As described above, lithium inhibits GSK-3 and inositol phosphate signalling and both pathways have therefore been suggested to be involved in BD. The best current hypothesis describing how lithium functions in the treatment of BD is the
'inositol depletion' hypothesis of Berridge et al.40 This theory suggests that the cause of BD may be overactive InsP signalling in the brain of these patients, and this may be reduced by the inhibitory effect of lithium on InsP signalling (Figure 1.4). In principle, therefore, lithium-based inositol-depletion effects should be reversed by addition of inositol to the test system, and this has been shown in many experiments. In vivo, it has been shown that lithium causes the suppression of rearing in rats, and this effect is overcome by intra-cerebroventricular injection of inositol. A more defined effect is seen with limbic seizures induced by pilocarpine, a compound that induces epileptic fits, which can be blocked by injection of lithium. Again, this effect can be suppressed by inositol. Using this 'inositol rescue' criterion, a number of brain physiological and behavioural effects of lithium have been ascribed to changes in InsP signalling. In reality, experiments using this 'inositol rescue' process are complicated by the fact that inositol uptake can be inhibited at high exogenous inositol levels,41 therefore causing similar effects to lithium treatment. Caution must therefore be taken when inositol addition fails to reverse lithium effects.
One way that scientists are trying to identify which of lithium's targets is responsible for mood control is by examining other BD drugs to see if they also affect these targets. This has proved to be a contentious area of research. In support of the involvement of InsP signalling as the therapeutic target of lithium, researchers have found that all three commonly used BD drugs (lithium, VPA and CBZ) function to increase the size of neuronal growth cones, the developing tip of a mammalian neuron.36 This increase was shown to be overcome by the addition of inositol to these cells, thus implicating inositol depletion as the common mechanism of action of BD drugs. Furthermore, both lithium and VPA decrease the amount of inositol in the rat brain43 and change membrane lipid concentration, a process directly linked to inositol signalling.44 Indeed, a recent study in BD patients suggests altered InsP signalling may be corrected by both VPA and lithium,45 and these patients show altered activity of PO (see section 4.2),37,39 an enzyme which controls InsP signalling.18,36,46 The common effect of structurally diverse BD drugs on InsP signalling therefore strongly suggests this is the therapeutic target of these drugs.
The case for lithium acting on GSK-3 in the treatment of BD is weaker and centred around two sets of observations. First, inhibition of GSK-3 alters the structure of cerebella neurons. If a similar process occurred in other parts of the brain, e.g. the hippocampus and the frontal cortex, this could change brain function. Secondly, lithium is a neuro-protective agent, and can reduce the hypersensitivity to toxic insults seen in cells that overexpress GSK-3. It is therefore possible that lithium could protect against disease-induced cell death. Studies have shown that both bipolar and unipolar depressed patients show a decreased volume of prefrontal cortex grey matter,47 and this may be associated with a reduction in the number of glial cells,48 and reduced numbers of both glial and neuronal cells have been found in postmortem studies of these patients.49 Lithium treatment has also been shown to increase the volume of grey matter in the human brain.50
Interestingly, GSK-3 has been implicated in the origins of schizophrenia. Both the Wnt receptor Frizzled-3 (Fz3) and PKB protein have been associated with schizophrenia51 53 (Figure 1.2). Although the Fz3 association is only genetic, PKB polymorphisms have been found to directly reduce PKB expression. Treatment with the anti-psychotic haloperidol increases activity of the kinase PDK-1, an upstream activator of PKB. As PKB inhibits GSK-3 activity, these observations suggest that GSK-3 may be elevated in schizophrenic patients. Early reports on the use of lithium suggest that it may be active against schizophrenic patients, but with the availability of many anti-psychotic drugs it is not in common usage.
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