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 neurochem...
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Published in | Neuropharmacology Vol. 51; no. 2; pp. 374 - 385 |
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Main Authors | , , , , , , , , , , |
Format | Journal Article |
Language | English |
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England
Elsevier Ltd
01.08.2006
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Abstract | 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. |
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AbstractList | 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. 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. |
Author | Chapin, Douglas S. Schmidt, Christopher J. Siuciak, Judith A. Stock, Jeffrey L. McNeish, John D. Strick, Christine A. James, Larry C. Williams, Robert D. McCarthy, Sheryl A. Fujiwara, Remie A. Menniti, Frank S. |
Author_xml | – sequence: 1 givenname: Judith A. surname: Siuciak fullname: Siuciak, Judith A. email: judith.a.siuciak@pfizer.com – sequence: 2 givenname: Sheryl A. surname: McCarthy fullname: McCarthy, Sheryl A. – sequence: 3 givenname: Douglas S. surname: Chapin fullname: Chapin, Douglas S. – sequence: 4 givenname: Remie A. surname: Fujiwara fullname: Fujiwara, Remie A. – sequence: 5 givenname: Larry C. surname: James fullname: James, Larry C. – sequence: 6 givenname: Robert D. surname: Williams fullname: Williams, Robert D. – sequence: 7 givenname: Jeffrey L. surname: Stock fullname: Stock, Jeffrey L. – sequence: 8 givenname: John D. surname: McNeish fullname: McNeish, John D. – sequence: 9 givenname: Christine A. surname: Strick fullname: Strick, Christine A. – sequence: 10 givenname: Frank S. surname: Menniti fullname: Menniti, Frank S. – sequence: 11 givenname: Christopher J. surname: Schmidt fullname: Schmidt, Christopher J. |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/16769090$$D View this record in MEDLINE/PubMed |
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Keywords | Striatum MK-801 Amphetamine Methamphetamine Schizophrenia PCP Conditioned avoidance |
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SubjectTerms | Amphetamine Amphetamine - pharmacology Animals Avoidance Learning Behavior, Animal Biogenic Monoamines - metabolism Brain - metabolism Central Nervous System Stimulants - pharmacology Conditioned avoidance Conditioning, Operant Corpus Striatum - enzymology Corpus Striatum - physiology Dizocilpine Maleate - pharmacology Excitatory Amino Acid Antagonists - pharmacology Maze Learning Methamphetamine Methamphetamine - pharmacology Mice Mice, Knockout MK-801 Motor Activity - drug effects PCP Phencyclidine - pharmacology Phosphoric Diester Hydrolases - genetics Phosphoric Diester Hydrolases - physiology Schizophrenia Striatum |
Title | Genetic deletion of the striatum-enriched phosphodiesterase PDE10A: Evidence for altered striatal function |
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