The Neuropharmacology of Sleep Disorders: Better Sleeping Through Chemistry?

Abstract

Sleep and wake states involve interaction among many brain centers via multiple neurotransmitters, including dopamine, norepinephrine, hypocretin, acetylcholine, histamine and serotonin (wake promoting), and γ amino butyric acid (GABA) and melatonin (sleep promoting). Most medications for insomnia or hypersomnia act on elements of these neural systems. Initial treatment of insomnia includes sleep hygiene measures. Cognitive-behavioral therapy for insomnia is useful. Medications approved by the Food and Drug Administration for insomnia act on GABA receptors or on melatonin receptors. A frequent cause of insomnia is restless legs syndrome, which is linked to reduced dopaminergic activity in brain structures; idiopathic restless legs syndrome is best treated with dopamine agonists such as ropinerole or pramipexole. Excessive daytime sleepiness is most often due to insufficient sleep hours or sleep apnea but is also caused by medications, illnesses, narcolepsy, or idiopathic hypersomnia. Stimulants generally act through enhanced dopamine action (amphetamines, methylphenidate) or acetylcholine action (caffeine). Modafinil may act through enhanced central histamine, hypocretin, and possibly dopamine action. A newer agent, γ -hydroxybutyrate (GHB), acts on GABA and GHB receptors to consolidate sleep, improving daytime sleepiness in narcolepsy. Improving knowledge of sleep/wake mechanisms should lead to more specific and rational treatments for sleep disorders.