Inhibition of the striatum-enriched phosphodiesterase PDE10A: A novel approach to the treatment of psychosis
Introduction
The phosphodiesterases (PDEs) are the enzymes that metabolically inactivate the ubiquitous intracellular second messengers cAMP and cGMP, a function that serves to regulate and compartmentalize the cyclic nucleotide signaling cascades. The PDEs are divided into 11 families based on sequence homology within the catalytic domain, which results in similar substrate specificity and sensitivity to pharmacological inhibitors within a family. Because inhibition of these enzymes can have a profound effect on cellular function, there is considerable interest in identifying family-specific PDE inhibitors to probe the physiology of these enzymes and to explore therapeutic utilities for such agents.
Of the 11 PDE families, PDE10A has the most restricted distribution. PDE10A mRNA is highly expressed only in brain and testes (Fujishige et al., 1999a, Fujishige et al., 1999b). In the brain, mRNA and protein are highly enriched in one population of neurons, the medium spiny projections neurons (MSNs) of the striatum (Fujishige et al., 1999a, Seeger et al., 2003). Within these neurons, the enzyme is distributed throughout the cell body, dendrites and axons. The striatal MSNs function as the principal input site of the basal ganglia, a series of interconnected subcortical nuclei that integrate cortical and dopaminergic inputs to facilitate planning and execution of relevant motor and cognitive patterns while suppressing unwanted or irrelevant patterns (Graybiel, 2000). The high level of expression of PDE10A in these neurons suggests that inhibition of this enzyme will result in changes in behaviors regulated by the activity of this circuit. This hypothesis is supported by results of studies in mice in which the gene for PDE10A is disrupted (PDE10A−/− mice; Siuciak et al., 2006—preceding report). PDE10A−/− mice are characterized by reduced locomotor activity in a number of behavioral paradigms and a reduced rate of acquisition of a conditioned avoidance response. This phenotype is interpreted to suggest that disruption of the PDE10A gene leads to increased activation of the MSNs and reduced behavioral responsiveness, which is consistent with the role of these neurons and the basal ganglia in regulating behavior.
The present studies were aimed at further investigating the function of PDE10A, in this case using a pharmacological approach. We identify papaverine as a selective and potent inhibitor of PDE10A, which was then used as a tool to study the effects of acute PDE10A inhibition in vivo. The results indicate that PDE10A regulates both cAMP and cGMP signaling in the MSNs and that inhibition of this enzyme causes behavioral effects consistent with an activation of striatal output. These results are discussed in regard to the hypothesis that PDE10A inhibitors may represent a novel approach to the treatment of psychosis.
Section snippets
PDE enzyme assay
Phosphodiesterases 1–4 and 7–11 were generated from recombinant clones transfected into SF9 cells as previously described (Fisher et al., 1998a, Fisher et al., 1998b, Fawcett et al., 2000, Seeger et al., 2003). PDE5 was isolated from human platelets and PDE6 from bovine retina as described (Boolell et al., 1996). PDE activity was measured using a scintillation proximity assay (SPA)-based method as previously described (Seeger et al., 2003). The effect of PDE inhibitors was investigated by
Papaverine is a selective inhibitor of rat PDE10A in vitro
To search for a useful inhibitor of PDE10A, a group of commercially available PDE inhibitors were screened for inhibition of cyclic nucleotide hydrolysis by recombinant rat PDE10A. As reported previously, dipyridamole and IBMX inhibited PDE10A with micromolar potency (Soderling et al., 1999). Papaverine, however, was found to be a particularly potent inhibitor of rat PDE10A with an IC50 of 36 nM. Inhibition by papaverine was competitive using either cAMP or cGMP as substrates (data not shown).
Discussion
In the preceding report (Siuciak et al., 2006) we began to investigate the function of PDE10A by evaluating the behavioral consequences of disrupting the PDE10A gene in mice. The most apparent phenotype of PDE10A−/− mice was a significant reduction in exploratory activity. Although the mice were slower at acquiring a conditioned avoidance task, there was no evidence of a general learning deficit in either passive avoidance or the Morris water maze. We proposed that this phenotype is consistent
Acknowledgements
We gratefully acknowledge the assistance of the following individuals involved with the making, validation and breeding of the PDE10A knockout mice: John McNeish, Jeffrey Stock, Christine Strick, Larry C. James, Robert Williams, Tina Walsh-Spivey and Linda Loverro. Portions of this work have been previously presented at the Society for Neuroscience 2002 and 2004 Meetings and the International Congress of Schizophrenia Research, March 2003.
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