The role of 5-HT neurotransmission in the regulation of the motivation for wheel running in mice

Abstract

Behavioral addiction, defined as an uncontrollable desire to repeat a certain behavior despite negative consequences, has become a social problem. Here, we investigated the role of 5-HT neurotransmission in the nucleus accumbens (NAc) in motivation for wheel running as a model of behavioral addiction in male C57BL/6J mice (> 6 weeks old). Systemic administration of a 5-HT_1A antagonist (WAY100635) increased wheel rotations, while a 5-HT_2A or 5-HT_2C antagonist (volinanserine or SB242084, respectively) decreased them. In the open field test (OFT), WAY100635 or volinanserine did not affect locomotion, but SB242084 increased it. Intra-NAc infusion of SB242084 reduced wheel rotations without altering locomotion in the OFT, whereas intra-NAc infusion of WAY100635 or volinanserine did not affect wheel rotations. Immunohistochemical analysis revealed that wheel running increased the number of c-Fos-positive cells in the NAc, and this increase was reduced by systemic administration of SB242084. Additionally, whole-cell recordings revealed that bath application of a 5-HT_2C receptor agonist (lorcaserin) increased the number of evoked action potentials and spontaneous excitatory postsynaptic currents in NAc neurons. Our results suggest that the activation of the NAc via 5-HT_2C receptor stimulation regulates the motivation for wheel running.