Just over 20 years ago it became accepted that receptor-receptor interactions were brought about by heterodimer formation which became the centres for signal integration. That the 5-HT1A receptor can have at least 10 different protomer interactions in the CNS has brought a whole new level of complexity to our understanding of how such hub receptors function.
‘It’s becoming more complex and, therefore, more exciting!” the session’s chairman Kjell Fuxe, Sweden, told the audience. Here we report some recent findings on the role of serotonin in depression and how new targets for its management are being uncovered.
siRNAs as anti-depressants
Considerable effort has gone into the development of anti-depressant drugs that specifically target serotonin and Francesc Artigas, Spain, outlined the considerable challenges accompanying research efforts. Pre- and postsynaptic 5-HT1A receptors play a major role in anti-depressant action, either by limiting (presynaptic 5-HT1A autoreceptors) or facilitating their effects (postsynaptic 5-HT1A receptors).
A promising new strategy for creating anti-depressants is based on use of small interfering RNA (siRNA) targeted to serotonin neurons. These siRNAs selectively reduced the expression and function of presynaptic but not postsynaptic 5-HT1A receptors. When siRNAs were injected into the raphe nuclei of mice, expression and function of 5-HT1A autoreceptors locally was attenuated, without affecting postsynaptic 5-HT1A receptors. This produced an anti-depressant-like effect in the mice - effects that are associated with enhanced forebrain 5-HT release.
When siRNAs were injected into the raphe nuclei of mice, expression and function of 5-HT1A autoreceptors locally was attenuated
Conjugated siRNA may enhance anti-depressant effect
A conjugated 5-HT1AR siRNA (C-1A-siRNA) molecule specific to serotonin neurons has also been created. The molecule - created by binding 5-HT1A receptor siRNA molecules to a 5-HT selective serotonin reuptake inhibitor (SSRI) - produced similar effects to the siRNA described earlier. However, SSRI administration to C-1A-siRNA-treated mice produced a greater elevation of extracellular 5-HT than in control animals showing how drug effects can be adapted and how promising such an approach might be.
SSRI administration to C-1A-siRNA-treated mice produced a greater elevation of extracellular 5-HT than in control animals showing how drug effects can be adapted and how promising such an approach might be
Galanin – fragmented approach may be more potent
Another promising strategy for the management of depression and anxiety involves the neuropeptide galanin and its receptors. Zaida Diaz-Cabiale, Spain, explained how activation of GALR1 and GALR3 promotes depression whereas activation of GALR2 has anti-depressant effects. However, the N-terminal fragment of GAL, GAL(1-15), is also active and animal data suggest that the effects of the fragments may be more potent than those of the complete molecule.
Of particular interest was the finding that GAL(1–15) enhanced the anti-depressant effects induced by the 5-HT1AR agonist 8-OH-DPAT in the forced swimming test. Again, the anti-depressant effects elicited by GAL(1-15) were stronger than those induced by GAL. Importantly, GALR2 was involved in these effects, since a specific GALR2 antagonist blocked GAL(1–15) mediated actions at the behavioral and at the receptor level.
Galanin – serotonin heteroreceptors enhances anti-depressant effect
Use of proximity ligation assay (PLA) suggest the enhanced anti-depressant effects of 8-OH-DPAT occur by GAL(1-15) acting on GALR1-GALR2-5-HT1AR heteroreceptors located at postjunctional sites and at the soma-dendritic level. The development of new drugs specifically targeting these heteroreceptor complexes offers another novel strategy for treating depression.
Enhanced anti-depressant effects of 8-OH-DPAT occur by GAL(1-15) acting on GALR1-GALR2-5-HT1AR heteroreceptors located at postjunctional sites
FGFR1 – 5-HT1AR - heteroreceptors with anti-depressant effects
Dasiel Borroto-Escuela, Sweden, outlined a further potential anti-depressant heteroreceptor target – this time incorporating brain fibroblast-growth factor receptor 1 (FGFR1).
5-HT1A-FGFR1 heterocomplexes were first described in the hippocampus and then in midbrain 5-HT neurons, where these heterocomplexes are enriched in 5-HT1A autoreceptors. Combined FGF-2 and 5-HT1A agonist treatment increased formation of these heterocomplexes, led to an enhancement of FGFR1 signaling and was associated with the development of anti-depressant effects.
Synergistic allosteric receptor-receptor interactions contribute to acute anti-depressant actions by recruiting 5-HT1A autoreceptors into FGFR1-5-HT1A complexes
Thus, 5HT1A heteroreceptor complexes may serve as targets in the management of depression. These complexes are of special interest as they are located in the midbrain raphe and hippocampal neuronal system. In particular, synergistic allosteric receptor-receptor interactions following coactivation of post-junctional FGFR1-5-HT1A heteroreceptor complexes in the hippocampus may exert rapid and robust anti-depressant actions. One drawback may be the development of hippocampal atrophy over time.
5-HT1A autoreceptor-FGFR1 heteroreceptor complexes are found in the midbrain 5-HT raphe cells and at the soma-dendritic level. Here, synergistic allosteric receptor-receptor interactions upon co-activation may contribute to acute anti-depressant actions by recruiting 5-HT1A autoreceptors into FGFR1-5-HT1A complexes.
Thus, the FGFR1-5-HT1A heteroreceptor complex is a new promising target for anti-depressant drugs including combined treatment with FGF2 and 5-HT1A agonists in major depression.