Retinal Dopamine Synthesis Research Articles

AB007. Visual signals modulate refractive error development through dopamine receptor signaling

: Myopia prevalence is dramatically increasing in recent years and in cases in which the refractive error is greater than −6.00 D this disease can lead to severe visual impairment as well as even blindness. Changes in visual input affect the balance between ocular growth and refractive power development. If a mismatch occurs during eye development, the severity of this error affects the degree of myopia. In different animal models of this disease, we found that spatial visual stimuli are essential for maintaining a stable refractive status and normal vision. This is evident because the effects of changes in temporal visual stimuli (e.g., flickering light) on this process depend on whether spatial information is present or absent in the visual environment. Furthermore, the frequency, wavelength and intensity of light are involved in controlling refraction development. However, the molecular mechanisms underlying light-induced refraction changes are still unclear. There is definitive evidence that dopamine (DA) is one of the regulators of this process. This retinal neurotransmitter released by dopaminergic amacrine cells appears to play an important role in vision-guided eye growth because its synthesis and release are positively associated with the light intensity and spatial stimuli impinging on the retina. We found that bright light enhances retinal DA synthesis, and attenuates form deprivation myopia (FDM) development via activation of the dopamine receptor 1 (D1R). A nonselective DA receptor agonist apomorphine (APO) inhibited FDM in dopamine receptor 2 (D2R) knockout mice. These individual similar effects of DA and APO in wildtype and D2R knockout mice suggest that D1R activation has a protective effect against myopia development. On the other hand, D2R activation instead appears to promote myopia development because either genetic D2R ablation or pharmacological inactivation of D2R also attenuates myopia development. Based on these results, we hypothesize that the visual environment regulates the retinal DA levels, which in turn affects the relative balance between D1R and D2R activation. When D1R is relatively hyperactivated, the ocular refractive status shifts towards hyperopia. In contrast, such an effect on D2Rpromotes the refractive status to shift in the opposite direction towards myopia.

An updated view on the role of dopamine in myopia

A large body of data is available to support the hypothesis that dopamine (DA) is one of the retinal neurotransmitters involved in the signaling cascade that controls eye growth by vision. Initially, reduced retinal DA levels were observed in eyes deprived of sharp vision by either diffusers (“deprivation myopia”, DM) or negative lenses (“lens induced myopia”, LIM). Simulating high retinal DA levels by intravitreal application of a DA agonist can suppress the development of both DM and LIM. Also more recent studies using knock-out mouse models of DA receptors support the idea of an association between decreased DA levels and DM. There seem to be differences in the magnitude of the effects of DA on DM and LIM, with larger changes in DM but the degrees of image degradation by both treatments need to be matched to support this conclusion. Although a number of studies have shown that the inhibitory effects of dopamine agonists on DM and LIM are mediated through stimulation of the D2-receptor, there is also recent evidence that the balance of D2- and D1-receptor activation is important. Inhibition of D2-receptors can also slow the development of spontaneous myopia in albino guinea pigs. Retinal DA content displays a distinct endogenous diurnal, and partially circadian rhythm. In addition, retinal DA is regulated by a number of visual stimuli like retinal illuminance, spatial frequency content of the image, temporal contrast and, in chicks, by the light input from the pineal organ. A close interaction was found between muscarinergic and dopaminergic systems, and between nitric oxide and dopaminergic pathways, and there is evidence for crosstalk between the different pathways, perhaps multiple binding of the ligands to different receptors. It was shown that DA agonists interact with the immediate early signaling molecule ZENK which triggers the first steps in eye growth regulation. However, since long treatment periods were often needed to induce significant changes in retinal dopamine synthesis and release, the role of dopamine in the early steps is unclear. The wide spatial distribution of dopaminergic amacrine cells in the retina and the observation that changes in dopamine levels can be locally induced by local retinal deprivation is in line with the assumption that dopaminergic mechanisms control both central and peripheral eye growth. The protective effect of outdoor activity on myopia development in children seems to be partly mediated by the stimulatory effect of light on retinal dopamine production and release. However, the dose–response function linking light exposure to dopamine and to the suppression of myopia is not known and requires further studies.

Antipsychotic-induced D2-receptor upregulation — differential effect of continuous versus transient D2-receptor blockade

A large body of data is available to support the hypothesis that dopamine (DA) is one of the retinal neurotransmitters involved in the signaling cascade that controls eye growth by vision. Initially, reduced retinal DA levels were observed in eyes deprived of sharp vision by either diffusers (“deprivation myopia”, DM) or negative lenses (“lens induced myopia”, LIM). Simulating high retinal DA levels by intravitreal application of a DA agonist can suppress the development of both DM and LIM. Also more recent studies using knock-out mouse models of DA receptors support the idea of an association between decreased DA levels and DM. There seem to be differences in the magnitude of the effects of DA on DM and LIM, with larger changes in DM but the degrees of image degradation by both treatments need to be matched to support this conclusion. Although a number of studies have shown that the inhibitory effects of dopamine agonists on DM and LIM are mediated through stimulation of the D2-receptor, there is also recent evidence that the balance of D2- and D1-receptor activation is important. Inhibition of D2-receptors can also slow the development of spontaneous myopia in albino guinea pigs. Retinal DA content displays a distinct endogenous diurnal, and partially circadian rhythm. In addition, retinal DA is regulated by a number of visual stimuli like retinal illuminance, spatial frequency content of the image, temporal contrast and, in chicks, by the light input from the pineal organ. A close interaction was found between muscarinergic and dopaminergic systems, and between nitric oxide and dopaminergic pathways, and there is evidence for crosstalk between the different pathways, perhaps multiple binding of the ligands to different receptors. It was shown that DA agonists interact with the immediate early signaling molecule ZENK which triggers the first steps in eye growth regulation. However, since long treatment periods were often needed to induce significant changes in retinal dopamine synthesis and release, the role of dopamine in the early steps is unclear. The wide spatial distribution of dopaminergic amacrine cells in the retina and the observation that changes in dopamine levels can be locally induced by local retinal deprivation is in line with the assumption that dopaminergic mechanisms control both central and peripheral eye growth. The protective effect of outdoor activity on myopia development in children seems to be partly mediated by the stimulatory effect of light on retinal dopamine production and release. However, the dose–response function linking light exposure to dopamine and to the suppression of myopia is not known and requires further studies.

Retinal dopamine and its metabolite contents in zitter rats and spontaneously epileptic rats.

In order to investigate the relationship between visual dysfunction and retinal DA metabolism in zitter rats and spontaneously epileptic rats (SER), we measured the amounts of retinal dopamine (DA) and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillate (HVA). DA, DOPAC and HVA contents were markedly decreased in zitter rats as compared with the controls, Kyo:Wistar or Sprague-Dawley rats. In contrast, in SER, retinal DA and its metabolite contents were not significantly different from those of Kyo:Wistar rats. SER showed higher levels of DA and its metabolites in comparison with Sprague-Dawley rats. Thus, it is suggested that the debilitation of retinal DA synthesis is at least partly related to the visual dysfunction observed in zitter rats, but not that of SER.

Alterations in retinal tyrosine and dopamine levels in rats consuming protein or tyrosine-supplemented diets.

The ad libitum ingestion of casein diets varying in protein content altered serum and retinal levels of tyrosine. The serum tyrosine level rose when protein ingestion was increased from 6 to 24% casein. In rats consuming high-protein diets (40% casein), no further increase in serum tyrosine level occurred, although the levels of other large neutral amino acids, which compete with tyrosine for retinal uptake, continued to rise. The activity of the liver enzyme tyrosine aminotransferase varied directly with the percentage of protein in the diet and may partially explain the failure of chronic high-protein feeding to increase serum tyrosine levels. The retinal tyrosine concentration was significantly correlated with the serum tyrosine level and with the serum tyrosine ratio at all levels of protein intake. Retinal 3,4-dihydroxyphenylalanine synthesis and dopamine (DA) level varied in parallel with the level of the precursor, tyrosine. Addition of pure L-tyrosine (1, 2, or 4%) to normal protein diets resulted in a stepwise increase in serum and retinal tyrosine levels and retinal DA turnover. Alterations of retinal tyrosine level as a result of change in amount of dietary protein or by its addition to the normal diet can influence retinal DA synthesis and release.

Diurnal alterations in retinal tyrosine level and dopamine turnover in diabetic rats

Retinal tyrosine level is correlated not only to its serum concentration, but also to the serum tyrosine ratio (the ratio of serum tyrosine to the sum of 5 neutral amino acids, leucine, isoleucine, valine, tryptophan and phenylalanine which compete with it for tissue uptake). In control animals, serum tyrosine ratio, retinal tyrosine, dopamine (DA) and its metabolites, and DOPA synthesis exhibit roughly parallel daily rhythms with night-time lows and peak levels occuring in the early portion of the daily light phase (L + 4 HR). In rats made diabetic by streptozotocin injection serum leucine, isoleucine and valine are elevated, lowering the serum tyrosine ratio and retinal tyrosine level by about 50% throughout the daily cycle. Parameters of DA turnover are still highest in the light phase but normal peak levels are delayed by 4 h until the latter half of the light phase (L + 8 HR). In diabetic rats, the normal increase in retinal DA synthesis and release upon exposure to light may be compromised by the decreased availability of its precursor, tyrosine.

Light-induced stimulation of retinal dopamine: a dose-response relationship

Light stimulates dopamine (DA) release in the retina. The purpose of this was to determine the threshold and dose-response relationship between ocular light exposure and retinal DA synthesis in vivo. Groups of dark-adapted rats were exposed to 0, 1, 3, 5, 10, 25, 50, 100 or 1000 microwatts per square centimeter (μW/cm 2 of white light for 15 min. Retinal DA and dihydroxyphenylalanine (DOPA) were subsequently quantified by liquid chromatography with electrochemical detection. Both the DA and DOPA data fit hyperbolic curves significantly ( Pˇ0.01). Exposure to white light at 25 μW/cm 2 or greater appears to elicit the maximum response of these neurons. Threshold irradiance is calculated to be 3–5 μW/cm 2. These results indicate that retinal DA synthesis and presumably DA neuron activity have a graded response to increasing irradiances of white light.

Ontogeny of mechanisms which regulate light/dark differences in retinal dopamine synthesis

The ability of bicuculline, a GABA antagonist, to enhance dopamine (DA) synthesis in retinas of rats 1, 4, 7, 15 and 60 days after eye opening was assessed and compared to the time course of postnatal development of the light-induced increase in DA synthesis. The accumulation of dihydroxyphenylalanine (DOPA) following administration of the L-aromatic amino acid decarboxylase inhibitor, NSD 1015, was used to estimate DA synthesis. In dark-adapted rats, neither bicuculline nor light enhanced DOPA accumulation 1 day after eye opening, but on the remaining days either treatment significantly augmented DA synthesis, and by day 15 effects were as great as those observed in adult retinas. At each time point, the magnitude of the drug effect on DA synthesis in the dark was similar to that observed following light exposure. These results suggest that an endogenous GABAergic inout to the DA neurons appears at the same time as the acquisition of the dopaminergic response to light. The effect of bicuculline treatment on DA synthesis in light-exposed animals was also assessed. At 4 and 7 days the drug significantly enhanced DOPA accumulation over that produced by exposure to light alone, but on later days bicuculline exerted no such additive effect. These data imply that early in the maturation of the light response mechanisms other than removal of an inhibitory GABAergic tone may be partially responsible for excitation of the DA neurons.

Effect of strychnine and of bicuculline on dopamine synthesis in retinas of dark-maintained rats

The intravitreal administration of strychnine produced a significant elevation of dopamine (DA) synthesis in the retinas of dark-adapted rats. Strychnine had no antagonistic effect on the ability of muscimol to suppress the normal increase in retinal DA synthesis observed after exposure of rats to light. This latter observation suggests that strychnine is not merely acting in a non-selective fashion to suppress the inhibitory GABAergic tone exerted on the DA neurons in darkness. These results suggest that there may be a direct or indirect strychnine-sensitive input to the retinal DA neurons in the dark. This input may not be glycinergic, however, as even high dosages of glycine did not suppress the light-mediated enhancement of DA synthesis in the retina.

Researches on the texture of iron

A large body of data is available to support the hypothesis that dopamine (DA) is one of the retinal neurotransmitters involved in the signaling cascade that controls eye growth by vision. Initially, reduced retinal DA levels were observed in eyes deprived of sharp vision by either diffusers (“deprivation myopia”, DM) or negative lenses (“lens induced myopia”, LIM). Simulating high retinal DA levels by intravitreal application of a DA agonist can suppress the development of both DM and LIM. Also more recent studies using knock-out mouse models of DA receptors support the idea of an association between decreased DA levels and DM. There seem to be differences in the magnitude of the effects of DA on DM and LIM, with larger changes in DM but the degrees of image degradation by both treatments need to be matched to support this conclusion. Although a number of studies have shown that the inhibitory effects of dopamine agonists on DM and LIM are mediated through stimulation of the D2-receptor, there is also recent evidence that the balance of D2- and D1-receptor activation is important. Inhibition of D2-receptors can also slow the development of spontaneous myopia in albino guinea pigs. Retinal DA content displays a distinct endogenous diurnal, and partially circadian rhythm. In addition, retinal DA is regulated by a number of visual stimuli like retinal illuminance, spatial frequency content of the image, temporal contrast and, in chicks, by the light input from the pineal organ. A close interaction was found between muscarinergic and dopaminergic systems, and between nitric oxide and dopaminergic pathways, and there is evidence for crosstalk between the different pathways, perhaps multiple binding of the ligands to different receptors. It was shown that DA agonists interact with the immediate early signaling molecule ZENK which triggers the first steps in eye growth regulation. However, since long treatment periods were often needed to induce significant changes in retinal dopamine synthesis and release, the role of dopamine in the early steps is unclear. The wide spatial distribution of dopaminergic amacrine cells in the retina and the observation that changes in dopamine levels can be locally induced by local retinal deprivation is in line with the assumption that dopaminergic mechanisms control both central and peripheral eye growth. The protective effect of outdoor activity on myopia development in children seems to be partly mediated by the stimulatory effect of light on retinal dopamine production and release. However, the dose–response function linking light exposure to dopamine and to the suppression of myopia is not known and requires further studies.