title: Effect of chronic antipsychotic treatment on striatal phosphodiesterase 10A levels: a [¹¹C]MP-10 PET rodent imaging study with ex vivo confirmation.
abstract: A number of phosphodiesterase 10A (PDE10) inhibitors are about to undergo clinical evaluation for their efficacy in treating schizophrenia. As phosphodiesterases are in the same signalling pathway as dopamine D2 receptors, it is possible that prior antipsychotic treatment could influence these enzyme systems in patients. Chronic, in contrast to acute, antipsychotic treatment has been reported to increase brain PDE10A levels in rodents. The aim of this study was to confirm these findings in a manner that can be translated to human imaging studies to understand its consequences. Positron emission tomography (PET) scanning was used to evaluate PDE10A enzyme availability, after chronic haloperidol administration, using a specific PDE10A ligand ([(11)C]MP-10). The binding of [(11)C]MP-10 in the striatum and the cerebellum was measured in rodents and a simplified reference tissue model (SRTM) with cerebellum as the reference region was used to determine the binding potential (BPND). In rats treated chronically with haloperidol (2 mg kg(-1) per day), there was no significant difference in PDE10A levels compared with the vehicle-treated group (BPND±s.d.: 3.57 ± 0.64 versus 2.86 ± 0.71). Following PET scans, ex vivo analysis of striatal brain tissue for PDE10A mRNA (Pde10a) and PDE10A enzyme activity showed no significant difference. Similarly, the PDE10A protein content determined by western blot analysis was similar between the two groups, contrary to an earlier finding. The results of the study indicate that prior exposure to antipsychotic medication in rodents does not alter PDE10A levels.
authors.affiliation: Department of Psychosis Studies, Institute of Psychiatry, King's College London, London, UK.
authors.forename: S
authors.identifier: 0000000174991714
authors.initials: S
authors.lastname: Natesan
authors.affiliation: Imanova Centre for Imaging Sciences, Hammersmith Hospital, London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Ashworth
authors.affiliation: Division of Synaptic Transmission, H. Lundbeck A/S, Copenhagen, Denmark.
authors.forename: J
authors.initials: J
authors.lastname: Nielsen
authors.affiliation: Imanova Centre for Imaging Sciences, Hammersmith Hospital, London, UK.
authors.forename: S-P
authors.initials: SP
authors.lastname: Tang
authors.affiliation: Imanova Centre for Imaging Sciences, Hammersmith Hospital, London, UK.
authors.forename: C
authors.initials: C
authors.lastname: Salinas
authors.affiliation: Department of Psychosis Studies, Institute of Psychiatry, King's College London, London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Kealey
authors.affiliation: Division of Synaptic Transmission, H. Lundbeck A/S, Copenhagen, Denmark.
authors.forename: J B
authors.initials: JB
authors.lastname: Lauridsen
authors.affiliation: Division of Synaptic Transmission, H. Lundbeck A/S, Copenhagen, Denmark.
authors.forename: T B
authors.initials: TB
authors.lastname: Stensbøl
authors.affiliation: 1] Imanova Centre for Imaging Sciences, Hammersmith Hospital, London, UK [2] Department of Medicine, Imperial College London, London, UK.
authors.forename: R N
authors.initials: RN
authors.lastname: Gunn
authors.affiliation: 1] Imanova Centre for Imaging Sciences, Hammersmith Hospital, London, UK [2] Department of Neuroimaging, Institute of Psychiatry, King's College London, London, UK.
authors.forename: E A
authors.initials: EA
authors.lastname: Rabiner
authors.affiliation: Department of Psychosis Studies, Institute of Psychiatry, King's College London, London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Kapur
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006220:Haloperidol / Q000008:administration & dosage / Q000494:pharmacology*; D017072:Neostriatum / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011485:Protein Binding; D011720:Pyrazoles; D011804:Quinolines; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C545121:2-((4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)phenoxy)methyl)quinoline; D014150:Antipsychotic Agents; D010726:Phosphodiesterase Inhibitors; D011720:Pyrazoles; D011804:Quinolines; C512064:PDE10A protein, rat; D010727:Phosphoric Diester Hydrolases; D006220:Haloperidol