The Roles of Extra-Synaptic Serotonin Receptors in Neuronal Signaling and Behavior

Abstract

Serotonin signaling is implicated in a variety of psychiatric conditions and regulates behaviors through both synaptic and extra-synaptic neurotransmission. Two serotonin receptors, the 5-HT1B and 5-HT6 receptors, are noted for their mediation of extra-synaptic serotonin signaling and unique localization. 5-HT1B receptors localize to axon terminals and inhibit the release of neurotransmitters. 5-HT6 receptors localize to neuronal primary cilia where they serve as excitatory receptors and are particularly abundant in the direct and indirect pathway neurons of the striatum. While many aspects of the serotonergic system have been well studied, the ways in which these extra-synaptic serotonin receptors modulate neuronal signaling and circuit-specific behaviors are poorly understood. We first describe the creation of neuronal cell lines with stable expression of 5-HT1B receptors and loss of either isoform of β-arrestin in order to elucidate the intracellular signaling mechanisms of 5-HT1B receptors. We next use these cell lines to show that 5-HT1B receptors activate ERK1/2 signaling in a Gαs- and β-arrestin-dependent manner. Finally, we demonstrate that 5-HT6 receptors modulate cocaine reinforcement in a pathway-specific manner; specifically, increased 5-HT6 receptor signaling in the indirect pathway of the nucleus accumbens reduces cocaine taking by increasing the reinforcing properties of the drug. Together, these findings increase our understanding of extra-synaptic serotonin receptors and the mechanisms by which they influence intracellular signaling cascades and circuit-specific behaviors.