NE
Red: theory; black, fact.
“Life is Difficulty”
The basic theory
I conjecture that the primordial function of any type of transmitter substance acting on the g-protein-coupled cell-surface receptors or nuclear receptors of neurons was to coordinate the whole-organism response to some class of perils.
Complications
Glutamate, GABA, and acetylcholine are usually considered neurotransmitters, not neuromodulators, but all three have G-protein-coupled receptors in addition to ionotropic receptors and are thus both.
In thermoregulation, hypothalamic glutamate and GABA act on the body via the serotonergic raphe pallidus nuclei. The implied connection with predation (See table) would be due to the fact that animals become torpid at extremes of temperature and thus easy prey. The larger predator would have a smaller surface to volume ratio and thus slower warming and cooling after leaving its refugium to hunt. The predator thermal advantage would have been the selection pressure for thermal sensitivity in the anti predation system, which eventually became upstream of temperature regulation effectors generally.
The functional assignments suggested in Table 1 would mostly pertain to a very primordial brain. The implication is that any modern biological function of the neuromodulator substance other than organizing the response to a specific type of peril was elaborated out of the primordial function over long-term evolution, which can act opportunistically to confer new functions on preexisting adaptations.
An example of such elaboration is shown for dopamine in the inferred social role. A pre-adaptation for this role split may have been breast-feeding.
Table 1.
| Peril | Substance | Failure mode |
| Extremes of heat and cold | glutamate and GABA | ? |
| Predator | serotonin | depression |
| Parasite | histamine | phobia |
| Rival conspecific | noradrenaline | paranoia |
Social isolation |
