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 ([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.

955. Striatal Phosphodiesterase 10A and Medial Prefrontal Cortical Thickness in Patients with Schizophrenia: A PET and MRI Study

“…However, previous studies of the effect of antipsychotics on PDE10A availability conflict with one study reporting an increase of PDE10A in rats exposed to both haloperidol and clozapine, 42 whereas Natesan et al observed no difference in PDE10A availability after chronic haloperidol administration to rats. 10 The latter concurs with a recent non-human primate study that did not detect any significant changes from haloperidol treatment. 43 It is not fully clear if clozapine and the other diazepines (olanzapine and quetiapine) that the patients were treated with in our study are D 1 agonists or antagonists, but a reasonable amount of data is pointing towards clozapine being a D 1 agonist as reviewed by Ahlenius et al…”

“…7 PDE10A has opposing effects on the output from these striatal pathways by regulating second messenger cascades, and inhibition of PDE10A does indeed seem to reduce positive and in some studies also negative symptoms in animal models of schizophrenia. [8][9][10][11][12] Moreover, patients with other striatal disorders, such as Parkinson's and Huntington's disease, have lower availability of striatal PDE10A early in the disease course. 13,14 Although PDE10A inhibition has shown promise as a novel target of the treatment of schizophrenia, 15 recently the first positron emission tomography (PET) study of PDE10A expression in patients with schizophrenia found no difference compared to healthy controls using the [ 11 C]IMA107 ligand.…”

[18F]JNJ42259152 binding to phosphodiesterase 10A, a key regulator of medium spiny neuron excitability, is altered in the presence of cyclic AMP

“…; Natesan et al . ). Despite the growing interest in PDE10A, little is known about the regulation of PDE10A enzymatic activity.…”

Phosphodiesterase‐1b deletion confers depression‐like behavioral resistance separate from stress‐related effects in mice

“…; Hebb & Robertson ; Natesan et al . ; Xu et al . ), and haloperidol or clozapine treatment increases Pde10a expression (Xu et al .…”