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Galanin (1–15) enhances the antidepressant effects of the 5-HT1A receptor agonist 8-OH-DPAT: involvement of the raphe-hippocampal 5-HT neuron system

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Abstract

Galanin N-terminal fragment (1–15) [GAL(1–15)] is associated with depression-related and anxiogenic-like effects in rats. In this study, we analyzed the ability of GAL(1–15) to modulate 5-HT1A receptors (5-HT1AR), a key receptor in depression. GAL(1–15) enhanced the antidepressant effects induced by the 5-HT1AR agonist 8-OH-DPAT in the forced swimming test. These effects were stronger than the ones induced by Galanin (GAL). This action involved interactions at receptor level since GAL(1–15) affected the binding characteristics and the mRNA levels of 5-HT1AR in the dorsal hippocampus and dorsal raphe. The involvement of the GALR2 was demonstrated with the GALR2 antagonist M871. Proximity ligation assay experiments indicated that 5-HT1AR are in close proximity with GALR1 and GALR2 in both regions and in raphe RN33B cells. The current results indicate that GAL(1–15) enhances the antidepressant effects induced by 8-OH-DPAT acting on 5-HT1AR operating as postjunctional or as autoreceptors. These results may give the basis for the development of drugs targeting potential GALR1–GALR2–5-HT1AR heteroreceptor complexes linked to the raphe-hippocampal 5-HT neurons for the treatment of depression.

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Acknowledgments

This study was supported by the Junta de Andalucia CVI-6476, UMA PP-05, PP-13, TV3-Marató 090130/31/32 and by and by the Swedish Royal Academy of Sciences (Stiftelsen B. von Beskows Fond and Stiftelsen Hierta-Retzius stipendiefond) and Karolinska Institutets Forskningsstiftelser 2012 and 2013 to D.O.B-E, by Grants from the Swedish Medical Research Council (04X-715), and Hjärnfonden 2012 to K.F.

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  1. Universidad de Málaga, Instituto de Investigación Biomédica de Málaga, Facultad de Medicina, Departamento de Fisiología, Campus de Teatinos s/n, 29071, Málaga, Spain

    Carmelo Millón, Antonio Flores-Burgess, Manuel Narváez, Belen Gago, José Angel Narváez & Zaida Díaz-Cabiale

  2. Department of Neuroscience, Karolinska Institute, Stockholm, Sweden

    Dasiel O. Borroto-Escuela & Kjell Fuxe

  3. Universidad de Málaga, Instituto de Investigación Biomédica de Málaga, Facultad de Psicología, Departamento de Psicobiología, Campus de Teatinos s/n, 29071, Málaga, Spain

    Luis Santín

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  1. Carmelo Millón
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Millón, C., Flores-Burgess, A., Narváez, M. et al. Galanin (1–15) enhances the antidepressant effects of the 5-HT1A receptor agonist 8-OH-DPAT: involvement of the raphe-hippocampal 5-HT neuron system. Brain Struct Funct 221, 4491–4504 (2016). https://doi.org/10.1007/s00429-015-1180-y

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