Neural Mechanisms of Circadian Regulation of Natural and Drug Reward

Figure 2

Potential mechanisms by which circadian rhythms impact reward. One of the primary mechanisms by which circadian rhythms might affect reward and reward-related behaviors is through monoaminergic signaling in the nucleus accumbens (NAc). In particular, circadian clock genes control regulatory processes involved in the synthesis, function, and degradation of dopamine (DA). Clock is thought to be a negative regulator of reward, since mutations in the Clock gene increase preference and drug taking. CLOCK and other related genes may be negatively regulating DA through their transcriptional actions. (a) Overall, dopaminergic signaling is reduced through CLOCK’s actions (and increased in ClockΔ19 mutant mice) because genes that increase dopaminergic signaling are negatively regulated by clock genes while genes that decrease dopaminergic signaling are positively regulated. (b) Tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of dopamine (DA), is negatively regulated, whereas monoamine oxidase A (MAOA), an enzyme which breaks down DA in the synapse and cholecystokinin (CCK), a regulatory peptide which negatively affects DA output is positively regulated by clock genes [114, 119]. (c) These changes in dopaminergic neurons in the VTA influence dopaminergic, and potentially glutamatergic, signaling in the NAc, which could mediate increases in reward seen in mice with mutations in clock genes. This could hold true in humans, with circadian disruptions or polymorphisms in circadian genes increasing dopaminergic signaling in the NAc, which leads to increased vulnerability to substance dependence.

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