Anxiolytic- and antidepressant-like profiles of the galanin-3 receptor (Gal ₃ ) antagonists SNAP 37889 and SNAP 398299

Abstract

The neuropeptide galanin mediates its effects through the receptor subtypes Gal 1 , Gal 2 , and Gal 3 and has been implicated in anxiety- and depression-related behaviors. Nevertheless, the receptor subtypes relevant to these behaviors are not known because of the lack of available galanin-selective ligands. In this article, we use behavioral, neurochemical, and electrophysiological approaches to investigate the anxiolytic- and antidepressant-like effects of two potent small-molecule, Gal 3 -selective antagonists, SNAP 37889 and the more soluble analog SNAP 398299. Acute administration of SNAP 37889 or SNAP 398299 enhanced rat social interaction. Furthermore, acute SNAP 37889 was also shown to reduce guinea pig vocalizations after maternal separation, to attenuate stress-induced hyperthermia in mice, to increase punished drinking in rats, and to decrease immobility and increase swimming time during forced swim tests with rats. Moreover, SNAP 37889 increased the social interaction time after 14 days of treatment and maintained its antidepressant effects during forced swim tests with rats after 21 days of treatment. In microdialysis studies, SNAP 37889 partially antagonized the galanin-evoked reduction in hippocampal serotonin (5-hydroxytryptamine, 5-HT), as did the 5-HT 1A receptor antagonist WAY100635. Their combination produced a complete reversal of the effect of galanin. SNAP 398299 partially reversed the galanin-evoked inhibition of dorsal raphe cell firing and galanin-evoked hyperpolarizing currents. These results indicate that Gal 3 -selective antagonists produce anxiolytic- and antidepressant-like effects, possibly by attenuating the inhibitory influence of galanin on 5-HT transmission at the level of the dorsal raphe nucleus.

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

“…However, the GalR3 expression is weak and restricted in the rat brain, compared to the GalR1 and the GalR2 subtypes (Wang et al, 1997;Smith et al, 1998; Waters Galanin receptor subtypes in depression-like behavior E Kuteeva et al and Krause, 2000;see O'Donnell et al, 2003). In the DR, presence of the GalR3 receptor was indicated by electrophysiological studies, using selective GalR3 antagonists (Swanson et al, 2005). Thus, the GalR3 antagonist SNAP37889 partially blocked the inhibitory action of galanin on DR neuronal firing and 5-HT release, suggesting that the GalR3 receptor contributes to the inhibitory effects of galanin in the DR.…”

“…However, galanin, as well as galanin-receptor selective ligands may affect depression-like behavior by directly influencing 5-HT neurotransmission. The available data indicate a profound inhibitory effect of galanin on 5-HT transmission under basal conditions, which is probably mediated by the GalR1/GalR3 receptors (Xu et al, 1998a, c;Kehr et al, 2002;Yoshitake et al, 2003;Mazarati et al, 2005;Swanson et al, 2005). The inhibitory effect of galanin on the DR 5-HT system after exposure to stress probably affects galanin receptor-mediated mechanism, since both the neurochemical and behavioral effects of i.c.v.…”

“…Electrophysiological, behavioral, and neurochemical studies have shown that galanin exerts modulatory (mainly inhibitory) effects on both the noradrenergic and serotonergic systems (Seutin et al, 1989;Sevcik et al, 1993;Pieribone et al, 1995;Xu et al, 1998c;Razani et al, 2001;Kehr et al, 2002;see Ö gren et al, 2006). Moreover, in vivo galanin can modulate 5-HT 1A preand postsynaptic receptor functions in an antagonistic manner (see Fuxe et al, 1998;Misane et al, 1998; The action of galanin is mediated via three G proteincoupled receptors, GalR1-GalR3 (see Branchek et al, 2000), which are expressed in the LC, DR, and their projection areas (Xu et al, 1998b, c;O'Donnell et al, 1999;Burazin et al, 2000;Larm et al, 2003;Hawes and Picciotto, 2004;Hawes et al, 2005;Swanson et al, 2005). Among these receptors, GalR1 and GalR3 mainly activate G i/o types of G proteins mediating inhibitory actions of galanin (Habert-Ortoli et al, 1994;Burgevin et al, 1995;Parker et al, 1995;see Branchek et al, 2000).…”

“…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.)…”

“…Recently, both peptidergic and non-peptidergic compounds with relatively high selectivity for galanin receptor subtypes have been developed (Lundström et al, 2005;Swanson et al, 2005;Barr et al, 2006;Sollenberg et al, 2006), allowing studies on selective involvement of galanin receptor subtypes in regulation of physiological functions. For instance, newly developed non-peptide GalR3 antagonists, when given by systemic routes, were shown to have an antidepressant-like activity in behavioral models of anxiety and depression (Swanson et al, 2005;Barr et al, 2006).…”