Localisation of β-catenin in the adult brain: a putative pharmacological target in mood disordes

Abstract

It has been proposed that the therapeutic effects of fluoxetine might be related to adaptive changes in serotonergic neurotransmission through the activation of the different serotonin receptor subtypes. 5-HT4 receptors are widely distributed in the central nervous system and are positively coupled to adenylate cyclase via Gs proteins. Previous studies have reported an increase of 5-HT4 receptor density and 5-HT4-dependent cAMP concentration in the brain from suicide victims. In addition, it has recently been reported that 5-HT4 receptor agonists show antidepressant-like effects. Thus, 5-HT4 receptors may play a relevant role in depression and/or the mechanism of antidepressant drugs. Here we describe the effects of chronic fluoxetine (10 and 5 mg/kg/day p.o.) in the postreceptorial mechanism coupled to 5-HT4 receptors in rat brain. In rat striatal membranes, chronic treatment (21 days) with fluoxetine (10 mg/kg/day) resulted in an attenuation of the level of 5-HT4-dependent Gαs activity (zacopride-induced stimulation of [35S]GTPγS binding) (% reduction = 62.5%; p<0.01). In addition, the level of activity of adenylate cyclase associated to this receptor (zacopride-induced cAMP accumulation) was also significantly reduced only with the higher dose assayed (% reduction = 38.4; p <0.05) in the fluoxetine-treated group. Moreover, extracellular recordings carried out in the pyramidal cells of CA1 of the hippocampus indicate that chronic fluoxetine also resulted in an attenuation of 10 μM zacopride-induced stimulation of population spike (% reduction = 41.4 % and 5 7.3 % for 10 and 5 mg/kg, respectively). In conclusion, these results demonstrate the existence of 5-HT4-receptor desensitisation following chronic fluoxetine. They also suggest that the interaction with these receptors could be of relevance in the mediation of the clinical effects of the drug.