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
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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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