Karolinska Institute, Sweden
Title: Multiple D2 heteroreceptor complexes in the ventral striatum: Relevance for schizophrenia and cocaine use disorder and their treatments
Biography: Kjell Fuxe
Statement of the Problem: Th e discovery of allosteric receptor-receptor interactions in GPCR heteroreceptor complexes in the
plasma membrane of nerve cells in the CNS gave a new dimension to brain integration, plasticity and neuropsychopharmacology.
Aim of this study is to test the hypothesis that diff erent types of D2 heteroreceptor complexes are new targets in the treatment
of schizophrenia and cocaine use disorder. D2 receptors in the complexes can also interact with ion channel receptors, receptor
tyrosine kinases and/or adapter proteins. Disturbances in the D2 complexes can contribute to schizophrenia development and
cocaine use disorder through changes in the balance of the activity of diverse D2 homo-and heteroreceptor complexes of the
ventral striatopallidal GABA anti-reward pathway regulating salience.
Methodology & Th eoretical Orientation: Proximity ligation assays and biochemical binding techniques were used with
Findings: Agonist activation of A2A protomer in the A2A–D2 heteroreceptor complex inhibits D2 Gi/o mediated signaling
but increases the D2 β-arrestin2 mediated signaling. Th rough this allosteric receptor–receptor interaction, the A2A agonist
becomes a biased inhibitory modulator of the Gi/o mediated D2 signaling, which may be the main mechanism for its atypical
antipsychotic properties. Th e dopamine (DA) and glutamate hypotheses of schizophrenia come together in the signal
integration in D2–NMDAR and A2A–D2–mGluR5 heteroreceptor complexes, especially in the ventral striatum. Cocaine selfadministration
diff erentially aff ected allosteric A2A-D2 receptor-receptor interactions in the ventral vs. the dorsal striatum.
Conclusion & Signifi cance: Dysregulation of the meso-limbic DA neurons and their post junctional D2 heteroreceptor targets
may be involved in producing the symptoms of schizophrenia. Potential diff erences in the composition and stoichiometry of
the A2A-D2 heteroreceptor complexes, including diff erential recruitment of sigma 1 receptor, to the ventral vs. dorsal striatum
may explain the selective antagonistic A2A-D2 receptor interactions observed aft er cocaine self-administration in nucleus
accumbens explaining the anti-cocaine actions of A2A agonists.