Brain lithium

Kakigi T, Tanimoto K, Maeda K The effect of various antidepressants on the concentration of somatostatin in the rat brain. Jpn J Psychiatry Neurol 44 145, 1990 Kalasapudi VD, Sheftel G, Divish MM, et al Lithium augments fos protoonocogene expression in PC 12 pheochromocytoma cells imphcations for therapeutic action of lithium. Brain Res 521 47-54, 1990... 

Atack, J.R., 1996, Inositol monophosphatase, the putative therapeutic target for lithium. Brain Res. Rev. 22 183-190. 

Electroconvulsive therapy (ECT) is the application of prescribed electrical impulses to the brain for the treatment of severe depression, mixed states, psychotic depression, and treatment-refractory mania in patients who are at high risk of suicide. It also may be used in pregnant women who cannot take carbamazepine, lithium, or divalproex. 

Mechanism of Action Lithium s pharmacologic mechanism of action is not well understood and probably involves multiple effects. Possibilities include altered ion transport, increased intraneuronal catecholamine metabolism, neuroprotection or increased brain-derived neurotrophic factor, inhibition of second messenger systems, and reprogramming of gene expression.29... 

Mechanism of Action The mechanism of action of divalproex is not well understood. It is known to affect ion transport and enhances the activity of y-aminobutyric acid. Like lithium, it also has possible neuroprotective effects through enhancement of brain-derived neurotrophic factor.31... 

Recent studies have demonstrated that lithium (and to a lesser extent VPA) produces, at therapeutically relevant concentrations, complex alterations in basal and/or stimulated DNA-binding of 12-o-tetradecanoyl-phorbol 13-acetate (TPA) response element (TRE) to AP-1 transcription factors. These alterations are produced not only in human SH-SY5Y cells in vitro, but also in rodent brain following chronic, in vivo administration [5, 7, 15-21]. Corresponding to an increase in basal AP-1 DNA-binding activity, lithium and VPA have been shown to increase the expression of a luciferase reporter gene driven by an SV40 promoter that contains TREs in a time- and concentration-dependent fashion. Mutations in the TRE... 

Fig. 20.2 Chronic lithium and valproate robustly increase bcl-2 immunoreactive neurons in the frontal cortex. Male Wistar Kyoto rats were treated with either Li2C03, valproate or saline by twice daily i.p. injections for four weeks. Rats brains were cut at 30 pm serial sections were cut coronally through the anterior portion of the brain, mounted on gelatin-coated glass slides and were stained with thio-nin. The sections of the second and third sets were incubated free-floating for 3 d at 4°C in 0.01 M PBS containing a polyclonal antibody against bcl-2 (N-19, Santa Cruz Biotechnology,...

In view of bcl-2 s major neuroprotective and neurotrophic roles, a study was undertaken to determine if lithium, administered at therapeutically relevant concentrations, affects neurogenesis in the adult rodent brain. To investigate the effects of chronic lithium on neurogenesis, mice were treated with therapeutic lithium (plasma levels 0.97 0.20 mM), for 4 weeks. After treatment with lithium for 14 days, the mice were administered single doses of BrdU (bromodeoxyuridine, a thymidine analog which is incorporated into the DNA of dividing cells) for 12 consecutive days. Lithium treatment continued throughout the duration of the... 

Fig. 20.3 Chronic lithium increases hippocampal neurogenesis. C57BL/6 mice were treated with lithium for 14 days, and then received once daily BrdU injections for 12 consecutive days while lithium treatment continued. 24 hours after the last injection, the brains were processed for BrdU immunohistochemistry.

Jope RS. Lithium and brain signal transduction systems. Biochem Pharm 1994 77 429-441. 

Ozaki N. Lithium increases transcription factor binding to AP-1 and cyclic AMP-responsive element in cultured neurons and rat brain. J Neurochem 1997 69 2336-2344. 

Williams MB. Circadian variation in rat brain AP-1 DNA binding activity after cholinergic stimulation modulation by lithium. Psychopharmacology (Berlin), 1995 122 363-368. 

Yuan PX, Manji HK. Lithium Stimulates Gene Expression Through the AP-1 Transcription Factor Pathway. Mol Brain Res 1998 58 225-230. 

Moore GJ, Hasanat K, Chen G, Seraji-Bozorgzad N, Wilds IB, Faulk MW, Koch S, Jolkovsky L, Manji HK. Lithium Increases N-Acetyl-Aspartate in the Human Brain In Vivo Evidence in Support of bcl-2 s Neurotrophic Effects. Biol Psychiatry 2000 48 1-8. 

Moore GJ, Wilds IB, Chen G, Manji HK Lithium-induced increase in Human Brain Gray Matter. Lancet 2000 356 1241-1242. 

Wang JF, Young LT. Identification of a novel lithium regulated gene in rat brain. Mol Brain Res 1999 70 66-73. 

It is known that 10B collects in brain tumors to a greater extent than in normal tissue. Research has been conducted on the use of the isotope 10B for treating brain tumors. Bombardment of the tumor with slow neutrons leads to the production of alpha particles (4He2+) and lithium nuclei that have enough energy to destroy the abnormal tissue. 

Berridge, M. J., Downes, C. P. and Hanley, M. R. Lithium amplifies agonist dependent phosphatidylinositol responses in brain and salivary glands. Biochem. J. 206 587-595,1982. 

Antidepressant treatment has, in recent studies, been shown to upregulate the cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) cascade and expression of BDNF [59]. This upregulation of CREB and BDNF raises the possibility that antidepressant treatment could oppose the cell death pathway, possibly via increased expression of the oncogene Bcl-2. Studies are necessary to determine if antidepressant treatment increases Bcl-2 expression. Increased expression of Bcl-2 in brain and cultured cells, and inhibition of apoptosis of cultured cerebellar granule neurons have been reported with lithium treatment [57]. Mice lacking the BDNF TrkB receptor fail to show behavioral and neurogenic responses to antidepressants. 

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. 

In a study of psychiatric patients after 1 week of lithium treatment, the serum Li+ level was typically 1 mM, whereas in brain and muscle the levels were 0.4 and 0.5 mM, respectively. Within the brain itself, the distribution of Li+ appears to be uneven however no particular region appears to accumulate Li+ to any significant extent [47]. It has been... 

Bonson KR, Buckholtz JW, Murphy DL. (1996). Chronic administration of serotonergic antidepressants attenuates the subjective effects of LSD in humans. Neuropsychopharmacology. 14(6) 425-36, Bonson KR, Murphy DL. (1996). Alterations in responses to LSD in humans associated with chronic administration of tricyclic antidepressants, monoamine oxidase inhibitors, or lithium. Behav Brain Res. 73(1-2) 229-33. 

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