title: Hallucinogenic 5-HT2AR agonists LSD and DOI enhance dopamine D2R protomer recognition and signaling of D2-5-HT2A heteroreceptor complexes.
abstract: Dopamine D2LR-serotonin 5-HT2AR heteromers were demonstrated in HEK293 cells after cotransfection of the two receptors and shown to have bidirectional receptor-receptor interactions. In the current study the existence of D2L-5-HT2A heteroreceptor complexes was demonstrated also in discrete regions of the ventral and dorsal striatum with in situ proximity ligation assays (PLA). The hallucinogenic 5-HT2AR agonists LSD and DOI but not the standard 5-HT2AR agonist TCB2 and 5-HT significantly increased the density of D2like antagonist (3)H-raclopride binding sites and significantly reduced the pKiH values of the high affinity D2R agonist binding sites in (3)H-raclopride/DA competition experiments. Similar results were obtained in HEK293 cells and in ventral striatum. The effects of the hallucinogenic 5-HT2AR agonists on D2R density and affinity were blocked by the 5-HT2A antagonist ketanserin. In a forskolin-induced CRE-luciferase reporter gene assay using cotransfected but not D2R singly transfected HEK293 cells DOI and LSD but not TCB2 significantly enhanced the D2LR agonist quinpirole induced inhibition of CRE-luciferase activity. Haloperidol blocked the effects of both quinpirole alone and the enhancing actions of DOI and LSD while ketanserin only blocked the enhancing actions of DOI and LSD. The mechanism for the allosteric enhancement of the D2R protomer recognition and signalling observed is likely mediated by a biased agonist action of the hallucinogenic 5-HT2AR agonists at the orthosteric site of the 5-HT2AR protomer. This mechanism may contribute to the psychotic actions of LSD and DOI and the D2-5-HT2A heteroreceptor complex may thus be a target for the psychotic actions of hallunicogenic 5-HT2A agonists.
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. Electronic address: Dasiel.Borroto-Escuela@ki.se.
authors.forename: Dasiel O
authors.initials: DO
authors.lastname: Borroto-Escuela
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. Electronic address: wromfdez@gmail.com.
authors.forename: Wilber
authors.initials: W
authors.lastname: Romero-Fernandez
authors.affiliation: Department of Physiology, School of Medicine, University of Málaga, Spain. Electronic address: mnarvaez@uma.es.
authors.forename: Manuel
authors.initials: M
authors.lastname: Narvaez
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Tartu, Estonia. Electronic address: juliaofli@gmail.com.
authors.forename: Julia
authors.initials: J
authors.lastname: Oflijan
authors.affiliation: IRCCS Lido, Venice, Italy. Electronic address: luigiagnati@tin.it.
authors.forename: Luigi F
authors.initials: LF
authors.lastname: Agnati
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. Electronic address: Kjell.Fuxe@ki.se.
authors.forename: Kjell
authors.initials: K
authors.lastname: Fuxe
mesh_terms: D000662:Amphetamines / Q000494:pharmacology*; D000818:Animals; D001479:Basal Ganglia / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D017930:Genes, Reporter; D057809:HEK293 Cells; D006213:Hallucinogens / Q000494:pharmacology*; D006801:Humans; D007650:Ketanserin / Q000494:pharmacology; D008156:Luciferases / Q000032:analysis / Q000235:genetics; D008238:Lysergic Acid Diethylamide / Q000494:pharmacology*; D008297:Male; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics*; D017448:Receptors, Dopamine D2 / Q000235:genetics*; D058826:Serotonin 5-HT2 Receptor Agonists / Q000494:pharmacology*; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology
chemical_list: D000662:Amphetamines; D006213:Hallucinogens; D044402:Receptor, Serotonin, 5-HT2A; D017448:Receptors, Dopamine D2; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D008238:Lysergic Acid Diethylamide; D007650:Ketanserin; D008156:Luciferases; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine
keywords: 2,5-Dimethoxy-4-iodoamphetamine; Allosteric modulation; Antipsychotic drugs; Dopamine D2 receptor; G-protein-coupled receptors; Heterodimerization; Heteroreceptor complexes; Lysergic acid diethylamide; Receptor–receptor interactions; Serotonin 5-HT2A receptor