A role for galanin in antidepressant actions with a focus on the dorsal raphe nucleus

Abstract

Selective serotonin reuptake inhibitors, such as fluoxetine (FLX), are the most commonly used drugs in the treatment of major depression. However, there is a limited understanding of their molecular mechanism of action. Although the acute effect of selective serotonin reuptake inhibitors in elevating synaptic serotonin concentrations is well known, the clinical amelioration of depressive symptoms requires 14 -21 days of treatment, suggesting that numerous other rearrangements of function in the CNS must take place. In the present study, we demonstrated that 14 days of FLX treatment up-regulated galanin mRNA levels by 100% and GalR2-binding sites by 50%, in the rat dorsal raphe nucleus, where galanin coexists with serotonin. Furthermore, a galanin receptor antagonist, M40, attenuated the antidepressant-like effect of FLX in the forced swim test, a rodent preclinical screen commonly used to evaluate antidepressant-like efficacy. Direct activation of galanin receptors by a galanin receptor agonist, galnon, was found to produce an antidepressant-like effect in the same task. Two other antidepressant treatments also affected the galaninergic system in the monoaminergic nuclei: Electroconvulsive shock elevated galanin mRNA levels in dorsal raphe nucleus, whereas sleep deprivation increased galanin mRNA levels in the locus coeruleus, further underlining the connection between activation of the galaninergic system and antidepressant action of various clinically proven treatments. O ur understanding of the molecular mechanism of action of fluoxetine (FLX), beyond its effect of elevating synaptic serotonin [5-hydroxytryptamine (5-HT)] concentration, is limited. The delay in the onset of clinical antidepressant effect suggests that transcriptional and translational events, leading to functional changes in signaling within the major serotoninergic nucleus dorsal raphe nucleus (DRN) and in its projection areas, may be required for these therapeutic effects (1-3). One potential player in mediating the long-term effects of FLX, besides 5-HT, is the neuropeptide galanin. Galanin, through its three G-protein-coupled receptors, GalR1, GalR2, and GalR3 (4), regulates homeostatic and motivated behaviors including pain perception, sleep, food intake, sexual activity, learning, and memory (5). Galaninergic transmission modulates the activity of monoaminergic neurons in the ventral tegmental area, DRN, and locus coeruleus (LC) (6-10). Galanin receptor subtypes GalR1 (7) and GalR2 are expressed in DRN neurons (11) that can be activated by galanin dendritically released from the dorsal raphe 5-HT neurons (9, 12) or from surrounding galanin immunoreactive terminals (7). In the noradrenergic nucleus LC, an area that is closely connected both structurally and functionally to DRN (13,14), GalR1 expression is induced by morphine withdrawal (15), and the galanin receptor agonist, galnon, was shown to attenuate several withdrawal signs (16). It is worth noting that drug withdrawal often precipitates symptoms of depression, and depression is a ...

Differential Role of Galanin Receptors in the Regulation of Depression-Like Behavior and Monoamine/Stress-Related Genes at the Cell Body Level

“…infusion of AR-M1896. Importantly, our results support recent data showing that repeated fluoxetine treatment upregulates GalR2 binding sites in the DR and thus un antidepressive role of the GalR2 (Lu et al, 2005a).…”

“…In contrast, the GalR2(R3) agonist AR-M1896 decreased immobility, similar to fluoxetine, and, importantly, the GalR2 antagonist M871 increased immobility time in the FST. The latter finding supports the hypothesis that stimulation of the GalR2 receptor has an antidepressant-like effect, in agreement with the study by Lu et al (2005a). The results with the GalR2 antagonist indicate that there exists a tonic activation of the GalR2 receptor under in vivo conditions of the forced swim, which is sufficiently strong to have physiological consequences.…”

“…In fact, the current pharmacotherapy of depression is also mainly based on use of compounds correcting dysfunctions in monoaminergic transmission, including selective serotonin reuptake inhibitors (SSRIs) (see Frazer, 1997;Millan, 2004). However, recent studies have also implicated several neuropeptides in the pathophysiology of depression and in the action of antidepressant drugs (see Heilig, 2004;Lu et al, 2005aLu et al, , 2007Nikisch et al, 2005;Ö gren et al, 2006).…”

“…A number of behavioral studies suggested a potential role of galanin in depression-like behavior in rodents (see Fuxe et al, 1998;Weiss et al, 1998Weiss et al, , 2005Yoshitake et al, 2004;Kuteeva et al, 2005Kuteeva et al, , 2007Lu et al, 2005aLu et al, , 2007Swanson et al, 2005;Barr et al, 2006;Karlsson and Holmes, 2006;Ö gren et al, 2006). Bilateral infusion of galanin into the ventral tegmental area (VTA) (Weiss et al, 1998), or intracerebroventricular (i.c.v.)…”

GAL 3 receptor KO mice exhibit an anxiety-like phenotype

“…Thus, i.p. administration of the GAL agonist galmic, which displays low affinity for the GAL 1 receptor, and of the nonselective agonist galnon, which also acts via non-GAL receptors, induced a decrease in immobility time in the FST in rats (36,37). There is also evidence for an antidepressant-like effect of GAL in men, as measured by the Hamilton Depression Rating Scale, and a suppression of rapid eye movement sleep after i.v.…”