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 HD, 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 M2 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 α2 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 M1 acetylcholine, 5‐HT2A serotonin, A2A adenosine, D1 and D2 dopamine, and GABAA 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 presynaptically localized cholinergic and noradrenergic receptors in the response to Huntington's disease pathology.

[1]  Horst Halling,et al.  Evaluation of 18F-CPFPX, a novel adenosine A1 receptor ligand: in vitro autoradiography and high-resolution small animal PET. , 2003, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[2]  S. Folstein,et al.  Neurotransmitter receptor alterations in Huntington's disease: Autoradiographic and homogenate studies with special reference to benzodiazepine receptor complexes , 1985, Annals of neurology.

[3]  D. Sibley,et al.  Striatal neurochemical changes in transgenic models of Huntington's disease , 2002, Journal of neuroscience research.

[4]  M. O'Neill,et al.  The role of neuronal nicotinic acetylcholine receptors in acute and chronic neurodegeneration. , 2002, Current drug targets. CNS and neurological disorders.

[5]  Ruth Luthi-Carter,et al.  Complex alteration of NMDA receptors in transgenic Huntington's disease mouse brain: analysis of mRNA and protein expression, plasma membrane association, interacting proteins, and phosphorylation , 2003, Neurobiology of Disease.

[6]  G. Sedvall,et al.  PET study of the pre- and post-synaptic dopaminergic markers for the neurodegenerative process in Huntington's disease. , 1997, Brain : a journal of neurology.

[7]  Steven Finkbeiner,et al.  Huntingtin Acts in the Nucleus to Induce Apoptosis but Death Does Not Correlate with the Formation of Intranuclear Inclusions , 1998, Cell.

[8]  Francesco Scaravilli,et al.  Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease , 2004, Nature Genetics.

[9]  R. Wetzel,et al.  Aggregated polyglutamine peptides delivered to nuclei are toxic to mammalian cells. , 2002, Human molecular genetics.

[10]  R. Faull,et al.  GABAA receptor subunit and gephyrin protein changes differ in the globus pallidus in Huntington's diseased brain , 2003, Brain Research.

[11]  Thomas Walther,et al.  Transgenic rat model of Huntington's disease. , 2003, Human molecular genetics.

[12]  R. Faull,et al.  Chemical and anatomical changes in the striatum and substantia nigra following quinolinic acid lesions in the striatum of the rat: a detailed time course of the cellular and GABAA receptor changes , 1999, Journal of Chemical Neuroanatomy.

[13]  S. Augood,et al.  Reduction in enkephalin and substance P messenger RNA in the striatum of early grade Huntington's disease: A detailed cellularin situ hybridization study , 1996, Neuroscience.

[14]  B. Harper.  Huntington Disease , 2005, Journal of the Royal Society of Medicine.

[15]  Carlos Cepeda,et al.  Transient and Progressive Electrophysiological Alterations in the Corticostriatal Pathway in a Mouse Model of Huntington's Disease , 2003, The Journal of Neuroscience.

[16]  K. Zilles,et al.  Recent results of the TierPET scanner , 1999, 1999 IEEE Nuclear Science Symposium. Conference Record. 1999 Nuclear Science Symposium and Medical Imaging Conference (Cat. No.99CH37019).

[17]  D. Brooks,et al.  Striatal D1 and D2 receptor binding in patients with Huntington's disease and other choreas. A PET study. , 1995, Brain : a journal of neurology.

[18]  M. Dragunow,et al.  The pattern of neurodegeneration in Huntington's disease: a comparative study of cannabinoid, dopamine, adenosine and GABAA receptor alterations in the human basal ganglia in Huntington's disease , 2000, Neuroscience.

[19]  Keiichi Oda,et al.  Adenosine A2A receptor imaging with [11C]KF18446 PET in the rat brain after quinolinic acid lesion: Comparison with the dopamine receptor imaging , 2002, Annals of nuclear medicine.

[20]  Harvey R Herschman,et al.  Molecular Imaging: Looking at Problems, Seeing Solutions , 2003, Science.

[21]  Simon R. Cherry,et al.  Deficits in Striatal Dopamine D2 Receptors and Energy Metabolism Detected by in Vivo MicroPET Imaging in a Rat Model of Huntington's Disease , 2000, Experimental Neurology.

[22]  M. Levivier,et al.  Quinolinic acid-induced lesions of the rat striatum: quantitative autoradiographic binding assessment. , 1998, Neurological research.

[23]  K. Zilles,et al.  Quantitative auto radiography of 11 different transmitter binding sites in the basal forebrain region of the rat—Evidence of heterogeneity in distribution patterns , 1991, Neuroscience.

[24]  Manish S. Shah,et al.  A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes , 1993, Cell.

[25]  F. Colpaert,et al.  Neuroprotective Effects of the α2-Adrenoceptor Antagonists, (+)-Efaroxan and (±)-Idazoxan, against Quinolinic Acid-Induced Lesions of the Rat Striatum , 1998, Experimental Neurology.

[26]  S. Augood,et al.  Dopamine D1 and D2 receptor gene expression in the striatum in Huntington's disease , 1997, Annals of neurology.

[27]  S. W. Davies,et al.  Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. , 1997, Science.

[28]  K. Vrana,et al.  Inhibition of tryptophan hydroxylase activity and decreased 5‐HT1A receptor binding in a mouse model of Huntington's disease , 2002, Journal of neurochemistry.

[29]  S. W. Davies,et al.  Altered neurotransmitter receptor expression in transgenic mouse models of Huntington's disease. , 1999, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[30]  F. Colpaert,et al.  α2-Adrenoceptor modulation of cortical acetylcholine release in vivo , 1999, Neuroscience.

[31]  R. Nickles.  The production of a broader palette of PET tracers , 2003 .

[32]  J. M. Crowder,et al.  Inhibitory effects of noradrenaline and dopamine on calcium influx and neurotransmitter glutamate release in mammalian brain slices. , 1987, European journal of pharmacology.

[33]  Nicola Pavese,et al.  Progressive striatal and cortical dopamine receptor dysfunction in Huntington's disease: a PET study. , 2003, Brain : a journal of neurology.

[34]  C. Cepeda,et al.  NMDA receptor function in mouse models of Huntington disease , 2001, Journal of neuroscience research.

[35]  H. Coenen,et al.  Tritium-labelled 8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine ([3H]CPFPX), a potent and selective antagonist for the A1 adenosine receptor , 2003 .

[36]  F. Colpaert,et al.  Acetylcholine Release in the Rat Prefrontal Cortex In Vivo: Modulation by α2‐Adrenoceptor Agonists and Antagonists , 1997, Journal of neurochemistry.

[37]  J. Penney,et al.  NMDA receptor losses in putamen from patients with Huntington's disease. , 1988, Science.

[38]  M. Eddleston,et al.  Molecular profile of reactive astrocytes—Implications for their role in neurologic disease , 1993, Neuroscience.

[39]  D. Eidelberg,et al.  [11C]Raclopride‐PET studies of the Huntington's disease rate of progression: Relevance of the trinucleotide repeat length , 1998, Annals of neurology.