Genetic deletion of the striatum-enriched phosphodiesterase PDE10A: evidence for altered striatal function.

PDE10A is a newly identified phosphodiesterase that is highly expressed by the medium spiny projection neurons of the striatum. In order to investigate the physiological role of PDE10A in the central nervous system, PDE10A knockout mice (PDE10A(-/-)) were characterized both behaviorally and neurochemically. PDE10A(-/-) mice showed decreased exploratory activity and a significant delay in the acquisition of conditioned avoidance behavior when compared to wild-type (PDE10A(+/+)) mice. However, in a variety of other well-characterized behavioral tasks, including the elevated plus maze (anxiety), forced swim test (depression), hot plate (nociception) and two memory models (passive avoidance and Morris water maze), PDE10A(-/-) mice performed similarly to wild-type mice. When challenged with PCP or MK-801, PDE10A(-/-) mice showed a blunted locomotor response in comparison to PDE10A(+/+) mice. In contrast, PDE10A(-/-) and PDE10A(+/+) mice responded similarly to the locomotor stimulating effects of amphetamine and methamphetamine. Our findings suggest that PDE10A is involved in regulating striatal output, possibly by reducing the sensitivity of medium spiny neurons to glutamatergic excitation. These results are discussed in relationship to the hypothesis that PDE10A inhibition presents a novel treatment for psychosis.

The activity of pramipexole in the mouse forced swim test is mediated by D2 rather than D3 receptors.

RATIONALE: Recent studies have reported antidepressant-like activities of the dopamine D2/D3 agonist pramipexole in the chronic mild stress model and in the forced swim test, suggesting that D3 receptor agonists may represent a new class of antidepressant drugs. However, the relative contribution of D2 or D3 receptors to the activity of pramipexole in these models is unclear. OBJECTIVES: The aim of the current studies was to explore the role of dopamine D2 and D3 receptors in the activity of pramipexole in the mouse forced swim test. METHODS: The effect of pramipexole (0.1-3.2 mg/kg) in the mouse forced swim test was examined both in conjunction with D2 and D3 receptor antagonists (haloperidol (0.1-1 mg/kg) and LU-201640 (A-437203, 5.6-17.8 mg/kg), as well as in D3 receptor knockout mice obtained on two different background strains (C57BL/6J and B6129SF2/J). Locomotor activity was also assessed following pramipexole administration. RESULTS. Pramipexole produced dose-dependent reductions in immobility in the forced swim test at doses that did not produce generalized increases in locomotor activity. LU-201640, the D3 selective antagonist, failed to block the antidepressant-like effects of pramipexole. In contrast, the efficacy of pramipexole in the forced swim test was completely blocked by the D2 antagonist, haloperidol. No baseline differences were observed between knockout and wild-type mice from either background strain in locomotor activity or in the forced swim test. Furthermore, in both background strains, pramipexole showed similar efficacy in the forced swim test for both wild-type and knockout mice. CONCLUSIONS: Taken together, these studies suggest that the D2 receptor rather than the D3 receptor is important for the antidepressant-like activity observed for pramipexole in the mouse forced swim test.