In vivo type 1 cannabinoid receptor mapping in the 6-hydroxydopamine lesion rat model of Parkinson's disease

Type 1 cannabinoid (CB1) receptors are expressed in high concentrations in the central nervous system, including the basal ganglia, and could have direct or indirect effects on motor behavior through modulation of dopaminergic, glutamatergic and GABA-ergic neurotransmission. Using the CB1 receptor radioligand [(18)F]MK-9470 and small-animal PET, we investigated for the first time in vivo cerebral changes in [(18)F]MK-9470 binding in the 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease (PD), parallel to dopamine transporter (DAT) imaging, tyrosine hydroxylase (TH) staining, and behavioral measurements. In the 6-OHDA model, relative [(18)F]MK-9470 PET binding decreased in the contralateral cerebellum (-9%, p<0.0004) and caudate-putamen bilaterally (ipsilateral -8%, contralateral -7%; p=0.001 and p<0.0003, respectively). The number of TH(+) neurons in the substantia nigra was inversely correlated to CB1 receptor binding in the ipsilateral cerebellum (p=1.10(-6)). The behavioral outcome was positively related to regional CB1 receptor binding in the contralateral somatosensory cortex (p=4.10(-6)). In vivo [(18)F]MK-9470 PET imaging points to changes in endocannabinoid transmission, specifically for CB1 receptors in the 6-OHDA model of PD, with mainly involvement of the caudate-putamen, but also distant regions of the motor circuitry, including the cerebellum and somatosensory cortex.

[1]  Johan Nuyts,et al.  Construction and evaluation of multitracer small-animal PET probabilistic atlases for voxel-based functional mapping of the rat brain. , 2006, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[2]  A. Kurz,et al.  Cannabinoid CB 1 receptors are early DownRegulated followed by a further UpRegulation in the basal Ganglia of mice with deletion of specific park genes , 2009 .

[3]  Vesna Sossi,et al.  Dopamine transporter relation to levodopa‐derived synaptic dopamine in a rat model of Parkinson’s: an in vivo imaging study , 2009, Journal of neurochemistry.

[4]  J. Ramos,et al.  Endocannabinoids and basal ganglia functionality. , 2002, Prostaglandins, leukotrienes, and essential fatty acids.

[5]  N. Wierup,et al.  Pharmacological validation of behavioural measures of akinesia and dyskinesia in a rat model of Parkinson's disease , 2002, The European journal of neuroscience.

[6]  N. Volkow,et al.  In vivo imaging of the brain cannabinoid receptor. , 2002, Chemistry and physics of lipids.

[7]  A. Kurz,et al.  Cannabinoid CB1 receptors are early downregulated followed by a further upregulation in the basal ganglia of mice with deletion of specific park genes. , 2009, Journal of neural transmission. Supplementum.

[8]  Koen Van Laere,et al.  Motor- and food-related metabolic cerebral changes in the activity-based rat model for anorexia nervosa: A voxel-based microPET study , 2007, NeuroImage.

[9]  S. Morgan,et al.  The interhemispheric projection from the substantia nigra to the caudate-putamen as depicted by the anterograde transport of [3H]leucine , 1990, Behavioural Brain Research.

[10]  P. Jenner,et al.  Increased cannabinoid CB1 receptor binding and activation of GTP‐binding proteins in the basal ganglia of patients with Parkinson's syndrome and of MPTP‐treated marmosets , 2001, The European journal of neuroscience.

[11]  R. Mechoulam,et al.  Cannabinoids provide neuroprotection against 6-hydroxydopamine toxicity in vivo and in vitro: Relevance to Parkinson's disease , 2005, Neurobiology of Disease.

[12]  Patrik Brundin,et al.  Behavioral characterization of a unilateral 6-OHDA-lesion model of Parkinson's disease in mice , 2005, Behavioural Brain Research.

[13]  Koen Van Laere,et al.  Metabolic–dopaminergic mapping of the 6-hydroxydopamine rat model for Parkinson’s disease , 2007, European Journal of Nuclear Medicine and Molecular Imaging.

[14]  A. Makriyannis,et al.  From cannabis to cannabinergics: new therapeutic opportunities. , 2002, Pharmacology & therapeutics.

[15]  E. Hirsch,et al.  Functional Activity of Zona Incerta Neurons Is Altered after Nigrostriatal Denervation in Hemiparkinsonian Rats , 2000, Experimental Neurology.

[16]  Miguel Angel Castellano,et al.  Nigrostriatal dopaminergic cell activity is under control by substantia nigra of the contralateral brain side: Electrophysiological evidence , 1991, Brain Research Bulletin.

[17]  M. Koch,et al.  The cannabinoid agonist WIN 55,212-2 reduces sensorimotor gating and recognition memory in rats , 2002, Behavioural pharmacology.

[18]  T. Schallert,et al.  Intervention Strategies for Degeneration of Dopamine Neurons in Parkinsonism , 2000 .

[19]  D. Piomelli,et al.  Reversal of Dopamine D2 Receptor Responses by an Anandamide Transport Inhibitor , 2000, The Journal of Neuroscience.

[20]  D. Centonze,et al.  The endocannabinoid pathway in Huntington's disease: A comparison with other neurodegenerative diseases , 2007, Progress in Neurobiology.

[21]  M. Mena,et al.  Cannabinoid CB1 receptors in the basal ganglia and motor response to activation or blockade of these receptors in parkin-null mice , 2005, Brain Research.

[22]  David Blum,et al.  Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: contribution to the apoptotic theory in Parkinson's disease , 2001, Progress in Neurobiology.

[23]  R. Burke,et al.  6-Hydroxydopamine lesion of the rat substantia nigra: time course and morphology of cell death. , 1995, Neurodegeneration : a journal for neurodegenerative disorders, neuroprotection, and neuroregeneration.

[24]  D. Mash,et al.  Expression of cannabinoid CB1 receptor mRNA in basal ganglia of normal and parkinsonian human brain , 2003, Journal of Neural Transmission.

[25]  L. Parsons,et al.  Dopamine activation of endogenous cannabinoid signaling in dorsal striatum , 1999, Nature Neuroscience.

[26]  G. Bormans,et al.  An in vivo [18F]MK-9470 microPET study of type 1 cannabinoid receptor binding in Wistar rats after chronic administration of valproate and levetiracetam , 2008, Neuropharmacology.

[27]  J. Fernández-Ruiz.  The endocannabinoid system as a target for the treatment of motor dysfunction , 2009, British journal of pharmacology.

[28]  P Boesiger,et al.  Striatal glucose metabolism and dopamine D2 receptor binding in asymptomatic gene carriers and patients with Huntington's disease. , 1996, Brain : a journal of neurology.

[29]  D. Manzoni.  The cerebellum and sensorimotor coupling: Looking at the problem from the perspective of vestibular reflexes , 2008, The Cerebellum.

[30]  G. Nikkhah,et al.  Restoration of complex sensorimotor behavior and skilled forelimb use by a modified nigral cell suspension transplantation approach in the rat parkinson model , 1993, Neuroscience.

[31]  Ignace Lemahieu,et al.  Experimental Performance Assessment of SPM for SPECT Neuroactivation Studies Using a Subresolution Sandwich Phantom Design , 2002, NeuroImage.

[32]  E. Esposito,et al.  The Unilateral Nigral Lesion Induces Dramatic Bilateral Modification on Rat Brain Monoamine Neurochemistry , 2009, Annals of the New York Academy of Sciences.

[33]  Masahiko Watanabe,et al.  Subcellular Arrangement of Molecules for 2-Arachidonoyl-Glycerol-Mediated Retrograde Signaling and Its Physiological Contribution to Synaptic Modulation in the Striatum , 2007, The Journal of Neuroscience.

[34]  D. Deutsch,et al.  Biochemistry of the Endogenous Ligands of Cannabinoid Receptors , 1998, Neurobiology of Disease.

[35]  T. Schallert,et al.  ‘Disengage’ sensorimotor deficit following apparent recovery from unilateral dopamine depletion , 1988, Behavioural Brain Research.

[36]  Seung-Up Kim,et al.  Transient Receptor Potential Vanilloid Subtype 1 Mediates Cell Death of Mesencephalic Dopaminergic Neurons In Vivo and In Vitro , 2005, The Journal of Neuroscience.

[37]  G. Bernardi,et al.  Immunolocalization of CB1 receptor in rat striatal neurons: A confocal microscopy study , 2004, Synapse.

[38]  J. Vanderhaeghen,et al.  Dopaminergic Regulation of Cannabinoid Receptor mRNA Levels in the Rat Caudate‐Plitamen: An In Situ Hybridization Study , 1993, Journal of neurochemistry.

[39]  J. Manzanares,et al.  Unilateral 6-hydroxydopamine lesions of nigrostriatal dopaminergic neurons increased CB1 receptor mRNA levels in the caudate-putamen. , 2000, Life sciences.

[40]  J. P. Huston,et al.  UNILATERAL 6-HYDROXYDOPAMINE LESIONS OF MESO-STRIATAL DOPAMINE NEURONS AND THEIR PHYSIOLOGICAL SEQUELAE , 1996, Progress in Neurobiology.

[41]  P. Calabresi,et al.  Experimental Parkinsonism Alters Endocannabinoid Degradation: Implications for Striatal Glutamatergic Transmission , 2002, The Journal of Neuroscience.

[42]  M. Herkenham,et al.  Localization of cannabinoid CB1 receptor mRNA in neuronal subpopulations of rat striatum: A double‐label in situ hybridization study , 2000 .

[43]  W. Byblow,et al.  Altered sensorimotor integration in Parkinson's disease. , 2002, Brain : a journal of neurology.

[44]  J. Brotchie,et al.  Striatal Cannabinoid CB1 Receptor mRNA Expression Is Decreased in the Reserpine-Treated Rat Model of Parkinson's Disease , 2001, Experimental Neurology.

[45]  J. Brotchie.  CB1 cannabinoid receptor signalling in Parkinson's disease. , 2003, Current opinion in pharmacology.

[46]  L. Ferraro,et al.  Neurochemical changes in the striatum of dyskinetic rats after administration of the cannabinoid agonist WIN55,212-2 , 2009, Neurochemistry International.

[47]  F. Rodríguez de Fonseca,et al.  Cannabinoid receptors in rat brain areas: sexual differences, fluctuations during estrous cycle and changes after gonadectomy and sex steroid replacement. , 1994, Life sciences.

[48]  C. Gerloff,et al.  Sensorimotor integration is abnormal in asymptomatic Parkin mutation carriers , 2007, Neurology.

[49]  M. Herkenham,et al.  Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study , 1991, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[50]  B. Ferrer,et al.  Experimental Parkinsonism Alters Anandamide Precursor Synthesis, and Functional Deficits are Improved by AM404: A Modulator of Endocannabinoid Function , 2004, Neuropsychopharmacology.

[51]  A. Howlett,et al.  Signal transduction interactions between CB1 cannabinoid and dopamine receptors in the rat and monkey striatum , 2001, Neuropharmacology.

[52]  J. Hoenicka,et al.  Depression in Parkinson's disease is related to a genetic polymorphism of the cannabinoid receptor gene (CNR1) , 2005, The Pharmacogenomics Journal.

[53]  L. Petrocellis,et al.  The endocannabinoid system and its therapeutic exploitation , 2004, Nature Reviews Drug Discovery.

[54]  S. Houle,et al.  In vivo evaluation of [11C]- and [18F]-labelled cocaine analogues as potential dopamine transporter ligands for positron emission tomography. , 1996, Nuclear medicine and biology.

[55]  E Sylvester Vizi,et al.  Involvement of Cannabinoid Receptors in the Regulation of Neurotransmitter Release in the Rodent Striatum: A Combined Immunochemical and Pharmacological Analysis , 2005, The Journal of Neuroscience.

[56]  G. Bormans,et al.  Improved synthesis and metabolic stability analysis of the dopamine transporter ligand [(18)F]FECT. , 2008, Nuclear medicine and biology.

[57]  Patrick Dupont,et al.  [18F]MK-9470, a positron emission tomography (PET) tracer for in vivo human PET brain imaging of the cannabinoid-1 receptor , 2007, Proceedings of the National Academy of Sciences.

[58]  M. Herkenham,et al.  Localization of cannabinoid CB(1) receptor mRNA in neuronal subpopulations of rat striatum: a double-label in situ hybridization study. , 2000, Synapse.

[59]  E. Hirsch,et al.  Ipsilateral and contralateral subthalamic activity after unilateral dopaminergic lesion , 2000, Neuroreport.