This seems like a no brainer. Dopamine is an arousal-promoting neurotransmitter (in most cases). It excites other nerve cells, and is the primary neurotransmitter of the central reward circuit. Dopamine agonists like modafinil have saturated the pharma market for years in order to combat daytime sleepiness and shift work.

ResearchBlogging.orgNowadays, the focus has shifted to how an animal’s genotype  confers sensitivity to arousal-promoting drugs like modafinil and caffeine. From my own 23andme profile, I have learned that I am hypersensitive to caffeine. In animal models, it has been shown that certain genetic murine and fly mutants–such as those that lack the dopamine transporter (DAT), preventing released dopamine from re-entering the neuron for degradation and thereby increasing the retention of dopamine in the synapse–are less sensitive to modafinil and caffeine. Sensitivity is measured from changes in sleep-wake and how the animals respond to sleep loss.

Well, a recent study in The Journal of Neuroscience recruited a group of socially drinking professionals in their mid-20s (had 3-4 drinks/wk; 1-2 cups of coffee/day) with different dopamine transporter (DAT) genotypes to sleep in a lab, take caffeine or modafinil, and be subjected to short-term sleep deprivation in the process. One group of the participants had a genotype that conferred a 15-20% reduction in DAT (homozygous) whereas the other (heterozygous) group did not.

First off, individuals with the homozygous DAT mutation were more sensitive to sleep deprivation. They had a larger sleep rebound–an increase in deep, slow-wave sleep. When the researchers examined the properties of each slow-wave, it was found that the difference did not manifest from the size of each wave, but rather the number of slow-waves.

For individuals who were given caffeine and modafinil, the results recapitulated what has previously been found in animal models. Although in this study, the results were differential for type of drug (caffeine vs. modafinil) with respect to genotype. For  example, while caffeine caused a reduction in slower EEG frequencies in both genotypes during waking, modafinil only reduced slower EEG frequencies during waking for individuals heterozygous for the DAT mutation. When the individuals were asleep, the individuals heterozygous for the DAT mutation were significantly more sensitive to caffeine and modafinal than the individuals homozygous for the DAT mutation, having faster EEG frequencies that are indicative of wake.

Genotypic, dopamine differences in sleep
In conclusion, the similarities in results across studies of modafinil’s and caffeine’s wake-promoting effects in non-mammalian and lower-order (mouse) and higher-order (human) mammalian models with differential dopamine genotypes, point to extra considerations that pharma companies and doctors must account for when prescribing meds to people.

Holst SC, Bersagliere A, Bachmann V, Berger W, Achermann P, & Landolt HP (2014). Dopaminergic role in regulating neurophysiological markers of sleep homeostasis in humans. The Journal of neuroscience : the official journal of the Society for Neuroscience, 34 (2), 566-73 PMID: 24403155