title: Decreased ipsilateral [¹²³I]iododexetimide binding to cortical muscarinic receptors in unilaterally 6-hydroxydopamine lesioned rats.
abstract: BACKGROUND
  Dysfunction of the cholinergic neurotransmitter system is present in Parkinson's disease, Parkinson's disease related dementia and dementia with Lewy bodies, and is thought to contribute to cognitive deficits in these patients. In vivo imaging of the cholinergic system in these diseases may be of value to monitor central cholinergic disturbances and to select cases in which treatment with cholinesterase inhibitors could be beneficial. The muscarinic receptor tracer [(123)I]iododexetimide, predominantly reflecting M1 receptor binding, may be an appropriate tool for imaging of the cholinergic system by means of SPECT. In this study, we used [(123)I]iododexetimide to study the effects of a 6-hydroxydopamine lesion (an animal model of Parkinson's disease) on the muscarinic receptor availability in the rat brain.
  
  
  METHODS
  Rats (n=5) were injected in vivo at 10-13 days after a confirmed unilateral 6-hydroxydopamine lesion. Muscarinic receptor availability was measured bilaterally in multiple brain areas on storage phosphor images by region of interest analysis.
  
  
  RESULTS
  Autoradiography revealed a consistent and statistically significant lower [(123)I]iododexetimide binding in all examined neocortical areas on the ipsilateral side of the lesion as compared to the contralateral side. In hippocampal and subcortical areas, such asymmetry was not detected.
  
  
  CONCLUSIONS
  This study suggests that evaluation of muscarinic receptor availability in dopamine depleted brains using [(123)I]iododexetimide is feasible. We conclude that 6-hydroxydopamine lesions induce a decrease of neocortical muscarinic receptor availability. We hypothesize that this arises from down regulation of muscarinic postsynaptic M1 receptors due to hyperactivation of the cortical cholinergic system in response to dopamine depletion.
  
  
  CONCLUSIONS
  In rats, dopamine depletion provokes a decrease in neocortical muscarinic receptor availability, which is evaluable by [(123)I]iododexetimide imaging.
  
  
  CONCLUSIONS
  This study may further underline the role of a dysregulated muscarinic system in patients with Lewy body disorders.
authors.affiliation: Department of Nuclear Medicine, University of Amsterdam, Academic Medical Center, Amsterdam, The Netherlands; Graduate School of Neurosciences, Amsterdam, The Netherlands; Department of Nuclear Medicine, Medical Center Alkmaar, Alkmaar, The Netherlands. Electronic address: r.j.j.knol@mca.nl.
authors.forename: Remco J J
authors.initials: RJ
authors.lastname: Knol
authors.forename: Kora
authors.initials: K
authors.lastname: de Bruin
authors.forename: Brent
authors.initials: B
authors.lastname: Opmeer
authors.forename: Pieter
authors.initials: P
authors.lastname: Voorn
authors.forename: Allert J
authors.initials: AJ
authors.lastname: Jonker
authors.forename: Berthe L F
authors.initials: BL
authors.lastname: van Eck-Smit
authors.forename: Jan
authors.initials: J
authors.lastname: Booij
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism*; D003909:Dexetimide / Q000031:analogs & derivatives* / Q000378:metabolism; D008297:Male; D016627:Oxidopamine / Q000633:toxicity*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011976:Receptors, Muscarinic / Q000378:metabolism*; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D011976:Receptors, Muscarinic; C066812:4-iododexetimide; D003909:Dexetimide; D016627:Oxidopamine
keywords: 6-OHDA; 6-hydroxydopamine; ACh; AChEI; AD; Acetylcholine; Acetylcholinesterase inhibitor; Alzheimer’s dementia; Basal nucleus of Meynert; Cholinergic; DLB; Dementia with Lewy bodies; Dexetimide; HC-3; Hemicholinium-3; Lewy body disorders; MFB; Medial forebrain bundle; NBM; PD; PDD; PET; Parkinson’s disease; Parkinson’s disease related dementia; QNB; Rats; SPECT; positron emission tomography; quinuclidinyl benzilate; single photon emission computed tomography