proved very helpful and has been abandoned in the treatment of cocaine dependence. 

Kosbash You mentioned briefly inositol monophosphatase. My impression from the literature, and in particular the recent Nature paper (Williams et al 2002), is that somewhat more than half of the people interested in brain neurochemistry and lithium would vote for the inositol pathway rather than GSK3. In any case, it is up for grabs. 

Lithium is readily absorbed from the gastrointestinal tract, reaching a peak plasma level in 2 to 4 hours. Distribution occurs throughout the extracellular fluid with no evidence of protein binding. Passage through the blood-brain barrier is limited, so that cerebrospinal fluid levels are 50% of plasma levels at steady state. 

Considerable effort over the years has been expended to identify specific neurotransmitter systems that might mediate the therapeutic action of lithium in the treatment of patients with bipolar disorder. As we critically review the evidence from these studies, it will be evident that lithium can affect a variety of neurotransmitter systems, but these effects may be secondary to more fundamental modulation of signal transduction responsible for regulating the balance of signaling in critical regions of the brain. 

Evidence accumulating from various laboratories points to a role for PKC in mediating the action of lithium in a number of cell systems and the brain (Manji and Lenox 1994, in press]. Currently available data suggest that short-term lithium exposure facilitates a number of PKC-mediated responses, whereas longer-term exposure results in an attenuation of phorbol ester-mediated responses, which may be accompanied by a downregulation of PKC (S. M. P. Anderson et al. 1988 J. A. Bitran et al. 1990 M. S. Evans et... 

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Eriedman E, Wang H-Y Effect of chronic lithium treatment on 5-hyroxytryptamine autoreceptors and release of 5-[3H]hydroxytryptamine from rat brain cortical, hippocampal, and hypothalamic slices. J Neurochem 50 195-201, 1988 Eriedman E, Dallob A, Levine G The effect of long-term lithium treatment on reser-pine-induced supersensitivity in dopaminergic and serotonergic transmission. life Sci 25 1263-1266, 1979... 

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