DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

inhibit glutamatergic neurotransmission (lamotrigine). The extent to
which any of these actions is necessary for antimanic or other mood
stabilizing activity is unknown, but the failure of phenytoin,
gabapentin, and topiramate to be effective antimanic and moodstabilizing
medications suggests that potent blockade of voltage-gated
Na + channels (which gabapentin and topiramate lack) is necessary but
not sufficient, since phenytoin is very active at these channels.
Lithium. Lithium (Li + ) is the lightest of the alkali metals
(group Ia); the salts of this monovalent cation share
some characteristics with those of Na + and K + . Li + is
readily assayed in biological fluids and can be detected
in brain tissue by magnetic resonance spectroscopy
(Soares et al., 2000). Traces of the ion occur normally
in animal tissues, but it has no known physiological
role. Lithium carbonate and lithium citrate currently are
used therapeutically in the U.S.
Mechanism of Action. Therapeutic concentrations of Li + have almost
no discernible psychotropic effects in individuals without psychiatric
symptoms. There are numerous molecular and cellular actions
of Li + , some of which overlap with identified properties of other
mood-stabilizing agents (particularly valproate), and are discussed
below. An important characteristic of Li + is that, unlike Na + and K + ,
Li + develops a relatively small gradient across biological membranes.
Although it can replace Na + in supporting a single action
potential in a nerve cell, it is not a substrate for the Na + pump
and therefore cannot maintain membrane potentials. It is uncertain
whether therapeutic concentrations of Li + (0.5-1.0 mEq/L) affect
the transport of other monovalent or divalent cations by nerve cells.
Hypotheses for the Mechanism of Action of Lithium, and Relationship
to Anticonvulsants. Plausible hypotheses focus on lithium’s impact
on monoamines implicated in the pathophysiology of mood disorders,
and on second-messenger and other intracellular molecular
mechanisms involved in signal transduction, gene regulation, and
cell survival (Quiroz et al., 2004). In animal brain tissue, lithium at
concentrations of 1-10 mEq/L inhibits the depolarization-provoked
and Ca ++ -dependent release of NE and DA, but not 5-HT, from nerve
terminals. Li + may even transiently enhance release of 5-HT, especially
in the limbic system, but has limited effects on catecholaminesensitive
adenylyl cyclase activity or on the binding of ligands to
monoamine receptors in brain tissue, although it does influence
response of 5-HT autoreceptors to agonists (Lenox and Wang, 2003).
Li + modifies some hormonal responses mediated by adenylyl cyclase
or PLC in other tissues, including the actions of vasopressin and
thyroid-stimulating hormone on their peripheral target tissues
(Quiroz et al., 2004). Li + can inhibit the effects of receptor-blocking
agents that cause supersensitivity in such systems. In part, the actions
of Li + may reflect its ability to interfere with the activity of both
stimulatory and inhibitory G proteins (G s
and G i
) by keeping them
in their inactive αβγ trimeric state (Jope, 1999).
Considered by many as relevant for lithium’s therapeutic efficacy
is its inhibition of inositol monophosphatase and interference
with the phosphatidylinositol pathway (Figure 16–1), leading to
decreased cerebral inositol concentrations (Williams et al., 2002).
Phosphatidylinositol (PI) is a membrane lipid that is phosphorylated
to form phosphatidylinositol bisphosphate (PIP 2
). Activated
phospholipase C cleaves PIP 2
into diacylglycerol and inositol
1,4,5- trisphosphate (IP 3
), with the latter stimulating Ca 2+ release
from cellular stores. IP 3
is dephosphorylated to inositol monophosphate
(IP) and thence to inositol by inositol monophosphatase.
Within its range of therapeutic concentrations, Li + uncompetitively
inhibits this last step (Chapter 3), with resultant decrease in available
inositol for resynthesis into PIP 2
(Shaldubina et al., 2001). The
inositol depletion effect can be detected in vivo with magnetic resonance
spectroscopy (Manji and Lenox, 2000). A recent genome-wide
association study has implicated diacylglycerol kinase in the etiology
of bipolar disorder, strengthening the association between Li +
actions and PI metabolism (Baum et al., 2008). Further support for
the role of inositol signaling in mania rests on the finding that valproate,
and valproate derivatives, decrease intracellular inositol concentrations
(Shaltiel et al., 2007). Unlike Li + , valproate decreases
inositol through inhibition of myo-inositol-1-phosphate synthase.
Carbamazepine exposure in cultured sensory neurons alters the
dynamic behavior of neuron growth cones, effects that are remediated
through inositol supplementation, implicating inositol depletion
as a mechanism underlying carbamazepine’s mood stabilizing
properties (Williams et al., 2002).
Stimulation of NMDA receptors results in IP 3
accumulation
in primate brain, leading some to postulate that lithium’s activity in
the inositol pathway might also relate to glutamatergic effects (Dixon
and Hokin, 1998). Subsequent experiments demonstrated the ability
of acute high lithium levels to increase synaptic glutamate in mice
and non-human primates, primarily through inhibition of glutamate
reuptake at presynaptic nerve terminals by lowering the V max
of glutamate
transport, but not glutamate binding to the transporter (Dixon
and Hokin, 1998). The impact of supratherapeutic Li + on synaptic
glutamate may be implicated in lithium-induced neurotoxicity
during overdose; conversely, chronic Li + administration at therapeutic
CNS concentrations results in increased glutamate uptake and
increased levels of glutamate in presynaptic synaptosomes (Dixon
and Hokin, 1998). This effect occurs at therapeutic Li + serum
concentrations, leading to speculation that the neuroprotective
effects of Li + seen in models of excitotoxic cell death may be mediated
through modulation of synaptic glutamate availability (Bauer
et al., 2003).
Li + treatment also leads to consistent decreases in the functioning
of protein kinases in brain tissue, including PKC, particularly
isoforms α and β (Jope, 1999; Manji and Lenox, 2000; Quiroz
et al., 2004). Among other proposed antimanic or mood-stabilizing
agents, this effect is also shared with valproic acid (particularly for
PKC) but not with carbamazepine (Manji and Lenox, 2000). Longterm
treatment of rats with lithium carbonate or valproate decreases
cytoplasm-to-membrane translocation of PKC and reduces PKC
stimulation–induced release of 5-HT from cerebral cortical and hippocampal
tissue. Excessive PKC activation can disrupt prefrontal
cortical regulation of behavior, but pretreatment of monkeys and rats
with lithium carbonate or valproate blocks the impairment in working
memory induced by activation of PKC in a manner also seen with
the PKC inhibitor chelerythrine (Yildiz et al., 2008). The impact of
Li + or valproate on PKC activity may secondarily alter the release of
amine neurotransmitters and hormones as well as the activity of tyrosine
hydroxylase (Manji and Lenox, 2000). A major substrate for
cerebral PKC is the myristolated alanine-rich C-kinase substrate
(MARCKS) protein, which has been implicated in synaptic and neuronal
plasticity. The expression of MARCKS protein is reduced by
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PHARMACOTHERAPY OF PSYCHOSIS AND MANIA
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