When we compared the effects in

When we compared the effects in FST induced by GAL and GAL(1–15), we observed that the increase in the immobility induced by GAL(1–15) was significantly higher than the one induced by GAL (Millon et al., 2015). Moreover, in climbing behaviour, GAL(1–15) also induced a stronger decrease in climbing response compared with GAL (Millon et al., 2015). In the open field test and in the light-dark box (Prut and Belzung, 2003), we observed that only GAL(1–15) and not GAL modifies the anxiety parameters (Millon et al., 2015) (Table 1). GAL produced anxiolytic-like effects only in animals tested under heightened stress conditions (Barrera et al., 2005, Millon et al., 2015), on contrary, GAL(1–15) induced an anxiogenic-like effect without a stress situation (Millon et al., 2015).
Effects of Galanin on monoamine systems The physiological/pathophysiological mechanisms underlying the action(s) of GAL most probably involves modulation of monoaminergic systems, in particular, the LC and DR nuclei. This was further supported by the fact that all three receptors are found in the DR and LC of rats (O'Donnell et al., 1999, Burazin et al., 2000, Mennicken et al., 2002) and that GAL is co-expressed in almost 40% of the serotonergic neurons in the DR (Xu and Hokfelt, 1997) and in around 80% of the noradrenergic neurons in the LC (Holets et al., 1988). I.c.v. GAL produced a reduction in basal NA release in the ventral hippocampus of the awake rat measured by microdialysis, and, significantly attenuated the increase of extracellular hippocampal NA levels evoked by desipramine (Yoshitake et al., 2003). These effects could involve the LC since GAL inhibits LC firing and produces an outward current in rat brain slices through GAL1–3 receptors. The application of GAL1–3 receptor agonist M961, but not GAL2 receptor agonist AR-M1896, caused hyperpolarisation of these LC neurons (Seutin et al., 1989, Sevcik et al., 1993, Pieribone et al., 1995, Ma et al., 2001). Moreover, Grenhoff et al. (1993) observed that “burst” firing of LC neurons (i.e., rapid firing of LC) released GAL from terminals on Cinobufagin of LC neurons projecting to the VTA, and that the hyperpolarizing influence of GAL on dopamine (DA) cell bodies in the VTA decreased the activity of these DA neurons. This finding suggested that the hyperactivity of LC neurons observed in depression might bring about such depression-related responses by decreasing the neural activity of dopaminergic cell bodies in the VTA as the result of GAL released from LC-derived terminals in the VTA (Weiss et al., 1998). In relation with the DR and the 5-HT system, i.c.v. GAL reduced 5-HT metabolism in ventral limbic cortex, hippocampal formation, and fronto-parietal cortex probably via direct inhibitory action on DR nerve cells reducing their firing rates (Fuxe et al., 1988b). This result is in agreement with other works where i.c.v. GAL into vicinity of the DR caused a dose-related and long-lasting inhibition of 5-HT release in the ventral hippocampus measured by microdialysis (Kehr et al., 2002). Moreover, immunohistochemistry experiments showed a strong GAL immunoreactivity staining was observed in the DR after GAL administration, suggesting that the DR was the site of action of GAL on hippocampal 5-HT release (Kehr et al., 2002). In agreement, i.c.v. GAL attenuates the increase in extracellular levels of 5-HT induced by SSRI citalopram, indicating that this inhibitory action persisted under conditions of serotonergic activation following reuptake inhibition by an SSRI (Yoshitake et al., 2003, Kuteeva et al., 2008). Electrophysiological experiments, where GAL inhibits the firing rate of 5-HT neurons, probably via G protein-coupled inwardly-rectifying potassium channel (GIRK) (Xu et al., 1998), could support these findings. The 5-HT1A receptor seems to be a key receptor in the GALR-5-HT interaction. In the DR, i.c.v. GAL induced a time-dependent reduction in affinity and an increase in the 5-HT1A autoreceptor density (Razani et al., 2000). At post-synaptic level GAL reduced the affinity of the 5-HT1A receptors in the ventral limbic cortex (Fuxe et al., 1988a, Hedlund and Fuxe, 1996). Moreover, in hypothermia, locomotor activity and passive avoidance, i.c.v. GAL blocked post-synaptic 5-HT1A receptor function (Misane et al., 1998, Razani et al., 2001, Kehr et al., 2002). This interaction can in part be due to the existence of GAL1-5-HT1AR heteroreceptor complexes in discrete brain regions (Borroto-Escuela et al., 2010).