Receptor–Receptor Interactions in Multiple 5-HT1A Heteroreceptor Complexes in Raphe-Hippocampal 5-HT Transmission and Their Relevance for Depression and Its Treatment

Abstract

Due to the binding to a number of proteins to the receptor protomers in receptor heteromers in the brain, the term “heteroreceptor complexes” was introduced. A number of serotonin 5-HT1A heteroreceptor complexes were recently found to be linked to the ascending 5-HT pathways known to have a significant role in depression. The 5-HT1A–FGFR1 heteroreceptor complexes were involved in synergistically enhancing neuroplasticity in the hippocampus and in the dorsal raphe 5-HT nerve cells. The 5-HT1A protomer significantly increased FGFR1 protomer signaling in wild-type rats. Disturbances in the 5-HT1A–FGFR1 heteroreceptor complexes in the raphe-hippocampal 5-HT system were found in a genetic rat model of depression (Flinders sensitive line (FSL) rats). Deficits in FSL rats were observed in the ability of combined FGFR1 and 5-HT1A agonist cotreatment to produce antidepressant-like effects. It may in part reflect a failure of FGFR1 treatment to uncouple the 5-HT1A postjunctional receptors and autoreceptors from the hippocampal and dorsal raphe GIRK channels, respectively. This may result in maintained inhibition of hippocampal pyramidal nerve cell and dorsal raphe 5-HT nerve cell firing. Also, 5-HT1A–5-HT2A isoreceptor complexes were recently demonstrated to exist in the hippocampus and limbic cortex. They may play a role in depression through an ability of 5-HT2A protomer signaling to inhibit the 5-HT1A protomer recognition and signaling. Finally, galanin (1–15) was reported to enhance the antidepressant effects of fluoxetine through the putative formation of GalR1–GalR2–5-HT1A heteroreceptor complexes. Taken together, these novel 5-HT1A receptor complexes offer new targets for treatment of depression.

The Role of Central Serotonin Neurons and 5-HT Heteroreceptor Complexes in the Pathophysiology of Depression: A Historical Perspective and Future Prospects

“…Modulation by serotonin VT of, e.g., glutamate and GABA synapses in the hippocampus involves 5-HT homoreceptor complexes and many different subtypes of 5-HT heteroreceptor complexes located on neurons and/or astroglia, like serotonin 1A receptor (5-HT1A)-fibroblast growth factor receptor 1 (FGFR1) [ 16 , 17 , 18 , 19 ], serotonin 1a receptor (5-HT1A)- serotonin 2A receptor (5-HT2A) [ 20 ], serotonin 1A receptor (5-HT1A)- galanin receptor 1 (GalR1) [ 21 , 22 , 23 , 24 ], serotonin 1A receptor (5-HT1A)- galanin receptor 1 (GalR1)- galanin receptor 2 (GalR2) [ 25 ], serotonin 1A receptor (5-HT1A)- G-protein coupled receptor 39 (GPR39) [ 26 ], serotonin 2C receptor (5-HT2C)- growth hormone secretagogue receptor 1A GHS-R1a) [ 27 , 28 , 29 ], serotonin 2A receptor (5-HT2A)- oxytocin receptor (OXTR) [ 30 ] and serotonin 2C receptor (5-HT2C)- oxytocin receptor (OXTR) [ 31 ] heteroreceptor complexes. One emerging concept in depression is that disturbances in allosteric receptor–receptor interactions in highly vulnerable 5-HT1A heteroreceptor complexes can contribute to causing depression and become novel targets for the treatment of depression and anxiety [ 19 , 32 , 33 ]. Moreover, the 5-HT2A and 5-HT2C receptors are steadily receiving more attention as a therapeutic target for mood disorders [ 34 ], and both the GHS-R1a OXTRs have also been implicated in anxiety [ 35 , 36 ].…”

“…Now we introduce a novel hypothesis that a few of these 5-HTR heterocomplexes can contribute to depression by changing their densities and/or allosteric receptor–receptor interactions in the plasma membrane in this disease [ 32 ]. Thus, they can be highly vulnerable, with altered function, and become novel targets for the treatment of depression.…”

<p>Galanin Receptors as Drug Target for Novel Antidepressants: Review</p>

“…46,49,81 In line with this, the existence of GAL-5HT1AR heterorecptor complex dysfunction leads to disturbance in mesolimbic neurotransmission of 5-HT. 82,83 Indeed, the modulation of auto-receptor function is distinctly regulated by the GalR1-GalR2-5-HT1AR heterotrimeric complex to elicit antidepressant effects. 46,83 Besides increasing hippocampal mRNA levels of post junctional serotonin receptors, co-administration of GAL1-15 and fluoxetine (FLX) help to enhance the agonist binding affinity of FLX in the dentate gyrus.…”

“…82,83 Indeed, the modulation of auto-receptor function is distinctly regulated by the GalR1-GalR2-5-HT1AR heterotrimeric complex to elicit antidepressant effects. 46,83 Besides increasing hippocampal mRNA levels of post junctional serotonin receptors, co-administration of GAL1-15 and fluoxetine (FLX) help to enhance the agonist binding affinity of FLX in the dentate gyrus. 81 According to the findings by Flores-Burgess et al the combination use of the three sc injections of FLX (10 mg/kg) and a single ICV injection of GAL1-15 (1 nmol) produced a significant increase in the 5-HT1AR mRNA levels in the median prefrontal cortex with a significant increase in the Kd value (F3,20 = 14.36, p < 0.001; post hoc p < 0.01) in mPFC (F3,19 = 6.418, p < 0.01; post hoc p < 0.01).…”

Abnormalities in FGF family members and their roles in modulating depression‐related molecules

“…FGF2 could directly reverse depression‐like behaviours and hippocampal damage in rats through the FGF2‐ERK2 signalling pathway (Tang, Lin, Zhang, Zhao, & Li, 2017). Moreover, FGF2 could exhibit an antidepressant function by regulating the expression of glucocorticoid receptors (GRs; Salmaso et al., 2016; Numakawa et al., 2018), 5‐hydroxytryptamine (5‐HT; Borroto‐Escuela et al., 2018), inflammatory factors (Anisman & Hayley, 2012) and other neurotrophic factors (Hisaoka et al., 2011; Hisaoka‐Nakashima et al., 2015).…”