High-dose ondansetron reduces activation of interoceptive and sensorimotor brain regions

Abstract

Several psychiatric disorders involve abnormalities of interoception and associated neural circuitry centered on the insula. The development of interventions modulating interoceptive circuits could lead to novel treatment approaches for these disorders. The 5-HT3 receptor antagonist ondansetron is a good candidate for the modulation of interoceptive circuits, as 5-HT3 receptors are located abundantly on sensory pathways and ondansetron has shown some clinical utility in disorders characterized by sensory and interoceptive abnormalities. The present study tested the ability of three different doses of ondansetron to engage neural regions involved in interoception to determine the drug's utility as a therapeutic agent to target circuit abnormalities in patients. Fifty-three healthy subjects were randomized to receive a single 8-mg (n = 18), 16-mg (n = 17), or 24-mg (n = 18) dose of ondansetron and placebo before MRI scanning on separate days. Subjects performed an fMRI task previously shown to engage interoceptive circuitry in which they viewed videos depicting body movements/sensation and control videos. The results revealed a highly significant relationship between dosage and activation in bilateral insula, somatosensory and premotor regions, cingulate cortex, and temporal cortex for control but not body-focused videos. These effects were driven by a robust reduction in activation for ondansetron compared to placebo for the 24-mg group, with weaker effects for the 16-mg and 8-mg groups. In conclusion, high-dose ondansetron reduces activation of several areas important for interoception, including insula and sensorimotor cortical regions. This study reveals the potential utility of this drug in modulating hyperactivity in these regions in patients.

Perceptual insensitivity to the modulation of interoceptive signals in depression, anxiety, and substance use disorders

“…However, there are a few other previous findings which could relate to this result. For example, one study found that a serotonergic receptor antagonist reduced activation in regions of the insula associated with interoception 85 , which could pertain to reduced perceptual accuracy. Another study found higher heart rate and lower heart rate variability in individuals on antipsychotic medications, and higher self-reported bodily awareness in individuals on antidepressant medications 74 .…”

Functional neural mechanisms of sensory phenomena in obsessive-compulsive disorder

“…The present investigation explored the relationship between SP and activation of the insula and sensorimotor cortical regions in a sample of OCD patients exhibiting varying severity of SP. Patients performed a functional magnetic resonance imaging (fMRI) task that has been shown to elicit activity in these circuits (Schaefer et al, 2012;Stern et al, 2018). This work represents a first step toward identifying the functional neural mechanisms of SP, with the long-term goal of identifying brain circuitry that could be targeted by future treatments for these impairing symptoms.…”

Perceptual insensitivity to the modulation of interoceptive signals in depression, anxiety, and substance use disorders

“…For example, one study found that a serotonergic receptor antagonist reduced activation in regions of the insula associated with interoception 85 , which could pertain to reduced perceptual accuracy. Another study found higher heart rate and lower heart rate variability in individuals on antipsychotic medications, and higher self-reported bodily awareness in individuals on antidepressant medications 74 .…”