title: Dopamine D2 heteroreceptor complexes and their receptor-receptor interactions in ventral striatum: novel targets for antipsychotic drugs.
abstract: This review is focused on the D2 heteroreceptor complexes within the ventral striatum with their receptor-receptor interactions and relevance for the treatment of schizophrenia. A "guide-and-clasp" manner for receptor-receptor interactions is proposed where "adhesive guides" may be amino acid triplet homologies, which were determined for different kinds of D2 heteroreceptor complexes. The first putative D2 heteroreceptor complex to be discovered in relation to schizophrenia was the A2A-D2 heteroreceptor complex where antagonistic A2A-D2 receptor-receptor interactions were demonstrated after A2A agonist treatment in the ventral striatum. The A2A agonist CGS 21680 with atypical antipsychotic properties may at least in part act by increasing β-arrestin2 signaling over the D2 protomer in the A2A-D2 heteroreceptor complex in the ventral striatum. The antagonistic NTS1-D2 interactions in the NTS1-D2 heteroreceptor complex in the ventral striatum are proposed as one molecular mechanism for the potential antipsychotic effects of NT. Indications were obtained that the psychotic actions of the 5-HT2AR hallucinogens LSD and DOI can involve enhancement of D2R protomer signaling via a biased agonist action at the 5-HT2A protomer in the D2-5-HT2A heteroreceptor complex in the ventral striatum. Facilitatory allosteric D2likeR-OTR interactions in heteroreceptor complexes in nucleus accumbens may have a role in social and emotional behaviors. By blocking the D2 protomers of these heteroreceptor complexes, antipsychotics can fail to reduce the negative symptoms of schizophrenia. The discovery of different types of D2 heteroreceptor complexes gives an increased understanding of molecular mechanisms involved in causing schizophrenia and new strategies for its treatment and understanding the side effects of antipsychotics.
authors: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. Electronic address: kjell.fuxe@ki.se.
authors: Kjell
authors: K
authors: Fuxe
authors: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors: Dasiel O
authors: DO
authors: Borroto-Escuela
authors: Russian Academy of Sciences, St Petersburg Institute for Informatics and Automatation, St. Petersburg, Russia.
authors: Alexander O
authors: AO
authors: Tarakanov
authors: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors: Wilber
authors: W
authors: Romero-Fernandez
authors: Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy.
authors: Luca
authors: L
authors: Ferraro
authors: Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy.
authors: Sergio
authors: S
authors: Tanganelli
authors: Department of Pathology, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors: Mileidys
authors: M
authors: Perez-Alea
authors: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Earth, Life and Environmental Sciences, Section of Physiology, Campus Scientifico 'Enrico Mattei', Urbino, Italy.
authors: Michael
authors: M
authors: Di Palma
authors: IRCCS San Camillo, Lido Venice, Italy.
authors: Luigi F
authors: LF
authors: Agnati
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D006801:Humans; D017448:Receptors, Dopamine D2 / Q000737:chemistry / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism*; D066328:Ventral Striatum / Q000378:metabolism*
chemical_list: D014150:Antipsychotic Agents; D017448:Receptors, Dopamine D2; D004298:Dopamine
keywords: D2 receptors; heteroreceptor complexes; receptor–receptor interactions; schizophrenia; ventral striatum