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

• Published in: Molecular imaging and biology 2015-06, Vol.17 (3), p.355-363
• Main Authors: Kim, Jongho, Horti, Andrew G., Mathews, William B., Pogorelov, Vladimir, Valentine, Heather, Brasic, James R., Holt, Daniel P., Ravert, Hayden T., Dannals, Robert F., Zhou, Luewi, Jedynak, Bruno, Kamiya, Atsushi, Pletnikov, Mikhail V., Wong, Dean F.
• Format: Article
• Language: English
• Subjects: Animals; Autoradiography; Brain - diagnostic imaging; Brain - metabolism; Cerebellum - diagnostic imaging; Cerebellum - metabolism; Crosses, Genetic; Dopamine - chemistry; Glutamine - chemistry; Homeostasis; Imaging; Ligands; Male; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Mice, Transgenic; Multimodal Imaging; Mutation; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - physiology; Neuroimaging; Neurons - metabolism; Positron-Emission Tomography; Radiology; Receptors, Cannabinoid - chemistry; Receptors, Nicotinic - chemistry; Research Article
• ISSN: 1536-1632; 1860-2002
• DOI: 10.1007/s11307-014-0786-4

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 (D 2/3 R)], glutamatergic [metabotropic glutamate 5 (mGluR 5 )], 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. Procedures The quantitative in vitro autoradiography was performed with positron emission tomography (PET) ligands using [ 11 C]raclopride (D 2/3 R), [ 11 C]ABP688 (mGluR 5 ), [ 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, mGluR 5 , 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 mGluR 5 and D 2/3 R 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 D 2/3 R (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 D 2/3 R. Multi-receptor mapping with PET ligands in relevant animal models could be a valuable translational approach for psychiatric drug development.