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.
- Disrupted-in-schizophrenia-1 (DISC1) gene