“The realization that the brain used so many different kind of chemicals, in addition to classical neurotransmitters, to communicate beween neurons was just the first step in a major conceptual shift in neuroscience. Many of these substances are neuropeptides, and most of those affect mood and behavior. The specificity of their effects resides not in the anatomical connectivity between neurons, but in the distribution of receptors within the brain. Different receptors have very different patterns of distribution, and the distributions differ between species in ways that correlate with differences in behavior.
The mere fact of a receptor-peptide mismatch in a particular brain area might have no great importance. It might be that many cells are promiscuous in the receptors that they express: If some receptors see no ligand, the cost to the cells is negligible. Profligate receptor expression might contribute to the evolvability of neural systems, and might be common because organisms with a liberal attitude to receptor expression are those most likely to acquire novels functions. Because extrasynaptic signaling does not require precise point-to-point connectivity, it is intrinsically 'evolvable': a minor mutation in the regulatory region of a peptide receptor gene, by altering the expression pattern, could have functional consequences without any need for anatomical rewiring.
That peptide receptors have distinctive patterns of expression, and that peptides produce coherent behavioral effects when given quite crudely into the brain, suggests that volume transmission is used as a signaling mechanism by many different populations of peptidergic neurons. We thus must see neuropeptides as 'hormones of the brain'.”