Neurochemicals of Wakefulness

There are several major neurochemicals involved in promoting wakefulness. These include:

• Glutamate

• Norepinephrine

• Acetylcholine

• Serotonin

• Dopamine

• Histamine

• Hypocretin / Orexin

• Other neuropeptides

Glutamate

• Major excitatory neurotransmitter of the CNS

• Used by the brainstem reticular formation, thalamus, cortex

• Locus coeruleus

• Projects to thalamus, subthalamus, hypothalamus, cortex

• Basal forebrain

– Projects to cortex directly and hippocampus

• Mesopontine cholinergic nuclei

– LDT/PPT

– Project mostly to thalamus (facilitates the glutamatergic thalamocortical projection neurons)

• Complex interactions with wakefulness and sleep

• Appears to have roles in both systems

• Located in the Ventral Tegmental Area (VTA)

– Projects to basal ganglia (including caudate) and frontal cortex

– Involved with behavioral arousal

• Amphetamines promote wakefulness by enhancing dopamine release and inhibiting its reuptake

• Located in the Tuberomammillary Nucleus (TMN) in the Posterior hypothalamus

• Diffuse projections, including the cerebral cortex, striatum, hippocampus and LDT/PPT

• The histaminergic TMN and the GABAergic VLPO in the anterior hypothalamus are antagonistic

• The TMN inhibits the VLPO and the VLPO inhibits the TMN

• Anti-histamines are sedating!

Hypocretin / Orexin

• New excitatory neuropeptide identified simultaneously by 2 groups in 1999

• Diffuse projections throughout the brain (mainly to activating areas) to promote wakefulness / activation

• Involved in arousal and control of REM

• Deficient in most cases of narcolepsy

Neuronal activity

References:

Kryger, Principles and Practice of Sleep Medicine, Elsevier 2005

Sleep Neurobiology for the Clinician. Espana and Scammell. Sleep 2004;27:811. (excellent review)

Hypocretins (orexins) and sleep-wake disorders. Lancet Neuro 2005; 4:673.

ACCP Sleep Medicine Board Review Syllabus 2007.