The chocoholic receptor?

Bingeing on chocolate — sometimes it refreshes the parts that other foods cannot reach. From Samuel Pepys, who noted his daily draught of chocolate in his seventeenth-century diary, to Henri de Toulouse-Lautrec, whose passion is said to have extended to inventing the chocolate mousse, most of us have experienced the rewards that overdosing on chocolate can bring. Several components of chocolate are potentially mood altering, including the 'trace amine' tyramine. Trace amines are closely related to biogenic amines, such as the classical neurotransmitters serotonin (5-HT), dopamine and noradrenaline, but are found at much lower levels in the body. Now, a study published in the Proceedings of the National Academy of Sciences, which reports the discovery of the first family of vertebrate G-protein-coupled receptors (GPCRs) for the trace amines, might explain how these molecules could mediate the addictive effects of chocolate. Much more importantly, the finding that trace amines are able to activate their own class of receptors indicates that, rather than simply interfering with neurotransmission by other biogenic amines, trace amines might be able to function as neurotransmitters in their own right. Trace-amine levels are known to be altered in a number of psychiatric disorders, and this makes their new receptors potentially exciting therapeutic targets.

Trace amines are hard to study, partly because of their low concentrations in the body. GPCRs for trace amines have long been known to exist in invertebrates, but no mammalian forms of such receptors had been found. Borowsky et al. discovered the new family of trace-amine receptors, which they named TA_1–15, while searching for new members of the 5-HT receptor family. By amplifying genomic DNA from humans, rats and mice using 'degenerate' primers in polymerase chain reactions — a technique that would allow the authors to find closely related DNA sequences — they hoped to fish out new 5-HT receptors that shared transmembrane domains with the 5-HT₁ receptor. Instead, they purified a group of 15 highly homologous receptors, some of which, on expression, were activated by trace amines, but not by 5-HT. Four of these TA receptors were identified in humans, and of these, only TA₁ seemed to be fully functional, responding most strongly to tyramine and β-phenylethylamine, two trace amines that are linked with depression and schizophrenia.

In the central nervous system, TA₁ is relatively heavily expressed in monoaminergic neurons in the dorsal raphe, locus coeruleus and ventral tegmental area — brain regions involved in mood regulation. The relatively strong level of expression of TA₁ in kidney might also help to explain why ingested trace amines can affect blood pressure: tyramine-containing foods such as cheese, red wine and chocolate are known to cause headaches in a subset of migraine patients, and to cause hypertension in those taking monoamine-oxidase-inhibitor antidepressants. And as for chocoholics? TA₁ is most concentrated in the amygdala, an area that is key to the associative processes, some leading to the emotional aspects of food reward, and others leading to dependence itself. It might, therefore, be the point at which chocolate works its own brand of magic.