The effects of galanin on anxiety

The effects of galanin on anxiety may depend on the site of drug administration, on the galanin receptor subtypes activated and on the animal models of anxiety employed (Barrera et al., 2005, Holmes and Picciotto, 2006, Soares et al., 2016a, Soares et al., 2016b). For instance, administration of galanin in the central amygdala induced an anxiogenic-like effect in rats evaluated in a modified Vogel test but not in the elevated plus-maze (EPM) (Moller et al., 1999). Infusion of galanin in the dorsal periaqueductal grey (Soares et al., 2016a, Soares et al., 2016b) or in the dorsal raphe nucleus (DRN) (Silote et al., 2013) impaired inhibitory avoidance of rats in the elevated T-maze, suggesting an anxiolytic-like effect. Additionally, intra-DRN administration of a selective GAL1 agonist (M617) enhanced anxiety-like behaviour in rats tested in the elevated T-maze, while administration of a preferential GAL2 agonist (AR-M1896) reduced this behaviour (Morais et al., 2016). Although some studies have implicated galanin in the modulation of learning, memory, neuroprotection and epilepsy (Elliott-Hunt et al., 2004, Mazarati et al., 2006, Mazarati and Lu, 2005, Ögren et al., 1998, Schott et al., 2000) in the hippocampus, to our knowledge, no previous study examined if this neuropeptide also affects anxiety-like behaviours in the dorsal hippocampus. The well-known involvement of dorsal hippocampus in memory and learning processes outshined its participation in anxiety (Graeff, 1997). Nevertheless, results from anatomical, behavioural and pharmacological studies support the role of dorsal hippocampus in modulating anxiety (Andrade et al., 2013, File et al., 2000). For instance, the dorsal hippocampus receives noradrenergic and serotonergic inputs from locus coeruleus (Page and Abercrombie, 1999) and from median raphe nucleus (Azmitia, 1981), respectively. Exposure to aversive stimuli increased noradrenaline and serotonin (Kalén et al., 1989) while exposure to novelty increased Merimepodib sale in the hippocampal formation (Giovannini et al., 2001). The infusion of 8-OH-DPAT, a 5-HT1A receptor agonist, in the dorsal hippocampus facilitated inhibitory avoidance acquisition in rats tested in the elevated T-maze (Dos Santos et al., 2008). Also, temporary pharmacological inhibition of neurons from dorsal hippocampus enhanced anxiety-like behaviours in rats tested in the elevated plus-maze (Zhang et al., 2014). The presence of galanin and its receptors, as well as its ability to regulate the release of neurotransmitters in the hippocampus, suggests that galanin signalling may also modulate behaviours related to anxiety in this brain region. Galanin immunoreactivity and binding sites have been demonstrated in the hippocampal formation, especially in the dorsal dental gyrus (Skofitsch and Jacobowitz, 1986, Xu et al., 2005). The hippocampus expresses at least GAL1 and GAL2 receptors, although GAL2 is the most abundant galanin receptor in the dorsal hippocampus (O’Donnell et al., 1999, Lu et al., 2005). Most galanin-positive fibres in the dorsal hippocampus overlap with noradrenergic terminals originating in the locus coeruleus (Xu et al., 1998). Additionally, galanin raises acetylcholine levels in the dorsal hippocampus, likely through GAL2 receptor activation (Ögren et al., 1998, Yoshitake et al., 2011). Thus, we investigated whether infusion of galanin in the dorsal hippocampus mediates anxiety-like behaviours in rats. For this purpose, we chose a widely used behavioural test, the EPM, to evaluate anxiety-related drug effects (Walf and Frye, 2007). Additionally, using a pharmacological approach, we examined the involvement of GAL2 receptors in the anxiogenic-like effect of galanin in the dorsal hippocampus. Although the selectivity of peptidergic galanin receptor ligands is a matter of concern (Kuteeva et al., 2008), in vitro and in vivo studies support the view that M871 acts as a GAL2 antagonist (Liu et al., 2001, Lundström et al., 2005, Sollenberg et al., 2006). First, we evaluated if M871 administered in the dorsal hippocampus would affect the anxiety-like behaviour of rats in the EPM. Finally, we tested whether pretreatment with the GAL2 antagonist M871 would block the anxiogenic-like effect of galanin in the dorsal hippocampus.