Long-Term Fluoxetine Treatment Modulates Cannabinoid Type 1 Receptor-Mediated Inhibition of Adenylyl Cyclase in the Rat Prefrontal Cortex through 5-Hydroxytryptamine_1AReceptor-Dependent Mechanisms

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 (CB 1 ) receptor density and functionality in the rat prefrontal cortex (PFC) and cerebellum. Long-term treatment with fluoxetine (10 mg/kg/day) enhanced CB 1 receptor inhibition of adenylyl cyclase (AC) in the PFC and reduced it in the cerebellum without altering receptor density and agonist stimulation of guanosine 5Ј-O-(3-[ oxetine-induced modulation of CB 1 receptor coupling to G␣ subunits and AC in the PFC but not in the cerebellum. These results indicate that increased CB 1 receptor signaling at the G␣ i -AC transduction level is a long-term adaptation induced by fluoxetine in the PFC and point to a role for 5-HT 1A 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 ⌬ 9 -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 CB 1 receptors in the PFC may participate in the regulation of the AC-PKA-CREB cascade induced by fluoxetine in this brain area.

Role of the Endocannabinoid System in Depression: from Preclinical to Clinical Evidence

“…The putative role of the ECS in depression is supported by evidence showing that the majority of available antidepressants also modify CB1 receptor expression and endocannabinoid content in brain regions related to mood disorders ( Table 5.2). While fluoxetine increased CB1 receptor binding and/or signaling in the limbic region [92,93], citalopram reduced CB1 receptor signaling in the hippocampus and hypothalamic paraventricular nucleus [94], suggesting a region-specific effect of SSRI on CB1 receptor-mediated signaling. Similarly, TCAs elicited different effects based on various brain regions: desipramine increased hippocampal and hypothalamic CB1 receptor binding [95], while imipramine reduced it within the hypothalamus, midbrain and ventral striatum and increased it within the amygdala [96].…”

Identification and quantitation of a benzoylindole (2-methoxyphenyl)(1-pentyl-1H-indol-3-yl)methanone and a naphthoylindole 1-(5-fluoropentyl-1H-indol-3-yl)-(naphthalene-1-yl)methanone (AM-2201) found in illegal products obtained via the Internet and their cannabimimetic effects evaluated by in vitro [35S]GTPγS binding assays

“…The standard [ 35 S]GTPcS binding assays were carried out in a 96-well microplate according to the procedure of Mato et al [13] and Nonaka et al [14] with minor modifications. Briefly, the assay buffer consisted of 20 mM HEPES (pH 7.6), 7 mM MgCl 2 , 100 mM NaCl, 1 mM EDTA, 0.2 mM DTT, 10 lM DPCPX, and 0.1% (w/v) BSA.…”

Targeting CB2-GPR55 Receptor Heteromers Modulates Cancer Cell Signaling

“…Membranes were stored at Ϫ80°C until used for analysis of LPI-induced stimulation of [ 35 S]GTP␥S binding. For this analysis, we followed a procedure published previously (24) in which cell membranes (20 g of protein/ml) were incubated for 120 min at 30°C in assay buffer (100 mM NaCl, 50 mM Tris-HCl, 10 mM MgCl 2 , 1 mM EGTA, 1 mM DTT, 50 M GDP, and 1 mg/ml BSA (pH 7.4)) containing 0.1 nM M) in the presence or absence of 10 Ϫ6 M ⌬ 9 -tetrahydrocannabinol (THC, The Health Concept, Richelbach, Germany). Nonspecific binding was determined in the presence of 10 M unlabeled GTP␥S.…”