It has long been known that drugs such as amphetamine and cocaine, which enhance the release or synaptic concentrations of the catecholamines, dramatically enhance and prolong wakefulness. Schematic representation of progressive decrease of aminergic neurotransmitter release in cerebral cortex as an animal passes from wakefulness through NREM to REM sleep. Cortical concentrations of norepinephrine and serotonin are highest in waking, lowest in REM sleep, and intermediate in NREM sleep. Nicotine, a cholinergic agonist, has long been known as a stimulant that produces prolonged and enhanced cortical activation. Blockers of both nicotinic, and even more so of muscarinic cholinergic receptors, diminish cortical activation and vigilance.
Histamine is located in neurons within the caudal hypothalamus.
These neurons project in a diffuse manner to the cerebral cortex. Drugs containing antihistamine produce drowsiness and a decrease in cortical activation. However, there is evidence that it may not be the pure antihistaminic action that is critical, but that other substances that are components of these drugs may be the important substances. Glutamate and aspartate are excitatory amino acids which are contained in many neurons that project to the cerebral cortex, forebrain and brainstem. They are released in greatest amounts during wakefulness.