Molecular Psychiatry (1999) 4, 117–128

 1999 Stockton Press All rights reserved 1359–4184/99 $12.00

MECHANISMS OF DRUG ACTION

Anti-bipolar therapy: mechanism of action of lithium

RS Jope
Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294,
USA

This review introduces the concepts that multiple actions of lithium are critical for its thera-
peutic effect, and that these complex effects stabilize neuronal activities, support neural plas-
ticity, and provide neuroprotection. Three interacting systems appear most critical. (i) Modu-
lation of neurotransmitters by lithium likely readjusts balances between excitatory and
inhibitory activities, and decreased glutamatergic activity may contribute to neuroprotection.
(ii) Lithium modulates signals impacting on the cytoskeleton, a dynamic system contributing
to neural plasticity, at multiple levels, including glycogen synthase kinase-3␤, cyclic AMP-
dependent kinase, and protein kinase C, which may be critical for the neural plasticity involved
in mood recovery and stabilization. (iii) Lithium adjusts signaling activities regulating second
messengers, transcription factors, and gene expression. The outcome of these effects
appears likely to result in limiting the magnitudes of fluctuations in activities, contributing to
a stabilizing influence induced by lithium, and neuroprotective effects may be derived from
its modulation of gene expression.
Keywords: lithium; bipolar disorder; inositol; glutamate; cyclic AMP; AP-1

Recent research suggests that understanding how lith-
ium works in the treatment of bipolar disorder requires
a different way of thinking about drug action. The vast
majority of drugs are designed, by evolution or syn-
thesis, to interact with single proteins, such as a spe-
cific receptor or enzyme. However, it now seems likely
that multiple sites affected by lithium contribute to its
mood-stabilizing action. Thus, the therapeutic action
of lithium in bipolar disorder appears not to result
from an effect at a single target site, but rather as the
culmination of an integrated re-orchestration of a com-
plex concert of events which effectively adjusts neu-
ronal activity at multiple levels. Numerous effects of
lithium have been identified, and some of these may
each provide a necessary, but individually insufficient,
component of the therapeutic response. One of the cur-
rent challenges is to distinguish those critical effects
from the many known biochemical actions of lithium,
many of which may have little discernible effect, con-
tribute to side effects, or lead to toxicity. Another chal-
lenge is to integrate the multiple effects of lithium into
a comprehensive picture of how neuronal function is
modulated by lithium. In retrospect, considering the
complexities of mood, it perhaps should not be surpris-
ing that mood stabilization by lithium is also a com-
plex process involving multiple actions. It is also
important to keep in mind that lithium has efficacy as
an antimanic agent, as a prophylactic agent for mania
Correspondence: Dr RS Jope, Department of Psychiatry and
Behavioral Neurobiology, Sparks Center 1057, University of
Alabama at Birmingham, Birmingham, AL 35294-0017, USA.
E-mail: jope얀uab.edu
Received 17 September 1998; accepted 14 October 1998
and depression, as a relatively weak antidepressant,
and as an augmenter of the effects of many antidepress-
ants. These multiple therapeutic effects of lithium
along with the complexities of mood disorders and the
multiplicity of affected systems inherent in these ill-
nesses suggest that it is unlikely that all these effects
are due to a single biochemical site of action.
This review focuses on advances made in recent
years and is organized to follow the steps of neuro-
transmission, beginning with presynaptic actions lead-
ing to receptor-coupled signaling systems which
eventually culminate in modulating gene expression.
Many comprehensive reviews1–15 discuss other aspects
of bipolar disorder and the use of lithium, and provide
detailed coverage of important earlier progress in this
field that set the stage for the recent developments that
are covered here. Because the therapeutic concen-
tration of lithium is near 1 mM, coverage focuses on
studies where significant effects were obtained using
lithium near this concentration. Two directly associa-
ted targets of lithium, signaling systems and gene
expression, have attracted the greatest amount of
investigative attention recently, and so are emphas-
ized. However, this emphasis should not detract from
other intriguing findings that remain to be investigated
more completely. In accordance with the many actions
of lithium that are discussed in this review, the author
suggests that it is the integration of multiple effects of
lithium which is necessary to achieve the neurochem-
ical balance facilitating the complex processes of mood
recovery and stabilization.
 Mechanism of action of lithium
RS Jope
118
Neurotransmitter effects
Much of the early research on the actions of lithium
focused on modulation of neurotransmitter synthesis,
release, and uptake. Lithium was found to influence to
some extent virtually every neurotransmitter that was
investigated, although most research focused on the
catecholamines and acetylcholine.2 This intensive
study of lithium’s presynaptic effects has largely, but
not entirely, been supplanted by other avenues of
research in recent years. This has occurred despite the
fact that many significant effects of lithium were ident-
ified without consensus conclusions being drawn.
One of the most provocative recent developments in
the study of neurotransmitter effects of lithium con-
cerns its modulation of glutamatergic neurotransmis-
sion. Hokin and colleagues found that lithium acutely
increased synaptic concentrations of glutamate which,
upon chronic lithium administration led to an increase
and stabilization in glutamate uptake transporter
capacity16–20 (Figure 1). They speculated that this could
mediate a reduction and stabilization in excitatory neu-
rotransmission after lithium treatment. This action
may contribute to a relatively large and diverse group
of findings in the literature indicating that lithium has
neuroprotective effects, an action of lithium that has
been observed most often, but not exclusively, in cer-
ebellar cells.21–30 For example, chronic lithium admin-
istration was found to block excitotoxicity induced by
glutamate agonists,26–28 although little protection was
afforded by lithium from kainate-induced damage.31
Perhaps most remarkable in these studies was the
recent finding that lithium administration to rats
reduced by 56% the size of the ischemic infarct meas-
ured 24 h after occlusion of the left middle cerebral
artery.29 In a study of its neuroprotective mechanisms,
Figure 1 Lithium modulates glutamatergic neurotransmission. The figure depicts a glutamatergic synaptic area, with the post-
synaptic sites containing N-methyl-d-aspartate (NMDA) receptors enlarged in the lower diagrams. Chronic lithium treatment
can increase the uptake of glutamate, and also can reduce the increase in intracellular calcium subsequent to activation of N-
methyl-d-aspartate receptors. These actions may provide mechanisms for lithium to reduce excitatory neurotransmission and
contribute to lithium’s neuroprotective effects against certain excitatory insults.
lithium was found to effectively inhibit glutamate-
induced neuronal calcium uptake and cell death28
(Figure 1). These discoveries raise the intriguing possi-
bility that modulation of excitatory glutamatergic neur-
otransmission constitutes an important therapeutic
action of lithium. Furthermore, it was recently shown
that glutamate receptors expressed in oocytes are
highly permeable to lithium, raising the possibility that
this may be an important mechanism and site for
localized accumulation of lithium.32 Taken together,
these reports indicate that some types of apoptosis and
excitatory neurodegeneration can be attenuated by lith-
ium. This neuroprotective action may be mediated by
increased glutamate uptake, attenuated increases in
intracellular calcium levels associated with excitatory
neurotransmission, and the recent finding that lithium
up-regulated the anti-apoptotic protein bcl-2.33,34
Investigations of other neurotransmitters have also
continued, although not with the intensity of previous
years. In accordance with earlier studies, recent reports
continue to find that lithium reduces dopaminergic
activity,35–38 and enhances cholinergic activity39–41 and
the activity of inhibitory GABAergic neurotransmis-
sion.23,42,43 Recent studies also report that lithium
alters serotonergic neurotransmission,44–48 but as
reviewed previously49 the varied observed effects of
lithium on this system remain to be incorporated into
a cohesive scheme.
Thus a clear outcome has not been reached concern-
ing which, if any, neurotransmitter synthesis, uptake,
and release processes contribute to the therapeutic
action of lithium, but the reported effects on cat-
echolamines, acetylcholine, and GABA, as well as the
recent findings with glutamate, suggest that these may
make important, if as yet not completely defined, con-
 Mechanism of action of lithium
RS Jope

tributions. The overall consequences of these actions
may be that lithium readjusts the balance between
excitatory and inhibitory activities, as well as the earl-
ier postulated balance between catecholamines and
acetylcholine, so that it is the adjusted balances
(increased GABA/glutamate and acetylcholine/
catecholamine activity ratios, in a generalized manner),
rather than actions on a single neurotransmitter, that
facilitate mood recovery and stabilization.
Signal transduction systems/protein
phosphorylation
A concerted effort has been directed towards under-
standing how lithium influences signal transduction
systems, especially the phosphoinositide and cyclic
AMP signaling systems, which followed earlier investi-
gations of lithium on receptors using binding methods
which failed to provide conclusive evidence about
whether or not lithium altered receptor-binding
properties.2,49 Instead of having a single target site
within each of these signaling systems, it appears that
multiple sites are affected by lithium and that the over-
all outcome has to do with the balances achieved
between negative and positive modulatory effects of
lithium rather than resulting from an individual site of
action15 (Figure 2).
119
There is little doubt that signals emanating from
receptors coupled to the phosphoinositide signal trans-
duction system are affected by lithium, but exactly how
this occurs remains under intense scrutiny. Sherman
and colleagues1 first found lithium to be a potent
inhibitor of inositol monophosphatase, the enzyme
that converts inositol monophosphates to free inositol.
This led to the ingenious proposal,50 known as the
inositol depletion hypothesis, that this action of lith-
ium might result in sequestration of inositol in the form
of inositol monophosphate. It was proposed that this
action may result in the depletion of inositol-contain-
ing lipids and thereby attenuate receptor-coupled
phosphoinositide signaling. However, only marginal
effects of lithium on phosphoinositide concentrations
have been found.11 Having explored this hypothesis in
exquisite detail, several groups suggested that lithium
may cause not a global depletion of phosphoinositides,
but rather highly selective localized depletions.51–56
This modification limits the hypothetical conse-
quences of lithium exposure to those cells with the
lowest endogenous sources of inositol, which may
make them most susceptible to inositol depletion,
and/or to cells experiencing the greatest stimulation of
phosphoinositide signaling activity, which would
make them most dependent on inositol recycling to
maintain signaling activity. An important strength of

Figure 2 Lithium can bimodally modulate signaling systems dependent on the endogenous level of basal and stimulated
activities. (a) Depiction of signaling with normal basal and stimulated activities. (b) Signaling system with depressed basal
activity can be corrected by lithium-induced increases in basal activity. (c) Signaling system with excessive response to a
stimulus can be corrected by lithium-induced inhibition of the maximal response. (d) Signaling system with depressed basal
activity and excessive response to a stimulus can be corrected by lithium-induced increases in basal activity and inhibition
of the maximal response. Evidence suggests that this bimodal mechanism of action of lithium may be applicable to its effects
on cyclic AMP production and AP-1 activation.
 Mechanism of action of lithium
RS Jope
120
this hypothesis is that it pinpoints a specific locus of
lithium action, the inhibition of inositol monophos-
phatase. Support for this modified inositol depletion
hypothesis has been obtained in a number of creative
experiments using model systems,51–56 but demonstrat-
ing such effects in more intact systems, especially in
human brain,57,58 has been less successful and remains
a formidable challenge. Nonetheless, an intriguing out-
growth of the inositol depletion hypothesis has been
the novel application of inositol as a pharmacological
agent which has shown promising utility in animal
models and therapeutic applications.13,59 Additionally,
the concentration and uptake of inositol differs among
regions of rat brain and reduced inositol levels in rat
brain following lithium administration were recently
reported to be limited to the hypothalamus,60–62 and
lithium was also found to reduce inositol in astro-
cytes.63 Thus, each of these factors, brain region, cell-
type, and endogenous inositol cycles, introduces com-
plexities in the relationship between lithium and inosi-
tol which have made it difficult to define precisely how
lithium’s inhibition of inositol monophosphatase
affects phosphoinositide signaling.
Besides possibly causing inositol depletion in some
cells, there is also substantial evidence that lithium can
attenuate phosphoinositide signaling by inhibiting the
activation of G-proteins that couple receptors to phos-
phoinositide-selective phospholipase C.5,64,65 The
majority of studies indicate that lithium reduces the
functional activity, not the level, of G-proteins
mediating phosphoinositide hydrolysis (but see66),
with evidence that lithium interferes with magnesium-
binding sites.67 Thus, lithium-induced impaired G-pro-
tein activity may contribute to some cases in which
lithium was reported to decrease phosphoinositide sig-
naling activity. At this time it may be most parsimoni-
ous to conclude from these studies that lithium has the
potential to reduce the activation of phosphoinositide
signaling by more than one mechanism.
However, not all evidence supports the conclusion
that lithium directly impedes phosphoinositide sig-
naling. In rat brain, in vivo levels of inositol tris-
phosphate derived from phosphoinositide hydrolysis
are not reduced by lithium treatment.68–70 Hokin and
colleagues16–18 have emphasized species differences in
the inositol-depleting effects of lithium and showed
that in primate brain slices lithium increases phospho-
inositide signaling through activation of glutamatergic
N-methyl-d-aspartate receptors. Therapeutic concen-
trations of lithium also increased muscarinic receptor-
stimulated phosphoinositide signaling in cultured cer-
ebellar granule cells.71 In studies using postmortem
human brain,72 a regionally-selective deficit in phos-
phoinositide signaling was evident in bipolar com-
pared with matched control tissue. Additionally, in the
affected brain region there was a direct relationship
between bipolar brain lithium levels and phosphoinos-
itide signaling activity so that the deficit was greatest
in tissues with the lowest lithium, suggestive of an
amelioration by lithium of deficient phosphoinositide
signaling activity. This also raises an additional com-
plexity in studies of lithium by indicating that only
abnormal signaling activity may be affected by lithium.
Although providing direct support in human brain for
the thesis that phosphoinositide signaling is abnormal
in bipolar brain, these methods lack the capability of
identifying more precisely the mechanism of action of
lithium, the sample number was small, it is difficult to
precisely correlate in vitro measures with in vivo sig-
naling activity, and the use of postmortem tissue
encompasses many uncontrollable factors concerning
disease and the drug history of each subject.
In part because of the ambiguities of if and how lith-
ium actually affects phosphoinositide signaling,
especially in human brain and in association with
bipolar disorder, many investigators have turned to
studying lithium’s effects on signaling processes down-
stream from phosphoinositide hydrolysis. Two pri-
mary second messengers produced by the phospho-
inositide signal transduction system are inositol
trisphosphate, which raises intracellular calcium levels
by releasing it from sequestered sites, and diacylgly-
cerol, which activates protein kinase C. Surprisingly
little has been published about lithium’s effects on cal-
cium, with a limited number of reports, mostly involv-
ing non-neuronal cells, indicating reductions in stimu-
lated increases in intracellular calcium concentrations
in tissue exposed to lithium.73–78 In contrast, modu-
lation of protein kinase C by lithium has been studied
extensively. Early studies found decreased protein kin-
ase C activity in lithium-treated tissues using a variety
of methods79–82 and evidence of activated protein kin-
ase C associated with mania.83 Subsequently, specific
isotypes of protein kinase C were reported to be
reduced by lithium.84 Since lithium was found to
reduce protein kinase C activity, a recent clinical
evaluation of tamoxifen, which is known to inhibit
protein kinase C, was undertaken to determine its effi-
cacy in bipolar disorder. Initial results indicate that
tamoxifen, at doses sufficient to inhibit protein kinase
C, had a striking, and in many cases, rapid antimanic
effect in 苲80% of the patients.85 Clearly the possible
contribution of estrogen receptor blockade or other
actions of tamoxifen cannot be ruled out, but these
intriguing results clearly warrant further studies
related to protein kinase C activity. One of the major
substrates of protein kinase C, myristoylated alanine-
rich C kinase substrate (MARCKS), has been studied
extensively and lithium was found to reduce the levels
of MARCKS, an effect that is also caused by direct acti-
vation of protein kinase C, suggesting a modulatory
effect of lithium on protein kinase C activity which
modulates MARCKS.81,86 MARCKS is involved in cyto-
skeletal architecture, indicating that this function may
be affected by lithium. MARCKS also inhibits phos-
phoinositide signaling,87 suggestive that lithium may
reduce this inhibitory influence on phosphoinositide
signaling as a consequence of down-regulating
MARCKS. The extent and consequences of lithium’s
effects on protein kinase C and its substrates remains
a topic of great interest.
Numerous studies have demonstrated that the cyclic

AMP second messenger system is modulated by lith-
ium.3,5,11 In general, these show that lithium increases
basal levels of cyclic AMP but impairs receptor-
coupled stimulation of cyclic AMP production (Figure
3). One hypothesis is that these dual effects of lithium
are due to inhibition by lithium of the G-proteins that
mediate cyclic AMP production. Receptor-mediated
production of cyclic AMP is controlled by a stimu-
latory G-protein, Gs, and a counter-balancing inhibi-
tory G-protein, Gi. Under basal conditions, cyclic AMP
production is tonically inhibited by the prevailing Gi
influence. Increased basal cyclic AMP levels caused by
lithium may occur at least in part because lithium
reduces the activity of Gi, apparently by shifting its
equilibrium between a free active conformation and an
inactive heterotrimeric conformation towards the inac-
tive form,5,66,88–90 but not all studies find such inhibi-
tory effects.91 Therefore, inhibitory effects of lithium
on Gi can elevate the basal level of cyclic AMP. On the
other hand, attenuation of stimulus-induced increases
Figure 3 The production of cyclic AMP is bimodally modu-
lated by lithium. (a) Basal cyclic AMP production is predomi-
nantly controlled by the action of the ␣-subunit of the inhibi-
tory G-protein, Gi. Lithium appears to facilitate the formation
of the inactive heterotrimeric conformation of Gi, resulting in
increased cyclic AMP production under basal conditions. (b)
Receptor activation can stimulate the heterotrimeric G-pro-
tein Gs to dissociate, allowing the active ␣-subunit to activate
adenylyl cyclase (AC) to increase cyclic AMP production.
Lithium appears to reduce receptor-activated stimulation of
Gs, resulting in decreased cyclic AMP production under
stimulated conditions. ␣␤␥ = heterotrimeric G-protein.
Mechanism of action of lithium
RS Jope
121
in cyclic AMP production, such as by norepinephrine,
may be caused by an inhibitory effect of lithium on
the activation of Gs,3,5,92,93 but the specific mechanism
mediating this action is not entirely clear. Direct
inhibitory effects of lithium on adenylyl cyclase also
may contribute to its modulatory effects on the pro-
duction of cyclic AMP.92 Overall, it appears that these
actions of lithium reduce the magnitude of fluctuations
in cyclic AMP levels by increasing the lowest basal lev-
els and decreasing maximal stimulated increases, thus
stabilizing the activity of this signaling system (Figures
2 and 3).
One intriguing mechanism by which lithium may
influence G-protein function is by modulating the post-
translational modification of ADP-ribosylation of G-
proteins catalyzed by endogenous enzymes (ie, not by
added ADP-ribosylating toxins such as pertussis toxin).
Administration of lithium was found to increase the
endogenous ADP-ribosylation of G-proteins.94,95
Although the ramifications of this modification on sig-
naling activities remain to be established, these find-
ings raise the possibility of a new mechanism for mod-
ulating G-protein function.
A primary action of cyclic AMP is to stimulate the
activity of cyclic AMP-dependent protein kinase
(protein kinase A). Several studies found that lithium
can modulate stimulated protein kinase A-mediated
protein phosphorylation.80,96–98 Especially interesting
are a series of reports that lithium inhibits protein kin-
ase A-induced phosphorylation of cytoskeletal pro-
teins,99,100 an action that may contribute to long-term
modulation of neuronal structure and function by lith-
ium.
An exciting new story is rapidly developing involv-
ing the regulation by lithium of cytoskeletal protein
phosphorylation and function, and the consequential
effects on neuronal architecture. Protein phosphoryl-
ation of cytoskeletal proteins was recently found to be
affected by a newly discovered inhibitory effect of lith-
ium on glycogen synthase kinase-3␤101 (Figure 4). In
addition to its originally described function of phos-
phorylating glycogen synthase, this kinase also phos-
phorylates several other proteins, including microtu-
bule-associated proteins (MAPs) such as tau and MAP-
1B, which contribute to regulating neuronal cytoskele-
tal networks. A long-overlooked report had shown that
lithium inhibits an unidentified kinase that phos-
phorylates glycogen synthase,102 which was later ident-
ified as glycogen synthase kinase-3␤ and recently
shown to be the kinase directly inhibited by lithium.101
Several recent studies found that inhibition of glycogen
synthase kinase-3␤ by lithium reduces tau phosphoryl-
ation.101,103–107 The majority of these studies have been
conducted by investigators interested in developmen-
tal effects of glycogen synthase kinase-3␤ or microtu-
bule dynamics, rather than lithium’s therapeutic
effects, so acute treatments and supra-therapeutic con-
centrations of lithium, generally 5–20 mM, were util-
ized. Nonetheless, the dramatic effects of lithium that
were observed suggest that lower concentrations of
lithium will have significant, though more subtle,
 Mechanism of action of lithium
RS Jope
122
Figure 4 Inhibition of glycogen synthase kinase-3␤ (GSK-3␤)
by lithium modulates the phosphorylation and function of
the microtubule-associated proteins tau and MAP-1B. GSK-
3␤ phosphorylates tau (␶), which decreases its binding to
microtubules, and phosphorylates MAP-1B, which increases
its binding to microtubules. By inhibiting GSK-3␤, lithium
decreases the phosphorylation of tau and MAP-1B, increasing
tau microtubule binding and decreasing MAP-1B microtubule
binding. Although each binds microtubules, tau and MAP-1B
are not functionally interchangeable and each of their actions
may predominate in different neuronal compartments.
modulatory effects on neuronal cytoskeletal modifi-
cations mediated by glycogen synthase kinase-3␤, and
evidence of such effects with 1 mM lithium were
reported briefly in some studies.101,103–105 Dephos-
phorylation of tau at the glycogen synthase kinase-3␤
sites, which is caused by lithium, enhances the binding
of tau to microtubules, which promotes microtubule
assembly.108 Therefore, this action of lithium suggests
that it may stabilize microtubule-based neuronal struc-
ture. However, inhibition of glycogen synthase kinase-
3␤ by lithium also dramatically decreased MAP-1B
phosphorylation.109,110 Dephosphorylation of MAP-1B,
in contrast to tau dephosphorylation, decreases its
ability to bind and stabilize microtubules and therefore
results in more dynamic microtubules, and this
response to lithium treatment also was reported to
cause increased axonal spreading and increased
growth cone area.109 These recent findings suggest that
neuronal cytoskeletal rearrangements may be a signifi-
cant consequence of lithium administration. The
opposing effects of dephosphorylation of tau and of
MAP-1B, promoting microtubule disassembly and
assembly, respectively, caused by lithium’s inhibition
of glycogen synthase kinase-3␤, support the theme of
this review that lithium acts at multiple sites to adjust
the balance between opposing influences rather than
having unidirectional effects (Figure 4). Undoubtedly
ongoing studies will shed more light on the precise
effects of lithium on these critical components of neu-
ronal structure.
Other signaling systems also have been shown to be
modulated by lithium. In accordance with earlier
reports, more recent evidence was obtained that lith-
ium may modulate the production of cyclic GMP111,112
as well as nitric oxide.41,113,114 In addition, new find-
ings indicate that lithium can inhibit phospholipase
A2, an enzyme that mediates the production of arachi-
donate.115,116 Since arachidonate can contribute to the
activation of protein kinase C, it was suggested that its
reduced production after lithium may contribute to
reduced activation of protein kinase C.116 Further
investigations of these signaling systems are needed to
clarify how their regulation is integrated into the over-
all metabolic and signaling activity modulatory effects
of lithium.
Transcription factors, gene expression, and
protein levels
Transcription factors fulfill the critical functions of
transmitting and regulating signals to the nucleus,
allowing cells to respond to a changing environment
through alterations in gene expression. Thus transcrip-
tion factors may be selectively influenced by lithium
both as a result of lithium’s modulation of the activities
of specific signaling systems and as targets for lithium
to modulate the expression of genes selectively.
Studies with lithium have focused on transcription
factors coded by immediate early genes, those
responding rapidly and transiently to cell signals, such
as the AP-1 transcription factor which is composed of
dimers of the Fos and Jun protein families. Following
the initial discovery that lithium increased c-fos mRNA
levels,117 several reports have appeared with a confus-
ing array of results after lithium treatment, including
increases, decreases, and no changes in c-fos mRNA
levels in a variety of cultured cells and in regions of
rat brain,118–128 but only limited information is avail-
able about the effects of lithium on the expression of
Jun family members.121,125,128 These inconsistent
results with c-fos may be related to cellular and brain
regional differences in the response to lithium com-
pounded by the complexity of factors regulating mRNA
levels and the activation of immediate early genes.
More functional information may be gained from
examining transcription factor DNA binding activity.
This was first employed only in 1995, but is now
receiving much attention. Stimulation of AP-1 DNA
binding activity in rat brain was found not only to be
attenuated by lithium, but also to be influenced by cir-
cadian rhythm.129 This attenuation of stimulated AP-1
by lithium was confirmed in cultured cells, but elev-
ated basal AP-1 DNA binding activity was noted as the
concentration of lithium was increased.125,130 Lithium
also increased basal AP-1 in several cultured cell lines
and in rat brain, although with evidence of differential
lithium concentration sensitivities among cell
types.126,128,131 The opposite actions of lithium on
stimulated (decrease) and basal (increase) AP-1 DNA
binding activity at first appeared to be contradictory.
However, these have been proposed to reflect actions
of lithium at different sites which are cellularly inte-
grated to reduce the magnitude of fluctuations in AP-
1, and consequently of AP-1-responsive gene
expression, so after lithium treatment minimal basal
levels are elevated and maximal stimulated levels are

dampened15 (Figure 2). The decrease in receptor-
coupled stimulation of AP-1 could result from inhi-
bition by lithium of phosphoinositide hydrolysis,
reduced second messenger activities (protein kinase C
or calcium), or other effects that regulate stimulation
of AP-1. On the other hand, the increased basal level
of AP-1 activity is likely due to inhibition by lithium
of glycogen synthase kinase-3␤, an enzyme that is con-
stituitively inhibitory towards AP-1, so blockade by
lithium can elevate basal AP-1. These combined effects
of lithium on basal and stimulated AP-1 may model
how multiple actions of lithium are integrated to stabil-
ize fluctuations in this, and other, signaling systems
which impact to also stabilize gene expression activi-
ties within a lithium-modified range of maximal and
minimal levels. Investigators are now in the process of
identifying other transcription factors and genes that
are regulated by lithium. Recently lithium was also
shown to modulate two other transcription factors, the
cyclic AMP responsive element and NF-␬B, confirming
that lithium’s effects doubtlessly extend to additional
transcription factors besides AP-1.126,130,132 Current
investigations should provide greater insight into the
mechanisms and outcomes of these modulatory effects
of lithium on transcription factors.
It seems likely that alterations in neuronal gene
expression and consequently protein levels induced by
lithium contribute to its therapeutic effect. Not surpris-
ingly considering the foregoing discussion, lithium has
been reported to alter the expression of a number of
genes and/or the levels of proteins, processes that may
underlie the necessity for long-term treatment with
lithium to achieve optimal therapeutic responses. This
time-delay may be required for neuronal proteins to
reach new steady state levels in the presence of lithium
that mediate structural and/or functional neuronal
alterations. However, it remains to be determined
which of these are therapeutically critical products.
As previously reviewed,10,11 lithium has been
reported to alter the expression of several proteins
involved in signaling systems, and recent reports con-
tinue to find effects on G-proteins.133–135 Lithium also
increased mRNA levels for nitric oxide synthase type-
2.114 It is difficult to know whether this preponderance
of evidence that the expression of proteins involved
in signaling systems is affected by lithium reflects a
predominant action of lithium on these proteins or
reflects the current interests of investigators examining
the effects of lithium. Nonetheless, it appears likely
that altered levels of signaling proteins contribute to
the signal and mood stabilizing actions of lithium.
Several additional mRNA or protein levels were
modulated by lithium. Glial fibrillary acidic protein
was increased by lithium136 and lithium modulated
stress-induced alterations in polyamine enzymes.137 In
PC12 cells, treatment with a high concentration of lith-
ium (20 mM) in combination with other agents
increased neurotensin/neuromedin N expression,138
increased melanin-concentrating hormone mRNA and
decreased tyrosine hydroxylase mRNA.139 Lower levels
of lithium increased tyrosine hydroxylase levels.140
Mechanism of action of lithium
RS Jope
123
The mRNA levels for neuropeptide Y and somatostatin
were increased, and cholecystokinin decreased, by
lithium administration in some rat brain regions.141,142
Especially intriguing is the recent discovery that lith-
ium increases levels of the anti-apoptotic protein bcl-
2 which may have important consequences for the neu-
roprotective actions of lithium.33,34 Additionally, the
method of differential display holds great promise as a
method capable of distinguishing drug-induced alter-
ations in the expression of specific genes, and the first
study with lithium using this method identified 2⬘,3⬘-
cyclic nucleotide 3⬘-phosphodiesterase, an enzyme
potentially involved in neuronal growth and repair, as
being up-regulated after lithium treatment.143
Overall, although a variety of effects of lithium on
mRNA and protein levels have been reported, there is
not yet a consensus about which of these may be of
primary importance in the therapeutic response, and
the mechanisms accounting for these changes caused
by lithium have not been identified. At present these
findings are most useful as leads for further investi-
gations aimed at identifying the critical affected pro-
ducts, as well as for confirming that lithium clearly
does have selective modulatory influences on neuronal
gene expression and protein concentrations.
Physiological effects
Potentially important additional actions of lithium
appear to warrant further investigation. Modulation by
lithium of the Na+-K+-ATPase remains a viable con-
tributory factor in lithium’s actions.144 There has been
surprisingly little research in recent years examining
hormonal effects of lithium, although hormonal fluc-
tuations likely contribute to susceptibility and episodic
onset. However, several reports provide confirmation
of earlier studies that thyroid hormone activity is affec-
ted by lithium.145–147 Circadian rhythm disturbances
may be a factor in bipolar disorder, and recent findings
continue to support earlier reports that the circadian
period can be altered by lithium.148 This limited num-
ber of recent studies clearly indicates the need for
further investigations of the hormonal and circadian
influences of lithium.
Summary
Although many clues have been obtained in recent
years, there is still not a clear understanding of the
mechanism of action of lithium. One of the primary
difficulties is that there is still no means to test which
of the multitude of described actions of lithium are
critical for its therapeutic effect, and there is a dearth
of schemes which consolidate this information. Thus,
from the many biochemical actions of lithium that have
been discovered, investigators are faced with the formi-
dable tasks of identifying which of these are critical for
lithium’s therapeutic actions and integrating these into
a comprehensive picture of how neuronal function is
modulated by lithium. There is clearly a need for ani-
mal models that would help to distinguish the actions
 Mechanism of action of lithium
RS Jope

124
of lithium that are critical for a therapeutic
response.4,149,150 There is also a need for information
about the intracellular concentrations of lithium that
are required for therapeutic responses. The intracellu-
lar concentration of lithium has traditionally been esti-
mated from gross measurements of extracts of brain
regions. Such estimates are clearly inaccurate, since in
recent years it has become evident that spatial, as well
as temporal, gradients of molecules are achieved in
neurons. Identifying the spatial and temporal gradients
of lithium’s distribution is a critical, and challenging,
issue. This limitation is emphasized by a recent study
addressing the intraneuronal concentration of lithium
which concluded that localized concentrations of lith-
ium near transport sites are likely to be much higher
than 1 mM.32
Even with these limitations, however, there is begin-
ning to emerge an understanding that rather than look-
ing for a single site of action, many actions of lithium
must, and can, be integrated to obtain a cohesive pic-
ture of how neuronal function is modulated by long-
term exposure to lithium (Figure 5). Three systems
appear especially enticing as critical sites of actions of
lithium which appear most likely to contribute to the
multiple therapeutic actions of lithium, and each of
which can influence the others. (1) Lithium seems to
alter the balance among neurotransmitter activities and
to have neuroprotective effects. Modulation of neuro-
transmitter balances, in conjunction with decreasing
glutamatergic activity and toxicity, is likely to modu-
late excitatory and inhibitory synapses and networks,
as well as contributing to neuroprotection. (2) The neu-
ronal cytoskeleton is much more than a structural
framework, but is a dynamic system contributing to
neural plasticity. Lithium modulates signals impacting
on the cytoskeleton at multiple levels, including sig-
nals from glycogen synthase kinase 3␤, cyclic AMP-
dependent kinase, and protein kinase C, and these
actions may be critical for the neural plasticity
involved in mood recovery and stabilization. (3) Lith-
ium adjusts signaling activities regulating second mess-
engers, transcription factors, and gene expression. The
outcome of these effects appears likely to result in lim-
iting the magnitudes of fluctuations in activities, con-
tributing to a stabilizing influence induced by lithium,
and neuroprotective effects of lithium may be derived
from its modulation of the expression of genes
involved in regulating degenerative and regenerative
mechanisms.
In summary, this review introduces the concepts that
multiple actions of lithium must be considered critical
in the therapeutic response, and that these complex
effects support neural plasticity and stabilize neuro-
transmitter balances, signaling activities, and gene
expression, each of which may make a necessary, but
individually insufficient, contribution to lithium’s
therapeutic effects (Figure 5). Multiple actions of lith-
ium, rather than a single site of action, may be neces-
sary because lithium has antimanic, antidepressant,
and prophylactic stabilizing actions, and because
bipolar disorder is a complex illness involving mul-
tiple systems. Thus, it may be too much to expect that
these multiple effects of lithium could be accounted for
by either an action that is unidirectional, rather than a
bimodal balancing action, or a single site of action,
rather than the culmination of multiple actions. The
critical property of lithium appears to be that it is able
to act at multiple sites to adjust the balance, and
dampen the magnitudes of fluctuations, of positive and
negative inputs to neuronal function, allowing it to

Figure 5 Summary of the major sites of action of lithium emphasized in this review. Evidence reviewed in this article indicates
that more than a single site of action of lithium is likely to contribute to its therapeutic effects. Furthermore, this review notes
that lithium has a widespread tendency to alter balances between opposing pathways, rather than having unidirectional actions,
to modulate the magnitudes of fluctuations in systems. The figure depicts sites of signaling systems that appear to be the most
critical sites of action of lithium. NT = neurotransmitter. Rec = receptor.

normalize the complex components of mood disorders
and to have multiple therapeutic effects.
Acknowledgements
I am very grateful to Drs John Challiss, De-Maw Chu-
ang, Lowell Hokin, and Trevor Young for their valuable
comments on an earlier version of this review, and
especially to Dr Husseini Manji for many stimulating
discussions regarding the contents of this review.
Research in the author’s laboratory was supported by
grants from the Theodore and Vada Stanley Foun-
dation and the National Institutes of Health
(MH38752).
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