Kjell Fuxe

Kjell Fuxe
Karolinska Institutet | KI · Department of Neuroscience

MD

About

1,850
Publications
107,094
Reads
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108,100
Citations
Citations since 2016
139 Research Items
14384 Citations
201620172018201920202021202205001,0001,5002,0002,500
201620172018201920202021202205001,0001,5002,0002,500
201620172018201920202021202205001,0001,5002,0002,500
201620172018201920202021202205001,0001,5002,0002,500
Additional affiliations
January 1999 - present
Karolinska Institutet
Position
  • Professor Emeritus

Publications

Publications (1,850)
Conference Paper
Full-text available
Recently, we described that Galanin(1-15)[GAL(1-15)] enhanced Escitalopram(ESC) effectiveness in depression symptoms. Moreover GAL(1-15) induces a substantial reduction in alcohol consumption. To investigate the effect of GAL(1-15) on ESC-activity in depression-alcoholism comorbidity, we used the ethanol self-administration test and the forced swim...
Article
Full-text available
Abstract: Alcohol use disorder (AUD) is highly prevalent, and over 50% of AUD patients also suffermajor depressive disorders. Selective 5-HT reuptake inhibitors (SSRIs) can reduce rodent ethanoldrinking but exert modest clinical efficacy in alcoholic individuals. Finding new pharmacologicalstrategies that could modulate alcohol consumption and depr...
Conference Paper
Full-text available
We have recently discovered that Galanin(1-15) [GAL(1-15)] induced depression-like behaviour in the Forced Swimming Test and Tail Suspension Test. Since anhedonia is a core feature of depression, we have analyzed in rats GAL(1-15) actions in anhedonic-like behaviour tests: Saccharin self-administration test, Novelty Suppressed Feeding (NSF) and Fem...
Article
Full-text available
The role of adenosine A2A receptor (A2AR) and striatal-enriched protein tyrosine phosphatase (STEP) interactions in the striatal-pallidal GABA neurons was recently discussed in relation to A2AR overexpression and cocaine-induced increases of brain adenosine levels. As to phosphorylation, combined activation of A2AR and metabotropic glutamate recept...
Article
Full-text available
The heteroreceptor complexes present a novel biological principle for signal integration. These complexes and their allosteric receptor–receptor interactions are bidirectional and novel targets for treatment of CNS diseases including mental diseases. The existence of D2R-5-HT2AR heterocomplexes can help explain the anti-schizophrenic effects of aty...
Chapter
Co-immunoprecipitation (Co-IP) is one of the most broadly used methodologies to identify, validate, and characterize protein–protein interactions (PPIs) in native conditions. In this technique, a protein of interest is immunocaptured from a tissue lysate using a specific antibody. The immunocomplex containing the antibody, the antigen of interest,...
Chapter
Membrane receptor, for example, G-protein-coupled receptors (GPCRs), operates via coordinated changes between the receptor expression, their modifications, and interactions between each other. Perturbation in specific heteroreceptor complexes and/or their balance/equilibrium with other heteroreceptor complexes and corresponding homoreceptor complex...
Article
Full-text available
The widespread distribution of heteroreceptor complexes with allosteric receptor-receptor interactions in the CNS represents a novel integrative molecular mechanism in the plasma membrane of neurons and glial cells. It was proposed that they form the molecular basis for learning and short-and long-term memories. This is also true for drug memories...
Article
Full-text available
To elucidate factors underlying the evolution of large brains in cetaceans, we examined 16 brains from 14 cetartiodactyl species, with immunohistochemical techniques, for evidence of non‑shivering thermogenesis. We show that, in comparison to the 11 artiodactyl brains studied (from 11 species), the 5 cetacean brains (from 3 species), exhibit an exp...
Article
Full-text available
Serotonin communication operates mainly in the extracellular space and cerebrospinal fluid (CSF), using volume transmission with serotonin moving from source to target cells (neurons and astroglia) via energy gradients, leading to the diffusion and convection (flow) of serotonin. One emerging concept in depression is that disturbances in the integr...
Article
Full-text available
The complexity of oxytocin-mediated functions is strongly associated with its modulatory effects on other neurotransmission systems, including the serotonin (5-hydroxytryptamine, 5-HT) system. Signalling between oxytocin (OT) and 5-HT has been demonstrated during neurodevelopment and in the regulation of specific emotion-based behaviours. It is sug...
Preprint
Full-text available
To elucidate causality underlying the evolution of large brains in cetaceans, we examined the brains of 16 cetartiodactyl species for evidence of non-shivering thermogenesis. In comparison to the artiodactyl brain, the cetacean brain exhibits an expanded expression of uncoupling protein 1 (UCP1, UCPs being mitochondrial inner membrane proteins that...
Article
A need for new antidepressants is necessary since traditional antidepressants have several flaws. Neuropeptide Y(NPY) Y1 receptor (NPYY1R) and galanin (GAL) receptor 2 (GALR2) interact in several regions of the limbic system, including the hippocampus. The current study assesses the antidepressant effects induced by GALR2 and NPYY1R coactivation, t...
Conference Paper
Full-text available
The Galanin N-terminal fragment (1-15)[GAL(1-15)] induces depressant-and anxiogenic-like actions in behavioural tests in rats. Since anhedonia is a core feature of depression, we have analyzed GAL(1-15) actions in anhedonic-like behaviour tests: saccharin Self-administration, Sucrose Preference test (SPT), Novelty suppressed feeding (NSF) and Femal...
Article
Full-text available
Several psychoactive drugs can evoke substance use disorders (SUD) in humans and animals, and these include psychostimulants, opioids, cannabinoids (CB), nicotine, and alcohol. The etiology, mechanistic processes, and the therapeutic options to deal with SUD are not well understood. The common feature of all abused drugs is that they increase dopam...
Article
Full-text available
In the 1980s and 1990s, the concept was introduced that molecular integration in the Central Nervous System could develop through allosteric receptor–receptor interactions in heteroreceptor complexes presents in neurons. A number of adenosine–dopamine heteroreceptor complexes were identified that lead to the A2A-D2 heteromer hypothesis of schizophr...
Article
Full-text available
Background Antagonistic adenosine A2A receptor (A2AR)-dopamine D2 receptor (D2R) receptor–receptor interactions have previously been demonstrated in A2AR–D2R heteroreceptor complexes in the rat dorsal striatum. They mainly involve a reduction of affinity in the high-affinity component of the D2R agonist binding site upon activation in vivo of the A...
Article
The majority of the fibroblast growth factor receptor 1-serotonin 1 A receptor (FGFR1-5-HT1AR) heterocomplexes in the hippocampus appeared to be located mainly in the neuronal networks and a relevant target for antidepressant drugs. Through a neurochemical and electrophysiological analysis it was therefore tested in the current study if astrocytic...
Article
Full-text available
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 (...
Article
Full-text available
G protein-coupled receptors modulate the synaptic glutamate and GABA transmission of the claustrum. The work focused on the transmitter–receptor relationships in the claustral catecholamine system and receptor–receptor interactions between kappa opioid receptors (KOR) and SomatostatinR2 (SSTR2) in claustrum. Methods used involved immunohistochemist...
Article
Full-text available
It was previously demonstrated that rat adenosine A2AR transmembrane V peptide administration into the nucleus accumbens enhances cocaine self-administration through disruption of the A2AR-dopamine (D2R) heteroreceptor complex of this region. Unlike human A2AR transmembrane 4 (TM4) and 5 (TM5), A2AR TM2 did not interfere with the formation of the A...
Article
Full-text available
Proceeding investigations of G protein-coupled receptor (GPCR) heterocomplexes have demonstrated that the dopamine D2 receptor (D2R), one of the hub receptors in the physiology of schizophrenia, interacts with both the neurotensin NTS1 (NTS1R) and the serotonin 5-HT2A receptor (5-HT2AR) in cell lines and rodent brain tissue. In situ proximity ligat...
Article
Full-text available
Alterations in circadian rhythms are closely linked to depression, and we have shown earlier that progressive alterations in circadian entrainment precede the onset of depression in mice exposed in utero to excess glucocorticoids. The aim of this study was to investigate whether treatment with the noradrenaline reuptake inhibitor desipramine (DMI)...
Article
Full-text available
The current study was performed to establish the actions of nanomolar concentrations of cocaine, not blocking the dopamine transporter, on dopamine D2 receptor (D2R)-sigma 1 receptor (δ1R) heteroreceptor complexes and the D2R protomer recognition, signaling and internalization in cellular models. We report the existence of D2R-δ1R heteroreceptor co...
Conference Paper
Full-text available
Galanin (1-15)[GAL(1-15)] induces depressant-and anxiogenic-like actions in several behavioural tests. Recently, we described that GAL(1-15) induces an anhedonic-like effect in saccharine self-administration and sucrose preference test in rats. In order to investigate whether the effect of GAL(1-15) in anhedonia was associated with the reward circu...
Article
Full-text available
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...
Article
Full-text available
Based on the work in the Central Nervous System with discoveries of allosteric receptor-receptor interactions in homo- and heteroreceptor complexes representing a major integrative mechanism in synapses and extrasynaptic regions, it is proposed that a similar mechanism may exist in the immunological synapses. We discuss a putative additional molecu...
Article
Full-text available
Neuroprotective M2‐skewed microglia appear as promising to alter the course of neurodegenerative diseases and G protein‐coupled receptors (GPCRs) are potential targets to achieve such microglial polarization. A common feature of adenosine A2A (A2AR) and cannabinoid CB2 (CB2R) GPCRs in microglia is that their expression is upregulated in Alzheimer's...
Article
Full-text available
The interplay between the dopamine (DA) and opioid systems in the brain is known to modulate the additive effects of substances of abuse. On one hand, opioids serve mankind by their analgesic properties, which are mediated via the mu opioid receptor (MOR), a Class A G protein-coupled receptor (GPCR), but on the other hand, they pose a potential thr...
Article
Preclinical data indicate that ethanol produces behavioral effects that can be regulated by many neurotransmitters and neuromodulators like adenosine (A). The most important receptors with respect to the rewarding effects of ethanol seem to be the A2A receptors. This study used a transgenic strategy, specifically rats overexpressing the A2A recepto...
Article
The dopaminergic system integrated by cell groups distributed in several brain regions exerts a modulatory role in brain. Particularly important for this task are the mesencephalic dopamine neurons, which from the substantia nigra and ventral tegmental area project to the dorsal striatum and the cortical/subcortical limbic systems, respectively. Do...
Article
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 t...
Article
Galanin (1-15) [GAL(1-15)] participates in mood regulation and depression. GAL(1-15) is also able to enhance the antidepressant effects induced by Fluoxetine (FLX) in the forced swimming test through interaction between GALR1-GALR2 and 5-HT1A receptors that induced changes in the binding characteristics and mRNA of the 5-HT1AR in the hippocampus. S...
Article
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 behaviours. Signalling crosstalk between their endogenous ligands, oxytocin (OT) and serotonin (5-hydroxytryptamine, 5-HT) highlights the complex interplay between...
Article
Full-text available
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...
Chapter
A large body of evidence indicates that G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) can form heteroreceptor complexes. In these complexes, the signaling from each interacting protomer is modulated to produce an integrated and therefore novel response upon agonist(s) activation. In the GPCR-RTK heteroreceptor complexes,...
Chapter
The isolation and characterization of GPCR heteroreceptor complexes, specially those present at the central nervous system, are of crucial relevance for the understanding of the molecular mechanisms behind several mental and neurodegenerative disorders. The existence of homo- and heteroreceptor complexes with allosteric receptor-receptor interactio...
Chapter
Aestivation is a survival strategy used by many invertebrates, e.g., the Cuban land snails of the genus Polymita, to endure arid and very dry environmental conditions. Key features of aestivation include strong metabolic rate suppression, strategies to retain body water, altered nitrogen metabolism, and mechanisms to preserve and stabilize organs,...
Article
Full-text available
Rationale and objectives Many studies indicated that adenosine via its A2A receptors influences the behavioral effects of cocaine by modulating dopamine neurotransmission. The hypothesis was tested that A2A receptors in the nucleus accumbens (NAc) or the prefrontral cortex (PFc) may modulate cocaine reward and/or cocaine seeking behavior in rats....
Article
The concept of allosteric receptor–receptor interactions in G protein-coupled receptor homo- and heteroreceptor complexes in which they physically interact provides a new dimension to molecular integration in the brain. The receptor–receptor interactions dynamically change recognition, pharmacology, signaling, and trafficking of the participating r...
Article
Full-text available
The A2A adenosine receptor (A2AR) is widely distributed on different cellular types in the brain, where it exerts a broad spectrum of pathophysiological functions, and for which a role in different neurodegenerative diseases has been hypothesized or demonstrated. To investigate the role of neuronal A2ARs in neurodegeneration, we evaluated in vitro...
Article
Full-text available
The A2A adenosine (A2AR) and D2 dopamine (D2R) receptors form oligomers in the cell membrane and allosteric interactions across the A2AR-D2R heteromer represent a target for development of drugs against central nervous system disorders. However, understanding of the molecular determinants of A2AR-D2R heteromerization and the allosteric antagonistic...
Chapter
Whereas ionotropic receptors have been considered as functional units consisting of interacting subunits, G protein-coupled receptors were considered as monomeric cell surface receptors. Experimental evidence from the end of the twentieth century has demonstrated that GPCR may also form dimers, trimers, and even high-order oligomers. Novel techniqu...
Chapter
There is a large body of biochemical and biophysical experimental evidences which establishes the existence of G protein-coupled receptors (GPCRs) as homo- and heteroreceptor complexes. The results indicate that there are allosteric interactions across the receptor–receptor interface of homo- and heteroreceptor complexes that modulate the binding p...
Chapter
During the last 50 years, microdialysis technique has been continuously improved to become a well-established method to monitor local concentrations of neurotransmitters. In respect to other currently used techniques, such as voltammetry, microdialysis has the advantage to be possibly applied to all measurable neurotransmitters and to allow local t...
Chapter
The allosteric receptor–receptor interactions in G protein-coupled receptor (GPCR) heteroreceptor complexes provided a new dimension for the integration of signaling at plasma membrane level of neurons in brain. Neuronal plasticity processes underlying brain functions, such as learning and memory, have been proposed to be based on rearrangement of...
Chapter
An important step forward in understanding synaptic transmission has been the discovery that within the realm of G-protein coupled receptors (GPCRs) agonist activation of a receptor type favors physical interactions with different types of neighboring GPCRs. Such receptor interactions lead to receptor oligomerization and formation of receptor heter...
Chapter
The gene silencing by RNA interference (RNAi) represents a new approach for inhibition of gene expression in cell culture and in vivo and it is a potential clinical tool for the treatment of illnesses, including neuropsychiatric disorders. In this chapter, we described an animal model using this technology to study the role of Galanin (1–15) [GAL(1...
Chapter
Receptor–receptor interactions that occur in G protein-coupled receptors (GPCRs) oligomers can be explored using three different functional approaches as starting point: (1) quantitative receptor autoradiography (saturation assay); (2) agonist-stimulated [³⁵S]GTPγS binding in autoradiography; and (3) immunohistochemistry. Together, they allow to ex...
Chapter
Synaptosomes are sealed presynaptic nerve terminals obtained by homogenizing selected brain regions under iso-osmotic conditions. This preparation has been extensively used to study the mechanism of neurotransmitter release in vitro because they preserve the biochemical, morphological, and electrophysiological properties of the synapse. This allows...
Chapter
In addition to their canonical intracellular signals involved in the regulation of neuronal plasticity, G-protein coupled receptors can also rapidly transactivate tyrosine kinase receptors and their downstream intracellular signaling in absence of specific ligands. Here we describe our protocol for dissociating and maintaining hippocampal primary n...
Chapter
GPCR’s receptosome operates via coordinated changes between the receptor expression, their modifications and interactions between each other. Perturbation in specific heteroreceptor complexes and/or their balance/equilibrium with other heteroreceptor complexes and corresponding homoreceptor complexes is considered to have a role in pathogenic mecha...
Chapter
The G protein-coupled receptor heterocomplex network database (GPCR-hetnet) is a database designed to store information on GPCR heteroreceptor complexes and their allosteric receptor–receptor interactions. It is an expert-authored and peer-reviewed, curated collection of well-documented GPCR–GPCR interactions that span the gamut from classical GPCR...
Chapter
G protein-coupled receptors (GPCRs) complexes and their allosteric receptor–receptor interactions represent a new fundamental principle in molecular medicine for integration of transmitter signals in the plasma membrane. The allosteric receptor–receptor interactions in heteroreceptor complexes give diversity, specificity, and bias to the receptor p...
Article
Full-text available
Antagonistic allosteric A2AR-D2R receptor-receptor interactions in heteroreceptor complexes counteract cocaine self-administration and cocaine seeking in rats as seen in biochemical and behavioral experiments. It was shown that the human A2AR transmembrane five (TM5) was part of the interface of the human A2AR-D2R receptor heteromer. In the current...
Article
Here we employed a range of immunohistochemical stains, focussing on tyrosine hydroxylase and dopamine‐β‐hydroxylase, to show that within the pons of tree pangolins clusters of noradrenergic neurons are present. No noradrenergic neurons were observed in the pontine periventricular grey matter (A6 and A4 groups missing), with all noradrenergic neuro...
Chapter
While adrenergic receptors were instrumental to start to understand the role of GPCRs, other receptors are taking the lead to understand why GPCR homo−/heteromers are needed and to address their physiological consequences in both healthy/homeostatic conditions and disease. Adenosine and dopamine receptors in the CNS are instrumental to understand p...
Article
Full-text available
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 discu...
Article
Full-text available
Abnormality of dopamine D2 receptor (D2R) function, often observed as D2R supersensitivity (D2RSS), is a commonality of schizophrenia and related psychiatric disorders in humans. Moreover, virtually all psychotherapeutic agents for schizophrenia target D2R in brain. Permanent D2RSS as a feature of a new animal model of schizophrenia was first repor...
Conference Paper
Full-text available
Galanin (GAL) is involved in drug abuse and addiction including alcohol intake. In this work, we have analysed the role of the N-terminal GAL fragment (1-15) [GAL(1-15)] in voluntary ethanol consumption in rats using the two-bottle choice paradigm as well as compare the effects of GAL(1-15) with GAL. The two-bottle choice test was used to determine...
Article
Full-text available
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 heterorec...
Article
Full-text available
Morphine binding to opioid receptors, mainly to μ opioid receptor (MOR), induces alterations in intracellular pathways essential to the initial development of addiction. The activation of the dopamine D4 receptor (D4R), which is expressed in the caudate putamen (CPu), mainly counteracts morphine-induced alterations in several molecular networks. Th...
Article
Full-text available
Anxiety is evoked by a threatening situation and display adaptive or defensive behaviors, found similarly in animals and humans. Neuropeptide Y (NPY) Y1 receptor (NPYY1R) and Galanin (GAL) receptor 2 (GALR2) interact in several regions of the limbic system, including the amygdala. In a previous study, GALR2 enhanced NPYY1R mediated anxiolytic actio...