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Kjell Fuxe - One of the best experts on this subject based on the ideXlab platform.
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Evidence for the existence of A2AR-TrkB Heteroreceptor complexes in the dorsal hippocampus of the rat brain: Potential implications of A2AR and TrkB interplay upon ageing.
Mechanisms of ageing and development, 2020Co-Authors: Michael Di Palma, Dasiel O Borroto-escuela, Kjell Fuxe, Manuel Narváez, Mariana Pita-rodríguez, Stefano Sartini, Davide Lattanzi, Riccardo Cuppini, Yoslandy Diaz-carmenate, Patrizia AmbroginiAbstract:Abstract Adenosine A2A receptors (A2AR) are crucial in facilitating the BDNF action on synaptic transmission in the rat hippocampus primarily upon ageing. Furthermore, it has been suggested that A2AR-Tropomyosin related kinase B receptor (TrkB) crosstalk has a pivotal role in adenosine A2AR-mediated modulation of the BDNF action on hippocampal plasticity. Considering the impact of the above receptors interplay on what concerns BDNF-induced enhancement of synaptic transmission, gaining a better insight into the mechanisms behind this powerful crosstalk becomes of primary interest. Using in situ proximity ligation assay (PLA), the existence of a direct physical interaction between adenosine A2AR and TrkB is demonstrated. The A2AR-TrkB Heteroreceptor complexes show a heterogeneous distribution within the rat dorsal hippocampus. High densities of the Heteroreceptor complexes were observed in the pyramidal cell layers of CA1-CA3 regions and in the polymorphic layer of the dentate gyrus (DG). The stratum radiatum of the CA1-3 regions showed positive PLA signal in contrast to the oriens region. The molecular and granular layers of the DG also lacked significant densities of PLA positive Heteroreceptor complexes, but subgranular zone showed some PLA positive cells. Their allosteric receptor-receptor interactions may significantly modulate BDNF signaling impacting on hippocampal plasticity which is impaired upon ageing.
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OSU-6162, a Sigma1R Ligand in Low Doses, Can Further Increase the Effects of Cocaine Self-Administration on Accumbal D2R Heteroreceptor Complexes.
Neurotoxicity research, 2019Co-Authors: Dasiel O Borroto-escuela, Wilber Romero-fernandez, Karolina Wydra, Małgorzata Filip, Zilong Zhou, Agata Suder, Kjell FuxeAbstract:Cocaine was previously shown to act at the Sigma1R which is a target for counteracting cocaine actions. It therefore becomes of interest to test if the monoamine stabilizer (-) OSU-6162 (OSU-6162) with a nanomolar affinity for the Sigma1R can acutely modulate in low doses the effects of cocaine self-administration. In behavioral studies, OSU-6162 (5 mg/kg, s.c.) did not significantly change the number of active lever pressing and cocaine infusions. However, a trend to reduce cocaine readouts was found after 3 days of treatment. In contrast, in maintenance of cocaine self-administration, the proximity ligation assay performed on brains from rats pretreated with OSU-6162 showed highly significant increases in the density of the D2R-Sigma1R Heteroreceptor complexes in the shell of the nucleus accumbens versus OSU-6162 induced increases in this region of yoked saline rats. In cocaine self-administration, highly significant increases were also induced by OSU-6162 in the A2AR-D2R Heteroreceptor complexes in the nucleus accumbens shell versus vehicle-treated rats. Furthermore, ex vivo, the A2AR agonist CGS21680 (100 nM) produced a marked and significant increase of the D2R Ki high values in the OSU-6162-treated versus vehicle-treated rats under maintenance of cocaine self-administration. These results indicate a substantial increase in the inhibitory allosteric A2AR-D2R interactions following cocaine self-administration upon activation by the A2AR agonist ex vivo. The current results indicate that OSU-6162 via its high affinity for the Sigma1R may increase the number of accumbal shell D2R-Sigma1R and A2AR-D2R Heteroreceptor complexes associated with further increases in the antagonistic A2AR-D2R interactions in cocaine self-administration.
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Oligomeric Receptor Complexes and Their Allosteric Receptor-Receptor Interactions in the Plasma Membrane Represent a New Biological Principle for Integration of Signals in the CNS.
Frontiers in molecular neuroscience, 2019Co-Authors: Dasiel O Borroto-escuela, Kjell FuxeAbstract:G protein-coupled receptors (GPCRs) not only exist as monomers but also as homomers and heteromers in which allosteric receptor-receptor interactions take place, modulating the functions of the participating GPCR protomers. GPCRs can also form Heteroreceptor complexes with ionotropic receptors and receptor tyrosine kinases modulating their function. Furthermore, adaptor proteins interact with receptor protomers and modulate their interactions. The state of the art is that the allosteric receptor-receptor interactions are reciprocal, highly dynamic and substantially alter the signaling, trafficking, recognition and pharmacology of the participating protomers. The pattern of changes appears to be unique for each heteromer and can favor antagonistic or facilitatory interactions or switch the G protein coupling from e.g., Gi/o to Gq or to beta-arrestin signaling. It lends a new dimension to molecular integration in the nervous system. Future direction should be aimed at determining the receptor interface involving building models of selected heterodimers. This will make design of interface-interfering peptides that specifically disrupt the heterodimer possible. This will help to determine the functional role of the allosteric receptor-receptor interactions as well as the integration of signals at the plasma membrane by the Heteroreceptor complexes, vs. integration of the intracellular signaling pathways. Integration of signals also at the plasma membrane seems crucial in view of the hypothesis that learning and memory at a molecular level takes place by reorganization of homo and Heteroreceptor complexes in the postsynaptic membrane. Homo and Heteroreceptor complexes are in balance with each other, and their disbalance is linked to disease. Targeting Heteroreceptor complexes represents a novel strategy for the treatment of brain disorders.
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Attenuation of Oxytocin and Serotonin 2A Receptor Signaling through Novel Heteroreceptor Formation.
ACS chemical neuroscience, 2019Co-Authors: Barbara Chruścicka, Dasiel O Borroto-escuela, Kjell Fuxe, Clémentine Druelle, Panagiota Stamou, Kenneth Nally, Timothy G. Dinan, John F. Cryan, Shauna E. Wallace Fitzsimons, Harriët SchellekensAbstract:The oxytocin receptor (OTR) and the 5-hydroxytryptamine 2A receptor (5-HTR2A) are expressed in similar brain regions modulating central pathways critical for social and cognition-related behaviors. Signaling crosstalk between their endogenous ligands, oxytocin (OT) and serotonin (5-hydroxytryptamine, 5-HT), highlights the complex interplay between these two neurotransmitter systems and may be indicative of the formation of Heteroreceptor complexes with subsequent downstream signaling changes. In this study, we assess the possible formation of OTR-5HTR2A heteromers in living cells and the functional downstream consequences of this receptor–receptor interaction. First, we demonstrated the existence of a physical interaction between the OTR and 5-HTR2A in vitro, using a flow cytometry-based FRET approach and confocal microscopy. Furthermore, we investigated the formation of this specific Heteroreceptor complex ex vivo in the brain sections using the Proximity Ligation Assay (PLA). The OTR-5HTR2A heterorecept...
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adenosine Heteroreceptor complexes in the basal ganglia are implicated in parkinson s disease and its treatment
Journal of Neural Transmission, 2019Co-Authors: Dasiel O Borrotoescuela, Kjell FuxeAbstract:The adenosine homo, iso and Heteroreceptor complexes in the basal ganglia play a highly significant role in modulating the indirect and direct pathways and the striosomal projections to the nigro-striatal DA system. The major adenosine receptor complexes in the striato-pallidal GABA neurons can be the A2AR–D2R and A2AR–D2R–mGluR5 receptor complexes, in which A2AR protomers and mGluR5 protomers can allosterically interact to inhibit D2R protomer signaling. Through a reorganization of these Heteroreceptor complexes upon chronic dopaminergic treatment a pathological and prolonged inhibition of D2R receptor protomer signaling can develop with motor inhibition and wearing off of the therapeutic effects of levodopa and dopamine receptor agonists. The direct pathway is enriched in D1R in and around glutamate synapses enhancing the ability of these GABA neurons to be activated and increase motor initiation. The brake on these GABA neurons is in this case exerted by A1R forming A1R–D1R Heteroreceptor complexes in which they allosterically inhibit D1R signaling and thereby reduce motor initiation. Upon chronic levodopa treatment a reorganization of the D1R Heteroreceptor complexes develops with the formation of putative A1R–D1R–D3 in addition to D1R–D3R complexes in which D3R enhances D1R protomer signaling and may make the A1R protomer brake less effective. Alpha-synuclein monomers–dimers are postulated to form complexes with A2AR homo and heteroprotomers in the plasma membrane enhancing alpha-synuclein aggregation and toxicity. The alpha-synuclein fibrils formed in the A2AR enriched dendritic spines of the striato-pallidal GABA neurons may reach the surrounding DA terminals via extracellular-vesicle-mediated volume transmission involving internalization of the vesicles and their cargo (alpha-synuclein fibrils) into the vulnerable DA terminals, enhancing their degeneration followed by retrograde flow of these fibrils in the DA axons to the vulnerable nigral DA nerve cells.
Dasiel O Borroto-escuela - One of the best experts on this subject based on the ideXlab platform.
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Evidence for the existence of A2AR-TrkB Heteroreceptor complexes in the dorsal hippocampus of the rat brain: Potential implications of A2AR and TrkB interplay upon ageing.
Mechanisms of ageing and development, 2020Co-Authors: Michael Di Palma, Dasiel O Borroto-escuela, Kjell Fuxe, Manuel Narváez, Mariana Pita-rodríguez, Stefano Sartini, Davide Lattanzi, Riccardo Cuppini, Yoslandy Diaz-carmenate, Patrizia AmbroginiAbstract:Abstract Adenosine A2A receptors (A2AR) are crucial in facilitating the BDNF action on synaptic transmission in the rat hippocampus primarily upon ageing. Furthermore, it has been suggested that A2AR-Tropomyosin related kinase B receptor (TrkB) crosstalk has a pivotal role in adenosine A2AR-mediated modulation of the BDNF action on hippocampal plasticity. Considering the impact of the above receptors interplay on what concerns BDNF-induced enhancement of synaptic transmission, gaining a better insight into the mechanisms behind this powerful crosstalk becomes of primary interest. Using in situ proximity ligation assay (PLA), the existence of a direct physical interaction between adenosine A2AR and TrkB is demonstrated. The A2AR-TrkB Heteroreceptor complexes show a heterogeneous distribution within the rat dorsal hippocampus. High densities of the Heteroreceptor complexes were observed in the pyramidal cell layers of CA1-CA3 regions and in the polymorphic layer of the dentate gyrus (DG). The stratum radiatum of the CA1-3 regions showed positive PLA signal in contrast to the oriens region. The molecular and granular layers of the DG also lacked significant densities of PLA positive Heteroreceptor complexes, but subgranular zone showed some PLA positive cells. Their allosteric receptor-receptor interactions may significantly modulate BDNF signaling impacting on hippocampal plasticity which is impaired upon ageing.
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OSU-6162, a Sigma1R Ligand in Low Doses, Can Further Increase the Effects of Cocaine Self-Administration on Accumbal D2R Heteroreceptor Complexes.
Neurotoxicity research, 2019Co-Authors: Dasiel O Borroto-escuela, Wilber Romero-fernandez, Karolina Wydra, Małgorzata Filip, Zilong Zhou, Agata Suder, Kjell FuxeAbstract:Cocaine was previously shown to act at the Sigma1R which is a target for counteracting cocaine actions. It therefore becomes of interest to test if the monoamine stabilizer (-) OSU-6162 (OSU-6162) with a nanomolar affinity for the Sigma1R can acutely modulate in low doses the effects of cocaine self-administration. In behavioral studies, OSU-6162 (5 mg/kg, s.c.) did not significantly change the number of active lever pressing and cocaine infusions. However, a trend to reduce cocaine readouts was found after 3 days of treatment. In contrast, in maintenance of cocaine self-administration, the proximity ligation assay performed on brains from rats pretreated with OSU-6162 showed highly significant increases in the density of the D2R-Sigma1R Heteroreceptor complexes in the shell of the nucleus accumbens versus OSU-6162 induced increases in this region of yoked saline rats. In cocaine self-administration, highly significant increases were also induced by OSU-6162 in the A2AR-D2R Heteroreceptor complexes in the nucleus accumbens shell versus vehicle-treated rats. Furthermore, ex vivo, the A2AR agonist CGS21680 (100 nM) produced a marked and significant increase of the D2R Ki high values in the OSU-6162-treated versus vehicle-treated rats under maintenance of cocaine self-administration. These results indicate a substantial increase in the inhibitory allosteric A2AR-D2R interactions following cocaine self-administration upon activation by the A2AR agonist ex vivo. The current results indicate that OSU-6162 via its high affinity for the Sigma1R may increase the number of accumbal shell D2R-Sigma1R and A2AR-D2R Heteroreceptor complexes associated with further increases in the antagonistic A2AR-D2R interactions in cocaine self-administration.
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Oligomeric Receptor Complexes and Their Allosteric Receptor-Receptor Interactions in the Plasma Membrane Represent a New Biological Principle for Integration of Signals in the CNS.
Frontiers in molecular neuroscience, 2019Co-Authors: Dasiel O Borroto-escuela, Kjell FuxeAbstract:G protein-coupled receptors (GPCRs) not only exist as monomers but also as homomers and heteromers in which allosteric receptor-receptor interactions take place, modulating the functions of the participating GPCR protomers. GPCRs can also form Heteroreceptor complexes with ionotropic receptors and receptor tyrosine kinases modulating their function. Furthermore, adaptor proteins interact with receptor protomers and modulate their interactions. The state of the art is that the allosteric receptor-receptor interactions are reciprocal, highly dynamic and substantially alter the signaling, trafficking, recognition and pharmacology of the participating protomers. The pattern of changes appears to be unique for each heteromer and can favor antagonistic or facilitatory interactions or switch the G protein coupling from e.g., Gi/o to Gq or to beta-arrestin signaling. It lends a new dimension to molecular integration in the nervous system. Future direction should be aimed at determining the receptor interface involving building models of selected heterodimers. This will make design of interface-interfering peptides that specifically disrupt the heterodimer possible. This will help to determine the functional role of the allosteric receptor-receptor interactions as well as the integration of signals at the plasma membrane by the Heteroreceptor complexes, vs. integration of the intracellular signaling pathways. Integration of signals also at the plasma membrane seems crucial in view of the hypothesis that learning and memory at a molecular level takes place by reorganization of homo and Heteroreceptor complexes in the postsynaptic membrane. Homo and Heteroreceptor complexes are in balance with each other, and their disbalance is linked to disease. Targeting Heteroreceptor complexes represents a novel strategy for the treatment of brain disorders.
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Attenuation of Oxytocin and Serotonin 2A Receptor Signaling through Novel Heteroreceptor Formation.
ACS chemical neuroscience, 2019Co-Authors: Barbara Chruścicka, Dasiel O Borroto-escuela, Kjell Fuxe, Clémentine Druelle, Panagiota Stamou, Kenneth Nally, Timothy G. Dinan, John F. Cryan, Shauna E. Wallace Fitzsimons, Harriët SchellekensAbstract:The oxytocin receptor (OTR) and the 5-hydroxytryptamine 2A receptor (5-HTR2A) are expressed in similar brain regions modulating central pathways critical for social and cognition-related behaviors. Signaling crosstalk between their endogenous ligands, oxytocin (OT) and serotonin (5-hydroxytryptamine, 5-HT), highlights the complex interplay between these two neurotransmitter systems and may be indicative of the formation of Heteroreceptor complexes with subsequent downstream signaling changes. In this study, we assess the possible formation of OTR-5HTR2A heteromers in living cells and the functional downstream consequences of this receptor–receptor interaction. First, we demonstrated the existence of a physical interaction between the OTR and 5-HTR2A in vitro, using a flow cytometry-based FRET approach and confocal microscopy. Furthermore, we investigated the formation of this specific Heteroreceptor complex ex vivo in the brain sections using the Proximity Ligation Assay (PLA). The OTR-5HTR2A heterorecept...
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Attenuation of Oxytocin and Serotonin 2A Receptor Signaling through Novel Heteroreceptor Formation
2019Co-Authors: Barbara Chruścicka, Dasiel O Borroto-escuela, Kjell Fuxe, Shauna Wallace E. Fitzsimons, Clémentine Druelle, Panagiota Stamou, Kenneth Nally, Timothy G. Dinan, John F. Cryan, Harriët SchellekensAbstract:The oxytocin receptor (OTR) and the 5-hydroxytryptamine 2A receptor (5-HTR2A) are expressed in similar brain regions modulating central pathways critical for social and cognition-related behaviors. Signaling crosstalk between their endogenous ligands, oxytocin (OT) and serotonin (5-hydroxytryptamine, 5-HT), highlights the complex interplay between these two neurotransmitter systems and may be indicative of the formation of Heteroreceptor complexes with subsequent downstream signaling changes. In this study, we assess the possible formation of OTR-5HTR2A heteromers in living cells and the functional downstream consequences of this receptor–receptor interaction. First, we demonstrated the existence of a physical interaction between the OTR and 5-HTR2A in vitro, using a flow cytometry-based FRET approach and confocal microscopy. Furthermore, we investigated the formation of this specific Heteroreceptor complex ex vivo in the brain sections using the Proximity Ligation Assay (PLA). The OTR-5HTR2A Heteroreceptor complexes were identified in limbic regions (including hippocampus, cingulate cortex, and nucleus accumbens), key regions associated with cognition and social-related behaviors. Next, functional cellular-based assays to assess the OTR-5HTR2A downstream signaling crosstalk showed a reduction in potency and efficacy of OT and OTR synthetic agonists, carbetocin and WAY267464, on OTR-mediated Gαq signaling. Similarly, the activation of 5-HTR2A by the endogenous agonist, 5-HT, also revealed attenuation in Gαq-mediated signaling. Finally, altered receptor trafficking within the cell was demonstrated, indicative of cotrafficking of the OTR/5-HTR2A pair. Overall, these results constitute a novel mechanism of specific interaction between the OT and 5-HT neurotransmitters via OTR-5HTR2A Heteroreceptor formation and provide potential new therapeutic strategies in the treatment of social and cognition-related diseases
Luigi Francesco Agnati - One of the best experts on this subject based on the ideXlab platform.
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the role of transmitter diffusion and flow versus extracellular vesicles in volume transmission in the brain neural glial networks
Philosophical Transactions of the Royal Society B, 2015Co-Authors: Dasiel O Orrotoescuela, Alexander O. Tarakanov, Luigi Francesco Agnati, Karl Echte, A Jansso, Kjell FuxeAbstract:Two major types of intercellular communication are found in the central nervous system (CNS), namely wiring transmission (point-to-point communication, the prototype being synaptic transmission with axons and terminals) and volume transmission (VT; communication in the extracellular fluid and in the cerebrospinal fluid (CSF)) involving large numbers of cells in the CNS. Volume and synaptic transmission become integrated inter alia through the ability of their chemical signals to activate different types of receptor protomers in Heteroreceptor complexes located synaptically or extrasynaptically in the plasma membrane. The demonstration of extracellular dopamine (DA) and serotonin (5-HT) fluorescence around the DA and 5-HT nerve cell bodies with the Falck–Hillarp formaldehyde fluorescence method after treatment with amphetamine and chlorimipramine, respectively, gave the first indications of the existence of VT in the brain, at least at the soma level. There exist different forms of VT. Early studies on VT only involved spread including diffusion and flow of soluble biological signals, especially transmitters and modulators, a communication called extrasynaptic (short distance) and long distance (paraaxonal and paravascular and CSF pathways) VT. Also, the extracellular vesicle type of VT was demonstrated. The exosomes (endosome-derived vesicles) appear to be the major vesicular carriers for VT but the larger microvesicles also participate. Both mainly originate at the soma–dendritic level. They can transfer lipids and proteins, including receptors, Rab GTPases, tetraspanins, cholesterol, sphingolipids and ceramide. Within them there are also subsets of mRNAs and non-coding regulatory microRNAs. At the soma–dendritic membrane, sets of dynamic postsynaptic Heteroreceptor complexes (built up of different types of physically interacting receptors and proteins) involving inter alia G protein-coupled receptors including autoreceptors, ion channel receptors and receptor tyrosine kinases are hypothesized to be the molecular basis for learning and memory. At nerve terminals, the presynaptic Heteroreceptor complexes are postulated to undergo plastic changes to maintain the pattern of multiple transmitter release reflecting the firing pattern to be learned by the Heteroreceptor complexes in the postsynaptic membrane.
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evidence for the existence of dopamine d2r and sigma 1 allosteric receptor receptor interaction in the rat brain role in brain plasticity and cocaine action
SpringerPlus, 2015Co-Authors: Luca Pinton, Luigi Francesco Agnati, Dasiel O Borrotoescuela, Manuel Narváez, Julia Oflijan, Kjell FuxeAbstract:Drug addiction is regarded as one of the most important neuropsychiatric diseases afflicting our society today. A prototypic drug of abuse is cocaine which directly acts on the brain reward system. In this work we present evidence on the existence of dopamine D2R- Sigma1R Heteroreceptor complexes which may play a role in the etiology of cocaine addiction. By means of BRET D2R-Sigma1R heteromers were demonstrated in HEK293 cells after receptor cotransfection. The existence of D2R-Sigma1R Heteroreceptor complexes was demonstrated also in discrete regions of the ventral and dorsal striatum with in situ proximity ligation assay. Through saturation binding assay it was clearly demonstrated that in membrane preparations of HEK293 cells co-expressing D2R-Sigma1R, cocaine (1nM) significantly increased the D2R Bmax values (998±40 fmol/mg protein) over D2R alone cells (664±37 fmol/mg protein). This effect was counteracted by the Sigma1R selective antagonist PD144418 (Bmax value: 728±39 fmol/mg protein). Furthermore, CREB reporter luc-gene assay indicated that the presence of D2R-Sigma1R significantly reduced the potency of the D2R like agonist quinpirole to inhibit the forskolin induced increase of the CREB signal. In contrast, the presence of a low concentration of cocaine (100nM) was found to markedly increase the quinpirole potency to inhibit the forskolin induced increase of the CREB signal in the D2R-Sigma1R cells. These dynamic changes in D2R-Sigma1R signalling produced by cocaine maybe explained by synergistic allosteric receptor-receptor interactions in the D2R-Sigma1R Heteroreceptor complexes at the plasma membrane level. An antagonistic allosteric receptor-receptor interaction between the dopamine D2R and the Sigma1R in absence of cocaine instead of can explain the reduced potency of quinpirole. These dual conformational changes in the D2R-Sigma1R Heteroreceptor complexes could be associated with the redistribution of both protomers from the intracellular compartment to the plasma membrane as indicated by means of confocal analysis of agonist induced D2RSigma1R trafficking and internalization. Overall, the dynamic of D2R-Sigma1R Heteroreceptor complexes may represent a mechanism that shapes neuronal and addictive responses to cocaine.
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Evidence for the existence of the A2A-A1 Heteroreceptor complex in the rat brain, and comparison of its distribution to that of the A2A-A2A homoreceptor complex
SpringerPlus, 2015Co-Authors: Julia Oflijan, Dasiel O Borroto-escuela, Michael Di Palma, Ismel Brito, Manuel Narváez, Miles Woolfenden, Luca Pinton, Fidel Corales, Antonio Jimenez-beristein, Luigi Francesco AgnatiAbstract:Adenosine receptors play critical roles in cellular processes and signaling and have been shown to form heteromers with diverse biochemical and/or pharmacological activities that are different from those of the corresponding homomers1. However, despite extensive experimental results supporting the formation of adenosine heteromers in heterologous systems, the existence of such Heteroreceptor complexes in the brain remains largely unknown, mainly because of the lack of appropriate methodology. Also no systematic study was carried out on heteromers form by adenosine receptor subtypes alone. In this study, we used several experimental approaches2 to investigate whether adenosine receptor A2A and A1 subtypes can form heteromers among themselves. In situ PLA clearly demonstrated that adenosine receptors (A2A-A2A, A2A-A1) exist as homo/Heteroreceptor complexes in rat brain. In the hippocampus, A2A-A1 Heteroreceptor complexes are mainly localized to the pyramidal cell layer of the Ammon´s horn and the hilo (PoDG). The complex was also observed throughout the piriformis layer. Several distinct differences were apparent between the distribution of the A2A-A1 Heteroreceptor complexes and that of the A2A-A2A homoreceptor complex, which could have important functional consequences. Furthermore, bioluminescence resonance energy transfer analysis of adenosine A2A receptors established that they can physically interact in HEK293T27 cells, as both homomers and heteromers. In addition, static/non-dynamical human GPCR data derived from this and other interaction studies were integrated in a large scale graph, called the GPCR heterodimer network (http://www.iiia.csic.es/~ismel/GPCR-Nets/index.html), which provides global insight into adenosine heteromer connectivity, topology and organization in the context of the adenosine receptor subfamily and the GPCR network as a whole.
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Increase of the FGFR1 signaling in the FGFR1-5-HT1A Heteroreceptor complex in midbrain raphe 5-HT neuron systems via allosteric receptor-receptor interaction
SpringerPlus, 2015Co-Authors: Dasiel O Borroto-escuela, Alexander O. Tarakanov, Luigi Francesco Agnati, Michael Di Palma, Manuel Narváez, Antonio Jiménez-beristain, Julia Oflijan, Luca Pinton, Giuseppa Mudò, Natale BelluardoAbstract:The ascending midbrain 5-HT neurons known to contain 5-HT1A autoreceptors may be dysregulated in depression due to a reduced trophic support. New findings show existence of FGFR1-5-HT1A Heteroreceptor complexes in the rat hippocampus with a partial characterization of their interface and in midbrain raphe 5-HT nerve cells. With in situ Proximity Ligation Assay (PLA) and supported by co-location of the FGFR1 and 5-HT1A immunoreactivities in midbrain raphe 5-HT cells, evidence for the existence of FGFR1-5-HT1A Heteroreceptor complexes were obtained in the dorsal and median raphe nuclei of the Sprague–Dawley rat. Their existence in the rat medullary raphe RN33B cell cultures was also established. After combined FGF-2 and 8-OH-DPAT treatment, a marked and significant increase in PLA positive clusters was found in the RN33B cells. Synergistic receptor-receptor interactions in these receptor complexes indicated their enhancing role in hippocampal plasticity. The existence of FGFR1-5-HT1A Heteroreceptor complexes also in midbrain raphe 5-HT nerve cells open up the possibility that antidepressant drugs by increasing extracellular 5-HT levels, can cause an activation of the FGF-2/FGFR1 mechanism in these nerve cells as well. Therefore, the agonist modulation of the FGFR1-5-HT1A Heteroreceptor complexes and their specific role is now determined in rat medullary raphe RN33B cells and in the caudal midline raphe area of the midbrain rich in 5-HT nerve cells. The combined icv treatment with FGF-2 and the 5-HT1A agonist 8-OHDPAT synergistically increased FGFR1 and ERK1/2 phosphorylation in the raphe midline area of the midbrain and in the RN33B cells. Cotreatment with FGF2 and the 5-HT1A agonist induced RN33B cell differentiation as seen from development of the increased number and length of extensions per cell and their increased 5-HT immunoreactivity. These signaling and differentiation events were dependent on the receptor interface since they were blocked by incubation with TMV but not by TMII of the 5-HT1A receptor. Taken together, the 5-HT1A autoreceptors by being part of a FGFR1-5-HT1A Heteroreceptor complex in the midbrain raphe 5-HT nerve cells appears to have also a trophic role in the central 5-HT neuron systems besides playing a key role in reducing the firing of these neurons.
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Enhancement of the FGFR1 signaling in the FGFR1-5-HT1A Heteroreceptor complex in midbrain raphe 5-HT neuron systems. Relevance for neuroplasticity and depression.
Biochemical and biophysical research communications, 2015Co-Authors: Dasiel O Borroto-escuela, Alexander O. Tarakanov, Francisco Ciruela, Luigi Francesco Agnati, Mileidys Pérez-alea, Manuel Narváez, Antonio Jiménez-beristain, Giuseppa Mudò, Natale Belluardo, Kjell FuxeAbstract:Abstract New findings show existence of FGFR1-5-HT1A Heteroreceptor complexes in 5-HT nerve cells of the dorsal and median raphe nuclei of the rat midbrain and hippocampus. Synergistic receptor–receptor interactions in these receptor complexes indicated their enhancing role in hippocampal plasticity. The existence of FGFR1-5-HT1A Heteroreceptor complexes also in midbrain raphe 5-HT nerve cells open up the possibility that antidepressant drugs by increasing extracellular 5-HT levels can cause an activation of the FGF-2/FGFR1 mechanism in these nerve cells as well. Therefore, the agonist modulation of the FGFR1-5-HT1A Heteroreceptor complexes and their specific role is now determined in rat medullary raphe RN33B cells and in the caudal midline raphe area of the midbrain rich in 5-HT nerve cells. The combined i.c.v. treatment with FGF-2 and the 5-HT1A agonist 8-OHDPAT synergistically increased FGFR1 and ERK1/2 phosphorylation in the raphe midline area of the midbrain and in the RN33B cells. Cotreatment with FGF2 and the 5-HT1A agonist induced RN33B cell differentiation as seen from development of an increased number and length of extensions per cell and their increased 5-HT immunoreactivity. These signaling and differentiation events were dependent on the receptor interface since they were blocked by incubation with TMV but not by TMII of the 5-HT1A receptor. Taken together, the 5-HT1A autoreceptors by being part of a FGFR1-5-HT1A Heteroreceptor complex in the midbrain raphe 5-HT nerve cells appears to have also a trophic role in the central 5-HT neuron systems besides playing a key role in reducing the firing of these neurons.
Manuel Narváez - One of the best experts on this subject based on the ideXlab platform.
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Evidence for the existence of A2AR-TrkB Heteroreceptor complexes in the dorsal hippocampus of the rat brain: Potential implications of A2AR and TrkB interplay upon ageing.
Mechanisms of ageing and development, 2020Co-Authors: Michael Di Palma, Dasiel O Borroto-escuela, Kjell Fuxe, Manuel Narváez, Mariana Pita-rodríguez, Stefano Sartini, Davide Lattanzi, Riccardo Cuppini, Yoslandy Diaz-carmenate, Patrizia AmbroginiAbstract:Abstract Adenosine A2A receptors (A2AR) are crucial in facilitating the BDNF action on synaptic transmission in the rat hippocampus primarily upon ageing. Furthermore, it has been suggested that A2AR-Tropomyosin related kinase B receptor (TrkB) crosstalk has a pivotal role in adenosine A2AR-mediated modulation of the BDNF action on hippocampal plasticity. Considering the impact of the above receptors interplay on what concerns BDNF-induced enhancement of synaptic transmission, gaining a better insight into the mechanisms behind this powerful crosstalk becomes of primary interest. Using in situ proximity ligation assay (PLA), the existence of a direct physical interaction between adenosine A2AR and TrkB is demonstrated. The A2AR-TrkB Heteroreceptor complexes show a heterogeneous distribution within the rat dorsal hippocampus. High densities of the Heteroreceptor complexes were observed in the pyramidal cell layers of CA1-CA3 regions and in the polymorphic layer of the dentate gyrus (DG). The stratum radiatum of the CA1-3 regions showed positive PLA signal in contrast to the oriens region. The molecular and granular layers of the DG also lacked significant densities of PLA positive Heteroreceptor complexes, but subgranular zone showed some PLA positive cells. Their allosteric receptor-receptor interactions may significantly modulate BDNF signaling impacting on hippocampal plasticity which is impaired upon ageing.
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Brain dopamine transmission in health and Parkinson's disease: modulation of synaptic transmission and plasticity through volume transmission and dopamine Heteroreceptors.
Frontiers in synaptic neuroscience, 2018Co-Authors: Dasiel O Borroto-escuela, Karolina Wydra, Gemma Navarro, Manuel Narváez, Miguel Pérez De La Mora, Paul R. Manger, Sarah Beggiato, Minerva Crespo-ramírez, Zaida Díaz-cabiale, Alicia RiveraAbstract:This perspective article provides observations supporting the view that nigro-striatal dopamine neurons and meso-limbic dopamine neurons mainly communicate through short distance volume transmission in the um range with dopamine diffusing into extrasynaptic and synaptic regions of glutamate and GABA synapses. Based on this communication it is discussed how volume transmission modulates synaptic glutamate transmission onto the D1R modulated direct and D2R modulated indirect GABA pathways of the dorsal striatum. Each nigro-striatal dopamine neuron was first calculated to form large numbers of neostriatal DA nerve terminals and then found to give rise to dense axonal arborizations spread over the neostriatum, from which dopamine is released. These neurons can through DA volume transmission directly influence not only the striatal GABA projection neurons but all the striatal cell types in parallel. It includes the GABA nerve cells forming the island-/striosome GABA pathway to the nigral dopamine cells, the striatal cholinergic interneurons and the striatal GABA interneurons. The dopamine modulation of the different striatal nerve cell types involves the five dopamine receptor subtypes, D1R to D5R receptors, and their formation of multiple extrasynaptic and synaptic dopamine homo and Heteroreceptor complexes. These features of the nigro-striatal dopamine neuron to modulate in parallel the activity of practically all the striatal nerve cell types in the dorsal striatum, through the dopamine receptor complexes allows us to understand its unique and crucial fine-tuning of movements, which is lost in Parkinson's disease. Integration of striatal dopamine signals with other transmitter systems in the striatum mainly takes place via the receptor-receptor interactions in dopamine Heteroreceptor complexes. Such molecular events also participate in the integration of volume transmission and synaptic transmission. Dopamine modulation of the glutamate synapses on the dorsal striato-pallidal GABA pathway involves D2R Heteroreceptor complexes such as D2R-NMDAR, A2AR-D2R, and NTSR1-D2R Heteroreceptor complexes. The dopamine modulation of glutamate synapses on the striato-entopeduncular/nigral pathway takes place mainly via D1R Heteroreceptor complexes such as D1R-NMDAR, A2R-D1R, and D1R-D3R Heteroreceptor complexes. Dopamine modulation of the island/striosome compartment of the dorsal striatum projecting to the nigral dopamine cells involve D4R-MOR Heteroreceptor complexes. All these receptor-receptor interactions have relevance for Parkinson's disease and its treatment.
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Receptor–Receptor Interactions in Multiple 5-HT1A Heteroreceptor Complexes in Raphe-Hippocampal 5-HT Transmission and Their Relevance for Depression and Its Treatment
Molecules (Basel Switzerland), 2018Co-Authors: Dasiel O Borroto-escuela, Wilber Romero-fernandez, Luca Ferraro, Ismel Brito, Manuel Narváez, Patrizia Ambrogini, Yuniesky Andrade-talavera, Antonio Flores-burgess, Carmelo Millón, Belén GagoAbstract: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.
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receptor receptor interactions in multiple 5 ht1a Heteroreceptor complexes in raphe hippocampal 5 ht transmission and their relevance for depression and its treatment
Molecules, 2018Co-Authors: Luca Ferraro, Dasiel O Borrotoescuela, Wilber Romerofernandez, Ismel Brito, Manuel Narváez, Patrizia Ambrogini, Yuniesky Andradetalavera, Antonio Floresburgess, Carmelo MillónAbstract: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.
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Effects of Long-Term Alcohol Drinking on the Dopamine D2 Receptor: Gene Expression and Heteroreceptor Complexes in the Striatum in Rats.
Alcoholism clinical and experimental research, 2018Co-Authors: Kristin Feltmann, Dasiel O Borroto-escuela, Kjell Fuxe, Manuel Narváez, Antonio Jiménez-beristain, Luca Pinton, Joëlle Rüegg, Thatiane De Oliveira Sergio, Tomas J. Ekström, Pia SteenslandAbstract:BACKGROUND Reduced dopamine D2 receptor (D2R) ligand binding has repeatedly been demonstrated in the striatum of humans with alcohol use disorder (AUD). The attenuated D2R binding has been suggested to reflect a reduced D2R density, which in turn has been proposed to drive craving and relapse. However, results from rodent studies addressing the effects of alcohol drinking on D2R density have been inconsistent. METHODS A validated alcohol drinking model (intermittent access to 20% alcohol) in Wistar rats was used to study the effects of voluntary alcohol drinking (at least 12 weeks) on the D2R in the striatum compared to age-matched alcohol-naive control rats. Reverse transcriptase quantitative PCR was used to quantify isoform-specific Drd2 gene expression levels. Using bisulfite pyrosequencing, DNA methylation levels of a regulatory region of the Drd2 gene were determined. In situ proximity ligation assay was used to measure densities of D2R receptor complexes: D2R-D2R, adenosine A2A receptor (A2AR)-D2R, and sigma1 receptor (sigma1R)-D2R. RESULTS Long-term voluntary alcohol drinking significantly reduced mRNA levels of the long D2R isoform in the nucleus accumbens (NAc) but did not alter CpG methylation levels in the analyzed sequence of the Drd2 gene. Alcohol drinking also reduced the striatal density of D2R-D2R homoreceptor complexes, increased the density of A2AR-D2R Heteroreceptor complexes in the NAc shell and the dorsal striatum, and decreased the density of sigma1R-D2R Heteroreceptor complexes in the dorsal striatum. CONCLUSIONS The present results on long-term alcohol drinking might reflect reduced D2R levels through reductions in D2R-D2R homoreceptor complexes and gene expression. Furthermore, based on antagonistic interactions between A2AR and D2R, an increased density of A2AR-D2R Heteroreceptor complexes might indicate a reduced affinity and signaling of the D2R population within the complex. Hence, both reduced striatal D2R levels and reduced D2R protomer affinity within the striatal A2AR-D2R complex might underlie reduced D2R radioligand binding in humans with AUD. This supports the hypothesis of a hypodopaminergic system in AUD and suggests the A2AR-D2R Heteroreceptor complex as a potential novel treatment target.
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Evidence for the existence of A2AR-TrkB Heteroreceptor complexes in the dorsal hippocampus of the rat brain: Potential implications of A2AR and TrkB interplay upon ageing.
Mechanisms of ageing and development, 2020Co-Authors: Michael Di Palma, Dasiel O Borroto-escuela, Kjell Fuxe, Manuel Narváez, Mariana Pita-rodríguez, Stefano Sartini, Davide Lattanzi, Riccardo Cuppini, Yoslandy Diaz-carmenate, Patrizia AmbroginiAbstract:Abstract Adenosine A2A receptors (A2AR) are crucial in facilitating the BDNF action on synaptic transmission in the rat hippocampus primarily upon ageing. Furthermore, it has been suggested that A2AR-Tropomyosin related kinase B receptor (TrkB) crosstalk has a pivotal role in adenosine A2AR-mediated modulation of the BDNF action on hippocampal plasticity. Considering the impact of the above receptors interplay on what concerns BDNF-induced enhancement of synaptic transmission, gaining a better insight into the mechanisms behind this powerful crosstalk becomes of primary interest. Using in situ proximity ligation assay (PLA), the existence of a direct physical interaction between adenosine A2AR and TrkB is demonstrated. The A2AR-TrkB Heteroreceptor complexes show a heterogeneous distribution within the rat dorsal hippocampus. High densities of the Heteroreceptor complexes were observed in the pyramidal cell layers of CA1-CA3 regions and in the polymorphic layer of the dentate gyrus (DG). The stratum radiatum of the CA1-3 regions showed positive PLA signal in contrast to the oriens region. The molecular and granular layers of the DG also lacked significant densities of PLA positive Heteroreceptor complexes, but subgranular zone showed some PLA positive cells. Their allosteric receptor-receptor interactions may significantly modulate BDNF signaling impacting on hippocampal plasticity which is impaired upon ageing.
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Cocaine self-administration specifically increases A2AR-D2R and D2R-sigma1R Heteroreceptor complexes in the rat nucleus accumbens shell. Relevance for cocaine use disorder.
Pharmacology biochemistry and behavior, 2017Co-Authors: Dasiel O Borroto-escuela, Michael Di Palma, Karolina Wydra, Joanna Jastrzębska, Małgorzata Filip, Manuel Narváez, Antonio Jiménez-beristain, Julia Pintsuk, Luca Pinton, Kjell FuxeAbstract:Adenosine 2A receptor (A2AR) agonists were indicated to reduce cocaine reward and cocaine seeking mainly through activation of antagonistic allosteric A2AR-dopamine D2R (D2R) interactions in A2AR-D2R Heteroreceptor complexes. Furthermore, it was shown that modulation of cocaine reward involves antagonistic A2AR-D2R interactions in the ventral but not the dorsal striatum in rats. In the current work the proximity ligation assay (PLA) was used to further study the A2AR-D2R Heteroreceptor complexes in the nucleus accumbens shell and core as well as the dorsal striatum under the influence of cocaine self-administration in rats. A significant increase in the A2AR-D2R PLA positive clusters was observed in the nucleus accumbens shell but not in the other regions vs yoked saline controls using the duolink software. Additionally, cocaine self-administration evoked a selective and significant increase in the density of D2R-sigma1R positive clusters in the nucleus accumbens shell vs yoked saline controls, while a significant reduction of the density of the D2R-sigma1R positive clusters was found in the dorsal part of the dorsal striatum. The results suggest that cocaine self-administration can reorganize A2AR and D2R into increased A2AR-D2R Heteroreceptor complexes in the nucleus accumbens shell associated with increases in the D2R-sigma1R Heteroreceptor complexes in this region. This reorganization can contribute to the demonstrated anti-cocaine actions of A2A receptor agonists and the putative formation of A2AR-D2R-sigma1R heterocomplexes.
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In Situ Proximity Ligation Assay to Study and Understand the Distribution and Balance of GPCR Homo- and Heteroreceptor Complexes in the Brain
Neuromethods, 2016Co-Authors: Dasiel O Borroto-escuela, Michael Di Palma, Manuel Narváez, Antonio Jiménez-beristain, Julia Oflijan, Beth Hagman, Miles Woolfenden, Luca Pinton, Kristin Feltmann, Stefano SartiniAbstract:The existence of homo- and Heteroreceptor complexes with allosteric receptor-receptor interactions increases the diversity of receptor function including recognition, traffi cking, and signaling. This phenomenon increases our understanding of how brain function is altered through molecular integration of receptor signals. An alteration in specifi c Heteroreceptor complexes or their balance/equilibrium with the corresponding homoreceptors is considered to have a role in the pathogenic mechanisms that lead to mental and neurological diseases, including drug addiction, depression, Parkinson’s disease, and schizophrenia. However, despite extensive experimental work supporting the formation of these receptor complexes in cellular models, their detection and visualization in the brain remained largely unknown until recent years, when a well-characterized in situ proximity ligation assay (in situ PLA) was adapted to validate the existence of GPCR homo- and Heteroreceptor complexes in their native environment. In this chapter we will describe the in situ PLA procedure as a high selectivity and sensitivity assay to detect and characterize GPCR homo- and Heteroreceptor complexes and their balance and distribution ex vivo in the brain by confocal laser microscopy. Herein, we outlined in detail the in situ PLA assay and how to use it in an optimal way on work with formalin-fixed free-floating rat brain sections
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Evidence for the existence of the A2A-A1 Heteroreceptor complex in the rat brain, and comparison of its distribution to that of the A2A-A2A homoreceptor complex
SpringerPlus, 2015Co-Authors: Julia Oflijan, Dasiel O Borroto-escuela, Michael Di Palma, Ismel Brito, Manuel Narváez, Miles Woolfenden, Luca Pinton, Fidel Corales, Antonio Jimenez-beristein, Luigi Francesco AgnatiAbstract:Adenosine receptors play critical roles in cellular processes and signaling and have been shown to form heteromers with diverse biochemical and/or pharmacological activities that are different from those of the corresponding homomers1. However, despite extensive experimental results supporting the formation of adenosine heteromers in heterologous systems, the existence of such Heteroreceptor complexes in the brain remains largely unknown, mainly because of the lack of appropriate methodology. Also no systematic study was carried out on heteromers form by adenosine receptor subtypes alone. In this study, we used several experimental approaches2 to investigate whether adenosine receptor A2A and A1 subtypes can form heteromers among themselves. In situ PLA clearly demonstrated that adenosine receptors (A2A-A2A, A2A-A1) exist as homo/Heteroreceptor complexes in rat brain. In the hippocampus, A2A-A1 Heteroreceptor complexes are mainly localized to the pyramidal cell layer of the Ammon´s horn and the hilo (PoDG). The complex was also observed throughout the piriformis layer. Several distinct differences were apparent between the distribution of the A2A-A1 Heteroreceptor complexes and that of the A2A-A2A homoreceptor complex, which could have important functional consequences. Furthermore, bioluminescence resonance energy transfer analysis of adenosine A2A receptors established that they can physically interact in HEK293T27 cells, as both homomers and heteromers. In addition, static/non-dynamical human GPCR data derived from this and other interaction studies were integrated in a large scale graph, called the GPCR heterodimer network (http://www.iiia.csic.es/~ismel/GPCR-Nets/index.html), which provides global insight into adenosine heteromer connectivity, topology and organization in the context of the adenosine receptor subfamily and the GPCR network as a whole.
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Increase of the FGFR1 signaling in the FGFR1-5-HT1A Heteroreceptor complex in midbrain raphe 5-HT neuron systems via allosteric receptor-receptor interaction
SpringerPlus, 2015Co-Authors: Dasiel O Borroto-escuela, Alexander O. Tarakanov, Luigi Francesco Agnati, Michael Di Palma, Manuel Narváez, Antonio Jiménez-beristain, Julia Oflijan, Luca Pinton, Giuseppa Mudò, Natale BelluardoAbstract:The ascending midbrain 5-HT neurons known to contain 5-HT1A autoreceptors may be dysregulated in depression due to a reduced trophic support. New findings show existence of FGFR1-5-HT1A Heteroreceptor complexes in the rat hippocampus with a partial characterization of their interface and in midbrain raphe 5-HT nerve cells. With in situ Proximity Ligation Assay (PLA) and supported by co-location of the FGFR1 and 5-HT1A immunoreactivities in midbrain raphe 5-HT cells, evidence for the existence of FGFR1-5-HT1A Heteroreceptor complexes were obtained in the dorsal and median raphe nuclei of the Sprague–Dawley rat. Their existence in the rat medullary raphe RN33B cell cultures was also established. After combined FGF-2 and 8-OH-DPAT treatment, a marked and significant increase in PLA positive clusters was found in the RN33B cells. Synergistic receptor-receptor interactions in these receptor complexes indicated their enhancing role in hippocampal plasticity. The existence of FGFR1-5-HT1A Heteroreceptor complexes also in midbrain raphe 5-HT nerve cells open up the possibility that antidepressant drugs by increasing extracellular 5-HT levels, can cause an activation of the FGF-2/FGFR1 mechanism in these nerve cells as well. Therefore, the agonist modulation of the FGFR1-5-HT1A Heteroreceptor complexes and their specific role is now determined in rat medullary raphe RN33B cells and in the caudal midline raphe area of the midbrain rich in 5-HT nerve cells. The combined icv treatment with FGF-2 and the 5-HT1A agonist 8-OHDPAT synergistically increased FGFR1 and ERK1/2 phosphorylation in the raphe midline area of the midbrain and in the RN33B cells. Cotreatment with FGF2 and the 5-HT1A agonist induced RN33B cell differentiation as seen from development of the increased number and length of extensions per cell and their increased 5-HT immunoreactivity. These signaling and differentiation events were dependent on the receptor interface since they were blocked by incubation with TMV but not by TMII of the 5-HT1A receptor. Taken together, the 5-HT1A autoreceptors by being part of a FGFR1-5-HT1A Heteroreceptor complex in the midbrain raphe 5-HT nerve cells appears to have also a trophic role in the central 5-HT neuron systems besides playing a key role in reducing the firing of these neurons.