Quantitative Multi-modal Brain Autoradiography of Glutamatergic, Dopaminergic, Cannabinoid, and Nicotinic Receptors in Mutant Disrupted-In-Schizophrenia-1 (DISC1) Mice

Jongho Kim, Andrew G. Horti, William B. Mathews, Vladimir Pogorelov, Heather Valentine, James R. Brasic, Daniel P. Holt, Hayden T. Ravert, Robert F. Dannals, Luewi Zhou, Bruno Jedynak, Atsushi Kamiya, Mikhail V. Pletnikov, Dean F. Wong

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)355-363
Number of pages9
JournalMolecular Imaging and Biology
Volume17
Issue number3
DOIs
StatePublished - Jun 1 2015

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Keywords

  • Autoradiography
  • CBR
  • DR
  • Disrupted-in-schizophrenia-1 (DISC1) gene
  • mGluR
  • nAChR

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

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