Recent Updates on The Role of Galanin and Its Receptors in Regulating Depressive Symptoms

Galanin (GAL) is a 29-amino acid neuropeptide that is co-expressed with neurotransmitters and neuropeptides, such as serotonin (5-HT), norepinephrine (NE), dopamine, and neuropeptide Y. GAL regulates various activities through three different G protein-coupled receptors (GalR1- 3) and plays an important role in mental diseases, including depression. GAL and its receptors have been regarded as a possible therapeutic target for depression for a long time; however, there are still no widely used GAL-type antidepressants. Presently, various studies have revealed the link between the GAL system and depression. Activation of GalR1 and GalR3 induced depression-like behavior, and activation of GalR2 inhibited depression. GalR1 activation may induce depression-like behavior by inhibiting serotoninergic neurons in the dorsal raphe nucleus, noradrenergic neurons in the locus coeruleus, and glutamatergic neurons in the ventral periaqueductal gray and prefrontal cortex. GalR3 activation may induce depression-like behavior by inhibiting serotoninergic neurons in the dorsal raphe nucleus. GalR2 activation may reduce depression by activating serotoninergic neurons in the dorsal raphe nucleus and increasing the level of 5-HT. GAL N-terminal fragment GAL (1-15) mediates a stronger effect of regulating depression than GAL by causing an imbalance of receptor signal through the GalR1-GalR2 heteromer. Conversely, GAL (1-15) can enhance the antidepressant effect of 5-HT1A receptor agonists or selective serotonin reuptake inhibitors by its GalR1-GalR2 heteromer interacting with 5-HT1A receptors or forming GalR1-GalR25-HT1AR heterotrimer. Besides the 5-HT system, GAL and its receptors can also interact with NE, neuropeptide Y, brain-derived neurotrophic factor, and dopamine to regulate depression. Although GAL and its receptors show great potential as a target for the treatment of depression, their regulatory effects on depression are different in different brain regions, and the mechanisms remain unknown. The development of GAL-type antidepressants also needs to be optimized. The following questions need to be addressed: first, whether the specific agonist SG2A for GALR2, which has a good antidepressant effect, will affect normal cognitive and emotional functions need to be explored. Second, as GAL and its receptors may have distinct sex-related effects, future research should distinguish the sex-related differences of GAL and its receptors on depression and further develop antidepressants accordingly. Third, and most important, in addition to designing agonists or antagonists targeting GAL receptors, the following will be of great significance for developing new antidepressants, enhancing the effects of traditional antidepressants, and improving their side effects: targeting enzymes that catalyze either the production of GAL (1-15) or GAL (1-16) or N-linked glycosylation and intracellular phosphorylation of GAL receptors, or factors affecting the formation of GalR1-GalR2 heteromer or GalR1-GalR2-5-HT1AR heterotrimer. This article reviews the regulatory effects of GAL and its receptors on depression, explores its possible mechanisms for regulating depression, and discusses the possibility of clinical application of antidepressant drugs developed for GAL and its receptors.