GABA lithium

Serretti, A., Lilli, R., Lorenzi, C. etal. (1999). Dopamine receptor D2 and D4 genes, GABA(A) alpha-1 subunit genes and response to lithium prophylaxis in mood disorders. Psychiatry Res., 87, 7-19. 

Use in combination with other drugs (e.g, anti-psychotics, lithium, valproate) for the acute treatment of mania or mixed episodes. Use as a short-term adjunctive sedativehypnotic agent. Binds to the benzodiazepine site and augments the action of GABA/, by increasing the frequency of Cl" channel opening which causes hyperpolarization (a less excitable state) and inhibits neuronal firing. 

GABA HMG-CoA HMPA HT LDA LHMDS LTMP NADH NBH NBS NCS NIS NK NMP PMB PPA RaNi Red-Al RNA SEM SnAt TBAF TBDMS TBS Tf TFA TFP THF TIPS TMEDA TMG TMP TMS Tol-BINAP TTF y-aminobutyric acid hydroxymethylglutaryl coenzyme A hexamethylphosphoric triamide hydroxytryptamine (serotonin) lithium diisopropylamide lithium hexamethyldisilazane lithium 2,2,6,6-tetramethylpiperidine reduced nicotinamide adenine dinucleotide l,3-dibromo-5,5-dimethylhydantoin A-bromosuccinimide A-chlorosuccinimide A-iodosuccinimide neurokinin 1 -methyl-2-pyrrolidinone para-methoxybenzyl polyphosphoric acid Raney Nickel sodium bis(2-methoxyethoxy)aluminum hydride ribonucleic acid 2-(trimethylsilyl)ethoxymethyl nucleophilic substitution on an aromatic ring tetrabutylammonium fluoride tert-butyldimcthyisilyl fert-butyldimethylsilyl trifluoromethanesulfonyl (triflyl) trifluoroacetic acid tri-o-furylphosphine tetrahydrofuran triisopropylsilyl A, N,N ,N -tetramethy lethylenediamine tetramethyl guanidine tetramethylpiperidine trimethylsilyl 2,2 -bis(di-p-tolylphosphino)-l,r-binaphthyl tetrathiafulvalene... 

So far attention has concentrated on the effects of lithium on excitatory transmitters. There is evidence that the drug can also facilitate inhibitory transmission, an effect that has been attributed to a desensitization of the pres)maptic gamma-aminobutyric acid (GABA) receptors, which results in an increase in the release of this inhibitory transmitter. The increased conversion of glutamate to GABA may also contribute to this process. Thus it would appear that lithium has a varied and complex action on central neurotransmission, the net result being a diminution in the activity of excitatory transmitters and an increase in GABAergic function. 

Belelh D, Lan N, Gee KW Anticonvulsant steroids and the GABA/benzodiazepine receptor-chloride ionophore complex. Neurosci Biobehav Rev 14 315-322, 1990 Bellaire W, Demisch K, Stoll K-D Carbamazepine vs. lithium. Application in the prophylaxis of recurrent affective and schizoaffective psychoses. Muenchener Medizinische Wochenschrift 132 S82-S86, 1990 Belmaker RH Receptors, adenylate cyclase, depression, and lithium. Biol Psychiatry 16 333-350, 1981... 

Bernasconi R The GABA hypothesis of affective illness influence of clinically effective antimanic drugs on GABA turnover, in Basic Mechanisms in the Action of Lithium. Edited by Emrich HM, Adenhoff JB, Lux HM. Amsterdam, Excerpta Medica, 1982, pp 183-192... 

Burns G, Herz A, Nikolarakis KE Stimulation of hypothalamic opioid peptide release by lithium is mediated by opioid autoreceptors evidence from a combined in vitro, ex vivo study. Neuroscience 36 691-697, 1990 Burt DR, Kamatchi GL GABA A receptor subtypes from pharmacology to molecular biology. EASEB J 5 2916-2923, 1991... 

Gottesfeld Z, Ebstein BS, Samuel D Effect of lithium on concentrations of glutamate and GABA levels in amygdala and hypothalamus of rat. Nature 234 124-125, 1971... 

Mitsushima D, Hei DL, Terasawa E GABA is an inhibitory neurotransmitter restricting the release of luteinizing hormone-releasing hormone before the onset of puberty. Proc Natl Acad Sci USA 91 395-399, 1994 Miura N, Nakata N, Tanaka Y, et al Improving effects of FG-7080 a serotonin reuptake inhibitor on scopolamine-induced performance deficits of memory tasks in rats. Jpn J Pharmacol 62 203-206, 1993 Mizuta T, Segawa T Chronic effects of imipramine and lithium on 5-HT receptor subtypes in rat frontal cortex, hippocampus and choroid plexus quantitative receptor autoradiographic analysis. Jpn J Pharmacol 50 315-326, 1989... 

Sheehan M, de Belleroche J Facilitation of GABA release by cholecystokinin and caerulein in rat cerebral cortex. Neuropeptides 3 429-434, 1983 Sherman AD, Petty F Additivity of neurochemical changes in learned helplessness and imipramine. Behav Neural Biol 35 344-353, 1982 Sherman WR Lithium and the phosphoinositide signaling system, in Lithium and the Cell. Edited by Birch NJ. London, Academic Press, 1991, pp 121-157 Sherman WR, Munsell LY, Gish BG, et al Effects of systemically administered lithium on phosphoinositide metabolism in rat brain, kidney, and testis. J Neurochem 44 798-807, 1985... 

GABA is a major CNS inhibitory neurotransmitter, which, among other effects, may attenuate catecholaminergic systems. VPA (perhaps by inhibition of this transmitter s degradation by GABA transaminase), CBZ, and lithium have all been reported to enhance GABA activity (see also the section Mechanism of Action in Chapter 12). 

Carbamazepine. The anticonvulsant carbamazepine was actually the first to be shown to be effective in the manic phase of bipolar disorder, but it has not been approved for this use by regulatory authorities such as the U.S. Food and Drug Administration (FDA). Its mechanism of action may be to enhance GABA function, perhaps in part by actions on sodium and/or potassium channels (Fig. 7—24). Because its efficacy is less well documented and its side effects can include sedation and hematological abnormalities, it is not as well accepted for first-line use in the treatment of mood disorders as either lithium or valproic acid. 

Reincorporation of the tin can be avoided by using a tri wry/stannane precursor.156 This means that the product organolithium can be trapped with other electrophiles, provided that the solvent is 10 1 hexane-ether, and not THF, which otherwise protonates the product organolithium.157 The hexane-ether mixture slows down the tin-lithium exchange reaction dramatically, and it proceeds only at room temperature. Cyclisation of 323 thus leads to the synthesis of a simple GABA uptake inhibitor 324. A-acyl pyrrolidines cannot be made directly from a-amido organolithiums, as these fail to cyclise, possibly because they are too well stabilised by O-Li coordination.138... 

Carbamazepine is licenced as an alternative to lithium for prophylaxis of bipolar affective disorder, although clinical trial evidence is actually stronger to support its use in the treatment of acute mania. Carbamazepine appears to be more effective than lithium for rapidly cycling bipolar disorders, i.e. with recurrent swift transitions from mania to depression. It is also effective in combination with lithium. Its mode of action is thought to involve agonism of inhibitory GABA transmission at the GABA-benzodiazepine receptor complex (see also Epilepsy, p. 417). 

Carbamazepine continues to be studied with regard to its actions on primary and secondary neurotransmitter systems and on sodium and potassium ion channels. It has a limited ability to block norepinephrine reuptake (Hollister 1992) and has been reported to decrease norepinephrine release (Post, Weiss, and Chuang 1992). Dopamine release is enhanced, and reuptake is blocked. As with lithium and valproate, long-term administration causes an increase in GABA receptors (upregula-tion) in the hippocampus, but not in the cortex (Post, Weiss, and Chuang 1992). 

Agents that increase GABA activity or decrease glutamate activity are used for the treatment of mania and for mood stabilization (e.g., benzodiazepines, lamotrigine, lithium, or valproic acid). 

I Increases GABA binding in some brain stmctrrres, most notably the hippocampus. I Like lithium, inhibits the formation of protein kinase C. 

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