Phosphodiesterase 10A inhibition is associated with locomotor and cognitive deficits and increased anxiety in mice.
Phosphodiesterase 10A (PDE10A) mRNA and protein levels decline in the striatum of R6/1 and R6/2 Huntington's disease (HD) mice prior to motor symptom development. In human HD, PDE10A protein levels are significantly decreased in the caudate-putamen of patients with grade 3 HD compared to age-matched controls. To test whether the loss of PDE10A activity in the striatum was detrimental to normal brain function, we treated wild-type (WT) mice with chronic administration of papaverine, which is a specific inhibitor of PDE10A. At 7 weeks of age, mice were introduced to a weekly battery of motor tests, including assessment of weight, locomotion, gait, and coordination. Beginning at 8 weeks of age, mice received 0, 5, 10 or 20 mg/kg papaverine once daily until the completion of behavioral testing. Following 14 days of papaverine injections, mice were assessed for deficits in cognitive performance as measured in the Morris water maze (MWM). All behavioral tests occurred either immediately prior to or 30 min following a subcutaneous papaverine challenge dose. Twenty-four hours following completion of the 2-3 week MWM protocol, mice were given a dose of papaverine and 30 min later psychological function assessed in the Light-Dark (LD) Test. Chronic administration of papaverine for 42 days was associated with distinct motor perturbations, mild cognitive disturbance and anxiety-like behaviors. Subsequently, we assessed the effect of 14 days papaverine (i.e. sub-chronic) treatment on psychological function of WT and R6/1 HD mice. While sub-chronic papaverine induced anxiety-like behavior in WT mice, it appeared to have little effect on the behavior of R6/1 HD mice. Finally, a separate group of 6-week old WT and R6/2 HD mice were treated for 21 days with saline or 10 mg/kg fluoxetine, an agent with anxiolytic and anti-depressant effects, in order to compare the effects of papaverine and fluoxetine on anxiety-like behavior in the LD test. CREB and PDE10A protein levels in striatum and hippocampus were determined by western blot. While papaverine treatment reduced CREB protein levels in the hippocampus and striatum, fluoxetine increased CREB in the hippocampus. These data suggest that papaverine and fluoxetine may produce quite different effects on behavior; these behaviors may be linked to CREB expression in brain regions associated with motor and cognitive functions. PDE10A protein levels were decreased by both papaverine and fluoxetine. Chronic PDE10A inhibition produced a variety of behavioral and central neurochemical deficits and these effects were exacerbated by stress. The unique localization of PDE10A and its apparent role in basal ganglia function may underlie its role in psychiatric and neurological disorders involving the basal ganglia.
Hebb
Andrea L O
AL
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
Robertson
Harold A
HA
Denovan-Wright
Eileen M
EM
D000704:Analysis of Variance; D000818:Animals; D001007:Anxiety / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D050882:CREB-Binding Protein / Q000378:metabolism; D003072:Cognition Disorders / Q000139:chemically induced / Q000201:enzymology*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D010208:Papaverine / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D011930:Reaction Time / Q000187:drug effects; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism
D010726:Phosphodiesterase Inhibitors; D014404:Tubulin; D010208:Papaverine; D050882:CREB-Binding Protein; C492284:Pde10a protein, mouse; D010727:Phosphoric Diester Hydrolases