5‐HT_1Areceptors couple to activation of Akt, but not extracellular‐regulated kinase (ERK), in cultured hippocampal neurons

Abstract

5-HT 1A receptors have been hypothesized to mediate some of the neuronal plasticity and behavioral responses stimulated by serotonin selective reuptake inhibitors. Although the cellular signaling pathways required for inducing these actions have not yet been determined, roles for the neuroprotective extracellular-regulated kinase (ERK) mitogenactivated protein (MAP) kinase and Akt pathways have been suggested. In the current studies we have utilized primary cultures to directly determine whether hippocampal 5-HT 1A receptors couple to activation of Akt and ERK. We found that E18 hippocampal neurons exhibit a twofold activation of Akt when exposed to nanomolar concentrations of 5-HT. The 5-HT 1/7 receptor-selective agonist 5-carboxamidotryptamine maleate (5-CT) and the 5-HT 1A/7 receptor-selective agonist 8-hydroxy-N,N-dipropyl-aminotetralin (8-OH-DPAT) maleate were found to activate Akt with equal efficacy, and similar potency, to 5-HT. p-MPPI and WAY-100635, antagonists selective for 5-HT 1A receptors, completely inhibited 5-CT-stimulated Akt activation. Activation of Akt was also inhibited by pretreatment with pertussis toxin as well as the phosphatidylinositol 3-kinase inhibitors, wortmannin and LY294002. In contrast, the 5-HT selective antagonist, SB269970, caused no inhibition. Although the density of 5-HT 1A receptors expressed by cultured neurons was sufficient to activate Akt, no activation of ERK was observed. These findings suggest that Akt, and not ERK, may be relevant to previous reports of hippocampal 5-HT 1A receptors mediating neurotrophic responses.

Paradoxical Striatal Cellular Signaling Responses to Psychostimulants in Hyperactive Mice

“…The physiological functions of 5HT are mediated by three ion channels receptors of the 5HT3 class and, at least, 13 different G protein-coupled receptors (39), some of which have been shown to activate ERK-mediated signaling in cell culture systems (40,41). However, the relevance of these observations to brain 5HT receptor signaling has remained mostly unexplored.…”

Anatomically Selective Serotonergic Type 1A and Serotonergic Type 2A Therapies for Parkinson's Disease: An Approach to Reducing Dyskinesia without Exacerbating Parkinsonism?

“…In contrast, 5-HT 1A receptors couple to inhibition of inositol phosphate synthesis in raphe but not in hippocampus (Johnson et al, 1997). In the case of extracellular signal-regulated kinase 1/2, 5-HT 1A receptors mediate phosphorylation of this kinase in the cerebral cortex but inhibit it in hippocampus (Chen et al, 2002;Cowen et al, 2005;Buritova et al, 2009).…”

Cumulative Activation of Akt and Consequent Inhibition of Glycogen Synthase Kinase-3 by Brain-Derived Neurotrophic Factor and Insulin-Like Growth Factor-1 in Cultured Hippocampal Neurons

“…Hippocampal neuronal cultures were prepared as described previously (Cowen et al, 2005), with some modification. Hippocampi were isolated from embryonic day 18 (E18) SpragueDawley rats obtained from Charles River Laboratories (Raleigh, NC), and 10 6 cells were plated per poly(D-lysine)-coated 35-mm Petri dish.…”