Skip to main content
profile image
Selected Works of Bruno Jedynak
Article
Quantitative Multi-modal Brain Autoradiography of Glutamatergic, Dopaminergic, Cannabinoid, and Nicotinic Receptors in Mutant Disrupted-In-Schizophrenia-1 (DISC1) Mice
Molecular Imaging and Biology (2015)
  • Jongho Kim, The Johns Hopkins University
  • Andrew G. Horti, The Johns Hopkins University
  • William B. Mathews, The Johns Hopkins University
  • Vladimir Pogorelov, The Johns Hopkins University
  • Heather Valentine, The Johns Hopkins University
  • James R. Brasic, The Johns Hopkins University
  • Daniel P. Holt, The Johns Hopkins University
  • Hayden T. Ravert, The Johns Hopkins University
  • Robert F. Dannals, The Johns Hopkins University
  • Luewi Zhou, The Johns Hopkins University
  • Bruno M. Jedynak, Portland State University
  • Atsushi Kamiya, The Johns Hopkins University
  • Mikhail V. Pletnikov, The Johns Hopkins University
  • Dean F. Wong, The Johns Hopkins University
Link Find in your library
Abstract
Purpose
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 (D2/3R)], glutamatergic [metabotropic glutamate 5 (mGluR5)], cannabinoid 1 (CB1R), and nicotinic acetylcholine (α4β2-nAChR) receptors in the brains of mice with inducible forebrain neuronal expression of dominant-negative mutant DISC1.

Procedures
The quantitative in vitro autoradiography was performed with positron emission tomography (PET) ligands using [11C]raclopride (D2/3R), [11C]ABP688 (mGluR5), [11C]OMAR (CB1R), and [18F]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 D2/3R, mGluR5, and α4β2-nAChR, while the midbrain was the reference tissue for CB1R, because of the high density of CB1R 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 CB1R and D2/3R (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 CB1R and D2/3R. Multi-receptor mapping with PET ligands in relevant animal models could be a valuable translational approach for psychiatric drug development.
Disciplines
Publication Date
June, 2015
DOI
10.1007/s11307-014-0786-4
Citation Information
Kim, J., Horti, A. G., Mathews, W. B., Pogorelov, V., Valentine, H., Brasic, J. R., & ... Wong, D. F. (2015). Quantitative Multi-modal Brain Autoradiography of Glutamatergic, Dopaminergic, Cannabinoid, and Nicotinic Receptors in Mutant Disrupted-In-Schizophrenia-1 (DISC1) Mice. Molecular Imaging And Biology: MIB: The Official Publication Of The Academy Of Molecular Imaging, 17(3), 355-363.