New therapeutic target for depression identified

Summary: A fragment of the neuropeptide Galanin appears to play a role in anhedonia in mouse models of depression. Galanin could be a potential target for the treatment of depression.

Source: University of Malaga

Depression is one of the most widespread disorders that affects society, according to the World Health Organization. In fact, it is estimated that 4 million people are affected in Spain.

There are different pharmacological treatments for depression, mainly therapies that act on the serotonin system -the so-called SSRIs (selective serotonin reuptake inhibitors). However, it has been evidenced that these antidepressants take around two weeks to have an effect and, what’s more, around 30% of patients are resistant to this drug.

Researchers of the Department of Human Physiology of the UMA Faculty of Medicine have taken a step closer to a new therapeutic target to face this mental disorder.

Particularly, the group of “Neurochemistry of the Transmission in the Central Nervous System”, co-directed by Professor Zaida Díaz-Cabiale, has evidenced that a fragment of the “Galanin” neuropeptide -an endogenous molecule of the brain- is involved in anhedonia, which is the loss of the capacity to feel pleasure in daily activities, for instance, meals, social activity or sex, and, thus, one of the main symptoms in depressed patients.

These researchers have demonstrated for the first time the role of “GAL (1-15)” in the brain reward system of an animal model.

“We have verified through different experiments how animals modify their response to high-reinforcement appetitive stimuli, such as saccharine or sexual attraction, after the administration of the Galanin fragment”, explains researcher Carmelo Millón, one of the authors of this study, published in Journal of Psychopharmacology.

A depressed man is shown here

These researchers have demonstrated for the first time the role of “GAL (1-15)” in the brain reward system of an animal model. The image is in the public domain.

Furthermore, in this article, in which a researcher of Karolinska Institute (Sweden) has participated, they have analyzed the brain reinforcement system at a molecular level, the circuit in charge of reinforcing positive behavior for individuals and species, and reaffirmed that the Galanin fragment acts directly on this neurological mechanism, reducing the circuit activity.

According to Millón, describing this fragment is essential to modulate the brain reward circuit, having interesting applications that go beyond treatments for depression, such as its possible use in drug-related addictions. “The understanding of these mechanisms opens the way for endless therapeutic strategies, hence its importance”, he says.

The research group of “Neurochemistry of the Transmission in the Central Nervous System” has been studying the Galanin molecule for more than two decades, originally in cardiovascular regulation. Its role in neuropsychiatric diseases, such as depression or anxiety, started to be investigated in the UMA in 2007.

About this neuroscience research article

Source:
University of Malaga
Media Contacts:
Maria Guerrero – University of Malaga
Image Source:
The image is in the public domain.

Original Research: Closed access
“Role of the galanin N-terminal fragment (1-15) in anhedonia: Involvement of the dopaminergic mesolimbic system”. Millón C, Flores-Burgess A, Gago B, Alén F, Orio L, García-Durán L, Narváez JA, Fuxe K, Santín L, Díaz-Cabiale Z.
Journal of Psychopharmacology. doi:10.1177/0269881119844188

Abstract

Role of the galanin N-terminal fragment (1-15) in anhedonia: Involvement of the dopaminergic mesolimbic system

Background:
Anhedonia is a core feature of depressive disorders. The galanin N-terminal fragment (1-15) plays a role in mood regulation since it induces depression and anxiogenic-like effects in rats. In this study, we analysed galanin N-terminal fragment (1-15) actions in anhedonic-like behaviours in rats using operant and non-operant tests and the areas involved with these effects.

Methods:
Galanin N-terminal fragment (1-15) effects were analysed in saccharin self-administration, sucrose preference, novelty-suppressed feeding and female urine sniffing tests. The areas involved in galanin N-terminal fragment (1-15)-mediated effects were studied with positron emission tomography for in vivo imaging, and we analysed the ventral tegmental area and nucleus accumbens. Galanin N-terminal fragment (1-15) had effects on the mRNA expression of the dopamine transporters Dat and Vmat2; the C-Fos gene; the dopamine receptors D1, D2, D3, D5; and the galanin receptors 1 and 2.

Results:

Galanin N-terminal fragment (1-15) at a concentration of 3 nmol induced a strong anhedonia-like phenotype in all tests. The involvement of galanin receptor 2 was demonstrated with the galanin receptor 2 antagonist M871 (3 nmol). The 18F-fluorodeoxyglucose positron emission tomography images indicated the action of galanin N-terminal fragment (1-15) over several nuclei of the limbic system. Galanin N-terminal fragment (1-15)-mediated effects also involved changes in the expression of Dat, Vmat2, D3 and galanin receptors in the ventral tegmental area as well as the expression of C-Fos, D1, D2 and D3 and TH immunoreactivity in the nucleus accumbens.

Conclusions:

Our results indicated that galanin N-terminal fragment (1-15) exerts strong anhedonic-like effects and that this effect was accompanied by changes in the dopaminergic mesolimbic system. These results may provide a basis for the development of novel therapeutic strategies using galanin N-terminal fragment (1-15) analogues for the treatment of depression and reward-related diseases.

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