Revisiting the Role of Serotonin in Attention-Deficit Hyperactivity Disorder: New Insights from Preclinical and Clinical Studies

Abstract

Attention-deficit hyperactivity disorder (ADHD) is characterized by core symptoms of inattention, hyperactivity, and impulsivity. Aberrant dopaminergic and noradrenergic neurotransmission are often implicated in the pathogenesis of these symptoms because ADHD treatments increase synaptic levels of these neurotransmitters in brain regions associated with attention and impulse control. However, some ADHD treatments also enhance serotonergic neurotransmission in these regions, which could contribute to their efficacy. Here, we review preclinical and clinical data highlighting functional interactions between the serotonergic and catecholaminergic systems in mediating ADHD phenotypes and responses to treatment. The potential utility of serotonergic compounds for treating distinct behavioral features and psychiatric comorbidities (e.g., depression) is also discussed. Overall, preclinical and clinical studies underscore important neuromodulatory effects of serotonin on the catecholaminergic system in mediating distinct ADHD behavioral phenotypes, notably hyperactivity-impulsivity and emotional dysregulation. Incorporating a basic understanding of dynamic monoaminergic interactions and their contributions to ADHD symptoms may identify new targets for treatment. Beyond ADHD core symptoms, emotional dysregulation, which is closely linked to serotonergic dysfunction, is common in ADHD and significantly contributes to negative outcomes across the lifespan. Therefore, an expanded conceptualization of ADHD that includes emotional dysregulation may facilitate insight into ADHD pathology and treatment.

Fig. 1

Brain regions implicated in attention deficit/hyperactivity disorder. Bs brain stem, Cb cerebellum, CC cingulate cortex, HPC hippocampus, NAc nucleus accumbens, OFC orbitofrontal cortex, PFC prefrontal cortex, Str striatum. Created with BioRender.com

Fig. 2

Monoaminergic signaling in the human brain. The monoaminergic systems highly overlap across brain regions implicated in ADHD, especially the cortex, midbrain, and brainstem. DA dopamine, NE norepinephrine, 5-HT serotonin. Created with BioRender.com

Fig. 3

Serotonergic modulation of dopamine signaling. Serotonin (5-HT) exerts modulatory effects, commonly associated with inhibitory action, on the dopaminergic system, as reviewed in [102]. Illustrated here are a few examples of how specific 5-HT receptors may modulate dopamine (DA) signaling in relation to ADHD phenotypes. There are significant reciprocal innervations and crosstalk between these two monoaminergic systems at the site of their primary nuclei, including the dorsal raphe (DR; 5-HT) and ventral tegmental area (VTA; DA; bottom right inset). Serotonergic projections modulate firing activity of dopaminergic neurons in the VTA via multiple receptors, including 5-HT2C receptors, which exhibit inhibitory effects [–446]. 5HT2C receptors are expressed on GABAergic interneurons, which, upon activation, inhibit firing of ventral tegmental neurons. Upon systemic application of SSRIs, DA firing in the ventral tegmental area has been observed to subtly decrease [447, 448], whereas lesions of the dorsal raphe enhanced DA activity in the ventral tegmental area [449]. Low doses of a 5-HT1A receptor agonist (8-OHDPAT), which hypothetically engages the autoreceptor and thus decreases 5-HT activity in the dorsal raphe, have been shown to increase DA firing rate and DA release in the ventral tegmental area under basal and stimulated conditions [–456]. Neurons from the ventral tegmental area and substantia nigra project to the striatum and nucleus accumbens (top right inset) and target medium spiny neurons, which release γ-aminobutyric acid (GABA). These medium spiny neurons also receive projections from glutamatergic neurons in the prefrontal cortex (as well as other areas), which appear to be modulated by serotonergic receptors, such as 5-HT1B. Engagement of these 5-HT1B receptors is implicated in altering ADHD-relevant phenotypes such as hyperactivity in preclinical models [140, 141]. Lastly, 5-HT2A receptors are heavily expressed in the cortex and have been shown to modulate activity of the nucleus accumbens, as well as send feedback signals to the dorsal raphe and ventral tegmental area, reviewed in [102]. Glu, glutamate. Created with BioRender.com

Fig. 4

In vitro pharmacology of select monoaminergic transporter inhibitors. Heatmap represents pK_i values (i.e., negative log of the inhibition constant of drugs that inhibit monoaminergic transporters and their selectivity between the three monoamine transporters. Binding affinity ranked by color. For the heatmap of pK_i values, higher binding affinities (i.e., high pK_i values) are shown in red and lower binding affinities (i.e., low pK_i values) are shown in blue. Data were acquired from the International Union of Basic and Clinical Pharmacology/British Pharmacological Society (IUPHAR/BPS) Guide to Pharmacology, except for viloxazine [413] and vortioxetine [norepinephrine transporter (NET) and dopamine transporter (DAT) data acquired from Trintellix’s label]. Data for atomoxetine are dissociation constant (K_d) rather than inhibition constant (K_i) values. All data were acquired using human transporters, except for the pK_i value of imipramine at DAT, which used rat transporters

Fig. 5

Binding affinity of select FDA-approved drugs at serotonergic receptors. Heatmap represents data as a ratio of binding affinity for the specific target in relation to its primary target [norepinephrine transporter or serotonin transporter; i.e., pK_i (negative log of the inhibition constant) of 5-HT2A/pK_i of serotonin transporter for vortioxetine]. These data were acquired using human receptor isoforms, except for fluoxetine, which utilized rat receptors. The ratio of binding affinity is ranked by color, with greater activity shown in dark-red and less activity shown with white. Data were acquired from the International Union of Basic and Clinical Pharmacology/British Pharmacological Society (IUPHAR/BPS) Guide to Pharmacology, except for viloxazine [413]