The effects of sleep deprivation on alertness, mood, and cognitive performance is well known, yet the brain mechanisms underlying the effects of sleep deprivation are not known. In an effort to determine the role of brain catecholamines in the effect of sleep deprivation on alertness, mood, and performance, a series of clinical studies were con- ducted in adult male healthy volunteers treated with the catecholamine synthesis inhibitor alpha-methyl-para-tyrosine (AMPT). AMPT was found to mimic the effects of sleep deprivation, and sleep deprivation significantly enhanced the effects of AMPT. L-Dopa/Carbidopa (Sinemet) reversed the effects of AMPT on alertness, mood, and cognitive performance. These data strongly implicate the role of the brain catecholamines in the decline of alertness, mood, and cognitive function associated with sleep deprivation.