Increased metabotropic glutamate receptor subtype 5 availability in human brain after one night without sleep

Sleep deprivation (wake therapy) provides rapid clinical relief in many patients with major depressive disorder (MDD). Changes in glutamatergic neurotransmission may contribute to the antidepressant response, yet the exact underlying mechanisms are unknown. Metabotropic glutamate receptors of subtype 5 (mGluR5) are importantly involved in modulating glutamatergic neurotransmission and neuronal plasticity. The density of these receptors is reduced in the brain of patients with MDD, particularly in brain structures involved in regulating wakefulness and sleep. We hypothesized that prolonged wakefulness would increase mGluR5 availability in human brain.

Metabotropic glutamate receptor subtype 5 binding was quantified with positron emission tomography in 22 young healthy men who completed two experimental blocks separated by 1 week. Two positron emission tomography examinations were conducted in randomized, crossover fashion with the highly selective radioligand, ¹¹C-ABP688, once after 9 hours (sleep control) and once after 33 hours (sleep deprivation) of controlled wakefulness. ¹¹C-ABP688 uptake was quantified in 13 volumes of interest with high mGluR5 expression and presumed involvement in sleep-wake regulation.

Sleep deprivation induced a global increase in mGluR5 binding when compared with sleep control (p<.006). In anterior cingulate cortex, insula, medial temporal lobe, parahippocampal gyrus, striatum, and amygdala, this increase correlated significantly with the sleep deprivation-induced increase in subjective sleepiness.

This molecular imaging study demonstrates that cerebral functional mGluR5 availability is increased after a single night without sleep. Given that mGluR5 density is reduced in MDD, further research is warranted to examine whether this mechanism is involved in the potent antidepressant effect of wake therapy.