This Article Abstract Figures Only Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chen, G. Articles by Manji, H. K. Search for Related Content PubMed PubMed Citation Articles by Chen, G. Articles by Manji, H. K. Related Collections Pharmacology Reviews

Regulation of Signal Transduction Pathways and Gene Expression by Mood Stabilizers and Antidepressants

From the Department of Psychiatry and Behavioral Neurosciences (G.C., K.A.H., J.M.B., G.J.M., D.G., H.K.M.), Pharmacology (H.K.M.), Radiology (G.J.M.), and Cellular and Clinical Neurobiology Program (G.C., G.J.M., H.K.M.), Wayne State University School of Medicine, Detroit, MI.

Address reprint requests to: Husseini K. Manji, MD, FRCPC, Director, Laboratory of Molecular Pathophysiology, Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, UHC 9B, 4201 St. Antoine Blvd., Detroit, MI 48201. Email: hmanji{at}med.wayne.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION TRANSMEMBRANE CELLULAR SIGNAL... ABNORMALITIES IN SECOND... ARE G PROTEIN-COUPLED SIGNAL... LITHIUM AND THE PHOSPHOINOSITIDE... LITHIUM AND PKC LITHIUM AND AC LITHIUM AND G PROTEINS VALPROIC ACID AND G... GSK3ß: A... EFFECTS OF CARBAMAZEPINE ON... EFFECTS OF MOOD STABILIZERS... CONCLUDING REMARKS ACKNOWLEDGMENTS REFERENCES

 
OBJECTIVE: To determine whether the currently available evidence supports the hypothesis that antidepressants and mood stabilizers may bring about some of their long-term therapeutic effects by regulating signal transduction pathways and gene expression in the central nervous system.

METHODS: To address this question, we reviewed the evidence showing that chronic administration of antidepressants and mood stabilizers involves alterations in signaling pathways and gene expression in the central nervous system.

RESULTS: A large body of data has shown that lithium and valproate exert effects on the protein kinase C signaling pathway and the activator protein 1 family of transcription factors; in contrast, antidepressants affect the cyclic adenosine monophospate pathway and may bring about their therapeutic effects by modulating cyclic adenosine monophosphate–regulated gene expression in the central nervous system.

CONCLUSIONS: Given the key roles of these signaling cascades in the amplification and integration of signals in the central nervous system, the findings have clear implications not only for research into the etiology and pathophysiology of the severe mood disorders but also for the development of novel and innovative treatment strategies.

Key Words: mood disorders • protein kinase C • gene expression • lithium • antidepressants • valproate.

Abbreviations: AC = adenylate cyclase; ADP = adenosine diphosphate; AP-1 = activator protein 1; cAMP = cyclic adenosinemonophosphate; CNS = central nervous system; CREB = cAMPresponse element–binding protein; DAG = diacylglycerol; DMI= desipramine; GAP-43 = growth-associated protein 43; GDP =guanosine diphosphate; GSK-3 = glycogen synthase kinase 3; GTP = guanosine triphosphate; IP3 = inositol1,4,5-trisphosphate; MARCKS = myristoylated alanine-rich C kinasesubstrate; PI = phosphatidylinositol; PIP₂ =phosphotidylinositol-4,5-bisphosphate; PKC = protein kinaseC; PLC = phospholipase C; RGS = regulator of G proteinsignaling; TPA = 12-o-tetradecanoyl-phorbol13-acetate; ßAR = ß-adrenergic; 5HT = serotonin.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION TRANSMEMBRANE CELLULAR SIGNAL... ABNORMALITIES IN SECOND... ARE G PROTEIN-COUPLED SIGNAL... LITHIUM AND THE PHOSPHOINOSITIDE... LITHIUM AND PKC LITHIUM AND AC LITHIUM AND G PROTEINS VALPROIC ACID AND G... GSK3ß: A... EFFECTS OF CARBAMAZEPINE ON... EFFECTS OF MOOD STABILIZERS... CONCLUDING REMARKS ACKNOWLEDGMENTS REFERENCES

 
Mood disorders are common, severe, chronic, and often life-threatening illnesses. Despite well-established genetic diatheses and extensive research, the biochemical abnormalities underlying the predisposition to, and the pathophysiology of, these disorders remain to be clearly established. Early biological theories regarding mechanisms of action of mood stabilizers and antidepressants focused on various neurotransmitters, in particular the biogenic amines. However, although a number of acute, in vitro effects of these agents are well established, their therapeutic effects are only seen after chronic administration, thereby precluding any simple mechanistic interpretations based on acute biochemical effects. The search for the mechanisms of action of mood stabilizers and antidepressants has been facilitated by a growing appreciation that rather than any single neurotransmitter system being responsible for depression or mania, multiple interacting and overlapping systems are likely involved in regulating mood and that most effective drugs likely do not work on any particular neurotransmitter system in isolation but rather affect the functional balance between interacting systems. Advances in our understanding of the cellular basis of neuronal communication have also led to a reconceptualization of the mechanisms by which neuronal function is regulated, and it has become increasingly appreciated that in addition to regulating the levels of neurotransmitters per se, the throughput of the extracellular signal can also be markedly regulated through alterations in intracellular signaling (1–5). In this context, signal transduction pathways are in a pivotal position in the CNS and thus represent attractive targets to explain the efficacy of pharmacological agents in treating multiple aspects of mood disorders (6–8). It is therefore not surprising that, in recent years, research aimed at elucidation of the cellular mechanisms underlying the therapeutic effects of mood stabilizers and antidepressants have focused on second messenger-generating systems. We now provide a brief overview of transmembrane signal transduction pathways and then discuss their potential involvement in mood disorders and as targets of mood stabilizers and antidepressants.

	TRANSMEMBRANE CELLULAR SIGNAL TRANSDUCTION

TOP ABSTRACT INTRODUCTION TRANSMEMBRANE CELLULAR SIGNAL... ABNORMALITIES IN SECOND... ARE G PROTEIN-COUPLED SIGNAL... LITHIUM AND THE PHOSPHOINOSITIDE... LITHIUM AND PKC LITHIUM AND AC LITHIUM AND G PROTEINS VALPROIC ACID AND G... GSK3ß: A... EFFECTS OF CARBAMAZEPINE ON... EFFECTS OF MOOD STABILIZERS... CONCLUDING REMARKS ACKNOWLEDGMENTS REFERENCES

 
There has been considerable recent progress in elucidation of the cellular mechanisms underlying neuronal communication, particularly with respect to defining the obligatory role of G proteins in the transduction of a vast array of extracellular, receptor-detected signals across cell membranes to intracellular effectors. Most of the molecules that initiate cellular signaling cannot penetrate the hydrophobic plasma membrane lipid bilayer but rather transmit their message via cell-surface receptors. These receptors facilitate the optimization and amplification of signal transmission by stimulating the production or modulation of one or, indeed, several intracellular second or third messengers. It has been estimated that about 80% of all known hormones, neurotransmitters, and neuromodulators elicit cellular responses through G proteins coupled to a variety of intracellular effectors (Table 1 ). Guanine nucleotide–binding proteins (G proteins) are a ubiquitous family of proteins that serve the critical role of transducers of information across the plasma membrane, coupling receptors to various effectors (1–5). The G proteins are heterotrimers localized to the inner surface of the plasma membrane and consist of an subunit, which binds (and hydrolyzes) GTP, and ß subunits, which form a tightly but noncovalently linked dimer (Figure 1 ).

View larger version (26K): [in this window] [in a new window]   Fig. 1. G protein activation/deactivation cycle. This figure depicts activation of the stimulatory G protein (Gs) by the ßAR receptor, but a similar activation/deactivation cycle is thought to occur with most (if not all) G proteins. The G protein subunit cycles between an inactive GDP-bound heterotrimeric (ß) form and an active GTP-bound monomeric form. At rest, an equilibrium exists between the receptor in the high-affinity state (coupled to the G protein) and the low-affinity (uncoupled) state. Activation of receptors by an agonist induces a conformational change in the receptor, allowing it to interact with the G protein, leading to the release of GDP, and the formation of a high-affinity ternary complex (agonist-receptor-G protein). This high-affinity state is short lived, and binding of GTP to the empty nucleotide site on the subunit of the G protein leads to a destabilization of the high-affinity complex and a dissociation of the G protein into s-GTP and ß subunits. It is now well established that both the s-GTP and ß subunits are able to regulate the activity of various effectors. To date, the best characterized effects of the G protein ß subunits are potentiation of the activity of ACs II and IV and activation of certain PLC isozymes, ion channels, and receptor kinases. s-GTP is shown to activate ACs in this figure, but there is also evidence demonstrating the direct activation of L-type Ca2+ channels by s-GTP (at least in certain tissues). The continued activation of effectors by -GTP is terminated by the action of a GTPase enzyme intrinsic to the a subunit. The formation of s-GDP causes its dissociation from AC; the reassociation of s-GDP with ß is thermodynamically stable and completes the cycle with the formation of the inactive GDP-bound heterotrimeric (ß) G protein. ATP = adenosine triphosphate; PLC ß = phospholipase C ß isoenzyme; s = subunit of stimulatory G protein; ß = G protein ß subunits.

	ABNORMALITIES IN SECOND MESSENGER-GENERATING SYSTEMS IN MOOD DISORDERS

TOP ABSTRACT INTRODUCTION TRANSMEMBRANE CELLULAR SIGNAL... ABNORMALITIES IN SECOND... ARE G PROTEIN-COUPLED SIGNAL... LITHIUM AND THE PHOSPHOINOSITIDE... LITHIUM AND PKC LITHIUM AND AC LITHIUM AND G PROTEINS VALPROIC ACID AND G... GSK3ß: A... EFFECTS OF CARBAMAZEPINE ON... EFFECTS OF MOOD STABILIZERS... CONCLUDING REMARKS ACKNOWLEDGMENTS REFERENCES

G Proteins in Mood Disorders
In view of the indirect evidence of abnormalities at postreceptor sites described above, it is not surprising that several independent laboratories have examined G proteins in patients with mood disorders (see Ref. 8 for an excellent review). Young et al. were the first to report increased levels of G_s in patients with bipolar affective disorder in two separate studies (8, 26). Compared with control subjects matched for age, postmortem interval, and brain pH, patients with bipolar affective disorder had increased levels of G_s in frontal, temporal, and occipital cortex, but not in hippocampus, thalamus, or cerebellum, in postmortem brain tissue. The investigators also found increases in forskolin-stimulated AC activity in postmortem brain tissue compatible with a postreceptor abnormality in patients with bipolar affective disorder. The findings of elevated G_s levels and/or function are also supported by the recent findings of Wang and Friedman (27), who found increased agonist-activated [³⁵S]GTP_S binding to G protein subunits in frontal cortical membrane preparations of postmortem brain tissue from patients with bipolar affective disorder. Garcia-Sevilla et al. (28) reported increased levels of G_i1/2 in prefrontal cortical samples obtained postmortem from depressed patients who committed suicide, effects that were apparently attenuated by antemortem antidepressant treatment. Overall, the findings in postmortem brain tissue in patients with unipolar depression have been less consistent (see Ref. 8 for a summary of postmortem findings). In keeping with the G protein abnormalities in brain tissue obtained postmortem from bipolar affective disorder patients, Schreiber et al. (29) reported "hyperfunctional" G protein function in leukocytes of untreated manic patients by demonstrating that agonist-stimulated binding of [³H]Gpp(NH)p (a stable, nonhydrolyzable analog of GTP) was enhanced in leukocyte membranes of untreated manic patients compared with control subjects. These findings suggest the presence of increased levels of G proteins and/or enhanced receptor-mediated activation of G proteins in leukocytes from untreated manic subjects. More recently, investigators have reported significantly higher levels of G_s in mononuclear leukocytes from patients with bipolar, but not unipolar, depression (30); another study (31) quantitatively measured the levels of the major G protein subunits in leukocytes and platelets from both untreated (predominantly manic) and lithium-treated, euthymic bipolar affective disorder patients; in both platelet and leukocyte membranes, this study observed higher levels of the 45-kd form of G_s in the overall group of bipolar affective disorder patients (treated or untreated) compared with control subjects. A recent study found elevated levels of G_s mRNA in granulocytes obtained from patients with bipolar, but not unipolar, depression (32). This study also found nonsignificant elevations in the levels of G_i2 in unmedicated bipolar patients, which intriguingly were modulated by lithium in bipolar (but not unipolar) patients. Studies of G protein levels in peripheral cells from unipolar depressed patients have revealed somewhat conflicting results, with one study reporting decreased levels of leukocyte G_s and G_i in patients with unipolar depression (33) and another reporting elevated platelet G_i2 in these patients (34). Similar to what has been observed in the CNS (3), one recent study evaluated the role of platelet G proteins as "signal coincidence detectors" and found this function to be impaired in depressed patients (35). Recent studies have also suggested that peripheral cell G protein measures are altered in patients undergoing treatment with antidepressants or electroconvulsive shock and, furthermore, that these changes may be associated with treatment response (34, 36, 37). Because it is unlikely that electroconvulsive shock directly alters peripheral cell G protein levels, it is likely that the changes following treatments are secondary to alterations in circulating factors (eg, catecholamines or glucocorticoids). Overall, the most consistent finding to emerge is that in both peripheral cells and postmortem brain tissue from patients with bipolar depression, elevations are observed in the predominant subspecies of G_s present in the tissues examined (see Ref. 8). Because G_s is a ubiquitously expressed protein, it may seem counterintuitive that an abnormality in this protein may play a role in the pathophysiology of bipolar affective disorder. However, there is already precedence for clinical disorders arising from abnormalities in the levels of G_s, which present with limited clinical manifestations, despite the ubiquitous expression of the protein (see Refs. 4 and 5 for excellent reviews on clinical manifestations associated with signaling abnormalities). These heterogeneous clinical effects and tissue-specific manifestations have been postulated to arise from differences in receptor, G protein, and effector stoichiometries in different tissues and to tissue-specific differences in the ability of different cells to compensate for the abnormality (4, 5). It should be emphasized, however, that there is, at present, no evidence to suggest that alterations in the levels of G_s are due to a mutation in the G_s gene itself (38). Indeed, numerous transcriptional and posttranscriptional mechanisms regulate the levels of G protein subunits (see Ref. 8), and the elevated levels of G_s could potentially represent the sequelae of alterations in any one of these other biochemical pathways. Thus, at this point, considerable caution is clearly required in interpretation of the data because they are derived primarily from peripheral cell models and may not adequately reflect CNS pathology. The possibility of the presence of aberrant biochemical pathways that regulate G_s levels in bipolar disorder is currently being studied (8).

Phosphoinositide/PKC Signaling Pathway
Peripheral cell and postmortem brain studies have generally revealed modest abnormalities in the phosphoinositide/PKC signaling system in bipolar affective disorder. Thus, one study measured membrane phospholipids in platelets of seven medication-free patients in the manic phase of bipolar affective disorder and seven healthy control subjects. These investigators found that the relative percentage of platelet membrane PIP₂ was significantly higher in manic patients than in control subjects (39). More recently, investigators from the same laboratory (40) studied PIP₂ membrane values in a patient with bipolar disorder during different mood states in a single case study. They found that the relative percentage of PIP₂ in platelet membranes increased with cycling from the euthymic into the manic state. After lithium treatment, the PIP₂ level decreased and was similar to that during the euthymic state. Consistent with these findings, van Calker et al. (41) found increased sensitivity to agonist stimulation of the Ca²⁺ response in neutrophils of manic-depressive patients, effects that were normalized by lithium treatment. Interestingly, in addition to lithium, other psychotropic drugs used in the treatment of bipolar affective disorder (including antidepressants, haloperidol, and valproate) have also been demonstrated to have complex effects on the phosphoinositide signaling system both ex vivo and in vitro (42–44). Investigators have also attempted to determine whether the altered phosphoinositide signaling found in peripheral cells from bipolar affective disorder patients is also present in the CNS. In this context, Mathews et al. (45) found increased G_q/11 immunoreactivity in postmortem occipital cortex from patients with bipolar affective disorder. However, these elevated levels of G_q/11 were accompanied by reduced agonist-induced PI turnover (46), although the potential effects of long-term lithium treatment remained to be fully delineated. To date, only two studies have directly examined PKC in bipolar affective disorder. Friedman et al. (47) investigated PKC activity and translocation in response to serotonin in platelets obtained from patients with bipolar affective disorder before and during lithium treatment. They found that the ratios of platelet membrane bound to cytosolic PKC activities were elevated in the manic patients compared with patients with schizophrenia and healthy control subjects. In addition, serotonin-elicited platelet PKC translocation was found to be enhanced in those subjects. Similar to the results observed in rodent brain, lithium treatment for up to 2 weeks resulted in a reduction in cytosolic and membrane-associated PKC activities and in an attenuated PKC translocation in response to serotonin. These preliminary results suggest that alteration in platelet PKC is associated with the manic phase of bipolar illness. More recently, investigators from the same laboratory measured PKC isozyme levels, activity, and translocation in postmortem brain tissue from patients with bipolar affective disorder; they found increased PKC activity and translocation, as well as elevated levels of cytosolic - and membrane-associated - and PKC isozymes, in brain tissue obtained postmortem from patients with bipolar affective disorder compared with tissue from control subjects (27). These results may be specific to bipolar affective disorder, because investigators from another laboratory recently found significantly decreased [³H]phorbol 12, 13-dibutyrate (PDBU)-binding sites in both membranous and cytosolic postmortem brain samples (Brodmann’s areas 8 and 9) obtained from teenage suicide victims compared with control subjects (48).

	ARE G PROTEIN–COUPLED SIGNAL TRANSDUCTION PATHWAYS TARGETS FOR ANTIDEPRESSANTS AND MOOD-STABILIZING AGENTS?

TOP ABSTRACT INTRODUCTION TRANSMEMBRANE CELLULAR SIGNAL... ABNORMALITIES IN SECOND... ARE G PROTEIN-COUPLED SIGNAL... LITHIUM AND THE PHOSPHOINOSITIDE... LITHIUM AND PKC LITHIUM AND AC LITHIUM AND G PROTEINS VALPROIC ACID AND G... GSK3ß: A... EFFECTS OF CARBAMAZEPINE ON... EFFECTS OF MOOD STABILIZERS... CONCLUDING REMARKS ACKNOWLEDGMENTS REFERENCES

 
Antidepressants and G Proteins
Long-term administration of a variety of antidepressant treatments, including tricyclics, monoamine oxidase inhibitors, and electroconvulsive shock, seem to downregulate or desensitize the ßARs in rat forebrain (49) and enhance the synaptic efficacy of serotonergic neurotransmission via the 5HT_1A receptor in rat hippocampus (50). These effects, however, do not explain the clinical efficacy of all antidepressants, and the dissociation between receptor number and their functional responsiveness has led to the investigation of possible postreceptor sites of action of these drugs. After long-term treatment, DMI is reported to cause a functional uncoupling of the ßAR from G_s in rat cortex (51, 52) and to interfere with the breakdown of the ßAR high-affinity ternary complex (53) and the subsequent activation of AC, perhaps by decreasing the affinity of G_s for guanine nucleotides (54). Okada et al. (55) reported that pertussis toxin treatment of rats overcomes DMI-induced ßAR desensitization (as assessed by measurements of isoproterenol-stimulated AC activity) without attenuating DMI-induced ßAR downregulation. These studies suggest that antidepressants modify the interactions between the ßAR and G_i/G_o and are intriguing in view of the recently defined role of G protein ß subunits in regulating receptor desensitization (56).

Recent studies have investigated the effects of long-term administration of antidepressants on the levels of G protein subunits. Overall, the results are far from conclusive and have tended to reveal a complex, regional- and tissue-specific pattern of effects on various G protein subunits and their mRNA levels after long-term treatment with various antidepressants (8, 34, 37, 57–65). This complex pattern of effects is not altogether surprising in view of the differing pharmacological profiles of the drugs (and their metabolites) with respect to receptor binding, monoamine reuptake blockade, and enzymatic (monoamine oxidase) inhibition (66). Thus, one study found that antidepressants tended to decrease the immunolabeling of G_s in the hippocampus (57), consistent with the recent report of postreceptor desensitization of hippocampal AC activity after long-term DMI treatment (52) and suggesting a coordinate downregulation of the ß-adrenoceptor-G_s-AC complex by antidepressants (49, 66). In this study, long-term antidepressant treatment tended to decrease the immunolabeling of G_i1/2, in hippocampus, whereas tricyclics (but not the monoamine oxidase inhibitor) tended to increase levels of G_o in the hippocampus (57). These findings are complementary to those of Okada et al. (55) described above and suggest the possible involvement of pertussis toxin substrates (G_i and G_o) in mediating the effects of DMI. Reductions in the levels of G_i2 have also been observed in platelets of depressed patients treated with citalopram, imipramine, or clomipramine (34). Additionally, the opposite effects of the antidepressants on the levels of G_i and G_o described above offer an explanation for the seemingly opposite effects of antidepressants on 5HT_1A signaling that have been observed when using functional biochemical (cAMP) or electrophysiological measures (50, 66, 67). Thus, long-term administration of antidepressants may produce a relative shift in the hippocampal 5HT_1A receptor response from those mediated by G_i toward those mediated by G_o. Other studies have found that long-term administration of fluoxetine reduces the levels of G_i, G_o, and G_z in the hypothalamus (58, 60) and reduces the levels of G_o and G_i in the midbrain (61). Long-term administration of imipramine has been reported to decrease G_o mRNA levels in CA1 and CA3 hippocampal subfields and dentate gyrus without affecting G_s or G_i mRNA levels in these regions (65). In contrast, repeated electroconvulsive shock has been reported to reduce G_s mRNA in CA1 and CA3, reduce the levels of G_o mRNA in dentate gyrus, and reduce the levels of G_i2 in both dentate gyrus and CA3 (63). Several studies, however, have not found any alterations in the levels of G subunits or their mRNA levels after long-term antidepressant administration (59, 62, 64, 68).

Although the precise effects of antidepressants on the levels of G proteins remain inconclusive, several elegant studies have demonstrated an enhanced coupling between G_s and the catalytic unit of adenylate cyclase after long-term administration of antidepressants (68–71). Several studies have also demonstrated that the postreceptor components of the cAMP system are regulated by long-term antidepressant treatments, including cAMP-dependent protein kinase enzyme activity (72, 73).Taken together, these results suggest that antidepressants, through their complex effects on G proteins and the AC signaling system, may attenuate ßAR-mediated activation of G_s while enhancing the effects of agents operating by pathways independent of the ßAR receptor.

Consistent with these results, recent data from Duman et al. (74) and Nibuya et al. (75) have demonstrated that long-term treatment of rats with a variety of antidepressants increases the levels of CREB mRNA, CREB protein, and cAMP response element DNA–binding activity in hippocampus. These effects were selective for antidepressants and were not observed with a variety of nonantidepressants, including cocaine, morphine, and haloperidol. These results suggest that genes regulated by CREB may, in fact, also be long-term targets of antidepressants. In this context, the same investigators (74, 75) have demonstrated that long-term treatment of rats results in an increase in the expression of two genes known to be regulated by CREB, namely BDNF (brain-derived neurotrophic factor) and its receptor (trkB). These investigators have postulated that upregulation of the expression of a neurotrophic factor and its receptor may increase the survival of hippocampal neurons or promote the sprouting of neurons that innervate the hippocampus, such as those of the major monoaminergic pathways. These exciting findings have led to a molecular and cellular hypothesis of depression (74), which posits that stress-induced vulnerability and the therapeutic action of antidepressant treatments occur via intracellular mechanisms regulating neurotrophic factors necessary for the survival and functioning of critical neurons, with important implications for future drug development.

	LITHIUM AND THE PHOSPHOINOSITIDE CYCLE

TOP ABSTRACT INTRODUCTION TRANSMEMBRANE CELLULAR SIGNAL... ABNORMALITIES IN SECOND... ARE G PROTEIN-COUPLED SIGNAL... LITHIUM AND THE PHOSPHOINOSITIDE... LITHIUM AND PKC LITHIUM AND AC LITHIUM AND G PROTEINS VALPROIC ACID AND G... GSK3ß: A... EFFECTS OF CARBAMAZEPINE ON... EFFECTS OF MOOD STABILIZERS... CONCLUDING REMARKS ACKNOWLEDGMENTS REFERENCES

 
Over the last decade, research on the molecular mechanisms underlying the therapeutic effects of lithium has focused on intracellular second messenger-generating systems, in particular receptor-coupled hydrolysis of PIP₂. Although inositol phospholipids are relatively minor components of cell membranes, they play a major role in receptor-mediated signal transduction pathways and are involved in a diverse range of responses in the CNS (reviewed in Ref. 76). Activation of a variety of neurotransmitter receptor subtypes (including muscarinic M₁, M₃, and M₅, noradrenergic ₁, serotonergic 5HT₂, and several metabotropic glutamatergic receptors) induces hydrolysis of membrane phospholipids. In brief, agonists such as acetylcholine, norepinephrine, serotonin, and glutamate bind to specific cell-surface receptors to stimulate certain isoforms of the enzyme PLC. Activated PLC catalyzes the conversion of PIP₂ to two second messengers, IP₃ and DAG. IP₃ stimulates mobilization of intracellular Ca²⁺, whereas DAG activates PKC. IP₃ can be phosphorylated and dephosphorylated, leading to other inositol phosphate compounds or to unphosphorylated inositol. Inositol, in turn, is converted to phosphatidylinositol, which is phosphorylated to phosphatidylinositolphosphate (PIP) and PIP₂ (Figure 2 ).

View larger version (36K): [in this window] [in a new window]   Fig. 2. Effects of lithium on the phosphoinositide cycle. In this scheme, occupancy of the receptor (R) by a specific agonist (A) initiates hydrolysis of PIP2 by PLC. Hydrolysis of PIP2 by PLC results in the formation of two major second messengers, IP3 and DAG. IP3 mobilizes calcium from intracellular stores, whereas DAG activates PKC (see text for details). IP3 is either dephosphorylated to form inositol 1,4-diphosphate (Ins 1,4,P2), inositol monophosphate (Ins P1), and, ultimately, free inositol, or phosphorylated to form inositol 1,3,4,5-tetraphosphate (Ins 1,3,4,5 P4), which is then dephosphorylated by sequential distinct pathways. Lithium, at therapeutically relevant concentrations, inhibits the dephosphorylation of inositol 1,3,4-triphosphate (Ins 1,3,4 P3), Ins 1,4,P2, and all three forms of inositol phosphatases (not shown in detail in the figure). Because the ability of a cell to maintain sufficient supplies of myoinositol is crucial to the resynthesis of the phosphoinositides, and because in most tissues inositol is derived primarily from recycling of inositol phosphates, one early consequence of lithium’s action is to reduce the levels of free inositol. As shown in the figure, inositol depletion can also perturb the DAG limb of the phosphoinositide turnover pathway. Thus, resynthesis of PI involves the transfer of the phosphatidic acidic moiety from cytidine diphosphate DAG to myoinositol. Presumably because of its effect of lowering levels of inositol, lithium treatment of a number of cells has been found to increase the levels of cytidine diphosphate DAG, and its interconvertible metabolite, DAG. Because DAG activates PKC, one consequence of lithium treatment is an activation of PKC. BBB = blood brain barrier.

However, numerous studies have examined the effects of lithium on receptor-mediated PI responses, and although some report a reduction in agonist-stimulated PIP₂ hydrolysis in rat brain slices after short- or long-term lithium administration, these findings have often been small and inconsistent and subject to numerous methodological differences (see Refs. 7 and 80 for excellent recent reviews). Thus, despite its attractiveness, the inositol depletion hypothesis as originally articulated has recently been questioned (7, 80, 81). A body of preclinical data, however, suggests that some of the initial actions of lithium may occur with a relative depletion of myoinositol (82–85); this relative depletion of myoinositol may initiate a cascade of secondary changes at different levels of the signal transduction process and gene expression in the CNS, effects that are ultimately responsible for lithium’s therapeutic efficacy (80, 81). Our research group has recently undertaken a series of studies using magnetic resonance spectroscopy to determine whether lithium reduces the levels of myoinositol in critical brain regions of individuals with bipolar affective disorder (despite the attractiveness of the inositol depletion hypothesis, it has never been demonstrated to occur in human brain). Our results show that the therapeutic administration of lithium does, indeed, produce a significant brain region–specific reduction in myoinositol levels in patients with bipolar affective disorder (86). However, the major lithium-induced reductions in myoinositol levels occur after 5 days of lithium administration, at a time when the patients’ clinical state is largely unchanged. These results clearly indicate that lithium’s therapeutic effects are not due to a lowering of myoinositol per se. Studies are currently under way to determine whether the early lithium-induced reductions in myoinositol levels are associated with ultimate therapeutic response (likely mediated by changes in PKC-induced gene expression).

	LITHIUM AND PKC

TOP ABSTRACT INTRODUCTION TRANSMEMBRANE CELLULAR SIGNAL... ABNORMALITIES IN SECOND... ARE G PROTEIN-COUPLED SIGNAL... LITHIUM AND THE PHOSPHOINOSITIDE... LITHIUM AND PKC LITHIUM AND AC LITHIUM AND G PROTEINS VALPROIC ACID AND G... GSK3ß: A... EFFECTS OF CARBAMAZEPINE ON... EFFECTS OF MOOD STABILIZERS... CONCLUDING REMARKS ACKNOWLEDGMENTS REFERENCES

 
Considerable recent research has clearly shown that, in addition to its effects on PI turnover, the PKC signaling pathway is a target for the actions of long-term lithium (reviewed in Refs. 7, 81, and 87; Table 3 ). PKC is highly enriched in brain and plays a major role in regulating pre- and postsynaptic aspects of neurotransmission (88–90). PKC is one of the major intracellular mediators of signals generated on external stimulation of cells through a variety of neurotransmitter receptor subtypes that induce the hydrolysis of membrane phospholipids. PKC is now known to exist as a family of closely related subspecies, has a heterogeneous distribution in brain (with particularly high levels in presynaptic nerve terminals), and plays a major role in the regulation of neuronal excitability, neurotransmitter release, and long-term alterations in gene expression and plasticity (88–90).

Using quantitative autoradiographic techniques, it has also been demonstrated that long-term (5-week) lithium administration results in a significant decrease in membrane-associated PKC in several hippocampal structures, most notably the subiculum and CA1 region, in the absence of any significant changes in the various other cortical and subcortical structures examined (96). Furthermore, immunoblotting using monoclonal anti-PKC antibodies has revealed isozyme-specific decreases in PKC and , which have been particularly implicated in facilitating neurotransmitter release, in the absence of significant alterations in PKC ß, PKC , PKC , or PKC . It is also noteworthy that exposure of neuroblastoma cells (97) or PC12 cells (98) to 1 mM lithium in vitro produces isozyme-selective decreases in PKC and, in the case of PC12 cells, PKC . In the absence of suitable animal models for the major psychiatric disorders, a major problem inherent in neuropharmacological research is the difficulty in precisely ascribing therapeutic relevance to any observed biochemical finding. One approach is to iden- tify common biochemical targets that are modified by drugs belonging to the same therapeutic class (eg, antimanic agents) but possessing distinct chemical structures (eg, lithium and valproate, the only two drugs approved by the US Food and Drug Administration for treatment of bipolar affective disorder) when administered in a "therapeutically relevant" paradigm. Although they likely do not work by precisely the same mechanisms, identifying the biochemical targets that are regulated in concert by these two chemically distinct agents may provide important clues about molecular mechanisms underlying mood stabilization in the brain. In view of the significant effects of lithium on PKC outlined above, the effects of valproate on various aspects of PKC functioning have also been investigated. It has been found that the structurally highly dissimilar agent, valproate, produces effects on the PKC signaling pathway that are strikingly similar to those of lithium (91, 99, 100; Table 4 ). Interestingly, long-term administration of lithium and valproate seems to regulate PKC isozymes by distinct mechanisms, with valproate’s effects seeming to be largely independent of myoinositol (100). This biochemical observation is consistent with clinical observations that some patients have a preferential response to one or the other agent and that additive therapeutic effects often occur when the two agents are coadministered.

	LITHIUM AND AC

TOP ABSTRACT INTRODUCTION TRANSMEMBRANE CELLULAR SIGNAL... ABNORMALITIES IN SECOND... ARE G PROTEIN-COUPLED SIGNAL... LITHIUM AND THE PHOSPHOINOSITIDE... LITHIUM AND PKC LITHIUM AND AC LITHIUM AND G PROTEINS VALPROIC ACID AND G... GSK3ß: A... EFFECTS OF CARBAMAZEPINE ON... EFFECTS OF MOOD STABILIZERS... CONCLUDING REMARKS ACKNOWLEDGMENTS REFERENCES

 
The other major receptor-coupled second messenger system on which lithium exerts significant effects is the cAMP-generating system (8, 81). Lithium has been demonstrated to exert complex effects on this system, and the preponderance of data demonstrates an elevation of basal AC activity with simultaneous attenuation of the receptor-mediated response (106–109). Lithium in vitro inhibits stimulation of AC by the poorly hydrolyzable analog of GTP, Gpp(NH)p, and also by Ca²⁺/calmodulin, suggesting that lithium in vitro is directly able to inhibit the catalytic unit of AC. Because these inhibitory effects of lithium in vitro can be overcome by Mg²⁺ (106, 110–114), they seem to be mediated (at least in part) by direct competition with magnesium (whose hydrated ionic radius is similar to that of lithium) for a binding site on the catalytic unit of AC (106, 110, 113, 114). However, the inhibitory effects of long-term lithium treatment on rat brain AC are not reversed by Mg²⁺ and still persist after the membranes are washed but are reversed by increasing concentrations of GTP (106, 113). These results suggest that the therapeutically relevant effects of lithium (ie, those seen with long-term administration that are not reversed immediately on discontinuation) may be exerted at the level of signal-transducing G proteins at a GTP-responsive step (81).

	LITHIUM AND G PROTEINS

TOP ABSTRACT INTRODUCTION TRANSMEMBRANE CELLULAR SIGNAL... ABNORMALITIES IN SECOND... ARE G PROTEIN-COUPLED SIGNAL... LITHIUM AND THE PHOSPHOINOSITIDE... LITHIUM AND PKC LITHIUM AND AC LITHIUM AND G PROTEINS VALPROIC ACID AND G... GSK3ß: A... EFFECTS OF CARBAMAZEPINE ON... EFFECTS OF MOOD STABILIZERS... CONCLUDING REMARKS ACKNOWLEDGMENTS REFERENCES

 
As noted above, abundant experimental evidence has shown that lithium attenuates receptor-mediated AC activity and PI turnover in rodents and humans in the absence of consistent changes in the density of the receptors themselves. There is considerable evidence that long-term (but not short-term) lithium administration affects G protein function (as assessed by second messenger function) (23, 107, 114–119; Table 5 ). At present, the possible effects of long-term lithium administration on the absolute levels of G protein subunits remain unclear; two independent laboratories have not observed any alterations (120, 121), whereas others have reported small but significant decreases in the levels of the _s, _i1, and _i2 in rat brain (122, 123). However, long-term lithium administration has been shown to alter mRNA levels of a number of G proteins in rat brain, including _s, _i1, and _i2 (120, 122, 123), suggesting that lithium produces complex transcriptional and posttranscriptional effects after long-term administration (vide infra).

Overall, the preponderance of data from cell culture, rodent, and human studies argues for an effect of long-term lithium administration on G protein function in both humans and rodents. Such allosteric modulation of G proteins may play a role in the long-term prophylactic efficacy of the cation in protecting susceptible individuals from spontaneous, stress-induced, and drug-induced (eg, by antidepressant and stimulants) cyclic affective episodes. These long-term effects of long-term lithium administration on G protein are likely attributable to an indirect posttranslational modification of the G proteins and a relative change in the dynamic equilibrium of the active and inactive states of protein conformation. In this context, it is noteworthy that investigators have demonstrated that lithium alters the levels of endogenous ADP-ribosylation in C6 glioma cells (131) and in rat brain (132), suggesting another mechanism by which long-term lithium administration may indirectly regulate the activity of these critical signaling proteins.

	VALPROIC ACID AND G PROTEINS

TOP ABSTRACT INTRODUCTION TRANSMEMBRANE CELLULAR SIGNAL... ABNORMALITIES IN SECOND... ARE G PROTEIN-COUPLED SIGNAL... LITHIUM AND THE PHOSPHOINOSITIDE... LITHIUM AND PKC LITHIUM AND AC LITHIUM AND G PROTEINS VALPROIC ACID AND G... GSK3ß: A... EFFECTS OF CARBAMAZEPINE ON... EFFECTS OF MOOD STABILIZERS... CONCLUDING REMARKS ACKNOWLEDGMENTS REFERENCES

 
Recent studies have examined the effects of valproate on components of the ßAR-coupled, cAMP-generating system (133). Long-term administration of valproate has been shown to produce a significant alteration of the ßAR-coupled, cAMP-generating system in cultured cells in vitro; these effects were observed at concentrations of valproate similar to those attained in the plasma in the clinical treatment of neuropsychiatric disorders. In contrast to what has been observed with chronic lithium treatment (discussed above), it was found that chronic valproate produced a significant reduction in the density of ßARs. Interestingly, the decrease in numbers of ßARs (approximately 30%) was accompanied by an even greater decrease in receptor- and postreceptor-mediated cAMP accumulation, suggesting that long-term valproate administration also exerts effects at the ßAR-G_s interaction or at postreceptor sites (eg, G_s or AC). Consistent with such a contention, it was indeed found that long-term, but not short-term, valproate incubation induced a marked decrease in the levels of G_s 45 but not any other G protein subunits examined (G_s 52, G_i1/2, G_o, or G_q/11). In view of the suggested involvement of G_s in the pathophysiology of manic-depressive illness (vide supra), as well as the effects of lithium on the ßAR-G_s-AC system, these effects may play a role in the therapeutic effects of valproate and are worthy of further study.

	GSK3ß: A THERAPEUTICALLY RELEVANT TARGET FOR THE ACTIONS OF LITHIUM?

TOP ABSTRACT INTRODUCTION TRANSMEMBRANE CELLULAR SIGNAL... ABNORMALITIES IN SECOND... ARE G PROTEIN-COUPLED SIGNAL... LITHIUM AND THE PHOSPHOINOSITIDE... LITHIUM AND PKC LITHIUM AND AC LITHIUM AND G PROTEINS VALPROIC ACID AND G... GSK3ß: A... EFFECTS OF CARBAMAZEPINE ON... EFFECTS OF MOOD STABILIZERS... CONCLUDING REMARKS ACKNOWLEDGMENTS REFERENCES

 
In the last 2 years, a hitherto completely unexpected target for the action of lithium has been identified. Klein and Melton (134) were the first to demonstrate that lithium, at therapeutically relevant concentrations, is an inhibitor of GSK3ß. GSK3ß is an evolutionarily, highly conserved kinase that was originally identified as a regulator of glycogen synthesis. It is now known to play a critical role in the CNS, by regulating various cytoskeletal processes via its effects on tau and synapsin I, as well as in long-term nuclear events, through phosphorylation of c-jun and nuclear translocation of ß-catenin (134–136). Thus, lithium’s inhibition of GSK3ß may underlie some of its transcriptional and posttranscriptional actions in the brain and thereby many of its long-term therapeutic effects; this is clearly an exciting area for future research (80).

	EFFECTS OF CARBAMAZEPINE ON THE cAMP-GENERATING SYSTEM

TOP ABSTRACT INTRODUCTION TRANSMEMBRANE CELLULAR SIGNAL... ABNORMALITIES IN SECOND... ARE G PROTEIN-COUPLED SIGNAL... LITHIUM AND THE PHOSPHOINOSITIDE... LITHIUM AND PKC LITHIUM AND AC LITHIUM AND G PROTEINS VALPROIC ACID AND G... GSK3ß: A... EFFECTS OF CARBAMAZEPINE ON... EFFECTS OF MOOD STABILIZERS... CONCLUDING REMARKS ACKNOWLEDGMENTS REFERENCES

 
Considerable data suggest that carbamazepine (an atypical anticonvulsant) is an alternative or adjunctive treatment to lithium, both for acute manic episodes as well as for long-term prophylaxis in bipolar affective disorder (137). Despite the widespread clinical use of carbamazepine, the cellular mechanisms underlying both its anticonvulsant and mood-stabilizing effects have not been identified (138). In contrast to the effects observed with lithium and valproate described above, it has been demonstrated that carbamazepine has very modest effects on the PKC signaling pathway or G proteins (H. K. Manji, unpublished observations). Carbamazepine has, however, been demonstrated to have many effects on the cAMP signaling pathway. The cAMP-generating system plays a major role in the regulation of neuronal excitability and has been postulated to play a role in the pathophysiology of both seizure disorders (139, 140) and bipolar affective disorder (6, 8). It is thus noteworthy that carbamazepine decreases the basal concentrations of cAMP in mouse cerebral cortex and cerebellum (141) and reduces cAMP production induced by norepinephrine (141, 142), adenosine (141, 143, 144), and the epileptogenic compounds ouabain (141, 145) and veratridine (146) in brain slices. In manic patients, carbamazepine decreased elevated levels of cAMP in cerebrospinal fluid (147). Recent studies have also demonstrated that carbamazepine inhibits forskolin-induced c-fos gene expression in cultured pheochromocytoma (PC-12) cells (148). Thus, overall, considerable evidence indicates that carbamazepine inhibits cAMP formation.

Recent studies have investigated the possible mechanisms by which carbamazepine inhibits the cAMP-generating system. It has been found that carbamazepine, at therapeutically relevant concentrations, inhibited both basal AC and forskolin-stimulated cAMP accumulation in C6 glioma cells (149). Within the clinical therapeutic range (approximately 50 µM), carbamazepine inhibited basal cAMP levels by 10% to 20% and forskolin-stimulated cAMP production by 40% to 60%. Together, these data indicate that carbamazepine is more effective in inhibiting the activated AC system, although the possibility of "floor effects" (ie, an inability to lower basal cAMP levels beyond certain levels in this system) cannot be ruled out. To further characterize the site at which carbamazepine exerts its inhibitory effects, ACs were purified from rat cerebral cortex using a forskolin affinity purification column. It was found that similar to the situation observed in intact C6 cells and C6 cell membranes, carbamazepine inhibited both basal and forskolin-stimulated activity of purified AC (149). Together, the data suggest that carbamazepine inhibits cAMP production by acting directly on AC and/or through factors tightly associated with or copurified with AC. Consistent with these results, it has been demonstrated that carbamazepine attenuates forskolin-induced c-fos (an immediate-early gene) expression in PC-12 cells (148) and inhibits FSK-induced phosphorylation of CREB in C6 glioma cells (149). Because c-fos and CREB are known to involved in mediating a number of long-term neuronal responses (150), these effects might be postulated to play a role in the delayed therapeutic effect of carbamazepine. The effects of mood stabilizers on long-term genomic events are discussed next.

	EFFECTS OF MOOD STABILIZERS ON TRANSCRIPTION FACTORS AND GENE EXPRESSION

TOP ABSTRACT INTRODUCTION TRANSMEMBRANE CELLULAR SIGNAL... ABNORMALITIES IN SECOND... ARE G PROTEIN-COUPLED SIGNAL... LITHIUM AND THE PHOSPHOINOSITIDE... LITHIUM AND PKC LITHIUM AND AC LITHIUM AND G PROTEINS VALPROIC ACID AND G... GSK3ß: A... EFFECTS OF CARBAMAZEPINE ON... EFFECTS OF MOOD STABILIZERS... CONCLUDING REMARKS ACKNOWLEDGMENTS REFERENCES

 
In recent years, it has become increasingly appreciated that any relevant biochemical models proposed for the effects of many psychotropic drugs (including mood stabilizers, antidepressants, and antipsychotics) must account for their special temporal clinical profile, in particular that the therapeutic effects require a lag period for onset of action and are generally not immediately reversed on drug discontinuation. Patterns of effects requiring such prolonged administration of the drug suggest alterations at the genomic level (8, 80, 81, 151; Figure 3 ). To investigate the putative effects of mood stabilizers on gene expression, investigators at several laboratories have examined their effects on the DNA-binding activity of transcription factors, especially the AP-1 family of transcription factors. AP-1 is a collection of homodimeric and heterodimeric complexes composed of products from two transcription factor families, Fos and Jun. These products bind to a common DNA site (known as the TPA response element) in the regulatory domain of the gene and activate gene transcription in response to PKC activators, growth factors, cytokines, and other agents (including neurotransmitters) (see Ref. 152 for an excellent recent review). Induction of c-fos is rapid and transient; Fos protein reaches its maximal levels within 30 minutes and decreases to low levels within 1 to 2 hours (152). Induction of c-jun is longer lasting and varies from a few hours to several days in a cell-type and stimulus-dependent manner (152). The c-jun gene is subject to positive autoregulation through an AP-1–binding site in its promoter. The genes known to be regulated by the AP-1 family of transcription factors in the brain include genes for various neuropeptides, neurotrophins, receptors, transcription factors, enzymes involved in neurotransmitter biosynthesis, and proteins that bind to cytoskeletal elements (152). Investigators from several independent laboratories have now demonstrated that lithium, at therapeutically relevant concentrations, regulates AP-1 DNA–binding activity (148, 153–159). It has recently been demonstrated that both lithium and valproate, at therapeutically relevant concentrations, produce a time- and concentration-dependent increase in the DNA binding of the TPA response element to AP-1 transcription in rat brain ex vivo and in cultured human neuroblastoma cells factors (158, 159). It has also been confirmed that these effects on AP-1 DNA–binding activity do, in fact, translate into changes at the gene expression level in cultured cells in vitro (158, 159).

View larger version (32K): [in this window] [in a new window]   Fig. 3. Effects of mood stabilizers on signaling pathways and gene expression. ATP = adenosine triphosphate; CBZ = carbamazepine; Gs = Gi-G proteins mediating stimulation or inhibition of adenylate cyclase; MAPK = mitogen-activated protein kinase; MAPKK = mitogen-activated protein kinase kinase; PKA = protein kinase A; PLCß = phospholipase C ß isozyme; Rq = receptors coupled to G protein Gq; Rs = Ri receptors coupled to stimulation or inhibition of AC; RSK = ribosomal S6 kinase; TrK = receptor tyrosine kinase; VPA = valproate.

	CONCLUDING REMARKS

TOP ABSTRACT INTRODUCTION TRANSMEMBRANE CELLULAR SIGNAL... ABNORMALITIES IN SECOND... ARE G PROTEIN-COUPLED SIGNAL... LITHIUM AND THE PHOSPHOINOSITIDE... LITHIUM AND PKC LITHIUM AND AC LITHIUM AND G PROTEINS VALPROIC ACID AND G... GSK3ß: A... EFFECTS OF CARBAMAZEPINE ON... EFFECTS OF MOOD STABILIZERS... CONCLUDING REMARKS ACKNOWLEDGMENTS REFERENCES

 
Regulation of signal transduction within critical regions of the brain affects the intracellular signal generated by multiple neurotransmitter systems; these effects thus represent attractive putative mediators of the therapeutic actions of currently available antidepressants and mood stabilizers, which are likely mediated by their effects on a network of interconnected neurotransmitter pathways. It is becoming increasingly clear that for many refractory patients with these disorders, new drugs simply mimicking the "traditional" drugs that directly or indirectly alter neurotransmitter levels and those that bind to cell surface receptors may be of limited benefit (169). This is because such strategies implicitly assume that the target receptors are functionally intact and that altered synaptic activity will thus be transduced to modify the postsynaptic "throughput" of the system. However, the existence of abnormalities in signal transduction pathways suggests that for patients refractory to conventional medications, improved therapeutics may be obtained only by direct targeting of postreceptor sites (Figure 3). Recent discoveries concerning a variety of mechanisms involved in the formation and inactivation of second messengers offers the promise for development of novel pharmacological agents designed to "site-specifically" target signal transduction pathways. Although this is clearly more complex than the development of receptor-specific drugs, it may be possible to design novel agents to selectively affect second messenger systems because they are quite heterogeneous at the molecular and cellular level, are linked to receptors in a variety of ways, and are expressed in different stoichiometries in different cell types. Additionally, because signal transduction pathways display certain unique characteristics depending on their activity state (eg, rate of guanine nucleotide exchange, G protein conformational states, GTP hydrolysis, interaction with different RGS proteins, and cytosol-to-membrane translocation of PKC isozymes and receptor kinases), they offer built-in targets for relative specificity of action, depending on the "set point" of the substrate. In summary, the rapid technological advances in both biochemistry and molecular biology have greatly enhanced our ability to understand the complexities of the regulation of neuronal function. The challenge for the next era in neuropsychopharmacology is to transform the knowledge gained from advances in neurobiology, cellular physiology, and molecular pharmacology into clinical use; these advances hold much promise for the development of novel, improved therapeutics for mood disorders as well as for our understanding of the pathophysiology of these life-threatening illnesses (74, 169, 170).

	ACKNOWLEDGMENTS

TOP ABSTRACT INTRODUCTION TRANSMEMBRANE CELLULAR SIGNAL... ABNORMALITIES IN SECOND... ARE G PROTEIN-COUPLED SIGNAL... LITHIUM AND THE PHOSPHOINOSITIDE... LITHIUM AND PKC LITHIUM AND AC LITHIUM AND G PROTEINS VALPROIC ACID AND G... GSK3ß: A... EFFECTS OF CARBAMAZEPINE ON... EFFECTS OF MOOD STABILIZERS... CONCLUDING REMARKS ACKNOWLEDGMENTS REFERENCES

 
The authors’ research is supported by the National Institute of Mental Heath, the Theodore and Vada Stanley Foundation, National Alliance for Research in Schizophrenia and Affective Disorders, and the Joseph Young Senior Foundation. The authors thank Celia Knobelsdorf for outstanding editorial assistance.

Received for publication September 11, 1998.

Revision received March 29, 1999.

	REFERENCES

TOP ABSTRACT INTRODUCTION TRANSMEMBRANE CELLULAR SIGNAL... ABNORMALITIES IN SECOND... ARE G PROTEIN-COUPLED SIGNAL... LITHIUM AND THE PHOSPHOINOSITIDE... LITHIUM AND PKC LITHIUM AND AC LITHIUM AND G PROTEINS VALPROIC ACID AND G... GSK3ß: A... EFFECTS OF CARBAMAZEPINE ON... EFFECTS OF MOOD STABILIZERS... CONCLUDING REMARKS ACKNOWLEDGMENTS REFERENCES

 

1. Bourne HR, Nicoll R. Molecular machines integrate coincident synaptic signals. Cell 1993; 72 (Suppl): 65–75.
2. Ross EM. Signal sorting and amplification through G protein-coupled receptors. Neuron 1989; 3: 141–52.[Medline]
3. Manji HK. G proteins: implications for psychiatry. Am J Psychiatry 1992; 149: 746–60.[Abstract/Free Full Text]
4. Spiegel AM, editor. G proteins, receptors, and disease. Totowa (NJ), Humana Press; 1998.
5. Weinstein LS. Alteration of G protein expression or function in pathophysiology. In: Spiegel AM, Jones TLZ, Simonds WF, Weinstein LS, editors. G proteins. Austin (TX), RG Landes; 1994. p. 118–28.
6. Hudson CJ, Young LT, Li PP, Warsh JJ. CNS signal transduction in the pathophysiology and pharmacotherapy of affective disorders and schizophrenia. Synapse 1993; 13: 278–93.[Medline]
7. Jope RS, Williams MB. Lithium and brain signal transduction systems. Biochem Pharmacol 1994; 77: 429–41.
8. Wang JF, Young LT, Li PP, Warsh JJ. Signal transduction abnormalities in bipolar disorder. In: Young LT, Joffe RT, editors. Bipolar disorder: biological models and their clinical applications. New York, Marcel Dekker; 1997. p. 41–79.
9. Simon MI, Strathmann MP, Gautam N. Diversity of G proteins in signal transduction. Science 1991; 252: 802–8.[Abstract/Free Full Text]
10. Potter WZ, Manji HK. Affective disorders and adrenergic function: an update. Clin Biochem 1994; 40: 279–87.
11. Siever LJ, Uhde TW, Jimerson DC, Lake CR, Siberman ER, Post RM, Murphy DL. Differential inhibitory noradrenergic responses to clonidine in 25 depressed patients and 25 normal control subjects. Am J Psychiatry 1984; 141: 733–41.[Abstract/Free Full Text]
12. Kafka MS, Paul SM. Platelet ₂-adrenergic receptors in depression. Arch Gen Psychiatry 1986; 43: 91–5.[Abstract/Free Full Text]
13. Charney DS, Heninger GR, Sternberg DE, Hafstad KM, Giddings S, Landis DH. Adrenergic receptor sensitivity in depression: effects of clonidine in depressed patients and healthy subjects. Arch Gen Psychiatry 1982; 39: 290–4.[Abstract/Free Full Text]
14. Siever LJ. Role of noradrenergic mechanisms in the etiology of the affective disorders. In: Meltzer HY, editor. Psychopharmacology: the third generation of progress. New York, Raven Press; 1987. p. 493–504.
15. Grossman F, Manji HK, Potter WZ. Platelet ₂-adrenoreceptors in depression: a critical examination. J Psychopharmacol 1993; 7: 4–18.
16. Pandey GN, Dysken MW, Garver DL, Davis JM. Beta-adrenergic receptor function in affective illness. Am J Psychiatry 1979; 136: 675–8.[Abstract/Free Full Text]
17. Extein I, Tallman J, Smith CC, Goodwin FK. Changes in lymphocyte ß-adrenergic receptors in depression and mania. Psychiatry Res 1979; 1: 191–7.[Medline]
18. Mann JJ, Brown RP, Halper JP, Sweeney JA, Kocsis JH, Stokes PE, Bilezikian JP. Reduced sensitivity of lymphocyte beta-adrenergic receptors in patients with endogenous depression and psychomotor agitation. N Engl J Med 1985; 313: 715–20.[Abstract]
19. Healy D, Carney PA, Leonard BE. Monoamine-related markers of depression: changes following treatment. J Psychiatr Res 1983; 17: 251–60.
20. Ebstein RP, Lerer B, Shapira B, Shemesh Z, Moscovich DG, Kindler S. Cyclic AMP second-messenger signal amplification in depression. Br J Psychiatry 1988; 152: 665–9.[Abstract/Free Full Text]
21. Halper JP, Brown RP, Sweeney JA, Kocsis JH, Peters A, Mann JJ. Blunted beta-adrenergic responsivity of peripheral blood mononuclear cells in endogenous depression: isoproterenol dose-response studies. Arch Gen Psychiatry 1988; 45: 241–4.[Abstract/Free Full Text]
22. Wright AF, Crichton DN, Loudon JP, Morten JE, Steel CM. Beta-adrenoceptor binding defects in cell lines from families with manic-depressive disorder. Ann Hum Genet 1984; 48(Pt 3): 201–14.[Medline]
23. Ebstein R, Oppenheim G, Ebstein BS, Amiri Z, Stessman J. The cyclic AMP second messenger system in man: the effects of heredity, hormones, drugs, aluminum, age and disease on signal amplification. Prog Neuropsychopharmacol Biol Psychiatry 1986; 10: 323–53.[Medline]
24. Berrettini WH, Bardakjian J, Cappellari CB, Barnett AL Jr, Albright A, Nurnberger JI Jr, Gershon ES. Skin fibroblast beta-adrenergic receptor function in manic-depressive illness. Biol Psychiatry 1987; 22: 1439–43.[Medline]
25. Berrettini WH, Cappellari CB, Nurnberger JI Jr, Gershon ES. Beta-adrenergic receptors on lymphoblasts: a study of manic-depressive illness. Neuropsychobiology 1987; 17: 15–8.[Medline]
26. Young LT, Li PP, Kish SJ, Siu KP, Kamble A, Hornykiewicz O, Warch JJ. Cerebral cortex G_s protein levels and forskolin-stimulated cyclic AMP formation are increased in bipolar affective disorder. J Neurochem 1993; 61: 890–8.[Medline]
27. Wang HY, Friedman E. Enhanced protein kinase C activity and translocation in bipolar affective disorder brains. Biol Psychiatry 1996; 40: 568–75.[Medline]
28. Garcia-Sevilla JA, Escriba PV, Ozaita A, La Harpe R, Walzer C, Eytan A, Guimon J. Up-regulation of immunolabeled alpha2A-adrenoceptors, Gi coupling proteins, and regulatory receptor kinases in the prefrontal cortex of depressed suicides. J Neurochem 1999; 72: 282–91.[Medline]
29. Schreiber G, Avissar S, Danon A, Belmaker RH. Hyperfunctional G proteins in mononuclear leukocytes of patients with mania. Biol Psychiatry 1991; 29: 273–80.[Medline]
30. Young LT, Li PP, Kamble A, Siu KP, Warsh JJ. Mononuclear leukocyte levels of G proteins in depressed patients with bipolar disorder or major depressive disorder. Am J Psychiatry 1994; 151: 594–6.[Abstract]
31. Manji HK, Chen G, Shimon H, Hsiao JK, Potter WZ, Belmaker RH. Guanine nucleotide-binding proteins in bipolar affective disorder: effects of long-term lithium treatment. Arch Gen Psychiatry 1995; 52: 135–44.[Abstract/Free Full Text]
32. Spleiss O, van Calker D, Scharer L, Adamovic K, Berger M, Gebicke-Haerter PJ. Abnormal G protein alpha(s)- and alpha(i2)-subunit mRNA expression in bipolar affective disorder. Mol Psychiatry 1998; 3: 512–20.[Medline]
33. Avissar S, Nechamkin Y, Roitman G, Schreiber G. Reduced G protein functions and immunoreactive levels in mononuclear leukocytes of patients with depression. Am J Psychiatry 1997; 154: 211–7.[Abstract]
34. Garcia-Sevilla JA, Walzer C, Busquets X, Escriba PV, Balant L, Guimon J. Density of guanine nucleotide-binding proteins in platelets of patients with major depression: increased abundance of the G alpha i2 subunit and down-regulation by antidepressant drug treatment. Biol Psychiatry 1997; 42: 704–12.[Medline]
35. Mooney JJ, Samson JA, McHale NL, Colodzin R, Alpert J, Koutsos M, Schildkraut JJ. Signal transduction by platelet adenylate cyclase: alterations in depressed patients may reflect impairment in the coordinated integration of cellular signals (coincidence detection). Biol Psychiatry 1998; 43: 574–83.[Medline]
36. Avissar S, Nechamkin Y, Roitman G, Schreiber G. Dynamics of ECT normalization of low G protein function and immunoreactivity in mononuclear leukocytes of patients with major depression. Am J Psychiatry 1998; 155: 666–71.[Abstract/Free Full Text]
37. Karege F, Bovier P, Stepanian R, Malafosse A. The effect of clinical outcome on platelet G proteins of major depressed patients. Eur Neuropsychopharmacol 1998; 8: 89–94.[Medline]
38. Ram A, Guedj F, Cravchik A, Weinstein L, Cao Q, Badner J, Goldin LR, Grisaru N, Manji HK, Belmaker RH, Gershon ES, Gejman PV. No abnormality in the gene for the G protein stimulatory subunit in patients with bipolar disorder. Arch Gen Psychiatry 1997; 54: 44–8.[Abstract/Free Full Text]
39. Brown AS, Mallinger AG, Renbaum LC. Elevated platelet membrane phosphatidylinositol-4,5-bisphosphate in bipolar mania. Am J Psychiatry 1993; 150: 1252–4.[Abstract/Free Full Text]
40. Soares JC, Dippold CS, Mallinger AG. Platelet membrane phosphatidylinositol-4,5-bisphosphate alterations in bipolar disorder—evidence from a single case study. Psychiatry Res 1997; 69: 197–202.[Medline]
41. vanCalker D, Forstner U, Bohus M, Gebicke-Harter P, Hecht H, Wark HJ, Berger M. Increased sensitivity to agonist stimulation of the Ca²⁺ response in neutrophils of manic-depressive patients: effect of lithium therapy. Neuropsychobiology 1993; 27: 180–3.[Medline]
42. Pandey SC, Davis JM, Schwertz DW, Pandey GN. Effect of antidepressants and neuroleptics on phosphoinositide metabolism in human platelets. J Pharmacol Exp Ther 1991; 256: 1010–8.[Abstract/Free Full Text]
43. Pandey GN, Pnadey SC, Davis JM. Effects of desipramine on inositol phosphate formation and inositol phospholipids in rat brain and human platelets. Psychopharmacol Bull 1991; 27: 255–61.[Medline]
44. Li R, Wing LL, Wyatt RD, Kirch DG. Effects of haloperidol, lithium, and valproate on phosphoinositide turnover in rat brain. Pharmacol Biochem Behav 1993; 46: 323–9.[Medline]
45. Mathews R, Li PP, Young LT, Kish SJ, Warsh JJ. Increased G alpha q/11 immunoreactivity in postmortem occipital cortex from patients with bipolar affective disorder. Biol Psychiatry 1997; 41: 649–56.[Medline]
46. Jope RS, Song L, Li PP, Young LT, Kish SJ, Pacheco MA, Warsh JJ. The phosphoinositide signal transduction system is impaired in bipolar affective disorder brain. J Neurochem 1996; 66: 2402–9.[Medline]
47. Freidman E, Hoau YW, Levinson D, Connell TA, Singh H. Altered platelet protein kinase C activity in bipolar affective disorder, manic episode. Biol Psychiatry 1993; 33: 520–5.[Medline]
48. Pandey GN, Dwivedi Y, Pandey SC, Conley RR, Roberts RC, Tamminga CA. Protein kinase C in the postmortem brain of teenage suicide victims. Neurosci Lett 1997; 228: 111–4.[Medline]
49. Sulser F. Antidepressant treatments and regulation of norepinephrine-receptor-coupled adenylate cyclase systems in brain. Adv Biochem Psychopharmacol 1984; 39: 249–61.[Medline]
50. Chaput Y, de Montigny C, Blier P. Presynaptic and postsynaptic modifications of the serotonin system by long-term administration of antidepressant treatments: an in vivo electrophysiologic study in the rat. Neuropsychopharmacology 1991; 5: 219–24.[Medline]
51. Okada F, Tokumitsu Y, Ui M. Desensitization of beta-adrenergic receptor-coupled adenylate cyclase in cerebral cortex after in vivo treatment of rats with desipramine. J Neurochem 1986; 47: 454–9.[Medline]
52. Tiong AH, Richardson JS. Beta-adrenoceptor and post-receptor components show different rates of desensitization to desipramine. Eur J Pharmacol 1990; 188: 411–5.[Medline]
53. Tsuchiya F, Ikeda H, Hatta Y, Saito T. Effects of desipramine administration on receptor adenylate cyclase coupling in rat cerebral cortex. Jpn J Psychiatr Neurol 1988; 42: 858–60.
54. Yamaoka K, Nanba T, Nomura S. Direct influence of antidepressants on GTP binding protein of adenylate cyclase in cell membranes of the cerebral cortex of rats. J Neural Transm 1988; 71: 165–75.
55. Okada F, Tokumitsu Y, Ui M. Possible involvement of pertussis toxin substrates (Gi, Go) in desipramine-induced refractoriness of adenylate cyclase in cerebral cortices of rats. J Neurochem 1988; 51: 194–9.[Medline]
56. Simonds WF, Manji HK, Lupas A, Garritsen A. G proteins and ßARK: a new twist for the coiled-coil. Trends Biochem Sci 1993; 18: 315–7.[Medline]
57. Lesch KP, Manji HK. Signal-transducing G proteins and antidepressant drugs: evidence for modulation of alpha subunit gene expression in rat brain. Biol Psychiatry 1992; 32: 549–79.[Medline]
58. Raap DK, Evans S, Garcia F, Li Q, Muma NA, Wolf WA, Battaglia G, Van De Kar LD. Daily injections of fluoxetine induce dose-dependent desensitization of hypothalamic 5-HT1A receptors: reductions in neuroendocrine responses to 8-OH-DPAT and in levels of Gz and Gi proteins. J Pharmacol Exp Ther 1999; 288: 98–106.[Abstract/Free Full Text]
59. Dwivedi Y, Pandey GN. Effects of subchronic administration of antidepressants and anxiolytics on levels of the alpha subunits of G proteins in the rat brain. J Neural Transm 1997; 104: 747–60.
60. Li Q, Muma NA, Battaglia G, Van de Kar LD. A desensitization of hypothalamic 5-HT1A receptors by repeated injections of paroxetine: reduction in the levels of G(i) and G(o) proteins and neuroendocrine responses, but not in the density of 5-HT1A receptors. J Pharmacol Exp Ther 1997; 282: 1581–90.[Abstract/Free Full Text]
61. Li Q, Muma NA, van de Kar LD. Chronic fluoxetine induces a gradual desensitization of 5-HT1A receptors: reductions in hypothalamic and midbrain Gi and G(o) proteins and in neuroendocrine responses to a 5-HT1A agonist. J Pharmacol Exp Ther 1996; 279: 1035–42.[Abstract/Free Full Text]
62. Emamghoreishi M, Warsh JJ, Sibony D, Li PP. Lack of effect of chronic antidepressant treatment on Gs and Gi alpha-subunit protein and mRNA levels in the rat cerebral cortex. Neuropsychopharmacology 1996; 15: 281–7.[Medline]
63. McGowan S, Eastwood SL, Mead A, Burnet PW, Smith C, Flanigan TP, Harrison PJ. Hippocampal and cortical G protein (Gs alpha, G(o) alpha and Gi2 alpha) mRNA expression after electroconvulsive shock or lithium carbonate treatment. Eur J Pharmacol 1996; 306: 249–55.[Medline]
64. Rasenick MM, Chaney KA, Chen J. G protein-mediated signal transduction as a target of antidepressant and antibipolar drug action: evidence from model systems. J Clin Psychiatry 1996; 57 (Suppl 13): 49–55.
65. Lason W, Przewlocki R. The effect of chronic treatment with imipramine on the G proteins mRNA level in the rat hippocampus—an interaction with a calcium channel antagonist. Pol J Pharmacol 1993; 45: 219–26.[Medline]
66. Sugrue MF. Chronic antidepressant therapy and associated changes in central monoaminergic function. Pharmacol Ther 1983; 21: 1–37.[Medline]
67. Newman ME, Lerer B, Lichtenberg P, Shapira B. Platelet adenylate cyclase activity in depression and after clomipramine and lithium treatment. Psychopharmacology 1992; 109: 231–4.[Medline]
68. Chen J, Rasenick MM. Chronic antidepressant treatment facilitates G protein activation of adenylyl cyclase without altering G protein content. J Pharmacol Exp Ther 1995; 275: 509–17.[Abstract/Free Full Text]
69. Menkes DB, Rasenick MM, Wheeler MA, Bitensky MW. Guanosine triphosphate activation of brain adenylate cyclase: enhancement by long-term antidepressant treatment. Science 1983; 219: 65–7.[Abstract/Free Full Text]
70. Ozawa H, Rasenick MM. Coupling of the stimulatory GTP-binding protein Gs to rat synaptic membrane adenylate cyclase is enhanced subsequent to chronic antidepressant treatment. Mol Pharmacol 1989; 36: 803–8.[Abstract]
71. Newman ME, Lerer B. Post-receptor-mediated increases in adenylate cyclase activity after chronic ad treatment: relationship to receptor desensitization. Eur J Pharmacol 1989; 162: 345–52.[Medline]
72. Nestler EJ, Terwilliger RZ, Duman RS. Chronic antidepressant administration alters the subcellular distribution of cyclic AMP-dependent protein kinase in rat frontal cortex. J Neurochem 1989; 53: 1644–7.[Medline]
73. Perez J, Tinelli D, Brunello N, Racagni G. cAMP-dependent phosphorylation of soluble and crude microtubule fractions of rat cerebral cortex after prolonged desmethylimipramine treatment. Eur J Pharmacol 1989; 172: 305–16.[Medline]
74. Duman RS, Heninger GR, Nestler EJ. A molecular and cellular theory of depression. Arch Gen Psychiatry 1997; 54: 597–606.[Abstract/Free Full Text]
75. Nibuya M, Nestler EJ, Duman RS. Chronic antidepressant administration increases the expression cAMP response element-binding protein (CREB) in rat hippocampus. J Neurosci 1996; 16: 2365–72.[Abstract/Free Full Text]
76. Fisher SK, Heacock AM, Agranoff BW. Inositol lipids and signal transduction in the nervous system: an update. J Neurochem 1992; 58: 18–38.[Medline]
77. Allison JH, Stewart MA. Reduced brain inositol in lithium treated rats. Nature 1971; 233: 267–8.[Medline]
78. Hallcher LM, Sherman WR. The effects of lithium ion and other agents on the activity of myo-inositol-1-phosphatase from bovine brain. J Biol Chem 1980; 255: 10896–901.[Abstract/Free Full Text]
79. Berridge MJ, Downes CP, Hanley MR. Neural and developmental actions of lithium: a unifying hypothesis. Cell 1989; 59: 411–9.[Medline]
80. Jope RS Anti-bipolar therapy: mechanism of action of lithium. Mol Psychiatry 1999; 4: 117–28.[Medline]
81. Manji HK, Potter WZ, Lenox RH. Signal transduction pathways: molecular targets for lithium’s actions. Arch Gen Psychiatry 1995; 52: 531–43.[Abstract/Free Full Text]
82. Pontzer NJ, Crews FT. Desensitization of muscarinic stimulated hippocampal cell firing is related to phosphoinositide hydrolysis and inhibited by lithium. J Pharmacol Exp Ther 1990; 253: 921–9.[Abstract/Free Full Text]
83. Kofman O, Belmaker RH. Biochemical, behavioral and clinical studies of the role of inositol in lithium treatment and depression. Biol Psychiatry 1993; 34: 839–52.[Medline]
84. Godfrey PP, McClue SJ, White AM, Wood AJ, Grahame-Smith DG. Potentiation by lithium of CMP-phosphatidate formation in carbachol-stimulated rat cerebral-cortical slices and its reversal by myo-inositol. Biochem J 1989; 258: 621–4.[Medline]
85. Tricklebank MD, Singh L, Jackson A, Oles RJ. Evidence that a proconvulsant action of lithium is mediated by inhibition of myo-inositol phosphatase in mouse brain. Brain Res 1991; 558: 145–8.[Medline]
86. Moore GJ, Bebchuk JM, Parrish JK, Faulk MW, Arfken CL, Strahl-Bevacqua J, Manji HK. Temporal dissociation between lithium-induced CNS myo-inositol changes and clinical response in manic-depressive illness. AM J Psychiatry. In press 1999.
87. Lenox RH, Manji HK. Lithium. In: CB Nemeroff, AF Schatzberg, editors. American Psychiatric Press textbook of psychopharmacology. 2nd ed. Washington (DC), American Psychiatric Press; 1998. p. 379–430.
88. Nishizuka Y. Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science 1992; 258: 607–14.[Abstract/Free Full Text]
89. Stabel S, Parker PJ. Protein kinase C. Pharmacol Ther 1991; 51: 71–95.[Medline]
90. Huang KP. The mechanism of protein kinase C activation. Trends Neurosci 1989; 12: 425–32.[Medline]
91. Manji HK, Chen G, Risby ED, Masana MI, Hsiao JK, Potter WZ. Regulation of signal transduction pathways by mood stabilizing agents: implications for the delayed onset of therapeutic efficacy. J Clin Psychiatry 1996; 57: 34–46.
92. Wang HY, Friedman E. Lithium inhibition of protein kinase C activation-induced serotonin release. Psychopharmacology 1989; 99: 213–8.[Medline]
93. Robinson PJ. The role of protein kinase C and its neuronal substrates dephosphin, B-50, and MARCKS in neurotransmitter release. Mol Neurobiol 1991; 5: 87–130.[Medline]
94. Lenox RH, Watson DG, Ellis J. Chronic lithium administration alters a prominent PKC substrate in rat hippocampus. Brain Res 1992; 570: 333–40.[Medline]
95. Watson DG, Lenox RH. Chronic lithium-induced down-regulation of MARCKS in immortalized hippocampal cells: potentiation by muscarinic receptor activation. J Neurochem 1996; 7: 767–77.
96. Manji HK, Etcheberrigaray R, Chen G, Olds JL. Lithium decreases membrane-associated protein kinase C in the hippocampus: selectivity for the alpha isozyme. J Neurochem 1993; 61: 2303–10.[Medline]
97. Leli U, Hauser G. Lithium modifies diacylglycerol levels and protein kinase C in neuroblastoma cells. Abstracts of the 8th International Conference on Second Messengers and Phosphoproteins; 1992 October; abstract Z187F. Glasgow, Scotland
98. Li X, Jope RS. Selective inhibition of the expression of signal transduction proteins by lithium in nerve growth factor-differentiated PC12 cells. J Neurochem 1995; 65: 2500–8.[Medline]
99. Chen G, Manji HK, Hawver DB, Wright CB, Potter WZ. Chronic sodium valproate selectively decreases protein kinase C and in vitro. J Neurochem 1994; 63: 2361–4.[Medline]
100. Watson DG, Watterson JM, Lenox RH. Sodium valproate down-regulates the myristoylated alanine-rich C kinase substrate (MARCKS) in immortalized hippocampal cells: a property of protein kinase C–mediated mood stabilizers. J Pharmacol Exp Ther 1998; 285: 307–16.[Abstract/Free Full Text]
101. Conn PJ, Sweatt JD. Protein kinase C in the nervous system. In: Kuo JF, editor. Protein kinase C. New York, Oxford University Press; 1994. p. 199–235.
102. Jordan VC. A current view of tamoxifen for the treatment of breast cancer. Br J Pharmacol 1994; 110: 507–17.[Medline]
103. Catherino WH, Jordan VC. A risk-benefit assessment of tamoxifen therapy. Drug Saf 1993; 8: 381–97.[Medline]
104. Couldwell WT, Weiss MH, DeGiorgio CM, Weiner LP, Hinton DR, Ehresmann GR, Conti PS, Apuzzo ML. Clinical and radiographic response in patients with recurrent malignant gliomas treated with high-dose tamoxifen. Neurosurgery 1993; 32: 485–9.[Medline]
105. Bebchuk JM, Arfken CL, Dolan-Manji S, Murphy J, Manji HK. A preliminary investigation of a protein kinase C inhibitor (tamoxifen) in the treatment of acute mania. Arch Gen Psychiatry. In press.
106. Mork A, Geisler A, Hollund P. Effects of lithium on second messenger systems in the brain. Pharmacol Toxicol 1992; 71 (Suppl 1): 4–17.
107. Risby ED, Hsiao JK, Manji HK, Bitran J, Moses F, Zhou DF, Potter WZ. The mechanisms of action of lithium. II. Effects of adenylate cyclase activity and beta-adrenergic receptor binding in normal subjects. Arch Gen Psychiatry 1991; 48: 513–24.[Abstract/Free Full Text]
108. Masana MI, Bitran JA, Hsiao JK, Mefford IN, Potter WZ. Lithium effects on noradrenergic-linked adenylate cyclase activity in intact rat brain: an in vivo microdialysis study. Brain Res 1991; 538: 333–6.[Medline]
109. Jope RS. A bimodal model of the mechanism of action of lithium. Mol Psychiatry 1999; 4: 21–5.[Medline]
110. Andersen PH, Geisler A. Lithium inhibition of forskolin-stimulated adenylate cyclase. Neuropsychobiology 1984; 12: 1–3.[Medline]
111. Geisler A, Klysner R, Andersen PH. Influence of lithium in vitro and in vivo on the catecholamine-sensitive cerebral adenylate cyclase systems. Acta Pharmacol Toxicol (Copenh) 1985; 56: 80–97.
112. Mork A, Geisler A. Mode of action on the catalytic unit of adenylate cyclase from rat brain. Pharmacol Toxicol 1987; 60: 241–8.[Medline]
113. Mork A, Geisler A. The effects of lithium in vitro and ex vivo on adenylate cyclase in brain are exerted by distinct mechanisms. Neuropharmacology 1989; 28: 307–11.[Medline]
114. Newman ME, Belmaker RH. Effects of lithium in vitro and ex vivo on components of the adenylate cyclase system in membranes from the cerebral cortex of the rat. Neuropharmacology 1987; 26: 211–7.[Medline]
115. Newman ME, Shapira B, Lerer B. Effects of lithium and desimipramine on second messenger responses in rat hippocampus: relation to G protein effects. Neurpharmacology 1991; 30: 1297–301.[Medline]
116. Ebstein RP, Moscovich D, Zeevi S, Amiri Z, Lerer B. Effect of lithium in vitro and after chronic treatment on human platelet adenylate cyclase activity: postreceptor modification of second messenger signal amplification. Psychiatry Res 1987; 21: 221–8.[Medline]
117. Casebolt TL, Jope RS. Long-term lithium treatment selectively reduces receptor-coupled inositol phospholipid hydrolysis in rat brain. Biol Psychiatry 1989; 25: 329–40.[Medline]
118. Greenwood AF, Jope RS. Brain G-protein proteolysis by calpain: enhancement by lithium. Brain Res 1994; 636: 320–6.[Medline]
119. Song L, Jope R. Chronic lithium treatment impairs phosphatidylinositol hydrolysis in membranes from rat brain regions. J Neurochem 1992; 58: 2200–6.[Medline]
120. Li PP, Young LT, Tam YK, Sibony D, Warsh JJ. Effects of chronic lithium and carbamazepine treatment of G protein expression in rat cerebral cortex. Biol Psychiatry 1993; 34: 162–70.[Medline]
121. Masana MI, Bitran JA, Hsiao JK, Potter WZ. In vivo evidence that lithium inactivates Gi modulation of adenylate cyclase in brain. J Neurochem 1992; 59: 200–5.[Medline]
122. Colin SF, Chang HC, Mollner S, Pfeuffer T, Reed RR, Duman RS, Nestler EJ. Chronic lithium regulates the expression of adenylate cyclase and Gi-protein alpha subunit in rat cerebral cortex. Proc Natl Acad Sci USA 1991; 88: 10634–7.[Abstract/Free Full Text]
123. Jakobsen SN, Wiborg O. Selective effects of long-term lithium and carbamazepine administration on G-protein subunit expression in rat brain. Brain Res 1998; 780: 46–55.[Medline]
124. Hsiao JK, Manji HK, Chen GA, Bitran JA, Risby ED, Potter WZ. Lithium administration modulates platelet Gi in humans. Life Sci 1992; 50: 227–33.[Medline]
125. Lonati-Galligani M, Emrich HM, Raptis C, Pirke KM. Effect of in vivo lithium treatment on (-)isoproterenol-stimulated cAMP accumulation in lymphocytes of healthy subjects and patients with affective psychoses. Pharmacopsychiatry 1989; 22: 241–5.[Medline]
126. Wang YC, Pandey GN, Mendels J, Frazer A. Effect of lithium on prostaglandin F1-stimulated adenylate cyclase activity of human platelets. Biochem Pharmacol 1974; 23: 845–55.[Medline]
127. Garcia-Sevilla JA, Guimon J, Garcia-Vallejo P, Fuster MJ. Biochemical and functional evidence of supersensitive platelet alpha 2-adrenoceptors in major affective disorder: effect of long-term lithium carbonate treatment. Arch Gen Psychiatry 1986; 43: 51–7.[Abstract/Free Full Text]
128. Ui M. Pertussis toxin as a valuable probe for G protein involvement in signal transduction. In: Moss J, Vaughn M, editors. ADP-ribosylation toxins and G proteins. Washington (DC), American Society for Microbiology; 1990. p. 45–79
129. Manji HK, Bebchuk JM, Moore, GJ, Glitz D, Hasanat KA, Chen G. Modulation of CNS signal transduction pathways and gene expression by mood stabilizing agents: therapeutic implications. J Clin Psychiatry 1999; 60 (Suppl 2): 27–39.
130. Kofman O, Li PP, Warsh JJ. Lithium, but not carbamazepine, potentiates hyperactivity induced by intra-accumbens cholera toxin. Pharmacol Biochem Behav 1998; 59: 191–200.[Medline]
131. Young LT, Woods CM. Mood stabilizers have differential effects on endogenous ADP ribosylation in C6 glioma cells. Eur J Pharmacol 1996; 309: 215–8.[Medline]
132. Nestler EJ, Terwilliger RZ, Duman RS. Regulation of endogenous ADP-ribosylation by acute and chronic lithium in rat brain. J Neurochem 1995; 64: 2319–24.[Medline]
133. Chen G, Manji HK, Wright CB, Hawver D, Potter WZ. Effects of valproic acid on ß-adrenergic receptors, G-proteins and adenylate-cyclase in rat C6 glioma cells. Neuropsychopharmacology 1996; 15: 271–80.[Medline]
134. Klein PS, Melton DA. A molecular mechanism for the effect of lithium on development. Proc Natl Acad Sci USA 1996; 93: 8455–9.[Abstract/Free Full Text]
135. Dale TC. Signal transduction by the Wnt family of ligands. Biochem J 1998; 329(Pt 2): 209–23.
136. Willert K, Nusse R. Beta-catenin: a key mediator of Wnt signaling. Curr Opin Genet Dev 1998; 8: 95–102.[Medline]
137. Post RM, Ballenger JC, Uhde TW, Bunney WE Jr. Efficacy of carbamazepine in manic-depressive illness: implications for underlying mechanisms. In: Post RM, Ballenger JC, editors. Neurobiology of mood disorder. Baltimore, Williams & Wilkins; 1984. p. 816.
138. Post RM, Weiss SR, Chuang DM. Mechanisms of action of anticonvulsants in affective disorders: comparisons with lithium. J Clin Psychopharmacol 1992; 12: 23S–35S.[Medline]
139. Kuriyama K, Kakita K. Cholera toxin induced epileptogenic focus: an animal model for studying roles of cyclic AMP in the establishment of epilepsy. In: Battistin L, editor. Neurochemistry and clinical neurology. New York, Alan R Liss; 1980. p. 141–55.
140. Ludvig N, Moshe SL. Different behavioral and electrographic effects of acoustic stimulation and dibutyryl cyclic AMP injection into the inferior colliculus in normal and in genetically epilepsy-prone rats. Epilepsy Res 1989; 3: 185–90.[Medline]
141. Palmer GC, Jones DJ, Medina MA, Stavinoha WB. Anticonvulsant drug actions on in vitro and in vivo levels of cyclic AMP in the mouse brain. Epilepsia 1979; 20: 95–104.[Medline]
142. Palmer GC. Interactions of antiepileptic drugs on adenylate cyclase and phosphodiesterases in rat and mouse cerebrum. Exp Neurol 1979; 63: 322–35.[Medline]
143. Elphick M, Taghavi Z, Powell T, Godfrey PP. Chronic carbamazepine down-regulates adenosine A2 receptors: studies with the putative selective adenosine antagonists PD115,199 and PD116,948. Psychopharmacology 1990; 100: 522–9.[Medline]
144. van Calker D, Steber R, Klotz K, Greil W. Carbamazepine distinguishes between adenosine receptors that mediate different second messenger responses. Eur J Pharmacol 1991; 206: 285–90.[Medline]
145. Lewin E, Bleck V. Cyclic AMP accumulation in cerebral cortical slices: effect of carbamazepine, phenobarbital, and phenytoin. Epilepsia 1977; 18: 237–42.[Medline]
146. Ferrendelli JA, Kinscherf DA. Inhibitory effects of anticonvulsant drugs on cyclic nucleotide accumulation in brain. Ann Neurol 1979; 5: 533–8.[Medline]
147. Post RM, Ballenger JC, Uhde TW, Smith C, Rubinow DR, Bunney WE Jr. Effect of carbamazepine on cyclic nucleotides in CSF of patients with affective illness. Biol Psychiatry 1982; 17: 1037–45.[Medline]
148. Divish MM, Sheftel G, Boyle A, Kalasapudi VD, Papolos DF, Lachman HM. Differential effect of lithium on fos protooncogene expression mediated by receptor and postreceptor activators of protein kinase C and cyclic adenosine monophosphate: model for its antimanic action. J Neurosci Res 1991; 28: 40–8.[Medline]
149. Chen G, Hawver D, Wright C, Potter WZ, Manji HK. Attenuation of adenylate cyclases by carbamazepine in vitro. J Neurochemistry 1996; 67: 2079–86.[Medline]
150. Sheng M, Greenberg ME. The regulation and function c-fos and other immediate early genes in the nervous system. Neuron 1990; 4: 477–85.[Medline]
151. Hyman SE, Nestler EJ. Initiation and adaptation: a paradigm for understanding psychotropic drug action. Am J Psychiatry 1996; 153: 151–62.[Abstract/Free Full Text]
152. Hughes P, Dragunow M. Induction of immediate-early genes and the control of neurotransmitter-regulated gene expression within the nervous system. Pharmacol Rev 1995; 47: 133–78.[Medline]
153. Jope RS, Song L. AP-1 and NF-B stimulated by carbachol in human neuroblastoma SH-SY5Y cells are differentially sensitive to inhibition by lithium. Mol Brain Res 1997; 50: 171–80.[Medline]
154. Ozaki N, Chuang D-M. Effect of lithium on transcription factor binding in cultured cerebellar granule cells and the brain of rats. J Neurochemistry 1997; 69: 2336–44.[Medline]
155. Unlap MT, Jope RS. Lithium attenuates nerve growth factor–induced activation of AP-1 DNA binding activity in PC12 cells. Neuropsychopharmacology 1997; 17: 12–7.[Medline]
156. Williams MB, Jope RS. Circadian variation in rat brain AP-1 DNA binding activity after cholinergic stimulation: modulation by lithium. Psychopharmacology 1995; 122: 363–8.[Medline]
157. Chen G, Yuan P, Hawver D, Potter WZ, Manji HK. Increase in AP-1 transcription factor DNA binding activity by valproic acid. Neuropsychopharmacology 1997; 16: 238–45.[Medline]
158. Yuan PX, Chen G, Manji HK. Lithium stimulates gene expression through the AP-1 transcription factor pathway. Mol Brain Res 1998; 58: 225–30.[Medline]
159. Chen G, Yuan PX, Jiang Y, Huang LD, Manji HK. Valproate robustly enhances AP-1 mediated gene expression. Mol Brain Res 1999; 64: 52–8.[Medline]
160. Kumer SC, Vrana KE. Intricate regulation of tyrosine hydroxylase activity and gene expression. J Neurochem 1996; 67: 443–61.[Medline]
161. Drevets WC, Price JL, Simpson JR Jr, Todd RD, Reich T, Vannier M, Raichle ME. Subgenual prefrontal cortex abnormalities in mood disorders. Nature 1997; 386: 824–7.[Medline]
162. Ketter TA, George MS, Kimbrell TA, Willis MW, Benson BE, Post RM. Neuroanatomical models and brain imaging studies. In: Joffe RT, Young LT, editors. Bipolar disorder: biological models and their clinical application. New York, Marcel Dekker; 1997. p. 179–217.
163. Chen G, Yuan PX, Jiang Y, Huang LD, Manji HK. Lithium increases tyrosine hydroxylase levels both in vivo and in vitro. J Neurochem 1998; 70: 1768–71.[Medline]
164. Lin A, Smeal T, Binetruy B, Deng T, Chambard JC, Karin M. Control of AP-1 activity by signal transduction cascades. Adv Second Messenger Phosphoprotein Res 1993; 28: 255–60.[Medline]
165. Hedgepeth CM, Conrad LJ, Zhang J, Huang HC, Lee VMY, Klein PS. Activation of the Wnt signaling pathway: a molecular mechanism for lithium action. Dev Biol 1997; 185: 82–91.[Medline]
166. Stambolic V, Laurent RR, Woodgett JR. Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells. Curr Biol 1996; 6: 1664–8.[Medline]
167. Boyle WJ, Smeal T, Defize LH, Angel P, Woodgett JR, Karin M, Hunter T. Activation of protein kinase C decreases phosphorylation of c-Jun at sites that negatively regulate its DNA-binding activity. Cell 1991; 64: 573–84.[Medline]
168. Chen G, Huang LD, Jiang YM, Manji HK. The mood stabilizing agent valproate inhibits the activity of glycogen synthase kinase 3. J Neurochem 1999; 72: 1327–30.
169. Nestler EJ Antidepressant treatments in the 21st century. Biol Psychiatry 1998; 44: 526–33.[Medline]
170. Manji HK, Moore GJ, Chen G. Lithium at 50: have the neuroprotective effects of this unique cation been overlooked? Biol Psychiatry. In press.

This article has been cited by other articles:

				O. G. Cameron Psychopharmacology Psychosom Med, September 1, 1999; 61(5): 585 - 590. [Full Text] [PDF]

This Article Abstract Figures Only Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chen, G. Articles by Manji, H. K. Search for Related Content PubMed PubMed Citation Articles by Chen, G. Articles by Manji, H. K. Related Collections Pharmacology Reviews