title: Quantitative Multi-modal Brain Autoradiography of Glutamatergic, Dopaminergic, Cannabinoid, and Nicotinic Receptors in Mutant Disrupted-In-Schizophrenia-1 (DISC1) Mice.
abstract: OBJECTIVE
  Disrupted-in-schizophrenia-1 (DISC1) is a promising genetic susceptibility factor for major psychiatric conditions, such as schizophrenia. We hypothesized that the mutant DISC1 alters the homeostasis of multi-receptor interactions between dopaminergic [dopamine 2/3 (D(2/3)R)], glutamatergic [metabotropic glutamate 5 (mGluR5)], cannabinoid 1 (CB(1)R), and nicotinic acetylcholine (α4β2-nAChR) receptors in the brains of mice with inducible forebrain neuronal expression of dominant-negative mutant DISC1.
  
  
  METHODS
  The quantitative in vitro autoradiography was performed with positron emission tomography (PET) ligands using [(11)C]raclopride (D2/3R), [(11)C]ABP688 (mGluR5), [(11)C]OMAR (CB(1)R), and [(18)F]AZAN (nAChR). Total binding (pmol/cc) from standard and binding index, defined as [(region of interest - reference) / reference], was analyzed in the parasagittal sections. The cerebellum was used as a reference for D(2/3)R, mGluR5, and α4β2-nAChR, while the midbrain was the reference tissue for CB(1)R, because of the high density of CB(1)R in the cerebellum.
  
  
  RESULTS
  We observed a significant positive correlation between mGluR5 and D2/3R in the nucleus accumbens (NAc) in mutant DISC1 (rho = 0.6, p = 0.04; y = 0.02 x + 6.7) and a trend of negative correlation between those receptors in the dorsal striatum (DS) in control animals (rho = -0.5, p = 0.09; y = -0.03 x + 23), suggesting a co-release of dopamine (DA) and glutamate (Glu) in the NAc, but not in the DS. There were trends of an inverse relationship between striatal CB(1)R and D(2/3)R (rho = -0.7, p = 0.07) as well as between dorsal thalamic nAChR and striatal D2/3R (rho = -0.5, p = 0.08). There was no statistically significant difference of the individual receptor density in the majority of brain regions.
  
  
  CONCLUSIONS
  The mutant DISC1 altered the homeostasis of multi-receptor interactions of coincident signaling of DA and Glu in the NAc, but not in the DS, and mutually negative control of striatal CB(1)R and D2/3R. Multi-receptor mapping with PET ligands in relevant animal models could be a valuable translational approach for psychiatric drug development.
authors.affiliation: Division of Nuclear Medicine, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, 601 North Caroline St. JHOC building Rm 3245, Baltimore, MD, 21287-0807, USA.
authors.forename: Jongho
authors.initials: J
authors.lastname: Kim
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Horti
authors.forename: William B
authors.initials: WB
authors.lastname: Mathews
authors.forename: Vladimir
authors.initials: V
authors.lastname: Pogorelov
authors.forename: Heather
authors.initials: H
authors.lastname: Valentine
authors.forename: James R
authors.initials: JR
authors.lastname: Brasic
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Holt
authors.forename: Hayden T
authors.initials: HT
authors.lastname: Ravert
authors.forename: Robert F
authors.initials: RF
authors.lastname: Dannals
authors.forename: Luewi
authors.initials: L
authors.lastname: Zhou
authors.forename: Bruno
authors.initials: B
authors.lastname: Jedynak
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kamiya
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Pletnikov
authors.forename: Dean F
authors.initials: DF
authors.lastname: Wong
mesh_terms: D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002531:Cerebellum / Q000000981:diagnostic imaging / Q000378:metabolism; D003433:Crosses, Genetic; D004298:Dopamine / Q000737:chemistry*; D005973:Glutamine / Q000737:chemistry*; D006706:Homeostasis; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D064847:Multimodal Imaging; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology; D059906:Neuroimaging; D009474:Neurons / Q000378:metabolism*; D049268:Positron-Emission Tomography; D043882:Receptors, Cannabinoid / Q000737:chemistry*; D011978:Receptors, Nicotinic / Q000737:chemistry*
chemical_list: C498794:Disc1 protein, mouse; D008024:Ligands; D009419:Nerve Tissue Proteins; D043882:Receptors, Cannabinoid; D011978:Receptors, Nicotinic; D005973:Glutamine; D004298:Dopamine