Dopamine

The neurotransmitter at the centre of the reward-system, and the most misread molecule in popular psychology. Lewis et al. 2021 give it "a central position" in mediating the reward value of food, drink, sex, social interaction and drugs — one clause after saying reward needs several neurotransmitters acting together.

Made, then broken down, on a schedule

Synthesis. Tyrosine hydroxylase (TH) is the rate-limiting enzyme. TH levels rise in the active phase.
Breakdown. Monoamine oxidase A (MAOA) clears it. Its transcription is regulated by NPAS2, BMAL1 and PER2.
Net effect. Dopamine in the substantia nigra and VTA oscillates over 24 hours, peaking in the active phase, along with its precursor and metabolites. High TH and low MAOA at the same time of day is why.

Delete Per2 in a mouse and MAOA goes missing during rest, which leaves basal dopamine in the nucleus accumbens elevated (Hampp et al. 2008). The molecule's daily availability is a clock output.

What sleep loss does to it

Added 2026-09-19 from tubbs-mind-after-midnight-2022, which reads the same molecule at the other end of the night. Dopamine peaks in the latter half of the dark period — consistent with the TH/MAOA schedule above — and sleep deprivation reduces available D2 receptors in the ventral striatum.

So the receptor pair below comes apart under a condition people put themselves in routinely. The inhibitory half is the one that thins, which is the molecular version of the behavioural claim in mind-after-midnight-hypothesis: wanting intact, braking degraded.

Two receptors, opposite jobs, both needed

D1R sits on direct-pathway medium spiny neurons, D2R on indirect-pathway ones. Their effects on the clock genes run in opposite directions — the D1R agonist SKF-38393 raises Per1, Clock, Bmal1 and Npas2; the D2R agonist quinpirole lowers Clock and Per1. Neither alone is sufficient: killing dopamine neurons with 6-OHDA abolishes PER2 oscillation, a D2R agonist rescues it, and D1R-null mice have reduced striatal Per2, so normal rhythm needs both.

D2R turns up in a place nobody would look for a reward receptor: it is required for masking, the light-induced suppression of locomotor activity. That is a lighting response, not a reward response.

Not the pleasure molecule

Three things this corpus can now state from a peer-reviewed source rather than from a trade book:

Dopamine's role is described as valence and priority — approach or avoid, and which stimulus goes first — not as the sensation of pleasure.
More dopamine does not mean more pleasure. Lembke's seesaw compresses the relationship past what the literature supports, and she conceded a version of the point publicly.
It is not optional. Mice with TH inactivated in VTA neurons, and mice lacking both D1R and D2R, die early of hypophagia. A system you cannot fast from is a poor candidate for a "dopamine fast," which is the second half of the same objection.

What raises it

Every drug of abuse, licit or illicit, by the chapter's own summary: "Drugs of abuse share one common mechanism: they raise dopamine levels in the brain." Also sugar and fat, ghrelin acting on VTA neurons, mating, and successful social interaction — including, on weaker evidence, the social interaction delivered by a phone.

reward-system · circadian-rhythm · lewis-borrelli-reward-2021 · dopamine-nation · mind-after-midnight-hypothesis · tubbs-mind-after-midnight-2022 · anna-lembke · synthesis