Neuropeptide and Small Transmitter Coexistence: Fundamental Studies and Relevance to Mental Illness

Abstract

Neuropeptides are auxiliary messenger molecules that always co-exist in nerve cells with one or more small molecule (classic) neurotransmitters. Neuropeptides act both as transmitters and trophic factors, and play a role particularly when the nervous system is challenged, as by injury, pain or stress. Here neuropeptides and coexistence in mammals are reviewed, but with special focus on the 29/30 amino acid galanin and its three receptors GalR1, -R2 and -R3. In particular, galanin’s role as a co-transmitter in both rodent and human noradrenergic locus coeruleus (LC) neurons is addressed. Extensive experimental animal data strongly suggest a role for the galanin system in depression–like behavior. The translational potential of these results was tested by studying the galanin system in postmortem human brains, first in normal brains, and then in a comparison of five regions of brains obtained from depressed people who committed suicide, and from matched controls. The distribution of galanin and the four galanin system transcripts in the normal human brain was determined, and selective and parallel changes in levels of transcripts and DNA methylation for galanin and its three receptors were assessed in depressed patients who committed suicide: upregulation of transcripts, e.g., for galanin and GalR3 in LC, paralleled by a decrease in DNA methylation, suggesting involvement of epigenetic mechanisms. It is hypothesized that, when exposed to severe stress, the noradrenergic LC neurons fire in bursts and release galanin from their soma/dendrites. Galanin then acts on somato-dendritic, inhibitory galanin autoreceptors, opening potassium channels and inhibiting firing. The purpose of these autoreceptors is to act as a ‘brake’ to prevent overexcitation, a brake that is also part of resilience to stress that protects against depression. Depression then arises when the inhibition is too strong and long lasting – a maladaption, allostatic load, leading to depletion of NA levels in the forebrain. It is suggested that disinhibition by a galanin antagonist may have antidepressant activity by restoring forebrain NA levels. A role of galanin in depression is also supported by a recent candidate gene study, showing that variants in genes for galanin and its three receptors confer increased risk of depression and anxiety in people who experienced childhood adversity or recent negative life events. In summary, galanin, a neuropeptide coexisting in LC neurons, may participate in the mechanism underlying resilience against a serious and common disorder, MDD. Existing and further results may lead to an increased understanding of how this illness develops, which in turn could provide a basis for its treatment.

Neuropeptide Y Is an Immunomodulatory Factor: Direct and Indirect

“…In the central nervous system (CNS), it is distributed in the hippocampus, cerebral cortex, hypothalamus, thalamus, brain stem, and cerebellum structures ( 2 ). In the peripheral nervous system, NPY is stored in the postganglionic sympathetic nerve, and co-stored and co-released with norepinephrine (NE) ( 3 ). An increasing number of studies have found widespread existence of NPY in peripheral tissues, such as the retina, smooth muscle, intestine, bone marrow, and thymus ( 4 – 7 ).…”

Elimination of galanin synthesis in noradrenergic neurons reduces galanin in select brain areas and promotes active coping behaviors

“…Prior studies using slice electrophysiology show that galanin has an inhibitory effect on LC neuron activity [34,51]. Additionally, it has been suggested that galanin can be released somatodentritically from large dense core vesicles in LC-NE neurons and thereby produce an autoinhibitory effect on LC neuron activity, although this hypothesis has yet to be tested directly [48,52].…”

“…piriform cortex, entorhinal cortex) [30], it is difficult to ascribe phenotypes to the subset of NE neurons that endogenously express galanin. The role of noradrenergic-derived galanin in normal and impaired brain function therefore remains unclear (for reviews see [2, [33][34][35].…”

Neuropeptidergic Control of an Internal Brain State Produced by Prolonged Social Isolation Stress

“…1; van den Pol 2012). Given that the behavior and function of a hardwired circuit can be altered via neuromodulatory control (Marder 2012), and that neuropeptides are able to exert their effects in a diffuse and slow-acting manner, neuropeptidergic signaling provides an attractive mechanism by which internal state conditions can flexibly and dynamically affect behavior (Hökfelt et al 2018).…”