Neurochemicals of Sleep

• GABA

• Serotonin

• Galanin

• Adenosine

• Other neuropeptides

GABA

• Major inhibitory neurotransmitter of the brain

• GABA-A and GABA-B receptors

• Sedative hypnotics are GABA-A agonists

• GHB (Xyrem) may function through GABA-B receptors

• Located in:

– Brainstem reticular formation (local interneurons inhibit ARAS glutamatergic neurons)

– Anterior hypothalamus and VLPO (projects to the posterior hypothalamus and other activating areas)

– GABAergic neurons in the hypothalamus, subthalamus and basal forebrain project to the cortex

– Septum

– Thalamic reticular nucleus (important in sleep spindle generation and fundamental SWS and loss of consciousness associated with SWS)

Serotonin

• Serotonergic neurons are found in the midline (or raphe) nuclei in the medulla, pons and midbrain

• Dorsal Raphe Nucleus (DRN) projects rostrally to the thalamus, hypothalamus, basal forebrain, cortex)

• Total lesions of the DRN in cats produce total insomnia

– This insomnia can gradually resolve

• Single unit recordings of serotonergic neurons indicate they decrease firing during SWS and paradoxical (REM) sleep indicating serotonin is not critical for sleep maintenance

• Serotonin’s role in sleep is complex and not fully elucidated, but serotonin appears to prepare the brain for sleep but is not essential for sleep maintenance

Adenosine

• Caffeine (methylxanthine) inhibits adenosine and acts as a stimulant

• Breakdown product from ATP utilization

• Is contained in neurons and the extracellular space

• Extracellular concentration progressively increases during waking and decreases with sleep

• May be the “sleep inducing substance” of the brain

• Suppresses transmission of excitatory synapses

– Inhibits cholinergic neurons in the brainstem and basal forebrain

– Hyperpolarizes projection neurons in the thalamus and cortex and can facilitate SWS

Galanin

• Peptide colocalized with GABA in the VLPO and promotes sleep

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.