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Research ArticleArticle

Long-Term Fluoxetine Treatment Modulates Cannabinoid Type 1 Receptor-Mediated Inhibition of Adenylyl Cyclase in the Rat Prefrontal Cortex through 5-Hydroxytryptamine1A Receptor-Dependent Mechanisms

Susana Mato, Rebeca Vidal, Elena Castro, Álvaro Díaz, Ángel Pazos and Elsa M. Valdizán
Molecular Pharmacology March 2010, 77 (3) 424-434; DOI: https://doi.org/10.1124/mol.109.060079
Susana Mato
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Rebeca Vidal
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Elena Castro
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Álvaro Díaz
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Ángel Pazos
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Elsa M. Valdizán
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Abstract

Increasing data indicate that brain endocannabinoid system plays a role in the effects of antidepressant medications. Here we examined the effect of in vivo exposure to the selective serotonin uptake inhibitor fluoxetine on cannabinoid type 1 (CB1) receptor density and functionality in the rat prefrontal cortex (PFC) and cerebellum. Long-term treatment with fluoxetine (10 mg/kg/day) enhanced CB1 receptor inhibition of adenylyl cyclase (AC) in the PFC and reduced it in the cerebellum without altering receptor density and agonist stimulation of guanosine 5′-O-(3-[35S]thio) triphosphate ([35S]GTPγS) in either area. Analysis of [35S]GTPγS-labeled Gα subunits allowed for the detection of up-regulated CB1 receptor coupling to Gαi2, Gαi3 in the PFC, and reduced coupling to Gαi3 in the cerebellum of fluoxetine-treated rats. Concomitant administration of the 5-HT1A receptor antagonist N-[2-[4- (2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate (WAY100635; 0.1 mg/kg/day) reduced fluoxetine-induced modulation of CB1 receptor coupling to Gα subunits and AC in the PFC but not in the cerebellum. These results indicate that increased CB1 receptor signaling at the Gαi-AC transduction level is a long-term adaptation induced by fluoxetine in the PFC and point to a role for 5-HT1A receptors in this effect. Basal AC activity, protein kinase A (PKA) catalytic subunit expression, and phospho-cAMP response element-binding protein (pCREB)/CREB ratio were also up-regulated in the PFC of fluoxetine-treated animals, whereas no differences were detected in the cerebellum. It is interesting that long-term Δ9-tetrahydrocannabinol treatment did not elicit antidepressant-like effects or modulated behavioral responses of fluoxetine in an animal model of depression (olfactory bulbectomy). These data suggest that altered signal transduction through CB1 receptors in the PFC may participate in the regulation of the AC-PKA-CREB cascade induced by fluoxetine in this brain area.

Footnotes

  • This work was supported by the Ministerio de Education y Ciencia [Grants CICYT SAF04-00941, SAF07-61862]; Plan Nacional sobre Drogas; and Fundación Marqués de Valdecilla [Grant API 05/23].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.109.060079

  • ABBREVIATIONS:

    AD
    antidepressant drug
    AC
    adenylyl cyclase
    BSA
    bovine serum albumin
    CB1
    cannabinoid type 1
    [3H]CP55,940
    [3H](1R,3R,4R)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl)cyclohexan-1-ol
    8-OH-DPAT
    8-hydroxydi-n-propylaminotetralin
    DTT
    dl-dithiothreitol
    [35S]GTPγS
    guanosine 5′-O-(3-[35S]thio)triphosphate
    PFC
    prefrontal cortex
    SR141716A
    N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride
    SSRI
    selective serotonin reuptake inhibitor
    Δ9-THC
    Δ9-tetrahydrocannabinol
    WAY100635
    N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate
    WIN55,212-2
    (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenyl-methanonemesylate
    PKA
    protein kinase A
    EC
    endocannabinoid
    ERK
    extracellular signal regulated-kinase
    OBX
    olfactory bulbectomy
    TCL
    total cell lysate
    ANOVA
    analysis of variance
    DRN
    dorsal raphe nucleus
    CHAPS
    3-[(3-cholamidopropyl)dimethylammonio]propanesulfonate
    CREB
    cAMP response element-binding protein
    5-HT
    5-hydroxytryptamine
    E-64
    N-(trans-epoxysuccinyl)-l-leucine 4-guanidinobutylamide.

    • Received August 4, 2009.
    • Accepted December 7, 2009.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 77 (3)
Molecular Pharmacology
Vol. 77, Issue 3
1 Mar 2010
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Research ArticleArticle

Long-Term Fluoxetine Treatment Modulates Cannabinoid Type 1 Receptor-Mediated Inhibition of Adenylyl Cyclase in the Rat Prefrontal Cortex through 5-Hydroxytryptamine1A Receptor-Dependent Mechanisms

Susana Mato, Rebeca Vidal, Elena Castro, Álvaro Díaz, Ángel Pazos and Elsa M. Valdizán
Molecular Pharmacology March 1, 2010, 77 (3) 424-434; DOI: https://doi.org/10.1124/mol.109.060079

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Research ArticleArticle

Long-Term Fluoxetine Treatment Modulates Cannabinoid Type 1 Receptor-Mediated Inhibition of Adenylyl Cyclase in the Rat Prefrontal Cortex through 5-Hydroxytryptamine1A Receptor-Dependent Mechanisms

Susana Mato, Rebeca Vidal, Elena Castro, Álvaro Díaz, Ángel Pazos and Elsa M. Valdizán
Molecular Pharmacology March 1, 2010, 77 (3) 424-434; DOI: https://doi.org/10.1124/mol.109.060079
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