Dopaminergic Transmission and Wake-Promoting Effects of Central Nervous System Stimulants
Pharmacological agents which increase dopaminergic neurotransmission by blocking dopamine re-uptake by the dopamine transporter (DAT), such as cocaine, amphetamines and modafinil, are potent wake-promoting substances in mammals and even in invertebrates such as Drosophila Melanogaster. In mammals, the cell bodies of dopamine neurons controlling the sleep-wake cycle are located in the midbrain and brainstem. Midbrain dopamine neurons express high levels of DAT and play a key role in emotional arousal in response to rewarding and aversive stimuli. They are strongly excited by wake-promoting neurotransmitters such as acetylcholine and orexins/hypocretins. However, their mean firing rate does not change across the sleep-wake cycle. In contrast, wake-active brainstem dopamine neurons in the dorsal raphe/periaqueductal gray have low DAT levels and play a tonic role in controlling wakefulness. Dopamine neurons increase arousal by inhibiting the nucleus accumbens, by exciting wake-promoting basal forebrain cholinergic and brainstem serotonin neurons and by inhibiting sleep-promoting neurons in the preoptic hypothalamus. Dopamine acts on D1 type (D1, D5) and D2-type (D2, D3, D4) receptors. Both types are involved in promoting arousal but D2 receptors in the shell of the nucleus accumbens appear to be particularly important. Dopamine D4 receptors modulate the amplitude of cortical gamma band (30–80 Hz) oscillations important for attention and inhibit GABAergic inputs from the globus pallidus to the thalamic reticular nucleus. Dopaminergic agents are widely used in clinical practice to modulate alertness in sleep and other disorders involving disrupted cortical activation. Thus, further work on their mechanism of action is warranted.
KeywordsNucleus Accumbens Ventral Tegmental Area Sleep Deprivation Excessive Daytime Sleepiness Dopamine Neuron
This work was supported by the US Veterans Administration (Merit Award I01BX001356) and by the US National Institutes of Health: NIMH R01 MH039683, R21 MH094803, NHLBI HL095491 and NINDS R21 NS093000. The contents of this review do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.
Conflicts of Interest
The author declares no competing financial interests.
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