Dorsal raphe serotonin neurons inhibit operant responding for reward via inputs to the ventral tegmental area but not the nucleus accumbens: evidence from studies combining optogenetic stimulation and serotonin reuptake inhibition

Abstract

The monoamine neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) exerts an inhibitory influence over motivation, but the circuits mediating this are unknown. Here, we used an optogenetic approach to isolate the contribution of dorsal raphe nucleus (DRN) 5-HT neurons and 5-HT innervation of the mesolimbic dopamine (DA) system to motivated behavior in mice. We found that optogenetic stimulation of DRN 5-HT neurons enhanced downstream 5-HT release, but this was not sufficient to inhibit operant responding for saccharin, a measure of motivated behavior. However, combining optogenetic stimulation of DRN 5-HT neurons with a low dose of the selective serotonin reuptake inhibitor (SSRI) citalopram synergistically reduced operant responding. We then examined whether these effects could be recapitulated if optogenetic stimulation specifically targeted 5-HT terminals in the ventral tegmental area (VTA) or nucleus accumbens (NAc) of the mesolimbic DA system. Optogenetic stimulation of 5-HT input to the VTA combined with citalopram treatment produced a synergistic decrease in responding for saccharin, resembling the changes produced by targeting 5-HT neurons in the DRN. However, this effect was not observed when optogenetic stimulation targeted 5-HT terminals in the NAc. Taken together, these results suggest that DRN 5-HT neurons exert an inhibitory influence over operant responding for reward through a direct interaction with the mesolimbic DA system at the level of the VTA. These studies support an oppositional interaction between 5-HT and DA systems in controlling motivation and goal-directed behavior, and have important implications for the development and refinement of treatment strategies for psychiatric disorders such as depression and addiction.

The Role of Dorsal Raphe Serotonin Neurons in the Balance between Reward and Aversion

“…We and others have shown that the optogenetic activation of DRN 5-HT neurons elicits antidepressant-like effects in mice and rats [31,43]. In addition to mental disorders, many reports have demonstrated that 5-HT neurons are involved in reward processing [8][9][10][11][32][33][34][35]. Some reports have shown that the activation of DRN 5-HT neurons elicits reward-related behaviors including self-stimulation and real-time place preference [9].…”

“…Indeed, previous reports have demonstrated that the activation of DRN 5-HT neurons induces an antidepressant-like effect in mice and rats [30,31]. Similar to an antidepressive effect, rewarding potency of DRN 5-HT neurons has been studied by using several lines of genetically-modified mice [9][10][11][32][33][34][35]. Liu et al and Li et al have shown that sucrose intake activates DRN 5-HT neurons and that the activation of DRN 5-HT neurons causes operant reinforcement using ePet1-Cre mice [9,10].…”

Addiction and the itch‐scratch cycle. What do they have in common?

“…5‐hydroxytryptamine is an important neurotransmitter for both addiction and itch. Serotoninergic projection from dorsal raphe nucleus (DRN) of the midbrain with the DRN being the primary brain region containing neurons positive for 5‐HT, DRN 5‐HT neurons exert an inhibitory influence over operant responding for reward through a direct interaction with the mesolimbic DA system at the level of the VTA . Decreases in serotonin synthesis have also been observed during chronic nicotine exposure .…”

“…5‐HT elicited itch when applied to human or mouse skin at lower doses . In addition, serotoninergic projection from DRN to IC and serotonergic signalling in the rostral ventromedial medulla (RVM) is involved in acute itch sensation processing in mice . Moreover, serotoninergic neurons in the brainstem nucleus raphe magnus (NRM) send descending projections to the spinal cord .…”

Kamikihito Enhances Cognitive Functions and Reward-Related Behaviors of Aged C57BL/6J Mice in an Automated Behavioral Assay System

“…SSRIs generally provoke a decrease in motivated behaviors for reward. This is mediated by the inhibitory effect of increased 5-HT on dopaminergic neurons in the ventral tegmental area ( Sanders et al., 2007 ; Browne et al., 2019 ). Similar reductions in motivation are observed with SNRIs ( Stromberg et al., 2002 ; Simon O’Brien et al., 2011 ).…”