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

• DOI: 10.1007/s11307-014-0786-4
• Publication Date: 2014-10-08T10:21:34Z
• Authors: 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
• Keywords: Male; Neurons; Dopamine; Glutamine; Brain; Mice, Transgenic; Nerve Tissue Proteins; Neuroimaging; Ligands; Multimodal Imaging; Mice, Inbred C57BL; Mice; 03 medical and health sciences; 0302 clinical medicine; Cerebellum; Positron-Emission Tomography; Mutation; Animals; Autoradiography; Homeostasis; Receptors, Cannabinoid; Crosses, Genetic

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.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.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.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.