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P M. Iuvone, Jane Abey, Fazila Aseem, Kanika Ghai, Jeffrey H. Boatright, Douglas G. McMahon, Chad R. Jackson; Visual Function in Mice with Conditional, Retina-specific Disruption of the Tyrosine Hydroxylase Gene: Differential Roles of Dopamine D1 and D4 Receptors. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1611.
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© ARVO (1962-2015); The Authors (2016-present)
Dopamine is a neuromodulator in the retina and the brain. This study was conducted to examine the effects on visual function of selective depletion of dopamine from the retina, with brain dopamine levels intact.
We generated a retina-specific disruption of the Th gene, which encodes tyrosine hydroxylase (TH), the rate limiting enzyme in the dopamine biosynthetic pathway. This was accomplished by breeding mice with floxed Th alleles [Th(lox/lox)] with mice expressing Cre recombinase driven by the Chx10 promoter. Visual acuity and contrast sensitivity were assessed by optokinetic tracking (OKT). Light adaptation was measured as the rate of increase in the b-wave amplitude of the electroretinogram (ERG) following exposure to a rod-saturating background light. Dopamine levels in the retina and brain were measured by HPLC with electrochemical detection.
Dopamine levels in retinas of Cre-Th(lox/lox) mice were reduced by >95% compared to Th(lox/lox) mice or wild type C57Bl/6 mice. Dopamine levels in brains of Cre-Th(lox/lox) mice were no different than in controls. Cre-Th(lox/lox) mice had reduced visual acuity and a large decrease in contrast sensitivity compared to Th(lox/lox) controls. Both contrast sensitivity and acuity increased to wild-type (WT)values when the mice were treated with L-dopa (1mg/ml in drinking water), the immediate precursor of dopamine and the TH reaction product. SKF38393 (1 mg/kg ip), a dopamine D1 receptor agonist, increased visual acuity in Cre-Th(lox/lox) mice to levels equal to those in Th(lox/lox) controls but had no effect on contrast detection. PD168,077 (1 mg/kg ip), a dopamine D4 receptor agonist, increased contrast sensitivity to control values in Cre-Th(lox/lox) mice but had no effect on visual acuity. The role of D4 receptors in contrast sensitivity was confirmed in D4 receptor-deficient Drd4 -/- mice, while visual acuity in Drd4 -/- mice was not significantly different from that in WT mice. Cre-Th(lox/lox) mice had reduced rates of light adaptation compared to Th(lox/lox) mice. Drd4 -/- mice also adapted to light more slowly than WT mice.
These observations establish roles for retinal dopamine in modulating visual acuity, contrast sensitivity, and light adaptation. Dopamine D1 receptors appear to play a predominant role in modulating acuity while contrast sensitivity and light adaptation are regulated, at least in part, by D4 receptors.
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