Regional and subtype selective changes of neurotransmitter receptor density in a rat transgenic for the Huntington's disease mutation

Huntington's disease (HD) is an autosomal dominantly inherited progressive neurodegenerative disorder caused by a CAG/polyglutamine repeat expansion in the gene encoding the huntingtin protein. We have recently generated a rat model transgenic for HID, which displays a slowly progressive phenotype resembling the human adult-onset type of disease. In this study we systematically assessed the distribution and density of 17 transmitter receptors in the brains of 2-year-old rats using quantitative multi-tracer autoradiography and high-resolution positron emission tomography. Heterozygous animals expressed increased densities of M-2 acetylcholine (increase of 148 +/- 16% of controls; p > 0.001; n = 7), nicotine (increase of 149 +/- 16% of controls; p > 0.01; n = 6), and alpha(2) noradrenergic receptors (increase of 141 +/- 15% of controls; p > 0.001; n = 6), respectively. Densities of these receptors were decreased in homozygous animals. Decreases of receptor density in both hetero- and homozygous animals were found for M, acetylcholine, 5-HT2A serotonin, A(2A) adenosine, D-1 and D-2 dopamine, and GABA(A) receptors, respectively. Other investigated receptor systems showed small changes or were not affected. The present data suggest that the moderate increase of CAG/polyglutamine repeat expansions in the present rat model of Huntington's disease is characterized by subtype-selective and region-specific changes of neuroreceptor densities. In particular, there is evidence for a contribution of predominantly presynapticaily localized cholinergic and noradrenergic receptors in the response to Huntington's disease pathology.