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 ([11C]MP-10). The binding of [11C]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.
Highlights
Antipsychotic drugs mediate their effects by blocking dopamineD2 receptors and in doing so they increase intracellular cyclic adenosine monophosphate levels
The cerebellum was chosen as the reference region given its very low PDE10A protein expression and supported by negligible levels of displaceable binding of [11C]MP-10 due to cold MP-10 administration in baboons.[5,17,28]
The main aim of this study was to verify the earlier observation that antipsychotic treatment induces elevation of striatal PDE10A levels.[7]
Summary
Antipsychotic drugs mediate their effects by blocking dopamineD2 receptors and in doing so they increase intracellular cyclic adenosine monophosphate (cAMP) levels. The duration and amplitude of cyclic nucleotide signalling is regulated by cellular phosphodiesterases (PDEs) that break down cAMP.[1,2] The brain expresses the most dense and diverse collection of PDEs in the body and the medium spiny neurons of the basal ganglia have the greatest density of PDEs as well as dopamine D2 receptors.[3,4] As PDEs are at the heart of the striatal dopamine D2 signalling pathway, it is possible that chronic D2 receptor blockade due to antipsychotic medication could alter PDE levels in the brain. Chronic haloperidol and clozapine treatment increased striatal PDE10A protein expression by 118% and 62%, respectively, but acute administration had no effect. There are several other instances where PDE levels have been influenced either by the disease process or by concurrent medication.[8,9] An example in the CNS is the alteration of brain PDE4 iso-enzyme levels due to repeated treatment with antidepressants in the mouse.[10]
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