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

Abstract

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.

Serotonin Heteroreceptor Complexes and Their Integration of Signals in Neurons and Astroglia—Relevance for Mental Diseases

“…However, it is important to notice that anhedonia-like behavior, demonstrated e.g., in saccharin self-administration and sucrose preference test after i.c.v. injection of Gal (1-15), was counteracted by the GalR2 antagonist M871 [46]. These results can best be interpreted by assuming that the GalR1-GalR2 heterocomplexes are mainly located on the GABA VTA interneurons innervating the VTA DA neurons.…”

“…As to a leading role of GalR2 vs. the GalR1 protomer in this regulation of the VTA DA neurons, it was found that Gal (1-15) reduced the mRNA expression of the DA transporter and vesicular monoamine transporter 2 that also reflect an increased GABA inhibition of the VTA DA neurons. Instead, there was a significant increase in the mRNA expression of D3R in the VTA by Gal (1-15) which can be explained by the fact that the D3R can operate mainly as an auto-receptor in VTA [46]. The results are compatible with the view that the VTA GalR2 protomer upon activation by Gal (1-15) induced an activation of the GABA interneurons causing inhibition of the VTA DA neurons leading to anhedonia-like behavior and a neurochemical down regulation of the meso-limbic DA reward neurons [46].…”

“…Instead, there was a significant increase in the mRNA expression of D3R in the VTA by Gal (1-15) which can be explained by the fact that the D3R can operate mainly as an auto-receptor in VTA [46]. The results are compatible with the view that the VTA GalR2 protomer upon activation by Gal (1-15) induced an activation of the GABA interneurons causing inhibition of the VTA DA neurons leading to anhedonia-like behavior and a neurochemical down regulation of the meso-limbic DA reward neurons [46]. These results are supported by the observations of a reduction of the mRNA levels of DAT and vesicular monoamine transporter 2 after Gal (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15) treatment.…”

“…Gal (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15) and Its Modulation of the Meso-Limbic DA Reward Neurons Causes Anhedonia It is of high interest that Millon et al [46] found that Gal (1-15) fragment given i.c.v. can cause anhedonia based especially on studies on saccharin self-administration and sucrose preference tests.…”

“…Activation of the GABA interneurons by GalR2 can then lead to inhibition of the VTA DA neurons contributing to anhedonia-like behavior. The blockade of the GalR2 by the antagonist can then cause a return of the activity in the VTA-limbic-cortical DA neurons which counteracts the anhedonia-like behavior [46]. As to a leading role of GalR2 vs. the GalR1 protomer in this regulation of the VTA DA neurons, it was found that Gal (1-15) reduced the mRNA expression of the DA transporter and vesicular monoamine transporter 2 that also reflect an increased GABA inhibition of the VTA DA neurons.…”