Serotonergic regulation of the dopaminergic system: Implications for reward-related functions

Abstract

Serotonin is a critical neuromodulator involved in development and behavior. Its role in reward is however still debated. Here, we first review classical studies involving electrical stimulation protocols and pharmacological approaches. Contradictory results on the serotonergic' involvement in reward emerge from these studies. These differences might be ascribable to either the diversity of cellular types within the raphe nuclei or/and the specific projection pathways of serotonergic neurons. We continue to review more recent work, using optogenetic approaches to activate serotonergic cells in the Raphe to VTA pathway. From these studies, it appears that activation of this pathway can lead to reinforcement learning mediated through the excitation of dopaminergic neurons by serotonergic neurons co-transmitting glutamate. Finally, given the importance of serotonin during development on adult emotion, the effect of abnormal early-life levels of serotonin on the dopaminergic system will also be discussed. Understanding the interaction between the serotonergic and dopaminergic systems during development and adulthood is critical to gain insight into the specific facets of neuropsychiatric disorders.

Keywords: Development; Dopamine; Raphe nuclei; Reward; Serotonin; Ventral tegmental area.

Figure 1:

RN to VTA projections can be serotonergic, glutamatergic or can co-transmit glutamate and 5-HT. Serotonergic release via 5-HT3 receptors, glutamatergic transmission (Glut) and glutamatergic-serotonergic co-transmission have been associated with reward in operant (either by nose poke or lever pressing) and place preference tasks and increased DA release into the nucleus accumbens. 5-HT3R: activation via 5-HT3 receptors, GlutR: activation via glutamatergic receptors. These papers show effects on behavior of activation of the following pathways: (1) DRNSerotonergic only : Nagai et al., 2020; Wang et al., 2020 ; (2) DRN-Glutamatergicserotonergic co-transmission: Liu et al., 2014; Wang et al., 2020; Cunha et al., 2020; (3) DRN-glutamatergic only: McDevitt et al., 2014; Qi et al., 2014.