Abstract
The FGFR1-5-HT1A heteroreceptor complexes are involved in neuroplasticity in the rat hippocampus and in the mesencephalic raphe 5-HT nerve cells. There exists a 5-HT1A protomer enhancement of FGFR1 protomer signaling. Acute and 10 day treatment with intracerebroventricular (i.c.v.) FGF-2 and the 5-HT1A agonist 8-OH-DPAT produced enhanced antidepressant effects in the forced swim test (FST). We studied in the current work the disturbances in the FGFR1-5-HT1A heterocomplexes in a genetic rat model of depression, the Flinders sensitive line (FSL) rats of Sprague-Dawley (SD) origin, by means of neurochemical, neurophysiological and behavioral techniques. In control SD rats, the FGFR1 agonist SUN11602 and FGF2 produced a significant reduction of G protein-coupled inwardly rectifying K+ channel (GIRK) currents induced by 8-OH-DPAT in the CA1 area of the hippocampus. In FSL rats, only i.c.v. 8-OH-DPAT alone treatment produced a significant reduction in the immobility time. The combined i.c.v. treatment (FGF2 + 8-OH-DPAT) in FSL rats did not cause a significant decrease in immobility time in the FST. However, in the SD rats this combined treatment produced a significant reduction. Furthermore, in the FSL rat a significant increase in the density of FGFR1-5-HT1A proximity ligation assay (PLA) positive clusters was only found after i.c.v. 8-OH-DPAT treatment alone in the CA2 and CA3 areas. In the SD rat a significant increase in the density of specific PLA clusters was only observed in the CA2 area of the i.c.v. combined treatment (FGF2 + 8-OH-DPAT) group. No treatment led to significant changes in the PLA clusters of the dorsal raphe in the FSL rat. However, significant changes in the density of specific PLA clusters were only found in the dorsal raphe of SD rats after combined treatment and treatment with 8-OH-DPAT alone. The results indicate that in FSL rats compared with SD rats alterations may develop in the ability of 8-OH-DPAT and combined FGFR1 and 5-HT1A agonist treatment to increase the density of FGFR1-5-HT1A heteroreceptor complexes of the dorsal raphe. It is proposed that such deficits in FSL rats may possibly reflect a failure of the combined agonist treatment to uncouple the 5-HT1A autoreceptors from the GIRK channels. This may contribute to the failure of producing antidepressant-like effects in the FSL rat by combined agonist treatment as seen in the SD rat. The antidepressant-like effects seen with the 5-HT1A agonist alone treatment in FSL but not in SD rats may instead involve significant increases in the FGFR1-5-HT1A complexes of the CA2 and CA3 areas of the hippocampus.
Highlights
In recent studies (Borroto-Escuela et al, 2012, 2013a,b,c) evidence is given for the existence of FGFR1-5-HT1A heterocomplexes based on the use of the in situ proximity ligation assay (PLA)
An uncoupling of the 5-HT1A Gi/o mediated opening of the GIRK channels may take place upon agonist coactivation in hippocampal CA1 neurons of the SD rat of the FGFR1-5HT1A protomers forming heteroreceptor complexes located on the CA1 pyramidal nerve cells
The 5-HT1A modulates the internal circuitries of the hippocampus upon activation by 5-HT released from widespread 5-HT nerve terminal networks (Steinbusch, 1981; Bjarkam et al, 2003) originating from the midbrain raphe region (Dahlstroem and Fuxe, 1964; Fuxe and Jonsson, 1974)
Summary
In recent studies (Borroto-Escuela et al, 2012, 2013a,b,c) evidence is given for the existence of FGFR1-5-HT1A heterocomplexes based on the use of the in situ proximity ligation assay (PLA). We have found that acute and a 10 day intracerebroventricular (i.c.v.) treatment with FGF-2 and the 5-HT1A agonist 8-OHDPAT in the SpragueDawley (SD) rat can produce enhanced antidepressant effects in the forced swim test (FST) vs 5-HT1A agonist treatment alone (Borroto-Escuela et al, 2012). This cotreatment may possibly result in more rapid and stronger antidepressant actions than found with SSRIs, provided the agonist regulation of these heteroreceptor complexes is not disturbed in depression. The raphe 5-HT1A autoreceptor when being part of the FGFR15-HT1A heteroreceptor complexes may have a beneficial role in depression by assisting in the recovery of 5-HT nerve cell trophism including 5-HT synthesis and storage (Fuxe et al, 2014; Borroto-Escuela et al, 2016b)
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