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Research ArticleNEUROPHARMACOLOGY

Inhibition of Phosphodiesterase 10A Increases the Responsiveness of Striatal Projection Neurons to Cortical Stimulation

Sarah Threlfell, Stephen Sammut, Frank S. Menniti, Christopher J. Schmidt and Anthony R. West
Journal of Pharmacology and Experimental Therapeutics March 2009, 328 (3) 785-795; DOI: https://doi.org/10.1124/jpet.108.146332
Sarah Threlfell
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Stephen Sammut
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Frank S. Menniti
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Christopher J. Schmidt
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Anthony R. West
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Abstract

The cyclic nucleotide phosphodiesterase 10A (PDE10A) is highly expressed in striatal medium-sized spiny projection neurons (MSNs), apparently playing a critical role in the regulation of both cGMP and cAMP signaling cascades. Genetic disruption or pharmacological inhibition of PDE10A reverses behavioral abnormalities associated with subcortical hyperdopaminergia. Here, we investigate the effect of PDE10A inhibition on the activity of MSNs using single-unit extracellular recordings performed in the dorsal striatum of anesthetized rats. Antidromic stimulation of the substantia nigra pars reticulata was used to identify striatonigral (SNr+) MSNs. Intrastriatal infusion of the selective PDE10A inhibitors papaverine or TP-10 [2-{4-[-pyridin-4-yl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline succinic acid] by reverse microdialysis did not affect spontaneous firing but robustly increased measures of cortically evoked spike activity in a stimulus intensity-dependent manner. Systemic administration of TP-10 also increased cortically evoked spike activity in a stimulus intensity- and dose-dependent manner. A robust increase in cortically evoked activity was apparent in SNr- MSNs (primarily striatopallidal). It is interesting that TP-10 administration did not affect cortically evoked activity in SNr+ MSNs. However, TP-10 administration increased the incidence of antidromically activated (i.e., SNr+) MSNs. These findings indicate that inhibition of striatal PDE10A activity increases the responsiveness of MSNs to depolarizing stimuli. Furthermore, given the lack of effect of TP-10 on SNr+ MSNs, we speculate that PDE10A inhibition may have a greater facilitatory effect on corticostriatal synaptic activity in striatopallidal MSNs. These data support further investigation of selective targeting of PDE signaling pathways in MSN subpopulations because this may represent a promising novel approach for treating brain disorders involving dysfunctional glutamatergic and dopaminergic neurotransmission.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant NS 047452]; by the Chicago Medical School; and by the National Alliance for Research on Schizophrenia and Depression, Pfizer Incorporated.

  • doi:10.1124/jpet.108.146332.

  • ABBREVIATIONS: PDE10A, cyclic nucleotide phosphodiesterase 10A; SNr+, striatonigral; MSN, medium-sized spiny projection neuron; SNr, substantia nigra pars reticulata; PDE, cyclic nucleotide phosphodiesterase; TP-10, 2-{4-[-pyridin-4-yl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline succinic acid; IT, intratelencephalic; PT, pyramidal tract; aCSF, artificial cerebral spinal fluid; ANOVA, analysis of variance.

    • Received September 17, 2008.
    • Accepted December 3, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 384 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 384, Issue 2
1 Feb 2023
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Research ArticleNEUROPHARMACOLOGY

Inhibition of Phosphodiesterase 10A Increases the Responsiveness of Striatal Projection Neurons to Cortical Stimulation

Sarah Threlfell, Stephen Sammut, Frank S. Menniti, Christopher J. Schmidt and Anthony R. West
Journal of Pharmacology and Experimental Therapeutics March 1, 2009, 328 (3) 785-795; DOI: https://doi.org/10.1124/jpet.108.146332

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Research ArticleNEUROPHARMACOLOGY

Inhibition of Phosphodiesterase 10A Increases the Responsiveness of Striatal Projection Neurons to Cortical Stimulation

Sarah Threlfell, Stephen Sammut, Frank S. Menniti, Christopher J. Schmidt and Anthony R. West
Journal of Pharmacology and Experimental Therapeutics March 1, 2009, 328 (3) 785-795; DOI: https://doi.org/10.1124/jpet.108.146332
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