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Galanin enhances and a galanin antagonist attenuates depression-like behaviour in the rat

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Abstract

The effect of intracerebroventricular infusion of galanin and/or the galanin antagonist M35 was studied in the forced swim test. Animals were pre-exposed to water for 15 min 24 h prior to test. Immobility and climbing were assessed during the second, 5 min exposure to water. Rats receiving a single infusion of galanin (3 nmol) displayed a significant increase of immobility. This effect was blocked by co-administration of M35 (1 nmol). M35 alone (1 nmol) produced a significant decrease of immobility. The results further support the hypothesis that galanin may play a role in mood disorders, and that galanin antagonists may represent new candidates for antidepressant treatment.

Introduction

A large body of evidence suggests that dysfunctions of brain serotonin (5-hydroxytryptamine, 5-HT) and noradrenaline (NA) neurones are involved in the aetiology of depressive disorders and in the action of antidepressant drugs (see Heninger et al., 1996). The mechanisms behind the dysfunction of (mono)aminergic neurotransmission in depression are still largely unknown. However, it is clear that both genetic and traumatic events contribute to the development of mood disorders (see Nestler et al., 2002). In this context, the neuropeptides which have the ability to act as modulators of monoaminergic systems and are sensitive to stress are of particular interest.

Both indirect and direct evidence suggest a role of the neuropeptide galanin (Tatemoto et al., 1983) in the regulation of brain 5-HT and NA systems implicated in depression (see Fuxe et al., 1998, Ögren et al., 1998). In the CNS, galanin coexists with NA in the locus coeruleus (LC) and 5-HT in the dorsal raphe (DR) nuclei (Melander et al., 1986, Xu et al., 1998b, Xu et al., 1998c), which extensively innervate the limbic forebrain and cortex (Dahlström and Fuxe, 1964). Galanin signalling can affect NA and 5-HT neurotransmission, since galanin receptors GalR1-GalR3 (see Branchek et al., 2000) are expressed in the LC and DR, as well as in their projection areas (see O'Donnell et al., 2003). Intracerebroventricular (i.c.v.) administration of galanin to the rat has shown that galanin is a potent and long-lasting inhibitor of 5-HT release in the projection areas, such as the hippocampus (Kehr et al., 2002). This inhibitory action on basal 5-HT release is probably related to activation of galanin receptors at the level of the DR, since galanin enhances an outward current in the 5-HT DR neurones (Xu et al., 1998c). In addition, i.c.v. galanin also modulates the DR 5-HT1A autoreceptors, which probably contribute to the inhibitory action of galanin on 5-HT synthesis and release (Razani et al., 2000). In the 5-HT terminal areas, i.c.v. galanin blocks 5-HT1A-mediated responses, suggesting that galanin regulates the postsynaptic 5-HT1A receptor in an antagonistic manner (Misane et al., 1998, Razani et al., 2001, Kehr et al., 2002).

Previous studies have shown that bilateral injection of galanin into the ventral tegmental area (but not i.c.v.) significantly increased immobility in the forced swim test (FST), while the galanin antagonist M15 (galanitide) produced an antidepressant-like effect (Weiss et al., 1998, Weiss et al., 2005). Also, recently developed non-peptide antagonists selective for the GalR3 receptor have shown antidepressant-like activity in several animal models (Swanson et al., 2005). Moreover, transgenic mice overexpressing galanin under the PDGF-B promoter display an increased immobility in the FST, indicative of depression-like behaviour (Kuteeva et al., 2005). In contrast, decreased immobility time in the FST in rats after systemic treatment with the synthetic non-peptide galanin agonists galmic and galnon has been reported (Bartfai et al., 2004, Lu et al., 2005), suggesting an antidepressant-like effect of galanin receptor stimulation.

In order to re-examine the contradictory results on the role of galanin in depression-like behaviour, we have studied the effect of i.c.v. administration of galanin and/or the putative galanin antagonist M35 (see Bartfai et al., 1992) on behaviour in the FST, using rats. Sub-chronic treatment with the antidepressant drugs desipramine and fluoxetine was used as a positive control.

Section snippets

Animals

Seventy-six adult male Sprague–Dawley rats (Scanbur, Sollentuna, Sweden), weighing 290–320 g at the time of surgery, were used in the experiments. The rats were housed in groups of four in standard plastic cages (Type IV Makrolon®) in a colony room under standardised conditions (12 h light/dark cycle (lights on at 07:00), temperature of 19 ± 0.5 °C and 40–50% relative humidity). Food and water were provided ad libitum. All animals were treated according to guidelines approved by a local ethics

Results

Depression-like behaviour was assessed during the second exposure to the water (5 min). Galanin-, galanin/M35- and M35-treated groups had independent aCSF-treated control groups. However, ANOVA did not find any significant difference for either immobility (F2,19 = 0.72, p = 0.49) or climbing (F2,19 = 0.18, p = 0.83) time for the three different control groups, and the data were pooled to create a single control group. An overall ANOVA revealed a significant effect of treatment for the peptide-injected

Discussion

The present results show that i.c.v. galanin administration results in an increase of immobility time in the FST in the rat, probably mediated by galanin receptors, since it was blocked by the galanin antagonist M35. Importantly, M35 alone showed an antidepressant-like effect, decreasing the time of immobility. Finally, the selective NA reuptake inhibitor (SNRI) desipramine and the selective 5-HT re-uptake uptake inhibitor (SSRI) fluoxetine decreased the time of immobility in agreement with

Conclusion

Taken together, the results support an involvement of brain galanin systems in depression-like behaviour in rodents, and that galanin might be involved in maladaptive reactions to inescapable stress, e.g. deficit in coping behaviour. The available data strongly suggest that GalR1 and GalR3 antagonists may have antidepressant properties. In addition, further studies are needed to define a potential role of GalR2 agonists as ‘enhancers’ of serotonergic transmission in the treatment of depression.

Acknowledgements

This study was supported by The Swedish Research Council (Grant number 04X-11588, 04X-2887), The Marianne and Marcus Wallenberg Foundation, Wallenberg Consortium North, Karolinska Institutet Funds and an EC Grant (NEWMOOD; LHSM-CT-2003-503474).

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