Signaling: cellular insights into the pathophysiology of bipolar disorder

Manji, Husseini K.; Lenox, Robert H.

doi:10.1016/s0006-3223(00)00929-x

Cited by 190 publications

(131 citation statements)

References 67 publications

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“…administration of thapsigargin, a compound which selectively inhibits Ca 2C uptake into the endoplasmic reticulum by inhibiting the sarco-endoplasmic reticulum ATPases (SERCAs) and thus increasing the intracellular Ca 2C concentration (Treiman et al, 1998), increased the mouse immobility time evidencing the induction of a depressant-like effect. These observations suggest that a supraspinal increase in intracellular calcium contents is involved in the modulation of mood leading to a depressant-like effect in laboratory animals further complementing and extending studies performed on peripheral blood cells from depressed subjects indicating that patients with affective disorders have an enhanced intracellular Ca 2C response (Emamghoreishi et al, 1997;Yamawaki et al, 1998;Manji and Lenox, 2000). Furthermore, these data indicate that an antidepressant-like effect can be obtained by blocking the release of Ca 2C from endoplasmic reticulum.…”

Section: Discussionsupporting

confidence: 69%

Blockade of intracellular calcium release induces an antidepressant-like effect in the mouse forced swimming test

2006

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The role of intracellular calcium in the modulation of a depressant-like condition was investigated in the mouse forced swimming test. I.c.v. administration of TMB-8 (0.23e46.3 nmol per mouse), a blocker of Ca 2C release from intracellular stores, decreased the mouse immobility time. I.c.v. injection of thapsigargin (0.003e3 nmol per mouse), compound which selectively inhibits Ca 2C uptake into the endoplasmic reticulum, produced, 60 min after administration, a depressant-like condition. Xestospongin C (1e100 pmol per mouse i.c.v.), an InsP 3 -receptor antagonist, decreased the mouse immobility time. By contrast, D-myo-inositol (5.4e540 pmol per mouse i.c.v.), compound which produces InsP 3 , resulted in a depressant-like effect. Similarly, ryanodine (0.1e600 pmol per mouse i.c.v.), an RyR antagonist, decreased the immobility time values whereas the administration of 4-chloro-m-cresol (0.1e100 pmol per mouse i.c.v.), an RyR agonist, showed an opposite effect. The antidepressant-like effects observed with TMB-8, xestospongin C and ryanodine were comparable to that produced by the antidepressant drugs amitriptyline and clomipramine. The treatments employed did not produce any behavioural impairment of mice as revealed by the rota-rod and hole board tests indicating that the antidepressant-and depressant-like effects were not due to a compromised locomotor activity and spontaneous motility of the treated animals. These results indicate that a central variation in intracellular calcium contents is involved in the modulation of a depressive-like condition in the mouse forced swimming test. In particular, the blockade of both InsP 3 Rs and RyRs appears to play an important role in the induction of an antidepressant-like effect, whereas the stimulation of these receptors is involved in a depressant-like response of mice.

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Section: Discussionsupporting

confidence: 69%

Blockade of intracellular calcium release induces an antidepressant-like effect in the mouse forced swimming test

2006

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“…The beta-1 adrenergic receptor is well known to show altered density and/or sensitivity in depression and is downregulated in several brain regions after long-term treatment with certain antidepressants (Ordway et al, 1988;Manji and Lenox, 2000;Banerjee et al, 1977). A recent clinical study found a tendency for a relationship between an adrb1 polymorphism and a better and more rapid response to antidepressant treatment (Zill et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Pharmacogenomic Evaluation of the Antidepressant Citalopram in the Mouse Tail Suspension Test

Crowley

Brodkin

Blendy

et al. 2006

Neuropsychopharmacol

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The identification of genetic variants regulating antidepressant response in human patients would allow for more individualized, rational, and successful drug treatments. We have previously identified the BALB/cJ inbred mouse strain as highly responsive to the selective serotonin reuptake inhibitor (SSRI) citalopram in the tail suspension test (TST), a widely used and well-established screening paradigm for detecting compounds with antidepressant activity. In contrast, A/J mice did not show a significant response to citalopram in this test despite exposure to equivalent plasma levels of the drug. To identify genetic determinants of this differential response, 506 F 2 mice from an intercross between BALB/cJ and A/J mice were phenotyped. Composite interval mapping of 92 mice from the phenotypic extremes revealed three loci on chromosomes 7, 12, and 19 affecting citalopram response in the TST. The quantitative trait locus (QTL) at the telomeric end of chromosome 19 showed the greatest level of significance. Three candidate genes residing in this locus include those for vesicular monoamine transporter 2 (VMAT2, slc18a2), alpha 2A adrenergic receptor (adra2a), and beta 1 adrenergic receptor (adrb1). The protein coding regions of these three genes in BALB/cJ and A/J mice were sequenced and two polymorphisms were found in VMAT2 (Leu117Pro and Ser505Pro), while the transcribed regions of adra2a and adrb1 were of identical sequence between strains. Follow-up studies are needed to determine if the VMAT2 polymorphisms are functional and if they could explain the chromosome 19 QTL. The present quantitative trait study suggests possible candidate genes for human pharmacogenetic studies of therapeutic responses to SSRIs such as citalopram.

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“…AMPA receptor subunit GluR1 and GluR2 trafficking is regulated by cAMP-dependent protein kinase (PKA), calcium-calmodulin-dependent protein kinase II (CAMKII), PKC, and ERK through phosphorylation of specific sites (Esteban et al, 2003;Lee et al, 1998;Malinow and Malenka, 2002). Notably, many of these cascades are targets for mood-stabilizing agents and antidepressants (Donati and Rasenick, 2003;Manji and Lenox, 2000;Shao et al, 2005). We therefore sought to investigate concurrently the effects of lamotrigine, riluzole, and valproate on surface AMPA receptors, AMPA phosphorylation, and AMPA function.…”

Section: Introductionmentioning

confidence: 99%

The Anticonvulsants Lamotrigine, Riluzole, and Valproate Differentially Regulate AMPA Receptor Membrane Localization: Relationship to Clinical Effects in Mood Disorders

Suzuki

Wei

et al. 2006

Neuropsychopharmacol

Self Cite

194

153

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A growing body of data suggests that the glutamatergic system may be involved in the pathophysiology and treatment of severe mood disorders. Chronic treatment with the antimanic agents, lithium and valproate, resulted in reduced synaptic expression of the AMPA(-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptor subunit GluR1 in the hippocampus, while treatment with an antidepressant (imipramine) enhanced the synaptic expression of GluR1. The anticonvulsants, lamotrigine (6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine) and riluzole (2-amino-6-trifluoromethoxybenzothiazole), have been demonstrated to have efficacy in the depressive phase of bipolar disorder. We therefore sought to determine the role of these anticonvulsants, compared to that of the predominantly antimanic anticonvulsant valproate, on AMPA receptor localization. We found that the agents with a predominantly antidepressant profile, namely lamotrigine and riluzole, significantly enhanced the surface expression of GluR1 and GluR2 in a time-and dose-dependent manner in cultured hippocampal neurons. By contrast, the predominantly antimanic agent, valproate, significantly reduced surface expression of GluR1 and GluR2. Concomitant with the GluR1 and GluR2 changes, the peak value of depolarized membrane potential evoked by AMPA was significantly higher in lamotrigine-and riluzole-treated neurons, supporting the surface receptor changes. Phosphorylation of GluR1 at the PKA (cAMP-dependent protein kinase) site (S845) was enhanced in both lamotrigine-and riluzoletreated hippocampal neurons, but reduced in valproate-treated neurons. In addition, lamotrigine and riluzole, as well as the traditional antidepressant imipramine, also increased GluR1 phosphorylation at GluR1 (S845) in the hippocampus after chronic in vivo treatment. Our findings suggest that regulation of GluR1/2 surface levels and function may be responsible for the different clinical profile of anticonvulsants (antimanic or antidepressant), and may suggest avenues for the development of novel therapeutics for these illnesses.

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Signaling: cellular insights into the pathophysiology of bipolar disorder

Cited by 190 publications

References 67 publications

Blockade of intracellular calcium release induces an antidepressant-like effect in the mouse forced swimming test

Blockade of intracellular calcium release induces an antidepressant-like effect in the mouse forced swimming test

Pharmacogenomic Evaluation of the Antidepressant Citalopram in the Mouse Tail Suspension Test

The Anticonvulsants Lamotrigine, Riluzole, and Valproate Differentially Regulate AMPA Receptor Membrane Localization: Relationship to Clinical Effects in Mood Disorders

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