Lithium. Mechanism of Action.
The precise mechanism of action of Li+ as a mood-stabilizing agent is currently unknown. It is possible that Li+ produces its effects by interacting with the transport of monovalent or divalent cations in neurons. An increasing number of scientists have come to the conclusion that the excitatory neurotransmitter glutamate is the key factor in understanding how lithium works. Lithium has been shown to change the inward and outward currents of glutamate receptors (especially GluR3), without a shift in reversal potential. Lithium has been found to exert a dual effect on glutamate receptors, acting to keep the amount of glutamate active between cells at a stable, healthy level, neither too much nor too little. It is postulated that too much glutamate in the space between neurons causes mania, and too little, depression. Another mechanism by which lithium might help to regulate mood include the non-competitive inhibition of an enzyme called inositol monophosphatase. Alternately lithium’s action may be enhanced through the deactivation of the GSK-3B enzyme. The regulation of GSK-3B by lithium may affect the circadian clock. GSK-3 is known for phosphorylating and thus inactivating glycogen synthase. GSK-3B has also been implicated in the control of cellular response to damaged DNA. GSK-3 normally phosphorylates beta catenin, which leads to beta catenin degratation. When GSK-3 is inhibited, beta catenin increases and transgenic mice with overexpression of beta catenin express similar behaviour to mice treated with lithium. These results suggest that increase of beta catenin may be a possible pathway for the therapeutic action of lithium.
Upon ingestion, lithium becomes widely distributed in the central nervous system and interacts with a number of neurotransmitters and receptors, decreasing norepinephrine release and increasing serotonin synthesis.
Unlike many other psychoactive drugs, Li+
typically produces no obvious psychotropic effects (such as euphoria) in normal individuals at therapeutic concentrations.
Dopamine and G-protein coupling.
During mania, there is an increase in neurotransmission of dopamine that causes a secondary homeostatic down-regulation, resulting in decreased neurotransmission of dopamine, which can cause depression. Additionally, the post-synaptic actions of dopamine are mediated through G-protein coupled receptors. Once dopamine is coupled to the G-protein receptors, it stimulates other secondary messenger systems that modulate neurotransmission. Studies found that in autopsies (which do not necessarily reflect living people), people with bipolar disorder had increased G-protein coupling compared to people without bipolar disorder. Lithium treatment alters the function of certain subunits of the dopamine associated G-protein, which may be part of its mechanism of action.
Glutamate and NMDA receptors.
Glutamate levels are observed to be elevated during mania. Lithium is thought to provide long-term mood stabilization and have anti-manic properties by modulating glutamate levels. It is proposed that lithium competes with magnesium for binding to NMDA glutamate receptor, increasing the availability of glutamate in post-synaptic neurons.
The NMDA receptor is also affected by other neurotransmitters such as serotonin and dopamine. Effects observed appear exclusive to lithium and have not been observed by other monovalent ions such as rubidium and caesium.
GABA receptors.
GABA is an inhibitory neurotransmitter that plays an important role in regulating dopamine and glutamate neurotransmission. It was found that patients with bipolar disorder had lower GABA levels, which results in excitotoxicity and can cause apoptosis (cell loss). Lithium counteracts these degrading processes by decreasing pro-apoptotic proteins and stimulating release of neuroprotectiveproteins.
Cyclic AMP secondary messengers.
The cyclic AMP secondary messenger system is shown to be modulated by lithium. Lithium was found to increase the basal levels of cyclic AMP but impair receptor coupled stimulation of cyclic AMP production. It is hypothesized that the dual effects of lithium are due the inhibition of G-proteins that then mediate cyclic AMP production. Over a long period of lithium treatment, cyclic AMP and adenylate cyclase levels are further changed by gene transcription factors.
Inositol depletion hypothesis.
Lithium treatment has been found to inhibit the enzyme inositol monophosphatase, involved in degrading inositol monophosphate to inositol required in PIP2 synthesis. This leads to lower levels of inositol triphosphate, created by decomposition of PIP2. This effect has been suggested to be further enhanced with an inositol triphosphate reuptake inhibitor. Inositol disruptions have been linked to memory impairment and depression. It is known with good certainty that signals from the receptors coupled to the phosphoinositide signal transduction is affected by lithium. myo-inositol is also regulated by the high affinity sodium mI transport system (SMIT). Lithium is hypothesized to inhibit mI entering the cells and mitigating the function of SMIT. Reductions of cellular levels of myo-inositol results in the inhibition of the phosphoinositide cycle.