Functional neuroanatomy of dopaminergic arousal systems: implications for the wake-promoting effect of psychostimulants, with particular reference to modafinil

Arousal involves activation of the cerebral cortex by inputs from subcortical (hypothalamic, brainstem) wake-promoting nuclei, utilizing monoamine (noradrenaline, dopamine, serotonin, histamine) and neuropeptide (orexin) neurotransmitters. Dopaminergic neurones of the midbrain, originating from distinct nuclei [pars compacta of substantia nigra (SNc), ventral tegmental area (VTA), and other clusters of dopaminergic neurones in the ventral periaqueductal gray (vPAG)] and the pontine dorsal raphe nucleus (DRN), constitute a powerful wake-promoting system. Cortical activation by dopaminergic neurones can be due to either direct projections from the VTA and vPAG/DRN, to the cerebral cortex, or indirect projections from the VTA via the nucleus accumbens (NAc)/ventral pallidum (VP) and from the SNc via the thalamus. Stimulation of the VP, by inputs from the VTA via the NAc, can activate wake-promoting noradrenergic and orexinergic neurones, and stimulation of the thalamus, by inputs from the SNc, can activate wake-promoting glutamatergic thalamocortical neurones. There is also a two-way mutually reinforcing connection between the VTA/NAc/VP and SNc/thalamus systems, indicating the key role of the NAc in dopaminergic arousal regulation. Dopaminergic psychostimulants (e.g., amphetamine, cocaine) are highly addictive drugs of abuse, that activate both reinforcement mechanisms and promote wakefulness, by enhancing dopaminergic neurotransmission. The addictive potential of psychostimulants is related to the stimulation of reinforcement processes. Modafinil, an atypical psychostimulant, enhances wakefulness without affecting reinforcement, and thus is devoid of addictive potential. Unraveling the mode of action of modafinil may give insight into the neural mechanisms controlling reinforcement and arousal. Recent evidence indicates that the powerful arousal-enhancing effect of psychostimulants may mainly be due to indirect cortical activation via the NAc and thalamus.